Focal segmental glomerulosclerosis

CHAPTER 27

FOCAL SEGMENTAL GLOMERULOSCLEROSIS Patrick E. Gipson and Debbie S. Gipson

1. What is focal segmental glomerulosclerosis? Focal segmental glomerulosclerosis (FSGS) is a class of glomerular diseases defined by focal and segmental patterns of scar in the kidney glomeruli. This disease spectrum includes primary, genetic, and secondary diseases. Primary FSGS is diagnosed in patients without a known cause. There are a number of genetic mutations that disrupt the structure and function of the glomerular podocyte and slit diaphragm that manifest as FSGS. Secondary FSGS may arise from various kidney insults that lead to a common end point of glomerular damage. These secondary insults include: • Viral infection: HIV, parvovirus • Drugs: heroin, pamidronate • Postinflammatory conditions: autoimmune diseases • Vascular issues: atheroembolic disease, hypertension, sickle cell disease • Reflux nephropathy The sclerosing type of C1q nephropathy may be grouped with primary or secondary FSGS with the distinguishing factor of C1q in the glomeruli revealed on kidney biopsy immunofluorescence staining and electron dense deposits with electron microscopy. The etiology of C1q nephropathy is unknown. Obesity-related glomerulopathy is also often considered a secondary FSGS that manifests with glomerular hypertrophy in addition to the sclerosis of FSGS. The common factor in these conditions is damage to the glomerular structure. 2. How common is FSGS? FSGS is a rare condition with an estimated incidence of 1.8/100,000 per year. The lifetime risk is estimated to be more than four times higher for African Americans compared with other races. FSGS is the underlying cause of approximately 4% of patients with end-stage kidney disease (ESKD) in the United States and up to 10.8% of those younger than 24 years. In adults, FSGS is the fourth most common cause of ESKD, following diabetes, hypertension, and glomerulonephritis not otherwise specified. Among children, FSGS is the second leading cause of ESKD, following congenital kidney anomalies. 3. What is the clinical presentation of FSGS? FSGS may present as nephrotic syndrome with edema, hypoalbuminemia, and hypercholesterolemia, or it may present in a patient with isolated proteinuria. Microscopic hematuria is found in approximately half of patients at diagnosis. However, gross hematuria is rare. Children are more likely to present with nephrotic syndrome, but the entire phenotypic spectrum of FSGS occurs in both children and adults. Kidney function as assessed by glomerular filtration rate may be normal but is impaired in up to 60% at presentation. ESKD at presentation is rare. Clinical clues may help distinguish whether a patient has primary or secondary FSGS. Patients with primary FSGS more often have low serum albumin levels (,3 g/dL) and edema, whereas patients with secondary FSGS more often present with albumin levels .3.5 g/dL, without edema, and with some historical evidence of a predisposing primary condition or exposure. 4. What is the cause of primary FSGS? There are likely several causes of primary FSGS. Research has focused on possible immune defects, such as T-cell dysregulation, and the presence of a circulating permeability factor, such as cardiotrophinlike cytokine 1, that induces changes in the glomerular filtration barrier with resultant proteinuria. Genetic and gene expression studies have identified structural abnormalities in the podocyte cytoskeleton and slit diaphragms, as well as signaling and inflammatory pathways that contribute to the cause of FSGS. 5. What genetic defects lead to sporadic and familial FSGS? Over the past decade, much of the biology of the glomerular filtration barrier has been explained and defects in multiple structural and functional components of this barrier have been implicated in FSGS.

186

FOCAL SEGMENTAL GLOMERULOSCLEROSIS  187 There are more than 50 genetic mutations associated with FSGS. Mutations may occur in podocyte structural components from genes such as NPHS2 (podocin), NPHS1 (nephrin), ACTN4 (alpha-actinin 4), TRPC6, alpha-5, beta-4 integrins, CD2AP may present as kidney-limited structural anomalies. Mutations in WT1, LAMB2, COQ2, and LMX1B have been identified as causative of syndromic conditions in which FSGS in only one of the multiple anomaly manifestations within an individual. Autosomal dominant inheritance patterns are documented in familial FSGS with ACTN4, TRPC6, and INF2, which were first implicated in adult-onset disease. Familial FSGS of childhood with NPHS1, NPHS2, and PLCE1 mutations are transmitted in an autosomal recessive pattern. Autosomal recessive and dominant inheritance patterns have been documented with child- and adult-onset FSGS (Table 27.1). The prevalence of specific gene mutations in patients with FSGS depends on the ancestry of the cohort being studied. For example, NPHS2 mutations are found in 26% of children from families of Eastern European and Middle Eastern descent with familial FSGS and 19% of sporadic cases in that population. These mutations are rare causes of FSGS in Asian, African-American, and EuropeanAmerican populations of the United States. Apolipoprotein L1 (APOL1) has alleles that increase the risk of FSGS. These risk alleles are found in African Americans of west African descent. APOL1 polymorphisms convey protection against Trypanosoma brucei.

Table 27.1.  List of Genes Implicated in Familial Focal Segmental Glomerulosclerosis GENE

PHENOTYPE

Autosomal Recessive NPHS1 (Nephrin) FSGS; Congenital Nephrotic Syndrome NPHS2 (Podocin)

FSGS; Congenital Nephrotic Syndrome

NPHS3 (PLCE1)

FSGS; Diffuse Mesangial Sclerosis

LAMB2

FSGS; Pierson Syndrome

MYH9

FSGS; Sensorineural Deafness; Macrothrombocytopenia; Epstein, Fechtner & Sebastian Syndromes

MYOE1

FSGS

ADCK4

FSGS

SGPL1

FSGS; Adrenal Insufficiency; Ichthyosis; Acanthosis; Immunodeficiency

COQ6

FSGS; Diffuse Mesangial Sclerosis; Sensorineural Deafness; Neurologic abnormalities

WDR73

FSGS; Galloway-Mowat Syndrome

NUP93

FSGS

NUP205

FSGS

Autosomal Dominant ACTN4 FSGS ANLN

FSGS

ARHGAP24

FSGS

CD2AP

FSGS

TRPC6

FSGS

INF2

FSGS; Charcot-Marie-Tooth Disease

LMX1B

FSGS; Nail-Patella Syndrome

PAX2

FSGS; Papillorenal Syndrome

WT1

FSGS; Denys–Drash, WAGR & Frasier Syndrome

FSGS, Focal segmental glomerulosclerosis.

188  PRIMARY GLOMERULAR DISORDERS Genotype/phenotype correlations are still being investigated and have not yet reached the point of guiding clinical care with a few notable exceptions: • Genetic testing of patients with FSGS may be considered during the assessment of infantile FSGS • FSGS that is part of a multiple congenital anomaly syndrome • Familial FSGS, in regions with a high prevalence of consanguinity • In some cases, prior to kidney transplantation to assess the risk of FSGS recurrence 6. How is FSGS diagnosed? A kidney biopsy is required to establish the diagnosis of FSGS. Patients presenting with sustained proteinuria, whether nephrotic (.3 g/day) or subnephrotic, will typically be evaluated for secondary forms of glomerular disease, including screens for systemic illnesses that may have a kidney component. Hepatitis B and C and HIV should be excluded by serology. Antinuclear antibody level should be obtained to screen for systemic lupus erythematosus (SLE). Complement C3 levels may be low in membranoproliferative glomerulonephritis, SLE, and postinfectious glomerulonephritis. In appropriateage adults, urine and protein electrophoresis and/or serum free light-chain measurements should be obtained to evaluate for paraproteinemias. Unfortunately, urine or blood biomarkers have not yet been developed and validated to support the diagnosis or prognosis of FSGS in clinical contexts. Biomarkers are being evaluated, but they must survive validation and independent replication, steps that have repeatedly flummoxed previous promising candidates. 7. What are the pathologic findings in FSGS? As noted by its descriptive name, FSGS initially is characterized by sclerotic lesions restricted to a segment of a subset (focal) of the glomeruli. Electron microscopy may confirm these changes and show widespread foot process effacement. There are some pathology clues that suggest the FSGS is secondary rather than primary: • Less diffuse foot process effacement • Foot process width may be normal • Glomeruli may be enlarged (glomerulomegaly) However, pathology alone cannot distinguish between the three categories of FSGS: primary, genetic, or secondary. There are a few exceptions: • Immunoglobulin A (IgA) nephropathy as a secondary cause of FSGS has IgA deposits identifiable by immunofluorescence • Obesity-related glomerulopathy and FSGS secondary to cyanotic congenital heart disease often have enlarged glomeruli in addition to the typical glomerular fibrosis As the disease progresses, involvement of more glomeruli and sclerosis of entire glomeruli may occur. Interstitial fibrosis with tubular atrophy is a frequent finding. No significant immunoglobulin deposits are found in cases of primary FSGS, and their presence suggests an alternative etiology or, at low amounts, trapping of immunoglobulin that is not pathogenic. 8. Does histopathology predict prognosis? FSGS is diagnosed through findings on the kidney biopsy. The glomerular scarring pattern has been classified as five variants of FSGS based solely on histologic description: • Collapsing • Tip • Cellular • Perihilar • FSGS not otherwise specified. These variants are defined by the location and type of glomerular scars. Unfortunately, FSGS variant assignment can be inconsistent between pathologists, and patient response to therapy is variable within groups of patients defined by FSGS pathology variants. Collapsing FSGS appears to represent a particularly virulent form of FSGS, and overall progression to ESKD is more rapid when compared with groups of FSGS patients with other variants. Increased tubular atrophy and interstitial scarring portend worse prognosis. 9. What is the clinical course of FSGS? Primary FSGS has a variable course. Clinical factors such as the degree of proteinuria at disease presentation, the amount of interstitial fibrosis and tubular atrophy noted on kidney biopsy, proteinuria reduction in response to therapy, and collapsing histologic variant are considered prognostic factors for kidney survival. Spontaneous remission is reported in less than 5% of patients with primary FSGS. Therapy may result in complete proteinuria remission (normal urinary protein excretion), partial

FOCAL SEGMENTAL GLOMERULOSCLEROSIS  189 remission, or resistance to therapy. Patients with complete remission have an expected 90% 10-year kidney survival. For patients with proteinuria in the nephrotic range that is resistant to treatment, the 10-year kidney survival is approximately 50%. Patients with partial proteinuria remission have intermediate 10-year kidney survival. Patients with high-risk APOL1 genotype have a poorer kidney survival relative to low-risk genotype. As in many kidney diseases, patients who present with an elevated serum creatinine have a poorer prognosis. 10. What therapies are indicated for primary FSGS? Angiotensin-converting enzyme (ACE) inhibitor/angiotensin receptor blocker (ARB) therapy has been shown to be beneficial in reducing proteinuria and slowing the decline in kidney function in proteinuric kidney diseases. There is only one randomized controlled trial of ACE therapy in adults with FSGS and one in children with steroid-resistant nephrotic syndrome. These studies document a reduction in urinary protein excretion by approximately 30%. Long-term data to assess a benefit in preventing a decline in kidney function are not available. Regardless, ACE inhibitor/ARB therapy is considered standard care for proteinuria control and hypertension management. Therapy targeted at a presumed immunologic basis of FSGS has been used clinically and in controlled and uncontrolled trials. Corticosteroids induce remission in 20% to 30% of patients. Treatment may begin with daily dosing and then progress to alternate-day therapy for primary FSGS. The duration of treatment may affect response to therapy with a typical initial course up to 3 months in children and 6 months in adults. A summary of common therapies is presented in the Fig. 27.1. Cyclosporine, tacrolimus, and mycophenolate mofetil have been reported to be effective in case reports. In a few small, randomized trials, calcineurin inhibitors, cyclosporine and tacrolimus, show combined complete and partial remission rates of 50% to 60% in primary FSGS. Mycophenolate appears to be less effective, with a combined complete and partial remission rate of approximately 33%. However, mycophenolate has less kidney toxicity than calcineurin inhibitors. There are several case reports and small case series of other therapeutic agents. Rituximab, a CD20 monoclonal antibody, adalimumab, a tumor necrosis factor (TNF) inhibitor, adrenocorticotropin hormone with potential action through corticosteroid-associated avenues, as well as melanocortin receptor agonism, and perfenidone as an antifibrotic agent have all been used in the treatment of FSGS. Plasmapheresis can be used to treat FSGS recurrence after kidney transplant. The mechanism of action is postulated to be removal of circulating factors that increase glomerular permeability. Therapy for dyslipidemia is also a component of standard therapy in patients with nephrotic syndrome, with a goal to improve nephrotic syndrome–associated dyslipidemia. Diuretics are indicated for control of edema in patients with nephrotic syndrome. Intravenous albumin infusion with diuretic therapy may be beneficial to control severe edema in select patients with nephrotic syndrome, but it has not been shown to have significant additive benefit in controlled trials and carries with it the risk of pulmonary edema and hypertensive crisis. 11. What are the therapeutic options for secondary forms of FSGS? Treatment of the secondary forms of FSGS is directed at the underlying disease. Resolution of FSGS manifestations can occur with weight loss in obesity-related glomerulopathy and following heart transplantation in cyanotic heart disease–associated FSGS. Mitochondrial dysfunction in animal models of obesity-related glomerulopathy is modifiable by mitochondrial-targeted antioxidants. Human investigations are needed to assess whether these findings can be translated to humans safely and effectively. In addition, therapies such as ACE inhibitors, ARBs, and lipid-lowering agents may be prescribed with a goal of reducing proteinuria, controlling blood pressure, and minimizing further cardiovascular or kidney insults. 12. Should those with FSGS be on a special diet? Low-protein diets may reduce proteinuria and slow the progression of proteinuric kidney disease. This was studied and failed in multiple, large, randomized controlled trials. If this is going to be attempted, special concern should be given to children, especially if they have profound proteinuria, to avoid protein malnutrition. All patients should be on low-salt diets to help with hypertension and edema and maximize the effectiveness of angiotensin converting enzyme inhibitor (ACEi) and angiotensin receptor blocker (ARB). 13. What is the role of the primary care physician in a patient with FSGS? Primary care physicians have an important role monitoring and maintaining therapy for hypertension, hyperlipidemia, and edema. They also should be aware of and monitor for other complications of

190  PRIMARY GLOMERULAR DISORDERS

Primary FSGS

FSGS All patients get RAAS blockade +/– diuretics +/– statin

Secondary FSGS Treat underlying disease

Full dose corticosteroid Rx Prednisone 1 mg/kg/day for 4–8 weeks Taper over 3 months

Remission

Steroids contraindicated

Steroid resistance

Steroid dependent

Consider adding CNI and taper corticosteroids to a minimum or discontinue

Stop corticosteroids surveillance to detect possible relapse

Calcineurin Inhibitor

Remission

No response

Continue CNI for 1–2 years

Consider alternative Rx

Figure 27.1.  Treatment algorithm for primary focal segmental glomerulosclerosis (FSGS). CNI, Calcineurin inhibitor; RAAS, renin angiotensin aldosterone system.

FSGS, including peritonitis, thromboembolism, and side effects of immunosuppressive therapy. Maintenance of appropriate immunizations is important, especially 23-valent pneumococcal and influenza. Before using live virus vaccines, doctors should consult the national vaccination guidelines for special populations. 14. Are there special issues in patients with FSGS with respect to kidney transplantation? Primary FSGS recurs in 10% of initial kidney allografts. Proteinuria may develop within minutes of allograft implantation. In this setting, circulating factors in the recipient cause acute glomerular capillary permeability, podocyte foot process effacement, and subsequent glomerulosclerosis. If uncontrolled, recurrent FSGS reduces allograft survival. Patients with a history of rapid FSGS recurrence have a very high risk for FSGS recurrence in subsequent kidney transplants. Patients with FSGS may receive an allograft from either deceased donors or living related donors. Concerns about using that living related donors may have increased risk of recurrence have not born out.

FOCAL SEGMENTAL GLOMERULOSCLEROSIS  191 Plasmapheresis can be used in the immediate pretransplant and posttransplant period in an attempt to remove the substances responsible for inducing proteinuria and recurrent FSGS. Rituximab has been used in the setting of posttransplant FSGS recurrence. These approaches have not been evaluated in randomized studies, but case series suggest they may be helpful in preventing and treating early FSGS recurrence. However, the addition of these therapies to standard kidney transplant induction immunosuppression leads to profound immunocompromised state increasing the risk for life-threatening infections.

KEY PO I N T S 1. FSGS represents a spectrum of primary, genetic, and secondary diseases that manifest with characteristic glomerular scaring and proteinuria. 2. FSGS is more common in African Americans, mostly due to a high-risk APOL1 genotype in individuals of African ancestry. 3. Proteinuria is the common clinical laboratory manifestation of FSGS and may be accompanied by edema, reduced glomerular filtration rate, and hypertension. 4. Mutations in multiple genes that direct the structure and function of the podocyte and slit diaphragm have been implicated in familial and sporadic FSGS. 5. Primary FSGS recurs in 10% of initial kidney allografts and increases the risk for allograft failure.

Bibliography Bierzynska, A., McCarthy, H. J., Soderquest, K., Sen, E. S., Colby, E., Ding, W. Y., . . . Saleem, M. A. (2017). Genomic and clinical profiling of a national nephrotic syndrome cohort advocates a precision medicine approach to disease management. Kidney International, 91(4), 937–947. D’Agati, V. D., Kaskel, F. J., & Falk, R. J. (2011). Focal segmental glomerulosclerosis. New England Journal of Medicine, 365(25), 2398–2411. doi:10.1056/NEJMra1106556. Review. PMID:22187987. Francis, A., Trnka, P., & McTaggart, S. J. (2016). Long-term outcome of kidney transplantation in recipients with focal segmental glomerulusclerosis. Clinical Journal of the American Society of Nephrology, 11(11), 2041–2046. PMID:27797890. Hickson, L. J., Gera, M., Amer, H., Iqbal, C. W., Moore, T. B, Milliner, D. S., . . . Griffin, M. D. (2009). Kidney transplantation for primary focal segmental glomerulosclerosis: Outcomes and response to therapy for recurrence. Transplantation, 87, 1232–1239. Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work Group. (2012). KDIGO clinical practice guideline for glomerulonephritis. Kidney International Supplement, 2, 139–274. Kitiyakara, C., Eggers, P., & Kopp, J. B. (2004). Twenty-one-year trend in ESRD due to focal segmental glomerulosclerosis in the United States. American Journal of Kidney Disease, 44(5), 815–825. Laurin, L. P., Gasim, A. M., Derebail, V. K., McGregor, J. G., Kidd, J. M., Hogan, S. L., . . . Nachman, P. H. (2016). Renal survival in patients with collapsing compared with not otherwise specified FSGS. Clinical Journal of American Society of Nephrology, 11(10), 1752–1759. Rubin, L. G., Levin, M. J., Ljungman, P., Davies, E. G., Avery, R., Tomblyn, M., . . . Infectious Diseases Society of America. (2014). 2013 IDSA clinical practice guideline for vaccination of the immunocompromised host. Clinical Infectious Diseases, 58(3), 309–318. doi:10.1093/cid/cit816. Erratum in: Clinical Infectious Diseases, 59(1), 144. PMID: 24421306. Swaminathan, S., Leung, N., Lager, D. J., Melton, L. J., 3rd, Bergstralh, E. J., Rohlinger, A., & Fervenza, F. C. (2006). Changing incidence of glomerular disease in Olmsted County, Minnesota: A 30-year renal biopsy study. Clinical Journal of the American Society of Nephrology, 1, 483–487. Thomas, D. B., Franceschini, N., Hogan, S. L., Ten Holder, S., Jennette, C. E., Falk, R. J., & Jennette, J. C. (2006). Clinical and pathologic characteristics of focal segmental glomerulosclerosis pathologic variants. Kidney International, 69, 920–926. Troyanov, S., Wall, C. A., Miller, J. A., Scholey, J. W., Cattran, D. C; Toronto Glomerulonephritis Registry Group. (2005). Focal and segmental glomerulosclerosis: Definition and relevance of a partial remission. Journal of the American Society of Nephrology, 16, 1061–1068. United States Renal Data System. (2010). USRDS 2010 Annual Data Report: Atlas of chronic kidney disease and end-stage renal disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. Yu, H., Artomov, M., Brähler, S., Stander, M. C., Shamsan, G., Sampson, M. G., . . . Shaw, A. S. (2016). A role for genetic susceptibility in sporadic focal segmental glomerulosclerosis. Journal of Clinical Investigation, 126(3), 1067–1078. doi:10.1172/JCI82592. Erratum in, 126(4), 1603. PMID: 26901816.