Kidney nontumor
Vascular disease
Thrombotic microangiopathy and acute endothelial injury
Scleroderma renal disease


Topic Completed: 24 September 2020

Minor changes: 24 September 2020

Copyright: 2020, PathologyOutlines.com, Inc.

PubMed Search: Scleroderma renal [title] pathology

Christine M. Lee, M.D.
Jonathan E. Zuckerman, M.D., Ph.D.
Page views in 2020 to date: 132
Cite this page: Lee CM, Zuckerman JE. Scleroderma renal disease. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/kidneysclerodermarenaldisease.html. Accessed October 29th, 2020.
Definition / general
  • Scleroderma is a multi-organ disease distinguished by vasculopathy and excess fibrosis (Rheumatology (Oxford) 2019;58:2099)
  • Scleroderma associated renal vasculopathy is often clinically insignificant but rarely manifests as scleroderma renal crisis, a thrombotic microangiopathic process which leads to renal ischemia, acute hypertension and rapidly deteriorating renal function (Lancet 2017;390:1685)
Essential features
  • Scleroderma associated renal disease is a spectrum of small arterial and arteriolar vasculopathy ranging from mild fibrointimal thickening to thrombotic microangiopathy (Am J Kidney Dis 2016;67:e19)
  • Scleroderma related thrombotic microangiopathy is characterized by mucoid intimal edema, onion skin-like intimal proliferation, fibrinoid necrosis and thrombosis
  • Glomerular changes include ischemic collapse and endothelial swelling and thrombosis, acutely and basement membrane duplication, chronically
  • Ischemic injury to tubules results in acute tubular injury or necrosis and eventually, interstitial fibrosis and tubular atrophy
Terminology
  • Scleroderma is also called systemic sclerosis
  • Scleroderma renal crisis is a clinical diagnosis that is encompassed by the pathological diagnosis scleroderma associated renal disease or scleroderma renal disease
ICD coding
  • ICD-10: M34 - systemic sclerosis [scleroderma]
  • ICD-10: M34.9 - systemic sclerosis, unspecified
  • ICD-10: M31.1 - thrombotic microangiopathy
Epidemiology
Sites
  • Diffuse versus limited cutaneous systemic sclerosis (Lancet 2017;390:1685)
    • Determined by extent of skin involvement
    • Diffuse cutaneous systemic sclerosis affects proximal sites
    • Limited cutaneous systemic sclerosis affects skin distal to elbows or knees with or without face and neck involvement
  • Scleroderma involves multiple organ systems (Lancet 2017;390:1685)
    • Pulmonary fibrosis, pulmonary arterial hypertension
    • Gastrointestinal symptoms, intestinal pseudo-obstruction, gastric antral vascular ectasia
    • Cardiac fibrosis
    • Renal vasculopathy, scleroderma renal crisis
    • Digital vasculopathy
  • Scleroderma renal disease (J Rheumatol 2014;41:1040)
    • Small arteries and arterioles (interlobular and arcuate arteries) are primarily and most significantly affected
    • Glomeruli may be affected by thrombotic microangiopathy
    • Glomeruli and tubules may also be secondarily affected by ischemic sequelae of severe vascular injury
Pathophysiology
  • Scleroderma
  • Scleroderma renal crisis
    • Endothelial injury or activation by unclear mechanism leads to intimal proliferation, increased permeability and edema (Rheumatology (Oxford) 2019;58:2099)
    • Vascular narrowing and hyperreactivity contribute to decreased renal perfusion and ischemic injury (J Rheumatol 2014;41:1040)
    • Decreased renal perfusion activates the renin-angiotensin-aldosterone system which can result in accelerated hypertension and progressive renal injury (Int J Rheumatol 2010;2010:543704)
    • Increased vascular permeability allows blood components to interact with extravascular connective tissue which can turn on the coagulation cascade and lead to vascular thrombosis as well as injury to adjacent connective tissue and stromal proliferation (Int J Rheumatol 2010;2010:543704)
    • Other precipitating factors (J Rheumatol 2014;41:1040)
      • Decreased intravascular volume (sepsis, dehydration, congestive heart failure)
      • Nephrotoxic drugs (nonsteroidal antiinflammatory drugs, cocaine, cyclosporine, corticosteroids)
Etiology
  • Etiology of scleroderma renal vasculopathy and specifically, scleroderma renal crisis is unknown (Nat Rev Nephrol 2016;12:678)
  • Pathogenesis of the vasculopathy may be immune mediated (Int J Rheumatol 2010;2010:543704)
    • Cellular and humoral immune activation is described in scleroderma
    • Specific autoantibodies are associated with scleroderma renal crisis
    • 85% of patients with scleroderma renal crisis are found to have anti-endothelial cell antibodies, which can cause endothelial cell apoptosis (Ann Rheum Dis 2010;69:319)
    • Endothelin and its receptors (endothelin receptors A and B) are overexpressed in the glomeruli, tubules and vessels of patients in scleroderma renal crisis (Hum Pathol 2011;42:95)
Clinical features
Diagnosis
  • Acute onset of hypertension with evidence of renal failure in a patient with scleroderma
  • Thrombotic microangiopathy of small renal arteries and arterioles, including interlobular and arcuate vessels and glomerular capillaries
Laboratory
Prognostic factors
  • Scleroderma renal crisis has high mortality (30 - 40% at 5 years) and low survival (65% 5 year survival) despite monitoring and appropriate therapy (QJM 2007;100:485)
  • Normotensive scleroderma renal crisis has a particularly unfavorable prognosis (Lancet 2017;390:1685, Hum Pathol 2009;40:332)
  • Clinical factors of poor prognosis (J Rheumatol 2014;41:1040)
    • Male gender
    • Older age
    • Congestive heart failure
    • Serum creatinine level > 3 mg/dl at the initiation of treatment
    • Difficulty controlling blood pressure beyond 3 days
  • ACE inhibitor use prior to the onset of scleroderma renal crisis is associated with poor prognosis
  • Patients who survive the first year of scleroderma renal crisis without requiring dialysis have a good long term outcome (J Rheumatol 2014;41:1040)
  • Features of severe vascular injury, vascular thrombosis and fibrinoid change, as well as subsequent ischemic changes (glomerular ischemic collapse and acute tubular necrosis) are predictive of poor outcome (Int J Rheumatol 2010;2010:543704, Hum Pathol 2009;40:332)
  • Peritubular C4d deposits may indicate a worse prognosis (Hum Pathol 2009;40:332)
  • Predictive risk factors for development of scleroderma renal crisis in scleroderma patients include (Nat Rev Nephrol 2016;12:678, J Rheumatol 2014;41:1040):
    • Diffuse and rapid skin involvement
    • Disease duration of < 4 years
    • New onset anemia
    • Cardiac events
    • Systemic inflammatory features
    • Anti-RNA polymerase III antibodies
  • Moderate to high doses of gluocorticoids (> 15 mg/day) with or without other nephrotoxic drugs (calcineurin inhibitors, antithymocyte globulin, etc.) can increase risk (Nat Rev Nephrol 2016;12:678)
Case reports
Treatment
Microscopic (histologic) description
  • Renal pathology findings in scleroderma patients without scleroderma renal crisis:
  • Scleroderma renal crisis (Int J Rheumatol 2010;2010:543704, Am J Kidney Dis 2016;67:e19):
    • Arterial / arteriolar injury
      • Acute / early
        • Endothelial swelling
        • Intimal mucoid change
        • Fibrin thrombi within arteries / arterioles or glomeruli
      • Subacute to chronic
        • Concentric intimal proliferation (onion skinning) and narrowing of the lumen
        • Fibrointimal sclerosis
    • Glomeruli
      • Acute
        • Ischemic corrugation
        • Endothelial swelling
        • Mesangiolysis
        • Glomerular capillary thrombosis
      • Chronic
        • Glomerular basement membrane duplication and glomerulosclerosis
    • Tubulointerstitium
      • Ischemic effect on tubules is acutely seen as acute tubular injury or necrosis
      • Ongoing injury can result in tubular atrophy and interstitial fibrosis
      • Mild interstitial lymphohistiocytic inflammatory infiltrate may be present
Microscopic (histologic) images

Contributed by Christine M. Lee, M.D. and Jonathan E. Zuckerman, M.D., Ph.D.

Onion skin change

Onion skin change in artery

Mucoid intimal edema

Double contours

Immunofluorescence description
  • Fibrinogen staining is in areas of vascular or glomerular thrombosis (Int J Rheumatol 2010;2010:543704, Am J Kidney Dis 2016;67:e19)
  • Peritubular C4d deposits may suggest antibody mediated injury and indicate a worse prognosis as staining appears to be increased in patients who died or had irreversible loss of renal function (Hum Pathol 2009;40:332)
  • Negative staining for immunoglobulins within glomeruli
Immunofluorescence images

Contributed by Christine M. Lee, M.D. and Jonathan E. Zuckerman, M.D., Ph.D.

Fibrinogen

Positive stains
  • Trichrome can highlight fibrin thrombi and interstitial fibrosis
  • Jones silver highlights onion skin change and glomerular double contours
Electron microscopy description
  • Endothelial cell injury (Int J Rheumatol 2010;2010:543704, Am J Kidney Dis 2016;67:e19)
    • Swollen endothelial cells
    • Expansion of subendothelial space within glomeruli with interporision of lucent material and cell processes
  • Platelet aggregates and fibrin tactoids in areas of thrombosis
  • Glomerular basement membrane duplication can be seen in cases of chronic injury
  • Swollen endothelial cells within vessels
  • Subendothelial edema and basement membrane remodeling within vessels
Electron microscopy images

Contributed by Christine M. Lee, M.D. and Jonathan E. Zuckerman, M.D., Ph.D.

Double contour

Artery remodeling

Sample pathology report
  • Left kidney, native, needle core biopsy:
    • Diffuse active chronic thrombotic microangiopathy (TMA), arterial predominant, consistent with scleroderma associated renal disease (see comment)
    • Comment: While the marked arterial changes are highly consistent with scleroderma associated renal disease, the differential diagnosis for these findings includes any potential cause of thrombotic microangiopathy (e.g. TTP, HUS, complement associated TMA, antiphospholipid antibody syndrome, drug toxicity, infection, etc.).
Differential diagnosis
Board review style question #1

Which is the primary histopathologic feature (shown above) of scleroderma renal crisis?

  1. Acute tubular necrosis
  2. Collapsing glomerulopathy
  3. Glomerulonephritis
  4. Necrotizing glomerular crescents
  5. Thrombotic microangiopathy of small arteries and arterioles
Board review answer #1
E. Thrombotic microangiopathy of small arteries and arterioles

Comment Here

Reference: Scleroderma renal disease
Board review style question #2
Which of the following is true about scleroderma renal crisis?

  1. Associated with low ADAMTS13 levels
  2. Can present with normal or only mildly elevated blood pressure
  3. Evidence of acute renal failure is not required for diagnosis
  4. Microangiopathic hemolytic anemia is seen in all cases
  5. More commonly seen in patients with limited rather than diffuse cutaneous systemic sclerosis
Board review answer #2
B. Can present with normal or only mildly elevated blood pressure

Comment Here

Reference: Scleroderma renal disease
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