Treatment of primary FSGS 2012. 07. 18 MN R4 우성애

J Floege et al. Clinical nephrology Subnephrotic proteinuria, renal biopsy에서 little damage -> steroid, immonosuppressive therapy의 role이 unclear. Some clinicians use cyclosporin as 1st line therapy in high risk pt(steroid Cx- such as concurrent DM, morbid obesity) 2ndary: primary cause치료가 우선/대개 non-nephrotic , no Sx, immunosuppressives의 role이 밝혀지지 않음, no RCT. 따라서 ARB등 supportive care J Floege et al. Clinical nephrology

Initial treatment ARB/ACEi Lipid lowering Should be given to all patients with primary FSGS, even as specific immunosuppressive therapy is undertaken Reduce proteinuria in primary/secondary FSGS rarely induce a remission without immunosuppressive treatment Slow the rate of progression to kidney failure in proteinuric renal dz Lipid lowering Hyperlipidemia is common(nephrotic syn) CKD is a/c a increase in cardiovascular risk, particularly in older pts statin therapy may slow the rate of progressive renal failure FSGS c persistent nephrotic syn and/or CKD should be treated c a statin

Prognostic factors Untreated primary FSGS often follows a progressive course to ESRD. Degree of proteinuria Nephrotic syn: 5yr/10yr renal survival rate 60-90%/ 30-55% no nephrotic syn c normal renal function: 10yr renal survival rate > 85% Spontaneous CR rate in nephrotic syn; probably less than 10% (most pts are treated) Severity of renal dysfunction at presentation More severe renal dysfunction → worse renal survival Cr > 1.3mg/dL 10yr renal survival rate 27% Cr <1.3mg/dL 10yr renal survival 100% <Korbet SM J Am Soc Nephrol 1998> renal dysfunction → greater extent of fibrosis on bx {more severe dz, longer duration, other factors such as HTN/aging} → less likely to respond to therapy Histologic findings(tubulointerstitial fibrosis )

Decision of immunosuppressive therapy immunosuppressive therapy for primary FSGS → patient with nephrotic range proteinuria ,generally Efficacy of immunosuppression in renal dysfunction (GFR < 25-35mL/min/1.73m2) is unclear {acuity of the renal failure, renal biopsy findings, patient’s risk related to immunosuppression} Don’t initiate immunosuppressive therapy Normal kidney function and less than nephrotic range proteinuria Decreased kidney function and less than nephrotic range proteinuria

Initial treatment Immunosuppressive therapy Prednisone, 1mg/kg per day(Max. 60-80mg/d) OR Prednisone, 2mg/kg every other day(Max. 80-120mg/d) at least 6-8 months Initial response rate: 40-80% Remission is associated with the use of high doses (more than 60 mg/day) for three months; therefore, if there is a concern about prolonged use, a reduction in dose to 0.5 mg/kg/day should be made only after three months (grade D) <Burgess E. Kidney Int Suppl. 1999;70:S26.> Although less responsive than minimal change dz, primary FSGS appears to respond to glucocorticoids, as well as other agents; however, more prolonged steroid therapy than in MCD is generally required to induce remission. -Steroid dose 및 duration에 대한 RCT는 없음. Observational study 및 other renal dz에서의 trial에 따름 -a MEDLINE search was conducted, and articles were reviewed using levels of evidence

Monitoring response to therapy Routine blood chemistries(plasma Cr), urine protein-to- creatinine ratio Prior to tapering immunosuppression, confirm the level of proteinuria(24hr urine collection) Response(or toxicity) evaluation q 2-4wks in initial 2- 3months Once drug therapy is stabilized and/or is being tapered, monitor q 1-2month.

Response to therapy Compete response: proteinuria < 200-300mg/d Partial response: proteinuria 50%이상 감소 and <3.5g/d Relapse: return of proteinuria to ≥ 3.5g/d in,,,CR or PR Steroid-dependence; relapse while on therapy or requirement for continuation of steroids to maintain remission Steroid-resistance; little or no reduction in proteinuria after 12-16 wks of adequate prednisone therapy, some reduction in proteinuria with more prolonged therapy who don’t meet the criteria for PR

Initial treatment CR within 12wks → initial dose를 1-2주 더 유지한 후 2-3개월에 걸쳐서 tapering(switch to alternate day dose, and then 2-3주마다 1/3씩 감량) PR within 12 wks → taper PDL slowly over 6-9mon (switch to alternate day dose, and then 6주마다 1/3씩 감량) if proteinuria increase at any time during the taper, stop the taper, maintain the current PDL dose, and add cyclosporin(GFR <40시 MMF) Although less responsive than minimal change dz, primary FSGS appears to respond to glucocorticoids, as well as other agents; however, more prolonged steroid therapy than in MCD is generally required to induce remission. -Steroid dose 및 duration에 대한 RCT는 없음. Observational study 및 other renal dz에서의 trial에 따름 -a MEDLINE search was conducted, and articles were reviewed using levels of evidence

Initial treatment substantial reduction in proteinuria at 12 to 16 weeks but don’t meet criteria for partial remission → continue high-dose prednisone? modify therapy ? (alternate-day PDL or cyclosporin/MMF) the risk of continued steroid therapy(severity of steroid toxicity) whether protein excretion is continuing to fall or has plateaued on 24- hour urine collections. little or no reduction in proteinuria after 12 to 16 weeks of daily prednisone ; steroid-resistant → add cyclosporine and switch to alternate day prednisone with a progressive taper(매주 1/3씩 감량) Although less responsive than minimal change dz, primary FSGS appears to respond to glucocorticoids, as well as other agents; however, more prolonged steroid therapy than in MCD is generally required to induce remission. -Steroid dose 및 duration에 대한 RCT는 없음. Observational study 및 other renal dz에서의 trial에 따름 -a MEDLINE search was conducted, and articles were reviewed using levels of evidence

Relapsing disease CR/PR to steroids, prednisone 중단 후 1년이상 remission유지 → repeat a course of prednisone CR/PR, but relapse during the taper or steroid 종료 1년이내 → steroid-dependent Significant steroid-induced toxicity / subsequent relapses → initially with cyclosporine + low dose prednisone (similar steroid-dependent/steroid-resistant)

Steroid-dependent/steroid-resistant Initial : Cyclosporin Response rate 20-70% , efficacy in preventing progression to ESRD is unknown

Steroid-dependent/steroid-resistant Cyclosporin group vs placebo group(RCT, n= 49) Cyclosporin 3.5mg/kg/d #2 trough level 125-225μg/L X 26wks, tapered over 4wks, prednisone 0.15mg/kg/d(max. 15mg) mean f/u duration 200wks CR+PR rate at 26wks 70% vs 4% (p <0.001) relapse rate 40% at 52wks, 60% at 78wks CrCl 50%감소; 25% vs 52% (p < 0.05) <Cattran DC et al. Kidney Int 1999.>

Steroid-dependent/steroid-resistant Cyclosporin vs placebo(n= 30, 15/15) Cyclosporin 3mg/kg q 12hrs, level 300-500ng/mL x 6Mo Cyclosporin level weekly for the first 4 wk, then monthly CR/PR 4/8 vs 0/2 (p <0.05), 12/12 completed. (proteinuria 70.7±19.2% 감소 vs 11.4 ±29%, p <0.05) CSA > 500ng/mL, Cr >0.3↑, GSPT >150, total bil >2.25 → 1.0mg/kg 감량, 2 주후에도 지속시 50%감량, 2주후에도 지속시 약물중단) CSA <100 ng/mL,→ 1.5mg/kg증량 CSA 100-200 → 1.0mg/kg증량 CSA 200-300 → 0.5mg/kg증량 <Lieberman KV et al. J Am Soc Nephrol 1996> Clinical nephrol

Steroid-dependent/steroid-resistant 45 Adults and children c steroid-resistant primary FSGS Cyclosporine 5mg/kg/d adult, 6mg/kg/d in child for 6 Mo, tapered by 25% q 2Mo CR/PR 59% vs 16% (p<0.001) Lack of antiproteinuric effect at 3 Mo → resistance to CSA (response occurs earlier, within 3 Mo) <Ponticelli C. et al. Kidney Int 1993>

Steroid-dependent/steroid-resistant Cyclosporin combined with low-dose prednisone Initiate cyclosporine 2-4mg/kg/d #2 or 100mg bid / {3-6mg/kg} CR후 최소 6개월, PR후 1년 유지, remission이 유지되는 최소용량 (preferably ≤ 3mg/kg/d) Prednisone 0.15mg/kg(max 15mg/d) 6개월후 5-7.5mg/d(10-15mg qod)로 taper하고 remission후 6-12개월간 CSA와 함께 유지 Serum level 100 - 175 μg/ml <uptodate> 150 - 300 μg/ml <Ellen B. KI 1999 evidence D> Unresponsive -> cyclophosphamide, chlorambucil, tacrolimus, mycophenolate, sirolimus Relapse rate가 높기 때문에 천천히 tapering

Steroid-dependent/steroid-resistant Tacrolimus No study for comparison efficacy of tacrolimus/cyclosporine Open-label uncontrolled study, n=25 Resistant /dependent to cyclosporine + steroid pts Tacrolimus(initiate 0.15mg/kg #2, level 5-10ng/ml) + steroid (prednisone 1mg/kg/d for 4 wks and then 1mg/kg qod until week 8, taper until 24week) therapy for 6 Mo 17(68%) proteinuria < 3g/d로 감소, 10/2(40/8%) CR/PR, 13(76%) relapsed after discontinuation; reinstitution of therapy for 1 yr ; 5/4(38/30%) CR/PR Reversible mild acute nephrotoxicity: 40% (inappropriately high starting dose) <Segarra A. et al Nephrol Dial Transplant 2002> Limited experience

Steroid-dependent/steroid-resistant Mycophenolate mofetil(MMF) Some observational studies have suggested a possible benefit of MMF given with or without steroid Uncontrolled prospective study (n= 18, nephrotic range proteinuria) - all resistant to prolonged steroids and 75% to a cytotoxic agent and/or a CNI - MMF for 8Mo(mean) - CR/PR 0/8 (44%) Retrospective study, (n=18 ) - steroid-resistant/dependence with or without cyclosporine - MMF 4-24Mo, variable doses - CR/PR 2/6 (11.1/33.3%), stabilized renal function, steroid can withdrawn without relapse in 8 of 12pts, at least in the short term MMF 750-1000mg twice daily for 6 Mo resistant to prednisone & not response to CSA/should not be exposed to CSA partial response to prednisone and/or CSA but have toxicity

Steroid-dependent/steroid-resistant Cytotoxic therapy; cyclophosphamide, chlorambucil Cyclophosphamide 2mg/kg/d for 8-12wks, CR/PR 75% in children c relapsing/steroid dependent idiopathic nephrotic syn Less effective in adult steroid-resistent FSGS(<25% benefit, 8-12wks) <Matalon A. et al Semin Nephrol 2000> Consider in partial response to PDL, extensive interstitial fibrosis and/or vascular dz on bx(at higher risk of CNI toxicity) {don’t recommand in primary FSGS who don’t respond to steroid} Add before the PDL has been discontinued, 8-12wks ( no benefit >12wks)

Steroid-dependent/steroid-resistant Cyclosporine A and chlorambucil (RCT n= 57) Group1(n=34), cyclosporin + steroids for 6Mo 5mg/kg/d, level 130-180ng/mL Group 2(n=23), chlorambucil + steroids 0.1-0.4mg/kg/d All chlorambucil group required cyclosporine(no response) → Chlorambucil: no benefit !

Summary Non-immunosuppressive therapy Immunosuppressive therapy Prednisone 1mg/kg per day(Max. 60-80mg/d) or 2mg/kg every other day(Max. 80-120mg/d), 12-16주 투여하면서 response확인후 tapering, 최 소 6-8 개월 유지 Steroid-dependent/resistant(12-16wk) Cyclosporin combined with low-dose prednisone Initiate cyclosporine 2-4mg/kg/d or 100mg bid / {3-6mg/kg} CR후 최소 6개월, PR후 1년 유지 Prednisone 0.15mg/kg(max 15mg/d) 6개월후 5-7.5mg/d(10-15mg qod)로 tapering, remission후 6-12개월간 Unresponsive -> cyclophosphamide, chlorambucil, tacrolimus, mycophenolate, sirolimus