Diseases of the Kidney & Urinary Tract

Acute Kidney Injury

Key points

• Acute kidney injury is defined as a rapid decrease in glomerular filtrate rate. 
• Acute kidney injury can be subdivided into acute kidney injury based on prerenal, intrinsic and post-renal disease.
• Diagnostics such as urinalysis and ultrasound of the kidneys are important in elucidating what is causing the acute kidney injury.
• Treatment should address the underlying cause of acute kidney injury.
• The prognosis is generally good if acute kidney injury is treated early.
• Acute kidney injury is potentially life-threatening and an initial inventory should include looking for signs of hypertension, pulmonary edema, and metabolic dysregulation.

General

Acute kidney injury (AKI) is defined as a rapid decrease in glomerular filtration rate (GFR). Thus, the production rate of metabolic waste products exceeds the renal excretion rate. AKI is characterized by a rise of markers of renal function, such as creatinine and urea and is often accompanied by an acute decrease in urine production. AKI is a risk factor for the development of chronic kidney disease (CKD). AKI is not a single disease entity but an entity with various underlying diseases or causes. Thus, the approach and treatment of a patient with AKI depend on the clinical context. 

Epidemiology

AKI is a widespread condition, especially among hospitalized patients. It can be seen in approximately 10-15% of all hospital admissions and in more than 50% of intensive care admissions.

Symptoms

The underlying cause often determines the clinical picture. Therefore, identifying the underlying cause is a crucial first step toward treating the patient. For example, in case of an urinary tract infection or pyelonephritis, patients may suffer from pain during voiding or localized pain in the affected kidney.

Other symptoms result from a decrease in GFR and thus decreased kidney function:

• Reduced excretion of waste products: increased potassium levels (hyperkalemia) can lead to cardiac arrhythmias and even death. Patients may suffer from the clinical syndrome of uremia. 
• Reduced excretion of fluid results in fluid overload. But intravascular underfilling (hypovolemia) may also be observed in patients with AKI. Patients often have oliguria or even anuria. However, relatively normal urine production may also be observed.

Symptoms specific to different causes of AKI are discussed under ‘diagnosis’.

Causes

AKI has numerous causes, commonly divided into 3 categories: prerenal, intrinsic and post-renal (obstructive).

Prerenal Acute Kidney Injury

Prerenal causes of AKI are the most common. Prerenal AKI is a physiological response to renal hypoperfusion. It is most often caused by hypovolemia or a decreased cardiac output, which both cause a lower renal blood flow. This results in lower intraglomerular hydrostatic pressure resulting in less plasma being filtered (figure 1). Prerenal AKI due to systemic vasodilation during a distributive shock is commonly seen in sepsis, hepatic failure (as discussed in hepatorenal syndrome) and acute pancreatitis.

Additionally, medication should always be considered as a cause of prerenal AKI. Several common drugs impair renal autoregulatory systems, thereby preventing the kidneys from reacting adequately to changes in renal blood flow. Afferent dilation of the afferent arteriole supplying the glomerulus (preglomerular) can be reduced by NSAIDs or calcineurin inhibitors. In contrast, angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) can reduce constriction of the efferent arteriole draining the glomerulus. Both lower the intraglomerular pressure and reduce GFR (see figure 1). These effects are mainly seen in patients with reduced kidney blood flow (for various reasons) and in whom the renin-angiotensin-aldosterone system (RAAS) is activated to keep up the filtration. 

Figure 1. Some common mechanisms of prerenal acute kidney injury. Created with Biorender.com

Lastly, patients with prerenal AKI should be worked up for changes in vasculature, such as renal artery dissection or stenosis, thrombosis and cholesterol embolism. Prerenal AKI is transient, meaning the kidney function will completely recover when the underlying cause is treated and normal renal perfusion is reestablished. This recovery may be seen one to two days after treatment. However, it should be noted that persistent or severe prerenal AKI can lead to structural changes in the kidney. A structural change may be ischemic acute tubular necrosis, an intrinsic form of AKI that translates to longer recovery time (weeks) and sometimes even permanent damage. Table 1 overviews the different mechanisms that can lead to prerenal AKI.

Prerenal mechanisms of acute renal injury i.e.,, lowering of renal perfusion	Disease
Decreased renal blood  flow	Shock (any type, i.e., hypovolemic, distributive, cardiogenic, obstructive)
	Cardiorenal syndrome
	Hepatorenal syndrome
	Renal artery stenosis, fibromuscular dysplasia (FMD)
	Aortic dissection with rupture into the renal artery
Intrarenal vasoconstriction	Norepinephrine, sepsis* , calcineurin inhibitors
			Low intraglomerular pressure due to impaired adaptive autoregulation	Medication in specific clinical settings: NSAIDs, calcineurin inhibitors, angiotensin converting enzyme inhibitors (ACE inhibitors), angiotensin receptor blockers (ARBs)
Hyperviscosity syndromes	Polycythemia vera, multiple myeloma, Waldenstrom macroglobulinemia

Table 1. Common mechanisms and their primary associated diseases leading to prerenal acute kidney injury. Note that many diseases cause renal failure through more than a single mechanism. This table only concerns major causes and their main mechanism of action. It is not a comprehensive list of all causes. *Sepsis induces renal hypoperfusion by a combination of systemic vasodilation and intrarenal vasoconstriction. On top, the release of endotoxins worsens the effects of ischemia. 

Intrinsic Acute Kidney Injury

Intrinsic AKI refers to processes that directly damage the kidney. It has many different etiologies (table 2 lists the most common ones), but acute tubular necrosis accounts for about 80% of all cases of intrinsic AKI. Other common etiologies include glomerulonephritis and interstitial nephritis. Although less prevalent, vascular complications can also cause damage to the renal parenchyma and lead to intrinsic AKI. In addition, endogenous and exogenous nephrotoxins, including certain classes of medication – especially antibiotics and NSAIDs – can directly impact the tubular cells of the kidney and cause intrinsic AKI. This spectrum is evolving as novel antimicrobial and anticancer agents, like immune checkpoint inhibitors, are extensively applied. Intrinsic AKI may also arise from using iodinated contrast agents in CT imaging. Typically, in this so-called contrast nephropathy an acute decline in GFR is seen within 48 hours. Patients with volume depletion or underlying chronic kidney disease, particularly diabetic nephropathy, are most at risk for contrast nephropathy. Therefore, if contrast-enhanced CT is necessary for chronic kidney disease patients, hydration regimens are applied to protect and preserve kidney function.

It should be noted that sepsis can contribute to AKI through a prerenal mechanism – i.e., temporarily reduced renal blood flow – and through an intrinsic pathway – prolonged reduced renal blood flow – combined with toxic endotoxins. In addition, renal AKI is seen in cases of intratubular obstruction due to crystal formation out of medication, or secondary due to significantly increased creatine kinase (CK) concentrations in rhabdomyolysis, hyperbilirubinemia as seen in bile duct obstruction, or uric acid as seen in tumor lysis syndrome can cause AKI. The same applies to light chain cast nephropathy in multiple myeloma. 

Intrinsic AKI mechanisms	Disease
Renovascular obstruction (large renal vessels)	Arterial	Arteriosclerosis and atheroembolism, cholesterol embolism, thromboembolism, vasculitis (Takayasu), dissection
	Venous	Renal vein thrombosis, compression
Glomerulopathy (glomeruli and renal microvasculature)	Glomerulonephritis, thrombotic microangiopathy, hyperviscosity
			Acute tubular necrosis	Ischemic	Prolonged renal hypoperfusion
	Toxic	Contrast (for imaging), drugs (calcineurin inhibitors, cisplatinum, aminoglycosides)
Interstitial nephritis	Drug-related	NSAIDs, antibiotics
	Infection	Viral or bacterial
	Immune-mediated	Lupus nephritis, M. Sjögren, sarcoidosis, granulomatosis, polyangiitis
	Infiltration	Leukemia, lymphoma
Intratubular obstruction	Endogenous	Multiple myeloma, rhabdomyolysis, tumor lysis syndrome, cholestasis (bile cast nephropathy), macroscopic glomerular hematuria.
	Exogenous	Oxalate (primary or secondary hyperoxaluria), drug-related crystal formation (acyclovir, amoxicillin or flucloxacillin)
Renal allograft rejection	Post-kidney transplantation
Urinary tract infection or pyelonephritis

Table 2. Main intrinsic acute kidney injury disease mechanisms and main associated diseases per mechanism. This is not a comprehensive list of all causes. Many diseases cause renal failure through more than one single mechanism — for instance, the combination of intratubular obstruction and simultaneous tubular toxicity.

Postrenal Acute Kidney Injury

Postrenal AKI is a result of suddenly blocked urine outflow. Congestion of urine within the renal system will lead to increased hydrostatic pressure within the glomerulus and impede glomerular filtration. Obstruction can happen anywhere along the urinary outflow tracts. Obstruction has to affect both kidneys to impact kidney function significantly. In cases of a partial obstruction of the urine outflow, kidney function may be unaltered – meaning these cases may be missed. 

Postrenal AKI is often caused by bladder neck obstruction or blockage of one or both ureters at the trigonum, all of which may be caused by benign prostatic hypertrophy (BPH) or prostate cancer. It can also be caused by kidney stones, obstructed bladder catheters, or compression of one or both ureters due to retroperitoneal fibrosis or other masses. In case of underlying chronic kidney disease, unilateral obstruction can result in postrenal AKI, as the loss in GFR can not be compensated for by a contralateral healthy kidney. Complete recovery may be seen in one or 2 days after relief of the underlying cause, provided that normal urinary outflow is reestablished before structural changes have occurred. During this phase, patients are often polyuric and a complicating additional prerenal AKI due to volume depletion can be averted by strict diuresis monitoring and adequate compensatory intravenous hydration. Table 3 overviews the different mechanisms that can lead to postrenal AKI.

Mechanisms	Disease
Blocked ureter	Urolithiasis, benign prostatic hyperplasia (BPH), blood clot(s), urothelial carcinoma, external compression, congenital ureteral valves.
Blocked bladder	Neurogenic bladder, urolithiasis, urothelial carcinoma.
Blocked urethra	Stricture, phimosis, congenital urethral valves, benign prostatic hyperplasia.

Table 3. Mechanisms and their associated diseases that can lead to postrenal AKI.

Diagnosis

The current Acute Kidney Injury Network (AKIN) definition and classification are used to diagnose and quantify AKI. This system is shown in table 4. Note that a minor increase in creatinine levels significantly contributes to morbidity and mortality risks.

Stage	Creatinine levels	Urine production
1 (Risk)	Serum creatinine rise of ≥ 0,3 mg/dL (≥ 26,4 μmol/L) or ≥ 1,5-2x from baseline.	< 0,5mL/kg per hour for > 6 hours.
2 (Injury)	Serum creatinine increases > 2-3x from baseline.	< 0,5mL/kg per hour for > 12 hours.
3 (Failure)	Serum creatinine increases to > 3x from baseline or ≥ 4,0mg/dL (≥ 354 μmol/L) with acute increase ≥ 0,5mg/dL (≥ 44 μmol/L).	< 0,3mL/kg per hour for ≥ 24 hours Or anuria for 12 hours.

Table 4. Acute Kidney Injury Network (AKIN) classification of acute kidney injury.

To determine the cause of AKI, history and physical examination are essential. Prerenal AKI should be considered in patients losing fluids through vomiting, diarrhea, or increased urine excretion in case of osmotic diuresis in diabetes mellitus or use of diuretics. On examination, the patient might show signs of dehydration with decreased skin turgor, dry mouth and lips, tachycardia and (orthostatic) hypotension. 

Full anuria and a history of kidney stones, benign prostate hyperplasia, or malignancy should raise the suspicion of a postrenal AKI. In addition, on physical examination, an enlarged bladder with percussion or palpable resistance in the lower abdomen may be found in postrenal AKI.

Laboratory tests show raised urea and creatinine levels in AKI. Depending on the severity of AKI, there might be marked acidosis. Electrolyte disturbances include hyperkalemia, hyperphosphatemia and hypocalcemia. Serum and urine sodium levels can help distinguish between the cause of AKI. In prerenal AKI, low renal perfusion will lead to sodium, urea and water retention. This retention results in low levels of sodium in the urine. This may be quantified as a low fractional excretion of sodium (Na) (FENa) < 1%, i.e., the percentage of sodium filtered by the kidney that is actually excreted in the urine. It should be noted that FENa is not always accurate, so history and other clinical findings should always be considered. A FENa above 1% suggests intrinsic or postrenal AKI. In patients using diuretics, a fractional excretion of urea (FEUrea) < 35% is used, as FENa is unreliable in this group.

Additionally, urine sediment can help elucidate the underlying pathology of AKI. Dysmorphic erythrocytes can be found during microscopic examination of a fresh urinary sediment and are pathognomonic for glomerular disease. Lastly, imaging, specifically ultrasound, is always part of the workup in AKI. In postrenal AKI, enlarged pyelum (hydronephrosis) is often seen unless the presentation is very acute or patients have concurrent severe intravascular fluid depletion. In that case, it is advisory to repeat the ultrasound after adequate fluid replacement. Both intravascular volume status and hydronephrosis can be easily assessed with bedside point of care ultrasound (POCUS) of the inferior caval vein and both kidneys. Kidney biopsy should be considered if the cause of AKI cannot be found using other modalities.

Treatment and Prognosis

There is no general treatment for AKI. It is important to look for the underlying cause and address it, if possible. So, consider fluid resuscitation in case of prerenal AKI. In case of postrenal AKI, the obstruction needs to be worked around quickly by providing a bladder catheter or – if necessary – a double J stent or nephrostomy catheter. Furthermore, it is vital to critically review the medication used by the patient and discontinue or adjust the dosage of those with potential nephrotoxic properties. In addition, the consequences of AKI should be identified and treated with optimization of hemodynamics and correction of electrolyte disturbances. If volume overload, hyperkalemia, or acidosis cannot be controlled with conventional therapy, dialysis should be considered. Dialysis should also be considered in case of toxic ingestions or when severe complications of uremia are present.

AKI may fully resolve. However, in patients with chronic kidney disease, renal function usually does not return to pre-existing values after an episode of AKI. Despite its reversibility, developing AKI is a poor prognostic marker regarding the risk of in-hospital and long-term mortality. In severe cases, patients subsequently have a high risk of progressive chronic kidney disease. Furthermore, up to 10% of these patients may develop end-stage kidney disease.

Complications

AKI is potentially life-threatening due to the risk of overhydration, hyperkalemia (with cardiac arrhythmias), and severe acidosis. Additionally, patients may develop uremic pericarditis.

An initial inventory of the need for urgent therapeutic interventions should be performed. This should include a simple physical examination – focused on signs of fluid overload (hypertension, pulmonic crackles, tachypnea) and pericarditis – and laboratory tests, including blood gas analysis, a full blood count and electrolytes. In addition, plain chest radiography and an electrocardiogram (ECG) should be performed to capture life-threatening arrhythmias and/or look for signs of pulmonary edema.

Acute Tubular Necrosis

Key points

• Acute tubular necrosis is commonly found among hospitalized patients.
• The initial phase of acute tubular necrosis is characterized by injury and an abrupt decrease in renal function. 
• The repair of tubular integrity characterizes the maintenance phase. 
• In the recovery phase, patients may become polyuric. Afterward, renal function gradually recovers.
• Prevention is crucial in acute tubular necrosis.
• If acute tubular necrosis develops, treatment is primarily symptomatic and ranges from dietary adjustments to dialysis.

General

Acute tubular necrosis (ATN) is the most common cause of intrinsic acute kidney injury. Together with prerenal kidney injury, ATN accounts for up to 65-75% of all cases of AKI causes.

Symptoms and Diagnosis

Though patients may have a recent history of volume depletion, in ATN they can easily tip over to volume overload. Urine production is commonly affected with oliguria (< 300 mL urine production per day) or anuria (no urine production). However, in up to 30-40% of all cases, urine production is unaffected, this is known as a non-oliguric ATN. 

Urine analysis may range from bland to epithelial cell casts or granular acellular casts. As tubular function fails the fractional excretions of sodium and urea are increased (FENa> 1%, FEUrea > 35%). The recovery phase is initiated by polyuria and can take weeks. 

Of note, iodinated contrast agents cause a typical reduction in kidney function in 1-2 hours after exposure, with a peak of 3-5 days and a recovery within 7 days.

Cause

ATN is a syndrome of intrinsic renal failure secondary to renal ischemia, sepsis or exposure to nephrotoxins. However, a strict distinction among these causes is too simplistic. For instance, many nephrotoxins (e.g calcineurin inhibitors and aminoglycosides) cause hypoxia due to reduced renal perfusion but are also associated with direct tubular toxicity. Most cases of ATN occur in patients suffering from comorbidities and may be superimposed upon chronic renal failure. Moreover, many patients have multiple hits: e.g., hypotensive episodes, nephrotoxic medication and the administration of iodinated contrast material.

Kidney Ischemia

Ischemic ATN is a common complication of severe or prolonged renal ischemia. It mainly develops in patients with hypotension after surgery, major trauma with hypovolemic shock, burns, pancreatitis or sepsis. Cardiac surgery using cardiopulmonary bypass and open aortic repair requiring suprarenal clamping have the highest risk for ATN. Systemic and renal hemodynamics should be optimized during and after surgery to mitigate this risk, especially in patients with comorbidities like chronic kidney disease, atherosclerosis and diabetes mellitus. Sepsis produces ischemia by the combination of distributive shock with reduced renal perfusion and altered intrarenal blood flow. On top, endotoxemia (the release of endotoxins associated with bacteria being killed) is thought to contribute to acute kidney injury in different ways. Calcineurin inhibitors and NSAIDs cause local hypoperfusion of the renal parenchyma due to vasoconstriction.

Nephrotoxins

Nephrotoxins cause renal injury through various combinations of renal vasoconstriction, direct tubular damage and intratubular obstruction. Aminoglycosides and chemotherapeutic agents, e.g., cisplatin and ifosfamide, have direct toxic effects on tubular cells. The main risk factors for toxicity caused by aminoglycosides are dose, duration of administration and co-medication, such as angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), diuretics and NSAIDs. In addition, sepsis, volume depletion and pre-existing chronic kidney disease are risk factors. Cisplatin accumulates in the proximal tubular cells and causes necrosis and apoptosis. Cisplatin may cause dose-dependent ATN that is usually non-oliguric. Therefore, it is essential to ensure hyperhydration during the administration of cisplatin. Iodinated contrast agents cause renal ischemia due to increased tubular working load. This mainly occurs in patients with chronic kidney disease (GFR < 30 mL/min/1,73 m2) in combination with volume depletion or patients suffering from diabetes mellitus.

Pathophysiology

The course of ATN can be divided into multiple phases: a prerenal state, followed by initiation and extension of injury, a maintenance state and then a recovery phase. These phases directly relate to cellular events during the injury and repair process. In the initial phase, prolonged hypoxia following a decrease in renal blood flow causes injury to the renal endothelial and tubular epithelial cells. The outer medullary region is affected the most because the proximal tubular cells have the highest oxygen consumption of all tubular cells. 

There is a mismatch between the degree of histological abnormalities on human biopsy samples and the extent of renal function decline. Despite subtle changes in the renal tubular epithelial cells, a major impact on renal function and acute kidney injury (AKI) is observed. First, the injuries lead to structural and functional changes in the tubular structures and – to a lesser degree – vascular changes. Second, an inflammatory response is initiated. Necrotic cellular debris may obstruct individual and collecting tubules and impair the filtration of multiple nephrons.

Moreover, proximal sodium and chloride reabsorption is hampered, which causes increased delivery to the macula densa and afferent arteriolar vasoconstriction via the tubuloglomerular feedback. Furthermore, glomerular filtrate may leak back into the interstitium. All these mechanisms have been postulated as causes of impaired renal function in ATN. During the maintenance phase, cells undergo repair, migration, apoptosis and proliferation to re-establish tubular integrity. The renal function remains stable at a level determined by the previous event. In the recovery phase, the cells re-establish intracellular homeostasis. Sodium and water may be wasted due to reduced reabsorption and concentration capacity of the kidneys. The osmolality of the urine remains the same as that of the plasma (isosthenuria), which manifests as polyuria and may last days to weeks.

Treatment 

Prevention of ATN is essential and includes identifying patients undergoing high-risk procedures and those with comorbidities that increase the risk of developing ATN, e.g., diabetes mellitus, heart failure, atherosclerosis and chronic kidney disease. Focus needs to be on optimization of hemodynamics, correction of fluid imbalances, discontinuation of nephrotoxic medication and dose adjustment of administered medication.

ATN management is primarily symptomatic. Dialysis may be needed in case of hyperkalemia, refractory acidosis, or volume overload.

Prognosis

ATN is associated with high morbidity and mortality. It can lead to severe kidney dysfunction and even necessitate dialysis. However, even in patients who require dialysis, kidney function may recover. Others may remain dialysis dependent. The severity of the initial event, pre-existing renal function, as well as when ATN was detected and what measures were taken to combat it, all determine whether the renal function is completely restored to pre-existing values.

Chronic Kidney Disease

Key points

• Chronic kidney disease is defined as an glomerular filtration rate (GFR) below 60 mL/min/1,73 m2 and a urinary albumin-creatinine ratio above 30 mg/g for over 3 months.
• Most cases of chronic kidney disease are secondary to diabetic nephropathy and hypertension.
• Risk factors of progressive chronic kidney disease include male sex, older age and non-Caucasian ethnicity.
• Chronic kidney disease does not cause symptoms unless it is severe.
• Like acute kidney disease, chronic kidney disease may lead to fluid retention, metabolic imbalances, and accumulation of waste products.

General

Chronic kidney disease (CKD) encompasses disorders progressively affecting kidney structure and function. CKD is defined as a reduced kidney function which is present for more than 3 months. In this definition reduced kidney function is defined as either:

• Glomerular filtration rate (GFR) < 60 mL/min/1.73 m2; or
• Urinary albumin-to-creatinine ratio > 30 mg/g.

CKD has health implications. A prognosis can be assigned based on the diagnosis and stage of the disease. CKD can lead to end-stage kidney failure and about 1% of CKD patients need renal replacement therapy.

Classification

The 2012 KDIGO guidelines proposed a grading system for CKD that combines a GFR-based and albuminuria-based classification (table 5). This system is currently used to grade the risk and progression of CKD.

			Persistent albuminuria categories
GFR categories (in ml/min/1.73m2)			A1 < 30 mg/g	A2 30-300 mg/g	A3 > 300mg/g
G1	Normal or high	≥ 90
G2	Mildly decreased	60-89
G3a	Mildly to moderately decreased	45-59
G3b	Moderately to severely decreased	30-44
G4	Severely decreased	15-29
G5	Kidney failure	<15

Table 5. Staging of chronic kidney disease according to the 2012 KDIGO guidelines. The GFR categories in the left column are also referred to as the KDIGO stages (G1= stage 1, and so on). Risk of developing chronic kidney failure is shown in color where green represents low risk, yellow a moderately increased, orange high, and red very high risk.

The improved classification of CKD has been beneficial in identifying prognostic indicators related to decreased kidney function and increased albuminuria. Chronic kidney disease patients are prone to end-stage renal failure and cardiovascular events.

Epidemiology

CKD affects 15–20% of adults globally.

Symptoms

Most early symptoms and signs in CKD follow the clinical picture of its underlying cause. Kidney damage is asymptomatic in the early stages of disease (KDIGO stage G1-G2 as shown in table 5). From KDIGO stage G4 there might be fatigue (due to anemia), and when CKD advances towards an end stage decreased appetite, malnutrition, pruritus and malaise are generally observed. Extracellular fluid expansion leads to hypertension and peripheral edema. Foamy urine is a sign of proteinuria. For the common complications of CKD and their treatment, see prognosis.

Risk factors

Risk factors for the development and progression of CKD include nephron loss due to increasing age, low nephron number at birth, kidney injuries caused by exposures to nephrotoxins and diseases like diabetes mellitus and hypertension. Risk factors associated with the progression of CKD can be divided into different categories which are shown in table 6.

Category	Risk factor
Sociodemographic and economic factors	Sex	Male patients may have a more rapid decline in kidney function compared to female patients.
	Ethnicity	Racial and ethnic minority populations in the United States are more likely to experience CKD progression compared to white people.
Behavioral	Lifestyle	Smoking, absence of regular physical activity and unhealthy weight.
	Diet	Unhealthy diet, especially high dietary sodium intake and low potassium intake.
	Sleep	Increased rates of sleep fragmentation and shorter sleep duration.
Genetic	APOL1* and RAAS** pathway genes	The APOL1 gene has been implicated in the higher risk of CKD progression observed in African American individuals.
Cardiovascular	Atrial fibrillation	Incidental atrial fibrillation was associated with a three-fold higher risk of kidney failure.
	Hypertension	Systolic blood pressure > 130 mmHg was associated with a higher risk of kidney failure.
	Heart failure	Heart failure is independently associated with a more pronounced decline in kidney function over time.
	Increase in albuminuria	Changes in albuminuria were consistently associated with subsequent risk of end-stage kidney disease.
Metabolic	Urinary oxalate
	Metabolic acidosis
	Diabetes mellitus
Acute kidney injury (AKI)

Table 6. Risk factors for progression of chronic kidney disease. *APOL 1: apolipoprotein L1, **RAAS: renin-angiotensin-aldosterone system.

Cause

Multiple diseases can cause the progression of CKD. The vast majority of progressive CKD is caused by diabetes mellitus, hypertension and arteriosclerosis. A progressive loss of functional nephrons and structural changes are observed in CKD. The remaining nephrons adapt and increase their individual GFR leading to relative hyperfiltration. As a result of this adaptation, the kidney will be able to adequately regulate the internal environment for a longer period of time. Hyperfiltration is associated with glomerular hypertension and can lead to proteinuria and glomerulosclerosis. In the long term, this hyperfiltration will shorten the lifespan of the remaining nephrons. This results in even more compensatory hyperfiltration in the remaining nephrons, creating a vicious circle. These mechanisms make CKD a progressive disease.

Diagnosis

If a patient presents with impaired renal function, it must first be determined whether there is acute or chronic kidney injury. After all, a diagnosis must be rapidly made in acute kidney injury (AKI). Previous plasma creatinine values and urinary albumin-creatinine ratios are helpful in this setting. If these are missing, indirect evidence can be sought. If an ultrasound shows smaller kidneys (< 9 cm), this strongly suggests CKD. Abnormal laboratory values such as nephrogenic anemia, hypocalcemia, hyperphosphatemia and hyperparathyroidism may also point toward a kidney function that has been disturbed for a longer period of time. Diagnostics focus on the cause and consequences if CKD is suspected. One should question whether there are therapeutic interventions that may inhibit the underlying disease, and if there are disturbances in the regulation of electrolytes, fluids or hemoglobin that should be taken care of. CKD also causes significant mineral bone abnormalities, resulting in CKD-mineral and bone disorder (MBD), discussed in more detail under ‘complications and prognosis’. 

Important laboratory parameters in CKD are hemoglobin, reticulocytes, iron status, urea, creatinine, bicarbonate, sodium, potassium, phosphate, calcium, albumin, and parathyroid hormone. In addition, a 24-hour urine collection provides information on the urea and creatinine clearances, the level of proteinuria, and an estimate of sodium consumption.

Treatment 

CKD may progress into end-stage renal disease requiring renal replacement therapy. Moreover, patients with CKD, even at their early stages, have an increased risk of cardiovascular disease. Since (early stage) CKD may be asymptomatic, it often remains undiagnosed for a long time and is not adequately managed. However, prevention and early detection of patients with CKD are of utmost importance. Timely treatment is warranted to reduce ongoing nephron loss and cardiovascular complications. Apart from lifestyle measures, disease-specific interventions (if possible), blood pressure control, inhibition of the renin-angiotensin-aldosterone system (RAAS) and initiation of sodium-glucose cotransporter-2 (SGLT2) inhibitors are the cornerstone of therapy. Dietary instructions include at least a sodium restriction and further depend on the individual situation.

Complications and Prognosis

Most patients with CKD have an increased risk of cardiovascular disease, e.g., coronary artery disease, peripheral artery disease, heart failure and arrhythmias. Their prognosis largely depends on the burden of comorbidities. Some of these complications and comorbidities are discussed below. In general, CKD reduces the quality of life and decreases life expectancy. In addition, it causes a high economic burden for society.

Hyperkalemia

If potassium intake is not altered in CKD each of the remaining nephrons needs to excrete more potassium, i.e., the fractional excretion per nephron increases. However, this increment in progressive CKD is insufficient in excreting potassium, leading to increased blood levels (hyperkalemia). 

In CKD, metabolic acidosis also contributes to hyperkalemia. In metabolic acidosis, hydrogen potassium (H+/K+) ATPase transports hydrogen ions from extracellular to intracellular, while at the same time potassium moves in the opposite direction. Hyperkalemia may result in life-threatening arrhythmias. For treatment of acute hyperkalemia, see the KDIGO summary. Treatment of chronic hyperkalemia consists of dietary interventions, diuretics, oral or rectal use of cation exchangers or oral sodium bicarbonate to correct the metabolic acidosis. 

Volume overload 

The majority of patients with CKD stage 4 or 5 suffer from hypertension. Hypertension is mainly caused by the activation of the renin-angiotensin-aldosterone system (RAAS), sympathetic nerve activation and volume overload. Sodium excretion in CKD is impaired. Reduced glomerular filtration of sodium and increased tubular reabsorption contribute to volume overload. Treatment most often includes dietary sodium restriction, RAAS blockade and diuretics. Dietary fluid restriction is introduced in dialysis patients when urine output is critically reduced. 

Mineral and bone disorder

The kidney plays a critical role in regulating calcium and phosphate serum levels. For this reason, CKD can lead to mineral and bone disorder (MBD). Multiple hormones are associated with CKD-MBD, including vitamin D, parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF-23). The exact working mechanisms have not been elucidated yet, but several hypotheses have been accepted. Fibroblast growth factor-23 (FGF23) is a relatively recently found bone marker produced by osteoblasts. FGF-23 plays an important role, especially in phosphate homeostasis. At an early stage of CKD, the reduction of nephrons and loss of their phosphate excretion can still be compensated for by, increased levels of FGF-23 decreasing the expression of a sodium-phosphate cotransporter-2 (NPT2) in the proximal tubule. Fewer NPT2 means less phosphate is reabsorbed into the plasma and more phosphate remains in the urine, where it is excreted. This increases the fractional phosphate excretion per nephron (figure 2). However, as CKD progresses, this compensation mechanism falls short, and phosphate levels will rise. Since phosphate binds calcium, this contributes to hypocalcemia and, as explained below, CKD-MBD.

Figure 2. Mechanism of hyperphosphatemia in chronic kidney disease. In early disease, FGF-23 upregulation can compensate for the loss of functional nephrons by increasing phosphate excretion of the remaining functioning nephrons. However, as CKD progresses, this mechanism is unable to keep up and results in hyperphosphatemia.

Inactive vitamin D (25-OH vitamin D) is converted into active vitamin D (1.25-OH vitamin D or calcitriol) by the kidneys. As CKD progresses, this conversion to active vitamin D decreases. The physiological role of parathyroid hormone (PTH) and vitamin D is the regulation of calcium homeostasis. Vitamin D enhances intestinal calcium and phosphate absorption and tubular calcium reabsorption. PTH increases plasma calcium concentration in various ways. First, PTH enhances intestinal calcium and phosphate absorption via stimulation of the conversion of inactive vitamin D into active vitamin D. Secondly, PTH enhances bone resorption and stimulates active renal calcium reabsorption. Both hyperphosphatemia and low levels of active vitamin D contribute to hypocalcemia, as shown in figure 3. 

Figure 3. Interplay of different feedback loops in CKD. Hypocalcemia results from various changes in hormones and electrolytes associated with the kidneys. In early disease compensatory mechanisms (dotted lines) may still be intact. However, in more advanced disease these may start to fail and deplete the bones of their calcium causing CKD-MBD.

Hyperphosphatemia, low levels of active vitamin D and hypocalcemia lead to bone disease in 2 different ways. First, hypocalcemia and active vitamin D leads to low bone turnover and abnormal mineralization of the bone, known as osteomalacia. Second, hypocalcemia will trigger the parathyroid glands to produce more PTH (hyperparathyroidism) to increase serum calcium levels. This may lead to osteitis fibrosa cystica, in which calcified support structures are replaced with fibrous tissue and cyst-like lesions (Brown tumors).

Treatment is primarily based on serum phosphate levels. Phosphate binders are used during all meals and snacks to lower serum phosphate levels. In non-dialysis CKD patients, the optimal PTH level is unknown. However, progressively rising PTH levels above the upper limit of normal should be evaluated for hyperphosphatemia, hypocalcemia and vitamin D deficiency. Reduced levels of active vitamin D can be corrected by alfacalcidol. The serum calcium will rise and PTH levels will drop.

Anemia

Most patients with CKD develop renal anemia. When the GFR falls below 30 mL/min/1,73 m2, anemia becomes clinically relevant to a greater or lesser extent. The origin of anemia is multifactorial: a reduced absorption of iron gastrointestinally due to increased hepcidin, increased inflammation, and an erythropoietin (EPO) deficiency. 

In healthy kidneys, hypoxia or anemia trigger the production of hypoxia-induced factor (HIF), a transcription factor which upregulates EPO production in the peritubular kidney cells and suppresses hepcidin. Subsequently, EPO stimulates red blood cell progenitor survival and their differentiation into red blood cells and thus increases hemoglobin (Hb) levels. However, in patients with CKD the kidneys may no longer be able to produce the appropriate amount of EPO. Meanwhile, hepcidin suppression increases iron availability, a fundamental building block for Hb. Iron metabolism and homeostasis are discussed in more detail in this chapter on hemochromatosis in the endocrinology section. Note that since hypoxia is one of the main triggers in EPO production, drugs that reduce hypoxia by increasing renal blood flow (like angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs)) reduce the stimulation of EPO production. Therefore, use of these drugs may mildly worsen anemia in CKD patients.

In addition, interstitial fibrosis, as observed in CKD, is associated with a reduction of EPO-producing cells. Therefore, patients may need iron supplementation or injections with erythropoiesis-stimulating agents (ESA) every few weeks. A HIF inhibitor orally taken 3 times a week is relatively new in this field. This reversible inhibitor regulates intracellular concentrations of the transcription factor HIF resulting in an increment of intrinsic EPO levels and a lowering of hepcidin levels.

Metabolic acidosis

The capacity to excrete acid is reduced in CKD. Consequently, metabolic acidosis develops. The reduced capacity to excrete acids has various causes. The proximal tubular cells produce ammonia (NH4+) and bicarbonate (HCO3–) to excrete acid. NH4+ is excreted and buffered with phosphate in the urine. HCO3– is reabsorbed into the circulation. In this way, the kidney can regulate acid loading. In CKD, the proximal tubule’s stimulated ammoniagenesis (NH4+) cannot compensate for the increased acid load per nephron. In addition, bicarbonate reabsorption is reduced in CKD. Metabolic acidosis causes hyperkalemia, protein catabolism, and has negative consequences for bone mineralization. Metabolic acidosis can be corrected by oral sodium bicarbonate suppletion.

Cardiovascular disease

CKD patients have an increased risk of cardiovascular disease (CVD), observed in almost half of those with CKD at stage 4 or 5. Furthermore, in CKD patients, cardiovascular mortality accounts for 50% of deaths, while this is only 26% in non-CKD patients. The connection between CKD and cardiovascular disease is complex. To find out which organ’s dysfunction started the vicious cycle in which these 2 organ systems participate is challenging, comparable to the chicken and egg paradox.

Nevertheless, several mechanisms that predispose CKD patients to cardiovascular disease have been described. First, risk factors for cardiovascular disease can also predispose patients to the development of CKD, comparable to the development of diabetes mellitus. Some risk factors are more prevalent in CKD patients, like dyslipidemia, hypertension, and arteriosclerosis. Therefore, controlling these risk factors is of the utmost importance. Though, they are not solely responsible for the high burden of cardiovascular disease in CKD patients. Second, CKD patients often have chronic inflammatory and uremic states and may develop mineral bone disease, leading to myocardial (fibrotic) remodeling and vascular calcifications, with extraordinary cardiovascular senescence. Third, left ventricular hypertrophy is increasingly present in CKD, even at the early stages of renal disease. This is thought to be mediated by factors related to the increased preload (due to intravascular fluid overload) and afterload (due to increased arterial stiffness and hypertension) seen in CKD patients. The presence of this hypertrophy is an independent predictor of cardiovascular mortality.

Renal Replacement Therapies

Key points

• Renal replacement therapies are treatment strategies to take over renal function in patients with end stage renal disease
• Dialysis, either via the bloodstream or peritoneal cavity, is a treatment in which renal filtration is mimicked to clear toxins and fluid from the body.
• In hemodialysis blood is pumped into an extracorporeal circuit containing a dialyzer. This is a semipermeable membrane that filters the blood and is continuously supplied with fresh dialysis fluid. Exchange of waste products takes place from the blood to the dialysate compartment through diffusion and convection over this membrane. 
• In peritoneal dialysis the peritoneal cavity is filled with a sterile dialysate fluid to which waste products and excess fluid are exchanged from the peritoneal capillaries. At the end of the session, the peritoneal cavity is drained and refilled with fresh dialysate.
• Renal transplantation is a more permanent option where the patient receives a donated kidney and will therefore need lifelong immunosuppressive therapy to prevent rejection of the ‘received’ kidney.

Dialysis

Dialysis treatment may be required in chronic end stage kidney disease as well as in acute renal failure. The purpose of dialysis is clearance of uremic toxins and excess fluid, and correction of electrolyte and acid-base disorders in patients whose kidneys can no longer perform these functions naturally. There are 3 different modalities of renal replacement therapy: hemodialysis, peritoneal dialysis and kidney transplantation. Besides personal preferences, choice (or feasibility) of therapy depends on many patient factors: e.g. general condition and life expectancy, autonomy and disabilities, housing situation and distance to a dialysis center. Hemodialysis and peritoneal dialysis are used in both acute and chronic renal failure, whereas transplantation is only applied in chronic renal failure. The use of continuous renal replacement therapies (CRRT) and slow low-efficiency dialysis (SLED) is specific to the management of acute renal failure and will not be addressed here.

In acute renal failure, refractory disbalanced electrolytes, acidosis and fluid overload are the most common indications for dialysis. Of note, uremic pericarditis is also an indication to start dialysis immediately. 

End stage renal disease causes the clinical syndrome of uremia. Uremia is characterized by the retention of numerous solutes normally excreted by the kidneys. These substances that have negative effects on biological functions are called uremic toxins. Uremia is named after the well known important toxin urea, a residual of protein metabolism. Uremia is associated with a wide range of complaints (i.e., encephalopathy, gastrointestinal complaints such as nausea, vomiting, anorexia, thrombophilia due to thrombopathy, skin abnormalities, muscle atrophy, tremors and itching). Uremia and refractory disbalanced electrolytes are both indications to initiate dialysis. Most patients have a creatinine clearance below 10 mL/min/1.73 m2. 

Complication	Indication for dialysis
Fluid retention	Clinical significant extracellular volume overload not responsive to diuretics
Accumulation of potassium	Clinical significant hyperkalemia unresponsive to conservative measures
Accumulation of hydrogen	Progressive metabolic acidosis refractory to medical therapy
Accumulation of uremic toxins	Uremic signs/symptoms
	Uremic bleeding diathesis
	Uremic pericarditis

Table 7. Overview of renal complications that warrant dialysis. 

The average mortality of a dialysis patient is very high: 15 to 20% per year. The prognosis of chronic hemodialysis patients is highly variable, partly depending on age, other underlying conditions and kidney disease. 

Hemodialysis

In hemodialysis, exchange of substances between blood and dialysate takes place across a semipermeable membrane in an artificial kidney or dialyser (figure 4) . This membrane divides a blood and a dialysate (aqueous solution with a balanced composition of electrolytes and bicarbonate) compartment. Exchange of substances between the blood and dialysate is driven by concentration differences over the membrane, a process known as diffusion. The rate and extent to which a substance diffuses not only depends on the concentration differences, but also on the permeability and surface area of ​​the membrane, the molecular size, the blood flow in the dialyser and the dialysis duration. The concentration difference is optimized by using the counter-current principle: blood and dialysate flow in opposite directions in the artificial kidney. During hemodialysis, fluid can be extracted from the body by ultrafiltration, by applying a negative pressure in the dialysate compartment relative to the blood compartment. Some solutes will ‘sail’ along with this water in a process known as convective clearance. The composition of dialysate varies and is adjusted to the patients’ needs.

Figure 4. Schematic overview of hemodialysis and the dialysis machine. The dialyzer is shown in more detail. Schematic dialysis machine based on Wikimedia commons by YassineMrabet, CC BY-SA 3.0. Created with Biorender.com.

The duration and frequency of the dialysis treatment depends on the residual renal function and the efficacy of the dialysis procedure. Most patients perform dialysis 3 times a week for 4 hours.

In acute dialysis a central venous catheter (inserted in the internal jugular, subclavian, or femoral vein) is used as vascular access. Long-term use of a catheter can lead to stenosis of the blood vessel. When dialysis is likely permanent, it is therefore in most cases preferable to use an arteriovenous (AV) fistula or graft as vascular access. As AV fistula maturation takes at least several weeks, in chronic renal failure a fistula is often created as soon as the need for HD is expected to arise in the near future. In some patients a central venous catheter may be preferred because of multimorbidity with a reduced life expectancy, or anyhow low chances of successfully creating a functional arteriovenous fistula.

Several complications can arise during dialysis. The most common is hypotension. Intradialytic hypotension is related to a decrease in intravascular volume and inadequate vascular responsiveness. Muscle cramps, nausea, vomiting and headaches are also common and often related to hypotension. The central venous catheter can be infected.

Peritoneal Dialysis

Peritoneal dialysis is performed by filling the abdominal intraperitoneal cavity with sterile dialysate (aqueous solution of electrolytes and glucose) as shown in figure 5. The peritoneum acts as a natural dialysis membrane between the blood in the peritoneal capillaries and the dialysate in the abdominal cavity. The membrane consists of the capillary endothelium, the capillary basement membrane, interstitial fluid and a layer of peritoneal mesothelial cells.

The transport of fluid (ultrafiltration) to the abdominal cavity is determined by the osmotic and hydrostatic pressure, as well as by outflow of lymphatics. The concentration differences in glucose and urea are maximal at the start of the dialysis and decrease during the dwelltime. Glucose is reabsorbed and the urea concentration in the dialysate increases. Excess fluid, uremic toxins and potassium accumulate in the dialysate. After completing the ‘dwell time’, the waste-saturated dialysate is removed and replaced by a fresh dialysate.

Figure 5. Schematic overview of peritoneal dialysis. Created with Biorender.com

Efficacy of the peritoneal membrane differs from patient to patient. When starting peritoneal dialysis, a peritoneal equilibrium test is performed to measure transfer rates across the peritoneal membrane. This test helps find the ideal “dwell time” (how long the dialysate dwells in the peritoneal cavity) for each patient. Most patients have multiple dwells per day. The duration of the dwells varies between 2 to 12 hours with a volume varying between 1 to 2 liters per dwell. There are different glucose concentrations dialysate available depending on the patient’s ultrafiltration needs. 

The dialysate is introduced through a mostly surgically inserted peritoneal catheter in the intraperitoneal abdominal cavity. There are two common methods of peritoneal dialysis. In continuous ambulatory peritoneal dialysis (CAPD), there is continuous dialysate in the abdominal cavity. The dialysate is changed on average 4 times a day. This is done by allowing the residual dialysate to maximally drain via a sterile line into an empty bag using gravity. Thereafter new dialysate is infused into the cavity and left in place for the next period of hours. In automated peritoneal dialysis (APD), a cycler apparatus is used. During the night the patient is connected to this machine via lines and several relatively shorter automatic dwells take place following an individual schedule. During the day the intraperitoneal space is kept empty or a longer dwell is performed. As CAPD/APD can be applied at home it offers the patients a little more flexibility, as they don’t need to visit the dialysis clinic multiple times per week. 

Complications may arise due to infection of the peritoneal catheter, causing peritonitis or non-peritonitis catheter associated infections. Most peritonitis cases can be treated at home with intraperitoneal or oral antibiotics. The majority of peritonitis episodes are caused by Gram-positive skin flora (S. epidermidis, S. aureus, Streptococcus species). If Gram-negative flora is cultured, there is a high probability of the existence of an interstitial perforation. Another complication is hyperglycemia due to the absorption of glucose from the dialysate. An exit-site leak refers to the appearance of any fluid around the peritoneal dialysis catheter identified as dialysate.

Renal Transplantation

Renal transplantation is generally preferable to dialysis. Transplantation greatly improves survival outcomes and quality of life when compared to risk-matched patients who remain on dialysis. A properly functioning renal graft has a much higher clearance of uremic toxins than dialysis. However, there is an important mismatch between the number of patients awaiting transplantation and the relatively few available kidneys. 

The average waiting time for a deceased donor may vary greatly (approximately 3 years in the Netherlands). Besides matching donor and recipient as closely as possible (favorable for graft survival and need of immunosuppressive medication), many factors are included in the calculations of the current ranking scores.

The use of living donors can be an excellent alternative and avoids important waiting time. Patients can be either transplanted pre-emptive (i.e., before the start of dialysis) or after initiation of dialysis. The renal transplant survival is better in living-donor compared to deceased-donor kidneys. Deceased-donor grafts have a 92% one-year survival and 10 year life expectancy while living-donor grafts have a 97% one-year survival and 14 year life expectancy.

Continuous exposure of the graft to the recipient’s immune system necessitates treatment with immunosuppressive drugs. Currently, patients are usually on a mixture of calcineurin inhibitors (tacrolimus, ciclosporin), mycophenolate acid, mTOR inhibitors (mTOR: mechanic target of rapamycin; like everolimus and sirolimus) and prednisolone. 

Despite a good match between donor and recipient, rejection can occur. A biopsy is necessary for the diagnosis of rejection. Distinction is made between acute and chronic rejection. Acute rejection is dominated by cellular or humoral response or a combination. The formation of antibodies often plays a role in chronic rejection. In the case of rejection the immune suppressive regimen will be increased. Graft failure after the first year of transplantation is described with the term chronic allograft nephropathy, which refers to a histopathological description with interstitial fibrosis and tubular atrophy and can be multifactorial in origin (acute rejections, immunosuppressive therapy especially calcineurin inhibitors).

Renal Drug Handling

Renal failure alters drug concentrations through various mechanisms. First, reduced glomerular filtration may impair drug clearance. Of note, this is not the only mechanism through which the nephron handles solutes as shown in figure 6. Second, renal failure alters intestinal and hepatic drug metabolism and transport. Lastly, alterations in the volume of distribution and unbound fraction of the drugs are seen (e.g., increment in free fraction in hypoalbuminemia in nephrotic syndrome). 

Figure 6. Methods of filtration and how these alter solute concentration in the plasma and urine. First filtration happens in the glomerulus, but other structures in the nephron play a role as well. Created with Biorender.com.

In renal failure medication might therefore accumulate within the bloodstream in higher and possibly toxic concentrations. For this reason, drug dosage quite often needs to be adjusted for kidney function. This can be done by giving drugs less frequently and/or in lower doses. Also when there is no strict advice for dose adjustment, careful dosing may be advisory, for instance in the case of haloperidol, lorazepam and many others. Table 8 gives an overview of some common drugs that will need their dose adjusted in cases of impaired renal function. More extensive details on the prescription of individual drugs in patients with renal failure (at all stages, including dialysis dependency) can be found in the renal drug handbook. Note that dialysis dependency may also necessitate alternative prescriptions (i.e., in timing or an extra dose) because of significant clearance of several drugs from the bloodstream, for instance antibiotics. Removal of a drug by dialysis depends on its characteristics like molecular weight, water solubility, level of protein binding and distribution volume.

Type	Drugs
Antibiotics	Aminoglycosides, ceftazidime, cefradine, meropenem, sulfamethoxazole, teicoplanin, vancomycin, trimethoprim, piperacillin, ticarcillin, quinolones, tetracyclines, fluconazole, pentamidine, aciclovir, tenofovir, indinavir
Antihypertensive agents	atenolol, captopril, sotalol
Antiarrhythmics	Digoxine, disopyramide, procainamide
Anti-epileptica	Lithium, primidone, trimethadione, phenytoin
Antiphlogistics	Penicillamine, gold
Cytostatics	Carboplatin, cisplatin, hydroxyurea, methotrexate
Other	Allopurinol, morphine,, metoclopramide, gabapentin

Table 8. Drugs that need their dose adjusted in case of impaired renal functioning.

Nephrogenic Hypertension

Key points

• Nephrogenic hypertension is a form of secondary hypertension which develops due to wrongful activation of the renin-angiotensin-aldosterone system (RAAS).
• It is often the result of renal artery stenosis or parenchymal kidney disease.
• The diagnosis should be considered in patients not responding to 3 or more antihypertensive agents. 
• ACE inhibitors may cause a sudden drop in eGFR in nephrogenic hypertension patients.
• Treatment primarily consists of lifestyle changes mitigating the formation of atherosclerosis.

General 

Nephrogenic hypertension is a form of secondary hypertension brought on by narrowing renal vessels, resulting in lowered renal blood flow, which activates the renin-angiotensin-aldosterone system (RAAS). As a consequence, renovascular hypertension occurs.

Epidemiology

It is difficult to get reliable data on the incidence of nephrogenic hypertension. According to large cohort studies, kidney disease was the cause of hypertension in 2.4 to 5.6% of all patients; renal artery stenosis caused nephrogenic hypertension in 0.2 to 4.0%. In patients with renal disease, hypertension is more frequently seen in glomerulonephritis compared to interstitial nephritis. The likelihood of hypertension is proportional to the reduction in kidney function. Up to 85% of patients with a glomerular filtration rate (GFR) below 55 mL/min/1.73 m2 have hypertension.

Symptoms

Hypertension and generalized kidney dysfunction are dominant symptoms. In addition, flash pulmonary edema may occur and can be an important clinical clue for renovascular hypertension.

Risk factors

Hypertension, diabetes mellitus and advanced age are all independent risk factors for atherosclerosis and thus nephrogenic hypertension. Nephrogenic hypertension due to fibromuscular dysplasia should be suspected in women under 50 – although it is not solely a disease of younger females – and is often observed in families.

Cause

There are different causes of nephrogenic hypertension. In renal artery stenosis, RAAS is activated as a response to reduced renal perfusion. For a refresher on the RAAS system please see the section on endocrine regulation of kidney function in the chapter on anatomy & physiology of the kidney. This would be an adequate adaptive mechanism in a situation where low systemic blood pressure causes low renal perfusion. However, in renal artery stenosis, systemic blood pressure is normal and will be raised through this mechanism. Renal artery stenosis is usually the result of atherosclerosis and is thus common in elderly patients. However, fibromuscular dysplasia (FMD) may also cause renal artery stenosis and should be considered in young female patients. FMD is a nonatherosclerotic and noninflammatory tortuous deforming, dissecting and stenotic disease of the arterial bed in which the renal and internal carotid arteries are most commonly involved. In atherosclerosis, the aortic orifice or proximal renal artery is mainly involved, whereas in FMD, lesions are found more distally. The video below gives some background information on FMD.

In parenchymal kidney disease, onset of hypertension is multifactorial. The most important factor seems to be impaired sodium excretion. Additionally, activation of the RAAS system, decreased production of blood pressure lowering agents and increased production of vasoconstrictive agents also seem to play a role.

Diagnosis

In general, secondary hypertension should be considered if hypertension is severe and resistant, if acute rises of blood pressure occur, or in case of early onset without a family history or obesity. The presence of epigastric or renal artery murmurs, indications of arteriosclerosis in the aorta or peripheral arteries, unexplained asymmetry in kidney sizes or acute episodes of pulmonary edema with blood pressure surges are all suggestive of kidney-induced hypertension. Given that the RAAS pathway induces hypertension, an acute rise of serum creatine after administering an angiotensin-converting enzyme (ACE) inhibitor suggests the diagnosis, as it reflects the characteristically low glomerular filtration rates and intraglomerular pressure. Considering parenchymal disease as a cause of nephrogenic hypertension, urinalysis will likely be abnormal and a rise in creatinine seen. Other forms of secondary hypertension need to be considered in the workup, like glomerulonephritis, hyperthyroidism, hyperaldosteronism, drugs, sleep apnea syndrome, pheochromocytoma, Morbus Cushing and coarctation of the aorta. 

Further diagnostics should be undertaken if the patient can undergo and will likely benefit from a corrective procedure. Renal arteriography is the gold standard. However, given its invasive nature, it should only be performed when there are no contraindications to an endovascular approach. Noninvasive approaches, such as MRI or CT angiography are highly accurate. However, one should always consider the possible drawbacks, like contrast-induced nephropathy and the option of gadolinium-induced nephrogenic systemic fibrosis. Doppler sonography is a viable option, but results are variable in sensitivity and contingent on the operator’s skill.

Treatment 

Blood pressure control is a primary concern when treating patients with nephrogenic hypertension. The medical regimen ideally contains a RAAS inhibitor, but kidney function might drop significantly. Therefore, renal revascularization should be considered if optimal medical therapy fails or is not tolerated, if there are episodes of flash edema, or if patients show refractory heart failure. Renal revascularization is mainly performed through percutaneous angioplasty and stenting.

In FMD, revascularization is a good treatment option in young patients to cure or better regulate the recent onset of resistant hypertension and in patients with progressive renal failure attributable to FMD. The most important interventions in atherosclerosis are lifestyle interventions focused on refraining from tobacco smoking, maintaining a healthy weight and diet and exercising.

Cardiorenal Syndrome

Key points

• Cardiorenal syndrome refers to a disease that involves both kidney and heart failure.
• Cardiorenal syndrome is complex and based on 3 hemodynamical mechanisms: reduced cardiac output, venous congestion and neurohormonal activation.
• There are 5 subgroups of cardiorenal syndrome. A distinction is made based on the causative process (heart, kidney, or systemic disease) and the acute or chronic nature of the disease.
• Treatment is tailored to the type of cardiorenal syndrome. Options include diuretics, RAAS inhibition, ultrafiltration, and inotropes.

General

Cardiorenal syndrome (CRS) comprises a group of disease states that involve simultaneous kidney and heart failure (HF). The kidney and the heart are in a “symbiotic” bi-directional relationship: the vitality of one organ ultimately and inevitably depends on the vitality of the other. In CRS, an acute or chronic dysfunction in the heart or the kidneys causes an acute or chronic dysfunction of the other organ. Cardiorenal syndromes have recently earned major clinical significance because of their complex management challenges and profound effects on mortality in patients suffering from concomitant heart and kidney diseases. 

Epidemiology

About 25% of patients hospitalized for acute decompensated heart failure develop acute kidney injury. Most cases result from acute worsening of chronic heart failure due to (non)ischemic heart disease. In addition, many patients suffer from pre-existing chronic kidney disease. The prevalence of chronic kidney disease in patients with chronic heart failure is estimated to be 40 to 60%.

Symptoms

The clinical picture of cardiorenal syndrome is characterized by fluid congestion in the body. The signs and symptoms of congestion are increased jugular vein pressure, extravascular fluid buildup (i.e., edema) and crackles on pulmonary auscultation. Patients may suffer from hepatomegaly, orthopnoea and dyspnea (on exertion). Many patients report oliguria.

Cause

The pathophysiology of cardiorenal syndrome is complex. Currently, 3 pathophysiological mechanisms contribute to the progression into cardiorenal syndrome: (1) hemodynamic alterations due to low cardiac output; (2) venous congestion; and (3) neurohormonal activation due to increased sympathetic output and activation of the renin-angiotensin-aldosterone system (RAAS). In addition to these pathophysiological mechanisms, local and systemic inflammation and metabolic changes like uremia, anemia and bone mineral disorder in chronic kidney disease (CKD-MBD) play a role in cardiorenal syndrome.

Renal blood flow (via cardiac output) and renal venous pressure (via right atrial pressure) link the kidney to cardiac function. Renal perfusion pressure is the gradient between aortic and renal venous pressures and is a significant determinant of renal blood flow. In cardiorenal syndrome, the renal blood flow is reduced. The decreased renal perfusion causes hypoxia of the renal parenchyma. In addition, neurohormonal activation causes increased resistance in the efferent arteriole, i.e., post-glomerular vasoconstriction, raising the intraglomerular and filtration pressure in order to stabilize glomerular filtration rate (GFR). The resulting intraglomerular hypertension causes accelerated destruction of nephrons in the long term. It is essential to realize that the neurohormonal activation causes additional Na+ reabsorption in the proximal tubule via upregulation of the sodium transporters. This results in a lower supply of NaCl to the macula densa and inadequate tubular glomerular feedback. This process creates a negative spiral with further Na+ retention, increasing plasma volume and central venous pressure. This implicates further venous congestion in the kidneys and lowering of the renal perfusion pressure. Raised central venous pressure is the strongest hemodynamic determinant of cardiorenal syndrome. Congestion causes increased cardiac filling pressure and cardiac output decreases, known as the Frank-Starling mechanism (see video). 

The kidney is sandwiched between congestion and decreased cardiac output, causing renal injury and a decreased glomerular filtration rate. The vicious circle causes decompensation of the cardiorenal system. Five subgroups are identified in CRS. Depending on the type of cardiorenal syndrome, the vicious circle starts from a different place in the pathophysiological cascade of the cardiorenal syndrome.

Figure 7. Pathophysiology of the cardiorenal connectors. Overview based on Wikidoc. Created with Biorender.com

Classification

Table 9 shows 5 subgroups that have been identified and further approved by the Acute Dialysis Quality Initiative (ADQI) in 2010 based on their presumed pathophysiology. In the first 2 groups, cardiac disease (acute and chronic) leads to kidney failure. Primary kidney disease (acute and chronic) leads to cardiac dysfunction in the third and fourth groups. Finally, the fifth group comprises the systemic conditions that cause contemporary heart and kidney dysfunction.

Type		Description
Type 1	Acute cardiorenal syndrome	Acute heart failure leads to acute kidney injury
Type 2	Chronic cardiorenal syndrome	Chronic heart failure leads to chronic renal failure
Type 3	Acute renocardiac syndrome	Acute kidney failure leads to acute heart failure
Type 4	Chronic renocardiac syndrome	Chronic kidney failure leads to chronic heart failure
Type 5	Secondary cardiorenal syndrome	A systemic disease leads to heart and kidney failure

Table 9. Overview of types of cardiorenal syndromes.

Cardiorenal Syndrome type 1

In CRS type 1, also called acute CRS, acute heart failure leads to acute kidney injury. Reduced cardiac output may lead to ineffective circulatory volume, raised central venous pressure and congestion. In congestive heart failure, neurohormonal activation induces vasoconstriction of the afferent arteriole (preglomerular vasoconstriction) – via increased sympathetic output – to maintain systemic blood pressure. Consequently, renal blood flow is further reduced and GFR declines despite post-glomerular resistance.

The terms congestion and volume overload are used interchangeably, which is incorrect. Increased sympathetic output leads to vasoconstriction in the splanchnic area resulting in blood redistribution from the splanchnic capacitance vasculature to the circulatory volume. Blood redistribution increases the effective circulation volume. In up to 50% of hospitalized patients with acute heart failure, less than 1 kg of weight gain is observed in the month prior to admission. This may suggest that congestion is sometimes caused by volume overload and redistribution. Of note, heart failure is often associated with cachexia, making interpretation of weight changes difficult. Congestion causes increased cardiac filling pressure and decreased cardiac output, according to the Frank Starling mechanism.

Cardiorenal Syndrome type 2

CRS type 2, sometimes dubbed chronic CRS, involves chronic heart dysfunction, which causes progressive chronic kidney disease. About 30% of chronic heart failure patients also have moderate to severe chronic kidney disease. In patients with chronic heart and kidney disease, it is often difficult to determine the primary disease. 

Cardiorenal Syndrome type 3

CRS type 3, or acute renocardiac syndrome, covers acute kidney injury that directly or indirectly precipitates or contributes to acute cardiac dysfunction. Cardiac dysfunction manifests in different ways: acute heart failure, acute coronary syndrome or arrhythmias. Venous congestion due to volume overload or redistribution, metabolic disturbances and inflammatory surge may lead to acute heart failure. Most patients suffer from pre-existing heart disease. 

In general, acute kidney injury is an independent mortality risk factor in acutely decompensated heart failure patients, especially those needing dialysis.

Cardiorenal Syndrome type 4

CRS type 4, or chronic renocardiac syndrome, represents chronic kidney failure leading to a broad spectrum of cardiovascular diseases, including coronary artery disease, valvular calcifications, heart failure or arrhythmias. The severity of chronic kidney disease is proportionally correlated to the prevalence of cardiovascular disease, which makes chronic kidney disease a strong independent risk factor for cardiovascular morbidity and mortality. Mortality in chronic kidney disease is due to major cardiovascular events in almost 50% of cases.

The cardiorenal connectors in CRS type 4 include: (1) salt and water retention causing chronic volume overload and hypertension; (2) hyperphosphatemia leading to hyperparathyroidism inducing vascular and valvular calcifications; (3) metabolic dysregulation and accumulation of uremic toxins; (4) chronic inflammation and endothelial dysfunction; and (5) anemia.

Cardiorenal Syndrome type 5

In CRS type 5, or secondary CRS, acute cardiac and renal dysfunction is due to acute or chronic systemic disorders. A broad spectrum of diseases, including sepsis, hepatorenal syndrome, diabetes mellitus, amyloidosis, lupus, sarcoidosis and Fabry’s disease, can cause CRS type 5 through many different pathways. Once the kidneys and the heart are damaged, a vicious cycle of further injury is induced.

The treatment of CRS type 5 focuses on the primary disease and its complications. For example, intravenous fluids and pressor agents might be helpful in sepsis, where acute kidney injury results from hemodynamic factors, inflammatory mediators, and myocardial dysfunction. In hepatorenal syndrome, which is often fatal, fulminant liver failure rapidly deteriorates kidney function. In these cases, temporary intravenous albumin and vasopressin analogs are appropriate while waiting for liver transplantation.

Diagnosis

Diagnosis of decompensation can often be made on clinical presentation. Specific tests may be elevated depending on the underlying cause and how far the CRS has progressed. NT-proBNP is a marker for cardiac decompensation in the left atrium especially. Likewise, anemia, metabolic acidosis, as well as increased creatinine, urea, potassium and phosphorus are observed in chronic kidney failure. On plain chest radiography, signs of congestion may be seen, which include prominent pulmonary veins, diffuse air space opacification with air bronchograms and pleural effusion.

Treatment

The greatest challenge is the therapeutic approach and pharmacological intervention required in favor of a CRS patient with a known poor prognosis. Today’s management strategies, despite proven efficacy, remain notorious for their deleterious effects on the target organs of CRS. An individualized approach requires a profound understanding of CRS and its pathophysiology. There is sparse evidence of specific treatment in populations suffering from cardiorenal syndrome. All therapeutic recommendations are based on treating chronic kidney disease or heart failure. In addition, limited data are available in patients with CKD stages 4 and 5. Interestingly, kidney transplantation can improve left ventricular ejection fraction in patients on dialysis suffering from heart failure with reduced ejection fraction. This confirms that improved kidney function is associated with cardiac remodeling independently of the classical cardiovascular risk factors. 

Preventive treatment strategies are therefore of utmost importance. In that respect, the complications associated with chronic kidney disease should be treated as discussed under complications and prognosis in CKD. 

A tailored approach is paramount and treatment options can be classified into the following categories:

Diuretics

In decompensated heart failure, adequate decongestion with diuretics improves survival despite a decline in GFR. This drop is likely predominantly hemodynamic and thus reversible in origin. Before initiating diuretic therapy to decongest, one should differentiate between volume overload or volume redistribution contributing to congestion. The goal is to achieve adequate decongestion and resolve the volume overload. Loop diuretics are primarily used in acute decompensated heart failure. Intravenous loop diuretics are effective within 1-2 hours. Early evaluation of diuretic response is essential to identify non-responders (< 500 ml urine production in 1-2 hours) in whom the diuretic threshold is not met. The dosage may then be increased, or a thiazide diuretic may be added to initiate sequential nephron blockade (a combination of diuretics that all work in a different part of the nephron). Electrolyte imbalances, especially potassium, often occur.

Ultrafiltration

Ultrafiltration is the mechanical removal of fluid, which may be attained through peritoneal dialysis. If the sequential nephron blockade approach fails, this therapy may help relieve congestion in heart failure patients. Of note, intermittent hemodialysis is often not feasible due to reduced cardiac output. 

RAAS inhibition

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARB) – alone or combined with a neprilysin inhibitor such as the prodrug sacubitril – are standard therapy for HF with a reduced ejection fraction. RAAS inhibition has beneficial effects on long-term outcomes like mortality and HF hospitalizations despite an initial rise in creatinine (due to a decrease in GFR). This early increase just reflects the inhibition of the adaptive mechanisms (post-glomerular vasoconstriction) to maintain glomerular filtration despite decreased renal perfusion. A small rise in creatinine does not worsen outcomes: it should therefore be monitored and not readily lead to discontinuation. Careful monitoring of serum potassium levels is mandatory. 

Mineralocorticoid receptor antagonists 

Mineralocorticoids, like aldosterone, have multiple effects, including sodium retention, but also stimulation of inflammation. Therefore, mineralocorticoid receptor antagonists (MRAs), which block these effects, are recommended in heart failure to counteract the actions of aldosterone initiated via neurohormonal activation.

SGLT2 inhibitors

Sodium glucose cotransporter 2 (SGLT2) inhibitors are relatively new drugs for cardiorenal syndrome. Increased activity of the SGLT2 channel is responsible for glomerular hyperfiltration. As SGLT2 causes increased sodium reabsorption in the proximal tubule, less sodium and chloride is delivered at the macula densa. This stimulates the glomerular filtrate rate increase via impaired tubuloglomerular feedback with preglomerular vasodilation. Hyperfiltration is observed in heart failure patients and is associated with increased nephron destruction. SGTL2 inhibitors directly intervene in this process and have been shown to reduce renal function decline and cardiovascular mortality. 

Beta-blockers

The mechanism of beta blockades is twofold. First, beta-blockade reversibly blocks the effects of sympathetic output. Secondly, it reduces oxygen consumption in heart failure patients. Beta-blockers used in heart failure are bisoprolol, carvedilol, metoprolol and nebivolol.

Other

Stabilizing both heart and kidney function is essential to prevent progression to CRS. Inotropic drugs stimulate and increase heart muscle contraction but play a limited role in CRS. However, there is some evidence that other therapies that improve cardiac function can improve kidney function. These include left ventricular assist device (LVAD), which helps pump the blood from the left ventricle into the aorta, and cardiac resynchronization therapy (CRT), which aims to make the heart contract in a more organized and efficient way. 

Decreased kidney function may be stabilized by treating the underlying disease and replacing the renal function with dialysis or transplant if necessary. There is increasing evidence that cardiac function improves in patients with primary kidney disease who receive a renal transplant. 

Hepatorenal Syndrome

Key points

• Hepatorenal syndrome refers to reduced blood flow to the kidneys due to the hemodynamic changes associated with liver failure.
• Ascites, hypotension and oliguria characterize hepatorenal syndrome. Bleeding or infection often triggers its onset.
• Hepatorenal syndrome is caused by arterial splanchnic vasodilation due to portal hypertension, which leads to impaired renal perfusion and renal failure.
• Hepatorenal syndrome can only be diagnosed if other causes of renal insufficiency have been excluded. There is no diagnostic test.
• Liver transplantation is the best definite treatment option for hepatorenal syndrome. 
• Patients may not be eligible for transplantation. In these cases, supportive therapy focuses on reducing portal hypertension and increasing renal perfusion.

General

Hepatorenal syndrome (HRS) is a relatively common and feared complication in patients with liver cirrhosis. This condition is considered the result of extreme hemodynamic changes due to liver failure, resulting in reduced kidney perfusion and failure. It holds a poor prognosis.

Epidemiology

Patients usually have portal hypertension due to liver cirrhosis, but HRS can be seen in severe hepatic failure from any cause. In one study, it was estimated that 18% of individuals with cirrhosis and ascites developed HRS within one year of their diagnosis with cirrhosis and 39% of these individuals developed HRS within 5 years of diagnosis.

Symptoms

Ascites, hypotension and oliguria characterize the clinical picture of HRS. In addition, patients show known signs of advanced liver failure like jaundice, increased bleeding tendency and hepatic encephalopathy. HRS is often exacerbated by a luxating moment, such as bleeding in the digestive tract or bacterial infection.

Cause

In patients with progressive liver cirrhosis, increasing pressure in the liver impairs blood flow through the liver. Impaired blood flow leads to portal hypertension which triggers vasodilation mediators like nitric oxide and inflammatory mediators to be released, which leads to vasodilation. This reduction in systemic vascular resistance is most pronounced in the arterial bed of the splanchnic region. Vasodilation induces an increased blood flow through the gastrointestinal system, leading to a reduced effective circulating volume and a progressive rise in cardiac output. Reduced effective circulating volume causes neurohormonal activation via the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system and increases the secretion of antidiuretic hormone (ADH) in the pituitary gland. These mechanisms are activated to increase the circulating volume and restore renal perfusion. However, due to the ongoing liver disease, the extra volume recruited in the kidney through neurohormonal activation and ADH is mainly lost to the abdominal cavity, causing ascites. Consequently, renal perfusion remains reduced despite compensatory mechanisms and the kidney’s chronic underfill leads to kidney failure.

Figure 8 gives an overview of the mechanisms involved in HRS. Notably, the release of the inflammatory mediators that contribute to this system is a response to the translocation of bacteria from the intestinal lumen to mesenteric lymph nodes. Infection or bleeding of the digestive tract can therefore be a luxating factor for vasodilation. 

Figure 8. Schematic overview of mechanisms that lead to kidney injury in hepatorenal syndrome. RAAS: renin-angiotensin-aldosterone system, ADH: antidiuretic hormone. Created with Biorender.com

Diagnosis

Laboratory results show hyponatremia and a rise in serum creatinine. Urine sediment is often normal and fractional sodium excretion is low. However, the diagnosis of HRS is made on clinical criteria: the presence of progressive renal failure (i.e.not improving after volume expansion with IV albumin and withdrawal of diuretics) and advanced hepatic failure with portal hypertension are both necessary to diagnose HRS. Importantly, it is also a diagnosis by exclusion; prerenal failure, shock and intrinsic renal failure need to be ruled out. The distinction between HRS and other causes of renal insufficiency is crucial because of its therapeutic implications and as it provides insight into the prognosis. Two forms of the hepatorenal syndrome have been described. Hepatorenal syndrome type 1 is a rapid decline of kidney function (doubling of creatinine in less than two weeks). Some patient may become oliguric. Hepatorenal syndrome type 2 is defined as renal function decline that is less severe than type 1. Type 2 is diuretic resistance state with build up of ascites. In cases of renal insufficiency, diuretics are usually withdrawn and patients are treated with albumin infusions for 48 hours to restore effective circulation volume. This therapy improves any prerenal insufficiency due to reduced effective circulating volume. However, in HRS, renal failure does not resolve with albumin infusion within this timeframe. Of note, gastrointestinal bleeding or septic shock – including spontaneous bacterial peritonitis – may cause acute tubular necrosis (ATN) but are also precipitating factors for HRS. In ATN, the tubular function and ability to concentrate urine are impaired. In HRS, the kidneys respond to the reduced effective circulating volume by reabsorbing sodium and water, leading to concentrated urine.

Treatment

Ideally, the liver function should improve due to treatment of decompensated hepatitis B, recovery of alcoholic hepatitis or liver transplantation. Unfortunately, this is not possible in the short term.

All antihypertensive agents are usually discontinued. Patients in the ICU unit are often treated with terlipressin, a vasopressin analogue that increases the tone of the splanchnic vessels. Consequently, effective circulation volume is increased, neurohormonal activation is reduced and renal perfusion is increased with the improvement of renal function. In addition, albumin is infused to increase effective circulating volume. It is advised to carefully monitor respiratory function when terlipressin is given.

Alternatively, if terlipressin is unavailable, midodrine, noradrenaline and octreotide can be given. Sometimes, a transjugular intrahepatic portosystemic shunt (TIPS) can be placed in patients not responding to medical therapy to reduce portal vascular pressure. TIPS connects the hepatic and portal vein to decompress some portal hypertension. Decompression leads to increased effective circulating volume and reduced neurohormonal activation. Liver transplantation is the best treatment for these patients. However, not all patients are eligible for liver transplantation; many die before a donor’s liver is available. If needed, hemodialysis may serve as a bridge to liver transplantation or liver recovery in reversible forms of liver disease.

Glomerular Disease

Key points

• Glomerular disease entails an impressive and diverse spectrum of disorders in which the glomeruli are injured.
• Primary or idiopathic glomerular disease occurs on its own. Beside these there are genetic forms based on genetic defects and secondary forms that manifest in the context of a systemic disease or medication.
• Glomerular disease is usually caused by immune mechanisms, such as the formation of immune complexes or damage caused by activated immune cells.
• Its presentation varies widely from nephritic to nephrotic syndrome and from asymptomatic urine abnormalities to rapidly progressive renal failure.
• Kidney biopsy is important in diagnosing and classifying glomerular disease.

General 

Glomerular diseases comprise a broad spectrum of disorders in which the glomerulus is involved. These can either be primary (idiopathic), be due to a genetic mutation (often inherited) or result secondary to one of many acquired diseases. Severity ranges widely from asymptomatic urine abnormalities to a nephrotic syndrome, or to a rapidly progressive glomerulonephritis, that necessitates immunosuppressive therapy and may result in end-stage kidney disease requiring renal replacement therapy. Extra-renal manifestations may occur.

Physiology

Before further discussing glomerular diseases, it is helpful to look at the anatomical structure of the glomerulus again, as it is complex and disease activity can occur at every single component and may progress beyond. The main locus of injury within the glomerulus is specific for each disease entity and markedly influences the clinical presentation; for example, damage exclusive to podocytes results in different symptoms than when the entire glomerulus is inflamed.

In short, the glomerulus is the basic filtering unit of the kidney and its main components are the following (also shown in figure 9):

• A tuft of capillary loops. Outside the inner layer of endothelial cells lies the glomerular basement membrane (GBM), which is a size-selective and charge-selective barrier. The outer side of the GBM is paved with the foot processes of the visceral epithelial cells that are in continuation with the parietal epithelial cells of Bowman’s capsule. Via their specialized intercellular junctions – slit diaphragms – they form another barrier to the filtration of macromolecules.
• Bowman’s capsule is the cup-like sac that collects the filtrate and passes it into the renal tubule. Its single layer of parietal epithelial cells is continuous with cells of the proximal tubule.
• Mesangium, with its specialized cells, forms the structural matrix supporting the capillary loops of the glomerulus.

Figure 9. Schematic overview of the anatomy of the glomerulus and filtration barrier (below). GBM: glomerular basement membrane. Created with Biorender.com

Pathophysiology

In many glomerular disorders, an immune mechanism elicits the actual disease, for instance, due to in situ formation of immunocomplexes (IC) in primary membranous glomerulopathy and anti-GBM nephritis. In lupus nephritis, circulating IC pre-formed elsewhere stick to parts of the glomerulus and inflict an inflammatory reaction. The constitution of IC in lupus, i.e., the type of nuclear antigens involved, determines their properties and, therefore, the glomerular structure they will land on. As this dictates the possibilities for both complement activation and the influx of inflammatory cells, a broad glomerular disease spectrum even within the ‘single’ entity of lupus nephritis can be seen.

Another inflammatory mechanism is the direct injury of massively activated neutrophils and macrophages on the glomerulus, as seen in ANCA-associated vasculitis. 

Glomerular failure can also result from podocyte dysfunction in genetic diseases in which an essential GBM protein is affected, e.g., collagen IV mutations in Alport syndrome. 

In primary forms of minimal change disease and focal segmental glomerulosclerosis, podocyte function is thought to be disrupted by an unknown circulating factor. Various systemic diseases, be they infectious, cancerous, or for instance, monoclonal gammopathy, can also result in different glomerulopathies. In case of a clear eliciting condition, the term secondary glomerular disease is applied. 

Glomerular inflammation and disruption start with the local proliferation of cells that may progress to scarring (glomerulosclerosis) and to extensive cell death (necrotizing glomerulonephritis). Based on the locus of disease activity, pathological patterns seen under a microscope can be either described as mesangial proliferative, endocapillary proliferative or extracapillary proliferative. In this last entity, rupture of the glomerular membrane has occurred with the accumulation of macrophages, fibroblasts, proliferating epithelial cells and fibrin within Bowman’s space. This process is called crescent formation (figure 10) and it represents severe injury and is devastating for glomerular function. Based on the degree of involvement of the glomerulus, histology is further described in terms of diffuse or focal (> or < 50% glomeruli involved) and global or segmental (> or < 50% of the individual glomerular tuft involved). Accompanying interstitial fibrosis is a poor prognostic sign.

Figure 10. Crescent formation (in teal) in a glomerulus. Periodic acid silver methenamine stain. Adapted from Wikimedia Commons.

Symptoms

Patient presentation ranges widely from asymptomatic – with incidental microscopic hematuria being the only clinical clue – to progressive malaise with all kinds of complaints. Patients often describe frothing of the urine on micturition and frequently present with edema as part of a nephrotic syndrome (see clinical definitions below). Most patients are hypertensive. As many glomerular diseases are not limited to the kidneys or are elicited by an underlying systemic disorder, many extra-renal findings may be present and must be traced actively per organ. In systemic vasculitis, the Birmingham Vasculitis Activity Score is very helpful in clinically assessing all possible disease manifestations. Other critical aspects to explore are medication – prescribed or over-the-counter – prior acute or chronic infection, allergies and features suggestive of a systemic disorder such as lupus erythematosus or diabetes mellitus.

Some clinical definitions:

Nephrotic syndrome

Nephrotic syndrome is characterized by massive proteinuria (> 3,5 g/24h) and overt hypoalbuminemia. In addition, patients have peripheral or periorbital edema. Sometimes patients suffer from pleural effusion or ascites. Other distinct findings are hyperlipemia and lipiduria. A general prothrombotic tendency may prompt the start of anticoagulation in severe hypoalbuminemia (< 20-25 g/L), especially in membranous nephropathy, to prohibit thrombotic complications.

Nephritic syndrome

In nephritic syndrome, glomerulonephritis, i.e., a glomerular inflammation results in (microscopic) hematuria, proteinuria to variable degrees – up to nephrotic range – and leukocyturia in the absence of a urinary tract infection. The disease course can be chronic and slowly progressive, acute and self-limiting, or fulminant, like in rapidly progressive glomerulonephritis. 

Rapidly Progressive Glomerulonephritis

Rapidly progressive glomerulonephritis (RPGN) is an acute glomerulonephritis presenting with acute kidney injury and morphologically extensive crescent formation. These features are most often due to ANCA-associated vasculitis or anti-GBM disease. Prompt action is warranted to prevent rapid progression to end-stage kidney disease or death. Pulmonary renal syndrome with possibly life-threatening lung bleeding is associated with RPGN. RPGN generally warrants the start of immunosuppressive drugs and, if indicated, plasma exchange. Renal replacement therapy is often needed. 

Diagnosis

Glomerular diseases manifest in the laboratory with different patterns:

• Isolated glomerular hematuria, i.e., with specific dysmorphic erythrocytes and red blood cell casts.
• Isolated non-nephrotic proteinuria (albuminuria).
• A combination of glomerular hematuria and proteinuria.
• Massive or nephrotic range proteinuria (> 3.5g/24h), either with or without a clinical nephrotic syndrome.
• Rapid deterioration of kidney function as in RPGN..

Some disorders, like lupus nephritis, may show different laboratory patterns over time. Apart from RPGN, glomerular diseases can present either acute or chronic and lead to various impairments of kidney function.

A kidney biopsy is often of great importance in diagnosing and classifying a glomerular disease. However, in specific situations, a definitive diagnosis can now be made by serology. For example, patients with an overt nephrotic syndrome and anti-phospholipase A2 receptor autoantibodies present can be diagnosed with membranous nephropathy without biopsy. A biopsy is generally not performed in patients with isolated glomerular hematuria since it is unlikely that a specific treatment needs to be instituted. The same goes for patients with advanced renal insufficiency and small kidneys on renal imaging. Sometimes, a biopsy needs to be deferred if the risks of a puncture at that time do not outweigh the benefits and treatment will then be started based on the presumptive diagnosis. 

The following additional laboratory tests are often done in patients with suspected glomerulonephritis: serum C3 and C4 complement levels, ANCA autoantibodies, anti-GBM autoantibodies, antinuclear antibodies, anti-dsDNA autoantibodies, HBV/HCV/HIV serology, serum free light chains and serum immunofixation. In addition, if thrombotic microangiopathy is considered, ADAM-TS13 activity should be urgently measured. Additionally, anti-PLA2R antibody testing needs to be done in case of nephrotic syndrome.

Treatment

General supportive measures include dietary sodium and protein restrictions, blood pressure control, minimization of proteinuria with the renin-angiotensin system inhibition and treatment of dyslipidemia. In nephrotic patients, edema is treated with loop diuretics or a combination of diuretics. In case of severe hypoalbuminemia, prophylactic anticoagulation must be considered to prevent thrombotic complications. 

The use of immunosuppressive drugs and other therapies like plasmapheresis are discussed in the following disease-specific chapters. When applying immunosuppressive drugs, remember to start prophylactic therapy with trimethoprim-sulfamethoxazole to prevent Pneumocystis jirovecii pneumonia (PCP). The same goes for osteoporosis prevention in long-term glucocorticoid therapy.

Overview of Glomerular Disease Entities

Making a solid clinical classification of glomerular diseases is difficult, as the various disease entities are mainly defined based on their similar pathogenesis or pathology findings. Table 10 below illustrates the differences and similarities in clinical presentation while highlighting the differentiating pathogenesis and biopsy findings. All entities will be discussed in detail in the following chapters.

Type		Cause	Presentation	Biopsy
IgAN	Primary	Pathologic IgA immune complexes	Gross hematuria after URTI OR microscopic hematuria and mild proteinuria Seldom nephrotic syndrome or RPGN	Mesangial IgA depositions
	Secondary	Liver cirrhosis, celiac’s disease
MN	Primary	Circulating antibodies to glomerular antigens (i.a. PLA2R)	Nephrotic syndrome (80%) or asymptomatic proteinuria (20%)	Diffuse thickening of the GBM (subepithelial immune deposits)
	Secondary	Drugs, infections, malignancies, autoimmune disease
MCD	Primary	Hypothesis: circulating factor that impacts the glomerular capillary wall	Sudden onset nephrotic syndrome	Normal on LM and IF, but diffuse effacement of podocytes on EM
	Secondary	Drugs, malignancies infections
FSGS	Primary	Hypothesis: circulating factor that impacts the glomerular capillary wall	Acute/progressive nephrotic syndrome	Sclerosis of portions of (at least one) glomeruli on LM On EM: *primary: diffuse effacement of foot processes *secondary: segmental effacement of foot processes
	Secondary	Adaptive Drugs, viral (HIV)	Mostly non-nephrotic range proteinuria
	Genetic	Inadequate production of podocyte or slit diaphragm proteins	Depends on age at presentation. Check for syndromic aspects.
	Unknown cause	Undetermined	Proteinuria without nephrotic syndrome
MPGN	Immunocomplex or monoclonal Ig mediated		Nephritic syndrome in active disease Variable proteinuria, sometimes nephrotic syndrome Extra renal manifestations in DDD	Mesangial hypercellularity, endocapillary proliferation and thickened GBM with immune depositions on IF and EM
	OR dysregulated complement system
	OR other mechanism
GPA	ANCA vasculitis, immunocomplex mediated and neutrophils mediated necrotising vasculitis in smaller arteries		ANCA titers Multiple organs may be affected	Diffuse necrotizing and crescentic glomerulonephritis Granuloma may be seen.
LN	Deposition of immune complexes between the GBM and the capillary endothelium.		Most often hematuria and proteinuria, but it depends on the class of LN	Depends on the class of LN
TMA	TTP	Thrombosis in the glomerular capillaries due to congenital, autoimmune, iatrogenic or disease mediated vascular damage and thrombus formation.	Fever, thrombocytopenia, hemolytic anemia, end-organ damage.	Thrombosis in glomerular capillaries. Secondary focal segmental sclerosis in TTP and HUS patients.
	HUS
	Secondary TMA		As above + symptoms depending on causative disease or process.
Anti- GBM	Circulating autoantibodies form complexes with antigens of the collagen type IV chain. The resulting inflammatory response impairs kidney function.		About 90% with RPGN, some with pulmonary symptoms	Crescentic glomerulonephritis with linear IgG deposits along the capillaries

Table 10. Overview of glomerular disease and their presentation and diagnostic differences. Disease abbreviations: IgAN = IgA nephropathy, RPGN: rapidly progressive glomerular nephropathy, MN = membranous nephropathy, MCD = minimal change disease, FSGS = focal segmental glomerulosclerosis, MPGN = membranoproliferative glomerulonephritis, DDD: dense deposit disease, GPA: granulomatosis with polyangiitis (Wegener), LN: lupus nephropathy, TMA: thrombotic microangiopathy, HUS: hemolytic uremic syndrome, anti-GBM: anti-glomerular basement membrane disease (Goodpasture). 

Other abbreviations: DDD: dense deposit disease, TTP: thrombotic thrombocytopenic purpura, HUS: hemolytic uremic syndrome, URTI: upper respiratory tract infection, GBM: glomerular basement membrane, LM: light microscopy, IF: immunofluorescence microscopy, EM: electron microscopy, ANCA: anti-neutrophil cytoplasm antibodies.

IgA Nephropathy

Key points

• IgA nephropathy is the most common primary glomerulonephritis. It is caused by mesangial deposition of predominantly polymeric IgA1.
• IgA nephropathy can also be secondary to celiac disease, liver cirrhosis, or HIV.
• A kidney biopsy is required to confirm the diagnosis; mesangial IgA deposition is pathognomonic.
• IgA nephropathy is often benign, but in 30% of patients, it progresses to end-stage kidney disease.
• Treatment focuses on preventing progression; immunosuppressive medication is reserved for patients at high risk for progressive disease despite supportive measures.

General

IgA nephropathy (IgAN), or Berger’s disease, is the most common form of primary glomerulonephritis. The typical immunofluorescence pattern of mesangial IgA depositions on kidney biopsy is pathognomonic. Of note, as the same image is found in several percent of biopsies in individuals with no apparent kidney disease, IgAN may also be ‘latent’ and go undiagnosed. 

Epidemiology

Males are twice as often affected as females in North America and Western Europe. The peak incidence is seen in the second and third decades. The disease is relatively common in East Asian individuals and rare in African populations, which is only partly influenced by worldwide differences in testing strategies in patients with isolated hematuria.

Symptoms

There are 3 ways in which patients with IgAN typically present. A common presentation is recurrent gross hematuria, which often follows an upper respiratory tract infection. Another frequent presentation is microscopic hematuria and mostly mild proteinuria, as either incidentally found during a health check or in a chronic kidney disease diagnostic workup. Seldom, patients present more dramatically with nephrotic syndrome or rapidly progressive glomerulonephritis. Of note, malignant hypertension may be the first symptom, mostly in longstanding disease that has gone undiagnosed. 

Cause

The initiating event in IgAN is the mesangial deposition of predominantly polymeric IgA1. In this respect and probably reflecting an underlying dysregulation of the immune system in IgAN, a high proportion of poorly hinge region O-galactosylated IgA1 is found in the serum and mesangium of patients. These pathologic IgA1 molecules have an increased tendency to self-aggregate and form immune complexes with IgA and IgG (see figure 11). The resulting macromolecular structures tend to deposit in the mesangium and are thought to eventually lead to disruption of the glomerular basement membrane (GBM) and, consequently, hematuria. 

Figure 11. Normal dimeric IgA on the left and galactose-deficient IgA on the right. The O-galactosylated (pink area) IgA molecules can form immune complexes with IgG (in green). Adapted from Wikimedia commons.

Most cases of IgAN are primary with unknown etiology. IgAN likely starts from a mucosal dysfunction of the immune system with mis-trafficking of ‘mucosal’ plasma cells to systemic sites due to a defective homing. Several environmental factors such as mucosal infections and dietary antigens may drive the generation of these pathogenic ‘mucosal-type’ IgA1 and immune complexes. Besides the production of pathogenic IgA1, which seems in part inheritable, there is evidence for a reduced systemic and mesangial clearance of IgA1. Moreover, in these patients, the accumulating IgA1 somehow induces local mesangial cells and activates the alternative and lectin pathways of the complement system, resulting in glomerular injury (figure 12). For this reason, IgAN could be described as a complex, polygenic and, in part, autoimmune disease.

IgAN can also occur secondary to many other diseases. Mesangial IgA depositions are often seen in liver cirrhosis and celiac disease, where most adult patients have no clinical manifestations of glomerular disease. Human immunodeficiency virus (HIV) infection is another example. Although the classic glomerulopathy seen in HIV infections is the collapsing variant of focal segmental glomerulosclerosis, IgAN is increasingly reported, most often subclinical.

Figure 12. Pathophysiology of IgAN: IgA-IgG immune complexes deposit into mesangial cells where they activate cells to produce more extracellular matrix and activate the immune system. This additional extracellular matrix and immune system activation leads to damage of the glomerular basement membrane and capillaries causing protein to leak into Bowman’s space. Created with BioRender.com.

Diagnosis

A suspicion of IgA nephropathy is often raised based on clinical presentation and laboratory results. Confirmation of the diagnosis of IgAN requires a kidney biopsy. However, as the course of IgAN in patients with isolated hematuria is generally benign, this is usually only performed if signs suggest a more progressive disease, i.e., elevated creatinine or persistent urine protein excretion of at least 1 g/day. No other diagnostic tools are recommended. Of note, IgAN needs to be differentiated from 2 other glomerulopathies that present with persistent isolated hematuria: Alport syndrome and thin-basement membrane nephropathy. This differentiation can be done through family history and by taking a biopsy.

Immunofluorescence microscopy typically shows IgA (co)dominant diffuse and global mesangial deposits. Subendothelial IgA deposits in the capillary walls are associated with a worse renal outcome. In later clinical presentations – with decreased glomerular filtration rate (GFR) and increased proteinuria – features of chronic disease are commonly seen, such as glomerulosclerosis, interstitial fibrosis and tubular atrophy (together: IFTA). Segmental necrosis with or without crescent formation is often seen in patients with a rapid decline in kidney function.

In idiopathic IgAN, the revised Oxford pathological classification (MEST-C score: a PowerPoint with the criteria can be downloaded here) is used to uniformly score and document the pathology findings: 

• Mesangial hypercellularity (M0, M1)
• Endocapillary hypercellularity (E0, E1)
• Segmental Sclerosis (S0, S1)
• Tubular atrophy/ interstitial fibrosis (T0, T1, T2) and 
• Crescents (C0, C1, C2). 

IgAN can be secondary; therefore, all patients must be checked for underlying causes, like HIV, hepatitis, liver cirrhosis, celiac disease and inflammatory bowel disease. Of note, as end-stage liver disease comes with coagulopathies, a kidney biopsy may not be feasible and a presumptive diagnosis is often made.

Treatment and Prognosis 

Although most often IgAN follows a benign course, in up to 30% of all patients, a slow progression to end-stage kidney disease is seen. There are several important risk factors for progression of the disease: persistent proteinuria (> 1 g/day) is a marker of the severity of glomerular disease, hypertension is another significant factor that influences disease outcomes, and lower GFR or persistent hematuria at presentation or during the disease course is associated with a worse prognosis.

The International IgAN Prediction Tool, which includes both clinical and histological data – such as the MEST-score – at diagnosis, can be used to quantify the risk of progression, i.e., 50% decline of eGFR or progression to end-stage kidney disease within 5 years. There is a modified version for children. Mind that there is no consensus about a threshold determining a high risk of progression, indicating the urge to start with immunosuppressive therapy. This instrument is primarily suitable for informing discussions with patients in shared decision-making and personalized medicine.

The primary focus of therapy is to prevent the progression to end-stage kidney disease. An essential part of the treatment of IgAN is supportive care, which entails optimal blood pressure control, RAAS inhibition and lifestyle modifications, including dietary sodium restriction and smoking cessation. When treatment goals are not obtained, adding a mineralocorticoid receptor antagonist or SGLT2 inhibitor must be considered. In addition, cardiovascular risk should be assessed and interventions started when needed. Therapeutic goals involve reducing proteinuria to less than 0,5-1,0 g/day and resolving microscopic hematuria. Of note, the utility of hematuria as an independent surrogate marker for treatment efficacy has not been proven. 

Immunosuppressive therapies – mainly glucocorticoids for 6 months – are reserved for those at high risk for progressive disease despite maximal supportive care for at least 3 months, and only if there is no evidence of irreversible kidney damage (GFR < 30 mL/min, small kidneys, severe IFTA or glomerulosclerosis on biopsy) and after discussing the possible side effects. Always consider the enrollment of a patient in a clinical trial. Immunosuppressive regimens are also applied in the variant forms of IgAN. These are IgAN with apparent minimal change disease and IgAN with rapidly progressive glomerulonephritis. In those cases, treatment conforms to therapeutic protocols for primary minimal change disease and ANCA-associated vasculitis, respectively. In IgAN with acute kidney injury, which may occur during gross hematuria, treatment is supportive. If renal function does not improve, a kidney biopsy is warranted to exclude crescents formation, in which case immediate therapy is necessary.

Considering adjunctive therapies, the focus has been on influencing the sources of pathogenic IgA1. For example, in Japan, a therapeutic effect of tonsillectomy was shown. Similarly, studies are underway on the effect of targeted-release formulation of budesonide to influence gut-associated lymphoid tissue. In addition, several inhibitors of the complement system that target the alternative or lectin pathways are currently being studied in clinical trials in IgAN. 

In case of secondary IgAN, the underlying disease should be treated optimally.

Recurrence after transplantation is a common finding on biopsy. Graft loss due to the recurrence of IgAN is reported to be up to 10% at 10 years after transplantation.

IgA Vasculitis 

Key points

• IgA vasculitis, or Henoch-Schonlein purpura, is a systemic disease generally affecting children.
• IgA vasculitis typically presents with the tetrad of palpable purpura, joint pain in the lower extremities, abdominal pain and glomerulonephritis.
• IgA depositions cause symptoms.
• The disease is often self-limiting, with a good prognosis in children. The disease course may be more complicated in adults.

IgA vasculitis (IgAV), formerly Henoch-Schönlein purpura, is similar to IgAN in clinical and laboratory findings. However, IgAV is mainly seen in children. It is the most common systemic vasculitis among children and can affect the skin, joints, intestines and kidneys. Besides glomerulonephritis, there are several typical extrarenal manifestations of this leukocytoclastic vasculitis. Palpable purpura refers to raised areas of bleeding underneath the skin (see figure 13), often accompanied by joint pain of the lower extremities or arthritis and abdominal pain due to intestinal vasculitis. IgAV seldom affects the lung or central nervous system. Juvenile IgAV more commonly involves the skin and gastrointestinal tract, whereas adults have a more complicated disease of the kidneys.

Figure 13. Typical purpura found in IgA vasculitis. Source: Wikimedia Commons.

IgAV is a small vessel vasculitis characterized by IgA1-dominant immune depositions at vessel walls. It is thought that the onset occurs due to an interplay between genetic disposition and an infectious trigger. IgAV has a similar pathogenesis to IgAN, so the findings on kidney biopsy are indistinguishable from IgAN.

Treatment in children involves symptom control and monitoring of renal function and blood pressure. It is usually self-limited in children and revolves within several 

Treatment of children with IgAV involves symptom control and monitoring of renal function and blood pressure. IgAV is usually self-limited in children and revolves within several weeks. Although adults mostly recover, there is a risk of developing significant renal involvement and, eventually, end-stage kidney disease. In adults, the vasculitis often complicates, relapses and persists over a long period. In severe cases, immunosuppressive agents may be necessary; however, their efficacy needs to be better investigated. 

IgAN needs to be differentiated from 2 other glomerulopathies that present with persistent isolated hematuria: Alport syndrome and thin-basement membrane nephropathy. These two disease entities are discussed next.

Alport Syndrome

Key points

• Alport syndrome is an inherited progressive glomerular disease due to abnormal collagen IV production, resulting in basal membrane defects in the kidney, cochlea and eyes. 
• Besides kidney disease at a young age, Alport syndrome can also cause sensorineural hearing loss and affect the eyes.
• A biopsy will show typical splitting of the lamina densa; staining for collagen will reveal the absence or abnormal distribution of alpha-chains.
• Treatment consists mainly of supportive measures or renal replacement therapy for those with end-stage kidney failure. Alport syndrome does not recur after transplantation.

Alport syndrome is an inherited progressive glomerular disease referred to as hereditary nephritis. It is a primary basement membrane disorder resulting from abnormal collagen IV production due to pathogenic variants in the encoding genes. Alport syndrome accounts for up to 3% of children and 0,3% of adults with end-stage renal disease in the US.

Alport syndrome is a heterogeneous disease with several characteristic extrarenal findings, such as sensorineural hearing loss and ocular abnormalities mostly involving the lens, retina and, more rarely, the cornea. The family history often follows the pattern of X-linked Alport syndrome, which means that males have hematuria, kidney failure and deafness, whereas female relatives often show persistent microscopic hematuria. Though, in female relatives, a more aggressive disease pattern may be seen. The heterogeneity of clinical findings in women is due to the process of lyonization, i.e., the activity of only one X-chromosome per cell. Kidney failure usually arises somewhere between 15 and 35 years of age. The institution of bilateral sensorineural hearing loss may be similar. Concerning the eyes, a pathognomonic anterior lenticonus, i.e., a conical protrusion of the lens, may be present, which can be complicated by subcapsular cataracts and vision loss. Retinal involvement with superficial granulations is primarily asymptomatic. Painful corneal erosions may occur.

Alport syndrome is caused by abnormalities in the alpha-3, alpha-4, or alpha-5 chains of the collagen IV protein in the basement membranes of the kidney, cochlea and eyes. Defective basement membranes at these sites lead to the clinical features mentioned above. Inheritance can be X-linked (COL4A5 gene on the X-chromosome, as in most patients), autosomal dominant (COL4A3 or COL4A4 genes), or autosomal recessive (COL4A3 or COL4A4 genes).

Alport syndrome can be diagnosed by genetic testing, skin or kidney biopsy. Next-generation sequencing is the preferred method of genetic testing in case of a known family history of Alport syndrome. Otherwise, a kidney biopsy can show the characteristic longitudinal splitting of the lamina densa (figure 14), seen as a lamellation of the basement membrane on electron microscopy. This may however not be present at an early age. In those cases, the collagen IV immunostaining will demonstrate the alpha-chains’ absence or abnormal distribution. On a skin biopsy, commercially available tests using alpha-5 (IV) chains directed monoclonal antibodies may be used to show their absence and less invasively diagnose an X-linked Alport syndrome. Complement levels are normal.

Figure 14. Electron microscopy of a patient with suspected Alport syndrome. On the right the irregular basement membrane is marked in blue. It has a split aspect, with alternating thick and thin segments. Image adapted from NTVG: Erfelijk nierlijden bij adolescenten en volwassenen, 2018.

The prognosis largely depends on the underlying genetic defect. Patients with autosomal recessive disease have a similar clinical presentation and course as those with X-linked disease. In the autosomal dominant form, the disease is more indolent with a more gradual loss of renal function; hearing loss and eye anomalies are unusual.

At this moment, there is no specific renal treatment available. Supportive measures, such as the early start of RAAS blockade, slow down disease progression. Patients may need hearing or visual aids. Follow-up of renal function is warranted. Kidney transplantation is a good option if renal replacement is needed. There will be no recurrent disease. However, there is a small risk of about 3% of developing anti-GBM antibody disease also known as Alport posttransplant nephritis. This usually occurs within the first year after transplantation. Living-donor transplantation can only be performed after carefully evaluating the donor’s situation.

Thin Basement Membrane Nephropathy

Key points

• Thin basement membrane nephropathy is a common and benign disease affecting about 5% of the general population.
• About 50% of patients have a positive family history of asymptomatic, microscopic hematuria.
• In thin basement membrane nephropathy, the glomerular basement membrane shows diffuse thinning.
• Generally, no treatment is needed and the prognosis is excellent.

Thin basement membrane nephropathy (TBMN) is a relatively common disease affecting an estimated 5% of the general population. The disorder is named after the typical appearance of the glomerular basement membrane (GBM) on electron microscopy. Up to 50% of patients have a positive family history of hematuria. Kidney failure and deafness are typically absent or occur relatively late in life. Therefore, TBMN was formerly known as benign familial hematuria. Although TBMN is mainly diagnosed on the incidental finding of asymptomatic microscopic hematuria, patients may present with gross hematuria and flank pain episodes. Like IgA nephropathy and post-streptococcal glomerulonephritis, TBMN manifestations can be preceded by an upper respiratory tract infection.

In about 50% of affected families, heterozygous variants in the COL4A3 or COL4A4 genes are responsible for TBMN. Therefore, patients with these types of hematuria with a thin GBM are sometimes considered to have autosomal Alport syndrome. Likewise, a thin GBM is seen at an early stage of the Alport syndrome. 

The typical diffuse thinning of the GBM is seen on electron microscopy images of a kidney biopsy. However, the diagnosis is often presumptively made based on hematuria with a benign renal course and a typical family history. Kidney biopsy is performed in patients who present with proteinuria. It is often difficult to differentiate from Alport syndrome as thin GBMs may be seen at an early stage of Alport syndrome. In TBMN, immunostaining with antibodies against alpha-3, alpha-4 and alpha-5 chains of type IV collagen is normal. However, this finding does not entirely exclude Alport syndrome. Other causes of isolated hematuria are IgA nephropathy and C3 glomerulopathy.

The prognosis is excellent in most patients with isolated hematuria and thin GBMs. The presence of proteinuria or a family history of chronic kidney failure may indicate a less favorable prognosis. Administration of RAAS blockade is likely beneficial in those patients.

Membranous Nephropathy

Key points

• Membranous nephropathy is a prevalent cause of the nephrotic syndrome.
• Of all cases of membranous nephropathy, 75% are primary, i.e., auto-immune mediated.
• Drugs, infections, auto-immune diseases and malignancies can cause secondary membranous nephropathy.
• Patients usually present with a slowly developing nephrotic syndrome.
• Diffuse thickening of the glomerular basement membrane on microscopy is typical.
• In primary membranous nephropathy, therapy consists of supportive measures; immunosuppressive drugs are reserved for patients at a high risk of progression to end-stage kidney disease.
• In secondary membranous nephropathy, the underlying disease is treated or offending drugs are stopped.

General

Membranous nephropathy (MN) is a prevalent cause of the nephrotic syndrome. The name of this disease is based on the diffuse thickening of the glomerular basement membrane (GBM) on microscopy. In about 75% of all cases, MN is primary, though many conditions can cause secondary MN. Associations between these conditions and MN are primarily based on the observation that the nephrotic syndrome resolves after the underlying disease is treated or the trigger is removed. 

Epidemiology

The primary form of MN, formerly called idiopathic but now recognized as an auto-immune disease, is more commonly seen in white males over 40 years of age. In the secondary forms of MN, epidemiology largely depends on the underlying disease. For instance, when a young female presents with MN, remember that lupus nephritis might be an underlying cause.

Symptoms

Most patients with MN present with nephrotic syndrome, whereas the remaining 20% are diagnosed based on asymptomatic proteinuria. The formation of glomerular basement membrane deposits and resulting podocyte damage happens gradually over time. Many patients are normotensive and acute kidney injury is uncommon. As a general prothrombotic tendency accompanies the disease, thrombotic complications, e.g., acute renal vein thrombosis, may occur.

Other diseases that present with a nephrotic syndrome include minimal change disease and primary focal segmental glomerulosclerosis. However, symptomatology in MN generally evolves slower than in these other disease entities.

Cause

The unraveling of the pathogenic mechanisms leading to MN in humans started in 1959 with ‘Heymann nephritis,’ a rat model of glomerulonephritis in rats immunized with renal antigens. The years showed that the disease was caused by the binding of circulating antibodies to specific glomerular components, resulting in subepithelial glomerular basement membrane (GBM) immune deposits and subsequent complement-mediated podocyte injury (see figure 15).

Figure 15. The normal glomerulus (left) and the glomerulus in membranous nephropathy (right). Antibodies that enter the glomerulus via the glomerular capillary aggregate with antigens in the glomerular basement membrane (GBM) and form immune complexes. This leads to diffuse thickening of the GBM that becomes more severe as disease progresses. Adapted from Wikimedia commons: normal, MN.

Video: https://www.youtube.com/watch?v=zucxZw069kw vanaf 1:41 tot 04:09

In primary MN, several glomerular antigens have been implicated. The podocyte phospholipase A2 receptor (PLA2R) is best known and its targeting anti-PLA2R auto-antibodies are found in up to 80% of all patients. These antibodies are not found in secondary MN. In addition, other antigens have been identified: thrombospondin type-1 domain containing 7A (THSD7A), responsible in 10% of anti-PLA2R negative patients and in case reports associated with malignancies and neural epidermal growth-like 1 protein (NELL1), responsible in 16% of anti-PLA2R negative patients. Interestingly, in NELL1 antigen-associated MN, a concurrent malignancy was reported in up to 33% of all cases. Lastly, semaphorin 3B antigen has been implicated in a form of PLA2R-negative primary MN that involves primarily children and young adults. Therefore, detecting semaphorin 3B antibodies can help to differentiate primary MN from the more common causes of nephrotic syndrome in children, such as minimal change disease and focal segmental glomerulosclerosis.

Secondary MN can be caused by various conditions related to drugs, infections, autoimmune diseases and malignancies. The main drugs implicated are NSAIDs and many other antirheumatic medications. The underlying mechanism is uncertain. Proteinuria generally starts in the first year of treatment but can also occur much later. After discontinuation of the drug, a resolution of the proteinuria is generally seen, although it may take some time as the subepithelial deposits need to be cleared and the GBM must be remodeled. Of note, NSAIDs can also lead to minimal change disease.

Secondary MN due to an infection is mainly seen in pediatric hepatitis B virus infections in endemic areas. The prognosis in MN secondary to hepatitis B is good in children, but disease is often progressive in adults.

Remarkably, in up to 5 to 20% of adult – especially older – patients presenting with MN, a malignancy is present. A malignancy-induced MN may result from tumor antigen deposition in the glomerulus, leading to immunocomplex formation and complement activation. The detection of tumor antigens in the GBM has been described in some cases. Alternatively, antibodies against tumor antigens may be produced and recognize similar antigens on the podocytes.

In secondary MN, several antigens have been identified in glomerular deposits so far. These are, for instance, double-stranded DNA in SLE and exostosin-1 (EXT1) and -2 (EXT2) in a subset of class V (i.e., membranous) lupus nephritis. The neural cell adhesion molecule 1 (NCAM1) is another target antigen in patients with secondary MN. The EXT1 and EXT2 antigens may also be seen in autoimmune diseases such as Sjögren’s syndrome.

Diagnosis

The suspicion of MN is often raised based on the clinical presentation of nephrotic syndrome. In MN, proteinuria ranges from subnephrotic to over 20 g/day, usually accompanied by severe hyperlipidemia. Additionally, microscopic hematuria may occur, but acute kidney injury is uncommon.

With such a clinical presentation and no evidence of secondary causes based on patient history and laboratory results, a definitive diagnosis of primary MN can nowadays be made on a serologic assay showing circulating anti-PLA2R autoantibodies. Otherwise, a kidney biopsy is needed. Of note, in early disease, all anti-PLA2R autoantibodies may be concentrated in the kidney – acting as a ‘sink’ – which results in low sensitivity of the serologic assay. Therefore, if the kidney biopsy is also negative for PLA2R-IgG4 immune deposits, additional staining for THSD7A and NELL-1 should be done. 

Pathology findings are characteristic: a diffuse thickening of the glomerular basement membrane with a granular IgG and C3 staining on immunofluorescence. Electron microscopy shows these electron-dense subepithelial immune complex deposits, surrounded by ‘spikes’ of extracellular matrix newly formed by the injured, effaced podocytes (figure 16). 

Figure 16. Light microscopy images of a normal glomerulus (top left) and a glomerulus with membranous nephropathy (top right). Thickening of the pink glomerular basement membrane (GBM) can be seen. Below is a silver stain that shows spike formation in the GBM. The reason these spikes are visible is that the silver stain only stains the GBM and not the immune complexes in the GBM, giving it a spiked appearance. Adapted from Wikimedia commons: normal glomerulus, membranous nephropathy, silver stain.

As the disease progresses, other light microscopy changes, such as sclerosis, manifest. In secondary forms, mesangial and subendothelial depositions may be seen and suggest a circulating immune complex. The presence of additional IgA, IgM and C1q, referred to as a ‘full house pattern’, suggests a secondary MN related to lupus nephritis. As described above, several antigens have been identified in glomerular deposits and related to various conditions eliciting a secondary MN. As MN may be seen secondary to a malignancy (primarily solid), further screening needs to be considered if MN cannot be classified otherwise.

Treatment and Prognosis

The clinical course of MN is often indolent and up to 30% and 40% of untreated patients reach respectively complete or partial spontaneous remission after 5 years. On the other hand, end-stage kidney disease occurs in 14% of patients with nephrotic syndrome at 5 years and even in 35% after 10 years, whereas in non-nephrotic patients, end-stage kidney disease is hardly seen. Therapy should therefore be based on the prognosis, i.e., the likelihood of progressive kidney injury. All patients must receive optimal supportive care and diuretics in case of edema. In contrast, possible toxic immunosuppressive therapy is restricted to those with primary MN regarded as at risk for progressive kidney disease. The risk assessment can be made based on several clinical and laboratory data and is leading in the treatment. A higher risk is found among elderly patients, males and those with nephrotic range proteinuria or renal failure at presentation, as shown in this figure of the KDIGO guideline. Anticoagulation should be started in severe hypoalbuminemia (albumin < 20 g/L) to prohibit thrombotic complications, as there is a general prothrombotic tendency.

Serologic immunoassays help monitor disease activity and have a prognostic and predictive value. Anti-PLA2R levels strongly correlate with the clinical disease status and lower levels correlate with higher spontaneous remission rates. A decline of titers during immunosuppressive therapy predicts and precedes a clinical response. Serial assessments of the anti-PLA2R titers are thus recommended and likely guide treatment decisions. Treatment goals are a complete remission (i.e., protein excretion reduced to ≤ 300 mg/day) or otherwise a partial remission (protein excretion < 3,5 g/day plus a ≥ 50 percent reduction from baseline) and for those with anti-PLA2R antibodies to achieve an immunologic remission. After complete remission, two-thirds of patients remain in remission; about 20% have a relapsing course without renal failure and about 13% develop kidney function impairment but no end-stage kidney disease.

In patients at very high risk of progression, treatment with immunosuppressive drugs (cyclophosphamide + glucocorticoids or calcineurin inhibitors) is started without delay unless contraindicated or if there are signs of irreversible kidney damage. In patients at high risk, treatment with rituximab is the first choice. For patients with a normal GFR and who do not have severe nephrotic syndrome, supportive measures are taken and the disease can be monitored for 3 to 6 months. After that, these patients are stratified again according to their risk of progression based on their clinical and serological parameters. Immune suppressive therapy is started if they are considered at a high risk of progressive disease. In case of a moderate risk, treatment depends upon the course of the disease so far. If the risk of progression is judged to be low, supportive therapy is continued without additional measures and patients are monitored periodically. For further details and treatment of relapsing or resistant MN, see the KDIGO sections.

In secondary MN, the focus is on treating the underlying disease or stopping the offending drug, which usually leads to improvement of the nephrotic syndrome.

After kidney transplantation, MN recurs in about 10-45%, generally after a more extended period (13-15 months).

Minimal Change Disease 

Key points

• Minimal change disease is a common cause of nephrotic syndrome in children but only accounts for 10% of adult nephrotic syndrome presentations.
• Minimal change disease is usually primary but can also occur secondary to another disease or drug use.
• Minimal change disease mainly presents with sudden onset nephrotic syndrome, often after an upper respiratory tract infection.
• Light microscopy shows normal tissue; on electron microscopy, characteristic diffuse effacement of podocytes is seen.
• Treatment consists of supportive measures, diuretics and glucocorticoid monotherapy; some patients have glucocorticoid-dependent or even glucocorticoid-resistant disease.
• When treated, minimal change disease has a favorable outcome; kidney function generally returns to normal.

General

Minimal change disease (MCD) is a podocytopathy that primarily affects the podocytes. The name minimal change disease refers to the glomerulus’s normal (‘healthy’) appearance on light microscopy. 

Epidemiology

In approximately 90% of all children, MCD is the major cause of nephrotic syndrome, whereas in adults, it accounts for only 10% of nephrotic syndrome presentations.

Symptoms

The most typical presentation of MCD is the sudden onset of nephrotic syndrome over days to 2 weeks. This onset is often seen following an infection, e.g., of the upper respiratory tract. The acute onset of MCD contrasts with what is mainly seen in other conditions associated with nephrotic syndrome, such as membranous nephropathy and most cases of focal segmental glomerulosclerosis. Microscopic hematuria may be present and serum creatinine may be elevated, though acute kidney injury is rare. Due to the nephrotic syndrome-related state of hypercoagulability, thromboembolic complications may be seen. Moreover, vulnerability to infections – especially with encapsulated organisms – is increased.

Cause

Most cases of MCD are primary or idiopathic. MCD results from a circulating factor that impacts the glomerular capillary wall. This glomerular permeability factor leads to foot process effacement, loss of the local anionic state and marked proteinuria. The production of this factor is thought to result from T-cell dysfunction. Though, given the effectiveness of rituximab in some MCD patients, an additional role for B-cells is likely. Interestingly, circulating autoantibodies targeting nephrin, an essential protein of the podocyte slit diaphragm, were found in a recent study in a subset of MCD patients. Biopsies showed IgG colocalizing with nephrin in these serologically positive patients, suggesting an autoimmune etiology for MCD.

In secondary MCD, nephrotic syndrome occurs following another disease or drug use. Many drugs have been associated with secondary MCD, including NSAIDs, antibiotics, bisphosphonates and lithium. Usually, stopping the drug will improve or resolve the nephrotic syndrome. MCD may be related to malignancies, particularly hematologic diseases like lymphoma and leukemia. Usually, the severity of the proteinuria parallels the hematologic disease state. MCD may also be seen secondary to various infectious diseases and allergies.

Video: https://www.youtube.com/watch?v=4Y4PWTXjyEc van 1:47 t/m 03:00

Diagnosis

MCD should be suspected in adults with an acute onset of nephrotic syndrome. General laboratory testing for glomerular diseases needs to be done. In addition, a kidney biopsy is required in adults to obtain a definitive diagnosis and rule out other causes of nephrotic syndrome. On light microscopy, the glomeruli appear surprisingly normal and immunofluorescence shows no deposits. On electron microscopy, however, a characteristic diffuse effacement of the podocytes, with flattening and fusion of the epithelial foot processes, is seen. For a schematic overview, see figure 17. Interestingly, with remission of the proteinuria, the podocytes retrieve their normal appearance.

Figure 17. Normal glomerular structure on the left, on the right changes in the podocytes as seen in minimal change disease. Adapted from Wikimedia commons: normal, MCD

After diagnosing MCD in adults, an evaluation for secondary causes needs to be started. Of note, sometimes, a primary focal segmental glomerulosclerosis may be mistaken for MCD due to a sampling error missing the characteristic light microscopy lesions. In addition, it is essential to realize that there is an ongoing debate on whether MCD and focal segmental glomerulosclerosis are separate entities. In this respect, some suggest that MCD could result from a mild injury that usually completely recovers but progresses in case of severe injury or defective mechanisms for repair resulting in focal segmental glomerulosclerosis. In children, a diagnosis is often made presumptively and a kidney biopsy is reserved for those with glucocorticoid-resistant nephrotic syndrome.

Treatment and Prognosis

All patients are started on glucocorticoid monotherapy unless contraindicated, which leads to complete remission in over 80% of adult patients in several months. 

Remission in children is much faster and occurs in over 95% of patients. 

Besides the general supportive interventions, edema is treated with adequately dosed loop diuretics or a combination of diuretics. In addition, anticoagulant therapy must be considered to prevent thrombotic complications in severe hypoalbuminemia.

The goal of therapy is to firmly reduce proteinuria and thereby induce remission of nephrotic syndrome. Complete remission is defined as proteinuria < 300 mg/d; partial remission by reducing proteinuria > 50% or < 3.5 g/d. Therefore, the clinical response needs to be closely monitored during therapy. A relapse is defined as a return of proteinuria > 3.5 g/d after a previous complete remission and occurs in over 50% of adult patients. Furthermore, about 25% of patients have a glucocorticoid-dependent disease, which means they relapse within 2 weeks after stopping therapy. Alternatively, patients can have a glucocorticoid-resistant disease, which means the disease persists despite 16 weeks of adequate steroid therapy, which may reflect focal segmental glomerulosclerosis.

Glucocorticoid-sparing regimens, including a calcineurin inhibitor or mycophenolate, have been invented as alternatives. They also tackle relapsing disease, glucocorticoid resistance and the adverse effects of steroid therapy. Other regimens containing cyclophosphamide or rituximab are available in case of frequent relapsing or glucocorticoid-dependent MCD. For more details on therapy, see the KDIGO sections online at KDIGO.org.

In adults, spontaneous early remission is seen in only a few patients, while untreated, several infectious, thrombotic or renal complications may occur. However, the outcome of treated MCD is favorable, with kidney function generally returning to normal. In the eventuality of kidney transplantation: de novo and recurrent MCD are rare.

Focal Segmental Glomerulosclerosis

Key points

• Focal segmental glomerulosclerosis (FSGS) is a histological lesion found in many adults presenting with nephrotic syndrome, especially in African Americans.
• FSGS can be subdivided into primary, secondary, genetic and of unknown cause. 
• Primary FSGS usually presents with acute nephrotic syndrome.
• Light microscopy is used to diagnose FSGS; electron microscopy can help differentiate the primary form, which shows diffuse foot process effacement, from the secondary form, which usually has segmental foot process effacement.
• Primary FSGS is treated with immunosuppressive medication. Some patients have glucocorticoid-dependent or even glucocorticoid-resistant disease. Immunosuppressive therapy is usually ineffective in genetic FSGS or FSGS without a known cause.
• In secondary FSGS, the underlying cause should be addressed.
• The prognosis depends on the type of FSGS and its histological features.

General

Though often brought forward as a specific disease entity, focal segmental glomerulosclerosis (FSGS) instead refers to the presence of a characteristic histological lesion, thus a pattern of injury. On light microscopy, there is at least one glomerulus (focal) that is in part (segmental) sclerosed (glomerulosclerosis), as shown in figure 18.

Figure 18. Histopathological coupe of a kidney biopsy of a patient with focal segmental glomerulosclerosis. Sclerosis is marked in blue in the right image. Jones methenamine silver stain, 400x. Image adapted from NTVG: Erfelijk nierlijden bij adolescenten en volwassenen, 2018.

Like minimal change disease, FSGS is a so-called podocytopathy, i.e., a glomerular disorder in which the podocytes are primarily affected.

Epidemiology

FSGS is found in many adults presenting with nephrotic syndrome, predominantly in the US and has an increasing incidence. It is most prevalent amongst those of African descent and in part related to the APOL-1 polymorphism seen in this population. In many other countries, membranous nephropathy is a more common cause of nephrotic syndrome in adults.

Symptoms

The clinical presentation depends strongly on the underlying cause of FSGS. A classical presentation is acute nephrotic syndrome seen in 70 to nearly 100% of patients with primary FSGS. In addition, Hematuria, hypertension and elevated creatinine levels are frequently observed. 

In most forms of secondary FSGS proteinuria and kidney impairment develop slowly over time and most patients do not present with a nephrotic syndrome. However, there are some exceptions. Genetic forms of FSGS may present with acute nephrotic syndrome in infancy or childhood. The symptoms and histology of adult-onset genetic FSGS vary widely.

Cause

FSGS is either of primary, secondary, genetic, or unknown origin. In primary FSGS, like in minimal change disease, a circulating factor is thought to incite podocyte injury. In secondary FSGS, a reduction in nephron capacity or glomerular injury leads to glomerular hypertrophy or hyperfiltration, which induces FSGS as an adaptive response, for instance, in situations with a single kidney or obesity. A range of drugs, toxins and viral infections can also cause secondary FSGS. An overview can be found in table 11 below.

Type		Usual presentation	Treatment
Primary		Nephrotic syndrome with hematuria, hypertension EM: diffuse foot process effacement	Immuno- suppression
Secondary	Adaptive* Viral** Drug induced**	Proteinuria without nephrotic syndrome (some exceptions!) EM: segmental foot process effacement	Underlying cause*
Genetic	Familial Syndromal Sporadic	Childhood: nephrotic syndrome Adolescence: mild proteinuria Positive family history	Supportive (except for specific mutations that are glucocorticoid responsive)
Unknown cause		Proteinuria without nephrotic syndrome No evidence of secondary cause Segmental foot process effacement	Supportive

Table 11. Overview of different causes of focal segmental glomerulosclerosis (FSGS). *Adaptive secondary FSGS is seen when there is glomerular hyperfiltration. In cases of adaptation due to fewer nephrons it is often due to reflux nephropathy, renal dysplasia, sickle cell disease, or age-related FSGS. If there is adaptive glomerular hyperfiltration but a normal number of nephrons it might be due to primary glomerular diseases, obesity or other systemic conditions, like diabetic nephropathy of hypertensive nephrosclerosis. **Viral secondary FSGS is usually caused by HIV, Parvo B19, CytoMegaloVirus, Epstein-Barr Virus. drug-induced FSGS is seen in heroin, lithium, anabolic steroids, and bisphosphonates use, among others. 

Several known genetic mutations lead to inadequate production of essential podocyte and slit diaphragm proteins and may cause genetic FSGS. These can occur familially, sporadically or as part of a syndromal disease. The worldwide prevalence of genetic FSGS varies. It is higher in areas with consanguinity (up to 30% of all FSGS patients) or regions with a founder mutation, e.g., the podocin NPHS2 gene mutation in central Europe. The likelihood of an underlying genetic mutation also depends on the age of onset and whether the disease occurs familial or sporadic. 

Sometimes, although the clinical presentation and electron microscopy findings are compatible with secondary FSGS, a clear etiology cannot be found and the cause of the FSGS remains undetermined (FSGS of unknown origin).

Diagnosis

Finding FSGS lesions should initiate an intensive search for the underlying cause to establish an accurate diagnosis. It is crucial to differentiate between primary, secondary or a genetic type of FSGS because this holds important therapeutic and prognostic implications. Moreover, it determines the eventual planning of future transplantation.

The clinical presentation may give significant clues about the underlying cause. Whereas a primary FSGS mainly presents with an acute-onset nephrotic syndrome, in secondary FSGS, there is most often non-nephrotic range proteinuria (< 3,5g/day), serum albumin levels within the normal range and no edema. However, nephrotic syndrome can be seen in drug-associated FSGS or viral FSGS, such as HIV-associated nephropathy. In case of a genetic origin, FSGS may present with nephrotic syndrome during childhood or with less outspoken proteinuria during adolescence and later. The presentation depends on the genetic mutation involved. 

Besides initial laboratory testing for glomerular diseases, additional specific testing may be needed based on a thorough patient history regarding a secondary or genetic origin of FSGS. It can be challenging to differentiate a genetic type from primary FSGS. A family history of proteinuria, early disease onset and glucocorticoid resistance are features that should raise suspicion of a genetic origin and prompt consultation of a clinical geneticist and genomic analysis for monogenic forms of FSGS. The same goes for patients with syndromic aspects and those not adequately classified after a clinicopathological assessment. 

On light microscopy, one cannot distinguish primary from secondary FSGS. However, in primary FSGS, there is diffuse foot process effacement on electron microscopy. In secondary FSGS, there tends to be segmental foot process effacement. FSGS was traditionally classified into 5 morphologic variants based on light microscopy: (1) FSGS not otherwise specified (NOS); (2) collapsing variant; (3) tip variant; (4) perihilar variant; and (5) cellular variant. The collapsing variant can be induced by HIV infection, resulting in damage to the entire glomerulus – thus more than segmental – and generally has a worse prognosis. Therefore, kidney biopsies need to contain enough – at least 15 – glomeruli to avoid a sampling error, which may lead, for instance, to the misclassification of FSGS as MCD. Moreover, FSGS lesions must be differentiated from focal global glomerulosclerosis (FGGS), which is seen in normal aging, hypertension and superimposed in other glomerular diseases. The entire glomerulus is involved in the latter histological lesion and foot processes are not effaced in unaffected glomeruli.

Treatment

The goal of therapy is remission of the proteinuria. An overview of how therapy response is classified can be found in table 12.

Response	Parameters
Complete remission (CR)	Proteinuria < 300 mg/day, stable creatinine, serum albumin > 3,5g/dL
Partial remission (PR)	Proteinuria > 50% reduction and < 3,5g/day
Relapse	Return of proteinuria > 3,5g/day after CR or increase > 50% after PR
Glucocorticoid-resistant disease	Disease persistence despite 16-week glucocorticoid therapy
Glucocorticoid-dependent disease	Relapse within 2 weeks after stopping glucocorticoid therapy

Table 12. Definitions of therapy response in focal segmental glomerulosclerosis.

Treatment is based on the type of FSGS. In presumed primary FSGS, immunosuppressive medication is the mainstay of therapy. Patients are initially mostly treated with high-dose glucocorticoids, or in case of high risk of glucocorticoid toxicity, a calcineurin inhibitor (CNI)-based regimen with or without low-dose steroids. As the duration and tapering of therapy are based on the clinical response, this needs to be closely monitored. In case of glucocorticoid resistance, a CNI can be added. Details and suggestions on therapy and alternative medications for the many specific conditions can be found online at kdigo.org. Moreover, for every type of FSGS, supportive measures, such as a sodium restriction, RAAS and SGTL2 blockade, are started.

In secondary FSGS, the underlying cause must be addressed, e.g., weight reduction, stopping an offending drug or treating the underlying condition. For example, in HIV-associated nephropathy (HIVAN), antiretroviral therapy is started early, regardless of CD4 count and adjusted to renal function. 

In genetic FSGS, immunosuppressive therapy is generally ineffective, except for specific mutations that may respond. Therefore, patients are primarily treated with supportive measures. The same goes for patients with FSGS with an unknown cause. 

Prognosis

Considering the prognosis, the natural history of primary FSGS is a course toward end-stage kidney disease and spontaneous remissions seldom occur. However, treatment may lead to a response rate of up to 70% and improves the overall prognosis. The initial response to immunosuppressive therapy is most predictive of the renal prognosis. Unless it is acute, more severe kidney impairment at diagnosis is associated with worse renal survival. Regarding histology findings, interstitial fibrosis and the histologic collapsing variant are associated with a worse prognosis. Outcomes tend to be more favorable in the tip variant of FSGS. 

Primary FSGS, which is attributed to a circulating factor, may return in the kidney allograft after kidney transplantation (this is termed recurrent FSGS). Recurrence occurs in 30 to 70% of all cases and is most often seen within the first months after transplantation. Patients will therefore undergo posttransplant surveillance of proteinuria to detect recurrence early. Plasmapheresis, in which the blood plasma is exchanged or components are removed, is a treatment option for recurrent FSGS. In contrast, in patients with a genetic FSGS, recurrence occurs in up to 8%.

Membranoproliferative Glomerulonephritis

Key points

• Membranoproliferative glomerulonephritis (MPGN) refers to immunoglobulin- and complement-mediated glomerular diseases with a membranoproliferative glomerulonephritis pattern of injury, not a specific disease.
• Immune complexes, monoclonal immunoglobulins or a dysregulated complement system usually cause MPGN.
• Patients often present with hypertension. In active disease, a nephritic and sometimes nephrotic syndrome is present. Symptoms may commence after an upper respiratory tract infection.
• Light microscopy shows mesangial hypercellularity, endocapillary proliferation and a thickened glomerular basement membrane. Immunofluorescence microscopy can significantly aid in distinguishing the cause of MPGN.
• All patients are given supportive measures. Therapy is directed at the underlying disease or defect if possible. Immunosuppressive therapy may be indicated in selected cases.

General

Membranoproliferative glomerulonephritis (MPGN) refers to a pattern of glomerular injury and not to a specific disease. The histological lesion is characterized by mesangial hypercellularity, endocapillary proliferation and a thickened glomerular basement membrane (GBM) on light microscopy. In line with these findings, this pattern is also known as mesangiocapillary glomerulonephritis. On finding an MPGN lesion, one should initiate a search for the underlying diagnosis

Symptoms 

Patients with active disease have nephritic syndrome: hematuria with dysmorphic erythrocytes or red cell casts, proteinuria to variable degrees – up to nephrotic range – and potentially elevated serum creatinine levels. Hypocomplementemia is often, but not always, seen. Patients often present with hypertension. Nephrotic syndrome may be present. Symptoms may start following an upper respiratory tract infection.

The clinical presentation is similar among the different forms of MPGN. One exception is that the dense deposit disease (DDD) variant is associated with drusen formation, as seen on fundoscopy and partial lipodystrophy. Of note, DDD is mainly, but not exclusively, seen in children.

Cause 

MPGN used to be classified based on electron microscopy findings in types I, II and III. Nowadays, along with growing understanding, a classification is made based on presumed pathogenesis. In that respect, MPGN can be mediated by immune complexes or monoclonal immunoglobulins. A second pathway is via a dysregulated complement system with ongoing alternative complement pathway activation. Seldom, neither of these is involved and another mechanism, such as endothelial injury, is responsible. Immunofluorescence microscopy primarily discriminates between these forms. This pathogenesis-based classification helps further evaluate the underlying condition and offers an essential rationale for treatment choices.

Immune Complex or Monoclonal Immunoglobulin-Mediated Membranoproliferative Glomerulonephritis

In the immunocomplex– or monoclonal immunoglobulin-mediated forms of MPGN, chronic deposition of these molecules in the kidney leads to classic pathway complement activation and inflammation. This mechanism can be seen in chronic infections, like HCV, HBV, bacterial, fungal and parasitic infections; autoimmune diseases, like SLE, Sjögren syndrome and rheumatoid arthritis; and monoclonal gammopathies.

Monoclonal gammopathies constitute a significant cause of MPGN. They can present in 2 ways: (1) with monoclonal immunoglobulin deposition, i.e., proliferative glomerulonephritis with monoclonal immune deposits (PGNMID); or (2) with isolated complement deposition. In the latter case, special techniques may reveal the ‘masked’ monoclonal immunoglobulin deposits and help correctly diagnose a monoclonal gammopathy-associated MPGN instead of a C3 glomerulopathy (see further). Of note, often, there are no extra-renal manifestations and no symptomatic hematological disease. The disorder is then also referred to as a monoclonal gammopathy of renal significance (MGRS). This naming aligns with the monoclonal gammopathy of unknown significance (MGUS), in which no disease manifestations are found at all. Figure 19 shows the pathophysiology of both immune complex-mediated MPGN and complement-mediated MPGN. 

Figure 19. Overview of the pathophysiology of both immune complex-mediated MPGN on the left, and complement-mediated MPGN on the right. Created with Biorender.com.

Dysregulated Complement System

In the less common complement-mediated MPGN, a dysregulation of the alternative pathway leads to continued complement activation. As a result, complement products C3 or C4d are found in the mesangium deposits and along the glomerulus’s capillaries (as shown in figure 19). A further classification is based on C3- or C4-dense deposit disease and (C3 or C4) glomerulonephritis on electron microscopy. 

In C3-dense deposit disease, a rare form of MPGN that is named after its appearance on electron microscopy (see figure X), specific antibodies are found in the plasma of up to 80% of all patients. These C3 nephritic factors (C3NeFs) stabilize C3 convertase, facilitating ongoing complement activation. In C3 glomerulonephritis (C3GN), the excessive activation of the alternative complement pathway is most often due to either mutations in or antibodies directed against complement-regulating proteins (figure 19). Especially in older patients, C3GN occurs in association with a monoclonal gammopathy. C3GN can also be familial due to an autosomal dominant inherited mutation in the complement factor H-related protein 5 (CFHR5) gene and is called CFHR5 nephropathy, primarily seen in patients of Cypriot origin. 

C4 glomerulopathy, which includes both C4 DDD and C4GN, is a rare disorder in which glomerular depositions of C4 are found in the absence of C3, C1q and immunoglobulins. These patients may have an overactive lectin complement pathway.

Other

Considering the third option, MPGN without immunoglobulin or complement deposition, it is good to realize that in the healing phase of several diseases, an MPGN-like histological pattern can be seen. For instance, in thrombotic thrombocytopenic purpura and hemolytic uremic syndrome, endothelial damage with subsequent repair can result in MPGN on light microscopy and negative immunofluorescence and electron microscopy findings. 

Diagnosis

A kidney biopsy is needed to find the glomerular injury pattern in MPGN. On light microscopy, a thickened glomerular basement membrane is visible due to the deposition of immunocomplex or complement factors, invasion of extraglomerular mesangial cells and new forming of the basement membrane. This often leads to a double contour (like splitting) appearance of the glomerular basement membrane. Moreover, there is an increased mesangial and endocapillary cellularity due to local mesangial proliferation and the influx of monocytes.

In immunocomplex- or immunoglobulin-mediated MPGN, immunoglobulins and complement deposits are visible on immunofluorescence microscopy. In contrast, in complement-mediated MPGN, primarily complement depositions – C3 or C4d and thus no significant immunoglobulin depositions – are visible. The immunofluorescence pattern – with staining for IgG, IgM, IgA, C1q, C3, C4, lambda light chains and kappa light chains – can help differentiate the underlying disease. When all those mentioned above are ‘positive’ on immunofluorescence microscopy, we call this a ‘full house’ pattern, which suggests autoimmune diseases. HCV-related MPGN mainly stains positive for IgM, C3, kappa and lambda light chains. 

Electron microscopy typically shows the deposits, located primarily subendothelial and mesangial. In autoimmune diseases, these may also locate subepithelial, e.g., in the combination of diffuse proliferative lupus nephritis with lupus membranous glomerulopathy. Electron microscopy generally does not discriminate between immunocomplex- or monoclonal immunoglobulin-mediated and complement-mediated MPGN. Though, linear and highly electron-dense sausage-shaped deposits are typically seen in C3 DDD.

On finding an MPGN lesion, a search for the underlying disorder is started. First, patients are classified based on their pathology findings (see figure 20 below).

Figure 20. Diagnostic biopsy flowchart with differentials in membranoproliferative glomerulonephritis. Based on the Kdigo guidelines, created with Biorender.com

Complement levels may help unravel the underlying disorder. In immunocomplex- or monoclonal immunoglobulin-mediated MPGN, the classic complement pathway is activated and therefore it typically presents with normal or slightly decreased C3 concentrations and low C4 levels. In C3GN, C4 levels are normal and C3 levels are low in <50% of all cases, which means that a normal C3 does not exclude a C3GN. Note that C3GN should be differentiated from post-infectious glomerulonephritis (see box below).

Further necessary work-up per suspected etiology is included in table 13.

Cause				Work-up
Immune complex- or monoclonal immunoglobulin-mediated membranoproliferative glomerulonephritis
Infectious		Viral		HBV and HCV serology
		Bacterial		Culture and blood culture: bear in mind the possibility of endocarditis or an abscess Recent history of sore throat or skin infection: serological testing for Streptococcal infection
		Fungi/parasites		Only if history is suggestive
Auto-immune				Often systemic lupus erythematosus, Sjögren’s syndrome or systemic sclerosis. Look for other manifestations of underlying disease and select appropriate autoimmune serology.
Monoclonal gammopathy				Serum and urine protein electrophoresis and immunofixation and serum free light chains. If positive; bone marrow to screen for underlying disease (like myeloma, lymphoma, or leukemia). However, most patients will have monoclonal gammopathy of renal significance (MGRS).
Complement-mediated membranoproliferative glomerulonephritis
				Measure C3 and C4 levels CH50: marker of classic pathway activation AH50: marker of alternative pathway activation Genetic analysis for mutation of complement factors Autoantibody assay against complement regulating proteins (factor H, I and C3 nephritic factor)
Membranoproliferative glomerulonephritis without immunoglobulin or complement deposition
				Evaluate chronic thrombotic microangiopathy Evaluate antiphospholipid antibody syndrome

Table 13. Overview of potential follow-up steps in membranoproliferative glomerulonephritis based on the presumptive underlying etiology. Note that this table does not encompass all diagnostic steps but aims to give a general overview.

Treatment and Prognosis 

All patients with MPGN are given supportive measures. In immunocomplex- or monoclonal immunoglobulin-mediated MPGN, therapy depends on the cause. Patients receive treatment specifically directed at the underlying disease if possible. Appropriate antimicrobial therapy is given in case of underlying infectious diseases. In hepatitis, immunosuppressive therapy is only given in selected cases, such as severe hepatitis C virus-associated mixed cryoglobulinemia or rapidly progressive glomerulonephritis, that are at a high risk of progressing to end-stage kidney disease. If MPGN is associated with an autoimmune disorder, immunosuppressive medication is often started. In idiopathic immunocomplex-mediated MPGN, patients with mild disease are generally treated supportively. On disease progression, a biopsy is repeated and immunosuppressive therapy needs to be considered. The same goes for the presentation with nephrotic syndrome or other poor prognostic signs, such as elevated creatinine levels or crescents on biopsy. Low-threshold consultation with a center of expertise is recommendable. 

Treatments for complement-mediated MPGN are based on the underlying defect and the disease presentation, e.g., mild vs. rapidly progressive glomerulonephritis. Again, it is recommended to consult a center of expertise. In general, the prognosis of patients with dense deposit disease (DDD) is poor, whereas it is variable in C3GN patients. 

For more detailed information and background about therapy and prognosis, see the KDIGO website.

The chance of recurrence after transplantation depends on the underlying disease and is less likely in infectious or autoimmune disease than in monoclonal gammopathy or complement-mediated MPGN. An underlying plasma cell disorder should be addressed first before considering renal transplantation.

BOX: Post-Infectious Glomerulonephritis

C3 glomerulonephritis (C3GN) needs to be distinguished from post-infectious glomerulonephritis. The latter is predominantly seen in children and generally occurs one to 2 weeks after an upper respiratory tract infection (commonly from a group A beta-hemolytic streptococcus). Glomerulonephritis classically presents with acute nephritic syndrome with hematuria, pyuria, oliguria, hypertension and edema.

Workup of post-infectious glomerulonephritis should include an antistreptolysin O titer (ASO) showing elevated antibodies against streptolysin O after a recent streptococcus infection and a blood urea nitrogen (BUN) test, which may show elevated urea nitrogen levels in case of an acute patient. Urine analysis shows microscopic or macroscopic hematuria, red blood cell casts and mild proteinuria. Massive proteinuria indicates the nephrotic syndrome, which can occur concomitant to the nephritic syndrome. 

A biopsy can help differentiate between C3GN and post-infectious glomerulonephritis. The latter is associated with both bright C3 staining and IgG deposition. Moreover, in post-infectious glomerulonephritis, EM shows clear subepithelial humps (see figure 21 below), contrasting with the large and widespread deposits in C3GN. Antibodies to complement factor B, a component of the C3 convertase of the alternative pathway, are often found in post-infectious glomerulonephritis and can help discriminate from a C3GN.

Figure 21. Normal glomerular structure on the left; on the right post-infectious glomerulonephritis with immune complexes deposited underneath the podocytes giving the typical ‘subepithelial humps’ that help distinguish post-infectious glomerulonephritis from membranoproliferative glomerulonephritis. Adapted from Wikimedia commons: normal, post-infectious glomerulonephritis.

Treatment of post-infectious glomerulonephritis focuses on symptom control via diuretics, salt restriction and antihypertensive agents. The prognosis in post-streptococcal glomerulonephritis is very good; patients usually recover completely in 6 to 8 weeks. Permanent renal failure is very uncommon.

BOX: Cryoglobulinemic Glomerulonephritis

Cryoglobulines are immunoglobulins that precipitate at cold temperatures and dissolve when rewarmed. Three types of cryoglublines can be distinguished. Type 1 is monoclonal immunoglobuline (IgM or IgG) associated kidney disease usually observed in hematological malignancy (M. Waldenstrom or multiple myeloma), a monoclonal gammopathy of undetermined significance. ( Although you can doubt it is of undetermined significance) or chronic lymphatic leukemia. The combination of both polyclonal IgG and monoclonal IgM (type II), or of polyclonal IgG and polyclonal IgM (type III) are  mixed type cryoglobulinemia. Mixed cryoglobulins are not only associated with infectious diseases (such as HCV, HIV), but are also seen in auto-immune diseases (Sjøgren, SLE, RA). Treatment is based on the underlying disease. Symptoms may be averted by preventive measures: protect extremities and avoid exposure to cold temperatures.

xtremities and avoid exposure to cold temperatures.

Granulomatosis with Polyangiitis 

Key points

• Granulomatosis with polyangiitis is one of the ANCA-associated vasculitides.
• Granulomatosis with polyangiitis has a granulomatous inflammation with necrotizing vasculitis as a consequence.
• Multiple organ systems may be affected.
• Diagnosis is based on history, physical examination and ANCA serology. Biopsy typically shows a pauci-immune pattern, i.e., very few to no immune complex deposits.
• Treatment mainly consists of immunosuppressive agents. Up to 20% of patients do not achieve remission despite aggressive therapy.

General

Granulomatosis with polyangiitis (GPA) was formerly known as Wegener’s disease. It is part of the spectrum of vasculitis syndromes provoked by so-called antineutrophil cytoplasmic antibodies (ANCA). GPA is a necrotizing vasculitis usually affecting multiple organ systems. These disorders are collectively called ANCA-associated vasculitides and all predominantly affect small-size arteries. Other disorders within this group are:

• Microscopic polyangiitis (MPA) which is more often seen in Asia,
• Renal-limited vasculitis, and
• Eosinophilic granulomatosis with polyangiitis (eGPA), which is associated with asthma.

Epidemiology

GPA most commonly presents in patients over 50 years of age. ANCA-associated vasculitis has an annual incidence rate of 4,5 to 25 per million, whereas eGPA has an incidence rate of 0,5 to 3,7 per million. Patients with GPA are typically older adults, whereas patients with eGPA tend to be younger.

Symptoms

Manifestations are primarily seen in the upper and lower respiratory tract and the kidneys but can be seen in almost any system. GPA may lead to organ failure and life-threatening situations. However, the disease can also be much milder. Patients generally present with non-specific complaints like fatigue, weight loss, and myalgias that have existed for some time, often leading to misdiagnosis. The granulomatous inflammation of the sinus, nasopharynx and lungs gives more specific complaints like rhinosinusitis, nasal crusting with bloody discharge, dyspnea, and hemoptysis. It often is not until late in disease, as the inevitable renal insufficiency becomes symptomatic with hematuria or frothing urine, that the diagnosis of ANCA-associated vasculitis may be considered. Other symptoms include neurological impairments (e.g., mononeuritis multiplex), skin lesions, ocular involvement, and polychondritis (inflammation of the cartilage throughout the body). A characteristic finding is a saddle nose due to bone and cartilage destruction over time, however due to more intensive treatment these findings are less frequently observed.

Patients frequently develop hearing loss. Ear, nose and throat manifestations are estimated to occur in about 90% of GPA patients. Kidney involvement is present at diagnosis in only a minority of GPA patients. However, it develops in up to 85% of GPA patients over time. The typical presentation at that point is that of a (rapidly progressive) glomerulonephritis. Alternatively, renal symptomatology may be of remitting asymptomatic hematuria with a normal kidney function. Proteinuria is mostly subnephrotic. In some patients, the disease manifests in a single organ, like in renal-limited vasculitis. 

Cause

ANCA-associated vasculitides are multifactorial and complex immune-mediated disorders. It is a second hit disease, as ANCA are observed in patients without vasculitis and having ANCAs is not required for ANCA-associated vasculitis. Nevertheless, there is ample evidence to support the pathogenicity of ANCAs. ANCAs are directed against proteins in the cytoplasmic granules of neutrophils. The exact mechanism has yet to be elucidated, but it involves numerous immune cells. B lymphocytes produce ANCAs which are seen at high titers. Neutrophil activation causes endothelial damage and enhanced formation of extracellular traps (i.e., NETosis) containing autoantigens. In addition, complement activation amplifies inflammation and injury. The combined result is a necrotizing vasculitis of the small-sized and medium-sized blood vessels found throughout the body. In GPA, the inflammation is typically granulomatous. ANCA-associated vasculitis can also be associated with certain drugs and cocaine, in which case it is termed drug-induced ANCA-associated vasculitis. The best-known autoantigens in GPA are neutrophil granule enzymes proteinase 3 (PR3) and myeloperoxidase (MPO). Corresponding antibodies are PR3-ANCA and MPO-ANCA. 

Diagnosis

The diagnosis of GPA is likely in patients with acute renal failure that present with symptoms of multiple affected systems. A thorough history and physical examination are of great importance for the diagnosis. Further staging of the disease is done using the Birmingham vasculitis activity score (BVAS) 3 scoring system. Urinalysis classically shows hematuria and red blood cell casts. A positive ANCA assay in the above setting is strongly indicative of disease and for most clinicians averts the need for biopsy. However, a negative outcome of the ANCA assay does not exclude GPA and may be found in at least 10% of all cases. In 65 to 75% of GPA cases, ANCA are against PR3, while ANCA are against MPO in the remainder. In renal-limited vasculitis, ANCA are 75% against MPO. In drug-induced AAV, most patients will have MPO-ANCA, except for cocaine users, who are usually positive for anti-elastase. In immunofluorescence testing of serum, the terms C-ANCA pattern (cytoplasmic staining pattern, caused by PR3-ANCA) and P-ANCA pattern (perinuclear staining pattern, pointing to the presence of MPO-ANCA) may be reported. 

Radiography may show one of the 4 following patterns: (1) nodules and cavitation (also visible on chest radiography, figure 22); (2) pulmonary hemorrhage; (3) reticulonodular pattern; and (4) peripheral wedge-like consolidation. The first 2 patterns are the most common.

Figure 22. (a) Left lung with an area of opacification in the left apex due to granulomatosis with polyangiitis (GPA) and (b) lungs that are diffusely affected by GPA. Images adapted from Wikimedia Commons: (a), (b).

Biopsy remains the gold standard for diagnosing GPA, but is not always necessary when the clinical pattern is typical. If necessary, a biopsy is generally taken from the kidney or skin. Pulmonary biopsies – preferably thoracoscopic instead of transbronchial – are another option. Unfortunately, less-invasive nasal biopsies are often falsely negative.

In addition to establishing the diagnosis, a kidney biopsy can be used to estimate the amount of acute and chronic injury. It may range from mild focal and segmental glomerulonephritis to diffuse necrotizing and crescentic glomerulonephritis. Granuloma may be seen. Immunofluorescence shows a pauci-immune pattern, meaning there is little to no staining for immunoglobulins or complement. Some patients show anti-GBM antibodies and a linear pattern of IgG and C3 on immunofluorescence, thus a double-positive anti-GBM and ANCA-associated disease. 

Treatment and Prognosis

First, treatment is categorized into organ and non-organ-threatening disease. In addition to steroids, methotrexate or mycophenolate mofetil is reserved for non-organ-threatening disease. Treatment for organ-threatening diseases consists of a course of induction therapy followed by maintenance therapy. Induction therapy with high-dose prednisolone in combination with cyclophosphamide or rituximab is advised for any organ-threatening disease to mitigate extensive damage to vital organs. In rapidly progressive kidney failure or pulmonary hemorrhage, plasmapheresis may be considered. Steroids are tapered to a low dose in 3 months. Unfortunately, 20% of all patients do not achieve remission. Recently, avacopan – a C5a receptor inhibitor – showed superior effects to tapered prednisone concerning sustained remission at one year after the start of induction therapy in ANCA-associated vasculitis.

After remission, maintenance therapy is started. Cyclophosphamide is switched to azathioprine or rituximab and is continued for 3 to 5 years. However, 50% of the patients have relapsed within 5 years after diagnosis. The use of immunosuppressive drugs increases the rate of (opportunistic) infections. Of all patients with severe ANCA-associated vasculitis, 25-50% suffer from an infection during the first year after induction therapy. During induction therapy, prophylactic use of trimethoprim–sulfamethoxazole is advised to prevent a Pneumocystis jirovecii pneumonia (PCP). In case of a double-positive anti-GBM and ANCA-associated disease, patients are treated according to anti-glomerular basement membrane (GBM) nephritis protocols.

Lupus Nephritis

Key points

• Lupus nephritis is the renal manifestation of systemic lupus erythematosus (SLE). 
• Major clinically relevant patterns are proliferative (histopathological type III and IV) and membranous lupus nephritis (type V).
• Symptoms range from mild proteinuria to end-stage renal disease, depending on the type of lupus nephritis and disease progression.
• Diagnosis is based on kidney biopsy. In case of proliferative nephritis, aggressive anti-inflammatory and immunosuppressive therapy is started.
• The prognosis of proliferative nephritis has much improved with immunosuppressive therapies, but the prognosis still varies between membranous subtypes.
• Other variants of lupus nephritis either have an excellent prognosis with minimal changes (type I and II) or a very poor prognosis in case of renal insufficiency (type VI).

General

Systemic lupus erythematosus (SLE) is an auto-immune disease with a complex immunopathogenesis, in which auto-antibodies and circulating immune complexes cause inflammation and tissue injury. SLE is a disease with a broad spectrum from mild auto-immunity to full-blown lupus with various organs and tissue involvement. Most patients suffer from exacerbations between remission of the disease (i.e., absence of symptoms). Patients often suffer from systemic symptoms, malaise, fever, weight loss, myalgias and arthralgias. This chapter will focus on the renal manifestations of SLE or lupus nephritis. The disease entity SLE with all its manifestations is discussed elsewhere.

Lupus nephritis has 6 different histopathological types ranging in disease severity. Of these types, class III and IV are known as proliferative lupus nephritis and class V as membranous lupus nephritis.

Epidemiology

SLE is more prevalent in female than male patients across all age groups and populations, with an estimated general prevalence of 15-50 per 100.000. However, the female-to-male ratio is highest (8:1) at reproductive age. In addition, the prevalence of lupus nephritis varies among different parts of the world and ethnicities. For example, people from African or Asian descent have a higher risk of developing lupus nephritis than white Europeans and Americans.

Symptoms

In up to 40% of patients with SLE, the kidneys are involved. The urine may be frothy due to proteinuria and progressive renal failure may lead to hypertension on physical examination. Otherwise, presentation is varied: patients may present with an active nephritic syndrome with all associated symptoms to a nephrotic syndrome range proteinuria.

Cause

The pathogenesis and etiology of SLE are complex. Interaction between genetic and environmental factors results in abnormal activation of the immune system: (1) the activation of the innate immunity with increased secretion of proinflammatory cytokines, TNF-α, interferon type 1 and 2 and B lymphocyte stimulator (BLyS); (2) the production of insufficient IL-2 by regulatory T-cells and natural killer cells, resulting in the sustained production of pathologic auto-antibodies and immune complexes; and (3) a reduction of the clearance of apoptotic cells and immune complexes. Finally, this cascade causes complement activation and chronic inflammation in the affected organs. 

Diagnosis

The clinical spectrum of SLE is broad. Classification criteria include characteristic clinical features and auto-antibodies; an overview is available in the section on SLE within the Rheumatology & Immunology chapter. This section will focus on diagnosis of lupus nephritis. 

Diagnostics commonly reveal proteinuria. However, an active urine sediment with red blood cell casts may be present as well. Blood works often reveal low levels of complement and high titers of anti-ds-DNA, though these are not obligatory for diagnosis. Lupus nephritis can be diagnosed by biopsy only. The current pathology classification criteria categorize lupus nephritis can be classified into 6 different histopathological patterns. This classification is used both in the treatment of patients and in their inclusion in trials. and are primarily used to include patients in trials. For an overview of these patterns, see table 14.

Clinically, the most important patterns are proliferative (histopathological type III and IV) and membranous (histopathological type V). Immunofluorescence in lupus nephritis typically reveals a full house pattern: concurrent positive staining of C3, C1q, IgA, IgG and IgM.

Class III is a focal (less than 50% of the glomeruli are involved) proliferative nephritis with endocapillary and extracapillary proliferation with subendothelial immune depositions. Patients suffer from hypertension, active sediment and proteinuria.

Class IV is diffuse proliferative nephritis with endocapillary and extracapillary proliferation with subendothelial immune depositions. More than 50% of the glomeruli are involved. Patients suffer from hypertension, active sediment and proteinuria.

Class V describes subepithelial immune depositions producing a membranous pattern similar to that in membranous nephropathy. Patients present with nephrotic range proteinuria. Only a minority has hypertension and renal function decline.

Patients can transform from one class into another and mixed variants of type III/IV and V are observed. Sometimes microthrombi are observed in lupus nephritis, possibly due to antiphospholipid antibodies. In these cases anticoagulant therapy should be applied.

Treatment

SLE cannot be cured. The aim of treatment is the remission of the disease, i.e., no active disease. Lupus nephritis treatment aims to prevent developing chronic kidney disease and end-stage renal disease. Chronic kidney disease occurs more frequently in proliferative lupus nephritis compared to membranous lupus nephropathy. Table 14 overviews the 6 forms of lupus nephritis, their presentation, treatment and prognosis.

Class	Presentation	Therapy	Prognosis
I. Minimal mesangial	None	None	Excellent
II. Mesangial proliferation
III. Focal nephritis	Hematuria and proteinuria in most patients; renal insufficiency and nephrotic syndrome are not unusual	Corticosteroids combined with either cyclophosphamide or mycophenolate mofetil.	Much improved with the use of intensive immunosuppression.
IV. Diffuse nephritis
V. Membranous nephritis	Proteinuria, often in the nephrotic range; hematuria is possible; usually no renal insufficiency.	Mycophenolate mofetil in combination with corticosteroids	Varies
VI. Sclerotic nephritis	Renal insufficiency; proteinuria and hematuria often present.	Dialysis or transplantation.	Poor

Table 14. Overview of the classification of renal SLE manifestations, their presentation, therapeutic options and prognosis.

All patients diagnosed with SLE should start treatment with hydroxychloroquine unless contraindicated. Several observational studies showed beneficial effects, including lower rates of disease flares, vascular complications and progressive kidney damage. In proliferative nephritis, the kidney is inflamed due to subendothelial immune depositions. Therefore, anti-inflammatory drugs are started to attenuate inflammation and allow recovery as much as possible immediately. In addition, immunosuppressive agents are started to disrupt pathways causing immune complex formation and causing a new cycle of inflammatory renal injury (or ‘flare’). Treatment consists of 2 steps, induction therapy lasting 3-6 months and maintenance therapy lasting years. 

Steroids are the main immunosuppressive drugs of choice, either with high doses of mycophenolate mofetil (MMF) or cyclophosphamide as induction therapy. When remission is achieved, lower doses of MMF (if used as induction therapy) or azathioprine are used as maintenance therapy to continue preventing immune complex formation and suppressing autoimmunity. In case of refractory disease, a combination of immunosuppressive drugs is used, including anti-B lymphocytes targeting biologicals.

Prognosis

Lupus nephritis is a major risk factor for morbidity and mortality. Up to 10% of patients with lupus nephritis develop end-stage renal disease. In patients with proliferative lupus nephritis, 44% will develop end-stage renal disease within 15 years. Patients with lupus nephritis have a higher mortality rate than SLE patients without nephritis. However, if remission is achieved, 10-year survival improves from 46% to 95%. Renal transplantation can be an option, though lupus nephritis may well reoccur.

Anti-GBM Nephritis

Key points

• Anti-glomerular basement membrane (anti-GBM) nephritis is a small vessel vasculitis that affects renal glomeruli and/ or pulmonary alveoli.
• It is also called Goodpasture’s syndrome if renal manifestations and pulmonary hemorrhage are present. Pulmonary involvement can be seen on chest radiography.
• It is caused by autoantibodies targeting collagen type IV (COL4) antigens expressed in glomerular and alveolar basement membranes. 
• Laboratory testing may show anti-glomerular basement membrane antibodies.
• A biopsy is the gold standard for diagnosis and shows crescentic glomerulonephritis with linear IgG deposits along the capillaries.
• Treatment consists of urgent plasmapheresis and immunosuppressants.

General

Anti-glomerular basement membrane (anti-GBM) nephritis is a small vessel vasculitis that affects the capillaries of the kidney and lungs. Circulating autoantibodies are directed against collagen type IV (COL4) antigens expressed in glomerular and alveolar basement membranes. 

This interaction can cause significant inflammation in the kidneys and lungs, though low concentrations of circulating antibodies do not necessarily cause disease. In anti-GBM nephritis antibodies lead to clinically significant renal vasculitis. If the lungs and kidneys are both involved, the disease is called Goodpasture’s syndrome. 

Epidemiology

Anti-GBM nephritis is rare but makes up 10-20% of rapidly progressive glomerulonephritis presentations. It is estimated to occur less than 2 cases per million. It has a double peak incidence of around 30–40 years and 60-80 years.

Patients that received a kidney transplantation for Alport’s disease may develop post-transplant anti-GBM nephritis.

Symptoms

About 90% of patients with anti-GBM disease have rapidly progressive glomerulonephritis. Besides acute renal failure, gross hematuria frequently occurs. The combination with alveolar hemorrhages in Goodpasture’s syndrome is present in 25-60% of patients with anti-GBM nephritis. Isolated pulmonary manifestations are seen in a small minority of patients with anti-GBM disease. Besides shortness of breath, hemoptysis and pulmonary infiltrates can be present. Anti-GBM disease accompanying systemic symptoms, such as malaise, mostly fade within weeks. In double-positive disease, i.e., with concomitant vasculitis (see below), features of systemic disease are more outspoken and lasting.

Cause

Circulating antibodies most strongly bind to a domain on the alpha-3 collagen type IV chain, mainly expressed in glomerular and alveolar basement membranes. These antibodies are polyclonal; the production is short-lived and believed to be in response to an unknown stimulus, e.g., intercurrent infection. Interestingly, the start of antibody production may precede clinical symptoms by several months.

In the kidneys, anti-GBM antibodies bind and activate complement systems and proteases. This inflammatory response results in renal failure and the clinical manifestations of hematuria and proteinuria. In the lungs, antibodies accumulate in the alveolar basement membrane, causing inflammation and leading to hemoptysis, cough and shortness of breath.

The variable pulmonary presentation, with or without alveolar hemorrhage, may depend on the access of antibodies to antigens in the alveolar basement membrane. Antigens are likely more exposed in preexisting pulmonary injury and lung bleeding is more frequently seen. In that respect, inhaled smoke, cocaine, metal dust and certain chemicals increase the risk of Goodpasture’s syndrome.

Diagnosis

Patients with a (sub-)acute nephritic syndrome (RPGN, with or without pulmonary hemorrhage) need to be tested for both ANCA- and anti-GBM antibodies, as granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and anti-GBM nephritis are the main differential diagnostic considerations. Moreover, 10-50% of patients with anti-GBM antibodies also test positive for ANCA and thus have a double-positive anti-GBM and ANCA-associated disease, which has therapeutic consequences. It should be treated as anti-GBM disease.

A biopsy is the gold standard for diagnosis and provides essential information about activity and chronicity to guide therapy. It shows crescentic glomerulonephritis with linear IgG deposits along the capillaries (figure 23). The material is also stained for anti-GBM antibodies as the accuracy of serological testing is variable. Figure 24 shows that chest radiography or an additional CT showing ground-glass or diffuse opacities can affirm pulmonary involvement.

Figure 23. (a) A glomerulus with extracapillary proliferation, the glomerular basement membrane has fragmented and there is fibrinoid necrosis. The latter is related to immune complex-associated disease. Bowman’s space is infiltrated by proliferating epithelial cells, leading to an interruption of the capsula. (b) Immunofluorescence staining shows linear, smoke-like IgG deposits along the capillaries. Adapted from NTVG ‘Wisselende presentaties van anti glomerulaire-basaalmembraan ziekte’ 2009.

Figure 24. Imaging studies in anti-GBM disease. Left shows chest radiography with alveolar consolidations (diffuse opacities) in both lower lung fields. On the right the same consolidations are shown on CT. Adapted from NTVG ‘Wisselende presentaties van anti glomerulaire-basaalmembraan ziekte’ 2009.

Therapy and Prognosis

Patients with rapidly proliferative glomerulonephritis or pulmonary hemorrhages are often critically ill and may need urgent hemodialysis and may require intubation and mechanical ventilation in the eventuality of respiratory failure. Generally, early diagnosis and treatment are crucial to optimize the prognosis. If left untreated, anti-GBM progresses rapidly to ESRD. Therefore, therapy should not be delayed awaiting diagnostic confirmation.

Treatment of anti-GBM nephritis consists of prednisolone and cyclophosphamide. 

Daily plasmapheresis is necessary to remove auto-antibodies immediately. Usually, within 8-10 sessions, auto-antibodies are no longer detectable and plasma exchange is stopped. However, immune suppressive therapy is continued for months. 

In case of double-positive anti-GBM and ANCA-associated disease, immunosuppressive therapy is continued into a maintenance phase, like in ANCA-associated vasculitis, to prevent vasculitis relapse.

The renal prognosis is good when the disease is identified early and prompt treatment is achieved. Overall survival and renal recovery are contingent on the degree of renal impairment on presentation. Renal recovery is sparse when presented with a high proportion of glomerular crescents or kidney failure requiring dialysis. Relapse of the disease is extremely rare. After transplantation in anti-GBM nephritis, there is a low rate of clinical recurrence.

Thrombotic Microangiopathy

Key points

• Thrombotic microangiopathies (TMA) are characterized by endothelial injury resulting in thrombosis of capillaries and arterioles. 
• TMA refers to syndromes with various etiologies.
• Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) are classic forms of thrombotic microangiopathies.
• Fever, thrombocytopenia, hemolytic anemia and end-organ damage of the kidneys or brain are typically present in thrombotic microangiopathies.
• Typically fragmented red blood cells called schistocytes are found on peripheral blood film.
• Treatment depends on the underlying etiology, ranging from supportive measures to plasmapheresis and immunosuppressants. The prognosis varies, but renal function (if involved) usually recovers.

General

Thrombotic thrombocytopenic microangiopathies (TMA) are a group of several disorders that show the same phenotype but have different etiologies. The TMA phenotype is histologically characterized by vascular damage with swelling of the endothelial cells that promote microvascular thrombus formation. This process induces 3 distinct features: (1) Thrombocytopenia because thrombocytes are consumed in the extensive forming of microthrombi; (2) Microangiopathic hemolytic anemia (MAHA) because erythrocytes are mechanically damaged as they pass platelet-rich thrombi. These fragmented erythrocytes are called schistocytes; (3) End-organ damage, which often affects the kidneys, heart, brain and gastrointestinal tract.

Classic TMA are thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS). OF note, TTP is discussed in more detail in the section on thrombocytopenia within the Hematology chapter. Other forms are secondary TMA which occurs in the context of an underlying disease such as an infection, malignant hypertension, malignancy, transplantation, auto-immune disease and drugs. At the other side of the spectrum is the atypical HUS, caused by a dysregulation of the alternative complement pathway and also referred to as complement-mediated TMA.

Epidemiology

TTP is more often seen in the adult population with a prevalence of approximately 1 in 100.000 and affects primarily young females (female:male ratio of 4:1). HUS is more common in children, around 1.5 in 100.000. Atypical HUS is a rare disease.

Symptoms

Thrombi in TMA may affect all capillaries and arterioles, but most often affect the brain, kidneys, heart and digestive tract. Therefore, patients may present to different medical departments, e.g., neurology, cardiology and gastroenterology. Neurological involvement may be mild to severe, and symptoms include confusion, headache, numbness, seizures, to stroke or even coma. Acute (severe) kidney injury may manifest as anuria or oliguria (producing no or very little urine, respectively).

Although the clinical pictures of all types of TMA partially overlap, the different causative underlying diseases can sometimes be elucidated based on patient history or specific symptoms (see below).

Thrombotic Thrombocytopenic Purpura

Patients with acute TTP present with fever in 50% of all cases and purpura due to easy bruising. Low platelets may also result in petechia. Platelet count is usually < 20-30 x 109/L. In addition, the patient often presents with neurological symptoms or visual disturbances. The central nervous system is affected in 70% of the cases, while the kidneys are rarely affected. About 10% of TTP cases are first observed during pregnancy.

Hemolytic Uremic Syndrome

Most HUS patients have complaints of often bloody diarrhea. Oliguria or anuria may be present due to severe kidney injury. In 50% of the cases, hemodialysis is initiated. Only a minority of patients presents with neurological symptoms in the acute phase. This generally recovers in the further course of the disease.

Atypical Hemolytic Uremic Syndrome or Complement-Mediated Thrombotic Thrombocytopenic Microangiopathies

Symptoms vary in atypical HUS. Most present with acute kidney injury and often (in 60%) require dialysis. Thrombocytopenia is less severe than in TTP, with a platelet count > 100 x10/L in most cases. Hemolysis is a more prominent feature in atypical HUS. Malignant hypertension and edema are frequently observed. Often, a triggering factor is described, such as a gastro-intestinal or respiratory tract infection, pregnancy or vaccination. A positive family history makes an atypical HUS more likely. Atypical HUS can relapse.

Cause

As mentioned, TMA is a phenotype of thrombocytopenia, microangiopathic hemolytic anemia (MAHA) and end-organ damage. There are different underlying mechanisms and causes of TMA. The most well-known causes are listed in table 15. TMA denotes endothelial injury that results in thrombosis in capillaries and arterioles. In all cases, there is an increased tendency to form thrombi (thrombogenecity) in vessels throughout the body. These thrombi consume thrombocytes, resulting in thrombocytopenia, circulate and obstruct small vessels. Passing red blood cells collide with them and are fragmented, forming schistocytes (see figure 26), which causes microangiopathic hemolytic anemia. 

Paradoxically, though TTP and HUS are diseases characterized by blood clot formation, the resulting thrombocytopenia makes patients more prone to (poorly controlled) bleeding.

TMA	Mechanism	Causes
TTP	Shortage of active ADAMTS-13, the Von Willebrand Factor cleaving protease. This results in ultra large VWF multimers accumulating on the endothelial surface promoting thrombus formation throughout the body.	Genetic: congenital TTP or Upschal-Shülman syndrome. Epidemiology: <5% in adults, more common in children
		Autoimmune: inhibitory anti-ADAMTS-13 antibodies. Epidemiology: 95% of cases
		Iatrogenic: chemotherapy, immunosuppression, quinine
ST-HUS (or STEC-HUS)	Shiga toxin producing bacteria cause damage to the vascular endothelial wall.	Europe and the USA: most often E. Coli (O157:H7,O111,O104:H4). Other agents: S. pneumoniae, HIV, CMV and parvovirus.
		Asia: Shigella.
aHUS (complement mediated TMA)	Uncontrolled activation of the alternative pathway of the complement system.	Acquired autoimmune: anti-factor H autoantibodies
		Genetic: mutations affecting complement regulatory proteins (e.g., CFH, CFI, CFB, C3, MCP)
Secondary TMA	In the context of another disease, e.g., an infection, autoimmune disease, malignant hypertension or malignancy. Also observed during pregnancy, or iatrogenic with certain drugs or after transplantation.	Autoimmune: SLE, APS
		Pregnancy: HELLP / (pre-)eclampsia
		Hypertension: activation of RAAS and subsequent endothelial injury plays a role in malignant hypertension.
		Malignancy/organ transplantation: exact mechanism unknown.
Drug-induced TMA (DITMA)	Antibody-mediated, independent of drug dose, development within 21 days after initiation.	Quinine, Clopidogrel, trimethoprim- sulfamethoxazole and penicillin.
	Toxic-mediated, direct dose-dependent toxicity, mainly occurs at high cumulative dose of single exposure to very high doses.	Immunosuppressives: tacrolimus, ciclosporin, sirolimus Cancer therapy: various cytostatic drugs and VEGF inhibitors  Drugs of abuse: e.g., cocaine.
	This website keeps an overview of drugs implicated in DITMA, including drugs of which only a few cases are known.

Table 15. Overview of forms of TMA and their causes. TMA: thrombotic microangiopathy, TTP: thrombotic thrombocytopenic purpura, ADAMTS-13: A Disintegrin And Metalloprotease with a ThromboSpondin type 1 motif, member 13, VWF: von Willebrand factor, HIV: human immunodeficiency virus, CMV: cytomegalovirus, ST-HUS: Shiga toxin hemolytic uremic syndrome, STEC-HUS: Shiga toxin E. Coli hemolytic uremic syndrome, aHUS: atypical hemolytic uremic syndrome, CFH: complement factor H, CFI: complement factor I, CFB: complement factor B, MCP: membrane cofactor protein, SLE: systemic lupus erythematosus, APS: antiphospholipid syndrome, HELLP: Hemolysis, Elevated Liver enzymes and Low Platelets, RAAS: renin-angiotensin aldosterone system, VEGF: vascular endothelial growth factor.

Diagnosis

Rapid recognition of the disease and the underlying cause is of vital importance. Prompt treatment is life-saving in TTP and can prevent irreversible renal loss in atypical HUS. Therefore, the medical status of patients with TMA should be analyzed and treated urgently at all times. 

Laboratory findings will show the classical triad of thrombocytopenia, hemolytic anemia, evidently shown by schistocytes (see figure 25), and a negative direct antiglobulin (or Coombs) test. Because the anemia is hemolytic in nature, markers of hemolysis like unconjugated bilirubin, lactate dehydrogenase (LDH) and reticulocytes are elevated, while haptoglobin levels are low. Additionally, there may be acute renal failure with non-specific urinary findings, such as hematuria and proteinuria. 

Disseminated intravascular coagulation (DIC), shown by prolonged coagulation times, high D-dimer and low fibrinogen, usually are not found in primary TMA. These findings should raise the suspicion of an alternative diagnosis presenting with MAHA and thrombocytopenia, such as secondary TMA in systemic infections or malignancies.

Figure 25. Peripheral blood smear showing schistocytes in a patient with Shiga toxin E. Coli hemolytic uremic syndrome (STEC-HUS). Adapted from NTVG ‘Een patiënt met een hemolytisch uremisch syndroom en infectie met enterohemorragische Escheria Coli’ 2011.

Analysis to reveal the cause of TMA should be performed immediately, which includes: (1) ADAMTS-13 activity, if < 10% TTP causes TMA; (2) stool culture and Shiga toxin testing, if ST-HUS causes present TMA; (3) complement C3, indicative for complement-mediated TMA if low; and (4) autoantibodies against CFH and genetic testing for complement mutations, testing for which is performed regularly when classical TMA is ruled out. In addition, the diagnosis of secondary TMA is always a diagnosis per exclusion based on clues in medical history and physical examination. 

Treatment 

Treatment of TMA depends on the underlying etiology. If TMA is suspected, it is essential to immediately start treatment through plasma exchanges or plasma infusions (if plasma exchanges are unavailable). Plasma exchanges through plasmapheresis are life-saving in TTP and can prevent irreversible renal function loss in atypical HUS; thus, treatment should be initiated as soon as possible (after blood is collected for ADAMTS-13 testing). In addition, high-dose glucocorticosteroids are started to prevent the new formation of auto-antibodies against ADAMTS-13. 

It should be noted that plasma exchanges are unnecessary when there is a strong suspicion of STEC-HUS, drug-induced TMA, pregnancy with evident HELLP (hemolysis, elevated liver enzymes and low platelet syndrome) or (pre-)eclampsia, malignant hypertension or strong suspicion of atypical HUS. Instead, these forms of TMA warrant treatment of the underlying disease.

Hemodialysis is performed on indication. Platelet transfusion is given when invasive procedures are needed or in case of bleeding. 

Thrombotic Thrombocytopenic Purpura

The mainstay of therapy in TTP patients is removing inhibitors and substituting ADAMTS-13 through plasmapheresis and glucocorticoids (immunomodulation). In recent years, a new and expensive drug – caplacizumab – was developed to treat acquired TTP. It interferes with the binding of the von Willebrand factor and platelets and as a result inhibits the microangiopathic process, which can result in rapid clinical improvement. When low levels of ADAMTS-13 are confirmed, caplacizumab is added to the plasma exchange and glucocorticosteroids regimen. The duration of therapy depends on hematologic and immunologic responses, which are evaluated after a minimum of 1 week of therapy. If there is no complete response, rituximab is added. 

Shiga Toxin Hemolytic Uremic Syndrome

Treating Shiga toxin hemolytic uremic syndrome (ST-HUS) requires adequate supportive care, including renal replacement therapy. Caution is advised regarding platelet transfusion, because it may trigger the exacerbation of ST-HUS. In addition, the efficacy of treatment with antibiotics in ST-HUS is doubtful. 

Atypical Hemolytic Uremic Syndrome or Complement-mediated Thrombotic Thrombocytopenic Microangiopathies

Since in atypical HUS, the alternative pathway of the complement is activated, treatment should be focused on the complement system. Eculizumab binds complement C5, thereby preventing the development of membrane attack complexes (MAC) downstream of the complement system. Of note, eculizumab is one of the most expensive drugs in the world.

Drug-induced Thrombotic Thrombocytopenic Microangiopathies

The management of drug-induced TMA consists of stopping the drug and providing supportive care.

Prognosis

The prognosis varies but is reasonable if TMA are treated early. Without treatment, acute TTP is fatal in 90% of cases. Currently, this life-threatening condition can be treated in 85% of patients if it is diagnosed timely. In HUS, the mortality rate in the acute phase is 2-5%. Patients suffer from morbidity and 2-3% will develop end-stage renal disease in later life. In atypical HUS, recurrence of the disease is not uncommon.

Tubulointerstitial Disease

Tubulointerstitial Nephritis

Key points

• Tubulointerstitial nephritis (TIN) is a group of kidney diseases characterized by inflammation of the kidney interstitium. 
• Acute TIN presents with acute kidney injury and mild proteinuria, leukocytes and cellular casts in the urine sediment.
• Chronic TIN is slowly progressive and may present with tubular dysfunction, Fanconi syndrome, nephrogenic diabetes insipidus, or non-anion gap metabolic acidosis type 1 or type 4. In the urine sediment, there is mild proteinuria.
• In case of drug-induced acute tubulointerstitial nephritis, renal function usually recovers within 6 to 8 weeks after stopping the offending drug.

General

Tubulointerstitial nephritis (TIN) is a group of kidney diseases characterized by inflammation of the kidney interstitium. The interstitium consists of intertubular, extra glomerular and extravascular space of the kidney filled with cells, extracellular matrix and interstitial fluid. TIN can be categorized based on underlying etiology or histology. The spectrum of disease presentation can range from tubular dysfunction and acute kidney injury to – in a minority of cases – chronic changes with subsequent development to chronic kidney disease.

Cause

Over 70% of all TIN cases are derived from pharmacological toxicity, especially beta-lactam antibiotics and NSAIDs. In addition, infectious or systemic auto-immune disease processes bring about other cases. Please refer to table 16 below for an overview of different causes per category.

Category		Example
Drug related	Antibiotics	Beta-lactams (penicillins, cephalosporins), sulfonamides (trimethoprim-sulfamethoxazole), fluoroquinolones (ciprofloxacin), macrolides (erytromycin), antitubercular medication (rifampin)
	Analgesia	NSAIDs, selective COX-2 inhibitors
	Other	Sulfonamide-containing diuretics, proton pump inhibitors, phenytoin, allopurinol
Infectious	Viral	CMV, EBV, HIV, hepatitis, hantavirus, polyomavirus
	Bacterial	Salmonella, Streptococcus, Yersinia, Brucella, Leptospirosis, Tuberculosis
Autoimmune disease		Lupus, M. Sjögren, sarcoidosis, IBD, granulomatosis polyangiitis, IgG4-mediated disease, TIN with uveitis (TINU)
Infiltration		Lymphoma, leukemia

Table 16. Different causes of tubulointerstitial nephritis. Non-steroid anti-inflammatory drugs together with beta-lactam antibiotics are the most common causes of tubulointerstitial nephritis. NSAIDs: non-steroidal anti-inflammatory drugs, COX-2: cyclooxygenase 2, CMV: cytomegalovirus, EBV: Epstein-Barr virus, HIV: human immunodeficiency virus, IBD: inflammatory bowel disease.

Symptoms and Diagnosis

Acute TIN may present with acute kidney injury and become oliguric or anuric (producing very little or no urine, respectively). The minority of the patients with a drug-related TIN develop a rash (15%), fever (27%) or eosinophilia (23%), the majority of patients are asymptomatic. Patients with non-drug-related TIN may have symptoms related to the underlying disease, such as an infection and auto-immune-related symptoms. Inflammatory infiltrates cause tissue edema, tubular injury, cellular debris and reduced tubular flow with obstruction due to casts or cellular debris. Urine sediment may show mild proteinuria, leukocytes and cellular casts, but no erythrocyte casts are observed. Kidney biopsy is the gold standard for diagnosing TIN (figure 26). Biopsy shows signs of interstitial edema and inflammatory infiltration. Glomeruli and blood vessels are usually not affected.

However, a biopsy is not always necessary to make a definite diagnosis. Patients with a documented onset of kidney failure after initiating a common offending drug have improved kidney function after stopping the drug.

Figure 26. Kidney biopsy showing spacing between the tubuli as a result of interstitial edema and inflammatory infiltration. The tubular epithelium looks heavily damaged with very irregular nuclei and flattening of the epithelium. Tamm-Horsfall proteins are present inside the tubular lumen. There are no glomerular abnormalities. Coupe with PAS stain, 100x. Image adapted from NTVG: Medicamenteuze tubulo-interstitiële nefritis, 2011.

Chronic TIN is slowly progressive. It may present with tubular dysfunction: proximal dysfunction with glucosuria, phosphaturia, hypokalemia and renal tubular acidosis type 2 (Fanconi syndrome), impaired urinary concentration capacity (nephrogenic diabetes insipidus) or renal tubular acidosis type 1 or type 4. In addition, there is mild proteinuria of fewer than 3 grams daily due to decreased tubular reabsorption. Renal ultrasound may show increased echogenicity of the renal parenchyma. Kidney biopsy shows gradual interstitial infiltration and fibrosis, tubular atrophy and dysfunction. Glomerular involvement (glomerulosclerosis) is more common in chronic than acute TIN.

Treatment

There is no standard treatment for TIN because treatment is based upon the underlying cause of the TIN. Drug-induced TIN may recover after cessation of the offending drugs, especially when identified early. Glucocorticosteroids may be initiated in patients who fail to improve after cessation of the offending drug or in cases with severely impaired kidney function. In TIN caused by an infection or autoimmunity, the underlying infection or autoimmune disease should be treated appropriately. 

Prognosis

In drug-induced acute TIN, renal function usually recovers within 6 to 8 weeks when the offending drug is withdrawn, although some residual scarring is common. Recovery may be incomplete, with persistent azotemia above baseline. When other factors cause acute TIN, histologic changes usually are reversible if the cause is recognized and removed; however, some severe cases progress to fibrosis and renal failure. Regardless of the cause, diffuse rather than patchy interstitial infiltrates, delayed response to prednisone and persistent acute renal failure (> 3 weeks) suggest irreversible injury. In chronic TIN, the prognosis depends on the cause and ability to recognize and stop the process before irreversible fibrosis occurs.

Renal Tubular Acidosis

Key points

• Renal tubular acidosis is an acid-base disorder caused by tubular dysfunction.
• Type 1 renal tubular acidosis is characterized by impaired hydrogen secretion in the distal tubule, which causes metabolic acidosis.
• Type 2 renal tubular acidosis is characterized by impaired proximal bicarbonate reabsorption, which causes metabolic acidosis. This bicarbonate deficit cannot be compensated in the distal tubule.
• Type 4 renal tubular acidosis is the most common type. Due to the absence or insensitivity to aldosterone, sodium and bicarbonate are not appropriately reabsorbed. In turn, potassium and hydrogen are not secreted as much resulting in metabolic acidosis.

Tubular Dysfunction

As noted previously, TIN may induce tubular dysfunction. The renal tubules play a pivotal role in maintaining the body’s acid-base balance by reabsorbing filtered bicarbonate (HCO3–) and removing excess hydrogen (H+) ions. Therefore, tubular dysfunctions causing acid-base disorders are commonly referred to as renal tubular acidosis (RTA). There are 3 major forms of RTA; types 1 and 2 may be inherited or acquired, whereas the most common type 4 is mainly acquired and associated with chronic kidney disease. 

Type 1 Distal Renal Tubular Acidosis 

In RTA type 1 distal tubular acidification is impaired. There are 2 types of RTA type 1 described: the first is a genetic form by a mutation which includes impaired H+-ATPase or Cl–-HCO3– anion exchange in the α-type intercalated cells of the collecting duct; and the second and most common is the acquired form associated with autoimmune disease, like Sjögren’s syndrome (auto-antibodies interfere with normal trafficking of  the H+-ATPase to the apical membrane), lupus nephritis and medullary sponge kidney. 

When the H+-ATPase is impaired, hydrogen ion secretion is reduced and metabolic acidosis results (plasma HCO3– < 15 mmol/L). Moreover, luminal potassium cannot be reabsorbed, causing kaliuresis and hypokalemia. Figure 27 depicts the normal function of the alpha intercalated cell in the collecting duct1.

Figure 27. Normal function of the type A intercalated cell in the collecting duct. In RTA type 1 there may be dysfunction of the H+ ATPases which disrupts H+ secretion and K+ reabsorption. The buffers shown on the luminal side (left) bind to H+ to buffer its acidity; this produces carbon dioxide (CO2), ammonium (NH4+), and/or dihydrogen phosphate (H2PO4–) which may be secreted with the urine or reabsorbed into the cells. Created with Biorender.com.

A second mechanism may also cause or contribute to hypokalemia. In acidemia, the capacity of the proximal tubule for HCO3– absorption is enhanced (note that this is a different part of the glomerulus). In contrast, NaCl reabsorption is inhibited, which increases distal Na+ and Cl– delivery and activates the renin-angiotensin-aldosterone system (RAAS). Both processes lead to increased K+ secretion and thus hypokalemia. 

Additionally, increased conversion of citrate to HCO3– in the proximal tubules leads to hypocitraturia. Calcium bicarbonate is released from the bone (osteomalacia) in the process of buffering the acidemia, and together with hypocitraturia predisposes to nephrolithiasis (calcium phosphate crystals). A low alkali (citrate or bicarbonate) therapy dose is necessary to correct metabolic acidosis.

Type 2 Proximal Renal Tubular Acidosis 

Usually, 85% to 90% of bicarbonate is reabsorbed at the proximal tubule and only 10% is reabsorbed at the distal tubule. In RTA type 2, the maximum of proximal HCO3– reabsorption is impaired. Impaired proximal HCO3– reabsorption cannot be compensated for by the absorptive power of the distal tubule and HCO3– is secreted in excess in the urine (high pH level). Consequently, the plasma HCO3– level drops to the new proximal resorption maximum level. No HCO3– is presented to the distal tubule and urine can be acidified. If exogenous HCO3– supplements are given to correct the acidemia, HCO3– is immediately excreted by the kidney (which raises urine pH) due to the reduced reabsorption of HCO3–. Due to the reduced HCO3– reabsorption, less Na+ is reabsorbed. Both the resulting higher distal Na+ load and hyperaldosteronism (due to hypovolemia) lead to renal potassium loss and hypokalemia. Proximal tubular cell function and its handling of HCO3– is shown in figure 28.

Figure 28. RTA type 2. Changes are driven by impaired HCO3– reabsorption. As this happens in the proximal tubule at the start of the process of filtration/reabsorption it has consequences for balances and processes further along in the glomerulus. The buffers shown on the luminal side (left) bind to H+ to buffer its acidity; this produces carbon dioxide (CO2) which can be reabsorbed into the cell. Created with Biorender.

RTA type 2 has several causes, there are genetic forms that present as a solitary defect, or storage diseases including cystinosis. However, most patients suffer from acquired forms of RTA type 2. These are associated with a more generalized dysfunction of the tubular cells (Fanconi syndrome) with aminoaciduria, uricosuria, phosphaturia, glycosuria and tubular proteinuria. A high dose alkali (citrate or bicarbonate) with additional potassium is necessary to correct metabolic acidosis. Most of the given alkali is not absorbed in proximal RTA, so providing such a large dose is necessary. 

Type 3 Mixed Renal Tubular Acidosis 

Another ‘mixed’ form of RTA exists, which includes features of both distal and proximal RTA. This type 3 mixed RTA is primarily seen in infants.

Type 4 Hyperkalemic Renal Tubular Acidosis 

RTA Type 4 is the most common type of RTA and is associated with hyperkalemia. It is due to the absence of aldosterone or insensitivity for aldosterone. Aldosterone normally promotes sodium reabsorption (figure 29). RTA type 4 causes a reduced sodium reabsorption with consequently insufficient exchange of potassium and hydrogen ions, leading to hyperkalemia and reduced acid excretion. Metabolic acidosis is mild, plasma HCO3– is usually > 17 mmol/L. The major cause of aldosterone resistance is pharmacologic: potassium sparing diuretics and trimethoprim. RTA type 4 is further observed in patients with a primary aldosterone deficiency (hypoaldosteronism). This may occur in patients suffering from M. Addison, hyporeninemic hypoaldosteronism as in diabetes mellitus , NSAID use, or in patients with impairment of the renin-angiotensin-aldosterone axis, like those on aldosterone antagonists, angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers, this impairment may also be seen in volume expansion. Treatment depends on the cause of the RTA type 4.

Figure 29. Main effects of aldosterone in the glomerular system. Aldosterone upregulates the activity of the Na+ channel, this means that if aldosterone is absent less Na+ is reabsorbed and less K+ needs to be excreted to maintain electrolyte balance. ROMK: renal outer medullary K+ channel; ENaC: epithelial Na+ channel. Created with Biorender.

Cystic Diseases of the Kidney

Key points

• Simple or solitary cysts are the most common type of renal cyst. These are usually asymptomatic and discovered incidentally during radiological studies.
• Renal cysts can be categorized as hereditary, acquired, syndromal or be associated with systemic disease.
• The most common hereditary cystic kidney disease is autosomal dominant polycystic kidney disease, caused by mutations in the PKD1 and PKD2 genes. 
• Disease progression of autosomal dominant polycystic kidney disease varies greatly.
• Other hereditary diseases causing renal cysts include tuberous sclerosis, von Hippau-Lindau syndrome, autosomal dominant tubulointerstitial kidney disease and nephronophthisis.
• Patients on long-term lithium can also develop renal microcysts.

General

Cystic kidney disease refers to a wide range of conditions. We differentiate among heritable, acquired and syndromal with mental handicaps and systemic diseases with various organs affected, as shown in table 17. Kidney cysts are newly formed pockets with fluid. Most cystic diseases are genetic and the result of mutations causing renal ciliopathies (CP) or tumor suppressor syndromes (TSS). Family history is, therefore, of utmost importance. Moreover, treating physicians are advised to perform a DNA confirmation test with a low-threshold, as it may hold therapeutic consequences for the descendants.

Type of cysts		Type	Prevalence
Heritable, predominantly kidney abnormalities
	Autosomal dominant polycystic kidney disease (ADPKD)	CP	1 : 1.000
	Autosomal recessive polycystic kidney disease (ARPKD)	CP	1 : 20.000
	Autosomal dominant tubulointerstitial kidney disease (ADTKD)	CP	1 : 100:000
	Nephronophthisis, autosomal dominant	CP	1 : 100:000
Syndromal, with (cognitive) handicap
	Joubert syndrome, autosomal dominant	CP	1 : 100.000
	Meckel-Gruber syndrome, autosomal recessive	CP	1 : 140.000
	Laurence-Moon/Bardet-Biedl syndrome, autosomal recessive	CP	1 : 160.000
	Senior Loken syndrome, autosomal recessive	CP	1 : 1.000.000
Systemic disease, multi-organ involvement
	Tuberous sclerosis, autosomal dominant	TSS	1-2 : 10.000
	Von Hippel-Lindau syndrome, autosomal dominant	TSS	1 : 200.000
Acquired, only renal abnormalities
	Benign simple cysts	> 50% over age 50
	Medullary sponge kidney		Rare
	Lithium-induced cysts		> 15%
	Malignancy; cystic renal cell carcinoma		Unknown

Table 17. Overview of nephropathies with cysts. CP: ciliopathy, TSS: tumor suppressor syndrome.

First, cysts may arise from cilia dysfunction. Cilia are present on the luminal side of the epithelial cell in the renal tubule to execute a sensory role. Dysfunction of the cilia causes cellular proliferation and growth causing cyst formation. Most ciliopathies cause urinary concentration defects with polyuria and polydipsia. The formed cysts block the renal tubules and stimulate inflammation causing chronic kidney and end-stage renal disease. Second, tuberous sclerosis and von Hippau-Linday syndrome are tumor suppressor syndromes. These entities share identical renal phenotypes due to shared dysregulation of signaling pathways.

Figure 30. Ultrasound images of different cystic entities in the kidneys. Source: wikimedia commons: simple cyst, ADPKD,, tuberous sclerosis, medullary sponge kidney.

Autosomal Dominant Polycystic Kidney Disease

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common hereditary kidney disease. Approximately one in 1000 people is affected. ADPKD is a systemic disorder characterized by progressive cyst formation in both kidneys leading to massive kidney enlargement. Figures 30 and 31 depict an ultrasound and MRI of ADPKD, respectively. There are 450.000 to 1.200.000 nephrons in the normal human kidney; however, in ADPKD, only a minority of these nephrons develop cysts. Cysts are formed predominantly in the distal tubule and collecting duct, probably already in utero. The cysts are scattered throughout the renal medulla and the cortex. During life, cysts may collect blood after trauma or a pyogenic infection may be located in these cysts. 

Cysts are formed predominantly in the distal tubule and collecting duct, probably already in utero. The cysts are scattered throughout the renal medulla and the cortex. During life, cysts may collect blood after trauma or pyogenic infection may be located in these cysts. 

Figure 31. MRI of a patient with ADPKD. Source: NTVG ‘Familiaire cystenieren: jongvolwassen familieleden screenen of niet?,’ 2017.

In that respect, other symptoms include kidney pain and gross hematuria (this means the hematuria is visible to the naked eye). In addition, ADPKD patients may have many other complications, e.g., hypertension, recurrent urinary tract infection, cardiac valve abnormalities, herniation of the anterior abdominal wall and intracranial aneurysms. Some patients have highly enlarged kidneys leaving too little space in the iliac fossa to allow implantation of a kidney transplant. Such patients need nephrectomy before kidney transplantation can be performed. Cyst formation is also found in the liver, with a prevalence of 95% by the age of 35 years, but only a minority of these patients suffer from polycystic liver disease. Rarely, cysts are found in the spleen, pancreas, brain or a combination of these sites. 

Two genes (PKD1 and PKD2) have been identified that may cause ADPKD. The pathogenesis responsible for cyst formation in ADPKD is complex. Due to mutations the polycystin-1 or polycystin-2 proteins are dysfunctional or non-functional and cause cellular proliferation. This leads to dilated tubules and, consequently, cysts formation. Expanding cysts are disconnected from their tubules and compress adjacent normal nephrons. These nephrons are obstructed, leading to a reduction in functioning renal parenchyma. From early on, maximal urine concentration capacity decreases. 

Most ADPKD subjects show progressive renal function decline. However, it is noteworthy that within families where members share the same mutation, the course of ADPKD is highly variable. Some members reach end-stage renal disease at least 6 to 10 years later than their family members. This variability in disease progression may be due to gender, genetic or environmental causes. In general, male patients have a more progressive type of disease. Approximately 70% of the patients develop end-stage renal disease between their fourth and seventh decade of life, for which renal replacement therapy is needed. It is generally assumed that this patient group accounts for around 10% of all subjects dependent on renal replacement therapy. 

Current therapies in ADPKD aim to reduce morbidity and mortality for patients. Patients are advised to drink 2-3 liters of water daily to prevent thirst because vasopressin stimulates cyst growth. Tolvaptan, a vasopressin V2 receptor antagonist, slows the increase in total kidney volume and the decline in kidney function. In this situation, renal replacement therapy is delayed by one year for every 3 years tolvaptan is used. The side effects are polyuria and polydipsia (up to 6-8 liters daily). 

Autosomal Recessive Polycystic Kidney Disease

Autosomal Recessive Polycystic Kidney Disease (ARPKD) is a disease primarily of infants and children with multiple organ involvement. The PKHD1 gene has been identified as a possible cause of ARPKD. The clinical presentation is highly variable. A high mortality rate is observed in neonates due to pulmonary hypoplasia secondary to oligohydramnios from intrauterine kidney failure, the so-called Potter sequence. If neonates survive, one in 3 patients will still develop end-stage renal disease. The kidneys are enlarged with cysts and portal hypertension develops due to periportal fibrosis. Up to 30% of the children suffer from congenital hepatic fibrosis (Caroli’s syndrome) without evident kidney involvement. The treatment of ARPKD is symptomatic. 

Autosomal Dominant Tubulointerstitial Kidney Disease

Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD), formerly known as medullary cystic kidney disease, causes progressive kidney disease leading to end-stage kidney disease between the second and seventh decade. A bland urine analysis with little to no proteinuria and small dense kidneys with frequent medullary cysts are typical for ADTKD. Three known subtypes are classified based on their genetic causes. Autosomal dominant medullary cystic kidney disease type 2 (MCKD2) is a tubulointerstitial nephropathy causing renal salt wasting, hyperuricemia, gout and end-stage renal failure, requiring symptomatic treatment with a low threshold for starting allopurinol. 

Nephronophthisis

Nephronophthisis (NPHP) is one of the most common genetic disorders causing end-stage renal disease in childhood and adolescence. NPHP is classified into 3 clinical forms based on the age of end-stage renal disease onset: infantile, juvenile and adolescent. Juvenile NPHP is most common: kidneys are normal-sized or smaller and hyperechogenic with corticomedullary cysts. Patients suffer from impaired urinary concentration and impaired sodium reabsorption. Proteinuria occurs later, leading to end-stage renal disease at a median of 13 years of age. Adolescent NPHP has the same signs and symptoms but progresses slowly to end-stage renal disease at a median of 19 years. 

Infantile NPHP shows enlarged kidneys on ultrasound (in utero) with cortical microcysts. There is oligohydramnios in utero with all its consequences, like in autosomal recessive polycystic kidney disease. End-stage renal disease is reached by a median age of 3.

The minority of NPHP patients also suffer from extrarenal manifestations, like oculomotor apraxia, ataxia, cognitive impairment (Joubert syndrome type 4), congenital hepatic fibrosis, encephalocele and polydactyly (Meckel-Gruber syndrome), visual impairment due to cone-rod dystrophy, polydactyly, obesity and hypogonadism (Laurence-Moon/Bardet-Biedl syndrome), or retinitis pigmentosa (Senior Loken syndrome).

Tuberous Sclerosis

Tuberous sclerosis is a systemic disease characterized by hamartomas, i.e., cellular overgrowth, in various organs, including the brain, heart, skin, eyes, kidney, lung and liver. The TSC1 and TSC2 genes are affectes, which encode for hamartin and tuberin, respectively. The hamartin-tuberin complex inhibits the mammalian target of the rapamycin pathway, which controls cellular proliferation and survival. Like ADPKD, the clinical course is highly variable. Signs, symptoms and severity can vary, even among relatives. The kidneys are affected in 80% of the patients. Renal tuberous sclerosis has 3 different phenotypes, of which, renal angiomyolipoma is the most common phenotype (figure 30). However, it may also present as renal cysts and renal cell carcinoma. If the kidneys are ‘filled’ with angiomyolipoma or cysts, the renal parenchyma is compressed and chronic kidney disease may occur. A minority of the patients may eventually develop renal cell carcinoma. 

Von Hippau-Lindau Syndrome

Von Hippau-Lindau syndrome is a highly variable disease characterized by abnormal angiogenesis, causing benign and malignant tumors in different organs. A mutation in the Von Hippau-Lindau (VHL) tumor suppressor gene causes the disease. This mutation leads to pheochromocytomas, hemangioblastomas in the central nervous system and retina, cysts and hemangiomas in the kidney. In addition, there is a high risk of developing renal cell carcinomas. Of note, the VHL mutation accounts for 60% of the spontaneous clear cell carcinomas of the kidney. Most patients have a positive family history, but up to 20% have a de novo mutation in the VHL gene. 

Simple or Solitary Cysts

The most common type of renal cyst is the simple cyst. Twenty-five percent of patients above 40 years and more than 50% of the population have a simple renal cyst by the time they are 50 years old. Simple cysts typically do not cause any symptoms. They are often incidental findings during radiological studies (figure 30). Simple cysts usually do not interfere with kidney function. Rarely a simple cyst can rupture, bleed, become infected or cause discomfort. The Bosniak classification system differentiates between a simple cyst and a malignancy based on imaging characteristics regarding septa and calcifications. CT and ultrasound are the mainstay diagnostic modalities to differentiate simple cysts from other cystic nephropathies and malignancies.

Medullary Sponge Kidney

The medullary sponge kidney is a benign disorder of unknown cause. It is characterized by cystic dilatation of the collecting tubules in one or both kidneys. In addition, hypocitraturia, incomplete distal renal tubular acidosis and stasis in the dilated collecting ducts contribute to calcium-containing nephrolithiasis. Most cases are asymptomatic and found incidentally on imaging (figure 30); symptomatic patients present with signs of nephrolithiasis. Treatment is also necessary for recurrent nephrolithiasis.

Lithium-Induced Cysts

Long-term lithium use is associated with urinary concentration defects, tubulointerstitial nephropathy and microcysts of 1-2 mm. The cysts are observed in one-third to two-thirds of patients using long-term lithium. The exact mechanism has yet to be elucidated. It might be related to lithium’s antiapoptotic effects, which may prevent renal tubular epithelial cells from undergoing apoptosis. No treatment is available and no monitoring is necessary.

Renal Cell Carcinoma

Key points

• Renal cell carcinoma is an umbrella term for all renal carcinomas. In practice, renal cell carcinomas are most often clear cell carcinomas arising from the epithelial cell of the proximal tubule.
• Most renal cell carcinomas are asymptomatic and found incidentally on radiography. If present, symptoms usually include hematuria, flank pain and an abdominal mass.
• All renal cell carcinomas are graded into prognostic groups I through IV according to their size and metastases.
• Grade I and II disease can be treated surgically. In higher-grade tumors, tyrosine kinase inhibitors and monoclonal antibodies are key.
• The prognosis ranges from a 5-year survival rate of 81% in grade I renal cell carcinomas to only 8% in type IV.

General

Up to 95% of renal cell carcinomas arise primarily from the kidney. Renal cell carcinomas (RCCs) often do not cause symptoms and are difficult to treat. Most prevalent is clear cell carcinoma, named for its clear bubble-like appearance on microscopy, which develops from the epithelial cells of the proximal tubules. In cases where the tumor is localized, radical or partial nephrectomy is a treatment option. In metastatic disease, tyrosine kinase inhibitors or monoclonal antibody therapies are used.

Epidemiology

A renal cell carcinoma is the most common malignant renal mass. Its incidence is highest in developed countries, male patients are affected twice as often and the peak incidence is between 50 and 70.

Symptoms

Patients often do not have symptoms and RCCs are most commonly found incidentally in imaging studies. However, some patients still present with symptomatic RCCs. The classic triad comprises hematuria, flank pain and a palpable abdominal mass.

Risk factors for RCC include tuberous sclerosis and end-stage renal disease due to acquired cystic disease of the kidney. In addition, the rare autosomal dominant Von Hippel-Lindau syndrome is also associated with neoplasms; about 35% of patients with Von Hippel-Lindau syndrome develop RCC.

Cause

RCCs are diverse and arise from different parts of the kidney. For example, epithelial cells of the proximal tubule might give rise to clear cell RCC (70% of all RCCs) or papillary RCC (10%). Chromophobe RCCs (≤ 5%) may develop from the distal tubules or cortical collecting duct. In 5 to 10% of all cases, oncocytic RCCs develop from the cortical collecting duct, while in less than 1% of all cases, collecting duct RCC may develop from the medullary collecting duct. RCCs rarely develop with cells of unknown origin, known as the microphthalmia transcription factor gene family (MiTF) translocation RCC. This type occurs in less than 1% of all RCCs.

Clear Cell Renal Cell Carcinoma

Clear cell carcinoma is the most prevalent form of all RCCs. In just over half the cases, clear cell RCCs arise after mutations that cause the inactivation of the VHL gene that codes for a tumor suppressor protein. This inactivation leads to increased activation of the vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptors, thereby promoting angiogenesis and tumor growth. Other implicated genes are PBRM1 (40% of clear cell RCC cases), SETD2 (15%) and BAP1 (15%).

It should be noted that even in patients with a clear cell RCC caused by a VHL mutation, a broad genetic variability is seen. One metastatic site may have a different genetic makeup than another, even within the same patient. It is thought that this tumor heterogeneity is one of the reasons for treatment resistance.

Diagnosis

Workup of patients with suspected RCC includes urine analysis, urine cytology, chest radiography and a CT scan of the abdomen and pelvis. Tumors are staged according to the TNM classification. Based on TNM classifications RCCs are subdivided into prognostic groups I to IV, as illustrated in table X below.

Stage		Corresponding TNM
I	Primary tumor ≤ 7cm, no metastases	T1	N0	M0
II	Primary tumor > 7cm, no metastases	T2	N0	M0
III	Any size tumor with regional lymph node involvement OR primary tumor involvement into major veins or perinephric tissues	T1 / T2 T3	N1 N0 / N1	M0 M0
IV	Any size tumor with distant metastases OR primary tumor invasion beyond the renal fascia	Any T T4	Any N Any N	M1 M0

Table 18. Stages of renal carcinoma and corresponding TNM classification.

Treatment

Management of stage I and II disease is either radical or partial nephrectomy. In this procedure, the kidney and the renal fascia and its contents are removed. However, partial nephrectomy or nephron-sparing surgery might be an option with a more timely diagnosis. This option preserves renal function and reduces the risk of late cardiovascular events. It is especially preferred in bilateral tumors, like papillary tumors, or in patients with impaired renal function or only one kidney.

Surgical intervention has a less prominent role in metastasized disease, though it might be used to reduce symptoms such as pain or hemorrhage. Treatment of metastasized disease is almost always palliative. Several tyrosine kinase inhibitors and monoclonal antibody therapy are now used in patients with metastatic disease. First-line therapy is usually monotherapy with a tyrosine kinase inhibitor. If the disease progresses, several combined drug regimes are available. No biomarkers are available yet to aid clinicians in choosing the right combination for their patients.

Prognosis

With the more widespread and frequent use of radiography, incidental findings of RCC are becoming more common. Because of this, tumors are also detected earlier, which has benefitted the prognosis. The overall 5-year survival rate is 74% across all RCCs. However, the numbers range significantly between the different prognostic groups. For example, survival rates in stages I and II are 81% and 74% 5-year survival, respectively, compared to a 53% survival rate in stage III and a poor survival rate of 8% in stage IV.

Multisystem Disease with Variable Kidney Involvement

Key points

• Diabetic nephropathy is one of the most common causes of chronic kidney failure. It is caused by the glycation of proteins in the glomerulus and renal vasculature, leading to hyperfiltration and damage. 
• Many patients who develop proteinuria reach end-stage kidney disease.
• Tuberculosis may manifest in the kidney and urogenital tract and cause damage. Renal tuberculosis constitutes 15 to 20% of all extra-pulmonary tuberculosis cases.
• In systemic lupus erythematosus, amyloidosis and plasma cell myeloma deposits in the kidney trigger an immune-mediated cascade that damages the kidney. It comprises deposits of immune complexes, fibrils, and light chains respectively.

Diabetic Nephropathy

Diabetic nephropathy is among the most common causes of chronic kidney failure in Western countries. Type 1 and type 2 diabetes can both cause diabetic nephropathy and damage caused is nearly indistinguishable on biopsy. In type 2 diabetes, there is often another non-diabetic kidney disease, leading to a more heterogeneous pattern on biopsy, e.g., vascular besides glomerular disease. Diabetic nephropathy is a clinical diagnosis and commonly presents with proteinuria in variable degrees up to nephrotic range, hypertension and a slow but progressive loss of renal function. A kidney biopsy to confirm the diagnosis is often not performed in patients with long-standing diabetes and no other likely etiology.

Several mechanisms play a role in the pathogenesis of diabetic nephropathy. Key histological findings are glomerular basement membrane thickening, mesangial matrix expansion and nodules, podocyte loss and arteriolar hyalinosis. Arteriolar hyalinosis directly results from high glucose levels in the bloodstream reacting with vascular smooth-muscle cell proteins in a process called glycation. The vascular wall becomes stiff and narrow through glycation, resulting in hyaline arteriolosclerosis. This mainly affects the efferent arteriole of the glomerulus, where the vascular resistance goes up, resulting in hyperfiltration, meaning a GFR > 120-140 mL/min/1,73 m2. This directly corresponds to the risk of clinically significant nephropathy. Hyperfiltration, in turn, will make the mesangial cells in the glomerulus respond by secreting more extracellular matrix, resulting in mesangial expansion and subsequent mesangial sclerosis. Some patients develop characteristic nodular glomerulosclerosis, also known as Kimmelstiel-Wilson nodules. Thickening of the glomerular basement membrane is likely the result of podocyte injury, although the exact mechanism is not yet understood. This membrane thickening is closely related to albuminuria as it is accompanied by a loss of heparan sulfate moieties that generally form the negatively charged filtration barrier that prevents albumin from passing through.

Therapy consists of blood sugar and blood pressure control and other cardiovascular risk management (CVRM) measures like lifestyle modification and lipid control to prevent further kidney damage. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) do particularly well in preserving kidney function since they mitigate the effect of angiotensin II, which results in lowered efferent arteriole resistance. 

In type 2 diabetes mellitus, a sodium-glucose cotransporter-2 (SGLT2) inhibitor may also be indicated. The same goes for a mineralocorticoid receptor antagonist (MRA) or a GLP-1 receptor agonist. For more details on the (contra)indications, see the KDIGO guideline 2022 on diabetes management in chronic kidney disease (CKD). Despite these options, many patients developing proteinuria still reach end-stage kidney disease. Moreover, patients with diabetic nephropathy have an exceptionally high risk of cardiovascular events. The prognosis for diabetic patients on dialysis is poor and they do less well than those without diabetes.

Tuberculosis

Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis bacteria. Although rarely seen in the developed world, it remains a significant health problem in developing countries. TB is one of the granulomatous inflammatory diseases and generally affects the lungs, but other organs can also be affected in extra-pulmonary TB. Extra-pulmonary TB is mainly seen in immunocompromised patients and 15 to 20% of all extra-pulmonary TB cases are renal.

Urogenital TB can involve the urinary collecting and genital system, with manifest ureteric strictures (strictures). The renal parenchyma is affected less frequently, appearing as interstitial nephritis and glomerulonephritis. It often presents with sterile pyuria (presence of pus in the urine) and is sometimes accompanied by microscopic hematuria. Diagnosis can be made through urinary analysis – acid-fast stain or PCR – and mycobacterial culture, which may take many weeks. Taking 3 to 6 early morning urine samples is advised to improve detection and accuracy. On ultrasound, renal TB might appear as pyelonephritis or look like renal cell carcinoma (pseudotumoral type). CT scanning can show obstructions of the urinary collecting system in urogenital TB.

Patients with renal TB should receive regular TB treatment, though dosages might have to be lowered in case of impaired renal function. In cases with abscesses or obstructive disease, surgical intervention may be necessary.

Amyloidosis

Amyloidosis is a group of diseases that result from the deposition of insoluble, abnormally folded proteins – so-called beta-sheet pleated amyloid fibrils – in various tissues, causing significant organ dysfunction. Several tens of precursor proteins are capable of forming amyloid fibrils. They have specific predisposing intrinsic features to do so. If these fibrils deposit in the kidneys, they cause amyloid nephropathy, which destroys almost all glomerular structures. It usually presents with proteinuria or nephrotic syndrome.

Among the many amyloidosis variants, 2 main types often lead to amyloid nephropathy. Firstly, immunoglobulin-associated amyloidosis includes the vast majority of renal amyloidosis in developed countries, mainly including light chain amyloidosis (AL), but also heavy chain amyloidosis (AH) and a mixture (AHL). AL results from clonal plasma cell disease with overproduction of light chains that deposit in the kidney. 

Amyloid A amyloidosis (AA) is seen in patients with chronic inflammatory conditions, e.g., infections, arthritis, vasculitis or neoplasia. In this variant, beta-pleated sheets of a cleavage product of serum amyloid A protein – an acute phase reactant – deposit in the kidney. It is mainly seen in rheumatoid arthritis, ankylosing spondylitis, or psoriatic arthritis. In Mediterranean regions, familial Mediterranean fever (FMF) is also a common cause.

The diagnosis of renal amyloidosis should be considered in patients with proteinuria or nephrotic syndrome and is generally made through a tissue biopsy. Always consider the possibility of other organ involvement, e.g., heart failure or neuropathy. In a biopsy, amyloid stained by Congo red shows apple-green birefringence in polarized light (figure 32). The diagnosis of AL is confirmed by immunofluorescence microscopy typing of the diffuse amorphous glomerular deposits, showing kappa or – far more frequent – lambda light chains. However, immunofluorescence microscopy results may sometimes be false negative. Free light chains can easily be found in blood and urine with high sensitivity. Electron microscopy demonstrates the fibrils.

Figure 32. Congo red stain (image b) of subcutaneous fatty tissue in a patient with AL amyloidosis showing the typical apple-green birefringence. Adapted from NTVG ‘AL amyloidose en de behandeling door eliminatie van het voorlopereiwit,’ 2007.

Treatment should focus on the underlying type of amyloidosis, targeting the production of the amyloid protein, and on supportive measures preserving renal function. AL can be treated with autologous stem cell transplantation, though many patients are not fit for this approach. An alternative is a chemotherapy regime similar to that used in multiple myeloma. In recent years novel drugs like bortezomib, a proteasome inhibitor, and daratumumab, a monoclonal antibody targeting plasma cell antigen CD38, have changed perspectives. In AA, treating the underlying chronic disease with anti-inflammatory drugs, immunosuppression, or biologics is the current standard of care. In addition, patients might be treated through the blockade of the renin-aldosterone-angiotensin system (RAAS) to preserve renal function. However, the prognosis is poor and amyloid nephropathy frequently leads to chronic renal disease and dialysis dependency. Therefore, kidney transplantation may be considered in renal amyloidosis, especially in patients with AL with a complete hematologic response.

Plasma Cell Myeloma / Light Chain Cast Nephropathy

Up to 50% of patients with multiple myeloma experience some form of kidney failure at some time in their disease course, whereas in several cases (up to 12%), this results in end-stage renal disease. Various types of kidney disease can be seen in plasma cell myeloma, including light chain cast nephropathy (LCCN) or myeloma kidney. Other examples are amyloidosis and light chain deposition disease (LCDD), illustrated by tissue deposits of light chains without fibril formation). In LCCN, monoclonal immunoglobulin light chains – also called Bence Jones proteins – and uromodulin – also called Tamm-Horsfall mucoproteins – form aggregates leading to intratubular cast formation. These not only block the tubules, which may then rupture, but also inflict a giant cell reaction, causing massive inflammation and fibrosis. LCCN usually arises when massive production of light chains, exceeding the proximal tubular reabsorption capacity, coincides with settings of hypovolemia, metabolic acidosis, infection, hypercalcemia, or after exposure to nephrotoxic drugs. Of note, LCCN can also develop without multiple myeloma, e.g., in a monoclonal gammopathy of renal significance (MGRS) or rarely in other lymphoproliferative disorders such as Waldenström macroglobulinemia, lymphoma or chronic lymphocytic leukemia.

Patients presenting with the classic triad of bone pain, kidney failure and hypercalcemia should be worked up for multiple myeloma. Normocytic anemia and infections, especially pneumonia and pyelonephritis, are also commonly seen. Serum and urine protein electrophoresis must be performed and serum-free light chains measured. Bone marrow biopsy is usually performed to estimate the percentage of plasma cells. A low-dose whole-body CT scan may show characteristic lytic bone lesions.

Treatment of LCCN in multiple myeloma includes bortezomib-based chemotherapy to decrease light chain production. Any predisposing factors contributing to kidney damage, such as hypovolemia, hypercalcemia or drugs, should be mitigated. Abundant fluid therapy is given unless contraindicated to maintain a high urine output. Contraindications are heart failure or no reversal of oliguria despite this regimen. All potentially nephrotoxic drugs need to be discontinued. Dialysis may be indicated. Some centers may use extracorporeal methods to remove light chains actively.

Sickle Cell Nephropathy

An autosomal recessive mutation in the hemoglobin beta-chain causes sickle cell disease (SCD). More specifically, it is a group of hemoglobinopathies with several genotypes, e.g., homozygous HbSS or coinheritance with other beta-globin mutations, in which hemoglobin S (HbS) is formed instead of hemoglobin A (HbA). In everyday situations, this mutation usually causes no issues. However, in low-oxygen settings, HbS irreversibly polymerizes into a sickle shape, a process known as ‘sickling’. These sickle cells are more rigid and, therefore, unable to squeeze through capillaries, which leads to vessel occlusion and ischemia, which causes pain and swelling, characteristic symptoms of a sickle cell crisis.

Kidney damage due to SCD is multifactorial and called sickle nephropathy. In the kidneys, the vasa recta in the renal medulla are especially prone to occlusion due to SCD. The local low pressure of oxygen and a high osmolarity prompt sickling and red blood cell adhesion to the vessel wall, platelet activation, inflammation and vasoconstriction is elicited. The net result is infarction of the medulla with progressive loss of function (associated with reduced glomerular filtration rate (GFR) and impaired concentration ability) that starts in childhood, where compensatory hyperfiltration is first seen. Close follow-up over the years is, therefore, essential. In sickle cell nephropathy, proteinuria is seen in about 20-30% of all patients. In addition, patients may present with macroscopic hematuria due to renal papillary necrosis or infection. Finally, ultrasound may show a hyperechoic aspect of the medulla and is needed to exclude obstructive uropathy. 

Hypertension is uncommon. If encountered, it can be treated with renin-angiotensin-aldosterone system (RAAS) blockade. Besides treating the underlying SCD with hydroxyurea, sickle cell nephropathy is mainly treated with fluids to prevent dehydration and further kidney damage. Exchange transfusion therapy is indicated in multi-organ failure. Up to one-fourth of SCD patients will have chronic kidney disease. Dialysis and transplantation are appropriate options in patients with end-stage renal disease. Erythropoiesis-stimulating agents (ESA) may be administered, but hyperviscosity may ensue with different target hemoglobin levels.