Podocytopathies

Abstract

Podocytopathies are kidney diseases in which direct or indirect podocyte injury drives proteinuria or nephrotic syndrome. In children and young adults, genetic variants in >50 podocyte-expressed genes, syndromal non-podocyte-specific genes and phenocopies with other underlying genetic abnormalities cause podocytopathies associated with steroid-resistant nephrotic syndrome or severe proteinuria. A variety of genetic variants likely contribute to disease development. Among genes with non-Mendelian inheritance, variants in APOL1 have the largest effect size. In addition to genetic variants, environmental triggers such as immune-related, infection-related, toxic and haemodynamic factors and obesity are also important causes of podocyte injury and frequently combine to cause various degrees of proteinuria in children and adults. Typical manifestations on kidney biopsy are minimal change lesions and focal segmental glomerulosclerosis lesions. Standard treatment for primary podocytopathies manifesting with focal segmental glomerulosclerosis lesions includes glucocorticoids and other immunosuppressive drugs; individuals not responding with a resolution of proteinuria have a poor renal prognosis. Renin-angiotensin system antagonists help to control proteinuria and slow the progression of fibrosis. Symptomatic management may include the use of diuretics, statins, infection prophylaxis and anticoagulation. This Primer discusses a shift in paradigm from patient stratification based on kidney biopsy findings towards personalized management based on clinical, morphological and genetic data as well as pathophysiological understanding.

Fig. 1 ∣. Worldwide prevalence of podocytopathies.

a ∣ Worldwide prevalence of podocytopathy with minimal change lesions (MCLs). b ∣ Worldwide prevalence of podocytopathy with focal segmental glomerulosclerosis (FSGS) lesions. Data are expressed as a percentage of total kidney biopsies and were obtained from international registries^,,-.

Fig. 2 ∣. Structure of the nephron, the glomerulus and the filtration barrier.

The kidney is comprised of functional units, nephrons, each of which is made of a glomerulus and a tubule. In healthy humans, the average number of nephrons is ~1 million (range 250,000 to <2.5 million). The glomerulus is composed of a tuft of capillaries covered by visceral epithelial cells — the podocytes — and surrounded by a capsule lined on the inner surface by parietal epithelial cells (PECs). The latter cell population contains podocyte progenitors, which are motile and progressively differentiate into podocytes in the region near the vascular pole of the glomerulus. The vascular pole of the glomerulus includes both the afferent and efferent arterioles (transverse section). The outermost layer is composed of podocytes adhering to the glomerular basement membrane (GBM) and interdigitating (longitudinal section), with the slit diaphragm spanning each gap between pairs of foot processes. The innermost layer is constituted by fenestrated endothelial cells.

Fig. 3 ∣. Mechanical podocyte stress.

a ∣ Under normal conditions, several kinds of physical stress are present in the glomerulus^,. The hydrostatic pressure gradient across the glomerular capillary and the Bowman (urinary) space outside the capillary creates circumferential stress on the podocyte foot processes (1). Fluid filtration across the glomerulus generates shear stress on the lateral aspects of the foot processes (2). Filtrate flow laterally across the podocyte cell body in the Bowman space confers shear stress (3). Podocyte-derived vascular endothelial growth factor (VEGF) acts on intravascular endothelial cells and is needed for maintaining the glomerular filtration barrier and keeping serum proteins such as albumin inside the vasculature (4). b ∣ Numerous medical conditions increase the filtration load to the kidneys, which translates into increasing filtration pressure at the level of individual glomeruli. As a trade-off, horizontal podocyte stress (1) increases as the number of podocytes remains constant. Such podocyte stretching ultimately leads to compromise of the filtration barrier, podocyte detachment and loss, and proteinuria. Proteinuria also increases oncotic pressure acting on podocytes (2), as protein in the Bowman space further increases the amount of fluid passing the filtration barrier, which defines single-nephron filtration. This mechanism is common to most forms of progressive chronic kidney disease, as the total effective glomerular filtration surface declines. Hyperfiltration is present early in some forms of chronic glomerular disease, including diabetes mellitus. GBM, glomerular basement membrane; PEC, parietal epithelial cell.

Fig. 4 ∣. Consequences of podocyte loss.

Following injury, podocyte loss can occur that can trigger two responses. First, the remaining podocytes adapt by increasing their size to cover the newly denuded glomerular basement membrane (podocyte hypertrophy). Second, parietal epithelial cells (PECs) along the Bowman capsule, which include a population of resident podocyte progenitors, supply new podocytes after injury and loss. These mechanisms contribute to podocyte functional recovery and reduce proteinuria following injury but can be inefficient or become maladaptive. Indeed, hypertrophic podocytes may be unable to maintain a normal foot process structure, leading to a further increase in local shear stress that triggers further podocyte detachment. In addition, differentiation of PECs into podocytes can be hampered by mechanical stress and proteinuria, leading to inefficient podocyte regeneration and scar formation. ECM, extracellular matrix.

Fig. 5 ∣. Monogenetic diseases and SRNS.

Identification of single-gene causes of steroid-resistant nephrotic syndrome (SRNS) placed the podocyte at the centre of SRNS pathogenesis because most of the implicated genes are expressed in podocytes. Foot processes interdigitate with those from neighbouring podocytes, forming the glomerular slit membrane, which is critical for filtering and retention of protein in the bloodstream. Its integrity is lost in nephrotic syndrome. Proteins encoded by genes that, if mutated, cause monogenic SRNS localize to specific subcellular sites of podocytes depicted here. CoQ₁₀, coenzyme Q₁₀; GBM, glomerular basement membrane; P, paxillin; T, talin; V, vilin. Adapted with permission from REF., Oxford University Press.

Fig. 6 ∣. Causes and risk factors underlying podocytopathies across the lifespan.

Patient age and sex are associated with an increased probability of different types of podocytopathies related to different causes or risk factors that can frequently even combine in the same patient. For example, genetic causes are more frequent in children and young adults, whereas immunological causes are more frequent in male children. On the other hand, podocytopathies related to inhibition of vascular endothelial growth factor (VEGF) are observed during pre-eclampsia and are, therefore, more prevalent in pregnant women. Major risk factors for the development of a podocytopathy, such as increased single-nephron glomerular filtration rate for obesity or diabetes, are more frequently observed in adult middle-age patients, whereas a low nephron mass endowment can cause a podocytopathy during adolescence or early adulthood. Finally, a susceptibility gene, such as APOL1, is prevalent in Black adult patients. HCV, hepatitis C virus; T_H, T helper; T_reg cell, regulatory T cell.

Fig. 7 ∣. Pathology of podocytopathies.

a ∣ The lesion pattern of diffuse mesangial sclerosis occurs only in young children and is usually associated with severe nephrotic syndrome. The glomerulus shows diffuse mesangial sclerosis (arrow) with prominent mesangial consolidation, closure of the capillary loops and overlying prominent immature podocytes. Periodic acid–Schiff staining; magnification ×400. b ∣ The lesion pattern of minimal changes on light microscopy shows a normal glomerulus. Haematoxylin and eosin staining; magnification ×200. c ∣ On electron microscopy, minimal change disease foot process effacement (arrows) is visible. Minimal change lesions are usually associated with steroid-sensitive nephrotic syndrome but can also be associated with isolated proteinuria or, rarely, with steroid-resistant nephrotic syndrome, particularly in the early phases of the disease. d ∣ The lesion pattern of focal segmental glomerulosclerosis (FSGS) is associated with diverse clinical presentations but most frequently with isolated proteinuria or steroid-resistant nephrotic syndrome. FSGS lesions (arrow) have been distinguished into five subtypes but the lack of accuracy to predict a specific cause of disease or outcome limits their clinical relevance. In addition, particularly in maladaptive FSGS, lesions typically start in juxtamedullary nephrons, which are sensitive to haemodynamic injury and harbour fewer podocyte progenitors, which explains why FSGS starts and is more frequently observed in juxtamedullary glomeruli. Perihilar and cellular variants share an intermediate prognosis and the former is associated with maladaptive (secondary) causes. Coarse segmental staining for IgM and C3 can occur with minimal or FSGS lesions. At electron microscopy, limited effacement with narrow foot processes is frequent in maladaptive podocytopathy with secondary FSGS lesions, whereas diffuse foot process effacement is typical of primary podocytopathies and virus-related or drug-related podocytopathy^-. Masson’s trichrome staining; magnification ×200. e ∣ The lesion pattern of collapsing glomerulopathy is less common and usually associated with severe steroid-resistant nephrotic syndrome. Traditionally, collapsing glomerulopathy has been associated with people of African descent and a fast rate of progression to end-stage kidney disease, whereas tip lesions (which are the result of proliferation of parietal epithelial cells at the urinary pole) are associated with white ethnicity, a low histological score at presentation and a better response to therapy. The collapse of the tuft is evident by the circular black lines (capillaries) and loss of the urinary space (arrows). Jones methenamine silver staining; magnification ×200.

Fig. 8 ∣. Diagnosis and management of paediatric patients with proteinuria or nephrotic syndrome.

In children with podocytopathies, persistent sub-nephrotic proteinuria of >0.5 g per day is treated with a renin–angiotensin system inhibitor (RASi), maximally titrated. Patients are longitudinally followed up. If the proteinuria is associated with other symptoms, such as hypertension, kidney biopsy is required to exclude other glomerular disorders, which are treated accordingly. The length and frequency of the follow-up is determined for each patient based on renal function and residual proteinuria but, at a minimum, yearly evaluation should be performed even in patients with long-standing complete remission and normal renal function. Paediatric patients with idiopathic nephrotic-range proteinuria or nephrotic syndrome are treated with steroids, the response to which defines further management. Steroid-resistant patients should undergo biopsy and genetic testing; treatment with second-line immunosuppressive agents can be started while awaiting the results of genetic testing and should be continued only if these tests are unrevealing. Uncertain or unexpected genetic diagnosis should be confirmed with re-evaluation of the patient and their family. When a genetic diagnosis is ascertained, management should be personalized on the gene identified. By contrast, paediatric patients with nephrotic-range proteinuria or nephrotic syndrome who achieve complete or partial remission should be followed up and re-treated with steroids in case of relapse. Steroid-sparing immunosuppressive agents should be considered only for frequently relapsing and steroid-dependent patients. Based on guidelines from Kidney Disease Improving Global Outcomes (KDIGO) and the International Pediatric Nephrology Association, updated and modified based on recent literature. ANA, antinuclear antibody; CNI, calcineurin inhibitor; DMS, diffuse glomerulosclerosis; FSGS, focal segmental glomerulosclerosis; Ig, immunoglobulin; LM, light microscopy; MC, minimal changes (with foot process effacement); MMF, mycophenolate mofetil; sCr, serum creatinine. ^a≥2 relapses in 6 months or ≥4 relapses in 12 months. ^b<2 relapses in 6 months or <4 relapses in 12 months.

Fig. 9 ∣. Diagnosis and management of adults with proteinuria or nephrotic syndrome.

Renal biopsy, laboratory examinations and renal imaging (and, potentially, genetic testing) exclude other glomerular disorders and rule out secondary aetiologies of podocytopathies, which are treated according to the cause. Sub-nephrotic proteinuria is generally treated with a renin–angiotensin system inhibitor (RASi), maximally titrated; patients are longitudinally followed up based on renal function and residual proteinuria; a yearly evaluation should be performed even in patients with long-standing complete remission and normal renal function. Patients with idiopathic nephrotic-range proteinuria and nephrotic syndrome are treated with a course of steroids and with RASi. Response to steroids defines further management: steroid-resistant patients should undergo genetic testing and treatment with second-line immunosuppressive agents should be considered only if these tests are unrevealing. When a genetic diagnosis is ascertained, management should be targeted to the gene identified. Conversely, patients who achieve complete or partial remission should be followed up and re-treated with steroids in case of relapse. Steroid-sparing immunosuppressive agents should be considered only for frequently relapsing and steroid-dependent patients. Based on Kidney Disease Improving Global Outcomes (KDIGO) guidelines, updated and modified based on recent literature. CNI, calcineurin inhibitor; FSGS, focal segmental glomerulosclerosis; MC, minimal changes (with foot process effacement); MMF, mycophenolate mofetil. ^a≥2 relapses in 6 months or ≥4 relapses in 12 months. ^b<2 relapses in 6 months or <4 relapses in 12 months.