Topic scleroderma and kidney

1. Chaken Maniyan, MD
Fellow, Division of Nephrology
Phramongkutklao Hospital and College of Medicine
Systemic sclerosis and kidney

2. Systemic autoimmune disease characterised by
Abnormal collagen deposition and fibrosis of
skin and internal organs
Inflammation
Vasculopathy
Systemic sclerosis (SSc)
Woodworth T, et al. Nature Reviews Nephrology. 2016 ;12(11):678-691.

3. Prevalence: 20 new cases /million /year
Susceptibility
age 35-65 years
gender - female : male = 4 : 1
genetic background (African American women)
environmental factors
Epidemiology
10 th edition Brenner and Rector's The Kidney

4. 2013 American College of Rheumatology/European league against Rheumatism
Classification Criteria
Total Score 9 need to definitive diagnosis
Comprehensive Rheumatology 2nd editino 2015

5. Classification of scleroderma
Systemic Sclerosis
Limited form Diffused form
systemic
sclerosis sine scleroderma
Environmental induce
scleroderma
Localized Scleroderma
Morphea Linear scleroderma
CREST syndrome
Felice G. et al Rheumatology 2017;56:v49 v52

6. Limited cutaneous systemic sclerosis
Felice G. et al Rheumatology 2017;56:v49 v52

7. Diffuse cutaneous systemic sclerosis
Felice G. et al Rheumatology 2017;56:v49 v52

8. Limited Vs Diffused SSc
Limited form Diffused form
ANA pattern Centromere Speckle
Auto Antibody Anti centromere Ab
Anti Scl70(Anti
Topoisomerase)
CREST Common Uncommon
Raynaud Phenomenon Onset > 10 yr Early common in 2 yr
Pulmonary Pul HT ILD
Renal Sparing SRC common
Oxford Textbook of Rheumatology 4th edition

9. Characteristic of Ab in SSc
Goldman-Cecil Medicine, 25th edition

10. Major complication of SSC

11. Result of internal organ involvement
pulmonary fibrosis
pulmonary arterial hypertension (PAH)
gastrointestinal dysfunction
various cancers
scleroderma renal crisis (SRC)
Morbidity and mortality in SSc
10 th edition Brenner and Rector's The Kidney

12. Scleroderma renal crisis
Normotensive scleroderma renal crisis
MPO-ANCA associated glomerulonephritis
Penicillamine-associated renal disease
Antiphospholipid-associated nephropathy
Isolated reduced GFR
Reduced renal functional reserve
Microalbuminuria and proteinuria
Abnormal renal vascular resistance indices and endothelial markers
Renal involvement of SSc
Woodworth T, et al. Nature Reviews Nephrology. 2016 ;12(11):678-691.

13. Uncommon but significant , More risk of mortality in SSc patients
5 -20 % of patients with diffuse cutaneous SSc
In USA SRCs - 10% of patients with diffuse scleroderma and 2% of patients
with limited disease
In Japan only 3.2%
Geographic differences anti-RNA polymerase III likely contribute to these
prevalence variations
Scleroderma renal crisis
Woodworth T, et al. Nature Reviews Nephrology. 2016 ;12(11):678-691.

14. Prevalence of SRC among country
Matthew Turk and Janet E. Pope at al, J Rheumatol 2016;43:1350–5; doi:10.3899/jrheum.151353

15. Onset of SRC
• 75% occurs within first four years of the onset of the disease
Median duration of 7.5 months from onset of the disease
Khanna D, et al , Curr Rheumatol Rev. 2010 May 1;6(2):138-144

16. SRC - Mortality
% Cumulative survival
1 2 3 4 5
Years after SRC
0.2
0.4
0.6
0.8
1.0
No lung, No heart , No Kidney n 141
6 7
lung, No heart , No Kidney n 98
heart , No Kidney n 43
All Kidney n 16
Adapted from Medsger, TA Jr, Masi, AT, Rodnan, GP, et al.. Ann Intern Med 1971; 75:369.

17. Obstruction to flow at level of interlobular arteries
Normal SRC

18. Mechanism of disease
Microvascular injury
Collagen Production
Immunologic
Cytokine

19. Pathophysiology

20. Pathophysiology

21. New onset HT defined as
>140/90 mmHg OR > 30 mmHg rise from baseline
increase in plasma renin activity (PRA) most of cases
often accompanied by manifestations of malignant hypertension such
as hypertensive retinopathy (hemorrhages and exudates) and
hypertensive encephalopathy
AKI
Non nephrotic range proteinuria / Few cells or casts
Oligo-anuria
MAHA
Typical SRC presentation
3 Major Finding
Woodworth T, et al. Nature Reviews Nephrology. 2016 ;12(11):678-691.

22. Proposed Diagnostic criteria of SRC
Diagnostic criteria (essential)
1. New onset BP >150/85 mmHg
or Increase ≥ 20 mmHg from usual systolic BP : at least twice over 24 hrs
2. Acute Kidney Injury stage 1 or higher (KDIGO 2012 definition)
>50% increase in serum creatinine from stable baseline or an absolute increase 0.3 mg/dL )
Supportive evidence (desirable)
1. MAHA on blood film, thrombocytopaenia and other biochemical findings consistent with haemolysis
2. Accelerated hypertension on retinal examination
3. Microscopic haematuria on urine dipstick and/or RBC
4. Oliguria or anuria
5. Renal biopsy with typical features of SRC including onion skin proliferation within the walls of
intrarenal arteries and arterioles, fibrinoid necrosis, glomerular shrinkage.
6 .Flash pulmonary oedema
2016 UK Scleroderma Study Group (UKSSG) Guidelines on the Diagnosis and Management of Scleroderma Renal Crisis

23. Risk factors for developing SRC
Characteristics Odds Ratio
Early, diffuse cutaneous disease 2.8
Rapid progression of skin thickening;
modified Rodnan skin score > 20
2.05
Steroid use > 15 mg/d 8.83
Serum anti-RNA polymerase III Ab 3.8
New onset anaemia 1.8
New cardiac event 2.1
Tendon friction rubs 3.1
Arthralgias/synovitis 4.2
Concomitant nephrotoxic drug CNI 2.1
Woodworth T, et al. Nature Reviews Nephrology. 2016 ;12(11):678-691.

24. Salt and volume retention( initiation or worsening
of hypertension)
Increase expression of endothelin receptors in
kidney
Glucocorticoid and development of SRC
Woodworth T, et al. Nature Reviews Nephrology. 2016 ;12(11):678-691.

25. Adapted from M. Hudson et al. / Seminars in Arthritis and Rheumatism 43 (2014) 666–
Prior exposure to ACEi in SRC increase risk of death at 1 year
Survival probability
0.2 0.4 0.6 0.8 1.0
Time to death (year)
0.2
0.4
0.6
0.8
1.0
No ACEi
ACEi

26. Risk factors for scleroderma renal crisis
S. Wangkaew et al. Scleroderma renal crisis in Thai SSc , International Journal of Rheumatic Diseases 2017; 20: 1562–1571

27. Outcome of 19 patients with scleroderma renal crisis (SRC)
S. Wangkaew et al. Scleroderma renal crisis in Thai SSc , International Journal of Rheumatic Diseases 2017; 20: 1562–1571

28. Vascular changes
Early : intimal myxoid material, thrombosis ,fibrinoid necrosis
Chronic : Onion-skin lesions , fibrointimal sclerosis with or without adventitial
fibrosis
Glomerular changes
Early : Endothelial swelling and glomerular capillary thrombosis
Chronic : GBM double contours (tram tracking) and glomerulosclerosis, ischemic
glomerular collapse.
JGA hyperplasia, increased renin production 12%
Tubulointerstitial changes
Early : ischemic acute tubular injury/necrosis
Chronic : IFTA, lymphohistiocytic interstitial inflammatory infiltrate
Key pathology of SRC

29. scleroderma crisis
(hematoxylin and eosin, ×100).
Diagnostic Atlas of Renal Pathology: A Companion to Brenner & Rector's The Kidney, chapter 2, 303-375

30. Diagnostic Atlas of Renal Pathology: A Companion to Brenner & Rector's The Kidney, chapter 2, 303-375

31. (Jones silver stain, ×400).
Diagnostic Atlas of Renal Pathology: A Companion to Brenner & Rector's The Kidney, chapter 2, 303-375

32. Diagnostic Atlas of Renal Pathology: A Companion to Brenner & Rector's The Kidney, chapter 2, 303-375

33. (Jones silver stain)
Diagnostic Atlas of Renal Pathology: A Companion to Brenner & Rector's The Kidney, chapter 2, 303-375

34. Poor prognosis
Acute vascular changes (myxoid intimal
thickening and thrombosis)
severe glomerular ischemic collapse
lesser extent ATI
Good prognosis : chronic pathological changes
Pathological prognostic factors
H. Penn, A. J. Howie, E. J. Kingdon et al. QJM, vol. 100, no. 8, pp. 485–494, 2007
H. Penn, A. J. Howie, R. J. Stratton, et al., Arhtritis and Rheumatism, vol. 56, pp. 53–54, 2007 .

35. ACEi rapidly as possible to control BP to <130/90
mmHg
Timely addition of CCB and other medications
(except β-blockers)
Monitoring of BP several times per day
Monitoring of SCr daily
Treatment of SRC

36. Kovalchik MT, et al . Ann Intern Med, 1978; 89: 881-7
Increase 30-40X of normal PRA in SRC

37. Survival benefit of ACEi after SRC
Adapted from Steen, VD, et al, . Ann Intern Med 1990; 113:352.
% Cumulative survival
1 2 3 4 5
Years after SRC
0.2
0.4
0.6
0.8
1.0
No ACEi N 53
ACEi N= 55
captopril or enalapril.

38. Outcome of patients with sclerodermal renal crisis
Steen, VD, et al, . Ann Intern Med 1990; 113:352.

39. Few case reports on use of ARBs, results are mixed
One case report describes blood pressure control
with an ACE inhibitor and failure of control with
losartan *
The other case report ** describes blood pressure
control and reversal of renal failure with losartan
Use of ARB in SRC patients
*Hasegawa S, et al.. Nippon Jinzo Gakkai Shi. 2000;42:60–65.
**Caskey FJ, et al. Lancet. 1997;349:620.

40. Routine use of ACEi significantly improved short-
term survival, but overall outcome remains poor
bosentan is safe and well tolerated when given in
addition to ACEi of SRC for 6 months
ET-1 receptor antagonist
Hassane Izzedine et al ; Am J Kidney Dis. 2010 ;62(2):394-400

41. non-selective ET-1 receptor antagonist in SRC
Bosentan in Renal Disease-1 (BIRD-1) trail
H Penn et al , Q J Med 2013; 106:839–848

42. Bosentan in Renal Disease-1 (BIRD-1) trail
H Penn et al , Q J Med 2013; 106:839–848

43. 2016 UK Scleroderma Study Group (UKSSG) Guidelines
on the Diagnosis and Management of Scleroderma Renal Crisis

44. 10-15 % of SRC
worse renal outcome and higher mortality
delayed recognition and treatment
cardiac failure
associated with ANCA-related crescentic
glomerulonephritis
Normotensive renal crisis
Woodworth T, et al. Nature Reviews Nephrology. 2016 ;12(11):678-691.

45. Risk factors and outcome of Thai patients with scleroderma
renal crisis: a disease duration-matched case control study
S. Wangkaew et al. Scleroderma renal crisis in Thai SSc , International Journal of Rheumatic Diseases 2017; 20: 1562–1571

46. Glomerular filtration rate
Renal functional reserve
Renal vascular resistance
Isolated proteinuria
Isolated hypertension
Functional renal involvement in SSc

47. Declines in renal function measured by calculated
GFR were mild and slow
Associated with comorbidities (HT,DM)
Comparable with general population.
SSc: GFR

48. Ability of kidney to respond to a protein challenge
Calculated as % increase in GFR after IV or oral of protein
load.
Could be used for early detection of clinically renal
vasculopathy
Renal functional reserve

49. Impaired RFR in SSc Patients
Livi, R. et al.. Ann. Rheum. Dis. 61, 682–686 (2002).

50. Mirrors of Raynaud phenomenon
Colour flow Doppler US show markedly increased
at various renal vascular sites (renal artery and
interlobar and cortical arteries) in patients with SSc
and normal creatinine clearance, compared to
healthy controls
Renal vascular resistance

51. Resistive index of SSc Vs control
Rivolta, R. et al. Arthritis Rheum. 39, 1030–1034 (1996).

52. More common in pts with LcSS
Subacute presentation with progressive renal
failure, normotension and proteinuria.
Postulated that scleroderma vasculopathy
exacerbates interaction of ANCA with endothelium
near vascular pole with neutrophil activation in
glomerulus.
MPO-ANCA associated glomerulonephritis

53. MPO- ANCA-related Crescentic Glomerulonephritis in a
Patient with SSc
Mai TOMIOKA, et a , Internal Medicine, Released March 04, 2005 Vol 43 Number 6

54. Survival on dialysis in SRC is worse than in other
forms ( 2 yr survival 49 % Vs 64 )
Important to continue ACEi
maintenance of normal blood pressure
recovery of renal function can occur after ACEi up
to 18 mo therapy and permitting discontinuation
of dialysis
Dialysis and SRC

55. Kidney Transplantation and SRC

56. Survival Benefit of KT in SRC
Gibney EM, et al. Am J Transplant 2004; 4:2027–2031

58. KT in SSc management

59. Chaken Maniyan, MD
Fellow, Division of Nephrology
Phramongkutklao Hospital and College of Medicine
Systemic sclerosis and kidney