Residency · Residency · Nephrology

Minimal Change Disease and Focal Segmental Glomerulosclerosis

Introduction

Minimal change disease and focal segmental glomerulosclerosis represent a spectrum of podocytopathies in which the primary pathologic process targets the podocyte. MCD is the most common cause of nephrotic syndrome in children, accounting for 70 to 90 percent of pediatric cases, and accounts for 10 to 15 percent of nephrotic syndrome in adults. FSGS is the most common primary glomerular disease leading to ESRD in the United States, with a disproportionate impact on African Americans, driven in large part by APOL1 risk variants. Both diseases present with nephrotic syndrome but are distinguished by their renal biopsy findings, clinical behavior, and prognosis.

Minimal Change Disease

Pathogenesis

The exact pathogenesis of MCD remains incompletely understood, though it is believed to involve T-cell dysfunction leading to the production of circulating permeability factor or factors that injure podocytes. The disease is associated with atopy, Hodgkin lymphoma, NSAID use, and lithium therapy. Cytokine-mediated podocyte injury is thought to be central, with proposed mediators including IL-13, TNF-alpha, and upregulation of CD80 (B7-1) on podocytes. The dramatic responsiveness to corticosteroids that characterizes MCD strongly supports an immune-mediated pathogenesis.

Clinical Presentation

MCD presents with the abrupt onset of full nephrotic syndrome, often with massive proteinuria exceeding 10 grams per day, severe edema or anasarca, and hypoalbuminemia. Hematuria is minimal or absent, and its presence should prompt consideration of an alternative diagnosis. Complement levels are normal and serologic testing is unremarkable. AKI occurs in 20 to 25 percent of adults, resulting from hypovolemia-induced acute tubular necrosis, interstitial edema, or direct tubular injury. Spontaneous remission is less common in adults than in children.

Renal Biopsy

On light microscopy, the glomeruli appear entirely normal, hence the name "minimal change." Proximal tubular cells may contain lipid droplets reflecting the heavy proteinuria. Immunofluorescence is negative or shows only trace non-specific staining. Electron microscopy reveals the characteristic finding of diffuse podocyte foot process effacement, exceeding 80 percent of the glomerular capillary surface, without electron-dense deposits. Biopsy is indicated in adults presenting with nephrotic syndrome; children are treated empirically with steroids, with biopsy reserved for steroid-resistant cases.

Treatment

The first-line treatment for MCD is corticosteroids. In adults, prednisone is initiated at 1 mg/kg/day with a maximum of 80 mg, or alternatively at 2 mg/kg every other day, and should be continued for at least 16 weeks before the patient is declared steroid-resistant, as per KDIGO 2021 guidelines. Complete remission is defined as proteinuria below 0.3 grams per day. The response rate in adults is 70 to 80 percent, compared to over 90 percent in children, and the median time to remission is 4 to 8 weeks, which is longer than in children. After remission is achieved, the steroid dose is tapered gradually over 6 months.

Relapse management depends on frequency. Infrequent relapsers receive a repeat steroid course. Frequent relapsers, defined as 2 or more relapses within 6 months or 4 or more within 12 months, and steroid-dependent patients, who relapse during taper or within 2 weeks of stopping steroids, require steroid-sparing agents.

Among steroid-sparing agents, calcineurin inhibitors (cyclosporine at 3 to 5 mg/kg/day or tacrolimus at 0.05 to 0.1 mg/kg/day) are the most commonly used but carry a high relapse rate upon discontinuation. Cyclophosphamide at 2 mg/kg/day for 8 to 12 weeks can induce prolonged remission but is limited to a single course due to cumulative toxicity. Rituximab is increasingly used for frequently relapsing and steroid-dependent MCD and is recommended by KDIGO 2021, as it allows withdrawal of steroids and CNIs in many patients. Mycophenolate mofetil at 1 to 2 grams per day is an alternative but is generally less effective than CNIs or rituximab for achieving sustained remission.

<image>Treatment algorithm for minimal change disease in adults. Start with initial presentation of nephrotic syndrome with biopsy-confirmed MCD. First-line: prednisone 1 mg/kg/day (max 80 mg) for minimum 16 weeks. If complete remission achieved: taper prednisone over 6 months. If no relapse: observe. If infrequent relapse: repeat steroid course. If frequent relapse (≥2 in 6 months) or steroid-dependent: add steroid-sparing agent. Show three parallel options: rituximab (375 mg/m2 x 4 weekly doses or 1000 mg x 2), calcineurin inhibitor (cyclosporine or tacrolimus for 1-2 years then slow taper), or cyclophosphamide (2 mg/kg/day x 8-12 weeks, one course only). If steroid-resistant (no remission after 16 weeks): rebiopsy to rule out FSGS, then consider CNI + low-dose prednisone. Include monitoring parameters: proteinuria, albumin, creatinine at each decision point.</image>

Focal Segmental Glomerulosclerosis

Classification

FSGS is classified into distinct forms based on etiology and pathogenesis. Primary or idiopathic FSGS is driven by a circulating permeability factor and is the most common form encountered in clinical practice. Secondary or adaptive FSGS results from conditions causing reduced nephron mass, such as a solitary kidney, reflux nephropathy, low birth weight, or prior nephrectomy, or from hyperfiltration states including obesity, sickle cell disease, and cyanotic congenital heart disease. Distinguishing features of secondary FSGS include lower proteinuria that is often subnephrotic, less edema, and less extensive foot process effacement on electron microscopy, typically below 50 percent. Genetic FSGS results from mutations in podocyte genes including NPHS1 (nephrin), NPHS2 (podocin), ACTN4 (alpha-actinin-4), TRPC6, INF2, WT1, LAMB2, and COL4A3-5, and does not respond to immunosuppression. APOL1-associated FSGS is driven by G1 and G2 risk variants on chromosome 22, where two risk alleles (homozygous or compound heterozygous) increase FSGS risk 17-fold in African Americans, with the collapsing variant being more common. Virus-associated FSGS includes HIV-associated nephropathy (HIVAN), which characteristically presents as the collapsing variant, as well as parvovirus B19, CMV, and COVID-19-associated collapsing glomerulopathy. Drug-associated FSGS may result from pamidronate, interferon, anabolic steroids, or lithium.

Histologic Variants (Columbia Classification)

The Columbia classification identifies five histologic variants. The NOS (not otherwise specified) variant is the most common, showing segmental sclerosis in some glomeruli without the defining features of other variants. The perihilar variant demonstrates sclerosis at the vascular pole and is the most common variant in adaptive or secondary FSGS. The cellular variant shows endocapillary hypercellularity with foam cells within a sclerotic segment. The tip variant displays sclerosis at the tubular pole, carries the best prognosis among all variants, and has the highest steroid responsiveness. The collapsing variant, characterized by collapse of the capillary tuft with overlying podocyte hypertrophy and hyperplasia forming a pseudocrescent, carries the worst prognosis and is associated with APOL1 risk variants, HIV, and COVID-19.

Pathogenesis of Primary FSGS

Primary FSGS is believed to be driven by circulating permeability factors, with proposed candidates including soluble urokinase plasminogen activator receptor (suPAR) and cardiotrophin-like cytokine factor 1 (CLCF1). SuPAR has been found elevated in some primary FSGS patients and activates podocyte beta-3 integrin, leading to foot process effacement. The strongest evidence for a circulating factor comes from the rapid recurrence of primary FSGS in 30 to 40 percent of kidney transplants, the response of recurrent disease to plasmapheresis, and the ability to transfer proteinuria to animal models using patient serum.

Clinical Presentation

Primary FSGS typically presents with nephrotic syndrome, while secondary FSGS more commonly manifests as subnephrotic proteinuria. Hypertension is common, occurring in approximately 50 percent of patients. Microscopic hematuria is present in 30 to 50 percent. Reduced GFR is found at presentation in 25 to 50 percent, and without effective treatment, approximately 50 percent of patients with steroid-resistant primary FSGS progress to ESRD within 5 to 10 years.

Renal Biopsy

Light microscopy demonstrates segmental solidification of the capillary tuft in some glomeruli, and the specific Columbia variant should be identified. Immunofluorescence shows non-specific trapping of IgM and C3 in sclerotic segments without true immune complex deposits. Electron microscopy reveals foot process effacement that exceeds 80 percent in primary FSGS but is typically below 50 percent in secondary or adaptive forms, without electron-dense deposits. Sampling error is an important consideration, as early FSGS lesions may be confined to juxtamedullary glomeruli that are deeper than the typical biopsy sample reaches, and a minimum of 20 glomeruli is recommended for adequate sampling.

<image>Comparison panel showing the five Columbia classification histologic variants of FSGS. Create five side-by-side illustrations of glomerular cross-sections: (1) NOS: segmental area of sclerosis with hyalinosis and foam cells in a portion of one capillary tuft. (2) Perihilar: sclerosis and hyalinosis at the vascular pole where afferent and efferent arterioles enter. (3) Cellular: endocapillary hypercellularity filling a segment of the capillary tuft with foam cells and infiltrating cells. (4) Tip: sclerosis at the tubular pole where the glomerular tuft meets the origin of the proximal tubule. (5) Collapsing: global or segmental collapse and wrinkling of the capillary tuft with overlying podocyte hypertrophy and hyperplasia forming a pseudocrescent. Label each variant with its relative prognosis (best to worst: tip > NOS > cellular > perihilar > collapsing).</image>

Treatment of Primary FSGS

First-line therapy for primary FSGS is corticosteroids, with prednisone at 1 mg/kg/day (maximum 80 mg) or 2 mg/kg every other day for at least 16 weeks. The response rate is 40 to 60 percent, substantially lower than in MCD. Steroid resistance is defined as no remission after 16 weeks of adequate-dose therapy.

For steroid-resistant primary FSGS, calcineurin inhibitors are the preferred second-line agents, with cyclosporine targeting a trough of 125 to 175 ng/mL or tacrolimus targeting a trough of 5 to 10 ng/mL, combined with low-dose prednisone for at least 6 months. If a response is achieved, treatment should continue for at least 12 months with slow taper. Rituximab has limited evidence in steroid-resistant FSGS but may benefit steroid-dependent cases. Mycophenolate combined with dexamethasone is an alternative for CNI-intolerant patients.

Treatment of secondary or adaptive FSGS does not involve immunosuppression. Instead, the underlying cause should be addressed, such as antiretroviral therapy for HIVAN or weight loss for obesity-related FSGS, combined with RAAS blockade for antiproteinuric effect and SGLT2 inhibitors.

Treatment of genetic FSGS is similarly non-immunosuppressive, relying on RAAS blockade and supportive care. Some CoQ10-related variants may respond to coenzyme Q10 supplementation.

Emerging Therapies

Sparsentan, a dual endothelin and angiotensin receptor antagonist, demonstrated superior proteinuria reduction compared to irbesartan in the DUPLEX trial for FSGS and is FDA-approved for IgA nephropathy with ongoing evaluation for FSGS. Inaxaplin (VX-147), an APOL1 inhibitor, blocks APOL1-mediated podocyte injury and has shown significant proteinuria reduction in phase 2/3 trials in patients with APOL1-mediated FSGS. Abatacept, a CTLA4-Ig fusion protein, has been reported in case reports to show efficacy in B7-1 (CD80)-positive podocytopathy, but this approach remains controversial and has not been widely adopted.

Distinguishing MCD from FSGS

Key Differences

Diagnostic Uncertainty

Early FSGS may appear as MCD on renal biopsy due to sampling error when the sclerotic lesions are limited to juxtamedullary glomeruli not captured in the biopsy specimen. Steroid-resistant "MCD" should undergo repeat biopsy to rule out missed FSGS. There is evidence that FSGS may evolve from MCD in some patients, reflecting a spectrum of podocyte injury rather than two entirely distinct diseases.

<image>Electron microscopy comparison showing the ultrastructural differences between MCD and primary FSGS. Left panel: MCD showing diffuse foot process effacement (>80%) along the entire GBM with no electron-dense deposits and a normal-thickness GBM. The podocyte cell body is shown with microvillous transformation. Right panel: Primary FSGS showing segmental foot process effacement, areas of GBM denudation (podocyte detachment), wrinkling of the GBM, and endothelial foam cells in a sclerotic segment. Include an inset showing the slit diaphragm disruption with displacement of nephrin and podocin. Label all key ultrastructural features clearly.</image>

Key Clinical Pearls

• MCD in adults requires at least 16 weeks of steroids before declaring steroid resistance; premature discontinuation is a common management error
• Rituximab has become an important steroid-sparing agent for frequently relapsing and steroid-dependent MCD in adults
• The collapsing variant of FSGS carries the worst prognosis and should prompt evaluation for APOL1 risk variants, HIV, and COVID-19
• Secondary/adaptive FSGS should NOT be treated with immunosuppression; look for obesity, reduced nephron mass, and other hyperfiltration states
• Primary FSGS recurs in 30-40% of transplants, often within hours to days; plasmapheresis is the treatment of choice; risk is highest in patients with rapid progression to ESRD, young age, and possible circulating factor

References

1. Vivarelli M, Massella L, Ruber B, et al. Is Focal Segmental Glomerulosclerosis a Single Disease? Kidney Int. 2017;91(6):1292-1298.
2. Rovin BH, Adler SG, Barratt J, et al. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int. 2021;100(4S):S1-S276.
3. D'Agati VD, Kaskel FJ, Falk RJ. Focal Segmental Glomerulosclerosis. N Engl J Med. 2011;365(25):2398-2411.
4. Dossier C, Jamin A, Deschenes G. Idiopathic Nephrotic Syndrome: The EBV Hypothesis. Pediatr Res. 2017;81(1-2):233-239.
5. Friedman DJ, Pollak MR. APOL1 Nephropathy: From Genetics to Clinical Applications. Clin J Am Soc Nephrol. 2021;16(2):294-303.

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