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Focal Segmental Focal Segmental GlomerulosclerosisGlomerulosclerosis ––Patterns, Patterns,
Pathogenesis, and Pathogenesis, and TherapyTherapy
GERALD APPEL, MDGERALD APPEL, MDProfessor of Clinical MedicineProfessor of Clinical MedicineColumbia University Columbia University ––College of College of Physicians and SurgeonsPhysicians and SurgeonsNYNY--Presbyterian HospitalPresbyterian Hospital
New York, New YorkNew York, New York
Minimal Change DiseaseMinimal Change Disease
Features,Treatment, and Outcome of Adult MCD
95 Bx MCD at Columbia U. from 1990-2005• GFR 72 cc/min Pcreat 1.4 mg/dl • 24h Prot 9.9 g/day hematuria 20% HBP 43% • ARF at presentation 17% (eventual 24%)
88 Rx Steroids 65 Daily v 23 QOD• No dfference in respone (76 v 74 % ) • No difference in time to response ( 11 v 16 wks )• No difference in percent relapse ( 75 v 63% )
Of responders 60% relapse , most respond again • 54% Rx w cyA, cytoxan, MMF, or Tacrolimus
• Waldman M…Appel GB Clinical JASN 2007
TIME TO REMISSION
0
10
20
30
40
50
60
70
80
90
100
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32
TIME (WEEKS)
REM
ISSI
ON
(%)
TIME TO REMISSION (ALL)TIME TO REMISISION (QD)TIME TO REMISISON (QOD)p = NS
Adult MCD – Time to Remission Waldman …Appel 2006
RELAPSE FREE SURVIVAL
50
60
70
80
90
100
1 7 13 19 25
TIME (WEEKS)
REL
APS
E FR
EE (%
)
RELAPSE FREE SURVIVAL (ALL)RELAPSE FREE SURVIVAL (QD)RELAPSE FREE SURVIVAL (QOD)
p = NS
Adult MCD – Relapse Free SurvivalWaldman …Appel 2006
MMF in FRNS or SDNS N = 32 81% FRNS 19% SDNSPre-Entry Relapses > 4 per yearTreatment Phase 28-week course of
MMF (dose based on body size) + 16-week tapering course of alternate day prednisone (starting at 1 mg/kg QOD)
Post-Treatment Phase Patient monitored to determine if a 28-week course of MMF therapy is protective against relapse of NS after MMF is stopped
Hogg R … CNC 2007 ASN
MMF/NS Study: Results• 8 patients completed follow-up off therapy without
relapse• Mean follow-up = 18.5 months
• 16 patients relapsed after MMF discontinued– 13 patients given MMF post-study by local MD
• 5 stayed in remission• 8 relapses (6 infrequent; 2 frequent)
• 8 patients relapsed while on MMF
• 24/32 (75%) of the patients stayed in remission on MMF
MEAN FOLLOW ONLY 18 MONTHS!Hogg R … CNC 2007 ASN
Nephrotic Syndrome: Main pathologies (%)
Span Italy1 Denmark6 Japan7 Kore
9 UA Emerits19
MCD 17.1 12 23.5 37.7 59.4 26.2
FGS 14.1 12.3 8 9 11.1 15.4
MN 22.9 32.9 22.4 23.3 15.9 28.3
IgAN 4.5 2.4 17.5 19.2 3.3 3.2
RIVERA F, LÓPEZ-GÓMEZ JM, PÉREZ-GARCÍA R Kidney Int 66:898; 2004
FSGS: Incidence in Olmstead MN
• A retrospective study of 195 native renal biopsies from 1974-2003.
• All adult patients residing in Olmstead County, MN .
• >90% Caucasian Pts.
1974-1983 1984-1993 1994-2003
5.7 % 17.9% 20.2%
Swaminathan S, et al – Mayo Clinic- Clinical JASN 2006.
Etiologic Classification of Secondary FSGSMediated by Adaptive Structural-Functional Responses
Reduced renal massUnilateral renal agenesisRenal dysplasiaReflux nephropathySurgical renal ablationAdvanced renal dis.w reduction in functioning nephrons
Initially normal renal massHypertensionAtheroemboliObesityCyanotic congenital HT. dis.Sickle cell anemia
Familial-GeneticMutations in α-actinin 4 Mutations in podocinMutations in TRPC6
Virus-Associated“HIV-associatedParvovirus B-19
Drug-Med. InducedHeroin (“Heroin nephropathy”)Pamidronate
Genetic Podocyte Mutations
• Alpha actinin 4 familial autosomaldominant FSGS.
• Podocin ( NPHS2 ) autosomal recessive steroid resistant nephrotic syndrome
• CD2-associated protein (CD2AP )• WTI splice site mutation in Frasier
Syndrome• TRPC6 channel defect – autosomal
dominant FSGS ( Nature Genetics 2005)
Obesity-related Glomerulopathy: An Emerging Epidemic
• Review >6800 Bxs 1986-2000• ORG 0.2% (1986-1990) 2.0% (1996-2000)
ORG (71) FSGS (50)Age /Race 43 yo /75% W 32 yo/52% W p<.01NS 5.6% 54% p<.01Salb 3.9 g/dl 2.9 g/dl p<.001
FSGS 18% 39%Glomerulomeg 100% 10%FPE 40% 75%
Double Pcreat 14% 50%ESRD 3.6% 42%
Kambham, Markowitz, Valeri et al. Kidney Int 59:1498-1509. 2001.
Renal survival (ie doubling of serum creatinine or ESRD) overtime in ORG, and I-
FSGS.
Kambham N et al Columbia University NY Kid Int 59:1498-1509, 2001
ORG an increasing problem
Kambham N et al Columbia University NY Kid Int 59:1498-1509, 2001
Strong association between NPHS2 R229Q and microalbuminuria in the general population with
increased BMI
Abhay Vats, MDChildren’s Hospital of Pittsburgh
ORG and Genetic Susceptibility
Given the presence of genetic susceptibility and/or reduced nephron mass, obesity may potentiate the development and progression of secondary FSGS
Several family members with disease causing mutations or polymorphisms may not manifest the disease (ACTN4, TRPC6, NPHS2)
Obesity may unmask such susceptibility
Predictors of Outcome in FSGS• Clinical
Proteinuria/ Nephrotic Syndrome Serum CreatinineBlack Race( Not age, sex, HBP, hematuria )
• HistopathologyInterstitial FibrosisTip Lesion Collapsing FSGS
• CourseRemission of Proteinuria
CrCl loss-1.2mls/min/yr
-5mls/min/yr-9mls/min/yr
All proteinuria is not the same…. arrow shows Increasing progression rate
Cattran CNC ASN 2007
Histology strongly influencesimpact of proteinuria on outcome
Kaplan-M eier P lotStratified by Serum C reatinine
0 24 48 72 96 120 144 168 192 216 240 264 2880
10
20
30
40
50
60
70
80
90
100
No rm al c reatinineElevated c reatinine
Follow-up Period (M onths)
Perc
ent W
ithou
t ESR
D
Figure 2: Kaplan-Meier plot, stratified by serum creatinine as shown above, with elevated creatinine defined as 1.5 mg/dL or higher. Follow-up period is listed in months, where t=0 represents date of renal biopsy. ⏐ represents censored events. Four patients had missing creatinine data and were not included in this figure. P=0.0001 by log-rank test.
Never Nephrotic Pts w iFSGSPts w iFSGS w/o NS felt to have better course. 289 iFSGS in
Toronto Registry. Follow (60-66mo ).
NN (N = 67 ; 23% ) NS ( N = 222 ; 77% )F 46 34 NSAge 40 44 .04MAP 108 107 NSCcr 71 78 NSUVp 1.6 4.8Immunorx 16% 62% .001ACEi/ARB 46% 46% NSMAP 102 101 NSSlope Ccr - 0.29 -0.65 .001 50% decGFR 33 41 NSESRD 21 26 NS
Troyanov S,… Cattran D, GN group Toronto Kidney Int 2004
FSGS - Tip variantFSGS - Tip variant
Frequency of Common Patterns of Idiopathic FSGS
UNC Columbia
Total FSGS 1555 717
Collapsing 159 (10%) 115 (16% )
Tip Lesion 111 ( 7% ) 20 ( 3%)
Value of New FSGS classification on Renal Survival
Thomas et al, JASN 2006
collapsing
NOS,Tip,Hilar
Thomas, Falk et al, KI 2006
Idiopathic Collapsing FSGSIdiopathic Collapsing FSGS
# patients 42 43 21 16
Age (yrs) 38 32 30 41
% black 57 61 86 81
u. prot (g/d) 13.3 10.2 14.3 13.2
s. creat (mg/dl) 5.4 4.2 3.8 3.5
Median renal 15.7 13.0 15.0 15.0survival (mos)
# patients 42 43 21 16
Age (yrs) 38 32 30 41
% black 57 61 86 81
u. prot (g/d) 13.3 10.2 14.3 13.2
s. creat (mg/dl) 5.4 4.2 3.8 3.5
Median renal 15.7 13.0 15.0 15.0survival (mos)
Laurinavicius(Boston,‘99)
Laurinavicius(Boston,‘99)
Valeri(NY,‘96)Valeri
(NY,‘96)Haas
(Chicago,‘95)Haas
(Chicago,‘95)Detwiler
(Chapel Hill,‘94)Detwiler
(Chapel Hill,‘94)
Injured podocytes may take different pathways
Podocyte injury
Collapse
Proliferation
Cell hypertrophy
Cell death/Detachment
Sclerosis
De-differentiation
FSGS CG
Differently from other podocytopathies, in CG podocytes are de-differentiated
Barisoni, Mundel et al. JASN 1999
Renal Survival Curve: Collapsing vs Control FSGS(Valeri…Appel …D’Agati, Kidney Int 50: 1734, 1996)Renal Survival Curve: Collapsing vs Control FSGS(Valeri…Appel …D’Agati, Kidney Int 50: 1734, 1996)
Time (months)Time (months)
Ren
al S
urvi
val (
%)
Ren
al S
urvi
val (
%) Control FSGSControl FSGS
P < 0.001P < 0.001
Collapsing FSGSCollapsing FSGS
100908070605040302010
0
100908070605040302010
00 12 24 36 48 60 720 12 24 36 48 60 72
Collapsing FSGS –Laurenivicius…Rennke Kidney Int 1999
Collapsing FSGS –Laurenivicius…Rennke Kidney Int 1999
Collapsing Glomerulopathy: Clinicopathological Findings
• 74 cases in 10 years period (1995-2005)• mean age 42 years. 41 M (56%) 33 F (44%). • 18/74 AA (24.4%)• Clinical associations: 39 idiopathic
10 viral infection8 autoimmune disease9 post-transplant4 pamidronate4 obese
• Conclusion: diverse group of disorders are associated with collapsing glomerulopathy, most have in common an altered immune status.
Soares, Sethi – Clin JASN 2007
Predictors of Outcome in FSGS• Clinical
Proteinuria/ Nephrotic Syndrome Serum CreatinineBlack Race( Not age, sex, HBP, hematuria )
• HistopathologyInterstitial FibrosisTip Lesion Collapsing FSGS
• CourseRemission of Proteinuria
K aplan-M eier P lotS tra tified by R em ission S ta tus
0 24 48 72 96 120 144 168 192 216 240 264 2880
10
20
30
40
50
60
70
80
90
100
N o re m iss io nR e m iss io n
F ollow-up P eriod (M onths)
Perc
ent W
ithou
t ESR
D
Figure 3: Kaplan-Meier plot, stratified by partial remission status. t=0 renal biopsy. ⏐ P=0.0004.
Renal survival in nephrotic FSGS pts based on remission
status (Chun et al. JASN 15: 2169, 2004)
Renal survival in nephrotic FSGS pts based on remission
status (Chun et al. JASN 15: 2169, 2004)
Troyanov…, Cattran, - Toronto GN Registry, JASN 2005
Partial Remission a Useful Outcome in FSGS
CompletePartial
No Remission
90%
78%
40%
Treatment of FSGS
• Corticosteroids ( daily – QOD )• Cyclophosphamide• Cyclosporine• Tacrolimus ( Prograf )• Mycophenolate Mofetil• Sirolimus ( Rapamycin )
Response to Steroid Treatment n Response to Steroid Treatment n Adult FSGSAdult FSGS
Study N complte partal No Resp
Miyata 32 44% 12% 44%Pei 18 39% 0% 61%Banfi 59 61% 0% 31%Agarwal 38 32% 26% 42%Rydel 30 33% 17% 50%
Total 177 45% 10 % 45%
Cyclophosphamide for Steroid Resistant FSGS
Adult Pts. – 8 Studies125 Pts. CR 17% PR 7%
Ped Pts. – 2 Studies42 Pts. CR 52% PR 17%
Matalon A, Valeri A, Appel GB. Sem. Nephrol. 2001.
CSA: 26 pts
Pbo: 23 pts
Cattran, Appel, Hebert et al, N Amer Nephrotic Synd Study Group Kidney Int 56:2220-2226, 1999
p <0.001
p <0.05
Cyclosporin in FSGS: Remission
52%
25%
p <0.05
CSA
Placebo
Cyclosporine in SR-FSGS
Cattran, Appel, Hebert et al, N Amer Neph Syn Study Group Kidney Int 56:2220-2226, 1999
p <0.05
Cyclosporine vs Chlorambucil in the Treatment of FSGS
Heering P et al. AJKD 43:10-18, 2004
Tacrolimus in steroid resistant(SR) nephrotic syndrome in Childhood
• Open label, consecutive patients (n=19)Renal Biopsy; 9 FSGS, 8 MCD, 3 Mes proliferativeTacrolimus 0.15-0.2 mg/kg x 6 mos, To 5-10 ng/ml
• 2/19 intolerant and Rx D/C ( 1 developed HUS)• 3/17 CR• 14/17 PR• GFR unchanged at 6 months
Gulati DS …Abstract ASN 2006
MMF for Steroid Resistant FSGS
16 Pts age 42 10B/4W/2OAll NS Uprot 9.4 g/d Screat. 0.8-3.1 mg/dlAll failed Pred. + others IS( 34 Course Rx Failed )MMF 750-2g/d av. 9 months
50% Improved by 6 mo.U prot decrease > 50% w/o NS = 4U prot decrease > 50% w NS = 2U prot decrease < 50% w/o NS = 2
Cattran , Appel, Briggs Clin Nephrol 2005
MMF Treatment for Primary Glomerular Disease
18 Pts FSGS 16-65 yo 67% M 72% W / 22% B
Up/cr 2.7 Scr 1.8 mg/dl
9 / 17 Nephrotic
12 / 18 + STDS 6 / 18 MMF Alone
Up/cr 2.7 to 0.8 (2 CR, 6 PR)
9 NS Up/cr 7.5 to 3.9 (1 CR)
Choi MJ, Eustace JA, Gimenez LF, et al. Kidney Int 61:1098-1114, 2002.
MMF in steroid dependent(SD) or steroid resistant (SR) pediatric nephrotic patients
SD (n=20); SR (n=20) (20 Dx = FSGS)• All previously treated with cyclophosphamide and/or
35/40 cyclosporine• MMF dose= 600 mg/m2 /d, X6-8mos+ARB+tapering
corticosteriodsSRNS
– 3/20 CR; 15/20 PR; 1/20 NRSDNS
– 13/20 CR; 6/20 PR; 1/20 NRAE’s minor, usual diarrhea, ↑ LFT’s, inf (15%)in-line
Guersoni et al. F PO1104(ASN abst 2006)
Comments Short follow-up, no biopsies
FSGS-NIH Sponsored Controlled Trial
12 Month Primary Outcome AssessmentTreatment Withdrawn (CYA/MMF/Dex)
6 months
Secondary Outcome AssessmentRemission/Relapse Status at 18 months
0
26
52
78
Week
CYA MMF + Dexamethasone
ACEi
Failures Depart
Cho…Kopp AJKD 2007
Sirolimus for Steroid Resistant FSGS
Sirolimus no significant effect on proteinuria in FSGS
Cho…Kopp AJKD 2007
21 Steroid-Resistant FSGS: Therapeutic Response to 6 Months of Oral Rapamycin
Complete Partial Tx FailureComplete/Partial
43%
57%
38%
19%
Perc
ent (
%) o
f Pat
ient
s
Sirolimus in steroid resistant idiopathic nephrotic syndrome (SRNS)
N = 24 80%FSGS 20% SR MCD • Prospective open label non randomized• Sirolimus for 6 months levels of 4-14 ngm / ml • + Oral prednisolone ( 60 mg/m2/day in
children and 1 mg/kg/day in adults ) - slowly tapered off once remission over 3 to 4 months
• Other therapy - statins and ACEI /ARB
Primary outcome proteinuria: CR<0.3, PR 50% decrease, versus NR
RK Sharma …ASN 2007
Sirolimus in SRNSResponse No. % RespondersComplete remission (CR)Partial remission (PR)
150807
62.5%33.3%29.2%
Non responders (NR) 09 37.5%
Response (%)
33.3
29.2
37.5
CR PR NR
Mean time to remission 3.2 mo Mean dose was 2.2 mg/day Mean follow up 110 days None lost to follow up
RK Sharma …ASN 2007
Sirolimus in SRNSGFR (ml/min/1.73 m2)
80.588.2
81.2
59.5
84.276.4
0102030405060708090
100
CR PR NR
Baseline At 6 month
P=0.122P=0.051 P=0.008
CR – Complete remission , PR – Partial remission , NR – Non responders
In NR:Drop in GFR 20mls/minconcern also in Tumlinstudy
Appel’s Treatment of FSGS
• Subnephrotic ACEi/ARB +Diuretics +Statin
• Classic FSGS – 6 mo QOD Prednisone( 120 QOD x 2mo,decrease by 20 q 2wks,
continue 40 QOD through 6 months )• Failures or relapsers or special groups (
DM , obese ) – CyA, Cytoxan, MMF. • Collapsing – CyA +strds, or CyA + MMF
Permeability Factor in Collapsing FSGS
• 17 Pts w collapsing FSGS f Presb. Hosp.• Av Age 37 9/17 M 12B/3 Hisp/2W• UV prot 14+ g/D Pcreat 3.0 mg/dl• Palb av. 0.63 ( 8 of 11 > 0.5 ) • Thus, pts with Collapsing FSGS have very
high Palb. And should have high recurrence rate in allograft.
Savin, Mcarthy, Schwimmer, Appel ISN Berlin 2003
Risk of Recurrent FSGS• 1140 Txps from 1997-2006 at CUMC• 93 (8%) FSGS, 67 ( 72% ) idiopathic FSGS.• 15/67 ( 22% ) of primary FSGS recurred.• Of pts <16yo onset 40% RFSGS vs 17% of pts > 16
yo at onset FSGS.• 86% R FSGS had L Donor vs 42% non RFSGS.• Of primary FSGS who reached ESRD < 2 yrs from
onset 33% RFSGS vs 20% of those >2yrs.• 31% primary FSGS in AA – only 6.4%
recurred.• 9/67 FSGS had collapsing – only 1 recurred!!!
• ASN Abstract Monahan…Appel 2007