Steroids, cyclophosphamide, cyclosporine, tacrolimus, and mycophenolate mofetil are options
By Gerald B. Appel, MD,
and Alice Sue Appel, PhD
FOCAL SEGMENTAL glomerulosclerosis (FSGS) is not a single disease but a histologic pattern of renal damage that initially affects the glomerulus and its tubulointerstitium (Nat Clin Pract Nephrol. 2005;1:44-54). FSGS is a leading cause of nephrotic syndrome worldwide and may be found in up to 35% of nephrotic individuals. The pathogenesis remains uncertain, and the identification of distinct variants of FSGS, including collapsing glomerulonephropathy and the glomerular tip lesion, illustrates the importance of classification of these glomerular lesions.
The diagnosis of FSGS is based on histopathologic findings, although the glomerular pathology may result from multiple different molecular or cellular processes and be unrelated to a particular disease. Histopathology alone is unlikely to predict the natural history of FSGS.
Important factors to consider in the treatment of FSGS include the identification of patients who are suitable candidates for therapy, establishing the goals of treatment (e.g., decreasing proteinuria, slowing disease progression, preventing ESRD), selecting an appropriate first-line therapy, and identifying suitable adjuvant treatments and salvage therapies.
Etiology and outcomes
The etiology of FSGS can have a major influence on therapeutic decision-making. The etiologic hallmark of primary idiopathic FSGS is podocyte injury while secondary types of FSGS (e.g., familial-genetic types, virus-associated FSGS, unilateral renal agenesis, and FSGS associated with renal dysplasia, surgical renal ablation, hypertension, and obesity) develop as a maladaptive response to glomerular “overwork.” The characteristic features of primary idiopathic FSGS include extensive foot process effacement, variable glomerulomegaly, and a clinical presentation consistent with full-blown nephrotic syndrome. In contrast, secondary FSGS is characterized by limited foot process effacement, glomerulomegaly, and proteinuria without hypoalbuminemia. For example, obesity-related glomerulopathy (ORG) is an emerging epidemic (Kidney Int. 2001;59:1498-1509) and should be distinguished from idiopathic FSGS. Compared with patients with idiopathic FSGS, those with ORG are significantly older, more often Caucasian, and have lower incidences of nephrotic syndrome and nephrotic range proteinuria, higher serum albumin, and lower serum cholesterol levels. On renal biopsy, patients with ORG have more glomerulomegaly, fewer lesions of segmental sclerosis, and less extensive foot process effacement.
Corticosteroids and immunomodulatory agents are the mainstays of treatment in patients with primary idiopathic FSGS while ACE inhibitors and angiotensin receptor-blockers are more commonly used in patients with secondary FSGS.
The outcomes of patients with FSGS can be predicted by a variety of clinical and histologic variables. Favorable outcomes in patients with FSGS are associated with lower levels of proteinuria and serum crea-tinine and glomerular tip lesions on histologic examination. Unfavor-able outcomes may be predicted by African-American race, interstitial fibrosis, and collapsing FSGS histopathology. Remission of proteinuria, either complete or partial, is a strong predictor of increased survival rate in patients with FSGS (Kidney Int. 2004;66:1199-1205).
Treatment options
Corticosteroids are now a mainstay of FSGS, a condition initially considered to be a steroid-resistant disease. Several studies have shown improved responsiveness to more prolonged courses of steroids. Partial or complete remission may be achieved in about 50% of adults with FSGS treated with long-term corticosteroid therapy (Semin Nephrol. 2000;20:309-317).
Cyclophosphamide has been used in the past as standard second-line therapy in patients with steroid-resistant FSGS, but complete response rates in adults are disappointing (Semin Nephrol. 2000;20:309-317). Higher response rates have been reported in pediatric patients with FSGS treated with cyclophosphamide. Cyclophosphamide may be useful in patients with FSGS who do not respond to other immunosuppressive therapies.
For patients with steroid-resistant or steroid-dependent FSGS, cyclosporine has shown efficacy in clinical trials. In a double-blind, randomized, controlled study of 49 patients with steroid-resistant FSGS randomized to 26 weeks of cyclosporine plus low-dose prednisone or placebo plus prednisone, complete or partial re-mission of proteinuria at 26 weeks was achieved in 70% of the treatment group and 4% of the placebo group (Kidney Int. 1999;56:2220-2226). Renal function was better preserved in the cyclosporine group than in the placebo group. A significant 50% reduction in baseline creatinine clearance was observed in 25% of the cyclosporine group and 52% of the placebo group.
Tacrolimus
Tacrolimus is an alternative immunosuppressive agent to cyclosporine. About 60% of patients with steroid-resistant FSGS treated with adjunctive tacrolimus achieve partial or complete remission. There are few differences between cyclosporine and tacrolimus in terms of partial and complete response rates and toxicity in patients with steroid-resistant FSGS. Tacrolimus may be useful in some cyclosporine-resistant patients with FSGS and in those who are intolerant of cyclosporine.
Alkylating agents
Alkylating agents have been used in the treatment of idiopathic FSGS but are not widely re-commended as standard second-line therapy. A group of 57 patients with FSGS were randomized to receive steroids and cyclosporine or steroids and chlorambucil for six months (Am J Kidney Dis. 2004; 43:10-18). At four years there were no significant differences between the groups in terms of mean creatinine and proteinuria levels, the proportions of patients who achieved partial or complete remission, and in the number of patients who developed (ESRD).
Mycophenolate mofetil
Mycophenolate mofetil (MMF) appears safe for use in patients with steroid-resistant FSGS and lowers proteinuria in about 44% of patients after six months of treatment (Clin Nephrol. 2004;62:405-411). Relapses are common, suggesting more prolonged or combination therapy may be needed. In patients with primary glomerular disease, empiric treatment with MMF may provide stabilization of renal function and the ability to withdraw steroids and is generally well tolerated (Kidney Int. 2002; 61:1098-1114). Several studies examining the use of sirolimus in patients with steroid-resistant FSGS have yielded disappointing results. About 50% of patients with refractory FSGS treated with sirolimus experienced acute renal failure with significant increases in serum creatinine level; decreases in glomerular filtration rate (GFR) and worsening proteinuria were also observed; however, in one prospective, open-label trial, 21 patients with idiopathic, steroid-resistant FSGS were treated with sirolimus (Clin J Am Soc Nephrol. 2006;1:109-116). After six months of treatment, four and eight patients achieved complete and partial remission, respectively. Among treatment responders, sirolimus decreased proteinuria and glomerular pore size and maintained GFR. Patients with complete remission had a higher GFR at the end of treatment compared with nonresponders.
Conclusion
The prognosis of untreated patients with FSGS is poor, and about 50%-70% of untreated nephrotic patients with FSGS progress to ESRD. Although FSGS was considered to be a steroid-resistant disease, several stud-ies have shown improved responsiveness to more prolonged courses of steroids. In subnephrotic patients with FSGS, treatment with a combination of ACE inhibitors or angiotensin receptor-blockers, diuretics, and statins should be considered. Patients with classic idiopathic FSGS may benefit from treatment with prednisone administered daily with taper or every other day for six months. Alternatives to steroids should be considered for first-line therapy in patients with FSGS who are obese or diabetic. For patients with steroid-resistant or steroid-dependent FSGS and in those with collapsing FSGS and markedly elevated serum creatinine levels, cyclosporine and cytotoxic agents have shown efficacy in clinical trials. The role of other agents used in patients with FSGS, including azathioprine, MMF, and tacrolimus, remains poorly defined.
Dr. Gerald Appel is director of clinical nephrology at the New York-Presbyterian Medical Center and professor of clinical medicine at the Columbia University College of Physicians and Surgeons in New York. Dr. Alice Appel is a senior research associate in the division of nephrology at Columbia University College of Physicians & Surgeons.