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Focal Segmental Glomerulosclerosis

Editor: Krishna M. Baradhi Updated: 8/28/2023 10:13:02 PM

Introduction

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] In FSGS, some (not all) glomeruli are sclerosed (focal), and each involved glomerulus is only partially affected (segmental).[2] FSGS is one of the commonest causes of primary glomerulopathy in adults.[3] FSGS can be broadly classified into primary (no known cause) or secondary. Causes of secondary FSGS include infections, drugs, hemodynamic adaptations in the kidney, and genetics.

Although clinical signs are suggestive, the confirmation of the diagnosis of FSGS is achieved only by histopathology findings.[4] Histologically, it is characterized by segmental scarring involving a part of the glomerulus. It 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.[5] Categorizing FSGS into primary and secondary forms carries prognostic and therapeutic implications.[6]

The most common clinical manifestation of FSGS (in over 70% of patients) is nephrotic syndrome, presenting as generalized or dependent edema, fatigue, and appetite loss. Hypertension is another common feature and could be severe, with diastolic blood pressure over 120 mmHg; this is common in patients of Afro-Caribbean origin, particularly those with kidney insufficiency.[7]

Etiology

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Etiology

Focal segmental glomerulosclerosis can be classified as primary (idiopathic), genetic, or secondary.

Primary (idiopathic) FSGS

Primary FSGS has been associated with the presence of circulating permeability factors/cytokines, which cause foot process effacement and proteinuria. These include corticotrophin-like cytokine factor 1, apoA1b, anti-CD40 Ab, and suPAR.[8][9][10] Primary (idiopathic) FSGS includes the following:

  • FSGS with hyalinosis
  • Progression from immunoglobulin M (IgM) nephropathy
  • Progression from minimal-change disease
  • Progression from mesangial proliferative glomerulonephritis
  • Superimposed on other primary glomerulonephritis conditions (e.g., immunoglobulin A [IgA] nephropathy)

Variants of primary FSGS include the following:

  • Collapsing form
  • Cellular variant
  • FSGS with mesangial hypercellularity
  • FSGS with glomerular tip lesions

Genetic

Several genes encoding proteins of slit diaphragm, cell membrane, cytoskeleton, nuclear, mitochondrial, and lysosomal origin have been identified to be abnormal/mutated, causing the loss of integrity of glomerular filtration barrier resulting in FSGS.[11] Examples include NPHS1 and NHPS2 mutations that lead to the absence of essential slit diaphragm components, causing severe congenital nephrotic syndrome. Moreover, polymorphisms in the APOL1 gene are usually found in people of African descent, which markedly increases the risk for FSGS.[4][12] The mutations may occur in proteins such as nephrin, podocin, α-actinin-4, and β-integrin. Patients with the genetic form of FSGS may have a relevant family history, and they are often young.[13][12]

Secondary FSGS

A range of factors, including drugs, inflammations, infections, toxins, and intrarenal hemodynamic alterations, may initiate injury to podocytes and lead to glomerulosclerosis.

Drugs associated with FSGS include the following:[14][15][16]

  • Intravenous heroin[17]
  • Analgesics
  • Pamidronate
  • Lithium[18]
  • Anabolic steroids
  • Doxorubicin, daunomycin

Viruses associated with FSGS include the following:

  • Hepatitis B and C
  • HIV[19][20]
  • Parvovirus B19[21]
  • Cytomegalovirus
  • SARS-CoV-2

Adaptive responses lead to glomerular hypertrophy. Histopathologically, these are characterized by large glomeruli, the predominance of perihilar scarring, and partial foot process effacement.[22][23] Hemodynamic factors in patients with decreased renal mass include the following:

  • Solitary kidney
  • Kidney allograft
  • Renal dysplasia
  • Renal agenesis
  • Oligomeganephronia
  • Segmental hypoplasia
  • Vesicoureteral reflux

Hemodynamic causes in patients without decreased renal mass include the following:

  • Obesity (especially morbid obesity)[24]
  • Sickle cell nephropathy
  • Congenital cyanotic heart disease

Lymphomas and other malignancies have an association with FSGS. Miscellaneous other conditions causing FSGS include the following:

  • Hypertensive nephrosclerosis
  • Alport syndrome
  • Sarcoidosis
  • Radiation nephritis

Epidemiology

The prevalence of focal segmental glomerulosclerosis seems to be increasing worldwide. The exact incidence and prevalence data of FSGS are difficult to ascertain due to significant racial and geographical differences.[25] The estimated incidence of FSGS is about 7 per 1 million, with a prevalence of 4%, as described by Kitiyakara et al. in 2003.[26]. 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 the development of therapy targeting mediators of such injury.

Australia has reported one of the highest incidences of FSGS, attributable to increased disease recognition due to a liberal kidney biopsy policy.[3] Typically, idiopathic FSGS is seen in persons aged 18-45; however, no age group is exempt. In the pediatric population, FSGS is found in 7 to 10% of all kidney biopsies; this incidence is much higher in those resistant to steroids and cyclophosphamide. In adults, FSGS is more common among men and is seen in 20-30% of nephrotic syndrome cases. FSGS is 3-7 times greater in young Black men than in Whites.[7] 

In one international literature review, the annual incidence of FSGS was observed between 0.2 and 1.8/100,000 population.[1] The yearly incidence of FSGS is 5 cases per million in Whites, as opposed to 24 cases per million in the Black population. In the US, ESRD due to FSGS was reported to be 1.9 per million population in Whites and 6.8 in Blacks.[26] This higher incidence is partly attributable to variants of two important podocyte proteins, apolipoprotein L1 (APOL1) and non-muscle myosin heavy chain-9, found in about 5% of White patients as opposed to 60% of African American patients.[27]

Mortality/Morbidity

The natural history of FSGS varies greatly. It involves edema, proteinuria refractory to steroids and other immunosuppressive agents, worsening hypertension, and progressively declining renal function.[28] In non-responsive cases, the average duration between the onset of gross proteinuria and ESRD is 6-8 years, although variations in the time course occur. Achievement of remission, whether spontaneous or induced, is associated with good renal outcomes.[29] The prognosis is much worse in the Black population compared with White patients. The collapsing form of FSGS is characterized by severe hypertension, a very poor response to corticosteroids, more massive proteinuria, and a much faster rate of progression to ESRD.

Pathophysiology

The pathogenesis of focal segmental glomerular sclerosis 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.[30][31] Foot process effacement and the proliferation of mesangial, endothelial, and epithelial cells earlier in the course of illness, followed by collapse/shrinkage of glomerular capillaries, all result in scarring (glomerulosclerosis).[32]

The proposed mechanism for podocyte injury includes viral- or toxin-mediated insult and intrarenal hemodynamic alterations, such as high intraglomerular capillary pressure and glomerular hyperperfusion. Many morphologic subsets, such as a collapsing variant (FSGS with mesangial hypercellularity), a cellular variant (endocapillary and extracapillary hypercellularity), and FSGS with tip lesions, are known.[4]

Understanding the pathophysiology of FSGS has improved with the discovery that mutations in several proteins responsible for maintaining podocyte structure, function, or both not only result in FSGS but can predict disease characteristics, such as steroid responsiveness.[33] For instance, FSGS with mutations in NPHS2 or TRPC6 is challenging to treat with immunosuppressive therapy; however, when such patients undergo kidney transplantation, the disease does not usually recur. APOL1 G1/G2 variants have been associated with a poor renal prognosis and steroid resistance in nephrotic syndrome/FSGS.[34] 

Proposed circulating factors linked to the development of FSGS include candidate molecules, such as hemopexin, cardiotrophin-like cytokine 1, and vascular endothelial growth factor. One molecule that has been extensively studied is a form of urokinase receptor (suPAR).[35]

Histopathology

Histologically, focal segmental glomerular sclerosis (FSGS) is characterized by sclerosis, hyalinosis, and adhesions/synechiae formation, resulting in segmental obliteration of glomerular capillaries. On electron microscopy (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; hence, inadequate sampling may miss focal lesions.

Histologically, FSGS is classified into five variants: perihilar, tip, cellular, collapsing, and not otherwise specified (NOS).[6][36][37]

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 near 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 Whites, presenting with diffuse foot process effacement and abrupt onset of nephrotic syndrome. These patients have lower baseline creatinine, an excellent response to treatment, and the lowest rate of progression.[38]

Cellular: This is the least common variant of FSGS, characterized by the hypercellular glomerulus, including endocapillary and glomerular epithelial cell hyperplasia. It presents with diffuse foot process effacement and full-blown nephrotic syndrome.[39]

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) and drug-associated forms of FSGS (IFN, pamidronate) and presents with diffuse effacement of foot processes, heavy proteinuria with the lowest rate of remission, and the worst prognosis.[40][41][42]

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.[43]

History and Physical

Children with focal segmental glomerular sclerosis (FSGS) typically present with full-blown nephrotic syndrome (edema, massive proteinuria, hypoalbuminemia, hypercholesterolemia). Adults can have nephrotic or sub-nephrotic proteinuria, hypertension, microscopic hematuria, or 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.[44]

Generally, edema develops over a few weeks; however, the onset may be abrupt, with sudden weight gain of 15-20 lbs (6.8 to 9 kg) or more. Frequently, a recent upper respiratory tract infection precedes edema.

Pleural effusion and ascites could be present, although pericardial effusions are rare. Gross edema could predispose patients to infections and ulcerations in dependent areas, such as the lower extremities. Abdominal pain may be a sign of peritonitis, a common finding in children. Rarely, xanthomas may be seen in cases of severe hyperlipidemia. In many patients, physical examination is normal except for edema. Severe hypertension is not uncommon, particularly in Black patients with renal impairment.[7] Rarely do patients experience severe renal failure with features of advanced uremia, such as nausea, vomiting, seizures, bleeding, or altered mental status. Patients with FSGS secondary to conditions such as reflux nephropathy, massive obesity, and renal dysplasia/agenesis usually present with non-nephritic proteinuria. These patients may often experience worsening renal function over the course of months to years.

Evaluation

In patients with focal segmental glomerulosclerosis, urinalysis shows large amounts of protein and casts (hyaline and broad waxy), although red blood cell (RBC) casts are usually absent. In advanced cases, broad casts may be evident. Serum creatinine (SCr) and creatinine clearance (CrCl) are usually within the reference range in the early stages. Features of nephrotic syndrome (proteinuria >3.5 g/day, serum albumin <30 g/L, with or without edema) may or may not be present.

In idiopathic FSGS, investigations for an underlying etiology are usually negative. Such conditions include the following:

  • Systemic lupus erythematosus (antinuclear antibody/anti-DNA titers, serum complement C4/C3 levels)
  • Hepatitis B or C infection
  • Vasculitis (serum protein electrophoresis, antineutrophil cytoplasmic antibody titers)

In patients suspected to have secondary FSGS, the following should be obtained:

  • HIV antibody, CD4, and viral load
  • Serology for hepatitis B and C
  • Parvovirus testing

FSGS in morbidly obese patients is diagnosed by excluding other causes. The common features in obesity-related FSGS include glomerular hyperfiltration and activation of the renin-angiotensin-aldosterone system.[45] FSGS may be considered in patients with proteinuria; however, in younger patients with no RBC casts and negative serologic studies, the definitive diagnosis is made on a kidney biopsy.

Histologic Findings

A kidney biopsy is the most diagnostic modality in FSGS, like in many other glomerulopathies. The characteristic finding in FSGS is segmental solidification of the glomeruli, typically in the perihilar region and occasionally in the peripheral areas, such as the tubular pole.[46] In the diseased glomeruli, the accumulation of acellular matrix and hyaline deposits obliterates capillaries in a segmental fashion. Coarsely granular deposits of C3 and IgM are often seen in these areas. Diffuse foot process fusion is seen predominantly in the sclerotic segments, whereas partial effacement is observed overlying normal-appearing lobules. 

In HIV-associated FSGS, electron microscopy of the kidney shows tubuloreticular inclusions in mesangial and endothelial cells, an indirect indication of viral disease.[47]

Ultrasonography

Earlier in the course of illness, ultrasonography will reveal normal or enlarged kidneys with increased echogenicity, indicating diffuse intrinsic medical renal disease.[48] In advanced renal failure, kidneys are shrunken and small, suggesting severe interstitial fibrosis and glomerular scarring. In HIV-associated FSGS, ultrasound study generally reveals large echogenic kidneys.

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 resistant or intolerant to steroids are treated with immunosuppressive therapy with calcineurin inhibitors (CNI), mycophenolate mofetil, or rituximab.[49][50][51](A1)

Corticosteroids

High-dose corticosteroid therapy with prednisolone is started at an initial dose of 1 mg/kg/day daily single dose (maximum 80 mg) or alternate day dose of 2 mg/kg/day (maximum 120 mg) for at least four weeks and until complete remission is achieved or a maximum of 16 weeks treatment, whichever is earlier.[52][53] Patients with the potential to remit would likely show some decline in proteinuria before 16 weeks of high-dose steroid therapy. Hence, it is unnecessary to persist with high-dose steroids treatment until 16 weeks if proteinuria persists or worsens. This becomes more important in patients who are experiencing side effects of steroids.[54](B2)

Tapering off steroids should start after at least four weeks of achieving remission with high-dose therapy or after two weeks of the disappearance of proteins, whichever is longer. Prednisolone is reduced by 5 mg every one to two weeks to complete a total duration of six months. If partial remission is achieved within eight to twelve weeks of high-dose steroid therapy, continue until 16 weeks to ensure complete remission. After that, the prednisolone dose is reduced by 5 mg every one to two weeks to complete a total six-month duration of 6 months.

Calcineurin Inhibitors

If the patient is steroid-resistant or develops adverse effects from steroids, alternative immunosuppression should be used, such as calcineurin inhibitors. The options include the following:

  • Cyclosporine - 3 to 5 mg/kg/day (target trough levels 100 to 175 ng/ml)
  • Tacrolimus - 0.05 to 0.1 mg/kg/day (target trough levels 5 to 10 ng/ml)[55]
  • (B2)

Trough levels should be monitored to prevent drug toxicity. The duration of determining the efficacy of cyclosporin or tacrolimus is at least six months, after which the patient can be labeled CNI-resistant. CNIs should be continued for at least 12 months in patients with partial or complete remission to prevent relapses. The dose of CNIs is to be slowly tapered over 6-12 months as tolerated.

In patients resistant or intolerant to CNIs, there is a lack of evidence regarding any particular agent. Mycophenolate mofetil, high-dose dexamethasone, rituximab, and adrenocorticotropic hormone (ACTH) have been studied.[56] In addition, rituximab, mTOR inhibitors, and plasmapheresis have been tried in select patients with varied results.

In patients with subnephrotic proteinuria, adaptive FSGS, a trial of renin-angiotensin system (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. In addition, 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.

Differential Diagnosis

In patients presenting with nephrotic syndrome, differentiating focal segmental glomerulosclerosis from other glomerulopathies, such as minimal change disease, membranoproliferative glomerulonephritis, mesangial proliferative glomerulonephritis, or membranous glomerulonephritis is clinically challenging. Therefore, the following differential diagnoses should be considered:

  • Mesangial proliferative glomerulonephritis
  • Membranoproliferative glomerulonephritis
  • Nephrotic syndrome
  • Systemic lupus erythematosus
  • Diabetes mellitus
  • IgA nephropathy
  • Amyloidosis

Prognosis

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 a better prognosis. Also, patients with primary FSGS did worse than those with adaptive/secondary causes of FSGS.[57][53]

Complications

Focal segmental glomerulosclerosis, like all other glomerulopathies, has the potential to lead to certain complications. The following is a list of potential complications of this disease:

  • Uncontrolled high blood pressure
  • Anemia
  • Advanced renal failure
  • Venous thromboembolism[58]
  • Recurrent infections[59]
  • Thrombotic microangiopathy[60]

Complications of prednisone therapy include:

  • Infections
  • Hypertension
  • Hyperglycemia

Complications of cyclophosphamide therapy include:

  • Infections
  • Leukopenia
  • Hemorrhagic cystitis[61]

Complications of cyclosporine therapy include:

  • Renal insufficiency
  • Gingival hyperplasia[62]
  • Infections

Deterrence and Patient Education

Providers should educate patients about controlling hypertension and lipids, chronic kidney disease, and options for renal replacement therapy, such as hemodialysis, peritoneal dialysis, and kidney transplantation. Patients should be made aware of the signs and symptoms and when to seek medical help. Dietary modifications should also be advised to the patients. Salt intake should be restricted.[63] Daily intake should be decreased to 2 g of sodium (5 g of salt). Potassium supplements may be needed in patients managed with diuretics who develop hypokalemia.

As high protein intake could further aggravate proteinuria, affecting renal function, current guidance calls for an intake of 1 to 1.3 grams of high biologic-value protein/kg of body weight. In addition, reduction of fat intake could help with dyslipidemia.

Enhancing Healthcare Team Outcomes

Focal segmental glomerular sclerosis 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 presentations, the condition is best managed by an interprofessional team that includes a nephrologist, internist, pathologist, nurses, and pharmacist. The various clinicians will be the primary directors of care, and nurses will help coordinate activities between the different disciplines while assisting in patient evaluation and offering patient counsel. Pharmacists will verify appropriate dosing, perform medication reconciliation, provide patient counseling and answer questions about the medications they are on. Every team member must maintain accurate and updated patient records so that everyone involved in care can access the same information. Open communication lines between all team members are crucial to optimal outcomes in the interprofessional model. [Level 5]

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 a better prognosis. Also, patients with primary FSGS did worse than those with adaptive/secondary causes of FSGS.[57][53] [Level 5]

References


[1]

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:26(2):414-30. doi: 10.1093/ndt/gfq665. Epub 2010 Nov 10     [PubMed PMID: 21068142]

Level 1 (high-level) evidence

[2]

Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work Group. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney international. 2021 Oct:100(4S):S1-S276. doi: 10.1016/j.kint.2021.05.021. Epub     [PubMed PMID: 34556256]

Level 1 (high-level) evidence

[3]

Rosenberg AZ, Kopp JB. Focal Segmental Glomerulosclerosis. Clinical journal of the American Society of Nephrology : CJASN. 2017 Mar 7:12(3):502-517. doi: 10.2215/CJN.05960616. Epub 2017 Feb 27     [PubMed PMID: 28242845]


[4]

Shabaka A, Tato Ribera A, Fernández-Juárez G. Focal Segmental Glomerulosclerosis: State-of-the-Art and Clinical Perspective. Nephron. 2020:144(9):413-427. doi: 10.1159/000508099. Epub 2020 Jul 28     [PubMed PMID: 32721952]

Level 3 (low-level) evidence

[5]

Wiggins RC. The spectrum of podocytopathies: a unifying view of glomerular diseases. Kidney international. 2007 Jun:71(12):1205-14     [PubMed PMID: 17410103]


[6]

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:43(2):368-82     [PubMed PMID: 14750104]


[7]

Freedman BI, Hicks PJ, Bostrom MA, Cunningham ME, Liu Y, Divers J, Kopp JB, Winkler CA, Nelson GW, Langefeld CD, Bowden DW. Polymorphisms in the non-muscle myosin heavy chain 9 gene (MYH9) are strongly associated with end-stage renal disease historically attributed to hypertension in African Americans. Kidney international. 2009 Apr:75(7):736-45. doi: 10.1038/ki.2008.701. Epub 2009 Jan 28     [PubMed PMID: 19177153]

Level 2 (mid-level) evidence

[8]

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. 2015:2015():714964. doi: 10.1155/2015/714964. Epub 2015 Jun 4     [PubMed PMID: 26146641]


[9]

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 1:6(256):256ra136. doi: 10.1126/scitranslmed.3008538. Epub     [PubMed PMID: 25273097]

Level 2 (mid-level) evidence

[10]

Königshausen E, Sellin L. Circulating Permeability Factors in Primary Focal Segmental Glomerulosclerosis: A Review of Proposed Candidates. BioMed research international. 2016:2016():3765608. doi: 10.1155/2016/3765608. Epub 2016 Apr 21     [PubMed PMID: 27200372]


[11]

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 1:126(4):1603. doi: 10.1172/JCI87342. Epub 2016 Mar 1     [PubMed PMID: 26927868]


[12]

Pollak MR. Familial FSGS. Advances in chronic kidney disease. 2014 Sep:21(5):422-5. doi: 10.1053/j.ackd.2014.06.001. Epub     [PubMed PMID: 25168831]

Level 3 (low-level) evidence

[13]

Han MH, Kim YJ. Practical Application of Columbia Classification for Focal Segmental Glomerulosclerosis. BioMed research international. 2016:2016():9375753. doi: 10.1155/2016/9375753. Epub 2016 May 9     [PubMed PMID: 27247945]


[14]

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:12(6):1164-1172. doi: 10.1681/ASN.V1261164. Epub     [PubMed PMID: 11373339]

Level 3 (low-level) evidence

[15]

Petersen CE, Amaral S, Frosch E. Lithium-induced nephrotic syndrome in a prepubertal boy. Journal of child and adolescent psychopharmacology. 2008 Apr:18(2):210-3. doi: 10.1089/cap.2007.0118. Epub     [PubMed PMID: 18439118]

Level 3 (low-level) evidence

[16]

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:2(2):326-33     [PubMed PMID: 17699432]


[17]

Crosson JT. Focal segmental glomerulosclerosis and renal transplantation. Transplantation proceedings. 2007 Apr:39(3):737-43     [PubMed PMID: 17445586]


[18]

Gong R, Wang P, Dworkin L. What we need to know about the effect of lithium on the kidney. American journal of physiology. Renal physiology. 2016 Dec 1:311(6):F1168-F1171. doi: 10.1152/ajprenal.00145.2016. Epub 2016 Apr 27     [PubMed PMID: 27122541]


[19]

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:460(4):429-35. doi: 10.1007/s00428-012-1213-3. Epub 2012 Mar 3     [PubMed PMID: 22388441]


[20]

Chandra P, Kopp JB. Viruses and collapsing glomerulopathy: a brief critical review. Clinical kidney journal. 2013 Feb:6(1):1-5     [PubMed PMID: 23372939]


[21]

Muehlig AK, Gies S, Huber TB, Braun F. Collapsing Focal Segmental Glomerulosclerosis in Viral Infections. Frontiers in immunology. 2021:12():800074. doi: 10.3389/fimmu.2021.800074. Epub 2022 Jan 13     [PubMed PMID: 35095882]


[22]

Brenner BM, Mackenzie HS. Nephron mass as a risk factor for progression of renal disease. Kidney international. Supplement. 1997 Dec:63():S124-7     [PubMed PMID: 9407439]


[23]

Kriz W, Lemley KV. Mechanical challenges to the glomerular filtration barrier: adaptations and pathway to sclerosis. Pediatric nephrology (Berlin, Germany). 2017 Mar:32(3):405-417. doi: 10.1007/s00467-016-3358-9. Epub 2016 Mar 23     [PubMed PMID: 27008645]


[24]

Verani RR. Obesity-associated focal segmental glomerulosclerosis: pathological features of the lesion and relationship with cardiomegaly and hyperlipidemia. American journal of kidney diseases : the official journal of the National Kidney Foundation. 1992 Dec:20(6):629-34     [PubMed PMID: 1462993]


[25]

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:68(4):533-544. doi: 10.1053/j.ajkd.2016.03.416. Epub 2016 Apr 30     [PubMed PMID: 27138468]


[26]

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:44(5):815-25     [PubMed PMID: 15492947]


[27]

Kopp JB, Nelson GW, Sampath K, Johnson RC, Genovese G, An P, Friedman D, Briggs W, Dart R, Korbet S, Mokrzycki MH, Kimmel PL, Limou S, Ahuja TS, Berns JS, Fryc J, Simon EE, Smith MC, Trachtman H, Michel DM, Schelling JR, Vlahov D, Pollak M, Winkler CA. APOL1 genetic variants in focal segmental glomerulosclerosis and HIV-associated nephropathy. Journal of the American Society of Nephrology : JASN. 2011 Nov:22(11):2129-37. doi: 10.1681/ASN.2011040388. Epub 2011 Oct 13     [PubMed PMID: 21997394]

Level 2 (mid-level) evidence

[28]

Del Rio M, Kaskel F. Evaluation and management of steroid-unresponsive nephrotic syndrome. Current opinion in pediatrics. 2008 Apr:20(2):151-6. doi: 10.1097/MOP.0b013e3282f4e6e4. Epub     [PubMed PMID: 18332710]

Level 3 (low-level) evidence

[29]

Deegens JK, Wetzels JF. Immunosuppressive treatment of focal segmental glomerulosclerosis: lessons from a randomized controlled trial. Kidney international. 2011 Oct:80(8):798-801. doi: 10.1038/ki.2011.191. Epub     [PubMed PMID: 21960168]

Level 1 (high-level) evidence

[30]

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:26(2):258-69. doi: 10.1681/ASN.2014030278. Epub 2014 Jul 24     [PubMed PMID: 25060060]


[31]

Kriz W, Gretz N, Lemley KV. Progression of glomerular diseases: is the podocyte the culprit? Kidney international. 1998 Sep:54(3):687-97     [PubMed PMID: 9734594]


[32]

Barisoni L, Schnaper HW, Kopp JB. Advances in the biology and genetics of the podocytopathies: implications for diagnosis and therapy. Archives of pathology & laboratory medicine. 2009 Feb:133(2):201-16     [PubMed PMID: 19195964]

Level 3 (low-level) evidence

[33]

Shankland SJ, Pollak MR. A suPAR circulating factor causes kidney disease. Nature medicine. 2011 Aug 4:17(8):926-7. doi: 10.1038/nm.2443. Epub 2011 Aug 4     [PubMed PMID: 21818086]

Level 3 (low-level) evidence

[34]

Gribouval O, Boyer O, Knebelmann B, Karras A, Dantal J, Fourrage C, Alibeu O, Hogan J, Dossier C, Tête MJ, Antignac C, Servais A. APOL1 risk genotype in European steroid-resistant nephrotic syndrome and/or focal segmental glomerulosclerosis patients of different African ancestries. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2019 Nov 1:34(11):1885-1893. doi: 10.1093/ndt/gfy176. Epub     [PubMed PMID: 29992269]


[35]

McCarthy ET, Sharma M, Savin VJ. Circulating permeability factors in idiopathic nephrotic syndrome and focal segmental glomerulosclerosis. Clinical journal of the American Society of Nephrology : CJASN. 2010 Nov:5(11):2115-21. doi: 10.2215/CJN.03800609. Epub 2010 Oct 21     [PubMed PMID: 20966123]

Level 3 (low-level) evidence

[36]

Stokes MB, D'Agati VD. Morphologic variants of focal segmental glomerulosclerosis and their significance. Advances in chronic kidney disease. 2014 Sep:21(5):400-7. doi: 10.1053/j.ackd.2014.02.010. Epub     [PubMed PMID: 25168828]

Level 3 (low-level) evidence

[37]

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:69(5):920-6     [PubMed PMID: 16518352]

Level 2 (mid-level) evidence

[38]

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:65(5):1690-702     [PubMed PMID: 15086908]

Level 2 (mid-level) evidence

[39]

Stokes MB, Valeri AM, Markowitz GS, D'Agati VD. Cellular focal segmental glomerulosclerosis: Clinical and pathologic features. Kidney international. 2006 Nov:70(10):1783-92     [PubMed PMID: 17021605]

Level 2 (mid-level) evidence

[40]

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:59(6):2126-33     [PubMed PMID: 11380814]


[41]

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:18(1):187-9     [PubMed PMID: 12480980]

Level 3 (low-level) evidence

[42]

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:5(4):607-15. doi: 10.2215/CJN.07311009. Epub 2010 Mar 4     [PubMed PMID: 20203164]

Level 2 (mid-level) evidence

[43]

Baradhi KM, Gary Abuelo J, Stillman IE. The Case: diabetic nephropathy in a nondiabetic smoker? Kidney international. 2012 Nov:82(10):1141-2. doi: 10.1038/ki.2012.333. Epub     [PubMed PMID: 23128123]

Level 3 (low-level) evidence

[44]

Guruswamy Sangameswaran KD, Hashmi MF, Baradhi KM. Focal Segmental Glomerulosclerosis. StatPearls. 2024 Jan:():     [PubMed PMID: 30335305]


[45]

Rüster C, Wolf G. The role of the renin-angiotensin-aldosterone system in obesity-related renal diseases. Seminars in nephrology. 2013 Jan:33(1):44-53. doi: 10.1016/j.semnephrol.2012.12.002. Epub     [PubMed PMID: 23374893]


[46]

Chen YM, Liapis H. Focal segmental glomerulosclerosis: molecular genetics and targeted therapies. BMC nephrology. 2015 Jul 9:16():101. doi: 10.1186/s12882-015-0090-9. Epub 2015 Jul 9     [PubMed PMID: 26156092]


[47]

Winston JA, Burns GC, Klotman PE. The human immunodeficiency virus (HIV) epidemic and HIV-associated nephropathy. Seminars in nephrology. 1998 Jul:18(4):373-7     [PubMed PMID: 9692350]


[48]

Hogan JJ. A Case of Focal Segmental Glomerulosclerosis. Clinical journal of the American Society of Nephrology : CJASN. 2021 Aug:16(8):1272-1274. doi: 10.2215/CJN.19591220. Epub 2021 Mar 9     [PubMed PMID: 33687967]

Level 3 (low-level) evidence

[49]

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:36(2):53-9     [PubMed PMID: 1934660]

Level 2 (mid-level) evidence

[50]

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:56(6):2220-6     [PubMed PMID: 10594798]

Level 1 (high-level) evidence

[51]

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 1:3(85):85ra46. doi: 10.1126/scitranslmed.3002231. Epub     [PubMed PMID: 21632984]

Level 2 (mid-level) evidence

[52]

Nagai R, Cattran DC, Pei Y. Steroid therapy and prognosis of focal segmental glomerulosclerosis in the elderly. Clinical nephrology. 1994 Jul:42(1):18-21     [PubMed PMID: 7923961]

Level 2 (mid-level) evidence

[53]

Troyanov S, Wall CA, Miller JA, Scholey JW, Cattran DC, Toronto Glomerulonephritis Registry Group. Focal and segmental glomerulosclerosis: definition and relevance of a partial remission. Journal of the American Society of Nephrology : JASN. 2005 Apr:16(4):1061-8     [PubMed PMID: 15716334]

Level 2 (mid-level) evidence

[54]

Costello R, Patel R, Humphreys J, McBeth J, Dixon WG. Patient perceptions of glucocorticoid side effects: a cross-sectional survey of users in an online health community. BMJ open. 2017 Apr 3:7(4):e014603. doi: 10.1136/bmjopen-2016-014603. Epub 2017 Apr 3     [PubMed PMID: 28373256]

Level 2 (mid-level) evidence

[55]

Ramachandran R, Kumar V, Rathi M, Nada R, Jha V, Gupta KL, Sakhuja V, Kohli HS. Tacrolimus therapy in adult-onset steroid-resistant nephrotic syndrome due to a focal segmental glomerulosclerosis single-center experience. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2014 Oct:29(10):1918-24. doi: 10.1093/ndt/gfu097. Epub 2014 Apr 24     [PubMed PMID: 24771498]

Level 2 (mid-level) evidence

[56]

Canetta PA, Radhakrishnan J. Impact of the National Institutes of Health Focal Segmental Glomerulosclerosis (NIH FSGS) clinical trial on the treatment of steroid-resistant FSGS. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2013 Mar:28(3):527-34. doi: 10.1093/ndt/gfs563. Epub 2012 Dec 16     [PubMed PMID: 23248028]


[57]

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:15(8):2169-77     [PubMed PMID: 15284302]

Level 2 (mid-level) evidence

[58]

Li SJ, Tu YM, Zhou CS, Zhang LH, Liu ZH. Risk factors of venous thromboembolism in focal segmental glomerulosclerosis with nephrotic syndrome. Clinical and experimental nephrology. 2016 Apr:20(2):212-7. doi: 10.1007/s10157-015-1149-4. Epub 2015 Jul 29     [PubMed PMID: 26220221]


[59]

Zhang Q, Zeng C, Cheng Z, Xie K, Zhang J, Liu Z. Primary focal segmental glomerulosclerosis in nephrotic patients: common complications and risk factors. Journal of nephrology. 2012 Sep-Oct:25(5):679-88. doi: 10.5301/jn.5000040. Epub     [PubMed PMID: 22009935]


[60]

Benz K, Amann K, Dittrich K, Dötsch J. Thrombotic microangiopathy as a complication in a patient with focal segmental glomerulosclerosis. Pediatric nephrology (Berlin, Germany). 2007 Dec:22(12):2125-8     [PubMed PMID: 17882457]


[61]

Matz EL, Hsieh MH. Review of Advances in Uroprotective Agents for Cyclophosphamide- and Ifosfamide-induced Hemorrhagic Cystitis. Urology. 2017 Feb:100():16-19. doi: 10.1016/j.urology.2016.07.030. Epub 2016 Aug 24     [PubMed PMID: 27566144]

Level 3 (low-level) evidence

[62]

Lauritano D, Palmieri A, Lucchese A, Di Stasio D, Moreo G, Carinci F. Role of Cyclosporine in Gingival Hyperplasia: An In Vitro Study on Gingival Fibroblasts. International journal of molecular sciences. 2020 Jan 16:21(2):. doi: 10.3390/ijms21020595. Epub 2020 Jan 16     [PubMed PMID: 31963361]


[63]

Meena J, Bagga A. Current Perspectives in Management of Edema in Nephrotic Syndrome. Indian journal of pediatrics. 2020 Aug:87(8):633-640. doi: 10.1007/s12098-020-03252-9. Epub 2020 Mar 30     [PubMed PMID: 32232733]

Level 3 (low-level) evidence