Focal segmental glomerulosclerosis (FSGS) should be understood as a histologic pattern, not as a disease. This histologic pattern is the result of a variety of pathologic processes that share a common damage on the podocytes; it involves the loss of glomerular filtrate selectivity and clinically it is manifested as proteinuria and long-term renal failure.1 Histologically, the loss of podocytes involves the migration of epithelial cells from the Bowman’s capsule to the glomeruli in an attempt to replace the damaged podocytes, however this attempt of regeneration is inefficient and produces patchy mesangial sclerosis of the glomerular tuft (segmental) that begins in some glomeruli but not all (focal).2 The KDIGO (Kidney Disease: Improving Global Outcomes) guidelines for the management of glomerular diseases published in 2021 propose a new etiopathogenic classification, and divided FSGS into four categories, which facilitates the diagnosis and therapeutic approach. Thus there should be different forms: primary, secondary, genetic and of undetermined cause.3 Family and personal history and the clinical presentation are not always sufficient to exclude a hereditary cause of the disease. The clinical presentation of FSGS with a genetic cause is extremely variable; with differences in age of presentation, degree of proteinuria, and progression of chronic kidney disease (CKD).

Initially the genetic forms were described as an onset during childhood, mainly associated with corticosteroid-resistant nephrotic syndrome. However, depending on the selection criteria, up to 30% of adult cases of FSGS may be associated with a genetic cause,4–8 so it remains a challenge to define the criteria to perform a genetic study. The clinical and histologic features that appear to better predict a genetic etiology are: the absence of response to immunosuppressive therapies, the presence of microhematuria, the absence of diffuse pedicellar fusion in the renal biopsy, and maintaining a normal serum albumin despite developing nephrotic range proteinuria6,9,10 although these last two characteristics may be modified depending on the time of diagnosis.

It is well established that recognizing the diagnosis of genetically caused FSGS is of vital importance for patients. It is clear that, early diagnosis avoids certain diagnostic tests such as scans and exposure to unnecessary immunosuppressive treatment, and also allows the diagnosis of asymptomatic carriers; screening for associated pathologies and facilitates genetic counseling. Unlike the primary forms of FSGS, recurrence of FSGS of genetic cause in renal transplantation is not a problem; but it is relevant in the development of other pathologies such as anti-glomerular basement membrane antibodies which occurs in 2%–3% of renal transplant patients with X-linked Alport syndrome.11 Finally, it also allows an adequate selection of potential living related kidney donors.

A correct classification of patients according to their clinical and histological characteristics is essential for decision making and the planning of a suitable decisions and the planning of an adequate therapeutic scheme. Unfortunately, many clinical trials have failed to because they included patients with different forms of FSGS without a correct stratification.

In the present document we propose recommendations, based on clinical and anatomopathological criteria, for the performance of a genetic study in adult patients with FSGS.

The etiology of FSGS of immunologic etiology, classically called “primary FSGS”; is not yet fully elucidated. In recent decades it has been assumed that it is caused by a circulating permeability factor, which is speculated to consist of a group of cytokines that abruptly alter podocyte function, increasing the permeability of the glomerular filtration membrane. This group of cytokines has not yet been defined, and there are several molecules that have been proposed as possible causes of the disease. These include cardiotropic-like cytokine factor-1 (CLCF-1), soluble urokinase-type plasminogen activator receptor (suPAR), the anti-CD40 antibody, apolipoprotein A1 and the soluble form of calcium/calmodulin-serine protein kinase (CASK).12 In recent years it has been identified that a proportion of patients with minimal change disease are caused by nephrin antibody13 and more recently it has been confirmed its role in in primary FSGS especially in relapses after transplant.14 However, recently it has been found that only 9% of patients with primary FSGS are caused by these antibodies,15 so it remains to be clarified which are the agents involved in this permeability factor that contributes to the remaining cases of FSGS.

Clinically, primary FSGS is presented abruptly in the form of complete nephrotic syndrome (proteinuria ≥3.5 g/day, hypoalbuminemia, hypercholesterolemia and edema). Histologically, under the light microscope there are no specific features that would distinguish it from the other other forms of FSGS; by electron microscopy it is highlighted the presence of a diffuse pedicellar fusion that occupies more than 80% of the surface of the glomerular membrane which differentiates it from the secondary forms, and it is a determinant finding. In a series of adult and predominantly white patients with primary FSGS, the median pedicellar fusion was 100%,16 however it must be taken into account that several hereditary forms of FSGS can also present with a diffuse pedicellar fusion.

A morphometric analysis of pedicle width that excluded patients with hereditary forms of FSGS, found wider pedicels in patients with primary FSGS compared to those with secondary FSGS. A pedicellar width >1500 nm adequately differentiated primary from secondary FSGS.17 Histologic findings such as podocyte vacuolization and microvillous transformation are related to the amount of proteinuria, and although nonspecific, it is more frequently seen in primary than in secondary forms.18

The treatment of primary FSGS is immunosuppression, and due to its poor prognosis observed in the absence of treatment, early initiation of immunosuppressive therapy is recommended in cases of FSGS that present with complete nephrotic syndrome.19

Treatment with glucocorticoids is the current cornerstone of the management of primary FSGS.3 However, this recommendation is based on observational studies and there are no studies that have compared prednisone with placebo in the treatment of primary FSGS.20 A small clinical trial found that the association of mycophenolate with lower doses of steroids achieved similar results with a lower cumulative steroid dose.21

The response to corticosteroid therapy is a characteristic feature of primary FSGS, which would rule out other causes of FSGS, although the definition of glucocorticoid resistance is sometimes difficult. Recent studies have even demonstrate a genetic variant in up to 42% of patients with glucocorticoid resistance,22 so that the genetic study would be particularly justified in this group of patients to avoid unnecessary treatment with immunosuppressants.

Calcineurin inhibitors (CNI) are the standard treatment for patients with contraindications, intolerance, or resistance to glucocorticoids.3 The mechanism of action of glucocorticoids and CNIs in primary FSGS is not entirely clear; presumably these therapies interfere with the cellular sites of the putative permeability factors. However, the information is somewhat ambiguous as to whether the benefit of immunosuppressives depends solely on their immunosuppressive effect or whether it is due to a local effect on podocyte function and the stabilization of synaptopodin.23 The different series have shown in FSGS a response rate to glucocorticoids and/or CNI of 40%–70% of cases19; although this proportion is probably underestimated because of the inclusion of patients with secondary or hereditary forms; and probably the rate of response to appropriate immunosuppressive therapy is higher in patients correctly classified as primary FSGS.

Once genetic and secondary causes have been ruled out, the recurrence rate of primary FSGS in renal transplantation is up to 80% in first transplants.24 Early recurrence in transplantation is the hallmark of primary FSGS. The best treatment for recurrent FSGS in transplantation is not yet known. Prophylactic plasmapheresis does not reduce the risk of recurrence, although therapeutic plasmapheresis is considered a good first-line option as a therapy to eliminate permeability factors, especially in very early recurrences with severe proteinuria.25 Prophylactic treatment with rituximab has not been shown to be effective in reducing the risk of recurrence.26

Most secondary forms of FSGS are due to a mismatch between glomerular load and glomerular capacity. The pathogenic mechanism is always common and consists of damage and adaptive podocyte loss secondary to increased demand on the glomerular demand (inability to adapt to glomerular size, ischemia due to hypoperfusion). This may occur due to circumstances that reduce renal mass, such as low nephron mass at birth, reflux nephropathy, renal dysplasia, or situations in which there is an increase in the glomerular filtration rate that exceeds the glomerular capacity; as in obesity, high protein intake or androgen abuse.27–29 Any chronic glomerular or tubular disease can reduce total nephron function and lead to maladaptive FSGS that overlaps with the primary disorder.30

Hyperfiltration and hypertension in the glomerular capillary represent the main mechanism of strain on the podocyte. Podocytes are extremely sensitive to the “shear stress” generated by increased filtration pressure through the clefts and on their apical surface.31,32

Maladaptive FSGS arises from the processes described above that involve an increase in the glomerular filtration rate of each nephron, leading to a vicious cycle of glomerular hypertrophy, podocyte hypertrophy, podocyte stress and glomerular filtration rate of each nephron, leading to a vicious circle of glomerular hypertrophy, podocyte hypertrophy, podocyte stress and depletion and its depletion with the eventual formation of synechiae and an excess deposition of extracellular matrix within the glomerulus.31,33

Viral infections can induce secondary FSGS, either directly or by release of inflammatory cytokines that interact with podocyte receptors. HIV (human immunodeficiency virus), parvovirus B-19, cytomegalovirus, Epstein–Barr virus, severe acute respiratory syndrome-associated coronavirus-2 (SARS-CoV-2) or simian virus 40 (SV40) are some examples of viral infections that can induce these lesions.1,34,35

There are some drugs that can induce FSGS, such as interferon-α, -β, or -γ, intravenous bisphosphonates, the anthracyclines, lithium, or mTOR (mammalian target of rapamycin) inhibitors. These lesions are usually reversible after discontinuation of treatment.28,35

There is no typical histologic pattern in secondary FSGS, but glomerulomegaly is characteristic of adaptive forms, the perihilar variant (Columbia classification) is also characteristic in this form of FSGS in which synechiae are predominantly present at the perihilar level.35 Collapsing forms are more common incases secondary to HIV or drugs such as bisphosphonates. In contrast, in all forms of secondary FSGS, the pedicellar fusion is patchy usually occupying <40% of the glomerular surface. The presence of diffuse pedicellar fusion exclude the maladaptive mechanism as a cause of primary FSGS.18,35

The biochemical characteristic that differentiates the secondary forms is the presence of normal serum albumin, unlike primary FSGS that debuts with nephrotic syndrome. The temporal presentation of clinical manifestations may also be of great also importance to distinguish between primary and secondary forms. Primary forms usually manifest with an abrupt onset nephrotic syndrome, whereas secondary forms, in particular maladaptive forms, often present with progressive proteinuria. These forms do not respond to immunosuppressive therapy and treatment should be directed, as far as possible, to resolve the underlying cause. Management is based on procedures that decrease glomerular hyperfiltration, withdrawal of the causative drug or treatment of the related infection. Achieving a complete response after treatment with blockade of the renin-angiotensin system (BSRAA), sodium-glucose cotransporter type 2 (iSGLT2) inhibitors36 or treatment of the underlying cause such as weight loss in patients with obesity, would support the diagnosis of secondary FSGS.18,37 Recently it has been published, a clinical trial in patients with FSGS in whom treatment with sparsertan (a dual endothelin A and angiotensin II blocker) significantly reduced proteinuria, but without delaying renal progression.38

Although this study was designed to study the effect of sparsentan in patients with presumably primary FSGS, the fact is the median proteinuria of the patients included was in the sub-nephrotic range (urine protein-to-creatinine ratio of 3.1 g/g with a serum albumin within the normal range of (3.49 g/g); indicating that a large proportion of the patients studied did not have primary FSGS but rather secondary or hereditary forms of FSGS, thus indicating its usefulness as an antiproteinuric in the management of these patients.

FSGS of genetic or hereditary cause is the least frequent, or perhaps the least diagnosed. In current algorithms, a genetic study is not established as part of the initial workup, so in this manuscript we want to emphasize that there are adult patients in whom a genetic study would be indicated as a first evaluation before suspicion of FSGS as well as renal biopsy.

Massive sequencing techniques have made it possible to identify more than 60 genes responsible for podocyte damage. The genes encoding proteins located in the podocyte, slit diaphragm, and glomerular basement membrane are the most important involved in genetically caused FSGS, the most frequent being the type IV collagen genes followed by the genes related to podocytopathies (ACTN4, INF2, NPHS1, NPHS2, TRPC6, LMXB1).8,39–41 One of the indications for genetic study in adult patients is non-response to immunosuppression, although there are some cases of genetic FSGS that might respond to corticosteroids (EMP2 or PLCG2)39 and some forms alsorespond to CNI (NPHS1, NPHS2, TRPC6, WT1) due to a local effect on the function of podocytes and the stabilization of synaptopodin,23 inducing a reduction in proteinuria, which can be labeled as partial remission,42 but in in genetic forms a complete remission will not be achieved.43,44

The prevalence of genetically caused FSGS is high in children (20%–30%),39 the prevalence in adults ranges from around 22% in patients with a family history of kidney disease to 10% in those with no family history or in undefined cohorts.8,40,45,46,41 Hence, genetic testing is generally recommended in patients with early-onset nephrotic syndrome, especially in steroid-resistant forms. However, in the population adult population, the recommendation is more complex. The KDIGO guidelines recommend making an individual assessment of each case to indicate genetic study, considering as characteristics to be taken into account the coexistence of syndromic conditions or family history. The presence of a family history increases the probability that a mutation is responsible for the podocyte damage; although in recently published series, up to 55% of the cases with genetic variants had no evidence of family history.22 This same publication has revealed that in patients with slowly progressive proteinuria without an obvious secondary cause, a genetic variant was found in 33% of the cases studied. This percentage was even higher when the patient had persistent microhematuria with dysmorphic red blood cells, a circumstance that should lead us to suspect a disease related to collagen IV.

Electron microscopy is not useful for diagnosing or suspecting FSGS of genetic etiology. Those forms with complete nephrotic syndrome at the time of renal biopsy will show extensive pedicellar fusion while those without nephrotic syndrome will show only partial pedicellar fusion. Occasionally, in FSGS associated with collagen IV mutations the electron microscopy shows a thin glomerular basement membrane (<180 nm in children and <250 nm in adults),47 which could be an indication for genetic study.

Currently the most widely used method for genetic diagnosis is massive sequencing. These techniques allow the simultaneous sequencing of the exons of a set of genes, or of all the exons (exome sequencing) or of the entire genome. The Sanger technique is currently used to sequence small genes or to confirm a variant previously identified by mass sequencing.48–50 Gene panels associated with various diseases have proven to be useful in nephrology, so they are a good tool when we are looking for diseases without a specific phenotype as in the case of FSGS of genetic cause.51,52

In accordance with the situations of routine clinical practice and the difficulties that may arise in certain centers regarding the access to genetic studies, we have proposed the following algorithm: (Fig. 1).

Fig. 1.

Proposed algorithm for genetic study in adults with focal segmental glomerulosclerosis (FSGS).

(0.3MB).

Although many of the genes that cause FSGS give rise to a disease with onset in childhood, the wide phenotypic spectrum does not allow us to rule out these genes as the cause of adult-onset disease. For this reason, gene panels should include all genes causing glomerular nephropathy.

Some genes that are the cause for other inherited diseases such as tubulopathies (CLCN5, OCRL), thrombotic microangiopathy (DKGE, CFH), ciliopathies (UMOD, NPHP4),53 deposit disease such as Fabry disease (GLA)39 and CAKUT-causing genes may present a FSGS pattern in the biopsy.54

Table 1 describes the genes that have been associated with FSGS of genetic cause and their clinical features. They have been divided according to whether patients present with extrarenal manifestations as part of a syndromic picture or whether they are the cause of FSGS as the only clinical expression. To date there are more than 60 associated genes; however, we have to take into account that as research progresses new genes are being discovered and FSGS may be due to alterations of the podocyte, the glomerular basement membrane and its components, but it may also be the scar of renal disease of any origin54 (Table 1).

In Table 2 we summarize the indications for genetic study in patients with FSGS.