Focal Segmental Glomerulosclerosis

Continuing Education Activity

Focal segmental glomerular sclerosis (FSGS) is histologically characterized by segmental scarring that involves a part of the glomerulus and only affects some but not all glomeruli sampled. Patients with this condition can present with the clinical manifestations of nephrotic syndrome or with hematuria, hypertension or renal insufficiency. This activity reviews the evaluation and management of focal segmental glomerular sclerosis and explains the role of the interprofessional team in improving care for patients with this condition.


  • Identify the etiology of focal segmental glomerular sclerosis.
  • Describe the role of podocytes, epithelial cells and basement membrane in the pathophysiology of focal segmental glomerular sclerosis.
  • Outline the use of steroids and immunosuppressive therapies in the management of focal segmental glomerular sclerosis.
  • Summarize the importance of collaboration and communication among the interprofessional team members to enhance the delivery of care for patients affected by focal segmental glomerular sclerosis.


Focal segmental glomerular sclerosis (FSGS) is a frequently encountered cause of nephrotic syndrome, accounting for 40% of cases in adults and 20% in children.[1] Histologically, it is characterized by segmental scarring, involving a part of the glomerulus, and affects some but not all glomeruli sampled. Recent research has shed light on the pathogenesis of FSGS which is podocyte injury and damage, leading to protein loss and subsequent development of focal sclerosing lesions.[2] FSGS is broadly categorized into primary (idiopathic) and secondary forms, and such distinction carries both prognostic and therapeutic implications.[3]


Recent research has shed light on the pathogenesis and etiology of focal segmental glomerular sclerosis (FSGS), which is podocyte injury. Several genetic and acquired causes of podocyte injury have been identified.


Several genes encoding slit diaphragm proteins, cell membrane proteins, cytoskeleton proteins, nuclear proteins, mitochondrial proteins, and lysosomal proteins have been identified to be abnormal/mutated leading to loss of integrity of glomerular filtration barrier resulting in FSGS.[4]

Circulating Permeability Factor

Primary FSGS has long been thought to be due to the presence of circulating permeability factors/cytokines which causes foot process effacement and proteinuria. These include cardiotrophin-like cytokine factor 1, apoA1b, anti-CD40 Ab and suPAR.[5][6][7]


Viral causes include HIV[8][9], parvo B19, CMV, EBV, hepatitis C, and Simian virus 40.


Drugs associated with FSGS include heroin, interferon, lithium, pamidronate, mTOR inhibitors, anabolic steroid.[10][11][12]

Adaptive response to several stimuli resulting in glomerular hypertension, hyperfiltration and eventual hypertrophy including diabetes mellitus, hypertension, obesity, renal aplasia, hypoplasia or dysplasia, renal artery stenosis, cholesterol emboli, and vascular disease can lead to FSGS. Histopathologically, these are characterized by large glomeruli, the predominance of perihilar scarring, and partial foot process effacement.[13][14]


The exact incidence and prevalence data of FSGS is difficult to ascertain due to significant racial and geographical differences in incidence.[15] The estimated incidence of FSGS is about 7 per 1 million with a prevalence of 4% as described by Kitiyakara et al. in 2003.[16]. In the United States, approximately 50% of nephrotic syndrome in AA is attributed to FSGS. However, the prevalence of FSGS has gradually increased over the years, and it is the most common primary glomerular process contributing to end-stage renal disease in the United States. The increasing incidence is likely due to improved recognition and detection of the entity, with a better understanding of the pathophysiology of podocyte injury and development of therapy targeting mediators of such injury.


The pathogenesis of focal segmental glomerular sclerosis (FSGS) involves a complex interplay of several cell types including podocytes, endothelial cells, and the basement membrane. Podocytes are terminally differentiated cells that provide structural support to the glomerulus and are essential in maintaining an intact glomerular filtration barrier essential to prevent nephrotic range proteinuria. Injury and loss of podocytes result in podocyte hypertrophy of remaining podocytes to cover the glomerular capillary surface resulting in effacement and protein loss.[17][18]


Histologically, focal segmental glomerular sclerosis (FSGS) is characterized by sclerosis, hyalinosis, adhesions/synechiae formation, resulting in segmental obliteration of glomerular capillaries. On EM, foot process effacement is the predominant finding without significant basement membrane abnormalities. Immunofluorescence shows staining for IgM and C3 in sclerotic areas. Juxtamedullary nephrons are affected first and hence inadequate sampling may miss focal lesions. 

Histologically, FSGS is classified into five variants: perihilar, tip, cellular, collapsing and NOS (not otherwise specified).[3][19][20]

Perihilar: The sclerosing lesion is located at the vascular pole of the glomerulus. This is commonly seen in adaptive FSGS due to increased pressure in the glomerulus which is in close proximity to the afferent arteriole. Foot process effacement is mild, resulting in subnephrotic proteinuria and relatively normal serum albumin levels. 

Tip: The segmental lesion involves the tubular pole of the glomerulus. This is commonly seen in Caucasians, presenting with diffuse foot process effacement and abrupt onset of nephrotic syndrome. These patients have lower baseline creatinine, have an excellent response to treatment, and the lowest rate of progression.[21]

Cellular: This is the least common variant of FSGS, characterized by hypercellular glomerulus including endocapillary and glomerular epithelial cell hyperplasia. It presents with diffuse foot process effacement and full-blown nephrotic syndrome.[22]

Collapsing:- This is characterized by hyperplasia and hypertrophy of visceral glomerular epithelial cells leading to the collapse of the glomerular tuft. This is commonly seen in viral (parvovirus B19, CMV, HIV)[23][24] and drug-associated forms of FSGS (IFN, pamidronate)[25] and presents with diffuse effacement of foot processes, heavy proteinuria with the lowest rate of remission, and the worst prognosis.

NOS: This is the most common subtype of FSGS and does not fit into any other morphological forms of FSGS. It presents with a variable degree of effacement and proteinuria.

Histopathology may sometimes resemble nodular sclerosis as in diabetes and other conditions.[26]

History and Physical

Children with focal segmental glomerular sclerosis (FSGS) typically present with the full-blown nephrotic syndrome (edema, massive proteinuria, hypoalbuminemia, hypercholesterolemia). Adults can have nephrotic or sub-nephrotic proteinuria, hypertension, microscopic hematuria, or present with renal insufficiency. Patients with primary FSGS often have profound hypoalbuminemia and edema, but these are rare in secondary forms.

It is essential to obtain an extensive history including birth history (low birth weight/premature birth, congenital renal malformations), family history, medical comorbidities, pre-existing renal disease, exposure to drugs/toxins, recent viral illnesses, and family history to identify secondary causes of FSGS.


  1. Basic laboratory tests including metabolic panel, lipid panel, serum albumin
  2. urinalysis with microscopy
  3. 24-hour urine collection for protein quantification
  4. Hepatitis and HIV serology
  5. Complement levels
  6. Serum and urine protein electrophoresis in elderly to rule out paraproteinemias

Ultimately, a kidney biopsy is required to confirm the diagnosis of FSGS.

Treatment / Management

Glucocorticoids (daily or every other day) are the first line of treatment in children and adults with focal segmental glomerular sclerosis (FSGS). Patients who are resistant or intolerant to steroids are treated with immunosuppressive therapy with calcineurin inhibitors (CNI), mycophenolate mofetil, or rituximab.[27][28][29]

  • Oral prednisone: 2 mg/kg/day for 6 weeks followed by 1 mg/kg/day on alternate days for 6 weeks in children and 1mg/kg/day for 3 to 6 months in adults
  • CNI: Tacrolimus (0.2 to 0.3 mg/kg/day) or cyclosporine (3 to 5 mg/kg/day) for 6 to 12 months
  • MMF: 25 to 35 mg/kg/day +/- dexamethasone

 In patients with subnephrotic proteinuria, adaptive FSGS, a trial of RAS inhibition, and sodium restriction can be tried. In other secondary forms of FSGS, removing the offending agent or treating the underlying disorder is recommended. Optimization of blood pressure, treatment of edema with diuretics, statin therapy for hypercholesterolemia and anticoagulation in select patients at risk for thrombosis/embolization are indicated. 

Children respond within a few weeks, but adults may take months to respond. Glucocorticoids are associated with a remission rate of approximately 30% compared to about 50% in patients treated with CNI. Rituximab, mTOR inhibitors, and plasmapheresis have been tried in select patients with varied results.

Differential Diagnosis

  • Hematuria
  • Mesangial proliferative glomerulonephritis
  • Membranoproliferative glomerulonephritis
  • Nephrotic syndrome
  • Nephropathy
  • Systemic lupus erythematosus


Several features predict outcome in FSGS including, race (Blacks have worse outcomes), degree of proteinuria, presence of renal insufficiency, histological variant (tip variant had the best outcome and collapsing variant had the worst outcome), degree of IFTA (interstitial fibrosis/tubular atrophy) and response to treatment with patients attaining partial or complete remission having better prognosis. Also, patients with primary FSGS did worse when compared to those with adaptive/secondary causes of FSGS.[30][31]

Enhancing Healthcare Team Outcomes

Focal segmental glomerular sclerosis (FSGS) is a frequently encountered cause of nephrotic syndrome, accounting for 40% of cases in adults and 20% in children.[1] Because of the numerous causes and varied presentation, the condition is best managed by an interprofessional team that includes a nephrologist, pharmacist, internist, and pathologist. 

Several features predict outcome in FSGS including, race (Blacks have worse outcomes), degree of proteinuria, presence of renal insufficiency, histological variant (tip variant had the best outcome and collapsing variant had the worst outcome), degree of IFTA (interstitial fibrosis/tubular atrophy) and response to treatment with patients attaining partial or complete remission having better prognosis. Also, patients with primary FSGS did worse when compared to those with adaptive/secondary causes of FSGS.[30][31] (Level V)

Article Details

Article Editor:

Krishna Baradhi


7/26/2021 3:07:28 PM



McGrogan A,Franssen CF,de Vries CS, The incidence of primary glomerulonephritis worldwide: a systematic review of the literature. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2011 Feb     [PubMed PMID: 21068142]


Wiggins RC, The spectrum of podocytopathies: a unifying view of glomerular diseases. Kidney international. 2007 Jun     [PubMed PMID: 17410103]


D'Agati VD,Fogo AB,Bruijn JA,Jennette JC, Pathologic classification of focal segmental glomerulosclerosis: a working proposal. American journal of kidney diseases : the official journal of the National Kidney Foundation. 2004 Feb     [PubMed PMID: 14750104]


Yu H,Artomov M,Brähler S,Stander MC,Shamsan G,Sampson MG,White JM,Kretzler M,Miner JH,Jain S,Winkler CA,Mitra RD,Kopp JB,Daly MJ,Shaw AS, A role for genetic susceptibility in sporadic focal segmental glomerulosclerosis. The Journal of clinical investigation. 2016 Apr 1     [PubMed PMID: 26927868]


Savin VJ,Sharma M,Zhou J,Gennochi D,Fields T,Sharma R,McCarthy ET,Srivastava T,Domen J,Tormo A,Gauchat JF, Renal and Hematological Effects of CLCF-1, a B-Cell-Stimulating Cytokine of the IL-6 Family. Journal of immunology research. 2015     [PubMed PMID: 26146641]


Delville M,Sigdel TK,Wei C,Li J,Hsieh SC,Fornoni A,Burke GW,Bruneval P,Naesens M,Jackson A,Alachkar N,Canaud G,Legendre C,Anglicheau D,Reiser J,Sarwal MM, A circulating antibody panel for pretransplant prediction of FSGS recurrence after kidney transplantation. Science translational medicine. 2014 Oct 1     [PubMed PMID: 25273097]


Königshausen E,Sellin L, Circulating Permeability Factors in Primary Focal Segmental Glomerulosclerosis: A Review of Proposed Candidates. BioMed research international. 2016     [PubMed PMID: 27200372]


Meehan SM,Kim L,Chang A, A spectrum of morphologic lesions of focal segmental glomerulosclerosis by Columbia criteria in human immunodeficiency virus infection. Virchows Archiv : an international journal of pathology. 2012 Apr     [PubMed PMID: 22388441]


Chandra P,Kopp JB, Viruses and collapsing glomerulopathy: a brief critical review. Clinical kidney journal. 2013 Feb     [PubMed PMID: 23372939]


Markowitz GS,Appel GB,Fine PL,Fenves AZ,Loon NR,Jagannath S,Kuhn JA,Dratch AD,D'Agati VD, Collapsing focal segmental glomerulosclerosis following treatment with high-dose pamidronate. Journal of the American Society of Nephrology : JASN. 2001 Jun     [PubMed PMID: 11373339]


Petersen CE,Amaral S,Frosch E, Lithium-induced nephrotic syndrome in a prepubertal boy. Journal of child and adolescent psychopharmacology. 2008 Apr     [PubMed PMID: 18439118]


Letavernier E,Bruneval P,Mandet C,Duong Van Huyen JP,Péraldi MN,Helal I,Noël LH,Legendre C, High sirolimus levels may induce focal segmental glomerulosclerosis de novo. Clinical journal of the American Society of Nephrology : CJASN. 2007 Mar     [PubMed PMID: 17699432]


Brenner BM,Mackenzie HS, Nephron mass as a risk factor for progression of renal disease. Kidney international. Supplement. 1997 Dec     [PubMed PMID: 9407439]


Kriz W,Lemley KV, Mechanical challenges to the glomerular filtration barrier: adaptations and pathway to sclerosis. Pediatric nephrology (Berlin, Germany). 2017 Mar     [PubMed PMID: 27008645]


Sim JJ,Batech M,Hever A,Harrison TN,Avelar T,Kanter MH,Jacobsen SJ, Distribution of Biopsy-Proven Presumed Primary Glomerulonephropathies in 2000-2011 Among a Racially and Ethnically Diverse US Population. American journal of kidney diseases : the official journal of the National Kidney Foundation. 2016 Oct     [PubMed PMID: 27138468]


Kitiyakara C,Eggers P,Kopp JB, Twenty-one-year trend in ESRD due to focal segmental glomerulosclerosis in the United States. American journal of kidney diseases : the official journal of the National Kidney Foundation. 2004 Nov     [PubMed PMID: 15492947]


Kriz W,Lemley KV, A potential role for mechanical forces in the detachment of podocytes and the progression of CKD. Journal of the American Society of Nephrology : JASN. 2015 Feb     [PubMed PMID: 25060060]


Kriz W,Gretz N,Lemley KV, Progression of glomerular diseases: is the podocyte the culprit? Kidney international. 1998 Sep     [PubMed PMID: 9734594]


Stokes MB,D'Agati VD, Morphologic variants of focal segmental glomerulosclerosis and their significance. Advances in chronic kidney disease. 2014 Sep     [PubMed PMID: 25168828]


Thomas DB,Franceschini N,Hogan SL,Ten Holder S,Jennette CE,Falk RJ,Jennette JC, Clinical and pathologic characteristics of focal segmental glomerulosclerosis pathologic variants. Kidney international. 2006 Mar     [PubMed PMID: 16518352]


Stokes MB,Markowitz GS,Lin J,Valeri AM,D'Agati VD, Glomerular tip lesion: a distinct entity within the minimal change disease/focal segmental glomerulosclerosis spectrum. Kidney international. 2004 May     [PubMed PMID: 15086908]


Stokes MB,Valeri AM,Markowitz GS,D'Agati VD, Cellular focal segmental glomerulosclerosis: Clinical and pathologic features. Kidney international. 2006 Nov     [PubMed PMID: 17021605]


Moudgil A,Nast CC,Bagga A,Wei L,Nurmamet A,Cohen AH,Jordan SC,Toyoda M, Association of parvovirus B19 infection with idiopathic collapsing glomerulopathy. Kidney international. 2001 Jun     [PubMed PMID: 11380814]


Tomlinson L,Boriskin Y,McPhee I,Holwill S,Rice P, Acute cytomegalovirus infection complicated by collapsing glomerulopathy. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2003 Jan     [PubMed PMID: 12480980]


Markowitz GS,Nasr SH,Stokes MB,D'Agati VD, Treatment with IFN-{alpha}, -{beta}, or -{gamma} is associated with collapsing focal segmental glomerulosclerosis. Clinical journal of the American Society of Nephrology : CJASN. 2010 Apr     [PubMed PMID: 20203164]


Baradhi KM,Gary Abuelo J,Stillman IE, The Case: diabetic nephropathy in a nondiabetic smoker? Kidney international. 2012 Nov     [PubMed PMID: 23128123]


Banfi G,Moriggi M,Sabadini E,Fellin G,D'Amico G,Ponticelli C, The impact of prolonged immunosuppression on the outcome of idiopathic focal-segmental glomerulosclerosis with nephrotic syndrome in adults. A collaborative retrospective study. Clinical nephrology. 1991 Aug     [PubMed PMID: 1934660]


Cattran DC,Appel GB,Hebert LA,Hunsicker LG,Pohl MA,Hoy WE,Maxwell DR,Kunis CL, A randomized trial of cyclosporine in patients with steroid-resistant focal segmental glomerulosclerosis. North America Nephrotic Syndrome Study Group. Kidney international. 1999 Dec     [PubMed PMID: 10594798]


Fornoni A,Sageshima J,Wei C,Merscher-Gomez S,Aguillon-Prada R,Jauregui AN,Li J,Mattiazzi A,Ciancio G,Chen L,Zilleruelo G,Abitbol C,Chandar J,Seeherunvong W,Ricordi C,Ikehata M,Rastaldi MP,Reiser J,Burke GW 3rd, Rituximab targets podocytes in recurrent focal segmental glomerulosclerosis. Science translational medicine. 2011 Jun 1     [PubMed PMID: 21632984]


Chun MJ,Korbet SM,Schwartz MM,Lewis EJ, Focal segmental glomerulosclerosis in nephrotic adults: presentation, prognosis, and response to therapy of the histologic variants. Journal of the American Society of Nephrology : JASN. 2004 Aug     [PubMed PMID: 15284302]


Troyanov S,Wall CA,Miller JA,Scholey JW,Cattran DC, Focal and segmental glomerulosclerosis: definition and relevance of a partial remission. Journal of the American Society of Nephrology : JASN. 2005 Apr     [PubMed PMID: 15716334]