RATIONALE AND OBJECTIVE: Angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy (renin-angiotensin-aldosterone system [RAAS] inhibitor) to control proteinuria in primary and genetic focal segmental glomerulosclerosis (FSGS) follows guidelines based on other proteinuria-related kidney diseases. There is no consensus on the efficacy and safety of RAAS inhibitor therapies in primary and genetic FSGS. This systematic review assessed the effects of RAAS inhibitor therapy on kidney outcomes in these patients. STUDY DESIGN: Systematic review of randomized controlled trials, interventional nonrandomized studies, observational studies, and retrospective studies. SETTING & STUDY POPULATIONS: Patients with primary and genetic FSGS. SELECTION CRITERIA FOR STUDIES: PubMed, Cochrane Library, and Embase. DATA EXTRACTION: 2 investigators independently screened studies and extracted data. ANALYTICAL APPROACH: Results were summarized as the ratio of means (ROM) between baseline and follow-up measurements or as the hazard ratio using random-effects models. RESULTS: 30 publications were selected; 5 were controlled trials (4 randomized controlled trials). 8 assessed RAAS inhibitor monotherapy, while the rest studied RAAS inhibitors in combination with other drugs, mainly immunosuppressants. On average, a 32% proteinuria reduction (ROM, 0.68; 95% CI, 0.47-0.98) and no change in creatinine clearance (ROM, 0.95; 95% CI, 0.77-1.16) from baseline to the last reported follow-up was observed in patients treated with RAAS inhibitor monotherapy. When a RAAS inhibitor was combined with other drugs, a 72% proteinuria reduction was observed from baseline to the last reported follow-up (ROM, 0.24; 95% CI, 0.08-0.75). The published data did not allow for the assessment of the effects of RAAS inhibitor monotherapy on estimated glomerular filtration rate and end-stage kidney disease risks. LIMITATIONS: Large study heterogeneity in design, patient populations, and treatment regimens. No access to individual patient-level data. CONCLUSIONS: This review supports the tendency to observe a proteinuria reduction with RAAS inhibitors in patients with primary FSGS. RAAS inhibitor monotherapy was associated with maintained kidney function, as shown by no change in creatinine clearance. Strong evidence to quantify the effects of RAAS inhibitor monotherapy on end-stage kidney disease and glomerular filtration rate was lacking. Larger, well-designed clinical trials are needed to better understand the effects of RAAS inhibitors on primary FSGS.

Charles University General University Hospital Prague Czech Republic

Columbia University Medical Center New York NY

Icahn School of Medicine at Mount Sinai New York NY

LatticePoint Consulting Geneva Switzerland

NYU Grossman School of Medicine NYU Langone Health New York NY

University of Louisville School of Medicine Louisville KY

See more in PubMed

Korbet S.M. Treatment of primary FSGS in adults. J Am Soc Nephrol. 2012;23(11):1769–1776. PubMed

KDIGO KDIGO clinical practice guideline for glomerulonephritis. Kidney Int Suppl. 2012;2(2)

Spino C., Jahnke J.S., Selewski D.T., Massengill S., Troost J., Gipson D.S. Changing the paradigm for the treatment and development of new therapies for FSGS. Front Pediatr. 2016;4:25. PubMed PMC

Gipson D.S., Chin H., Presler T.P., et al. Differential risk of remission and ESRD in childhood FSGS. Pediatr Nephrol. 2006;21(3):344–349. PubMed

Troyanov S., Wall C.A., Miller J.A., Scholey J.W., Cattran D.C. Toronto Glomerulonephritis Registry Group. Focal and segmental glomerulosclerosis: definition and relevance of a partial remission. J Am Soc Nephrol. 2005;16(4):1061–1068. PubMed

Trachtman H., Nelson P., Adler S., et al. DUET: a phase 2 study evaluating the efficacy and safety of sparsentan in patients with FSGS. J Am Soc Nephrol. 2018;29(11):2745–2754. PubMed PMC

Bagga A., Mudigoudar B.D., Hari P., Vasudev V. Enalapril dosage in steroid-resistant nephrotic syndrome. Pediatr Nephrol. 2004;19(1):45–50. PubMed

Gipson D.S., Trachtman H., Kaskel F.J., et al. Clinical trial of focal segmental glomerulosclerosis in children and young adults. Kidney Int. 2011;80(8):868–878. PubMed PMC

Trachtman H., Vento S., Herreshoff E., et al. Efficacy of galactose and adalimumab in patients with resistant focal segmental glomerulosclerosis: report of the font clinical trial group. BMC Nephrol. 2015;16(1):111. PubMed PMC

Milliner D.S., Morgenstern B.Z. Angiotensin converting enzyme inhibitors for reduction of proteinuria in children with steroid-resistant nephrotic syndrome. Pediatr Nephrol. 1991;5(5):587–590. PubMed

Huang J., Lin L., Xie J., et al. Glucocorticoids in the treatment of patients with primary focal segmental glomerulosclerosis and moderate proteinuria. Clin Exp Nephrol. 2018;22(6):1315–1323. PubMed

Bagchi S., Agarwal S., Kalaivani M., et al. Primary FSGS in nephrotic adults: clinical profile, response to immunosuppression and outcome. Nephron. 2016;132(2):81–85. PubMed

Gellermann J., Ehrich J.H., Querfeld U. Sequential maintenance therapy with cyclosporin A and mycophenolate mofetil for sustained remission of childhood steroid-resistant nephrotic syndrome. Nephrol Dial Transplant. 2012;27(5):1970–1978. PubMed

Montané B., Abitbol C., Chandar J., Strauss J., Zilleruelo G. Novel therapy of focal glomerulosclerosis with mycophenolate and angiotensin blockade. Pediatr Nephrol. 2003;18(8):772–777. PubMed

Troost J.P., Trachtman H., Spino C., et al. Proteinuria reduction and kidney survival in focal segmental glomerulosclerosis. Am J Kidney Dis. 2021;77(2):216–225. PubMed PMC

Chandar J., Abitbol C., Montané B., Zilleruelo G. Angiotensin blockade as sole treatment for proteinuric kidney disease in children. Nephrol Dial Transplant. 2007;22(5):1332–1337. PubMed

Crenshaw G., Bigler S., Salem M., Crook E.D. Focal segmental glomerulosclerosis in African Americans: effects of steroids and angiotensin converting enzyme inhibitors. Am J Med Sci. 2000;319(5):320–325. PubMed

Delucchi A., Cano F., Rodriguez E., Wolff E., Gonzalez X., Cumsille M.A. Enalapril and prednisone in children with nephrotic-range proteinuria. Pediatr Nephrol. 2000;14(12):1088–1091. PubMed

Ferder L.F., Inserra F., Daccordi H., Romano L., Fernández A., Tessler J. Effects of enalapril on renal parameters in patients with primary glomerulopathies associated with chronic renal failure. Drugs. 1990;39(Suppl 2):40–46. PubMed

Ferder L.F., Inserra F., Daccordi H., Smith R.D. Enalapril improved renal function and proteinuria in chronic glomerulopathies. Nephron. 1990;55(Suppl 1):90–95. PubMed

Futrakul N., Tosukhowong P., Valyapongpichit Y., Tipprukmas N., Futrakul P., Patumraj S. Oxidative stress and hemodynamic maladjustment in chronic renal disease: a therapeutic implication. Ren Fail. 2002;24(4):433–445. PubMed

Futrakul N., Siriviriyakul P., Deekajorndej T., Futrakul P. Hemodynamic maladjustment and disease progression in nephrosis with FSGS. Ren Fail. 2004;26(3):231–236. PubMed

Futrakul N., Futrakul P., Siriviriyakul P. Correction of peritubular capillary flow reduction with vasodilators restores function in focal segmental glomerulosclerotic nephrosis. Clin Hemorheol Microcirc. 2004;31(3):197–205. PubMed

Greenwood A.M., Gunnarsson R., Neuen B.L., Oliver K., Green S.J., Baer R.A. Clinical presentation, treatment and outcome of focal segmental glomerulosclerosis in Far North Queensland Australian adults. Nephrology (Carlton) 2017;22(7):520–530. PubMed

Hogg R.J., Friedman A., Greene T., et al. Renal function and proteinuria after successful immunosuppressive therapies in patients with FSGS. Clin J Am Soc Nephrol. 2013;8(2):211–218. PubMed PMC

Hori C., Hiraoka M., Yoshikawa N., et al. Significance of ACE genotypes and medical treatments in childhood focal glomerulosclerosis. Nephron. 2001;88(4):313–319. PubMed

Huissoon A.P., Meehan S., Keogh J.A. Reduction of proteinuria with captopril therapy in patients with focal segmental glomerulosclerosis and IgA nephropathy. Ir J Med Sci. 1991;160(10):319–321. PubMed

Kangovi S., Edwards M., Woloszynek S., et al. Renin-angiotensin-aldosterone system inhibitors in pediatric focal segmental glomerulosclerosis. Pediatr Nephrol. 2012;27(5):813–819. PubMed

Praga M., Hernández E., Montoyo C., Andrés A., Ruilope L.M., Rodicio J.L. Long-term beneficial effects of angiotensin-converting enzyme inhibition in patients with nephrotic proteinuria. Am J Kidney Dis. 1992;20(3):240–248. PubMed

Praga M., Hernández E., Morales E., et al. Clinical features and long-term outcome of obesity-associated focal segmental glomerulosclerosis. Nephrol Dial Transplant. 2001;16(9):1790–1798. PubMed

Ren H., Shen P., Li X., Pan X., Zhang W., Chen N. Tacrolimus versus cyclophosphamide in steroid-dependent or steroid-resistant focal segmental glomerulosclerosis: a randomized controlled trial. Am J Nephrol. 2013;37(1):84–90. PubMed

Supavekin S., Surapaitoolkorn W., Tancharoen W., Pattaragarn A., Sumboonnanonda A. Combined renin angiotensin blockade in childhood steroid-resistant nephrotic syndrome. Pediatr Int. 2012;54(6):793–797. PubMed

Usta M., Ersoy A., Dilek K., et al. Efficacy of losartan in patients with primary focal segmental glomerulosclerosis resistant to immunosuppressive treatment. J Intern Med. 2003;253(3):329–334. PubMed

Wasilewska A.M., Zoch-Zwierz W.M. Transforming growth factor-beta1 in nephrotic syndrome treated with cyclosporine and ACE inhibitors. Pediatr Nephrol. 2004;19(12):1349–1353. PubMed