Scleroderma Renal Scleroderma Renal CrisisCrisis

Mathini Jayaballa Mathini Jayaballa Renal Advanced TraineeRenal Advanced Trainee

Scleroderma OverviewScleroderma Overview UncommonUncommon

F>M, peak onset 3F>M, peak onset 3rdrd - 5 - 5thth decade decade

Uncontrolled accumulation of collagen and other Uncontrolled accumulation of collagen and other CT proteins which leads to fibrosis in the skin and CT proteins which leads to fibrosis in the skin and other visceral organsother visceral organs

Widespread vascular lesionsWidespread vascular lesions

ClassificationClassification Localised SclerodermaLocalised Scleroderma Systemic Scleroderma – Limited and Diffuse Systemic Scleroderma – Limited and Diffuse

Scleroderma Renal CrisisScleroderma Renal Crisis Renal involvement Renal involvement 50%, usually 50%, usually

mild: mild: proteinuriaproteinuria mild elevation in Crmild elevation in Cr HT HT

Severe renal disease Severe renal disease 10-20% 10-20% diffuse cutaneous SSc >> LcSScdiffuse cutaneous SSc >> LcSSc

Clinical Features of Clinical Features of Scleroderma Renal Crisis Scleroderma Renal Crisis

(SRC):(SRC): Occurs early – within 5 yrsOccurs early – within 5 yrs Can be the initial presentationCan be the initial presentation

SRC:SRC: Progressive ARF Progressive ARF Abrupt onset mod-severe HTN Abrupt onset mod-severe HTN Urine sediment – usually blandUrine sediment – usually bland

Normal Renal Biopsy (H&E stain)

SRC Renal Biopsy

Renal AngiogramRenal AngiogramNormal SRC

Risk Factors for SRCRisk Factors for SRC Diffuse or advancing skin involvementDiffuse or advancing skin involvement Glucocorticoid >15mg/dayGlucocorticoid >15mg/day Large joint contractures Large joint contractures New cardiac conditions New cardiac conditions New onset anemia New onset anemia Anti-RNA polymerase or fine speckled Anti-RNA polymerase or fine speckled

ANA patternANA pattern Decreased prevalence of anti-centromere Decreased prevalence of anti-centromere

AbAb

Characteristic FindingsCharacteristic Findings New onset BP > 150/85 New onset BP > 150/85 Decline in renal functionDecline in renal function New proteinuria +/- hematuriaNew proteinuria +/- hematuria Retinal changes of malignant Retinal changes of malignant

hypertension hypertension Flash pulmonary edema Flash pulmonary edema MAHA +/- thrombocytopeniaMAHA +/- thrombocytopenia CNS involvement - seizuresCNS involvement - seizures

Differentials:Differentials: TTP/HUSTTP/HUS ANCA-associated crescentic GNANCA-associated crescentic GN D-penicillamine-related GND-penicillamine-related GN

SRC ManagementSRC Management Untreated Untreated ESKD 1-2mths, death in 1 yr ESKD 1-2mths, death in 1 yr Prompt & aggressive BP control is Prompt & aggressive BP control is

mainstay of Rxmainstay of Rx reduce BP <72hrsreduce BP <72hrs ACE-I is 1ACE-I is 1stst choice choice

Better renal function recovery & improves survival Better renal function recovery & improves survival Resistant / Malignant HTN – Add IV agent Resistant / Malignant HTN – Add IV agent Long term, low-dose ACE-I even if BP Long term, low-dose ACE-I even if BP

controlled controlled 10% normotensive10% normotensive

Steen Ann Intern Med 1990; 113:352.

Helfrich DJ, Arthritis Rheum 1989; 32:1128.

SRC ProgressSRC Progress 20-50% progress to ESKD despite 20-50% progress to ESKD despite

ACE-I ACE-I Inferior 5YS DSSc on dialysis:Inferior 5YS DSSc on dialysis:

40% with SRC40% with SRC90% w/out SRC90% w/out SRC

Survival SSc on dialysis is worse Survival SSc on dialysis is worse than othersthan others

Delayed renal recovery possible Delayed renal recovery possible can take up to 18mcan take up to 18m

Penn H, QJM 2007; 100:485.

Abbott KC, J Nephrol 2002; 15:236.

TransplantationTransplantation Better survival cf dialysisBetter survival cf dialysis

3YS 80% vs 55% 3YS 80% vs 55% Worse survival than other primary diseasesWorse survival than other primary diseases Risk factors for recurrence/damage to Risk factors for recurrence/damage to

allograft:allograft: progressive skin thickeningprogressive skin thickening new onset anemianew onset anemia cardiac complicationscardiac complications

Strategies to reduce recurrent disease Strategies to reduce recurrent disease Avoid CNI, high dose steroidsAvoid CNI, high dose steroids Continue ACE-I indefinitelyContinue ACE-I indefinitely

Gibney Am J Transplant 2004; 4:2027.

Total SScDialysis

14,010 33

Tx 4,254 8Incident patients ANZ 2006-2010 (ANZDATA)

Imatinib in Systemic Imatinib in Systemic SclerosisSclerosis

A protein tyrosine A protein tyrosine kinase inhibitorkinase inhibitor

Interferes with the Interferes with the signaling PDGF, signaling PDGF, TGF-TGF-ββ

Limited data on Limited data on use in SSc or its use in SSc or its effect on renal effect on renal functionfunction

Imatinib in Systemic Imatinib in Systemic SclerosisSclerosis

Case Report - Rx of refractory DcSScCase Report - Rx of refractory DcSSc Improvement in skin thickening, physical function, FVC Improvement in skin thickening, physical function, FVC Within 3m, maintained at 9mWithin 3m, maintained at 9m

Spiera et al - open-label prospective studySpiera et al - open-label prospective study 30 patients with DcSSc, no controls30 patients with DcSSc, no controls Improvement in skin thickening, FVC after 12mImprovement in skin thickening, FVC after 12m

Pope et al – double-blind RCT, proof-of-concept Pope et al – double-blind RCT, proof-of-concept pilot studypilot study Single center, active DcSScSingle center, active DcSSc Only 10 pts enrolledOnly 10 pts enrolled Early termination: poor tolerability, AE++ Early termination: poor tolerability, AE++ No benefit in skin thickening, CRP/ESR, global No benefit in skin thickening, CRP/ESR, global

assessment at 6massessment at 6m

Sfikakis PP, Rheumatology (2008) 47 (5): 735-737. Spiera RF, Ann Rheum Dis 2011; 70:1003.

Take home messages Take home messages about SRC:about SRC:

Rare but high M&MRare but high M&M Mainstay of Rx is BP control with Mainstay of Rx is BP control with

ACE-IACE-I High rate of progression to ESKDHigh rate of progression to ESKD Delayed renal recovery possibleDelayed renal recovery possible Renal transplant should be Renal transplant should be

consideredconsidered

ReferencesReferences Steen VD, Costantino JP, Shapiro AP, Medsger TA Jr. Outcome of renal

crisis in systemic sclerosis: relation to availability of angiotensin converting enzyme (ACE) inhibitors. Ann Intern Med 1990; 113:352.

Helfrich DJ, Banner B, Steen VD, Medsger TA Jr. Normotensive renal failure in systemic sclerosis. Arthritis Rheum 1989; 32:1128.

Penn H, Howie AJ, Kingdon EJ, et al. Scleroderma renal crisis: patient characteristics and long-term outcomes. QJM 2007; 100:485.

Abbott KC, Trespalacios FC, Welch PG, Agodoa LY. Scleroderma at end stage renal disease in the United States: patient characteristics and survival. J Nephrol 2002; 15:236.

Gibney EM, Parikh CR, Jani A, et al. Kidney transplantation for systemic sclerosis improves survival and may modulate disease activity. Am J Transplant 2004; 4:2027.

Spiera RF, Gordon JK, Mersten JN, et al. Imatinib mesylate (Gleevec) in the treatment of diffuse cutaneous systemic sclerosis: results of a 1-year, phase IIa, single-arm, open-label clinical trial. Ann Rheum Dis 2011; 70:1003.

Kay J, High WA. Imatinib mesylate treatment of nephrogenic systemic fibrosis. Arthritis Rheum 2008; 58:2543.

Sfikakis PP, Gorgoulis VG, Katsiari CG, et al. Imatinib for the treatment of Sfikakis PP, Gorgoulis VG, Katsiari CG, et al. Imatinib for the treatment of refractory, diffuse systemic sclerosis. Rheumatology (2008) 47 (5): 735-737refractory, diffuse systemic sclerosis. Rheumatology (2008) 47 (5): 735-737