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.
Similar content being viewed by others
Introduction
The majority of diseases underlying chronic kidney disease (CKD) present with proteinuria, that is, loss of plasma proteins into the urine. Proteinuric kidney diseases can be divided into glomerular or non-glomerular forms, depending on whether protein loss occurs across the glomerular filtration barrier or results from insufficient reabsorption of filtered protein by the proximal tubule1. Glomerular proteinuria is defined by a predominance of albumin whereas, in non-glomerular forms, albumin is only a minor component.
Proteinuria and proteinuria-related symptoms are the only or the main clinical presentation of diseases affecting podocytes, which are ‘octopus-like’ highly specialized cells in the glomerulus that act as part of the filter2,3,4. Causes of podocyte injury include all forms of immune complex glomerulonephritis that engender distinct histopathological patterns; for example, subepithelial localization of immune complexes in membranous nephropathy causes direct podocyte injury and massive proteinuria. By contrast, podocyte injuries without immune complex deposits produce different histopathological lesion patterns evident on biopsy, of which four types can be distinguished: diffuse mesangial sclerosis (DMS), which presents early in life and is characterized by mesangial matrix expansion and podocyte hypertrophy5; minimal changes (also referred to as minimal change disease), which are predominantly present in children and are so-called owing to a seeming paucity of histopathological abnormalities that can only be visualized by ultrastructural analysis5,6; focal segmental glomerulosclerosis (FSGS) lesions, which involves sclerotic lesions evident in segments of glomeruli4; and collapsing glomerulopathy, which presents as collapse of the glomerular capillaries and hyperplasia of parietal epithelial cells migrating to the tuft to give the appearance of ‘pseudocrescents’4,5. The stratification of patients with these histological lesions has been complemented by clinical criteria, particularly the response to immunosuppressive therapy2,4,6. For example, most patients with minimal changes who respond to steroids have a favourable prognosis6 but, for those resistant to steroids, the information from the kidney biopsy falls short in adequately allowing a personalized prediction of prognosis and the selection of optimal treatments directed to the specific cause of proteinuria.
Increasing knowledge about monogenetic causes of proteinuria or nephrotic syndrome as a molecular diagnosis has revealed that the histomorphological lesions of DMS, minimal changes, FSGS or collapsing glomerulopathy are unspecific lesions and represent different patterns of podocyte injury rather than defining a unique disease cause or diagnosis that would imply a specific therapy. Indeed, all these pathological patterns can be associated with the same genetic disease or the same pathological pattern can be associated with many different genetic diseases or treatment responses2,3,4. Thus, it has become important to rename this family of diseases as ‘podocytopathies’3,5,7, which accomplishes several objectives. This classification localizes the injury to the podocyte and implies a cellular target for therapy. The classification also helps to overcome the outdated notion that DMS, minimal changes, FSGS or collapsing glomerulopathy are ‘diseases’ or define a diagnosis. Finally, this approach prompts a diagnostic workup to identify the causative trigger or triggers of podocyte injury and to define individualized prognosis and treatment.
In this Primer, we present a conceptual reappraisal of the evolving knowledge concerning the podocytopathies usually referred to as DMS, minimal changes, FSGS and collapsing glomerulopathy in kidney biopsy reports. The literature often refers to these lesions as if they were definite diagnoses, yet they are not. The combination of proteinuria and the presence of any of these lesions on kidney biopsy defines podocyte injury as a unifying underlying mechanism that can result from numerous different causes and risk factors, each of which defines a different diagnosis and, possibly, a specific treatment. As such, the conceptual attempt of this Primer is to move away from the traditional view that considered tissue lesions as diagnoses and uses the term ‘podocytopathies’. This approach requires a diagnostic workup to identify the underlying disease process and/or risk factors that produce the unspecific clinical and histological constellations. Our goal is to facilitate the understanding, clinical assessment and effective management of these disorders. We do not discuss podocyte injury secondary to systemic disorders, such as diabetes, immune complex glomerulonephritis, monoclonal gammopathies, amyloidosis or metabolic storage diseases, in detail as these are defined systemic disease entities that need other disease-specific treatment approaches (Box 1).
Epidemiology
Prevalence
Reliable epidemiological data for podocytopathies are lacking. Pathological diagnosis is based on kidney biopsy and many patients, particularly children and individuals in low-resource settings, do not undergo biopsy. This reality introduces a bias towards steroid-resistant cases and under-reports the incidence of minimal change lesions in children. International biopsy registries report FSGS or minimal change lesions; the two rarer subtypes (DMS and collapsing glomerulopathy) are usually included among FSGS in international registries (Fig. 1). Despite this limitation, the prevalence of podocytopathies, both relative to other glomerular disease entities and in absolute terms, seems to be increasing worldwide and they are major contributors to end-stage kidney disease (ESKD)4. This increased prevalence is partly due to the increased diagnosis given the increased global availability of kidney biopsy and pathological examination4 and partly due to the increased prevalence of risk factors for podocyte injury8. However, the available data may underestimate the prevalence of podocytopathies. Indeed, idiopathic nephrotic syndrome in children (0–18 years of age) has a prevalence of 10–50 cases per 100,000 population globally6 and is most commonly associated with minimal changes, although, in the majority of these cases, the pathological lesion pattern is not established by kidney biopsy6. Idiopathic nephrotic syndrome in children has a male predominance with a ratio of 3:1, for unknown reasons, and is an interesting research question, the answer to which might lead to pathogenetic insights6. Globally and considering all age groups, FSGS is the most common lesion (Fig. 1), representing 10–40% of all the biopsies, except in Asia, where IgA nephropathy is prevalent9.
Risk factors
Podocytopathies can have a single cause, as frequently in the many monogenetic forms manifesting early in life (see Supplementary Table 1) or in the forms arising from a single environmental risk factor. Alternatively, podocytopathies can have a combination of multiple genetic and/or environmental risk factors causing podocyte injury, acting in concert to reach a threshold effect for the development of proteinuria.
Susceptibility genes
Genome-wide association studies have identified several susceptibility genes associated with podocytopathies10,11,12,13,14. These genetic variants seemingly cannot cause a podocytopathy per se but represent important risk factors in the presence of a ‘second hit’. The best-studied association is with APOL1 (encoding apolipoprotein L1), which involves protein-changing mutations (G1 and G2 alleles) that have an unusually large effect for common genetic variants. Individuals with sub-Saharan ancestry, and particularly west African ancestry, carry a 3–5-fold higher risk for FSGS lesions and CKD than European populations15, with this disparity being largely explained by these APOL1 genetic variants16,17. The frequency of APOL1 risk alleles (G1 and G2 variants combined) is ~35% among African Americans, 26% in central African populations and ~50% in west African populations18. The enhanced protective effect of these gene variants against African sleeping sickness caused by Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense likely explains their strikingly high allele frequency in these populations16. In areas of Africa with a high frequency of APOL1 risk alleles, CKD prevalence reaches 16%19.
High-risk APOL1 alleles in kidney transplant recipients are linked to shorter allograft survival and lower post-donation estimated glomerular filtration rate (GFR)20. Transgenic animal studies in mice and flies indicate that the expression of either APOL1 risk variant is sufficient to induce FSGS, global glomerulosclerosis and CKD; in these models, disease severity increases with increased APOL1 expression levels21,22. In clinical studies, kidney biopsy manifestations of APOL1-associated kidney disease include FSGS lesions, collapsing glomerulopathy and non-specific focal global glomerulosclerosis (affecting the entire glomerular tuft) with arterionephrosclerosis23, similar to that observed in ageing and so-called hypertensive nephropathy24,25. Indeed, APOL1 podocytopathy is a major cause among African Americans of what was formerly called hypertensive CKD26,27.
Obesity and diabetes
Conditions of increased single-nephron GFR and hence increased podocyte shear stress confer an increased risk of developing a podocytopathy. The increasing global prevalence of obesity contributes to the increasing prevalence of podocytopathies as well as to serving as a factor that accelerates CKD progression8. Obesity is associated with a substantial increase in body mass causing single-nephron hyperfiltration, which in turn causes podocyte hypertrophy and podocyte shear stress28. Obesity drives foot process effacement (FPE), the earliest morphological pattern of podocyte injury, and subsequent FSGS lesions29,30,31,32. The regression of proteinuria after bariatric surgery suggests that the earlier stages of this process are reversible30. Although progression is typically slow, ESKD develops in 10–33% of those with obesity-related CKD30,32. Likewise, diabetes mellitus is associated with glomerular hyperfiltration33. The GFR increase is driven by enhanced proximal tubular glucose and sodium reabsorption, mediated by sodium/glucose cotransporters (SGLTs) that lead to a reduction in afferent arteriolar resistance and an increase in single-nephron GFR through the inhibition of tubuloglomerular feedback34. Increased GFR in single remnant nephrons promotes podocyte stress driving FPE and podocyte detachment, leading to macroalbuminuria that accelerates renal function decline in long-standing and poorly controlled diabetes34. Hence, even recent onset of diabetes can promote proteinuria and podocyte loss, whereas the ‘diabetic nephropathy’ can take several years to develop.
Low nephron mass and nephron loss
Conditions such as congenital kidney hypoplasia, unilateral agenesis and reflux nephropathy predispose to podocytopathy with proteinuria, hypertension and secondary FSGS lesions at biopsy (so-called secondary, because the podocyte is not primarily affected but is injured by external factors). Surgical studies in rodents and humans suggest that losing >75% of renal mass (nephrons) poses the greatest risk for developing proteinuria, glomerulosclerosis and, in some cases, progressive loss of kidney function35. Living kidney donors or patients who lose 50% of their kidney mass are at increased risk of proteinuria and hypertension but rarely develop progressive CKD, suggesting that, for most healthy individuals, a 50% reduction in renal mass is not sufficient to trigger progressive hyperfiltration injury36. Similarly, low nephron endowment due to low birthweight and pre-term birth are associated with CKD and FSGS lesions at biopsy, suggesting an adaptive podocytopathy37. The same process operates in all forms of CKD as nephron loss increases single-nephron GFR in the remnant nephrons. As ageing is also associated with nephron loss, adaptive FSGS lesions can also occur at older age. Sickle cell disease38, glucose-6-phosphatase deficiency, glycogen storage disease type I, von Gierke disease39, cyanotic heart disease40, familial dysautonomia and extreme muscular hypertrophy (most commonly associated with body building)41 are associated with podocytopathy in conditions in which single-nephron glomerular pressure and filtration rate as well as podocyte shear stress are all increased, ultimately causing nephron loss.
Mechanisms/pathophysiology
Podocytes are terminally differentiated epithelial cells, the primary and secondary processes of which extend to wrap around the basement membrane of glomerular capillaries in the glomerulus7,25,42 (Fig. 2). Podocytes possess primary, secondary and tertiary foot processes, all of which contain an extensive actin cytoskeleton and interdigitate with the foot processes of adjacent podocytes. The ~200 nm gap between adjacent foot processes is spanned by the tri-laminar slit diaphragm, which serves as an ~60 kDa size-selective filter. The barrier is selective for both molecular size and electric charge, the latter property being conferred by anionic charges that retard the passage of anionic proteins. Even in the healthy glomerulus, podocytes must withstand circumferential stress and shear stress (Fig. 3). Podocyte loss following injury increases mechanical stress on the remaining podocytes.
Podocyte effacement, detachment and loss
Foot process simplification and FPE are the earliest morphological patterns of podocyte injury and can be associated with massive proteinuria even without podocyte loss. Incident injuries can induce FPE, which causes the podocytes to resemble immature podocytes of the developing kidney at the ultrastructural level42. The reorganization of the actin cytoskeleton plays a key part in FPE43. A functional imbalance among key regulators of the actin cytoskeleton, such as the Rho family of small GTPases, including RhoA, CDC42 and RAC1, is usually observed and can result in FPE44,45. RAC1 activity promotes the formation of a branched actin network as present in the podocyte lamellipodia43. RhoA activity favours actin polymerization and the formation of actin bundles43. A finely tuned balance between active RAC1 and active RhoA seems to maintain normal foot process morphology and function43.
Although FPE is potentially reversible, podocyte detachment or death implies irreversible podocyte loss46,47. Indeed, live and dead podocytes appear in the urine of patients with glomerular disorders45, which is thought to occur through a substantial increase in the mechanical forces of fluid filtration, leading to glomerular tuft expansion or podocyte fragility. Genetic, metabolic, toxic or inflammatory factors, such as increased expression of NOTCH and WNT/β-catenin by podocytes, promotes podocyte dedifferentiation and protects cells from cell death under injury conditions; however, as cells dedifferentiate into an earlier developmental stage, the concomitant loss of markers such as nephrin and podocin occurs, leading to functional defects48. These defects are also thought to contribute to podocyte detachment and loss49 (Fig. 4).
The same mechanical forces that trigger the onset of a podocytopathy also accelerate established glomerular injury46,47. First, the fluid drag of oncotic pressure generated by albumin in the Bowman space increases shear stress on podocytes and hyperfiltration46,47,49 (Fig. 3). Second, nephron loss during CKD progression and normal ageing reduces the total glomerular filtration surface, which increases filtration and the vertical podocyte shear stress at the level of the single nephron46,47. Third, remnant nephrons undergo an increase in size (hypertrophy) to compensate the nephron loss-related decline in filtration surface, which has the potential to lead to maladaptive podocyte hypertrophy. In addition, podocyte loss reduces podocyte density in the glomerular tuft, a process that results in increased horizontal stress forces on the remaining podocytes46,47. The podocyte hypertrophic capacity is limited; hypertrophic podocytes may also be unable to maintain a normal foot process structure, increasing local shear stress50, which triggers further podocyte detachment51.
Podocytes are postmitotic cells and, although they can replicate DNA, they cannot complete cytokinesis25. When podocytes are lost, a subset of parietal epithelial cells along the Bowman capsule, which are resident podocyte progenitors, can supply new podocytes52,53,54,55,56. However, regeneration is frequently inefficient or can drive focal scarring. Indeed, the proliferation, migration and differentiation of parietal epithelial cells towards the podocyte lineage are tightly temporally and spatially regulated. The chemokine CXCL12 is normally constitutively produced by healthy podocytes and serves as a podocyte-to-progenitor feedback mechanism to maintain local podocyte progenitors in a quiescent state and to suppress their intrinsic capacity to generate new podocytes53. After podocyte loss, the reduced expression of CXCL12 promotes NOTCH activation in parietal epithelial cells, which drives their proliferation and migration towards the glomerulus. Podocyte loss also permits the passage of circulating retinol through the damaged glomerular filtration barrier, which is transformed into the Bowman space to retinoic acid; this acts as a powerful inducer of parietal epithelial cell differentiation into podocytes56,57. In addition, activated parietal epithelial cells synthesize retinoic acid to self-promote their differentiation into podocytes56,57. Retinoic acid induces NOTCH gene downregulation, cell cycle arrest and the upregulation of podocyte markers in parietal epithelial cells56,57. However, with high-grade proteinuria, retinoic acid is sequestered by albumin in the Bowman space58 and parietal epithelial cell differentiation into podocytes is impaired. The absence of APOL1 also promotes parietal epithelial cell quiescence; the microRNA miR-193a suppresses APOL1 translation59. Under conditions of mechanical stress60, impaired APOL1–miR-193a axis (for example, in those with the G1 or G2 genotype)59 or persistent NOTCH expression61, activated parietal epithelial cells cannot properly differentiate into podocytes and contribute to the formation of hyperplastic lesions and fibrous lesions, including FSGS58,62, by synthesizing and releasing extracellular matrix63 (Fig. 4). Interestingly, superficial and mid-cortical nephrons retain a potent capacity for podocyte regeneration, which may explain why juxtamedullary nephrons are particularly susceptible to glomerulosclerosis53.
Podocyte injury
In addition to associations with low nephron number and increased body mass, podocyte injury can result from genetic, immunological, infectious (for example, hepatitis C virus (HCV) infection) and toxic (for example, from various drugs and metals) causes. The prevalence of these syndromes differs across the lifespan and different contributing factors (and with different relative contributions) can occur in combination to reach a threshold of podocyte injury and loss.
Genetic causes
Next-generation sequencing techniques have greatly facilitated the identification of ≥50 causal genes in hereditary podocytopathies (Supplementary Table 1). Moreover, DNA sequencing has revealed mutations in unexpected genes64,65 and has widened the extrarenal phenotypes associated with podocyte gene mutations. For example, these approaches have identified that genes expressed in podocytes as well as genes expressed in other tissues in the context of syndromic disorders are affected. Additionally, many small effect variants, mostly non-coding, conferring susceptibility for podocytopathies have been described in adults.
More than 50 genes mutated in hereditary podocytopathies have been identified to date, encompassing genes expressed in podocytes (Fig. 5). The discovery of these genes as monogenetic causes of steroid-resistant nephrotic syndrome (SRNS) has shown that particular proteins are critical for glomerular function. For example, the identification of mutations in NPHS1 (encoding nephrin) and NPHS2 (encoding podocin) demonstrated the central role of the slit diaphragm in glomerular function. Identification of ACTN4 (encoding α-actin 4) and ANLN (encoding anillin) mutations emphasized the importance of the podocyte actin cytoskeleton in kidney physiology and pathophysiology64,66,67,68,69. A rare subset of patients carrying mutations in genes encoding Rho-like small GTPases are, at least partially, sensitive to immunosuppression, suggesting that glucocorticoids may also directly affect podocyte function70. Rare cases of steroid-sensitive nephrotic syndrome (SSNS) with apparent Mendelian transmission also exist but the gene or genes involved are unknown71. The discovery of recessive mutations in genes that participate in coenzyme Q10 biosynthesis (namely COQ2, COQ6 and ADCK4) illustrates the opportunity for a ‘personalized medicine approach’ to specific podocytopathies as these patients may respond to oral coenzyme Q10 supplementation72,73. Thus, the availability of effective therapies for several genetic podocyte diseases supports the notion that genetic discovery can enable personalized medicine.
In the context of a syndromic disorder involving multiple organs, pathogenetic variants in genes expressed in other tissues can also cause podocytopathies74 (Supplementary Table 1). For example, Alport syndrome, Dent disease and Fabry disease can all present as a podocytopathies, sometimes with minimal or absent extrarenal manifestations, and may manifest isolated FSGS lesions as a pattern of injury64. Often, there is an extra-renal phenotype in an organ that expresses the affected gene, for instance, sensorineural deafness in Alport syndrome, due to mutations in genes encoding collagen75. However, SRNS or isolated proteinuria, even in the nephrotic range, can sometimes be the only evident clinical sign of these disorders, at least at the time of presentation65.
Immunological and soluble factors
The effectiveness of glucocorticoids and other immunosuppressive drugs in many podocytopathies for which a genetic cause can not be determined suggests a central role of the immune system in the pathogenesis of these disorders; the direct effects of these agents on cultured podocytes have also been demonstrated76 and, therefore, a local, non-immune effect is also possible. Several genome-wide association studies have revealed that HLA-DR and HLA-DQ are the strongest susceptibility loci for childhood SSNS in various populations11,12,13,14. These features, along with the absence of immune complex deposition and the spontaneous remission of proteinuria after measles infection, originally led to the consideration of these forms as T cell-mediated diseases77. Early studies proposed a 60–160 kDa glomerular permeability factor released from T cells isolated from a patient with nephrotic syndrome and minimal change lesions6. In a rat model, this factor induced proteinuria and tertiary FPE of podocytes but the causative protein has not been conclusively identified6.
Subsequently, alterations in circulating T cell subsets and in cytokine profiles have been described in patients with podocytopathies, suggesting a shift towards a T helper 2 cytokine profile with a possible role for IL-4 or IL-13 as the circulating permeability factors78,79,80. Indeed, peripheral CD4+ and CD8+ T cells in children with SSNS express IL-13, a cytokine that can, upon experimental overexpression, induce a podocytopathy in rats81. The number of regulatory T cells (those that suppress immune responses) is also reduced in patients with podocytopathies compared with healthy controls and tends to normalize when remission of proteinuria is achieved79,82,83. Consistently, renal disorders including podocytopathy with a minimal changes lesion pattern and SSNS are reported in 20% of individuals with immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, a rare congenital immunodeficiency with severe regulatory T cell defects84.
Evidence of persistent remission of proteinuria after treatment with rituximab or ofatumumab85,86, both of which deplete B cells, sparked renewed interest in the role of B cells in these disorders. However, these agents may have effects independent of their effects on B cells. Rituximab has been reported to stabilize the podocyte actin cytoskeleton through its binding to a cross-reactive epitope of sphingomyelin phosphodiesterase acid-like 3b (SMPDL3b)87. Ofatumumab was also effective in rituximab-resistant nephrotic syndrome88; whether it also binds to SMPDL3b remains unknown88. B cell-derived IL-4 promotes proteinuria in mice89; however, human studies have not been reported and so its relevance to proteinuria in humans remains to be established. Selective extracorporeal immunoadsorption induces the remission of nephrotic syndrome relapses, suggesting that the factor responsible for proteinuria could be an immunoglobulin or could bind to immunoglobulins90. B cells can also act as antigen-presenting cells and their depletion may also modify T cell function in patients with steroid-dependent nephrotic syndrome (SDNS)91. In a subset of patients, hyposialylated IgM on the surface of T cells predisposes patients to steroid dependence92; rituximab can reverse this phenomenon and improve outcomes. Furthermore, B cells may contribute to podocyte injury by other mechanisms; activated antigen-specific B cells can induce FPE and proteinuria through local release of IL-4 in vivo89.
Other observations suggest a role for circulating permeability factors in patients with primary podocytopathies. First, some patients experience a relapse of nephrotic syndrome immediately after kidney transplantation but enter remission following plasma exchange93. Second, kidneys with minimal changes from deceased donors can undergo remission of proteinuria after transplantation into a non-proteinuric recipient94. At least three candidates for circulating permeability factors have been put forwards: cardiotrophin-like cytokine 1, soluble urokinase plasminogen activator receptor (suPAR) and anti-CD40 IgG95. Serum suPAR levels are reportedly higher in patients with FSGS than in those with other forms of proteinuric kidney disease such as membranous nephropathy96,97, although numerous subsequent studies have attributed this finding to differences in GFR98. One study reported angiopoietin-related protein 4 (ANGPTL4), a glucocorticoid-sensitive secreted glycoprotein, as a circulating permeability factor in minimal change lesions99 but this was not confirmed by other studies100. Overall, none of the proposed permeability factors elicits consistent proteinuric effects in vitro or in vivo and further testing of these interesting hypotheses is needed, including in large cohorts that encompass patients with FSGS and glomerular and non-glomerular disease controls98.
Infectious agents
Viral infections are common causes of podocytopathies, especially with a lesion pattern of collapsing glomerulopathy101. HIV infection can cause a characteristic podocytopathy with nephrotic syndrome and rapid disease progression. Histologically, HIV-associated nephropathy presents as the combination of collapsing glomerulopathy and marked tubular-interstitial disease, including microcystic tubular dilatation102. Other patients who are HIV-positive develop FSGS lesions without collapsing features102. Both forms of glomerular disease are associated with APOL1 high-risk status, with 72% of African Americans with these disorders carrying two APOL1 risk alleles102. Additionally, HIV infects podocytes in vivo and elicits cytotoxicity102. The associated type 1 interferon-mediated antiviral immune response promotes APOL1 gene transcription, inducing inflammatory cell death pathways21; in addition, it further promotes podocyte death by mitotic catastrophe103. The estimated global prevalence of HIV-related CKD is of 6–12% of people who are HIV-positive104. HIV-related CKD is particularly prevalent in sub-Saharan Africa, where the high prevalence of both uncontrolled HIV1 infection and APOL1 risk alleles predispose to CKD and to rapid progression to ESKD105.
Chronic HCV infection also causes several immune-mediated glomerular disorders, including podocytopathy with FSGS lesions106,107. Although the pathogenic mechanisms are unclear, it is hypothesized that, similar to HIV, HCV directly injures podocytes, leading to glomerulosclerosis107. Eliminating HCV using antiviral medications can clear the virus from >95% of individuals with chronic HCV infection and improve the outcome by reducing proteinuria and preventing or delaying CKD106.
Podocytopathy with FSGS and collapsing glomerulopathy may also occur as a consequence of the common childhood infection with parvovirus B19 (refs108,109), with DNA evidence of parvovirus B19 in kidney tissue109. However, only a few individuals who are infected develop FSGS lesions and the predisposing factors to glomerular injury are unknown. Clearance of the virus can be associated with an improvement of proteinuria108. Epstein–Barr virus, cytomegalovirus infection and SARS-CoV-2 (the virus that causes COVID-19)110 also cause podocytopathy101. SARS-CoV-2 can directly infect podocytes or indirectly harm them by promoting cytokine secretion, causing proteinuria with the pathological feature of a collapsing glomerulopathy110. Other pathogens that can trigger podocytopathies include Borrelia spp.111, the plasmodium Schistosoma mansoni and filarial nematodes4.
Pregnancy-related VEGF inhibition
Renal physiological changes characteristic of pregnancy include increased renal blood flow and increased glomerular filtration. Factors that oppose the actions of podocyte trophic factors may cause podocyte injury and detachment. For example, podocyte-expressed vascular endothelial growth factor (VEGF)112 acts in paracrine and autocrine ways to protect podocytes113. Pre-eclampsia is a disorder of pregnancy characterized by the onset of hypertension and often manifests with high proteinuria. Increased plasma levels of soluble FMS-like tyrosine kinase 1 (sFLT1), produced by the hypoxic placenta, antagonize VEGF action and cause podocyte loss and proteinuria113. In these patients, a podocytopathy can result from the combination of VEGF antagonism and pregnancy-related glomerular hyperfiltration, particularly when associated with excessive weight gain, diabetes or a multiple pregnancy, all of which increase glomerular hyperfiltration113. In other contexts, treatment with anti-VEGF or anti-VEGF receptor agents, which are commonly used to prevent vascular proliferation in tumours and retinal diseases, can cause proteinuria and hypertension114 and are associated with renal thrombotic microangiopathy and with podocytopathies, chiefly minimal change lesions and collapsing glomerulopathy115.
Drugs
Certain drugs can cause podocytopathies via direct toxic effects4. Interferon therapy can be associated with the development of collapsing glomerulopathy; indeed, IFNβ promotes podocyte death and IFNα inhibits the migration of podocyte progenitors. In addition, interferon inhibits the differentiation of podocyte progenitors into podocytes6,116. Finally, interferon is a potent stimulus to APOL1 gene expression, driving podocyte damage in individuals with two APOL1 risk alleles117.
Bisphosphonate therapy, which is used to treat the loss of bone density, is rarely associated with a toxic podocytopathy and presents histologically as minimal change lesions with FPE, FSGS lesions or collapsing glomerulopathy116; the molecular mechanisms remain obscure. Lithium therapy to treat conditions such as bipolar disorders rarely causes proteinuria and minimal changes or FSGS lesions, which can resolve within weeks after stopping the drug118; however, the mechanism is controversial119,120. Sirolimus, doxorubicin and daunomycin can each cause a podocytopathy with FSGS lesions by directly inducing podocyte death121,122,123. Doxorubicin, used as a cancer chemotherapy in humans, is a podocyte toxin that is widely used to induce podocyte injury lesions in mice; it promotes mitotic catastrophe in podocytes, with consequent detachment, followed by FSGS lesions124. As already mentioned, VEGF antagonists cause a usually transient podocytopathy114.
Clinical manifestations
Substantial proteinuria, with at least 50% of the protein being albumin, is the defining feature of the podocytopathies. The magnitude of urinary protein excretion defines a spectrum of conditions with increasing degrees of severity: sub-nephrotic proteinuria, nephrotic-range proteinuria and nephrotic syndrome (Table 1). In addition, podocyte injury and loss can contribute to a range of other clinical manifestations, including oedema and hyperlipidaemia, and increase the risk of infection.
Hypoalbuminaemia
When the amount of albumin lost in the urine exceeds the capacity of the liver to replace the losses, the level of plasma albumin declines. The prevalence of hypoalbuminaemia varies even among patients with the same genetic disorder65 for reasons that are unknown. One factor may be a variability in the capacity of the proximal tubule to catabolize albumin, returning amino acids to the circulation125. Why the liver, which normally produces ~15 g per day of protein in an adult, is unable to compensate for protein loss of 4–6 g per day in some patients but not in others is also unclear. One hypothesis is that TNF and IL-1 expression may suppress hepatic albumin synthesis and contribute to hypoalbuminaemia, at least in podocytopathies associated with inflammatory conditions126.
Oedema
Two main factors contribute to oedema development. First, sodium reabsorption in the renal tubules is influenced by proteinuria and proteasuria (overfill scenario)127,128; these patients are more likely to show arterial hypertension as a sign of hypervolaemia128. In adults, the onset of proteinuria is typically gradual and causes a parallel drop of oncotic pressure in plasma and in the renal interstitium, such that substantial extra-cellular volume shifts and acute kidney injury (AKI) do not typically occur. In adults, oedema develops from a positive sodium balance via increased sodium retention in the kidney. In children, acute onset of massive proteinuria typically develops together with severe hypoalbuminaemia (often <1 g/dl) without an equivalent drop of albumin in interstitial tissues throughout the body; this leads to a fluid shift from plasma to the relatively hyperoncotic interstitium129.
An extracellular volume shift is the second factor contributing to oedema and is associated with a hypovolaemic state (underfill scenario). In some cases, hypovolaemia may present as shock, with hypotension, tachycardia, peripheral vasoconstriction, oliguria (including AKI), and compensatory elevations of plasma renin and aldosterone130. Intravascular hypovolaemia, despite total body sodium excess, may be sustained by diuretic therapy, sepsis or diarrhoea131. Interstitial oedema, ischaemic tubular injury, and the use of NSAIDs, diuretics and a renin–angiotensin system inhibitor (RASi) may contribute to AKI in such patients127.
Thromboembolism
Patients with nephrotic syndrome, even if asymptomatic, have a hypercoagulable state132 related to a multitude of factors. These factors include urinary losses of endogenous anticoagulants, such as antithrombin III, plasminogen, protein C and protein S, as well as increased platelet activation, hyperfibrinogenaemia, inhibition of plasminogen activation by type 1 plasminogen activator inhibitor (PAI1) and the presence of high-molecular-weight fibrinogen moieties in the circulation133. The exit of saline from the glomerular capillaries into the urinary space, due to reduced plasma oncotic pressure, promotes haemoconcentration in the post-glomerular circulation, which is worsened by diuretic therapy. All of these factors likely contribute to the tendency to form thrombi, particularly in the renal vein134.
Hyperlipidaemia
Marked elevations in the plasma levels of cholesterol, LDL, triglycerides and lipoprotein A often occur in nephrotic syndrome135. Decreased plasma oncotic pressure probably stimulates hepatic lipoprotein synthesis, resulting in hypercholesterolaemia135. HDL cholesterol levels are usually normal or reduced in nephrotic syndrome and there is often a pronounced decline in the cardioprotective HDL2 fraction135. Nephrotic syndrome may manifest elevated levels of apolipoproteins B, C-II and E, which are associated with VLDL and LDL particles; on the other hand, the levels of the major apolipoproteins associated with HDL (apolipoproteins A-I and A-II) are usually normal136. ANGPTL4 contributes to a feedback loop driven by hypoalbuminaemia and free fatty acid concentrations that promotes hypertriglyceridaemia137. Altogether, these changes in lipid and lipoprotein profiles increase the risk of thromboembolism, premature atherosclerosis and progressive kidney disease135.
Anaemia
Patients with persistent nephrotic syndrome may develop anaemia due to urinary losses of iron, transferrin, erythropoietin, transcobalamin and other metals such as copper138.
Endocrine disturbances
Due to thyroglobulin loss in the urine, thyroid hormone (total T4 and T3) levels may be low, with normal serum free T4 and T3 and thyrotropin (thyroid-stimulating hormone) concentrations, and, as a result, patients are usually clinically euthyroid. Serum 25-hydroxyvitamin D and total calcitriol concentrations may also be reduced, but the functionally relevant free calcitriol concentrations are typically normal139. Hypocalcaemia is common owing to hypoalbuminaemia; this does not affect the physiologically important ionized calcium concentration. For these reasons, vitamin D replacement therapy is not routinely recommended to these patients.
Infections
Patients with nephrotic syndrome, particularly children, are at increased risk of developing serious bacterial infections, including pneumonia, empyema and peritonitis140. Sepsis, meningitis and cellulitis are other serious infections that can occur in children with nephrotic syndrome141. Bacteriuria is common140,141. The increased risk for infection is related to renal losses of IgG leading to hypogammaglobulinaemia, reduced levels of the alternative complement factors B and D lost in urine, and the use of immunosuppressive therapy, all of which promote a state of acquired immunodeficiency. Loss of opsonizing factors may specifically increase the susceptibility to encapsulated bacterial infection, in particular to pneumococcal infections that are potentially lethal142,143.
Diagnosis screening and prevention
The approach to patients with substantial proteinuria or nephrotic syndrome can be different depending on the resources available, which may limit the ability to make a tissue diagnosis as well as management (Box 2). Importantly, different risk factors and/or causes of podocytopathies can present at certain phases of life or be preferentially associated with a certain sex or ethnicity. Risk factors frequently combine in the same patient and the individual constellation determines the onset of proteinuria and its severity (Fig. 6). Recognizing the likelihood of these causes or risk factors throughout the lifespan can help to improve diagnostic accuracy.
Clinical features and initial assessment
In children, podocytopathies frequently present with periorbital and/or peripheral oedema because of hypoalbuminaemia and saline excess. Less commonly, proteinuria is discovered on a routine urinalysis. It must be considered that a positive dipstick for protein on a random urinalysis (defined as ≥1 on dipstick testing) will be positive in 5–10% of normal school-age children and adolescents. However, only 0.1% of such children will have persistent proteinuria144, defined as repeated detection in at least two exams over a period of >3 months, and only these children should be considered as possibly having a podocytopathy. Patients with deafness or with syndromic features should undergo phenotyping for other manifestations of a specific syndrome and, when proteinuria is noted, should be referred to a paediatric nephrologist. A careful patient and family history for kidney diseases or extrarenal manifestations, particularly visual or hearing problems, is important and should prompt evaluation for a syndromic podocytopathy64,65,67,145.
By contrast, in adults, both sub-nephrotic and nephrotic-range proteinuria (Table 1) may be incidental findings on a routine urinalysis as adults develop overt nephrotic syndrome less frequently. In these patients, it is important for the initial clinical assessment to investigate possible causes of podocytopathies such as exposure to drugs and toxins, syndromic features, elevated body mass index, signs and symptoms of viral and bacterial infections, autoimmune disorders, and malignancy. Kidney ultrasonography may identify a reduced renal size, renal masses or malformations, or cystic disease, which more typically present with non-nephrotic proteinuria29,50 and are more prevalent in adults than in children. On the other hand, the onset of nephrotic syndrome with marked oedema, and sometimes anasarca, venous thrombosis or infections, should prompt investigation for a podocytopathy of immunological or genetic origin146,147. A positive sodium balance and hypertension are usually present in patients with podocytopathies146.
Kidney biopsy
In children with persistent non-nephrotic proteinuria, the decision about whether and when to proceed to kidney biopsy is controversial148. Many experts recommend close monitoring of blood pressure, protein excretion and GFR in children with a urinary protein excretion of <500 mg/m2 per day; if any of these parameters shows evidence of progressive disease, a kidney biopsy may be warranted149. Retrospective analyses suggest that children with sub-nephrotic proteinuria and a urinary protein to creatinine ratio of ≥0.5 g/g can have a podocytopathy, typically expressed as FSGS lesions150 (Fig. 7). By contrast, in patients with a urinary protein to creatinine ratio of <0.5 g/g, the risk of FSGS lesions at biopsy is low150,151. DMS shows a histological pattern of small, sclerosed glomeruli that have a reduced number of capillary loops with often prominent podocytes lining the tuft (Fig. 7) and is sometimes diagnosed in small children with genetic podocytopathies5. Biopsy is initially not performed in children with isolated nephrotic syndrome lacking other features because 75–80% of podocytopathies with minimal changes respond to standard steroid therapy with complete remission6,152. In addition, the response to initial steroid therapy is a better predictor of long-term prognosis than the results of kidney renal biopsy6,152. In those 10–20% of children with idiopathic nephrotic syndrome who do not respond to steroids, a kidney biopsy shows minimal change lesions (Fig. 7) in 25% and FSGS lesions in most others6,152.
As the differential diagnosis of proteinuric nephropathies in adults is broad, kidney biopsy is generally performed in all adults presenting with nephrotic-range proteinuria to guide management and provide a prognosis. Common biopsy findings suggesting a podocytopathy include minimal change lesions, FSGS lesions and collapsing glomerulopathy (Fig. 7). Podocytopathies can be distinguished from other glomerular diseases based on the light microscopy appearance and immunoglobulin staining; electron microscopy provides additional information about the extent of FPE and abnormalities of the glomerular basement membrane. A detailed differential diagnosis of the type of podocytopathy may require a family history, serological testing and imaging exams as well as, in some cases, genetic analyses.
Genetic testing
Genetic testing is highly advised in all children or young adults (<30 years of age) who do not respond to a course of glucocorticoids (Fig. 8) because, in these individuals, the possibility of making a molecular diagnosis of a genetic disorder can reach 30–60%65,67,68. The proportion of patients newly diagnosed with genetic podocytopathies declines with age at onset. Nevertheless, pathogenetic mutations occur in 14–21% of adults with steroid-resistant glomerular disorders and, therefore, genetic testing is warranted in adults with treatment-resistant proteinuria68,153,154 (Fig. 9). A family history of kidney disease and syndromic features should also trigger genetic testing155. Next-generation sequencing with computational filtering for a panel of all known genes causing podocytopathies plus collagen genes has a diagnostic rate of ~30%64,65,67,68,145.
Genetic variants in >50 nuclear and mitochondrial genes have been associated with FSGS and most cases are resistant to steroid therapy65,67,156. Inheritance patterns include autosomal recessive, autosomal dominant and sex-linked. Genetic causes of FSGS can be identified using gene panel testing, which involves resequencing a limited set of genes in which mutations are known to cause a podocytopathy. The gene panels may differ by age of podocytopathy onset. This approach has the advantages of being relatively fast, requiring a fairly simple consent form and having results that can often be conveyed by a nephrologist. Alternatively, whole-exome sequencing yields copious amounts of data, including on novel variants in genes associated in podocytopathies and novel variants in genes not previously associated with podocytopathies. Expanding the analysis for other genetic syndromes reported to occasionally present with isolated SRNS (that is, as phenocopies of podocytopathies) can double the diagnostic rate to 60%65. In these patients, re-evaluation of the patient and their family upon indication of genetic testing is mandatory to establish the correct diagnosis65. Thus, whole-exome sequencing is now the first choice in every centre where this analysis is possible for an isolated case or the first case in a family. However, the correct interpretation of variants of unknown clinical significance or in unexpected genes remains challenging and patients need to be counselled about the possibility of genetic diagnoses unrelated to kidney disease.
A different approach to African Americans with FSGS on kidney biopsy is warranted, as 72% of these individuals have two copies of APOL1 renal risk alleles. For these individuals, it makes sense to proceed directly to APOL1 testing for the G1 and G2 variant alleles.
Management
Progressive CKD is infrequent in children or adults with minimal change lesions6,152 but it is common among those with a podocytopathy, persistent proteinuria and FSGS lesions157. Response to glucocorticoids is critical in defining patient subsets158 and prognosis156, as those who achieve remission (75–92% with minimal change lesions146,159 and 47–66% in those with FSGS lesions160) do not usually develop ESKD161. Conversely, resistance to steroids is the strongest independent predictor of kidney function decline, with a kidney survival of 30% at 10 years from diagnosis. Massive proteinuria, impaired kidney function and interstitial fibrosis with tubular atrophy on kidney biopsy are also associated with progression to ESKD162,163. The prognosis of patients with a genetic podocytopathy is generally poor, with >50% of patients developing ESKD within 5 years of the diagnosis; patients who lack a genetic cause of the disease have a better prognosis, particularly when they are responsive to immunosuppressive treatment65,164. In syndromic podocytopathies, the overall prognosis is also affected by extrarenal manifestations; the prognosis reflects that of the underlying disorder65. Recently, a novel subset of patients has challenged the concept that podocytopathies with a defined genetic cause have a poor prognosis. For example, C-terminal CUBN pathogenetic variants, although associated with FSGS at biopsy, are characterized with albuminuria and normal GFR in large population-based cohorts, even in the absence of response to immunosuppressive treatments and to angiotensin-converting enzyme inhibitors165.
Current guidelines rely on clinical trial evidence and adhere to a ‘one-fits-all’ concept. However, it is becoming evident that, beyond the initial treatment with steroids, a substantial proportion of patients with podocytopathies needs a personalized approach to avoid drug toxicity from unnecessary medications and to apply specific treatments64,65,72,73,164,166. As personalized medicine for podocytopathies has only recently been in development, we will first describe the traditional approach.
Non-nephrotic proteinuria
Children and adults with persistent, non-nephrotic proteinuria are treated with a RASi and salt restriction157, which are frequently effective even in patients with maladaptive podocytopathies with FSGS lesions167. A low-dose thiazide diuretic (such as hydrochlorothiazide) will potentiate the anti-proteinuric effect of these therapies and may be tolerated even in normotensive patients. Such secondary podocytopathies require treatment of the underlying disorder whenever available (Figs 8,9).
New-onset nephrotic syndrome
Oral steroid therapy for at least 2–3 months is typically initiated with new-onset nephrotic syndrome without histological confirmation by kidney biopsy in children and adolescents, in patients without hypertension, gross haematuria or marked elevation in serum creatinine, in patients with normal complement levels, and in patients with no extrarenal symptoms168. Approximately 80–90% of patients will experience complete remission within the 4 weeks of initiating therapy169 but some centres also administer three intravenous pulses of methylprednisolone every other day at this point169. Patients who do not undergo complete remission (and perhaps those with only a modest partial remission) are categorized as having SRNS and require prompt kidney biopsy and genetic testing170,171. Only 30% of children with SSNS maintain remission, 10–20% will have fewer than four relapses and the remaining will have frequent relapses (frequently relapsing nephrotic syndrome, FRNS) or will relapse while on a steroid taper (SDNS). The doses and length of treatment are personalized for each child as the clinical behaviour and response to steroids are heterogeneous (Fig. 8).
In adults, kidney biopsy at the time of presentation and identification of the underlying cause of the podocytopathy are essential to guide treatment (Fig. 9). In cases in which a specific cause cannot be identified, glucocorticoids represent the first-choice treatment157. Recommended regimens158 derive from paediatric trials as only few adequately powered studies in adults are available172,173,174. Response to therapy is typically slower in adults than in children, justifying prolonged steroid courses before defining treatment failure. Mycophenolate mofetil (an immunosuppressant) combined with low-dose steroids may induce disease remission in adult podocytopathies at rates comparable with standard therapy175,176, possibly alleviating the risk of steroid-related adverse effects such as diabetes and hypertension in high-risk patients. Slow tapering of immunosuppressive drugs over 6 months is a widely accepted measure to reduce the risk of relapse177.
SDNS and FRNS
Approximately 80% of steroid-responsive children and 70% of adult patients178,179 undergo one or more relapses, which typically remain sensitive to steroids180,181. However, many patients become steroid dependent146 or experience frequent relapses182 (Table 1) after treatment discontinuation. The risk of relapse is greatest in children aged <5 years at onset, for reasons unknown. Almost all children with FRNS experience a progressive decrease in the number of relapses over time and many ultimately go into sustained or even permanent remission160,183. Limited long-term outcome data in adults suggests that patients who have frequent relapses or SDNS during childhood are at risk of experiencing relapses during adulthood and adverse drug effects183,184,185 (Table 2). Kidney function remains normal in adulthood as long as patients remain responsive to treatment and long-term sequelae are generally related to medication adverse effects184,185.
Various glucocorticoid regimens have been used to treat FRNS and SDNS186,187. Frequent relapses usually require steroid dose adjustment above the individual threshold. Alternate-day steroid dosing (in children) and steroid-sparing agents are commonly used to avoid long-term steroid toxicity. These agents include immunosuppressive drugs such as calcineurin inhibitors (ciclosporin or tacrolimus), rituximab, levamisole and cyclophosphamide. Calcineurin inhibitors are frequently chosen as steroid-sparing agents based on evidence from small trials188 despite relapse rates as high as 75% upon discontinuation. These events often lead to prolonged treatment courses, which pose a considerable risk of calcineurin inhibitor-induced nephrotoxicity (Table 2). An increasing number of studies strongly suggests that rituximab can effectively reduce the number of relapses in SDNS and FRNS85,86, minimizing the steroid dose, but relapses can occur after stopping rituximab.
Low-quality evidence supports the use of alkylating agents such as cyclophosphamide in SDNS and FRNS podocytopathies to reduce the cumulative dose of steroids146 but these regimens have been progressively abandoned in developed countries owing to their unfavourable safety profile (Table 2). In paediatric patients, mycophenolate mofetil seems equally as effective as levamisole189 but not as effective as ciclosporin in achieving remission190,191,192, although the evidence is still limited157. In addition, higher doses of mycophenolate mofetil than those used in kidney-transplanted recipients seem to be necessary in children with nephrotic syndrome to achieve remission192. Adrenocorticotropic hormone has been used but its efficacy is controversial because studies yielded conflicting results193,194. Finally, in a very small number of cases, patients who were initially steroid sensitive become steroid resistant but can be usually successfully treated with alternative immunosuppressive therapies195. However, these patients are at increased risk for ESKD195.
SRNS
Steroid resistance is defined as the lack of complete remission despite full-dose steroids for an adequate period of time (Figs 8,9). Screening for genetic mutations should be performed in all children as well as in adults with SRNS before considering additional immunosuppressive therapies as these are rarely effective in podocytopathies with a genetic cause. However, as genetic testing results take at least 4–6 weeks to become available, it may be appropriate to start a second-line therapy in selected patients in the interim. In patients in whom a genetic mutation is identified, immunosuppressive treatments can usually be discontinued and anti-proteinuric regimens with a RASi become the mainstay of therapy to attenuate CKD progression.
Approximately 60% of steroid-resistant patients may respond to ciclosporin or tacrolimus at moderate doses with reduced proteinuria and slower or halted CKD progression196. A genetic cause is usually not found in these patients65,67,156. As relapse is frequent after the withdrawal of these drugs196, prolonging treatment for 1–3 years after remission is achieved is advisable157. Mycophenolate mofetil alone achieves remission in fewer than half of patients197,198 but its use as maintenance treatment might reduce the calcineurin inhibitor dose and limit nephrotoxicity199. Thus, mycophenolate mofetil in combination with calcineurin inhibitors may be a rescue approach. The initial report of abatacept efficacy in treating SRNS182 was challenged by subsequent studies200,201 and the effect of other therapies such as rituximab202 and adalimumab (targeting TNF)203 seems to be limited, especially in adult patients. Instead of immunosuppression, SRNS requires rigorous control of glomerular hyperfiltration with a RASi and by reducing dietary salt. Recently, sparsentan, a dual endothelin type A (ETA) and angiotensin I type 1 receptor antagonist showed a robust anti-proteinuric effect in a phase II clinical trial compared with monotherapy with the angiotensin receptor blocker irbesartan204. In secondary podocytopathies, management is focused on treating the underlying disorder.
Personalized treatment
Genetic testing identifies the diagnosis underlying SRNS in up to 30–60% of children and young adults, and some of these patients may benefit from avoiding unnecessary immunosuppressant therapies and from receiving specific treatments65. For example, patients with pathogenetic mutations in coenzyme Q10 biosynthesis (COQ2, COQ6 and ADCK4) may respond to oral coenzyme Q10 supplementation72,73,166. Patients with pathogenetic mutations in collagen genes benefit from early diagnosis and administration of a RASi, while avoiding calcineurin inhibitors to prevent CKD progression154,205. Patients with Dent disease should be treated to avoid failure to thrive and kidney stones64,65,206. Similarly, patients with Fabry disease or cystinosis will likely benefit from early treatment, with enzyme replacement therapy or cysteamine depleting therapy, respectively65,207. Patients with pathogenetic mutations in exon 8 or 9 of WT1 will benefit from regular screening for Wilms tumour and some may undergo prophylactic nephrectomy208. In addition, some patients with moderate proteinuria may benefit from genetic testing. For example, early recognition of patients with C-terminal CUBN pathogenetic variants is paramount as they tend to have a good prognosis without any treatment165. This underscores the need to personalize the diagnosis of distinct types of podocytopathies owing to the important implications for prognosis and treatment.
Complications
Nephrotic syndrome requires additional treatment for symptoms and to prevent complications.
Oedema
Patients are initially treated with loop diuretics and dietary sodium restriction to ~2 g per day and are monitored closely for clinical signs of hypovolaemia209. Most patients require high doses of diuretics owing to hypoalbuminaemia, expanded extracellular volume (larger volume of drug distribution) and a slower rate of delivery to the target cells within the kidney210. Thiazide diuretics or, alternatively, triamterene 211 or acetazolamide212 can be combined with loop diuretics in patients with refractory oedema. As proteasuria activates the amiloride-sensitive epithelial sodium channel, amiloride can also be useful213,214.
Dyslipidaemia
Hyperlipidaemia is problematic in patients with nephrotic proteinuria as it increases the risk for progressive loss of renal function and cardiovascular disease135. Statins are the treatment of choice if hyperlipidaemia persists after treatment of the underlying kidney disorder with immunosuppressive therapy and/or a RASi135,215. Drug interactions, for example, with cytochrome P3A4 inhibitors such as cyclosporin, increase plasma levels of statins and require dose adaptations of the statins. Pro-protein convertase subtilisin/kexin type 9 (PCSK9) inhibitors may have a role when statins are insufficient or are not tolerated but these agents are currently very expensive135.
Thromboembolism
Adults with nephrotic syndrome have a high incidence (10–40%) of arterial and venous thrombosis, particularly deep vein and renal vein thrombosis, in some cases leading to pulmonary embolism216. By contrast, venous and arterial thromboses are reported in only 2–3% of children with nephrotic syndrome, although this may be an underestimate because many episodes are asymptomatic217. Venous thrombosis, particularly of the renal vein, deep leg veins, inferior vena cava and cerebral vein, account for most cases217. Thromboses of the pulmonary, femoral, iliac, cerebral and meningeal arteries are less common218. Adults and infants with congenital nephrotic syndrome are at increased risk for renal vein thrombosis but this complication is rare in children218. Pulmonary embolism should be suspected in patients with pulmonary or cardiovascular symptoms and can be confirmed by radioisotope scanning219. Prophylactic anticoagulation with oral anticoagulants is recommended only after the first thromboembolic episode or when albumin concentration is <2 g/dl, fibrinogen is >6 g/l or antithrombin III is <70% of normal, and is continued for as long as these alterations persist220.
Infections
To prevent pneumococcal infections, children with nephrotic syndrome should receive 1–2 doses of conjugate 13-valent pneumococcal vaccine (PCV13) preceding the 23-valent polysaccharide (PPSV23) pneumococcal vaccine, if not previously immunized. Varicella can also cause major morbidity and mortality in these patients221. Adults with nephrotic proteinuria who have not been previously immunized should receive both pneumococcal vaccines, with PCV13 followed 8 weeks later by PPSV23.
Although the use of live attenuated viral vaccines has been discouraged in the past for children receiving immunosuppressive therapy, a recent prospective study suggested that two doses of varicella vaccine can be safely administered to children with a CD4+ T cell count of >500/mm3, a normal lymphocyte blast transformation in response phytohemagglutinin (to assess cell-mediated immune responses), and serum IgG levels of >300 mg/dl (ref.222).
Centre-specific guidelines on influenza vaccination should be followed. In general, vaccinations pose a minimal risk for relapse of nephrotic syndrome; further, the protection gained greatly outweighs this risk222.
Relapse after transplantation
Up to one-third of patients with FSGS lesions at biopsy who undergo kidney transplantation show recurrent nephrotic syndrome in the allograft223. The strongest predictive clinical feature of relapse for patients who undergo kidney transplantation is a previous response to steroids or immunosuppressive drugs for the nephrotic syndrome that caused ESKD223. This finding suggests that the podocytopathy is related to one or several immunological or circulating factors. A younger age at diagnosis, severe hypoalbuminaemia and rapid progression to ESKD (for example, within 3 years of diagnosis) are also more common in patients who experience recurrence after transplantation. Apolipoprotein A-Ib, a high-molecular-weight form of apolipoprotein A-I, was recently proposed as a possible biomarker for recurrent forms of podocytopathies after kidney transplantation224. Typically, relapses occur in the first 2 weeks after kidney transplantation and often respond to combined treatment with plasma exchange, rituximab and intensified immunosuppression, although the response may be transient225,226. Post-transplantation relapses are exceptional in those with a definite genetic diagnosis or with forms of podocytopathies related to increased single-nephron GFR or a low nephron mass226,227.
Quality of life
The symptoms of nephrotic syndrome and the relapsing nature of most podocytopathies greatly compromise the quality of life of patients and their families. In general, patient-reported questionnaires identify oedema as the symptom that most negatively affects the quality of life228. Certain patients are at higher risk of developing drug-related adverse events linked to dose and length of exposure229,230. In steroid-dependent patients, the adverse effects of steroids frequently occur with long-term exposure (that is, prednisone doses of >5 mg per day for ≥3 months)231. These adverse events include cataracts, delayed growth in children, obesity, Cushingoid features, osteoporosis and psychological disturbances232,233. In adolescents, steroid-induced striae rubrae (stretch marks) and ciclosporin-related hypertrichosis (hair growth) can greatly affect self-confidence and mood234. Aesthetic medicine interventions and psychological support can improve these psychosocial impacts. In multidrug-resistant patients, nephrotoxicity from the prolonged use of calcineurin inhibitors may contribute to CKD progression and ESKD229.
For patients with ESKD, dialysis (peritoneal dialysis, centre haemodialysis or home-haemodialysis) negatively affects the quality of life235. However, when patients reach ESKD, oedema and other symptoms of nephrotic syndrome typically improve because urinary protein losses decline and finally cease with progressive oligo-anuria. Kidney transplantation can improve the quality of life and longevity in these patients164,236. However, the recurrence of nephrotic syndrome after transplantation is an important risk factor for allograft loss and the need to return to dialysis223, with a major negative effect on quality of life and increasing the need for psychological support.
Outlook
The concept of ‘podocytopathies’ replacing DMS, FSGS, minimal changes and collapsing glomerulopathy as clinical entities is based on research and will continue to evolve. Indeed, with recent advances in our understanding of molecular and cellular mechanisms, the time is now to move from histologically defined entities of proteinuria to identifying and treating each patient’s podocytopathy. Each podocytopathy arises from some combination of genetic, epigenetic, transcriptional, proteomic, physiological, metabolic, immunological, viral and, possibly, psychological factors — and perhaps other factors that we do not yet appreciate.
Mechanisms
Knowledge about the genetic basis of glomerular disease is rapidly evolving and has generated new opportunities as well as new challenges for clinicians and patients. Close contact between clinicians and geneticists are neither available everywhere nor are genetic evaluations always affordable. These limitations imply that patients with SRNS are not being treated optimally in every region and may have to travel longer distances to reach a specialized centre. Access to geneticists is important, for example, when trying to interpret the clinical relevance of genetic test results, including the many ‘variants of unknown significance’. The rapidly increasing knowledge of human genetics has clearly given rise to the need for genetically oriented nephrologists or nephrogeneticists, similar to nephropathologists, to follow the latest advances in data and interpretation in a highly dynamic field. Initiatives like ClinGen and ClinVar, US NIH-funded initiatives dedicated to building a central resource, can define the clinical relevance of genes and variants for use in precision medicine and research and will make access to genetic information more readily and widely available.
Diagnosis
The promise of personalized diagnosis and management puts into question several aspects of the traditional morphology-based disease classifications and guideline-based patient management. Genetic testing may provide a precise molecular diagnosis and protect the patient from unnecessary immunosuppressive treatments. However, a genetic diagnosis may generate new questions for families, including whether to test other family members. Benefits of genetic testing include the opportunity for early diagnosis through screening and for selecting the optimal therapy. Risks include anxiety about test results, access to health insurance in some countries and the possibility of unexpected information about biological relationships among family members. The universal right to not know, especially for clinically unaffected family members, should be respected.
Big data
We need to better understand the primary nephrotic diseases at the molecular, cellular and clinical levels, addressing the symptoms, signs and effects on physical function and psychosocial well-being in a holistic approach. In the past decade, extensive resources have been brought to bear on these issues, including investigator and patient efforts, to answer questions not yet satisfactorily addressed by single-centre studies. The Nephrotic Syndrome Study Network (NEPTUNE) brings together investigators from throughout North America to enrol children and adults with nephrotic syndrome, currently numbering >500 patients, in a long-term natural history study that encompasses clinical, genetic, transcriptional, proteomic and metabolomic approaches to understand the pathogenesis, to enable testing of novel therapies and to determine the optimal treatment strategies237. The Cure Glomerulopathy (CureGN) consortium brings together investigators from 70 sites, predominantly in the United States as well as in Canada and Europe, with a mandate to enrol 2,400 children and adults with prevalent glomerular diseases, including minimal changes, FSGS, membranous nephropathy and IgA nephropathy, for prospective natural history studies238. Both studies will serve as valuable platforms to develop new knowledge, to bring new investigators into the nephrotic syndrome field and to provide training to the next generation of researchers.
In Europe, the European Rare Kidney Disease Reference Network (ERKNet), a virtual network involving health-care providers across Europe co-funded by the European Commission, was founded with the aim to facilitate discussion on complex or rare renal diseases and conditions that require highly specialized treatment, concentrated knowledge and resources. The ERKnet has facilitated the exchange of information between nephrologists in Europe and permits the review of patients’ diagnoses and treatments by virtual advisory panels of medical specialists across different disciplines, using a dedicated platform and telemedicine tools.
Pharmaceutical and biotechnology companies have shown increasing interest in developing novel therapies for podocyte disorders and will be the major source of the development of innovative therapies. Governmental funding agencies are essential partners. Patient organizations have an important role as they are highly motivated by the unmet medical needs and are strong advocates for the relevance of patient-oriented outcomes; they play essential and formal parts in the NEPTUNE and CureGN studies mentioned above. In nephrology, patient groups, including NephCure, the American Kidney Fund, the National Organization for Rare Disorders, the National Kidney Foundation, the Dutch Kidney Foundation, the Federation for Each Renal Genetic Disease, the Nephrotic Syndrome Association Italy, and La Nuova Speranza non-profit foundation, have served as powerful and compelling ambassadors, sources of research funding, and supporters of scientific meetings that stimulate international exchange and collaborations.
Management
Given the value of rituximab as a treatment in SSNS and immune-mediated podocytopathies, other CD20-targeting or B cell-targeting drugs are being considered. Ofatumumab is a more potent CD20+ B cell depleter and may replace rituximab in patients with drug hypersensitivity88,239. Another agent, belimumab (which targets B cell-activating factor), is an established maintenance therapy in systemic lupus erythematosus and reduces proteinuria in lupus nephritis240 and might control B cell activity also in other forms of nephrotic syndrome.
Many attempts to find new treatments for podocytopathies beyond the traditional immunosuppressive drugs have been unsuccessful. One likely contributing factor is the fact that patients in clinical trials were stratified based on unspecific pathological patterns; in reality, these individuals likely had diverse disorders and potentially required specific therapeutic approaches. Successful trials will possibly require the selection of agents that target specific molecular pathways shown to be altered in the underlying podocytopathy, with enrolment of only those patients who manifest alterations in these pathways. We do not yet have all the tools needed to make such selections but some approaches for selection include genetic studies, kidney transcription profiling and urinary single-cell transcriptional profiling. Encouragingly, several clinical trials for podocytopathies are ongoing (Table 3).
Another high priority is to develop specific podocyte-directed therapies to protect podocytes from injury, detachment and loss. These strategies include stem cell therapy for genetic disorders, the use of genetically modified cells, induced pluripotent stem cells, small interfering RNA therapeutics and other approaches, although none has reached the domain of clinical podocytopathies. Intriguingly, a recent study reported that lowering APOL1 expression using antisense oligonucleotides significantly ameliorated kidney disease in a transgenic animal model of APOL1 podocytopathy117.
Another promising area is the promotion of cell regeneration. The discovery that lost podocytes are potentially replaceable from a pool of local progenitor cells within the parietal epithelial cells is raising new hope to stimulate that system therapeutically, especially in non-genetic podocytopathies53,62. To avoid unwanted effects in other progenitor cell niches, such an appropriate drug target should be specific for podocyte progenitors. Whether such treatments would increase the risk of kidney cancer is currently unknown and will be an important consideration.
In conclusion, this is an exciting era for podocytopathy research and clinical care. New therapies to slow and possibly halt the progression of podocyte injury are in clinical trials and, in the future, therapies to stimulate podocyte regeneration may become available. Renewed energy from patients and patient organizations, academic researchers, pharmaceutical and biotechnology companies, and government agencies is spurring collaboration to develop novel, safe and effective therapies for patients with podocytopathies.
References
Pallet, N. et al. Proteinuria typing: how, why and for whom? Ann. Biol. Clin. 77, 13–25 (2019).
Sethi, S., Glassock, R. J. & Fervenza, F. C. Focal segmental glomerulosclerosis: towards a better understanding for the practicing nephrologist. Nephrol. Dial. Transpl. 30, 375–384 (2015).
Muller-Deile, J., Schenk, H. & Schiffer, M. Minimal change disease and focal segmental glomerulosclerosis. Internist 60, 450–457 (2019).
Rosenberg, A. Z. & Kopp, J. B. Focal segmental glomerulosclerosis. Clin. J. Am. Soc. Nephrol. 12, 502–517 (2017).
Barisoni, L., Schnaper, H. W. & Kopp, J. B. A proposed taxonomy for the podocytopathies: a reassessment of the primary nephrotic diseases. Clin. J. Am. Soc. Nephrol. 2, 529–542 (2007). This paper is the first proposal for the reclassification of podocytopathies.
Vivarelli, M., Massella, L., Ruggiero, B. & Emma, F. Minimal change disease. Clin. J. Am. Soc. Nephrol. 12, 332–345 (2017).
Wiggins, R. C. The spectrum of podocytopathies: a unifying view of glomerular diseases. Kidney Int. 71, 1205–1214 (2007).
Sim, J. J. et al. Distribution of biopsy-proven presumed primary glomerulonephropathies in 2000-2011 among a racially and ethnically diverse US population. Am. J. Kidney Dis. 68, 533–544 (2016).
Pesce, F. & Schena, F. P. Worldwide distribution of glomerular diseases: the role of renal biopsy registries. Nephrol. Dial. Transpl. 25, 334–336 (2010).
Qiu, C. et al. Renal compartment-specific genetic variation analyses identify new pathways in chronic kidney disease. Nat. Med. 24, 1721–1731 (2018).
Gbadegesin, R. A. et al. HLA-DQA1 and PLCG2 are candidate risk loci for childhood-onset steroid-sensitive nephrotic syndrome. J. Am. Soc. Nephrol. 26, 1701–1710 (2015).
Debiec, H. et al. Transethnic, genome-wide analysis reveals immune-related risk alleles and phenotypic correlates in pediatric steroid-sensitive nephrotic syndrome. J. Am. Soc. Nephrol. 29, 2000–2013 (2018).
Dufek, S. et al. Genetic identification of two novel loci associated with steroid-sensitive nephrotic syndrome. J. Am. Soc. Nephrol. 30, 1375–1384 (2019).
Jia, X. et al. Strong association of the HLA-DR/DQ locus with childhood steroid-sensitive nephrotic syndrome in the Japanese population. J. Am. Soc. Nephrol. 29, 2189–2199 (2018).
Parsa, A. et al. APOL1 risk variants, race, and progression of chronic kidney disease. N. Engl. J. Med. 369, 2183–2196 (2013).
Genovese, G. et al. Association of trypanolytic ApoL1 variants with kidney disease in African Americans. Science 329, 841–845 (2010).
Tzur, S. et al. Missense mutations in the APOL1 gene are highly associated with end stage kidney disease risk previously attributed to the MYH9 gene. Hum. Genet. 128, 345–350 (2010).
Siemens, T. A., Riella, M. C., Moraes, T. P. & Riella, C. V. APOL1 risk variants and kidney disease: what we know so far. J. Bras. Nefrol. 40, 388–402 (2018).
Abd ElHafeez, S. et al. Prevalence and burden of chronic kidney disease among the general population and high-risk groups in Africa: a systematic review. BMJ Open 8, e015069 (2018).
Tedla, F. M. & Yap, E. Apolipoprotein L1 and kidney transplantation. Curr. Opin. Organ. Transpl. 24, 97–102 (2019).
Beckerman, P. & Susztak, K. APOL1: the balance imposed by infection, selection, and kidney disease. Trends Mol. Med. 24, 682–695 (2018).
Beckerman, P. et al. Transgenic expression of human APOL1 risk variants in podocytes induces kidney disease in mice. Nat. Med. 23, 429–438 (2017).
Fogo, A. et al. Accuracy of the diagnosis of hypertensive nephrosclerosis in African Americans: a report from the African American Study of Kidney Disease (AASK) Trial. AASK Pilot Study Investigators. Kidney Int. 51, 244–252 (1997).
Hodgin, J. B. et al. Glomerular aging and focal global glomerulosclerosis: a podometric perspective. J. Am. Soc. Nephrol. 26, 3162–3178 (2015).
Lasagni, L., Lazzeri, E., Shankland, S. J., Anders, H. J. & Romagnani, P. Podocyte mitosis - a catastrophe. Curr. Mol. Med. 13, 13–23 (2013).
Freedman, B. I. & Cohen, A. H. Hypertension-attributed nephropathy: what’s in a name? Nat. Rev. Nephrol. 12, 27–36 (2016). An extensive critical reassessment of the role of APOL1 not only in FSGS but also in hypertension-attributed nephropathy.
Bick, A. G. et al. Association of APOL1 risk alleles with cardiovascular disease in blacks in the Million Veteran Program. Circulation 140, 1031–1040 (2019).
Burton, J. O. et al. Association of anthropometric obesity measures with chronic kidney disease risk in a non-diabetic patient population. Nephrol. Dial. Transpl. 27, 1860–1866 (2012).
Praga, M. et al. Clinical features and long-term outcome of obesity-associated focal segmental glomerulosclerosis. Nephrol. Dial. Transpl. 16, 1790–1798 (2001).
Xu, T., Sheng, Z. & Yao, L. Obesity-related glomerulopathy: pathogenesis, pathologic, clinical characteristics and treatment. Front. Med. 11, 340–348 (2017).
Kriz, W. & Lemley, K. V. Potential relevance of shear stress for slit diaphragm and podocyte function. Kidney Int. 91, 1283–1286 (2017).
D’Agati, V. D. et al. Obesity-related glomerulopathy: clinical and pathologic characteristics and pathogenesis. Nat. Rev. Nephrol. 12, 453–471 (2016).
Tonneijck, L. et al. Glomerular hyperfiltration in diabetes: mechanisms, clinical significance, and treatment. J. Am. Soc. Nephrol. 28, 1023–1039 (2017).
Vallon, V. & Thomson, S. C. The tubular hypothesis of nephron filtration and diabetic kidney disease. Nat. Rev. Nephrol. https://doi.org/10.1038/s41581-020-0256-y (2020).
Novick, A. C., Gephardt, G., Guz, B., Steinmuller, D. & Tubbs, R. R. Long-term follow-up after partial removal of a solitary kidney. N. Engl. J. Med. 325, 1058–1062 (1991).
Argueso, L. R. et al. Prognosis of patients with unilateral renal agenesis. Pediatr. Nephrol. 6, 412–416 (1992).
Luyckx, V. A. et al. A developmental approach to the prevention of hypertension and kidney disease: a report from the Low Birth Weight and Nephron Number Working Group. Lancet 390, 424–428 (2017). A position paper that supports the essential role of nephron mass in determining the risk for FSGS and CKD.
Aygun, B., Mortier, N. A., Smeltzer, M. P., Hankins, J. S. & Ware, R. E. Glomerular hyperfiltration and albuminuria in children with sickle cell anemia. Pediatr. Nephrol. 26, 1285–1290 (2011).
Chen, Y. T., Coleman, R. A., Scheinman, J. I., Kolbeck, P. C. & Sidbury, J. B. Renal disease in type I glycogen storage disease. N. Engl. J. Med. 318, 7–11 (1988).
Morgan, C., Al-Aklabi, M. & Garcia Guerra, G. Chronic kidney disease in congenital heart disease patients: a narrative review of evidence. Can. J. Kidney Health Dis. 2, 27 (2015).
Schwimmer, J. A. et al. Secondary focal segmental glomerulosclerosis in non-obese patients with increased muscle mass. Clin. Nephrol. 60, 233–241 (2003).
Mundel, P. & Shankland, S. J. Podocyte biology and response to injury. J. Am. Soc. Nephrol. 13, 3005–3015 (2002).
Falkenberg, C. V. et al. Fragility of foot process morphology in kidney podocytes arises from chaotic spatial propagation of cytoskeletal instability. PLoS Comput. Biol. 13, e1005433 (2017).
Lin, J. S. & Susztak, K. Podocytes: the weakest link in diabetic kidney disease? Curr. Diab Rep. 16, 45 (2016).
Susztak, K., Raff, A. C., Schiffer, M. & Bottinger, E. P. Glucose-induced reactive oxygen species cause apoptosis of podocytes and podocyte depletion at the onset of diabetic nephropathy. Diabetes 55, 225–233 (2006).
Kriz, W. & Lemley, K. V. Mechanical challenges to the glomerular filtration barrier: adaptations and pathway to sclerosis. Pediatr. Nephrol. 32, 405–417 (2017).
Endlich, K., Kliewe, F. & Endlich, N. Stressed podocytes-mechanical forces, sensors, signaling and response. Pflug. Arch. 469, 937–949 (2017).
Sweetwyne, M. T. et al. Notch1 and Notch2 in podocytes play differential roles during diabetic nephropathy development. Diabetes 64, 4099–4111 (2015).
Jefferson, J. A. & Shankland, S. J. The pathogenesis of focal segmental glomerulosclerosis. Adv. Chronic Kidney Dis. 21, 408–416 (2014).
De Vriese, A. S., Sethi, S., Nath, K. A., Glassock, R. J. & Fervenza, F. C. Differentiating primary, genetic, and secondary FSGS in adults: a clinicopathologic approach. J. Am. Soc. Nephrol. 29, 759–774 (2018). A critical reappraisal of diagnostic criteria for the recognition of many forms of podocytopathies.
Nishizono, R. et al. FSGS as an adaptive response to growth-induced podocyte stress. J. Am. Soc. Nephrol. 28, 2931–2945 (2017).
Ronconi, E. et al. Regeneration of glomerular podocytes by human renal progenitors. J. Am. Soc. Nephrol. 20, 322–332 (2009).
Romoli, S. et al. CXCL12 blockade preferentially regenerates lost podocytes in cortical nephrons by targeting an intrinsic podocyte-progenitor feedback mechanism. Kidney Int. 94, 1111–1126 (2018).
Kaverina, N. V. et al. Dual lineage tracing shows that glomerular parietal epithelial cells can transdifferentiate toward the adult podocyte fate. Kidney Int. 96, 597–611 (2019).
Eng, D. G. et al. Glomerular parietal epithelial cells contribute to adult podocyte regeneration in experimental focal segmental glomerulosclerosis. Kidney Int. 88, 999–1012 (2015).
Dai, Y. et al. Retinoic acid improves nephrotoxic serum-induced glomerulonephritis through activation of podocyte retinoic acid receptor alpha. Kidney Int. 92, 1444–1457 (2017).
Zhang, J. et al. Retinoids augment the expression of podocyte proteins by glomerular parietal epithelial cells in experimental glomerular disease. Nephron Exp. Nephrol. 121, e23–e37 (2012).
Peired, A. et al. Proteinuria impairs podocyte regeneration by sequestering retinoic acid. J. Am. Soc. Nephrol. 24, 1756–1768 (2013).
Kumar, V. & Singhal, P. C. APOL1 and kidney cell function. Am. J. Physiol. Renal Physiol. 317, F463–F477 (2019).
Melica, M. E. et al. Substrate stiffness modulates renal progenitor cell properties via a ROCK-mediated mechanotransduction mechanism. Cells 8, 1561 (2019).
Niranjan, T. et al. The Notch pathway in podocytes plays a role in the development of glomerular disease. Nat. Med. 14, 290–298 (2008).
Lasagni, L. et al. Podocyte regeneration driven by renal progenitors determines glomerular disease remission and can be pharmacologically enhanced. Stem Cell Rep. 5, 248–263 (2015). A proof-of-concept study that shows podocyte regeneration occurs after damage and can be pharmacologically enhanced.
Smeets, B. et al. Renal progenitor cells contribute to hyperplastic lesions of podocytopathies and crescentic glomerulonephritis. J. Am. Soc. Nephrol. 20, 2593–2603 (2009).
Warejko, J. K. et al. Whole exome sequencing of patients with steroid-resistant nephrotic syndrome. Clin. J. Am. Soc. Nephrol. 13, 53–62 (2018).
Landini, S. et al. Reverse phenotyping after whole-exome sequencing in steroid-resistant nephrotic syndrome. Clin. J. Am. Soc. Nephrol. (2019). A study reporting the high prevalence of genetic cases caused by unrecognized syndromic disorders in up to 60% of patients with SRNS.
Assady, S., Wanner, N., Skorecki, K. L. & Huber, T. B. New insights into podocyte biology in glomerular health and disease. J. Am. Soc. Nephrol. 28, 1707–1715 (2017).
Giglio, S. et al. Heterogeneous genetic alterations in sporadic nephrotic syndrome associate with resistance to immunosuppression. J. Am. Soc. Nephrol. 26, 230–236 (2015).
Sadowski, C. E. et al. A single-gene cause in 29.5% of cases of steroid-resistant nephrotic syndrome. J. Am. Soc. Nephrol. 26, 1279–1289 (2015). A large-scale study reporting the presence of primary genetic podocytopathies in 29.5% of cases of SRNS.
van der Ven, A. T. et al. Whole-exome sequencing identifies causative mutations in families with congenital anomalies of the kidney and urinary tract. J. Am. Soc. Nephrol. 29, 2348–2361 (2018).
Ashraf, S. et al. Mutations in six nephrosis genes delineate a pathogenic pathway amenable to treatment. Nat. Commun. 9, 1960 (2018).
Dorval, G. et al. Clinical and genetic heterogeneity in familial steroid-sensitive nephrotic syndrome. Pediatr. Nephrol. 33, 473–483 (2018).
Doimo, M. et al. Effect of vanillic acid on COQ6 mutants identified in patients with coenzyme Q10 deficiency. Biochim. Biophys. Acta 1842, 1–6 (2014).
Atmaca, M. et al. Follow-up results of patients with ADCK4 mutations and the efficacy of CoQ10 treatment. Pediatr. Nephrol. 32, 1369–1375 (2017).
Boyer, O. et al. INF2 mutations in Charcot-Marie-Tooth disease with glomerulopathy. N. Engl. J. Med. 365, 2377–2388 (2011).
Nozu, K. et al. A review of clinical characteristics and genetic backgrounds in Alport syndrome. Clin. Exp. Nephrol. 23, 158–168 (2019).
Yoo, T. H. & Fornoni, A. Nonimmunologic targets of immunosuppressive agents in podocytes. Kidney Res. Clin. Pract. 34, 69–75 (2015).
Shalhoub, R. J. Pathogenesis of lipoid nephrosis: a disorder of T-cell function. Lancet 2, 556–560 (1974).
Kemper, M. J., Zepf, K., Klaassen, I., Link, A. & Muller-Wiefel, D. E. Changes of lymphocyte populations in pediatric steroid-sensitive nephrotic syndrome are more pronounced in remission than in relapse. Am. J. Nephrol. 25, 132–137 (2005).
Shao, X. S. et al. The prevalence of Th17 cells and FOXP3 regulate T cells (Treg) in children with primary nephrotic syndrome. Pediatr. Nephrol. 24, 1683–1690 (2009).
Araya, C. E. et al. A case of unfulfilled expectations. Cytokines in idiopathic minimal lesion nephrotic syndrome. Pediatr. Nephrol. 21, 603–610 (2006).
Lai, K. W. et al. Overexpression of interleukin-13 induces minimal-change-like nephropathy in rats. J. Am. Soc. Nephrol. 18, 1476–1485 (2007).
Liu, L. L. et al. Th17/Treg imbalance in adult patients with minimal change nephrotic syndrome. Clin. Immunol. 139, 314–320 (2011).
Tsuji, S. et al. Regulatory T cells and CTLA-4 in idiopathic nephrotic syndrome. Pediatr. Int. 59, 643–646 (2017).
Hashimura, Y. et al. Minimal change nephrotic syndrome associated with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome. Pediatr. Nephrol. 24, 1181–1186 (2009).
Iijima, K. et al. Rituximab for childhood-onset, complicated, frequently relapsing nephrotic syndrome or steroid-dependent nephrotic syndrome: a multicentre, double-blind, randomised, placebo-controlled trial. Lancet 384, 1273–1281 (2014).
Ruggenenti, P. et al. Rituximab in steroid-dependent or frequently relapsing idiopathic nephrotic syndrome. J. Am. Soc. Nephrol. 25, 850–863 (2014). A study establishing the efficacy of rituximab for treatment of FRNS.
Fornoni, A. et al. Rituximab targets podocytes in recurrent focal segmental glomerulosclerosis. Sci. Transl Med. 3, 85ra46 (2011).
Bonanni, A., Rossi, R., Murtas, C. & Ghiggeri, G. M. Low-dose ofatumumab for rituximab-resistant nephrotic syndrome. BMJ Case Rep. 2015, bcr2015210208 (2015).
Kim, A. H. et al. B cell-derived IL-4 acts on podocytes to induce proteinuria and foot process effacement. JCI Insight 2, e81836 (2017).
Dantal, J. et al. Antihuman immunoglobulin affinity immunoadsorption strongly decreases proteinuria in patients with relapsing nephrotic syndrome. J. Am. Soc. Nephrol. 9, 1709–1715 (1998).
Bhatia, D. et al. Rituximab modulates T- and B-lymphocyte subsets and urinary CD80 excretion in patients with steroid-dependent nephrotic syndrome. Pediatr. Res. 84, 520–526 (2018).
Colucci, M. et al. Atypical IgM on T cells predict relapse and steroid dependence in idiopathic nephrotic syndrome. Kidney Int. 96, 971–982 (2019).
Savin, V. J. et al. Circulating factor associated with increased glomerular permeability to albumin in recurrent focal segmental glomerulosclerosis. N. Engl. J. Med. 334, 878–883 (1996).
Ali, A. A. et al. Minimal-change glomerular nephritis. Normal kidneys in an abnormal environment? Transplantation 58, 849–852 (1994).
Delville, M. et al. A circulating antibody panel for pretransplant prediction of FSGS recurrence after kidney transplantation. Sci. Transl Med. 6, 256ra136 (2014).
Wei, C. et al. Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis. Nat. Med. 17, 952–960 (2011).
Hahm, E. et al. Bone marrow-derived immature myeloid cells are a main source of circulating suPAR contributing to proteinuric kidney disease. Nat. Med. 23, 100–106 (2017).
Maas, R. J., Deegens, J. K. & Wetzels, J. F. Permeability factors in idiopathic nephrotic syndrome: historical perspectives and lessons for the future. Nephrol. Dial. Transpl. 29, 2207–2216 (2014).
Clement, L. C. et al. Podocyte-secreted angiopoietin-like-4 mediates proteinuria in glucocorticoid-sensitive nephrotic syndrome. Nat. Med. 17, 117–122 (2011).
Cara-Fuentes, G. et al. Angiopoietin-like-4 and minimal change disease. PLoS ONE 12, e0176198 (2017).
Chandra, P. & Kopp, J. B. Viruses and collapsing glomerulopathy: a brief critical review. Clin. Kidney J. 6, 1–5 (2013).
Cohen, S. D., Kopp, J. B. & Kimmel, P. L. Kidney diseases associated with human immunodeficiency virus infection. N. Engl. J. Med. 377, 2363–2374 (2017).
Migliorini, A. et al. The antiviral cytokines IFN-α and IFN-β modulate parietal epithelial cells and promote podocyte loss: implications for IFN toxicity, viral glomerulonephritis, and glomerular regeneration. Am. J. Pathol. 183, 431–440 (2013).
Ekrikpo, U. E. et al. Chronic kidney disease in the global adult HIV-infected population: a systematic review and meta-analysis. PLoS ONE 13, e0195443 (2018).
An, P. et al. Impact of APOL1 genetic variants on HIV-1 infection and disease progression. Front. Immunol. 10, 53 (2019).
Angeletti, A., Cantarelli, C. & Cravedi, P. HCV-associated nephropathies in the era of direct acting antiviral agents. Front. Med. 6, 20 (2019).
Gupta, A. & Quigg, R. J. Glomerular diseases associated with hepatitis B and C. Adv. Chronic Kidney Dis. 22, 343–351 (2015).
Sanchez, C., Fenves, A. & Schwartz, J. Focal segmental glomerulosclerosis and parvovirus B19. Proc. (Bayl. Univ. Med. Cent.) 25, 20–22 (2012).
Tanawattanacharoen, S., Falk, R. J., Jennette, J. C. & Kopp, J. B. Parvovirus B19 DNA in kidney tissue of patients with focal segmental glomerulosclerosis. Am. J. Kidney Dis. 35, 1166–1174 (2000).
Nasr, S. H. & Kopp, J. B. COVID-19-associated collapsing glomerulopathy: an emerging entity. Kidney Int. Rep. 5, 759–761 (2020).
Kwiatkowska, E., Golembiewska, E., Ciechanowski, K. & Kedzierska, K. Minimal-change disease secondary to Borrelia burgdorferi infection. Case Rep. Nephrol. 2012, 294532 (2012).
Bartlett, C. S., Jeansson, M. & Quaggin, S. E. Vascular growth factors and glomerular disease. Annu. Rev. Physiol. 78, 437–461 (2016).
Craici, I. M., Wagner, S. J., Weissgerber, T. L., Grande, J. P. & Garovic, V. D. Advances in the pathophysiology of pre-eclampsia and related podocyte injury. Kidney Int. 86, 275–285 (2014).
Ollero, M. & Sahali, D. Inhibition of the VEGF signalling pathway and glomerular disorders. Nephrol. Dial. Transpl. 30, 1449–1455 (2015).
Izzedine, H. et al. Kidney diseases associated with anti-vascular endothelial growth factor (VEGF): an 8-year observational study at a single center. Medicine 93, 333–339 (2014).
Markowitz, G. S. et al. Collapsing focal segmental glomerulosclerosis following treatment with high-dose pamidronate. J. Am. Soc. Nephrol. 12, 1164–1172 (2001).
Aghajan, M. et al. Antisense oligonucleotide treatment ameliorates IFN-γ-induced proteinuria in APOL1-transgenic mice. JCI Insight 4, e126124 (2019).
Hurcombe, J. A. et al. Podocyte GSK3 is an evolutionarily conserved critical regulator of kidney function. Nat. Commun. 10, 403 (2019).
Sakarcan, A., Thomas, D. B., O’Reilly, K. P. & Richards, R. W. Lithium-induced nephrotic syndrome in a young pediatric patient. Pediatr. Nephrol. 17, 290–292 (2002).
Xu, W., Ge, Y., Liu, Z. & Gong, R. Glycogen synthase kinase 3β dictates podocyte motility and focal adhesion turnover by modulating paxillin activity: implications for the protective effect of low-dose lithium in podocytopathy. Am. J. Pathol. 184, 2742–2756 (2014).
Letavernier, E. et al. High sirolimus levels may induce focal segmental glomerulosclerosis de novo. Clin. J. Am. Soc. Nephrol. 2, 326–333 (2007).
Puelles, V. G. et al. mTOR-mediated podocyte hypertrophy regulates glomerular integrity in mice and humans. JCI Insight 4, e99271 (2019).
Muller-Krebs, S. et al. Cellular effects of everolimus and sirolimus on podocytes. PLoS ONE 8, e80340 (2013).
Mulay, S. R. et al. Podocyte loss involves MDM2-driven mitotic catastrophe. J. Pathol. 230, 322–335 (2013).
Kaysen, G. A., Gambertoglio, J., Jimenez, I., Jones, H. & Hutchison, F. N. Effect of dietary protein intake on albumin homeostasis in nephrotic patients. Kidney Int. 29, 572–577 (1986).
Moshage, H. J., Janssen, J. A., Franssen, J. H., Hafkenscheid, J. C. & Yap, S. H. Study of the molecular mechanism of decreased liver synthesis of albumin in inflammation. J. Clin. Invest. 79, 1635–1641 (1987).
Hinrichs, G. R., Jensen, B. L. & Svenningsen, P. Mechanisms of sodium retention in nephrotic syndrome. Curr. Opin. Nephrol. Hypertens. 29, 207–212 (2020).
Bockenhauer, D. Over- or underfill: not all nephrotic states are created equal. Pediatr. Nephrol. 28, 1153–1156 (2013).
Vande Walle, J. G., Donckerwolcke, R. A. & Koomans, H. A. Pathophysiology of edema formation in children with nephrotic syndrome not due to minimal change disease. J. Am. Soc. Nephrol. 10, 323–331 (1999).
Vande Walle, J. G. et al. Volume regulation in children with early relapse of minimal-change nephrosis with or without hypovolaemic symptoms. Lancet 346, 148–152 (1995).
Yamauchi, H. & Hopper, J., Jr, Hypovolemic shock and hypotension as a complication in the nephrotic syndrome. report of ten cases. Ann. Intern. Med. 60, 242–254 (1964).
Chen, T. Y., Huang, C. C. & Tsao, C. J. Hemostatic molecular markers in nephrotic syndrome. Am. J. Hematol. 44, 276–279 (1993).
Loscalzo, J. Venous thrombosis in the nephrotic syndrome. N. Engl. J. Med. 368, 956–958 (2013).
Singhal, R. & Brimble, K. S. Thromboembolic complications in the nephrotic syndrome: pathophysiology and clinical management. Thromb. Res. 118, 397–407 (2006).
Agrawal, S., Zaritsky, J. J., Fornoni, A. & Smoyer, W. E. Dyslipidaemia in nephrotic syndrome: mechanisms and treatment. Nat. Rev. Nephrol. 14, 57–70 (2018). An extensive critical reassessment of the pathogenetic mechanisms of dyslipidaemia in nephrotic syndrome.
Joven, J. et al. Abnormalities of lipoprotein metabolism in patients with the nephrotic syndrome. N. Engl. J. Med. 323, 579–584 (1990).
Clement, L. C. et al. Circulating angiopoietin-like 4 links proteinuria with hypertriglyceridemia in nephrotic syndrome. Nat. Med. 20, 37–46 (2014).
Iorember, F. & Aviles, D. Anemia in nephrotic syndrome: approach to evaluation and treatment. Pediatr. Nephrol. 32, 1323–1330 (2017).
Selewski, D. T. et al. Vitamin D in incident nephrotic syndrome: a Midwest Pediatric Nephrology Consortium study. Pediatr. Nephrol. 31, 465–472 (2016).
Alwadhi, R. K., Mathew, J. L. & Rath, B. Clinical profile of children with nephrotic syndrome not on glucorticoid therapy, but presenting with infection. J. Paediatr. Child. Health 40, 28–32 (2004).
Wilfert, C. M. & Katz, S. L. Etiology of bacterial sepsis in nephrotic children 1963-1967. Pediatrics 42, 840–843 (1968).
Ballow, M., Kennedy, T. L. III, Gaudio, K. M., Siegel, N. J. & McLean, R. H. Serum hemolytic factor D values in children with steroid-responsive idiopathic nephrotic syndrome. J. Pediatr. 100, 192–196 (1982).
Anderson, D. C., York, T. L., Rose, G. & Smith, C. W. Assessment of serum factor B, serum opsonins, granulocyte chemotaxis, and infection in nephrotic syndrome of children. J. Infect. Dis. 140, 1–11 (1979).
Vehaskari, V. M. & Rapola, J. Isolated proteinuria: analysis of a school-age population. J. Pediatr. 101, 661–668 (1982).
Trautmann, A., Lipska-Zietkiewicz, B. S. & Schaefer, F. Exploring the clinical and genetic spectrum of steroid resistant nephrotic syndrome: the PodoNet Registry. Front. Pediatr. 6, 200 (2018).
Waldman, M. et al. Adult minimal-change disease: clinical characteristics, treatment, and outcomes. Clin. J. Am. Soc. Nephrol. 2, 445–453 (2007).
Korbet, S. M. & Whittier, W. L. Management of adult minimal change disease. Clin. J. Am. Soc. Nephrol. 14, 911–913 (2019).
Hogg, R. J. et al. Evaluation and management of proteinuria and nephrotic syndrome in children: recommendations from a pediatric nephrology panel established at the National Kidney Foundation conference on proteinuria, albuminuria, risk, assessment, detection, and elimination (PARADE). Pediatrics 105, 1242–1249 (2000).
Leung, A. K., Wong, A. H. & Barg, S. S. Proteinuria in children: evaluation and differential diagnosis. Am. Fam. Physician 95, 248–254 (2017).
Hama, T. et al. Renal biopsy criterion in children with asymptomatic constant isolated proteinuria. Nephrol. Dial. Transpl. 27, 3186–3190 (2012).
Lee, Y. M. et al. Analysis of renal biopsies performed in children with abnormal findings in urinary mass screening. Acta Paediatr. 95, 849–853 (2006).
Nephrotic syndrome in children: prediction of histopathology from clinical and laboratory characteristics at time of diagnosis. A report of the International Study of Kidney Disease in Children. Kidney Int. 13, 159–165 (1978).
Santin, S. et al. Clinical utility of genetic testing in children and adults with steroid-resistant nephrotic syndrome. Clin. J. Am. Soc. Nephrol. 6, 1139–1148 (2011).
Gribouval, O. et al. Identification of genetic causes for sporadic steroid-resistant nephrotic syndrome in adults. Kidney Int. 94, 1013–1022 (2018).
Connaughton, D. M. et al. Monogenic causes of chronic kidney disease in adults. Kidney Int. 95, 914–928 (2019).
Mason, A. E. et al. Response to first course of intensified immunosuppression in genetically-stratified steroid resistant nephrotic syndrome. Clin. J. Am. Soc. Nephrol. https://doi.org/10.2215/CJN.13371019 (2020).
Radhakrishnan, J. & Cattran, D. C. The KDIGO practice guideline on glomerulonephritis: reading between the (guide)lines–application to the individual patient. Kidney Int. 82, 840–856 (2012).
Zhao, J. & Liu, Z. Treatment of nephrotic syndrome: going beyond immunosuppressive therapy. Pediatr. Nephrol. 35, 569–579 (2020).
Mak, S. K., Short, C. D. & Mallick, N. P. Long-term outcome of adult-onset minimal-change nephropathy. Nephrol. Dial. Transpl. 11, 2192–2201 (1996).
Korbet, S. M. Treatment of primary FSGS in adults. J. Am. Soc. Nephrol. 23, 1769–1776 (2012).
Troyanov, S. et al. Focal and segmental glomerulosclerosis: definition and relevance of a partial remission. J. Am. Soc. Nephrol. 16, 1061–1068 (2005).
Wehrmann, M. et al. Long-term prognosis of focal sclerosing glomerulonephritis. An analysis of 250 cases with particular regard to tubulointerstitial changes. Clin. Nephrol. 33, 115–122 (1990).
Chitalia, V. C., Wells, J. E., Robson, R. A., Searle, M. & Lynn, K. L. Predicting renal survival in primary focal glomerulosclerosis from the time of presentation. Kidney Int. 56, 2236–2242 (1999).
Trautmann, A. et al. Long-term outcome of steroid-resistant nephrotic syndrome in children. J. Am. Soc. Nephrol. 28, 3055–3065 (2017).
Bedin, M. et al. Human C-terminal CUBN variants associate with chronic proteinuria and normal renal function. J. Clin. Invest. 130, 335–344 (2020). This paper identified a genetic form of proteinuria and podocytopathy that does not progress to ESKD.
Heeringa, S. F. et al. COQ6 mutations in human patients produce nephrotic syndrome with sensorineural deafness. J. Clin. Invest. 121, 2013–2024 (2011).
Praga, M. et al. Nephrotic proteinuria without hypoalbuminemia: clinical characteristics and response to angiotensin-converting enzyme inhibition. Am. J. Kidney Dis. 17, 330–338 (1991).
Tune, B. M. & Mendoza, S. A. Treatment of the idiopathic nephrotic syndrome: regimens and outcomes in children and adults. J. Am. Soc. Nephrol. 8, 824–832 (1997).
Murnaghan, K., Vasmant, D. & Bensman, A. Pulse methylprednisolone therapy in severe idiopathic childhood nephrotic syndrome. Acta Paediatr. Scand. 73, 733–739 (1984).
Hodson, E. M., Hahn, D. & Craig, J. C. Corticosteroids for the initial episode of steroid-sensitive nephrotic syndrome. Pediatr. Nephrol. 30, 1043–1046 (2015).
Larkins, N., Kim, S., Craig, J. & Hodson, E. Steroid-sensitive nephrotic syndrome: an evidence-based update of immunosuppressive treatment in children. Arch. Dis. Child. 101, 404–408 (2016).
Palmer, S. C., Nand, K. & Strippoli, G. F. Interventions for minimal change disease in adults with nephrotic syndrome. Cochrane Database Syst. Rev. 2008, CD001537 (2008).
Black, D. A., Rose, G. & Brewer, D. B. Controlled trial of prednisone in adult patients with the nephrotic syndrome. Br. Med. J. 3, 421–426 (1970).
Medjeral-Thomas, N. R. et al. Randomized, controlled trial of tacrolimus and prednisolone monotherapy for adults with de novo minimal change disease: a multicenter, randomized, controlled trial. Clin. J. Am. Soc. Nephrol. 15, 209–218 (2020).
Remy, P. et al. An open-label randomized controlled trial of low-dose corticosteroid plus enteric-coated mycophenolate sodium versus standard corticosteroid treatment for minimal change nephrotic syndrome in adults (MSN Study). Kidney Int. 94, 1217–1226 (2018).
Senthil Nayagam, L. et al. Mycophenolate mofetil or standard therapy for membranous nephropathy and focal segmental glomerulosclerosis: a pilot study. Nephrol. Dial. Transpl. 23, 1926–1930 (2008).
Rovin, B. H. et al. Management and treatment of glomerular diseases (part 2): conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney Int. 95, 281–295 (2019).
Glassock, R. J. Therapy of relapsing minimal-change disease in adults: a new approach? Kidney Int. 83, 343–345 (2013).
Rydel, J. J., Korbet, S. M., Borok, R. Z. & Schwartz, M. M. Focal segmental glomerular sclerosis in adults: presentation, course, and response to treatment. Am. J. Kidney Dis. 25, 534–542 (1995).
Dossier, C. et al. Five-year outcome of children with idiopathic nephrotic syndrome: the NEPHROVIR population-based cohort study. Pediatr. Nephrol. 34, 671–678 (2019).
Hodson, E. M., Willis, N. S. & Craig, J. C. Corticosteroid therapy for nephrotic syndrome in children. Cochrane Database Syst. Rev. 4, CD001533 (2007).
Yu, C. C. et al. Abatacept in B7-1-positive proteinuric kidney disease. N. Engl. J. Med. 369, 2416–2423 (2013).
Korsgaard, T., Andersen, R. F., Joshi, S., Hagstrom, S. & Rittig, S. Childhood onset steroid-sensitive nephrotic syndrome continues into adulthood. Pediatr. Nephrol. 34, 641–648 (2019).
Ruth, E. M., Kemper, M. J., Leumann, E. P., Laube, G. F. & Neuhaus, T. J. Children with steroid-sensitive nephrotic syndrome come of age: long-term outcome. J. Pediatr. 147, 202–207 (2005).
Kyrieleis, H. A. et al. Long-term outcome of biopsy-proven, frequently relapsing minimal-change nephrotic syndrome in children. Clin. J. Am. Soc. Nephrol. 4, 1593–1600 (2009).
Lombel, R. M., Gipson, D. S. & Hodson, E. M., Kidney Disease: Improving Global Outcomes. Treatment of steroid-sensitive nephrotic syndrome: new guidelines from KDIGO. Pediatr. Nephrol. 28, 415–426 (2013).
Samuel, S. et al. Canadian society of nephrology commentary on the 2012 KDIGO clinical practice guideline for glomerulonephritis: management of nephrotic syndrome in children. Am. J. Kidney Dis. 63, 354–362 (2014).
Ponticelli, C. et al. Cyclosporin versus cyclophosphamide for patients with steroid-dependent and frequently relapsing idiopathic nephrotic syndrome: a multicentre randomized controlled trial. Nephrol. Dial. Transpl. 8, 1326–1332 (1993).
Sinha, A. et al. Efficacy and safety of mycophenolate mofetil versus levamisole in frequently relapsing nephrotic syndrome: an open-label randomized controlled trial. Kidney Int. 95, 210–218 (2019).
Pravitsitthikul, N., Willis, N. S., Hodson, E. M. & Craig, J. C. Non-corticosteroid immunosuppressive medications for steroid-sensitive nephrotic syndrome in children. Cochrane Database Syst. Rev. 10, CD002290 (2013).
Fujinaga, S. et al. Cyclosporine versus mycophenolate mofetil for maintenance of remission of steroid-dependent nephrotic syndrome after a single infusion of rituximab. Eur. J. Pediatr. 172, 513–518 (2013).
Dorresteijn, E. M. et al. Mycophenolate mofetil versus cyclosporine for remission maintenance in nephrotic syndrome. Pediatr. Nephrol. 23, 2013–2020 (2008).
Hogan, J. et al. Treatment of idiopathic FSGS with adrenocorticotropic hormone gel. Clin. J. Am. Soc. Nephrol. 8, 2072–2081 (2013).
Kittanamongkolchai, W., Cheungpasitporn, W. & Zand, L. Efficacy and safety of adrenocorticotropic hormone treatment in glomerular diseases: a systematic review and meta-analysis. Clin. Kidney J. 9, 387–396 (2016).
Straatmann, C. et al. Treatment outcome of late steroid-resistant nephrotic syndrome: a study by the Midwest Pediatric Nephrology Consortium. Pediatr. Nephrol. 28, 1235–1241 (2013).
Ponticelli, C. et al. A randomized trial of cyclosporine in steroid-resistant idiopathic nephrotic syndrome. Kidney Int. 43, 1377–1384 (1993).
Segarra, A. et al. Efficacy and safety of ‘rescue therapy’ with mycophenolate mofetil in resistant primary glomerulonephritis – a multicenter study. Nephrol. Dial. Transpl. 22, 1351–1360 (2007).
Gipson, D. S. et al. Clinical trial of focal segmental glomerulosclerosis in children and young adults. Kidney Int. 80, 868–878 (2011).
Gellermann, J., Ehrich, J. H. & Querfeld, U. Sequential maintenance therapy with cyclosporin A and mycophenolate mofetil for sustained remission of childhood steroid-resistant nephrotic syndrome. Nephrol. Dial. Transpl. 27, 1970–1978 (2012).
Delville, M. et al. B7-1 blockade does not improve post-transplant nephrotic syndrome caused by recurrent FSGS. J. Am. Soc. Nephrol. 27, 2520–2527 (2016).
Benigni, A., Gagliardini, E. & Remuzzi, G. Abatacept in B7-1-positive proteinuric kidney disease. N. Engl. J. Med. 370, 1261–1263 (2014).
Kronbichler, A. et al. Rituximab treatment for relapsing minimal change disease and focal segmental glomerulosclerosis: a systematic review. Am. J. Nephrol. 39, 322–330 (2014).
Trachtman, H. et al. Efficacy of galactose and adalimumab in patients with resistant focal segmental glomerulosclerosis: report of the font clinical trial group. BMC Nephrol. 16, 111 (2015).
Trachtman, H. et al. DUET: a phase 2 study evaluating the efficacy and safety of sparsentan in patients with FSGS. J. Am. Soc. Nephrol. 29, 2745–2754 (2018).
Gross, O., Perin, L. & Deltas, C. Alport syndrome from bench to bedside: the potential of current treatment beyond RAAS blockade and the horizon of future therapies. Nephrol. Dial. Transpl. 29 (Suppl. 4), iv124–iv130 (2014).
Solanki, A. K. et al. A novel CLCN5 mutation associated with focal segmental glomerulosclerosis and podocyte injury. Kidney Int. Rep. 3, 1443–1453 (2018).
du Moulin, M. et al. The mutation p.D313Y is associated with organ manifestation in Fabry disease. Clin. Genet. 92, 528–533 (2017).
Hu, M. et al. Prophylactic bilateral nephrectomies in two paediatric patients with missense mutations in the WT1 gene. Nephrol. Dial. Transpl. 19, 223–226 (2004).
Crew, R. J., Radhakrishnan, J. & Appel, G. Complications of the nephrotic syndrome and their treatment. Clin. Nephrol. 62, 245–259 (2004).
Keller, E., Hoppe-Seyler, G. & Schollmeyer, P. Disposition and diuretic effect of furosemide in the nephrotic syndrome. Clin. Pharmacol. Ther. 32, 442–449 (1982).
Hoorn, E. J. & Ellison, D. H. Diuretic resistance. Am. J. Kidney Dis. 69, 136–142 (2017).
Fallahzadeh, M. A. et al. Acetazolamide and hydrochlorothiazide followed by furosemide versus furosemide and hydrochlorothiazide followed by furosemide for the treatment of adults with nephrotic edema: a randomized trial. Am. J. Kidney Dis. 69, 420–427 (2017).
Artunc, F., Worn, M., Schork, A. & Bohnert, B. N. Proteasuria – the impact of active urinary proteases on sodium retention in nephrotic syndrome. Acta Physiol. 225, e13249 (2019).
Bohnert, B. N. et al. Aprotinin prevents proteolytic epithelial sodium channel (ENaC) activation and volume retention in nephrotic syndrome. Kidney Int. 93, 159–172 (2018).
Wheeler, D. C. & Bernard, D. B. Lipid abnormalities in the nephrotic syndrome: causes, consequences, and treatment. Am. J. Kidney Dis. 23, 331–346 (1994).
Llach, F. Hypercoagulability, renal vein thrombosis, and other thrombotic complications of nephrotic syndrome. Kidney Int. 28, 429–439 (1985).
Kerlin, B. A. et al. Epidemiology and risk factors for thromboembolic complications of childhood nephrotic syndrome: a Midwest Pediatric Nephrology Consortium (MWPNC) study. J. Pediatr. 155, 105–110 (2009).
Suri, D. et al. Thromboembolic complications in childhood nephrotic syndrome: a clinical profile. Clin. Exp. Nephrol. 18, 803–813 (2014).
Rai Mittal, B., Singh, S., Bhattacharya, A., Prasad, V. & Singh, B. Lung scintigraphy in the diagnosis and follow-up of pulmonary thromboembolism in children with nephrotic syndrome. Clin. Imaging 29, 313–316 (2005).
Kelddal, S., Nykjaer, K. M., Gregersen, J. W. & Birn, H. Prophylactic anticoagulation in nephrotic syndrome prevents thromboembolic complications. BMC Nephrol. 20, 139 (2019).
Close, G. C. & Houston, I. B. Fatal haemorrhagic chickenpox in a child on long-term steroids. Lancet 2, 480 (1981).
Kamei, K. et al. Prospective study of live attenuated vaccines for patients with nephrotic syndrome receiving immunosuppressive agents. J. Pediatr. 196, 217–222.e1 (2018).
Bierzynska, A. & Saleem, M. A. Deriving and understanding the risk of post-transplant recurrence of nephrotic syndrome in the light of current molecular and genetic advances. Pediatr. Nephrol. 33, 2027–2035 (2018).
Jacobs-Cacha, C. et al. A misprocessed form of apolipoprotein A-I is specifically associated with recurrent focal segmental glomerulosclerosis. Sci. Rep. 10, 1159 (2020).
Kienzl-Wagner, K. et al. Successful management of recurrent focal segmental glomerulosclerosis. Am. J. Transpl. 18, 2818–2822 (2018).
Kashgary, A. et al. The role of plasma exchange in treating post-transplant focal segmental glomerulosclerosis: a systematic review and meta-analysis of 77 case-reports and case-series. BMC Nephrol. 17, 104 (2016).
Mann, N. et al. Whole-exome sequencing enables a precision medicine approach for kidney transplant recipients. J. Am. Soc. Nephrol. 30, 201–215 (2019).
Canetta, P. A. et al. Health-related quality of life in glomerular disease. Kidney Int. 95, 1209–1224 (2019).
Kengne-Wafo, S. et al. Risk factors for cyclosporin a nephrotoxicity in children with steroid-dependant nephrotic syndrome. Clin. J. Am. Soc. Nephrol. 4, 1409–1416 (2009).
Ishikura, K. et al. Morbidity in children with frequently relapsing nephrosis: 10-year follow-up of a randomized controlled trial. Pediatr. Nephrol. 30, 459–468 (2015).
Huscher, D. et al. Dose-related patterns of glucocorticoid-induced side effects. Ann. Rheum. Dis. 68, 1119–1124 (2009).
Hyams, J. S. & Carey, D. E. Corticosteroids and growth. J. Pediatr. 113, 249–254 (1988).
Ng, J. S. et al. Ocular complications of paediatric patients with nephrotic syndrome. Clin. Exp. Ophthalmol. 29, 239–243 (2001).
Polito, C., Oporto, M. R., Totino, S. F., La Manna, A. & Di Toro, R. Normal growth of nephrotic children during long-term alternate-day prednisone therapy. Acta Paediatr. Scand. 75, 245–250 (1986).
Hogan, J. et al. Effect of center practices on the choice of the first dialysis modality for children and young adults. Pediatr. Nephrol. 32, 659–667 (2017).
Morello, W. et al. Post-transplant recurrence of steroid resistant nephrotic syndrome in children: the Italian experience. J. Nephrol. https://doi.org/10.1007/s40620-019-00660-9 (2019).
Gadegbeku, C. A. et al. Design of the Nephrotic Syndrome Study Network (NEPTUNE) to evaluate primary glomerular nephropathy by a multidisciplinary approach. Kidney Int. 83, 749–756 (2013).
Mariani, L. H. et al. CureGN study rationale, design, and methods: establishing a large prospective observational study of glomerular disease. Am. J. Kidney Dis. 73, 218–229 (2019).
Wang, C. S. et al. Ofatumumab for the treatment of childhood nephrotic syndrome. Pediatr. Nephrol. 32, 835–841 (2017).
Blair, H. A. & Duggan, S. T. Belimumab: a review in systemic lupus erythematosus. Drugs 78, 355–366 (2018).
KDIGO Clinical Practice Guideline for Glomerulonephritis. Kidney International Supplements (Elsevier, 2020).
Trautmann, A. et al. IPNA clinical practice recommendations for the diagnosis and management of children with steroid-resistant nephrotic syndrome. Pediatr. Nephrol. 35, 1529–1561 (2020).
Fakhouri, F. et al. Steroid-sensitive nephrotic syndrome: from childhood to adulthood. Am. J. Kidney Dis. 41, 550–557 (2003).
Abeyagunawardena, A. S., Hindmarsh, P. & Trompeter, R. S. Adrenocortical suppression increases the risk of relapse in nephrotic syndrome. Arch. Dis. Child. 92, 585–588 (2007).
Niaudet, P. Treatment of childhood steroid-resistant idiopathic nephrosis with a combination of cyclosporine and prednisone. French Society of Pediatric Nephrology. J. Pediatr. 125, 981–986 (1994).
Ishikura, K. et al. Two-year follow-up of a prospective clinical trial of cyclosporine for frequently relapsing nephrotic syndrome in children. Clin. J. Am. Soc. Nephrol. 7, 1576–1583 (2012).
Gellermann, J. et al. Mycophenolate mofetil versus cyclosporin A in children with frequently relapsing nephrotic syndrome. J. Am. Soc. Nephrol. 24, 1689–1697 (2013).
Braun, N. et al. Immunosuppressive treatment for focal segmental glomerulosclerosis in adults. Cochrane Database Syst. Rev. 2008, CD003233 (2008).
Sinha, M. D., MacLeod, R., Rigby, E. & Clark, A. G. Treatment of severe steroid-dependent nephrotic syndrome (SDNS) in children with tacrolimus. Nephrol. Dial. Transpl. 21, 1848–1854 (2006).
Bock, M. E., Cohn, R. A. & Ali, F. N. Treatment of childhood nephrotic syndrome with long-term, low-dose tacrolimus. Clin. Nephrol. 79, 432–438 (2013).
Sobiak, J. et al. Monitoring of mycophenolate mofetil metabolites in children with nephrotic syndrome and the proposed novel target values of pharmacokinetic parameters. Eur. J. Pharm. Sci. 77, 189–196 (2015).
Perez-Aytes, A. et al. In utero exposure to mycophenolate mofetil: a characteristic phenotype? Am. J. Med. Genet. A 146A, 1–7 (2008).
Kamei, K. et al. Rituximab-associated agranulocytosis in children with refractory idiopathic nephrotic syndrome: case series and review of literature. Nephrol. Dial. Transpl. 30, 91–96 (2015).
McGrogan, A., Franssen, C. F. & de Vries, C. S. The incidence of primary glomerulonephritis worldwide: a systematic review of the literature. Nephrol. Dial. Transpl. 26, 414–430 (2011).
Cunningham, A., Benediktsson, H., Muruve, D. A., Hildebrand, A. M. & Ravani, P. Trends in biopsy-based diagnosis of kidney disease: a population study. Can. J. Kidney Health Dis. https://doi.org/10.1177/2054358118799690 (2018).
Woo, K. T. et al. A global evolutionary trend of the frequency of primary glomerulonephritis over the past four decades. Kidney Dis. 5, 247–258 (2019).
O’Shaughnessy, M. M. et al. Glomerular disease frequencies by race, sex and region: results from the International Kidney Biopsy Survey. Nephrol. Dial. Transpl. 33, 661–669 (2018).
Polito, M. G., de Moura, L. A. & Kirsztajn, G. M. An overview on frequency of renal biopsy diagnosis in Brazil: clinical and pathological patterns based on 9,617 native kidney biopsies. Nephrol. Dial. Transpl. 25, 490–496 (2010).
Perkowska-Ptasinska, A. et al. Clinicopathologic correlations of renal pathology in the adult population of Poland. Nephrol. Dial. Transpl. 32, ii209–ii218 (2017).
Zink, C. M. et al. Trends of renal diseases in Germany: review of a regional renal biopsy database from 1990 to 2013. Clin. Kidney J. 12, 795–800 (2019).
Ozturk, S. et al. Demographic and clinical characteristics of primary glomerular diseases in Turkey. Int. Urol. Nephrol. 46, 2347–2355 (2014).
Rychlik, I. et al. The Czech registry of renal biopsies. Occurrence of renal diseases in the years 1994-2000. Nephrol. Dial. Transpl. 19, 3040–3049 (2004).
Lovric, S., Ashraf, S., Tan, W. & Hildebrandt, F. Genetic testing in steroid-resistant nephrotic syndrome: when and how? Nephrol. Dial. Transpl. 31, 1802–1813 (2016).
D’Agati, V. D., Fogo, A. B., Bruijn, J. A. & Jennette, J. C. Pathologic classification of focal segmental glomerulosclerosis: a working proposal. Am. J. Kidney Dis. 43, 368–382 (2004).
Fogo, A. B. Causes and pathogenesis of focal segmental glomerulosclerosis. Nat. Rev. Nephrol. 11, 76–87 (2015).
D’Agati, V. D., Kaskel, F. J. & Falk, R. J. Focal segmental glomerulosclerosis. N. Engl. J. Med. 365, 2398–2411 (2011).
Hommos, M. S. et al. Global glomerulosclerosis with nephrotic syndrome; the clinical importance of age adjustment. Kidney Int. 93, 1175–1182 (2018).
Deegens, J. K. et al. Podocyte foot process effacement as a diagnostic tool in focal segmental glomerulosclerosis. Kidney Int. 74, 1568–1576 (2008).
Acknowledgements
J.B.K. was supported by the NIDDK Intramural Research Program, NIH, Bethesda, MD (project ZO1 DK043308). K.S. is supported by NIDDK grants R01DK076077, R01 DK087635 and DP3 DK108220. H.-J.A. was supported by the Deutsche Forschungsgemeinschaft (AN372/24-1). F.H. was supported by the NIH through grant RO1-DK076683. This work was supported by the European Research Council under the Consolidator Grant RENOIR to P.R. (ERC-2014-CoG, grant number 648274). The authors thank A. M. Buccoliero, Meyer Children’s Hospital and Fiammetta Ravaglia, Florence, Italy, for help with histopathological images.
Author information
Authors and Affiliations
Contributions
Introduction (J.B.K., H.-J.A., K.S. and P.R.); Epidemiology (P.R.); Mechanisms/pathophysiology (J.B.K., H.-J.A., K.S., F.H. and P.R.); Diagnosis, screening and prevention (J.B.K., H.-J.A., M.A.P., G.R., F.H. and P.R.); Management (J.B.K., H.-J.A., M.A.P., G.R., F.H. and P.R.); Quality of life (H.-J.A. and P.R.); Outlook (J.B.K., H.-J.A., K.S. and P.R.); Overview of the Primer (P.R.). J.B.K. and H.-J.A. contributed equally.
Corresponding author
Ethics declarations
Competing interests
F.H. is a co-founder and member of the scientific advisory board of Goldfinch-Bio. The other authors declare no competing interests.
Additional information
Peer review information
Nature Reviews Disease Primers thanks A. Bagga, K. Iijima, Moin Saleem and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Related links
The American Kidney Fund: https://www.kidneyfund.org/
ClinGen: https://clinicalgenome.org
The Dutch Kidney Foundation: https://nierstichting.nl
European Rare Kidney Disease Reference Network: https://www.erknet.org/
The Federation for Each Renal Genetic Disease: http://federg.org
La Nuova Speranza non-profit foundation: http://www.lanuovasperanza.org
The National Kidney Foundation: https://www.kidney.org
The National Organization for Rare Disorders: https://rarediseases.org/
NephCure: https://nephcure.org/
The Nephrotic Syndrome Association, Italy: http://www.asnit.org
Supplementary information
Glossary
- Chronic kidney disease
-
(CKD). Abnormalities in kidney structure or function (urine composition or impaired excretory function) lasting >3 months; progression is based on the cumulative degeneration of nephrons, the independent functional units of the kidney.
- Glomerular filtration barrier
-
The parts of the nephron in which the filtration process of the blood takes place and the primary filtrate is formed; podocytes and their interdigitating foot processes, connected by the slit diaphragm, are essential components of the size-selective and charge-selective filtration barrier in the glomerulus.
- Nephrotic syndrome
-
A clinical syndrome defined by symmetrical oedema, hypoalbuminaemia, hyperlipidaemia and proteinuria of >3 g per day, caused by podocyte injury (from any cause) and leading to severe alterations of the glomerular filtration barrier.
- End-stage kidney disease
-
(ESKD). When nephron loss during chronic kidney disease reaches the point that homeostasis can no longer be maintained, presenting as renal failure (uraemia).
- Glomerular filtration rate
-
(GFR). The central parameter of excretory kidney function that can be accurately measured as the clearance of injected tracers over time or can be estimated from a number of clinical and laboratory parameters, including creatinine and cystatin C.
- Podocyte shear stress
-
The hydrostatic pressure gradient across the glomerular filtration barrier that podocytes must withstand to avoid detachment and loss into the urine.
- Hyperfiltration
-
An elevated total glomerular filtration rate (GFR) is called hyperfiltration and implies hyperfiltration of every nephron; however, reduced total GFR implies compensatory hyperfiltration of the remnant nephrons, as a central mechanism for the progression of chronic kidney disease by promoting podocyte shear stress, podocyte detachment and adaptive focal segmental glomerulosclerosis.
- Oncotic pressure
-
The pressure resulting from the difference within the extracellular fluid between the protein contents of plasma and interstitial fluid.
- Syndromic disorders
-
Genetic diseases with manifestations in different organ systems due to the expression of the mutated gene in diverse tissues.
- Mitotic catastrophe
-
A type of cell death that occurs during mitosis, resulting from DNA damage or deranged spindle formation and linked to checkpoint failure.
- Overfill scenario
-
Nephrotic syndrome associated with oedema secondary to a positive sodium balance, mainly due to sodium retention; patients present with intravascular hypervolaemia (hypertension) and interstitial hypervolaemia (oedema).
- Acute kidney injury
-
(AKI). An abrupt decrease in kidney function, resulting in the retention of urea and other nitrogenous waste products in the blood and in the dysregulation of extracellular volume and electrolytes.
- Underfill scenario
-
Nephrotic syndrome associated with oedema secondary to a rapid fall in blood oncotic pressure with volume shifts into the interstitial compartments; patients present with intravascular hypovolaemia and interstitial oedema.
- Renin–angiotensin system
-
The hormone system that regulates blood pressure, volume and electrolyte balance, and systemic vascular resistance.
- Anasarca
-
General swelling of the whole body that can occur when the tissues of the body retain too much fluid.
- Cushingoid features
-
Weight gain, hypertension, cutaneous striae rubrae and easy bruising.
Rights and permissions
About this article
Cite this article
Kopp, J.B., Anders, HJ., Susztak, K. et al. Podocytopathies. Nat Rev Dis Primers 6, 68 (2020). https://doi.org/10.1038/s41572-020-0196-7
Accepted:
Published:
DOI: https://doi.org/10.1038/s41572-020-0196-7
This article is cited by
-
Modeled microgravity unravels the roles of mechanical forces in renal progenitor cell physiology
Stem Cell Research & Therapy (2024)
-
Relations between glomerular hyperfiltration and podocyte injury: potential role of Piezo1 in the Rac1-mineralocorticoid receptor activation pathway
Hypertension Research (2024)
-
RNAi-based drug design: considerations and future directions
Nature Reviews Drug Discovery (2024)
-
New insights into the immune functions of podocytes: the role of complement
Molecular and Cellular Pediatrics (2023)
-
The role of N-methyladenosine modification in acute and chronic kidney diseases
Molecular Medicine (2023)