Chapter 25. Focal Segmental Glomerulosclerosis

• Focal segmental glomerulosclerosis (FSGS) can be primary or secondary.
• Diagnosis requires the presence of the characteristic histopathologic lesion.
• Genetic abnormalities in podocyte proteins may account for 25% of primary FSGS.
• The presenting complaint is usually proteinuria or nephrotic syndrome.
• Nearly 50% of cases progress to end-stage renal disease (ESRD) over 5–10 years and disease recurs in 30% of those who receive a kidney transplant.
• Failure to respond to corticosteroid treatment is a poor prognostic sign and there is no proven therapy in these patients.

Epidemiology

FSGS is an important glomerulopathy because it has a high risk of progression to ESRD. It is not a distinct disease but rather represents a pattern of response to injury that probably originates in the podocyte. FSGS occurs in all ethnic groups, both genders, and all geographic locales. Recent data indicate that the incidence of FSGS is rising, especially in black patients. This has been confirmed in reviews of renal biopsy findings in the United States and Canada that demonstrate a 2- to 3-fold increase in the incidence of FSGS over the period from 1984 to 2002. In addition, according to the North American Pediatric Renal Transplant Collaborative Study, FSGS is the most frequent form of acquired renal disease necessitating renal replacement therapy in pediatric patients. Similarly, it is the most common cause of idiopathic nephrotic syndrome in adults and is a major cause of ESRD.

Presenting Complaints

FSGS usually presents with asymptomatic proteinuria or overt nephrotic syndrome. In those patients who are diagnosed with isolated proteinuria, the abnormality is usually detected on a routine urinalysis. The clinical picture in those who present with nephrotic syndrome is almost indistinguishable from those with minimal change nephrotic syndrome (MCNS). Hematuria, evidence of tubular dysfunction such as glycosuria, hypertension, and mild azotemia, may be present in 15–30% of patients with new-onset nephrotic syndrome and these features may increase the clinical suspicion that a patient has FSGS. However, the key feature that prompts further investigation to establish the diagnosis of FSGS is failure to respond to a standard course of corticosteroids. It is this clinical finding that triggers the performance of a diagnostic renal biopsy; however, the utilization and timing of this procedure may differ among those who care for children or adults. Although the prognosis may be better in patients who present with subnephrotic-range proteinuria versus nephrotic syndrome, this difference has not been confirmed in patients of all ages.

Pathologic Findings

The diagnosis of FSGS requires histopathologic evidence of segmental glomerular sclerosis and hyalinosis. The lesion often manifests in juxtamedullary nephrons during the early stages of disease and it can be associated with periglomerular scarring, tubular atrophy, and interstitial fibrosis in the vicinity of the affected glomerulus (Figure 25–1). Generally, immunofluorescence studies are unrevealing. Electron microscopy demonstrates foot process effacement, the absence of immune deposits, and mesangial sclerosis.

In view of the widely divergent clinical course that patients with FSGS may follow, an attempt has been made to classify FSGS into distinct histologic subcategories. A scheme that has been proposed includes five variants: Perihilar, tip, cellular, collapsing, and not otherwise specified. Additional studies are necessary to determine whether this categorization provides information that can be used to guide treatment or clarify the long-term prognosis.

Primary Focal Segmental Glomerulosclerosis

This form has also been called idiopathic FSGS. Based on clinical evidence of variable response to immunosuppressive medications, the presumption has been that primary FSGS reflects a disturbance in the immune system. However, unlike MCNS, no consistent abnormality has been demonstrated except for altered synthesis and release of tumor necrosis factor (TNF)–α in peripheral blood leukocytes. In addition, various circulating factors including hemopexin, and immunoglobulin-like molecules have been isolated from the sera of patients with FSGS. Removal of these circulating factors, using plasmapheresis or immunoadsorption columns, has been associated with disease remission and infusion into animals has resulted in glomerular proteinuria. Further work on the nature of these substances may help identify the cause of proteinuria in FSGS and define better treatments.

Exciting findings over the past 10 years underscore the pivotal role of the podocyte in maintaining the integrity of the glomerular permselective barrier. A number of proteins have been identified that are components of the cell membrane or actin cytoskeleton of the podocyte. These include nephrin, α-actinin-4, podocin, CD2AP, Wilms tumor suppressor (WT1), and TRPC6 (Figure 25–2). Mutations in the genes for these proteins, occurring in autosomal dominant and recessive patterns, have been associated with steroid-resistant nephrotic syndrome and biopsy-proven FSGS (Table 25–1). Recent series suggest that up to 25% of familial and sporadic cases of steroid-resistant nephrotic syndrome in Europe are related to these genetic abnormalities. Moreover, the response to standard immunosuppressive medications and the risk of recurrent disease after transplantation may be markedly lower in patients with a genetic basis for FSGS. Clarification of these issues is imperative in designing an optimal approach to the evaluation and treatment of patients with FSGS.

Secondary Focal Segmental Glomerulosclerosis

The FSGS lesion represents a nonspecific response to podocyte injury and can arise in a variety of disease states. These include infections with viral agents including HIV and parvovirus B19. A variety of medications including lithium, pamidronate, and illicit drugs such as heroin have been associated with FSGS. Reduced renal mass secondary to surgical ablation (eg, surgery, trauma), reflux nephropathy, and low birth weight can lead to FSGS. Finally, secondary FSGS can occur in patients with a normal renal mass but who have obesity, sickle cell anemia, or cyanotic congenital heart disease (Table 25–2). Identification of these causes and treatment of reversible conditions leads to regression of the FSGS lesions.

Symptoms and Signs

The presentation of FSGS can be subtle with few or no presenting symptoms or may be apparent with the typical findings of nephrotic syndrome. Overtly nephrotic patients may manifest edema, ascites, and weight gain secondary to fluid retention. Edema is typically dependent in the lower extremities when upright and in the periorbital and presacral areas when supine. Edema of the scrotum and labia may also be present. Hypertension is found in approximately 60% of patients at presentation even among the nonedematous patients. Freshly voided urine may be foamy secondary to the effects of significant proteinuria.

Laboratory Findings

Urine

The urine contains from 1 to over 20 g of protein in a 24-hour collection. Determination of proteinuria can be screened with a simple urinalysis but should be verified with a measurement of urine protein as either a single voided specimen or 24-hour timed urine collection for quantification of protein and creatinine. Proteinuria of 1 g/day/1.73 m2 or a urine protein-to-creatinine ratio of 1 or more is considered a level suggestive of a glomerular lesion. Microscopic hematuria is found in approximately 20%, but gross hematuria is rare. Oval fatbodies and hyaline casts are commonly found when proteinuria is >3 g/day/1.73 m2.

Blood

Blood chemistries may reveal the typical findings of hypoalbuminemia and dyslipidemia in patients with frank nephrotic syndrome. Serum albumin may be less than 1.0 g/dL. Serum cholesterol, triglycerides, and very low-density lipoproteins are elevated in patients with severe hypoalbuminemia. Total serum calcium is low because of the hypoalbuminemia; however, the ionized calcium is not reduced proportionately. Serum sodium may be low due to water retention. However, pseudohyponatremia secondary to hyperlipidemia is no longer a concern because automated serum chemistry analyzers use an ion selective electrode. At diagnosis FSGS patients may have an elevated serum creatinine representing a loss of kidney function that may be acute or chronic.

Hematocrit may be elevated in patients with volume contraction or depressed in the patient with chronic loss of kidney function. Platelet counts may be significantly elevated as are coagulation factors V, VII, VIII, X and fibrinogen. Antithrombin III and factors XI and XII may be decreased. These changes in clotting factors are related to the severity of the proteinuria and contribute to the risk of thrombosis in the grossly nephrotic patient.

The laboratory evaluation of a patient with FSGS may aid in the diagnosis of a primary or secondary lesion. Secondary forms of FSGS may be identified or confirmed by laboratory tests specific to the primary disease such as serology for HIV-associated FSGS. Although an unusual etiology, parvovirus B19 or SV40 can be confirmed by polymerase chain reaction (PCR).

Imaging Studies

Radiographic procedures such as renal ultrasound or computerized tomography may serve to exclude secondary or alternative conditions. For example, the patient with vesicoureteral reflux nephropathy may have evidence of hydronephrosis, hydroureter, or renal parenchymal scarring suggesting a urinary tract abnormality. Any patient with advanced glomerular sclerosis, whether from FSGS or from an alternative cause, may have small kidneys with a pattern of increased echogenicity in the kidney ultrasound.

Special Tests

The assessment of genetic markers of familial FSGS is not universally available. In 2006 the only gene test associated with FSGS available in commercial laboratories in the United States was the NPHS2 (podocin). Research laboratories make other candidate gene testing available in a limited fashion but not for clinical use.

Special Examinations

The diagnosis of FSGS is based on the kidney biopsy finding of glomerular scaring in portions (segmental) of some (focal) of the glomeruli. Indeed, the finding of a single glomerulus with a segmental scar may be adequate to establish the diagnosis. Immunofluorescence staining is minimal and electron microscopy shows only foot process effacement. The pattern of scarring lesions has been used to classify FSGS into five subtypes. Using either the traditional classification or the newest classification scheme, the pattern of collapsing FSGS with glomerular capillary collapse and visceral epithelial cell hyperplasia has been associated with the worst prognosis among patients with primary FSGS. Collapsing FSGS has also been associated with HIV infection. All patients with FSGS should be evaluated for HIV as the treatment considerations differ according to etiology. The FSGS tip lesion has been considered the subtype most likely to respond to corticosteroid therapy with reduction or normalization of urine protein excretion and long-term kidney survival.

Distinguishing primary from secondary FSGS has important therapeutic and prognostic implications. Primary FSGS is defined by confirmation by biopsy of the kidney pathology; the medical history, serology, and imaging studies confirm the absence of an alternative cause.

Disease entities such as Alport's syndrome or immunoglobulin A (IgA) nephropathy may be associated with the finding of focal glomerulosclerosis on kidney biopsy but additional findings of glomerular basement membrane abnormalities on electron microscopy in Alport's syndrome or IgA staining on immunofluorescence microscopy will identify the primary pathologic entity.

Although controversy exists, C1q nephropathy is considered a distinct pathologic entity wherein patients may present with nephrotic-range proteinuria, nephritis with cellular casts and proteinuria, or hematuria alone. Although kidney tissue from patients with C1q nephropathy may not have a focal sclerosing lesion, those with an FSGS lesion will also have C1q dominant staining on immunofluorescence microscopy, which ensures the distinct diagnosis of this secondary lesion. Other investigators do not distinguish primary FSGS based on the presence or absence of C1q deposits. Further study is required to clarify this issue.

Obesity-related glomerulopathy is an entity that causes glomerulomegaly in addition to focal sclerotic lesions. Patients with obesity-related glomerulopathy tend to have a nonedematous body mass index of 40 kg/m2 or greater. These patients may demonstrate a resolution of proteinuria with significant weight loss and, even without effective weight loss programs, tend to have a better long-term prognosis compared to those with the primary FSGS lesion. Immunosuppression therapy is not warranted in this obesity-induced lesion.

Infection

Bacterial infections causing spontaneous bacterial peritonitis, sepsis, and cellulitis may complicate nephrotic syndrome from FSGS. Episodes of peritonitis typically manifest with abdominal pain, rebound tenderness, guarding, and anorexia with or without fever. The diagnosis can be confirmed by performing a paracentesis, which demonstrates leukocytosis of the peritoneal fluid with a predominance of neutrophils and a positive peritoneal fluid culture. The most common causes of peritonitis in patients with nephrotic syndrome are Streptococcus pneumoniae, Escherichia coli, and a variety of Gram-negative rods. The exclusion of alternate abdominal pathology is critical as a ruptured appendix, for example, may also present with abdominal pain, rebound tenderness, and guarding.

Thrombosis

Venous and arterial thrombosis and thromboemboli occur in <2% of patients with significant proteinuria. The increased risk of formation of thrombus is thought to be secondary to the urinary loss of factors responsible for inhibition of coagulation such as antithrombin III, protein S, and protein C. Increased platelet activation and a reduction in plasmin-mediated fibrinolysis may also play a role. Additional risk factors may relate to decreased mobility in the grossly edematous patient.

Acute Kidney Failure

Acute renal failure may be present at diagnosis or with episodes of severe volume contraction. The restoration of circulating volume is the treatment of choice in these cases. Chronic renal failure may be present at the time of diagnosis of FSGS. Kidney biopsy may assist in determining the likelihood for renal function recovery based on the severity of the glomerular and tubulointerstitial fibrosis.

Corticosteroids

The course of untreated FSGS is generally one of persistent proteinuria and progressive kidney failure. Less than 5% of patients experience a spontaneous remission. The therapy of FSGS remains controversial because there are few randomized trials to support an evidence-based practice. Use of corticosteroids as initial therapy in pediatric and adult aged patients is common for primary disease. The treatment course is typically between 6 weeks and 6 months with increasing response rates of 25–40% and diminishing relapse rates as the steroid treatment duration increases. Regional differences have been reported in steroid responsiveness, which may relate to duration of corticosteroid administration or varying prevalence of underlying genetic or other etiologic factors.

Persistent proteinuria after a course of corticosteroids is observed in the majority of patients with FSGS. The selection of a second-line therapy may include immunosuppressive agents, agents to control symptoms alone such as diuretics, antifibrotic therapy, and plasmapheresis (Table 25–3).

Calcineurin Inhibitors

Cyclosporine is the standard second-line therapy for patients with steroid-resistant FSGS. A 50% or greater reduction in urinary protein excretion with preservation of kidney function is expected in approximately 70% of patients treated with cyclosporine. The risk for relapse after discontinuation of the treatment may be related to the duration of therapy and the degree of control of the proteinuria. The desire to continue therapy to maintain a remission is offset by the risk for cyclosporine-induced nephrotoxicity, which may be severe and depend on duration of drug exposure. In short-term studies, kidney function was better preserved in those treated with cyclosporine. Generalization of this response to the other calcineurin inhibitor, tacrolimus, has theoretical merit but is without sufficient supporting evidence.

Cyclophosphamide

A nonrandomized study using combined high-dose corticosteroids and cyclophosphamide suggested improved control of proteinuria compared with historical controls. In a randomized trial of cyclophosphamide plus alternate day steroids versus alternate day steroids alone, cyclophosphamide was not found to improve renal survival or control proteinuria better than the steroid-only group.

Mycophenolate Mofetil

Anecdotal reports of mycophenolate mofetil have suggested that this agent may improve proteinuria and preserve renal function in steroid-dependent or -resistant nephrotic syndrome. At present an ideal approach to immunomodulatory therapy for FSGS has not been identified.

Diet and Diuretics

Sodium-restricted diet is the mainstay of therapy to control edema in a patient with hypoalbuminemia and edema. Even with sodium restriction, additional therapy with diuretic agents may be required until proteinuria excretion is controlled.

Antihypertensive Agents

Angiotensin-converting enzyme inhibitors and angiotensin receptor blockade are part of the standard regimen in steroid-resistant FSGS patients. In isolation or combination, these agents have been shown to reduce proteinuria up to 50% from baseline and lower the risk for progression to kidney failure in diabetic and nondiabetic kidney disease. Monitoring should include assessment of serum potassium to allow early identification of a need for potassium restriction and measurement of serum creatinine to ensure preservation of the glomerular filtration rate. A small rise in serum creatinine is expected on these agents but the change should be less than 20% and should be reversible if the agent(s) are discontinued. Despite a mild increase in serum creatinine, the agents are to be continued with the goal of long-term preservation of kidney function. If therapy with angiotensin-converting enzyme inhibitors and angiotensin receptor blockade does not control hypertension, additional antihypertensive agents should be prescribed. Aldosterone antagonists may reduce proteinuria and prevent renal fibrosis, although this effect has not been evaluated specifically in patients with FSGS.

Lipid Control

Lipid-lowering agents have been included in the nephrotic syndrome armamentarium to control hyperlipidemia. Hypercholesterolemia in animal models has been shown to cause glomerulosclerosis. Therapy with the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, statins, diminishes the effects of lipemia on the kidney even with persistent hypercholesterolemia in animal and human investigation.

Vitamin E

Vitamin E is also considered a means of controlling proteinuria and progressive kidney disease through the antioxidant mechanism. One open-label pilot study reported a 50% reduction in protein excretion in 11 children with FSGS, while others have found no beneficial effect. Controversy continues to exist regarding the efficacy of vitamin E.

In general, a combination therapy approach may be resorted to for corticosteroid-resistant FSGS patients. Cyclosporine, angiotensin-converting enzyme inhibitor, angiotensin receptor blockade, and statin combination are commonly used.

Plasmapheresis

The patient with FSGS-induced rapid progression to kidney failure has a 30% risk of FSGS recurrence in the kidney transplant and an 18% risk of graft failure from recurrent disease. In an effort to diminish the risk for recurrent disease and to preserve the survival of the transplanted organ, plasmapheresis may be used in the peritransplant period as a preventive therapy or in response to rapid return of proteinuria. The success of this approach is apparently better in children than adults. Occasionally, long-term plasmapheresis has been used to sustain a response.

Nearly 50% of cases of FSGS progress to ESRD over 5–10 years. Those at greatest risk to progress to kidney failure include those who show resistance to therapy with continued proteinuria and those with collapsing variant FSGS. For patients with progression to kidney failure, dialysis and transplant support are options for therapy. Unfortunately, those who receive a kidney transplant may have a recurrence of FSGS in the transplanted kidney. Patients with FSGS who present with azotemia or progress rapidly to ESRD are more susceptible to disease recurrence in a kidney transplant. The impact of age, ethnicity, and donor type is controversial. The presence of a genetic mutation has been associated with a diminished, but not absent, risk for FSGS recurrence in the kidney transplant recipient.