Focal segmental glomerulosclerosis, widely known as FSGS, is one of the most challenging kidney diseases in clinical nephrology. Rather than a single discrete condition, FSGS is a pattern of glomerular injury — a histological finding reflecting damage to specific filtering units of the kidney called glomeruli. Its heterogeneous nature means it can arise from diverse causes, follow unpredictable clinical courses, and respond very differently to treatment. For patients, a diagnosis of FSGS can carry serious consequences, including progressive kidney function loss and, in many cases, end-stage renal disease (ESRD) requiring dialysis or transplantation.
Over the past two decades, advances in molecular genetics have fundamentally transformed our understanding of FSGS. The International Society of Nephrology has been at the forefront of this transformation, supporting research, developing clinical practice guidelines, and raising awareness about genetic testing in appropriate patient populations. This article explores the genetic landscape of FSGS and how ISN (International Society of Nephrology) is helping guide the field toward precision nephrology.
What Is FSGS and Why Does It Matter?
To understand why genetics plays such a central role in FSGS, it helps to first understand what the disease actually is and what happens in the kidneys of affected individuals.
The kidneys filter blood through tiny structures called glomeruli — microscopic bundles of capillaries surrounded by specialized cells. Among the most critical are podocytes, which form a highly selective filtration barrier that retains proteins in the bloodstream while allowing water and small molecules to pass. When podocytes are damaged, proteins — particularly albumin — leak into the urine, a condition called proteinuria. In FSGS, this damage leads to scarring of segments of the glomeruli, progressively impairing kidney function.
Clinically, FSGS typically presents with heavy proteinuria, often reaching the threshold of nephrotic syndrome, which is defined by:
- Protein loss in the urine exceeding 3.5 grams per day in adults
- Low blood albumin levels (hypoalbuminemia)
- Swelling caused by fluid retention (edema)
- Elevated blood lipid levels (hyperlipidemia)
Without effective treatment, FSGS frequently progresses to ESRD. It accounts for a substantial proportion of nephrotic syndrome cases in adults and is particularly prevalent among individuals of African ancestry, a disparity that, as we will explore, has a significant genetic explanation.
The Genetic Architecture of FSGS: Key Discoveries
The recognition that FSGS could be caused by mutations in single genes — so-called monogenic forms of the disease — was a pivotal moment in nephrology. It meant that for some patients, particularly children with steroid-resistant disease, the underlying cause was not an immune dysfunction but rather a structural defect in podocyte biology encoded in their DNA.
Podocin and the NPHS2 Gene
A landmark paper published in Nature Genetics in 2000 by Boute and colleagues identified mutations in a gene called NPHS2, which encodes a protein known as podocin, as the major monogenic cause of autosomal recessive steroid-resistant nephrotic syndrome. Podocin is a critical structural protein in the podocyte filtration apparatus; without functional podocin, the filtration barrier breaks down, leading to proteinuria and eventual glomerulosclerosis.
This discovery had immediate clinical implications. Children with NPHS2 mutations typically do not respond to corticosteroid therapy — the standard first-line treatment for nephrotic syndrome — because their disease is not driven by immune mechanisms but by a fixed structural defect. Treating them with prolonged courses of steroids and immunosuppressive agents would therefore expose them to significant side effects without clinical benefit.
Beyond Podocin: Expanding the Genetic Landscape
Following the identification of NPHS2, subsequent research uncovered a growing list of genes whose mutations can cause FSGS or related glomerular diseases:
| Gene | Encoded Protein | Associated Condition | Inheritance Pattern |
|---|---|---|---|
| NPHS2 | Podocin | Steroid-resistant nephrotic syndrome | Autosomal recessive |
| NPHS1 | Nephrin | Congenital nephrotic syndrome | Autosomal recessive |
| WT1 | Wilms Tumor protein 1 | FSGS with extrarenal features (e.g., Denys-Drash syndrome) | Autosomal dominant |
| TRPC6 | Transient receptor potential cation channel 6 | Adult-onset FSGS | Autosomal dominant |
| INF2 | Inverted formin 2 | FSGS, sometimes with Charcot-Marie-Tooth disease | Autosomal dominant |
These findings collectively established that FSGS is a genetically heterogeneous condition, with different mutations affecting different components of the podocyte cytoskeleton, slit diaphragm, or signaling pathways. This heterogeneity has important implications for how patients are diagnosed and managed.
The Role of Genetic Testing in Clinical Practice
Given the diversity of genetic causes of FSGS, next-generation sequencing (NGS) has become an increasingly valuable diagnostic tool. NGS technologies allow clinicians to simultaneously analyze dozens or even hundreds of genes in a single test, dramatically improving diagnostic efficiency and yield.
A study by Trautmann and colleagues published in the Journal of the American Society of Nephrology in 2018 evaluated a panel of 40 genes in a large cohort of children with nephrotic syndrome. Among those with steroid-resistant disease, causative genetic variants were identified in approximately 25 percent — a clinically meaningful proportion with direct consequences for management. These findings informed decisions about whether to pursue immunosuppressive therapy and guided evaluation of potential living-related kidney donors.
This last point deserves emphasis: if a child with FSGS carries a pathogenic mutation such as in NPHS2, a parent who carries the same variant may themselves face elevated kidney disease risk. Identifying such mutations before proceeding with living-donor transplantation is therefore not merely academic — it is an ethical imperative protecting both donor and recipient.
When Should Genetic Testing Be Considered?
The International Society of Nephrology, through its active involvement in the Kidney Disease: Improving Global Outcomes (KDIGO) collaborative framework, has helped shape clinical recommendations around genetic testing in FSGS. The KDIGO Clinical Practice Guidelines for Glomerulonephritis, published in 2012 and updated in 2021, recommend genetic evaluation in pediatric FSGS patients when any of the following features are present:
- Early age of onset (particularly in infants and young children)
- Family history of nephrotic syndrome or kidney failure
- Extrarenal features suggesting a syndrome (such as hearing loss, eye abnormalities, or genital anomalies)
- Failure to respond to standard corticosteroid therapy
These criteria reflect a rational approach to genetic testing — focusing resources on patients most likely to benefit from a genetic diagnosis while acknowledging that not every case of FSGS requires a full genomic workup.
APOL1: Genetics, Ancestry, and Health Disparities
Among the most consequential genetic discoveries in nephrology in recent years is the identification of the APOL1 gene as a major risk factor for FSGS and other kidney diseases in individuals of recent African ancestry. This finding has reshaped our understanding of racial disparities in kidney disease and opened new avenues for targeted therapy.
The Discovery of APOL1 Risk Variants
In a landmark 2010 paper published in Science, Genovese and colleagues identified two specific variants in the APOL1 gene — referred to as G1 and G2 risk alleles — that are present at relatively high frequencies in populations of West African descent. Individuals who inherit two copies of these risk alleles (one from each parent) face a substantially elevated risk of developing non-diabetic ESRD, FSGS, and HIV-associated nephropathy compared to those with zero or one risk allele.
This discovery provided a compelling genetic explanation for the long-observed disparity in FSGS prevalence and kidney disease progression between Black and non-Black Americans. Black Americans are significantly overrepresented among FSGS patients and those who reach ESRD at younger ages, and a substantial fraction of this disparity is attributable to APOL1 high-risk genotypes. The G1 and G2 alleles appear to have been positively selected in West African populations because they confer protection against certain forms of sleeping sickness — a classic evolutionary trade-off where protection against a historically deadly infection carries a cost in the form of elevated kidney disease risk.
APOL1 and the Promise of Targeted Therapy
Understanding the mechanism by which APOL1 risk variants damage the kidney has opened the door to therapeutic intervention. The protein encoded by APOL1 forms pores in cellular membranes, and the risk variants alter its activity in ways that appear to be toxic to podocytes and other kidney cells under certain conditions — a phenomenon sometimes described as a “second hit” model, where additional factors trigger disease in genetically susceptible individuals.
A phase 2 clinical trial published in the New England Journal of Medicine in 2023 by Freedman and colleagues evaluated inaxaplin, a small-molecule inhibitor designed to block the activity of the APOL1 risk variant protein. The trial demonstrated meaningful reductions in proteinuria among participants with APOL1 high-risk genotypes and FSGS, representing a significant step toward precision therapy for this population. While the treatment is not yet in routine clinical use, this study demonstrated the principle that targeting the specific molecular mechanism of APOL1-associated kidney disease is both feasible and clinically meaningful.
Ethical Dimensions of APOL1 Genetic Testing
The identification of APOL1 as a major kidney disease risk gene has raised important ethical questions. The International Society of Nephrology has been active in highlighting these through educational publications and scientific symposia.
One of the most pressing concerns involves living kidney donation. If a potential donor carries two APOL1 risk alleles, their own lifetime risk of developing kidney disease may be elevated. Proceeding with donation in such cases requires careful counseling and individualized risk assessment, weighing the benefit to the recipient against long-term risk to the donor. A review published in the Clinical Journal of the American Society of Nephrology in 2021 by Doshi and colleagues examined these considerations in depth, reflecting a growing consensus that APOL1 testing should be incorporated into pre-donation evaluations — with appropriate genetic counseling — rather than used as a blanket exclusion criterion.
There are also broader concerns about how ancestry-linked genetic information might be interpreted. APOL1 risk variants are associated with African ancestry, but ancestry is not a simple category, and the relationship between genetic ancestry and self-identified race is complex. ISN has emphasized that genetic information must be used to reduce health disparities — never to reinforce them.
Precision Nephrology: A New Paradigm
The International Society of Nephrology has embraced precision nephrology as a strategic priority, recognizing that a one-size-fits-all approach to FSGS is insufficient. Different genetic subtypes have different prognoses, respond differently to immunosuppression, and carry distinct implications for family members. A patient whose FSGS is caused by an NPHS2 mutation should not receive the same treatment as one driven by APOL1 risk variants or an uncharacterized immune mechanism — even if their kidney biopsies appear identical.
ISN’s educational programs, clinical practice guidelines developed through the KDIGO framework, and global research collaborations are all oriented toward making precision nephrology a clinical reality — not only in well-resourced settings, but worldwide. Equitable access to genetic testing and targeted therapies remains a significant challenge, particularly in low- and middle-income countries where kidney disease burden is high but diagnostic resources are limited.
Looking Ahead: Research Priorities and Unanswered Questions
Despite the remarkable progress of recent years, many questions in the genetics of FSGS remain unanswered. Even with comprehensive NGS panels, causative variants are found in only a minority of FSGS patients, leaving the underlying mechanisms in most cases unexplained. Not all individuals with APOL1 high-risk genotypes develop kidney disease, which points to the importance of gene-environment interactions that are not yet well understood. Phase 2 trial data for inaxaplin are promising, but larger, longer-term studies are needed to establish safety and durability of response. Perhaps most importantly, ensuring equitable global access to genetic testing and emerging precision therapies remains a fundamental challenge for the field.
Conclusion
Focal segmental glomerulosclerosis is no longer simply a histological pattern seen under the microscope — it is a window into the molecular diversity of podocyte biology, the evolutionary history of human populations, and the future of personalized medicine in nephrology. The genetic discoveries of the past two decades have transformed how clinicians approach FSGS, enabling more precise diagnoses, more rational treatment decisions, and the first steps toward therapies designed for specific molecular subtypes of disease.
The International Society of Nephrology has played a central role in translating these discoveries into clinical practice through guideline development, global educational initiatives, and a sustained commitment to the ethical dimensions of genetic medicine in kidney disease. As precision nephrology continues to evolve, ISN remains dedicated to ensuring its benefits are shared equitably across all patient populations — regardless of geography, ancestry, or economic circumstance. For patients living with FSGS and the clinicians who care for them, the era of genetic medicine in nephrology offers genuine and growing reason for optimism.