Focal Segmental Glomerulosclerosis

Jai Radhakrishnan, MD, MS, MRCP, FACC, FASN

Associate Professor of Clinical Medicine

Columbia University, New York

www.glomerularcenter.org

Objectives

Diagnosis and epidemiology of FSGS Principles of therapy using a stepwise

approach.

Changing Epidemiology of FSGS

Prevalence of FSGS: Arkansas 2001-2005Impact of Race

0

20

40

60

80

100

120

AA Cau Hisp Asian Other Total

IgAN

FSGS

Nair R.. Kidney International (2006) 69, 1455–1458

Nair R.. Kidney International (2006) 69, 1455–1458

Prevalence of FSGSImpact of Age

Changing Incidence of Glomerular Disease in Olmsted County

Swaminathan S. Clin J Am Soc Nephrol 1: 483-487, 2006

Clinical history

A Caucasian female in her 30’s developed abrupt onset of full nephrotic syndrome

July of 2002 24 hr urine protein 13 g/day Renal biopsy: 8/8 normal glomeruli

100 % foot process effacement on EM Minimal change disease Rx: oral prednisone, resulting in thrush, skin breakdown,

cellulitis September of 2002

Cyclosporine 100 mg/day, leading to ARF (creatinine=4.4 mg/dL, cyclosporine=107ng/ml).

Cyclosporine stopped; creatinine declined to 1.7mg/dl

Clinical history

January 2003: Came to Columbia University Medical Center for a 2nd opinion Physical exam: emaciated, 3+ edema with ascites,

skin breakdown 24 hour urine protein= 17 g/day Albumin= 1.9 mg/dL Creatinine= 1.7 mg/dL

Focal Segmental Glomerulosclerosis NOS (not otherwise specified)

Location: portion (segment) some (focal), but not all

glomeruli. The scar:

increased mesangial matrix collapsed glomerular

capillaries adhesion between tuft and

Bowman’s capsule Hyaline deposits.

Accompanying features: mesangial hypercellularity foam cells.

FSGS (NOS) FSGS perihilar variant FSGS cellular variant FSGS tip variant FSGS collapsing variant

“ Columbia” Classification of FSGS

D'Agati VD, Fogo AB, Bruijn JA, Jennette JC. Am J Kidney Dis. 2004 Feb;43(2):368-82.

FSGS collapsing variant

Only 1 glomerulus showing Segmental or global

obliteration of the glomerular capillary lumina by wrinkling and collapse of glomerular basement membranes

Hypertrophy and hyperplasia of the overlying podocytes

FSGS tip variant

Exclude collapsing variant

At least 1 glomerulus with a segmental lesion of cellular or sclerosing nature involving the tip domain.

Perihilar location sclerosis rules out the tip variant

FSGS cellular variant

Tip and collapsing variants be excluded

At least 1 glomerulus with endocapillary hypercellularity involving at least 25% of the tuft and causing occlusion of the capillary lumen/lumina

FSGS- perihilar variant

At least 1 glomerulus with perihilar hyalinosis, with or without sclerosis

Greater than 50% of segmental lesions showing perihilar sclerosis and hyalinosis

Cellular variant, tip variant, and collapsing variant be excluded.

Outcomes of FSGS Variants:Columbia University

01020304050607080

ALL FSGS CELL COLL TIPLESION

NOS

REMISSION ESRD

Kidney International (2006) 70, 1783–1792.

Diffuse Mesangial Sclerosis

Postnatal proteinuria ESRD by age 3 Steroid refractory Autosomal recessive

PLCE1: DMS WT-1

(Frasier syndrome and Denys-Drash syndrome ) LAMB2 (Pierson)

What is her prognosis?

Prognosis in Primary FSGSClinical Features

Troyanov.. J Am Soc Nephrol. 2005 Apr;16(4):1061-8

Focal and segmental glomerulosclerosis: definition and relevance of a partial remission.

Troyanov S.. J Am Soc Nephrol. 2005 Apr;16(4):1061-8.

Survival from Renal Failure No Remission vs. PR with a relapse

Troyanov S.. J Am Soc Nephrol. 2005 Apr;16(4):1061-8.

Treatment of FSGS

Stepwise Approach to FSGS Treatment

Step 1: Exclude Secondary FSGS Step 2: Conservative therapy Step 3: Immunosuppressive therapy Recurrent FSGS after renal transplant

Secondary FSGS1. Familial

α-actinin 4 nephrin Podocin TRPC6 INF2

Lmx1b(Nail-Patella Syndrome)

Mitochondrial cytopathies

JASN, 13:3005-3015, 2002

Molecular Biology of the Podocyte

Genetic Screening in Steroid-Resistant FSGS? Results of NPHS2 studies

AUTHORS GROUP FAMILIAL NON FAMILIAL

SS SRWeber S.KI (2004) 66, 571–579;

Children 43%

(n=81, AR)

ND 10.5%

(n=172)

He N.CJASN 2: 31-37, 2007

Adult 0%

(N=9)

13%

(N=15)

10%

(n=63)

Tsukaguchi HJCI. 2002 Dec;110(11):1659-66.

Adult 27%

(n=33)

6% (control 1.6-3.9%)

(n=91)

Monteiro EJ.J Nephrol. 2006 May-Jun;19(3):366-71

Adult Only 1 mutation in familial

(n=39)

27

PURPOSE: To identify genetic variants predisposing to idiopathic and HIV associated FSGS

METHODS: Mapping by Admixture Linkage-Disequilibrium (MALD) genome scans performed in 190 AA with FSGS and 222 controls.

RESULTS: A region was identified centered on MYH9 (Myosin Heavy Chain 9) Chrom 22.

MYH9 is a functional candidate gene expressed on podocytes

Kopp et al, ASN 08, FC-254; Nature Genetics 40:1175, 2008

MYH9 is a Major Risk Gene for FSGS and Hypertensive ESRD

28

MYH9 is biologically plausible candidate gene

MYH9 binds actin and has been localized to podocytes and mesangium

Actin/myosin cytoskeleton is enriched in podocyte foot processes

MYH9 mutations associated with glomerulonephritis

Kopp et al, ASN 08, FC-254; Nature Genetics 40:1175, 2008

29

MYH9 alleles and Extended (E) Haplotypes: Risk and Protection

Haplotype Frequency Odds ratioiFSGS

AA EA AA EA

E1 60% 4% 5 7.6

E2 21% 69% 0.2 0.4

E3 12% 27% NS NS

E4 4% <1% NS NS

E5 3% <1% NS NS

Increased Risk

Reduced Risk

Abbreviations: AA, African American; EA, European American

Kopp et al, Nature Genetics 40:1175, 2008

E1 Haplotype Predicts FSGS+HIVAN

35% 73%

Winkler, Kopp et al, ASN 09, FC 232, PO 1389

Copies of alleles

0 1 2

Disease Continental origin

Cases/controls

OR

(recessive model)

P

HIVAN Africa 53/511 6.6 7 x 10-8

Idiopathic FSGS Africa 188/511 4.1 9 x 10-16

Idiopathic FSGS Europe 125/221 7.7 0.052

HTN- ESKD Africa 241/192 2.2 7 x 10-5

DM-2 ESKD Africa 284/192 1.3 0.02

MYH9 Risk Variant is Strongly Associated with Kidney Disease

Kopp, Nature Genetics 2008

(*In DM2 with larger cohort Freedman, NDT 2009)

32

Clinical Implications of MYH9

Lifetime risk estimates in AA Pts

0 risk alleles 1 risk allele 2 risk alleles

HIVAN 0% 5%1:20

20%1:5

FSGS 0.2%1:500

0.4%1:250

1.6%1:62

HTN attributed-ESKD

1.4%1:71

1.9%1:53

3.1%1:32

Kopp, ASN 09

33

Hypothetical Pathways of MYH9-Associated FSGS

Cytokines

Viral infection

Environmental toxins

Medications

Fragile podocyte (footing)- Reduced adhesion/mobility

- Altered proliferation Sickle cell anemia

Obesity, HTN

FSGS

HIV-1

Kopp, ASN 09

Secondary FSGS2. Virus-associated

Parvovirus B19 HIV-associated nephropathy

Association of parvovirus B19 infection with idiopathic collapsing glomerulopathyISH

78.26%

15.79%22.22%

25.93%

0.00%

10.00%

20.00%

30.00%

40.00%

50.00%

60.00%

70.00%

80.00%

CG HIVAN FSGS Controls

Moudgil A. Kidney Int. 2001 Jun;59(6):2126-33.

Antiretroviral therapy in the treatment of HIV-associated nephropathy

Atta M. Nephrology Dialysis Transplantation 2006 21(10):2809-2813

Secondary FSGS3. Medications

Heroin nephropathy Interferon-α Lithium Pamidronate / alendronate

Lithium nephrotoxicity: A Progressive Combined Glomerular and Tubulointerstitial Nephropathy (n=24)

Renal insufficiency 100%

Mean SCr initial (mg/dl) 2.8(range, 1.3 to 8.0)

Proteinuria (>1 g/24 h) 41.70%

24-h urine protein 0 to 0.5

0.5 to 1.01.0 to 3.0> 3.0

 41.70%16.70%16.70%

25%

Nephrotic syndrome 12.50%

Clinical evidence of NDI 87%

Markowitz GS, Radhakrishnan J.. J Am Soc Nephrol. 2000 Aug;11(8):1439-48

Lithium nephrotoxicity: S Creatinine >2.5 mg/dl is a significant predictor of progression to ESRD

(P = 0.008).

Markowitz GS, Radhakrishnan J.. J Am Soc Nephrol. 2000 Aug;11(8):1439-48

Collapsing FSGS following Treatment with High-dose Pamidronate

7 White pts 49-77 Treated with pamidronate

90mg (usual dose) followed by (180-360mg)

15-48 months later developed full NS

4 pts reached ESRD 2 of 3 pts improved after

discontinuing Pamidronate

Markowitz GS…. J Am Soc Nephrol 2001 Jun;12(6):1164-72

11 patients (7F, 10 Black) IFN-α: hepatitis C virus infection (n = 5),

malignant melanoma (n =1) IFN-β for multiple sclerosis (n=3) IFN-γ for idiopathic pulmonary fibrosis (n=2)

Duration: mean 4.0, median 12.6 months AKI (Cr 3.5mg/dL), nephrotic proteinuria (9.7g) After stopping IFN: 9/10 creat improved, prot 3.0g

1 complete remission 2 partial

No benefit with immunosuppression (4/7)

Clin J Am Soc Nephrol. 2010 Mar 4. [Epub ahead of print]

Secondary FSGS4. Adaptive structural-functional responses likely mediated by glomerular hypertrophy or hyperfiltration

Reduced renal mass Oligomeganephronia Unilateral renal agenesis Renal dysplasia Cortical necrosis Reflux nephropathy

Surgical renal ablation Chronic allograft nephropathy Any advanced renal disease

with reduction in functioning nephrons

Initially normal renal mass

Diabetes mellitus Hypertension Obesity, Body Builders Cyanotic congenital heart

disease Sickle cell anaemia

1998

Obesity Trends* Among U.S. AdultsBRFSS, 1990, 1998, 2006

(*BMI 30, or about 30 lbs. overweight for 5’4” person)

2006

1990

No Data <10% 10%–14 15%–19% 20%–24% 25%–29% ≥30%

Obesity-Glomerular “Stress”

Secondary FSGSObesity-related Glomerulopathy at Columbia

Obesity-related glomerulopathy: An emerging epidemic

Definition: Obesity BMI> 30 kg/m2. Obesity-related glomerulopathy

(ORG) FSGS + Glomerulomegaly (N = 57) Glomerulomegaly alone (N = 14).

71 cases (mean age 43 y, 75% White)

50 Controls with Classic FSGS

Kambham N, Markowitz GS, Valeri AM, Lin J, D'Agati VD. Kidney Int. 2001 Apr;59(4):1498-509

Compared to Classic FSGS:More Caucasians

(75% vs 52%)Less nephrotic-range proteinuria

(48% vs 66%)Less nephrotic syndrome

(5.6% vs 54%)

Obesity-related glomerulopathy: An emerging epidemic

Kambham N, Markowitz GS, Valeri AM, Lin J, D'Agati VD.Kidney Int. 2001;59(4):1498-509

Obesity-related glomerulopathy: An emerging epidemic

4 patients lost wt: proteinuria reduced by >50%

ACE-I reduced proteinuria by 1g

Kambham N, Markowitz GS, Valeri AM, Lin J, D'Agati VD.Kidney Int. 2001 Apr;59(4):1498-509

51

FSGS Associated with Anabolic Androgenic Steroid Use in Bodybuilders

10 pts (W-6, H-4), long-term AAS use, BMI-35 kg/m2 UPro-10 g/d (1-26 g/d), 5 pts with NS SCr- 3 mg/dl (1.3-8) FSGS-9 and/or glomerulomegaly-5

Perihilar-4, collapsing-3, 7 had >40% interstitial fibrosis Follow-up in 8 pts of 2 yrs

1 progressed to ESRD rapidly Off AAS, 7 had stable/improved SCr and UPro with ACEi

FSGS may result from post-adaptive glomerular changes due to increased BMI and toxic effects of AAS

Herlitz, D’Agati al, ASN 09, PO 163

Treatment Principles Primary FSGS

Spontaneous remission is rare <5% Any remission is better than no remission

Conservative Treatment(In all cases of FSGS)

The Role of Blood Pressure Control Progression of Non-Diabetic Proteinuric CKDMetanalysis of 11 studies (1860 pts)

Ann Intern Med. 2003 Aug 19;139(4):244-52.

REIN Study: ACE I nhibition in REIN Study: ACE I nhibition in ProteinuricProteinuricNonNon--Diabetic NephropathyDiabetic Nephropathy

91.3

92.4

Baseline DBP

148.0

149.8

Baseline SBP

-3.4 mmHg-3.4 mmHgPlacebo

-4.2 mmHg-5.8 mmHgRamipril

∆ DBP∆ SBP

00 66 1212 1818 2424 3030 3636

100

80

60

40

20

0

100

80

60

40

20

0

RamiprilRamipril

PlaceboPlacebo

P=0.02P=0.02

The GISEN Group. Lancet. 1997;349:1857– 1863.

% o

f pa

tien

ts w

itho

utco

mbi

ned

endp

oint

*

* Combined endpoint = doubling of baseline serum creatinine concentration or end stage renal failure

www.hypertensiononline.org

Combination ACE-i/ARBCOOPERATE (Non diabetic glomerular disease- 14% FSGS)-

Nakao N et al. Lancet. 2003;361:117–124.

Doubling of Serum Creatinine or Progression to ESRD

0

5

10

15

0 5 12 18 24 30 36

20

25

30

Pro

po

rtio

n R

eac

hin

g

En

dp

oin

t, %

Months After Randomization

Trandolapril

Losartan

Combination

P = 0.02

ACE-I in HIVAN

Wei A… Kidney Int. 2003 Oct;64(4):1462-71.

The nephrotic syndrome, lipids, and risk factors for cardiovascular disease

0

10

20

30

40

50

60

70

80

90

100

>200mg/dl >300mg/dl >400mg/dl

ALL

Membranous

FSGS

Radhakrishnan J..Am J Kidney Dis. 1993 Jul;22(1):135-42.

The increased risk of CHD associated with nephrotic syndrome

Ordonez J.. Kidney International (1993) 44, 638–642

Effects of Atorvastatin on Proteinuria and Progression of Kidney Disease

N=56 idiopathic

N.S., (not biopsied)

ACE &/or ARB >1 year

Bianchi S.. Am J Kidney Dis. 2003 Mar;41(3):565-70.

Bianchi S.. Am J Kidney Dis. 2003 Mar;41(3):565-70.

Effects of Atorvastatin on Proteinuria and Progression of Kidney Disease

Primary FSGS: Treatment Options

Corticosteroids Cytotoxic agents

Cyclophosphamide Chlorambucil

Cyclosporine/Tacrolimus Plasmapheresis

Steroid Treatment of FSGSResponse in Adults

Korbet S. Kidney International (2002) 62, 2301–2310

Steroid Treatment of FSGSHow long should I treat?

Studies before 1980, CR <20% Duration < 2 months

Studies after 1980, CR > 40% Average duration 5-9 months

Steroid “Resistance” is generally defined when Prednisone 1mg/kg x 4 months fails.

Prognosis in FSGSResponse to Corticosteroids

3

25

60

30

0

10

20

30

40

50

60

70

80

90

100

PE

RC

EN

TA

GE

COMPLETE PARTIAL NONE ALL

Korbet, S.. Nephrol Dial Transplant 1999;14 [Suppl 3]: 68–73

Steroid Resistant FSGS Cyclophosphamide

Adult Pts. – 8 Studies

125 Pts. CR 17% PR 7%

Ped Pts. – 2 Studies

42 Pts. CR 52% PR 17%

Matalon A, Valeri A, Appel GB. Sem. Nephrol. 2001.

Steroid-resistant FSGSCyclosporine (North American Collaborative Trial)

49 patients with steroid-resistant FSGS 26 weeks of CYA + low-dose prednisone vs

placebo plus prednisone. F/U 200 weeks

Cattran DC, Appel GB,.. Kidney Int. 1999 Dec;56(6):2220-6.

Cattran DC, Appel GB.. Kidney Int. 1999 Dec;56(6):2220-6.

Steroid-resistant FSGSCyclosporine (North American Collaborative Trial)Remission Rates

Cyclosporine vs Chlorambucil in the Treatment of FSGS Heering P et al. AJKD 43:10-18, 2004

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 months U prot decrease > 50% w/o NS = 4 U prot decrease > 50% w NS = 2 U 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.

• 33 Nephrotic FSGS after ACEi/ ARBs for 6 months

• Therapy:• MMF 1 g BID x 6 mo + steroids 0.5

mg/kg/d x 2-3 months OR• Steroids 1 mg/kg/d x 3-6 mo

MMF v Steroids in Primary FSGS

Nayagam, et al, NDT 2007

MMF v Steroids in Primary FSGS

Nayagam, et al, NDT 2007

Remission

MMF= 71%

Pred= 60%

MMF

Pred

FSGS-NIH Sponsored Controlled Trial

12 Month Primary Outcome Assessment

Treatment 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

Cattran DC, Appel GB.. Kidney Int. 1999 Dec;56(6):2220-6.

Steroid-resistant FSGSCyclosporine (North American Collaborative Trial)50% Decline in Creatinine Clearance

Treatment of Steroid Refractory or Relapsing Patients.Response to Cytotoxic and Cyclosporine therapy

Steroid Refractory/Dependent FSGSMycophenolate Mofetil (MMF)

N=18 CR: 2 PR: 6

Proteinuria reduction Pre: 7.5 (2.7 to 20.3) Post: 3.9 (0.1 to 8.2)

Choi M.. Kidney International (2002) 61, 1098–1114;

Steroid Refractory Patients n=21Sirolimus (Rapamycin)

Tumlin J.. Clin J Am Soc Nephrol. 2006 Jan;1(1):109-16.

Acute Rapamycin Nephrotoxicity

11 Pts with GN and progressive renal failure (GFR decline >5ml/y)-FSGS, IgAN, IMN, MPGN were entered into a 12 month study.

Target rapa levels: 7-10

Nephrol Dial Transplant (2004) 19: 1288-1292

56%: Stabilized eGFR slopes

Phase I trial of adalimumab FONT study group

Dose: 24 mg/m2 SQ every 14 day (max 40 mg) x 16 weeks

Phase I trial of Rosiglitazone FONT (Novel Therapies in Resistant FSGS)study group

3 mg/m2 /d twice a day (max 8 mg/d)

Clinical history

Developed ARF with low dose tacrolimus

No respond to oral cyclophosphamide

Renal replacement therapy started in June of 2003 (12 months after onset)

Clinical History

The patient became progressively anuric on dialysis after which she improved clinically Normal serum albumin 20 lb weight gain

Several family members offered her a kidney including an HLA-identical sister

Post-transplant course

12/9/04: Zero-mismatch living donor transplant, 18 month after the start of RRT Simulect (basiliximab) induction Sirolimus and tacrolimus maintenance

Rapid steroid taper 12/12/05: Creatinine decreased to 1.5mg/dL 12/13/05: Urine output dropped to 200ml/8 hours

• Wt gain 25 lbs / 1+ edema• Creatinine increased to 1.8 mg/dL• Hematocrit=27%; platelets= 300x 109/L Albumin=2.4 g/L(4.0 pre-transplant) Sirolimus 3.2ng/ml; tacrolimus 3.6 ng/ml

1.6

19.5

22.8

0

5

10

15

20

25

Uri

ne

pro

tien

(g

/g c

reat

.)

DEC 10 DEC 11 DEC 12

Post-transplant course

Renal allograft biopsy performed on 12/13/04

Diagnosis & findings

90% foot process effacement, highly suggestive of early recurrent FSGS

What therapy would you recommend for this patient?

Recurrent FSGS in the allograft

Recurrence rate estimated at 30% Probably higher when 20 FSGS excluded Risk factors for recurrence:

Age < 20 years Rapid progression to ESRD of < 3 yrs Previous recurrence in a transplant Caucasian

No difference in cadaveric versus living donor transplantation

> 90% of recurrences occur in first 3 months post-transplant

Plasmapheresis with Recurrent FSGS after Transplantation

Savin V.. N Engl J Med 1996; 334: 878– 883.

50 kd

91

Cardiotrophin-like Cytokine-1(CLC1): Candidate for the FSGS Permeability Factor

CLC1 is a member of the IL-6 family CLC1 was overexpressed in peripheral blood cells of 15

FSGS pts compared to controls (p <0.03). Increasing doses of recombinant CLC1 incrementally

increased glomerular permeability (Palb) Monoclonal Ab to CLC1 blocked the increase in Palb by

CLC1 and FSGS serum Incubation of CLC1 with glomeruli decreased nephrin and

podocin expression IV- CLC1 in rats increased UPCR by 3 fold

Savin et al, ASN 08, FC-260

92

CONCLUSION: CLC1 is a strong candidate for the permeability factor in FSGS.

Future studies will be required to: Verify the clinical significance of CLC1. Define the mechanism of action of CLC-1. Develop specific therapies (antibodies, cytokine traps

or affinity based strategies) to prevent progression and permit successful transplantation.

Cardiotrophin like cytokine-1: Candidate for the focal glomerular sclerosis permeability factor

Savin et al, ASN 08, FC-260

Plasmapheresis for Recurrent FSGSThe Columbia Experience

12/15 (80%) of the patients received 4 to 48 plasmapheresis treatments. Complete Remission: 3/12 Partial remission: 5/12

3 of these 8 patients who responded to PTE subsequently experience a relapse after discontinuing PTE.

4 patients progressed to ESRD and 2 patients ultimately died with graft failure.

Mean P. Creatinine at last follow for the other 11 patients was 1.9 mg/dl ( range 0.7 to 3.8 mg/dl ).

ASN 2007.

Post-transplant course

The patient rapidly diuresed 30lbs

Creatinine peaked at 2.3mg/dL and then declined to 1.3mg/dL on 1/5/05

Albumin improved to 3.6 g/dL

Proteinuria decreased from peak 22.8 g/day to 7.6 g/day

1.6

19.5

22.8

3.9

9.7

13.4

7.6

0

5

10

15

20

25

DEC10

DEC11

DEC12

DEC16

DEC27

JAN3

JAN10

PLASMAPHERESIS

Post Transplant Monitoring

Vincenti F, Am J Transplant. 2005 Jun;5(6):1179-85

Suggested Algorithm for Nephrotic FSGS

FSGS ON BIOPSY

PRIMARY SECONDARY

Conservative Therapy

Prednisone 1mg/kg

Cyclosporine

Sirolimus

Mycophenolate

Cytotoxics

Initial Treatment of patients with FSGS and nephrotic syndrome

FSGS.2.1 We suggest prednisone or prednisolone be given as a daily single dose of 1 mg/kg (maximum 80 mg) or alternative day dose of 2 mg/kg (maximum 120 mg) (2C)

FSGS 2.2 We suggest the initial high dose of corticosteroids be given for a minimum of 4 weeks up to a maximum period of 16 weeks, as tolerated, if remission has not been achieved (2D).

FSGS 2.3 After achieving complete remission, we suggest corticosteroids be tapered slowly over a total period of 6 months. (2D)

FSGS 2.4 For patients with relative contraindications or intolerance to high dose corticosteroids (uncontrolled diabetes, psychiatric conditions, severe osteoporosis), we suggest calcineurin inhibitors (CNI) (2D), as discussed in steroid resistant FSGS.

Treatment for steroid-resistant FSGS

FSGS.4.2 We suggest that in steroid resistant patients a CNI (cyclosporine at 3-5 mg/kg/day or tacrolimus at 0.1 mg/kg/day in divided doses) should be given for at least 4-6 months (2B).

FSGS.4.3 In patients with at least a partial remission, we suggest to continue CNI treatment for at least 12 months and then taper slowly (2D).

Conclusions

FSGS is a pathological diagnosis Secondary causes need to be ruled out Steroid responsiveness defines a better

prognostic subset of patients Calcineurin inhibitors, cytotoxic agents and

mycophenolate are options in steroid-refractory/dependent pts