What is the pathophysiology of scleroderma renal crisis?

Pathophysiology of Scleroderma Renal Crisis

Scleroderma renal crisis (SRC) is fundamentally a thrombotic microangiopathy driven by acute vascular injury, leading to intrarenal vasoconstriction, activation of the renin-angiotensin system, and subsequent malignant hypertension with acute kidney injury. 1

Core Pathophysiologic Mechanisms

Vascular Injury and Thrombotic Microangiopathy

• The primary lesion in SRC is acute vascular endothelial injury affecting small renal vessels, particularly arterioles and interlobular arteries. 1

• This vascular injury manifests histologically as:

  • Mucoid intimal thickening in arteries (associated with poorer renal outcomes) 2
  • Fibrinoid necrosis in arterioles (also predictive of worse prognosis) 2
  • "Onion skin" lesions representing concentric smooth muscle cell proliferation 1
  • Fibrointimal sclerosis and intravascular thrombi 1

• The thrombotic microangiopathy process is detected in approximately 43% of SRC cases, representing activation of the coagulation cascade. 3

Renin-Angiotensin System Activation

• Acute vascular injury and renal ischemia trigger massive renin secretion from juxtaglomerular cells, creating a self-perpetuating cycle of vasoconstriction and further ischemia. 1

• This renin-angiotensin activation drives:

  • Severe intrarenal vasoconstriction that reduces glomerular perfusion 4
  • Malignant hypertension in most cases (though normotensive SRC occurs in a subset of patients) 5
  • Progressive acute kidney injury through ongoing ischemia 3

Increased Vascular Permeability

• SRC is characterized by increased vascular permeability, which contributes to intravascular volume depletion despite apparent volume overload. 1

• This permeability change exacerbates renal hypoperfusion and can be triggered or worsened by:

  • Nephrotoxic drugs 3
  • Intravascular volume depletion 3
  • High-dose glucocorticoids (≥15 mg/day prednisone increases risk 4.4-fold) 5

Clinical Manifestations of the Pathophysiology

Renal Manifestations

• Acute kidney injury with oligo/anuric renal failure develops as the direct consequence of severe intrarenal vasoconstriction and ischemia. 3

• Malignant hypertension occurs in the majority of cases, though 16-64% may present with normotensive SRC (particularly those on high-dose steroids ≥30 mg/day). 5

Systemic Manifestations

• SRC should be conceptualized as a systemic syndrome extending beyond kidney involvement alone. 6

• Systemic features include:

  • Left ventricular insufficiency as a typical clinical feature 3
  • Hypertensive encephalopathy 3
  • Microangiopathic hemolytic anemia (though not predictive of renal outcome) 2

Risk Factors and Triggers

Patient Characteristics

• SRC occurs in approximately 5% of systemic sclerosis patients, predominantly in those with diffuse cutaneous disease (78% of cases). 2

• The crisis typically develops in the first 4-5 years of disease, particularly with rapidly progressive skin thickening. 7

• Anti-RNA polymerase III antibodies are present in 59% of SRC cases and represent a significant risk marker. 2

Medication-Related Triggers

• Glucocorticoid exposure is the most significant modifiable risk factor, with doses ≥15 mg/day prednisone conferring a 4.4-fold increased risk (OR 4.4; 95% CI 2.1-9.4). 5

• High-dose steroids (≥30 mg/day) are particularly associated with normotensive SRC, which carries worse prognosis. 5

• The mechanism by which steroids trigger SRC likely involves exacerbation of renin-angiotensin activation. 4

Common Pitfalls

• Do not confuse SRC with preeclampsia in pregnant patients with systemic sclerosis—both present with hypertension and renal dysfunction, but SRC requires immediate ACE inhibitor therapy despite pregnancy. 5

• Lower blood pressure at presentation paradoxically predicts poorer renal outcomes, as normotensive SRC represents more severe underlying vascular injury. 2

• Renal biopsy is not necessary when SRC presents with classical features (acute hypertension, renal failure, diffuse cutaneous disease), but can help define prognosis in atypical presentations. 3