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

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0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32

TIME (WEEKS)

REM

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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

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1 7 13 19 25

TIME (WEEKS)

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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

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No rm al c reatinineElevated c reatinine

Follow-up Period (M onths)

Perc

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ithou

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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

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val (

%) Control FSGSControl FSGS

P < 0.001P < 0.001

Collapsing FSGSCollapsing FSGS

100908070605040302010

0

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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

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N o re m iss io nR e m iss io n

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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

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%) 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