Focal segmental glomerulosclerosis is a pattern of scarring seen on kidney biopsy — focal meaning only some of the glomeruli are affected, and segmental meaning only part of each affected one. It is not a single disease but a common endpoint of several different processes, and it is one of the leading causes of nephrotic syndrome in adults and of kidney failure worldwide. The critical division is between primary FSGS, in which something circulating in the blood attacks the podocytes and causes sudden heavy protein loss; secondary FSGS, in which the kidney is responding to being overworked, as in obesity or after losing nephrons; and genetic FSGS, caused by inherited mutations in podocyte proteins. These look similar on the biopsy slide but need entirely different treatment.

Why does it matter whether FSGS is primary or secondary?

Because the treatments are opposites, and giving the wrong one causes harm. Primary FSGS may respond to immunosuppression — high-dose steroids, calcineurin inhibitors, sometimes rituximab — because there is an immune-mediated circulating factor to suppress. Secondary FSGS has no such factor: the scarring is an adaptive response to hyperfiltration from obesity, reduced kidney mass, reflux or sickle cell disease, and immunosuppression provides no benefit while exposing the patient to infection, diabetes, bone loss and other serious toxicity. The clues that distinguish them: primary FSGS begins abruptly with heavy proteinuria, low albumin and marked swelling, and shows diffuse podocyte damage on electron microscopy, whereas secondary FSGS creeps up with lower-level proteinuria, a normal albumin and no oedema.

What is sparsentan and why is its approval significant?

Sparsentan is a dual receptor antagonist — it blocks both the endothelin type A receptor and the angiotensin II type 1 receptor, two pathways that independently damage podocytes and drive protein leakage. In April 2026 it became the first drug ever approved by the FDA specifically for focal segmental glomerulosclerosis, a disease that until then had no approved therapy at all: everything used was borrowed from other conditions and prescribed off-label. Its significance is therefore twofold. Clinically, it offers a non-immunosuppressive oral option that can be used across a broader group of patients than steroids or calcineurin inhibitors. Strategically, it establishes a regulatory pathway using proteinuria reduction as the endpoint, which makes further approvals in rare glomerular diseases feasible where waiting for kidney failure endpoints would take decades.

What is APOL1 and why does it matter?

APOL1 is a gene whose G1 and G2 variants became common in West African populations because they protect against the parasite causing African sleeping sickness — a clear evolutionary trade-off. Carrying two copies of these risk variants substantially increases the risk of FSGS, HIV-associated kidney disease, kidney disease attributed to hypertension, and progression to kidney failure. This explains a significant part of the well-documented excess burden of kidney failure in people of African ancestry, which had previously been attributed largely to social and healthcare factors — though access, deprivation and quality of care remain enormously important and are not replaced by this finding. Practically, APOL1 genotyping is increasingly used when evaluating living kidney donors of African ancestry, and drugs that inhibit APOL1 are now in clinical trials.

If FSGS caused my kidney failure, can it come back after a transplant?

Yes, if it was primary FSGS — and this is one of the most striking phenomena in nephrology. Roughly thirty to fifty per cent of patients with primary FSGS develop recurrent proteinuria in the transplanted kidney, sometimes within hours or days of surgery, in a kidney that is genetically completely normal. This is the strongest clinical evidence that a circulating factor in the blood causes the disease. Recurrence is treated with plasma exchange or immunoadsorption to remove the factor, often combined with rituximab, and works best when started immediately. Importantly, genetic FSGS rarely recurs and secondary FSGS does not recur at all, which is exactly why establishing the underlying form before transplantation matters so much for counselling and planning.

How does GMJ News cover FSGS?

GMJ News covers FSGS as a pattern rather than a disease, the primary-secondary-genetic distinction and its treatment implications, the April 2026 sparsentan approval as the first ever for FSGS, APOL1 risk variants and kidney disease disparity, genetic testing in steroid-resistant nephrotic syndrome, post-transplant recurrence and the circulating permeability factor, Columbia histological variants including collapsing FSGS, podocyte biology and foot process effacement, obesity-related glomerulopathy and its management by weight loss rather than immunosuppression, HIV-associated nephropathy, and proteinuria as both therapeutic target and regulatory endpoint. Relevant to PHIG's kidney health, genetics and health equity programmes.

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Focal Segmental Glomerulosclerosis

GMJ News knowledge hub · last reviewed September 2026 · Georgian Medical Journal

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Focal segmental glomerulosclerosis (FSGS) is a pattern of glomerular scarring rather than a single disease, and is the commonest cause of primary nephrotic syndrome in adults in many countries and a leading cause of end-stage kidney disease, with a critical clinical division between primary FSGS (driven by a circulating permeability factor, presenting with abrupt heavy nephrotic-range proteinuria and diffuse podocyte foot process effacement, and potentially responsive to immunosuppression) and secondary or genetic forms (adaptive responses to obesity, reflux, reduced nephron mass, viral infection or drugs, where immunosuppression is inappropriate and harmful) (WHO). Two developments define the modern field: the recognition that APOL1 risk variants, carried at high frequency in people of West African ancestry, substantially increase FSGS and kidney failure risk and explain a major part of the racial disparity in kidney disease; and the April 2026 FDA approval of sparsentan as the first therapy ever approved specifically for FSGS, offering a non-immunosuppressive oral option for a disease that previously had no approved treatment.

Key messages

FSGS is a pattern of injury, not a single disease — and the distinction determines treatment

Focal (some glomeruli) and segmental (part of each affected glomerulus) sclerosis is a histological pattern with several distinct causes, and treating them identically causes harm. Primary FSGS: driven by a circulating permeability factor, presenting abruptly with heavy nephrotic-range proteinuria, hypoalbuminaemia and oedema, with DIFFUSE podocyte foot process effacement on electron microscopy — potentially responsive to immunosuppression. Secondary FSGS: an adaptive response to hyperfiltration (obesity, reduced nephron mass, reflux nephropathy, sickle cell disease) or to viruses and drugs — presenting with slowly rising subnephrotic proteinuria, preserved albumin, and only segmental foot process effacement. Genetic FSGS: podocyte gene mutations. Immunosuppression is appropriate ONLY in primary disease.

Sparsentan — the first therapy ever approved specifically for FSGS

In April 2026 the FDA approved sparsentan for focal segmental glomerulosclerosis — the first approval ever granted specifically for this indication, and the only non-immunosuppressive oral option for a disease that previously had no approved therapy at all. Sparsentan is a dual endothelin type A and angiotensin II type 1 receptor antagonist, targeting two pathways that both drive podocyte injury and proteinuria. Its significance extends beyond the drug itself: it establishes proteinuria reduction as an accepted regulatory endpoint in rare glomerular disease and opens a route for further approvals in a field that has had almost none.

APOL1 risk variants explain a major part of the racial disparity in kidney disease

Two APOL1 variants (G1 and G2), carried at high frequency in people of West African ancestry because they confer protection against trypanosomal infection, substantially increase the risk of FSGS, HIV-associated nephropathy, hypertension-attributed kidney disease and progression to kidney failure when two risk alleles are present. This is one of the clearest examples of a genetic factor accounting for a major health disparity previously attributed largely to social determinants alone — though environment and access still matter enormously. Practical implications include kidney donor evaluation, where APOL1 genotyping of living donors of African ancestry is increasingly performed, and the emergence of APOL1 inhibitors in clinical trials.

Steroid resistance should prompt genetic testing, not escalating immunosuppression

A substantial proportion of steroid-resistant nephrotic syndrome, particularly in children and young adults, is caused by mutations in podocyte structural genes — NPHS1 (nephrin), NPHS2 (podocin), WT1, INF2, TRPC6, ACTN4 and others. These patients do not respond to any immunosuppression, and continued escalation exposes them to serious cumulative toxicity for no benefit. Genetic testing therefore changes management decisively: it avoids futile treatment, informs prognosis, guides family counselling and — importantly — predicts a very low risk of post-transplant recurrence, in contrast to primary FSGS. Genetic testing should be considered in all steroid-resistant cases, congenital and infantile presentations, and familial disease.

Post-transplant recurrence is a defining feature of primary FSGS

Primary FSGS recurs in the transplanted kidney in roughly 30-50% of cases, sometimes within hours to days of transplantation — powerful clinical evidence for a circulating permeability factor, since the new kidney is genetically normal. Recurrence rates rise further in second transplants if the first was lost to recurrence. Treatment: plasma exchange or immunoadsorption to remove the putative factor, often combined with rituximab, with best results when started immediately. By contrast, genetic FSGS rarely recurs, and secondary FSGS does not — which is why establishing which form the patient has before transplantation is not academic but directly determines counselling and post-transplant planning.

Obesity-related FSGS is increasing and is managed entirely differently

Obesity-related glomerulopathy is a growing cause of secondary FSGS worldwide, driven by glomerular hyperfiltration, glomerulomegaly and podocyte stress. Its presentation is distinctive and frequently misread: slowly progressive subnephrotic proteinuria, preserved serum albumin and absent oedema even at substantial protein loss, and a perihilar sclerosis pattern on biopsy. Management is emphatically not immunosuppression but weight reduction — including bariatric surgery and, increasingly, GLP-1 receptor agonists — together with RAS blockade and SGLT2 inhibitors. Substantial weight loss can reduce proteinuria markedly and stabilise function, making this one of the more reversible forms of proteinuric kidney disease.

Key statistics

FDA April 2026

sparsentan approved as the first-ever therapy specifically for FSGS

FDA 2026

Primary vs secondary

immunosuppression is appropriate ONLY in primary FSGS — harmful in secondary and genetic forms

KDIGO

30-50%

post-transplant recurrence rate in primary FSGS — evidence of a circulating factor

KDIGO/AJT

APOL1 G1/G2

two risk alleles substantially increase FSGS and kidney failure risk in West African ancestry

NEJM/Science

Genetic testing

indicated in steroid-resistant nephrotic syndrome — avoids futile immunosuppression

KDIGO/IPNA

Obesity-related

FSGS presents with subnephrotic proteinuria and PRESERVED albumin — treat with weight loss, not steroids

KDIGO

FSGS — distinguishing primary from secondary and genetic forms

Source: KDIGO. Onset, albumin, oedema and electron microscopy findings separate forms that require opposite treatment.

Glossary of key terms

Histological variants of FSGS
PathologyThe Columbia classification defines five morphological variants with prognostic significance. Collapsing variant: segmental or global collapse of the capillary tuft with podocyte hyperplasia — the most aggressive form, associated with HIV, APOL1 high-risk genotype, interferon therapy, parvovirus and pamidronate; poor prognosis. Tip variant: lesion at the proximal tubular origin — the most steroid-responsive, best prognosis. Perihilar variant: at the vascular pole — characteristic of adaptive or secondary FSGS from hyperfiltration, including obesity-related disease. Cellular variant: endocapillary hypercellularity. Not otherwise specified (NOS): the commonest, and a diagnosis of exclusion. Variant alone does not determine treatment — clinical context and electron microscopy remain essential — but it contributes meaningfully to prognostication.

Podocytes and the filtration barrier
PhysiologyThe glomerular filtration barrier has three layers: fenestrated endothelium, glomerular basement membrane, and podocytes — specialised epithelial cells whose interdigitating foot processes are bridged by the slit diaphragm, a molecular sieve built from nephrin, podocin, CD2AP and associated proteins. Podocytes are terminally differentiated and essentially cannot be replaced, so podocyte loss is cumulative and irreversible — the central reason FSGS progresses. When podocytes are injured, foot processes retract and fuse (effacement), the slit diaphragm is lost, protein escapes, and denuded areas of basement membrane adhere to Bowman's capsule, initiating the sclerotic lesion. The distinction between diffuse effacement (primary, circulating factor) and segmental effacement (secondary, adaptive) is one of the most clinically consequential findings in renal pathology.

Circulating permeability factor
Research/NephrologyThe strongest evidence for a circulating factor in primary FSGS comes from clinical observation rather than the laboratory: recurrence of proteinuria within hours of transplanting a normal kidney; remission when plasma exchange removes the factor; and the remarkable documented cases in which a kidney transplanted from a donor with FSGS, then retransplanted into a recipient without it, ceased to be proteinuric. Candidate factors have included soluble urokinase plasminogen activator receptor (suPAR), cardiotrophin-like cytokine-1, anti-CD40 antibodies and anti-nephrin antibodies — the last attracting substantial recent interest, since circulating anti-nephrin antibodies have been identified in a proportion of patients with minimal change disease and primary FSGS, potentially reframing these as autoimmune podocytopathies.

Treatment of primary FSGS
KDIGOFirst-line is high-dose corticosteroids — prednisolone approximately 1 mg/kg daily (maximum 80 mg) or alternate-day equivalent, continued for a minimum of 4 weeks and up to 16 weeks before declaring steroid resistance, since responses in adult FSGS are characteristically slow. Complete remission rates are modest, around 30-40%, and partial remission is a clinically meaningful outcome strongly associated with better kidney survival. Second-line: calcineurin inhibitors (ciclosporin or tacrolimus) for steroid-resistant or steroid-dependent disease, with response rates around 50-60% but a high relapse rate on withdrawal and cumulative nephrotoxicity. Rituximab, mycophenolate and adrenocorticotrophic hormone have been used with variable evidence. All patients receive maximal supportive therapy regardless of immunosuppression.

HIV-associated nephropathy
Infectious disease/NephrologyHIVAN classically presents as collapsing FSGS with heavy proteinuria, rapid decline in kidney function and, characteristically, large echogenic kidneys without the shrinkage expected in chronic disease. It occurs almost exclusively in people of African ancestry with APOL1 high-risk genotypes, illustrating a gene-environment interaction in which viral infection triggers disease only in genetically susceptible hosts. Antiretroviral therapy transformed HIVAN from a rapidly progressive cause of kidney failure into an uncommon complication, and is the primary treatment; ACE inhibitors and, in some cases, corticosteroids are adjuncts. Other kidney complications in HIV must be distinguished: immune complex disease, tenofovir-associated proximal tubulopathy, and the nephrotoxicity of some antimicrobials.

Proteinuria as treatment target and endpoint
Nephrology/RegulatoryReduction of proteinuria is both the therapeutic goal and, increasingly, the accepted regulatory endpoint in glomerular disease. The rationale: proteinuria is not merely a marker of glomerular damage but is directly nephrotoxic, driving tubulointerstitial inflammation and fibrosis — and interstitial fibrosis, more than the glomerular lesion, determines long-term outcome. Achieving partial remission (usually defined as proteinuria below 3.5 g/day with a 50% reduction, or below 1 g/day in some definitions) is associated with substantially better kidney survival even without complete remission. Because trials using kidney failure as an endpoint would require decades in slowly progressive rare diseases, regulators have accepted proteinuria reduction as reasonably likely to predict clinical benefit — the pathway through which sparsentan and comparable agents have reached approval.

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