Scleroderma and Renal Crisis

Etiology

Most cases of scleroderma renal crisis occur in patients with diffuse scleroderma (10% to 25%) as compared to only 1% to 2% of patients with limited disease. The disease usually occurs early in the course of scleroderma, up to 75% of cases of scleroderma renal crisis developing within the first 4 years from the diagnosis with the median duration of scleroderma at the time of diagnosis of scleroderma renal crisis being 8 months. It may sometimes be the initial presenting feature of scleroderma (scleroderma renal crisis sans scleroderma).

Factors predictive of scleroderma renal crisis include diffuse skin involvement, especially with rapid progression, the presence of anti-RNA polymerase III antibod­ies, corticosteroid therapy in doses greater than 15 mg a day, tendon friction rubs, new onset anemia, pericarditis, and congestive heart failure.[1][2][3][4][5]

Epidemiology

Scleroderma renal crisis was reported to occur in as many as 20% of patients with scleroderma in the older literature, but the prevalence of this disease seems to be decreasing and currently reported to occur in about 5- 10 % of patients with scleroderma. Early studies suggested that African-American patients and males were more likely to develop scleroderma renal crisis but later studies have not born this out. The prevalence rate also is different in different countries, and there is a seasonal variation in presentation with a greater number of patients presenting in winter and fall months.

Pathophysiology

The pathogenesis of scleroderma renal crisis is not well understood. Injury to the endothelial cells results in structural changes in the blood vessels (intimal thickening and proliferation, fibrin deposition) in the initial stages. Decreased blood flow from the structural changes in the blood vessels as well as renal vasospasm (“Raynaud’s phenomenon”) causes renal ischemia, hyperplasia of the juxtaglomerular apparatus, activation of the renin-angiotensin-aldosterone system (RAAS), and rise in BP. The critical rise in BP causes further damage to renal blood vessels and initiates a vicious cycle eventually leading to malignant hypertension.[1]

Histopathology

Changes are seen characteristically in small interlobular and arcuate arteries, and the predominant pathologic changes are similar to those observed in malignant hypertension and other thrombotic microangiopathies.[1][2][6][7][8]

Myxoid intimal proliferation with luminal narrowing occurs early and as the lesions progress, smooth muscle cell infiltration and deposition of collagen occurs in the intima, resulting in the appearance of concentric fibrosis or “onion skin” appearance. Superimposed fibrin thrombi and fibrinoid necrosis of the media are also seen.[1][2][6][7]

Glomeruli may show ischemic collapse or fibrinoid necrosis. The tubules show changes due to ischemic injury with tubular degeneration and necrosis in acute stages. In the chronic stages, tubular atrophy and interstitial fibrosis develop and are proportional to vascular injury.[7]

History and Physical

The typical presentation of scleroderma renal crisis is a combination of abrupt onset of severe hypertension associated with oligo-anuric acute renal failure in a patient with diffuse scleroderma. Non-nephrotic proteinuria and hematuria with benign urine sediment are common. Other clinical features include hypertensive retinopathy, encephalopathy with a headache, confusion, change in mental status and altered vision, congestive heart failure, thrombocytopenia, and microangiopathic hemolytic anemia.[[1][2].

Evaluation

Renal biopsy is not necessary in a classic setting but may be needed in patients with an atypical presentation, for example, a patient with scleroderma with rising serum creatinine who is normotensive or has either active urine sediment or nephrotic range proteinuria.[7]

Treatment / Management

Activation of RAAS plays a crucial role in the pathogenesis of scleroderma renal crisis. Furthermore, the use of angiotensin-converting enzyme inhibitors (ACEIs) in this condition has dropped 1-year mortality to 24% from 85% before the use of these drugs. Therefore, the current practice is to lower blood pressure rapidly with ACEIs and maintain it.[1][3][9]

Once the diagnosis of scleroderma renal crisis is made, the patient should be hospitalized, and ACEI therapy started. It is usual, to begin with, short-acting ACEI like captopril and rapidly titrate the dose to lower systolic blood pressure (BP) by about 20 mm Hg in 24 hours and reaching goal BP of 120/70 mm Hg within 72 hours while avoiding hypotension. Once BP is at goal and dose stabilized, long-acting ACEI can be substituted in equivalent doses.

If BP cannot be controlled with maximum doses of ACEI, a dihydropyridine calcium channel blocker can be added. Diuretics should be avoided (unless dictated by the need to control volume status) because they may further stimulate RAAS.

ACEI therapy may result in further decline in function to the point of necessity to initiate dialysis therapy. Continued therapy is recommended as approximately 50% of these patients may recover sufficient kidney function over 3 to 18 months to discontinue dialysis.

Even though the use of these ACEIs has resulted in improvement in outcome of patients with scleroderma renal crisis, they do not prevent the disease and may increase the risk of death if used before the development of scleroderma renal crisis. This may be due to delay in making a diagnosis of this disease due to normalization of BP.

Elevated circulating endothelin-1 have been described in scleroderma and endothelin receptor antagonists may have a role in the management of scleroderma renal crisis. A vasodilating prostaglandin (prostacyclin) may provide both rapid control of blood pressure and improved renal blood flow.

Renal recovery may occur as long as 24 months after development of scleroderma renal crisis, and decisions about renal transplantation should be postponed until that time.

There is significant survival benefit of successful renal transplantation compared with long-term dialysis. Renal transplant recipients, however, have lower graft survival rates compared to non-scleroderma patients and patient survival rates are lower as well, most likely due to the progression of disease in other visceral organs. Recurrence of scleroderma renal crisis in the transplanted kidney is uncommon (5%) but has been described, particularly in patients who had a more aggressive disease before transplantation.[2][3].

Differential Diagnosis

Thrombotic microangiopathy, malignant hypertension, and rapidly progressive glomerulonephritis frequently enter into the differential diagnosis of scleroderma renal crisis.

BP is markedly elevated in both malignant hypertension and scleroderma renal crisis, and it may be difficult to distinguish between the two unless there is a clear-cut history of antecedent poorly controlled hypertension.

In rapidly progressive glomerulonephritis, blood pressure is mildly elevated, urine sediment is nephritic, and there is a greater degree of proteinuria compared to scleroderma renal crisis. In cases that are not clear, serological testing for various causes of rapidly progressive glomerulonephritis would be indicated.

In patients who develop scleroderma renal crisis as the initial manifestation of scleroderma, renal biopsy may be the only way to clinch the diagnosis.

Prognosis

ACEIs have changed the outcome of patients with scleroderma renal crisis. Before the use of these drugs, a 1-year survival rate of patients with this disease did not exceed 10%; whereas, patients treated with ACE inhibitors now can anticipate 85% survival at 1 year and 65% survival at 5 years.[10]

Up to two-thirds of patients with scleroderma renal crisis may require renal replacement therapy. Half of these patients will eventually recover sufficient renal function to discontinue dialysis. Dialysis status affects the mortality rate in scleroderma renal crisis, mortality being greater in dialyzed patients versus those who do not need dialysis, and being lesser in those whose renal function improved and were able to come off dialysis versus those who needed to continue dialysis. Risk factors for poor outcome in scleroderma renal crisis include the following[1]:

• Serum creatinine greater than 3 mg/dl at presentation
• Delay in initiating antihypertensive treatment
• Inadequate BP control
• Older age
• Male gender
• Congestive heart failure
• Scleroderma renal crisis occurring without hypertension
• Renal biopsy findings showing arteriolar fibrinoid necrosis, severe glomerular ischemic collapse or severe tubular atrophy and interstitial fibrosis