1. Treatment of primary FSGS
MN R4 우성애

2. 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

3. 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

4. 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 )

5. 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

6. Initial treatment Immunosuppressive therapy
Prednisone, 1mg/kg per day(Max mg/d) OR
Prednisone, 2mg/kg every other day(Max mg/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

7. 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.

8. 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 wks of adequate prednisone therapy, some reduction in proteinuria with more prolonged therapy who don’t meet the criteria for PR

9. 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

10. 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

11. 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)

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

13. Steroid-dependent/steroid-resistant
Cyclosporin group vs placebo group(RCT, n= 49)
Cyclosporin 3.5mg/kg/d #2
trough level μg/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.>

14. Steroid-dependent/steroid-resistant
Cyclosporin vs placebo(n= 30, 15/15)
Cyclosporin 3mg/kg q 12hrs, level ng/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 → 1.0mg/kg증량
CSA → 0.5mg/kg증량
<Lieberman KV et al. J Am Soc Nephrol 1996>
Clinical nephrol

15. 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>

16. 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 μg/ml <uptodate>
μg/ml <Ellen B. KI 1999 evidence D>
Unresponsive -> cyclophosphamide, chlorambucil, tacrolimus, mycophenolate, sirolimus
Relapse rate가 높기 때문에 천천히 tapering

17. 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

18. 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 mg 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

19. 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)

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

21. Summary Non-immunosuppressive therapy Immunosuppressive therapy
Prednisone 1mg/kg per day(Max mg/d) or 2mg/kg every other day(Max mg/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