Scleroderma Renal Crisis

Abstract

Abrupt onset of severe uncontrolled hypertension and rapidly progressive oliguric renal failure characterizes scleroderma renal crisis. The etiology is unclear, but very high renin levels are present. While scleroderma is more common in women and whites, there is no difference in the prevalence of scleroderma renal crisis by gender. However, there appears to be a higher prevalence of scleroderma renal crisis among African Americans than whites. Survival was dismal prior to the introduction of the vigorous treatment of hypertension and use of converting‐enzyme inhibitors. However, most data on the benefit of these medications are derived from uncontrolled and unblinded studies. Prospective, randomized controlled trials are needed to assess the role of angiotensin receptor blockers. Prevention trials could define the role of various drugs in decreasing the rate of scleroderma renal crisis.

Figure 1 shows typical facial and hand features of scleroderma in a patient presenting with scleroderma renal crisis (SRC). Severe uncontrolled hypertension (stage 3) and rapidly progressive oliguric renal failure characterize this syndrome. The onset of hypertension is abrupt and is usually associated with flame‐shaped retinal hemorrhages, retinal infarcts (“cotton wool spots”), and papilledema. ¹ Microangiopathic hemolytic anemia is present in 45% of cases. ² The histologic picture includes fibrinoid necrosis of the afferent arterioles, intimal proliferation, and/or collagen deposition in the interlobular and arcuate arteries of the kidney. ¹ Similar findings have been observed in normotensive scleroderma patients with normal renal function. ³

Figure 1.

A patient is hospitalized because of increased dyspnea, a blood pressure of 224/108 mm Hg, flame‐shaped hemorrhages, rales, an S₃ gallop, and blood urea nitrogen/creatinine of 66/4.2. What is the diagnosis? Which antihypertensive agent should she receive? The patient has the “tight pursed‐lip” appearance due to perioral fibrosis and facial telangiectasias typical of scleroderma (A). The hands show digital ulceration, depigmentation, and finger contractures (B).

Between 1972 and 1982, 60 patients (10%) of 596 progressive systemic sclerosis patients developed SRC. ⁴ The interval to SRC after the onset of scleroderma was 3.2 years in this retrospective study. In comparing scleroderma patients with and without renal involvement, hypertension, elevated plasma renin activity (PRA), corticosteroid use, isolated proteinuria, or microscopic hematuria were not predictive of the development of SRC. The identified predictors of SRC were shorter duration of disease, new cardiac involvement, anemia, and greater skin involvement, especially with a rapid increase in the extent and severity of skin thickening.

Accelerated or malignant hypertension and rapidly deteriorating renal function is thought to result from very high levels of PRA, either causing or resulting from cortical renal ischemia. ⁵ , ⁶ One study compared seven patients with SRC, seven scleroderma patients with chronic renal disease, and nine scleroderma patients with normal renal function. ⁵ The PRA was very high among subjects with SRC (45 ng/mL/hr) compared to the chronic renal disease group (7 ng/mL/hr) and the group with normal renal function (3.7 ng/mL/hr). A high PRA in the groups with SRC predicted the subsequent development of SRC. Another study measured PRA in hypertensive (n=8) and normotensive (n=6) scleroderma patients without SRC and compared them to a control group of 26 subjects with essential hypertension. ⁶ The PRA was similar among all three groups. In one report of nine normotensive scleroderma patients with normal renal function undergoing renal biopsy, the presence of increased PRA or a marked increase of PRA after cold pressure testing was associated with mild or prominent vascular abnormalities. ³

The treatment of SRC prior to the 1980s was associated with a dismal outcome. ⁷ In one series of 68 patients with SRC between 1955 and 1981, 84% did not survive. The occurrence of SRC was less likely in the summer months, with an average age of onset of 49 years. Typically more women were affected (71%) and 16% were black. ¹ There was a higher rate of SRC among blacks compared to whites (20.8% vs. 7.4%). Development of SRC in this study was similar between gender, affecting 9.5% of women and 7.8% of men. Bilateral nephrectomy was advocated as the only treatment, but other investigators recommended intense treatment with antihypertensive drugs and hemodialysis. ⁸ , ⁹ Vigorous treatment of hypertension with a multidrug regimen has been associated with an improved overall survival rate. ¹⁰

The use of captopril, an angiotensin‐converting enzyme (ACE) inhibitor, has received the most attention. Early case reports suggested that captopril might be useful to reverse peripheral vascular and renal crises of scleroderma and avoid dialysis. ¹¹ , ¹² In a series of 23 patients with SRC receiving diuretics, ¹³ 87% experienced a drop in their diastolic blood pressure to levels of 10 mm Hg less than 105 mm Hg for 8 hours after each dose of captopril 25–150 mg every 8 hours; other drugs were added if necessary. Another study ¹⁴ examined seven patients with malignant hypertension and five patients without malignant hypertension and scleroderma. PRA was higher among the SRC cohort (32.5 ng/mL/hr) than the hypertensive scleroderma cohort (4.2 ng/mL/hr; p<0.01). Among all 12 patients, the pretreatment PRA predicted the degree of blood pressure decline with captopril: the higher the PRA, the greater the blood pressure descent. Treatment with captopril in the seven patients with SRC averted renal failure in only two patients despite good blood pressure control. None of the five patients without SRC developed SRC. Raynaud's phenomenon and cutaneous ulcerations improved with extended treatment.

The use of ACE inhibitors or the attainment of good blood pressure control have not universally resulted in favorable outcomes. ¹⁵ , ¹⁶ Out of a cohort of 1068 consecutive patients with scleroderma, 10% experienced SRC. ¹⁷ Of the 108 subjects with SRC, 51% received either captopril or enalapril. As shown in Figure 2, outcome was improved on an ACE inhibitor. Survival at 1 and 5 years was 76% and 65% for ACE‐inhibitor treated patients compared to 15% and 10% for patients not treated with ACE inhibitors (p<0.001). The predictors of decreased survival included older age, higher blood pressure, and the failure to use ACE inhibitors. However, 44% of patients receiving ACE inhibitors had a poor outcome and progression of renal disease. Of the patients receiving ACE inhibitors, the independent predictors of a poor outcome were older age and the presence of heart failure. More recent data from the same center ² compared 145 patients with SRC who received ACE inhibitors and 662 scleroderma patients without renal involvement. ² The mean age of the patients with SRC was 50 years. Only 25% were men and 8% were not white. The duration of scleroderma prior to SRC was 2.4 years. Diffuse scleroderma was present in 88% of this cohort. Of the 145 subjects, 38% did not require dialysis, 23% required temporary (2–18 months) dialysis, 19% required permanent dialysis, and 19% died within 3 months of diagnosis of SRC. The 80%–85% 8‐year survival of patients who did not require dialysis or required temporary dialysis was similar to the scleroderma patients not experiencing SRC. It should be remembered that many of the patients in the above studies also received other agents (especially a diuretic) in addition to the ACE inhibitor.

Figure 2.

Outcome of patients with sclerodermal renal crisis. ACE=angiotensin‐converting enzyme Data derived from Steen et al. ¹⁷

A small prospective study of seven hypertensive scleroderma patients and mild renal insufficiency observed stabilization or improvement in renal function after treatment with captopril. ¹⁸ A prospective, double‐blind study randomized 19 nonhypertensive scleroderma patients to placebo or antihypertensive medication (propranolol, α‐methyldopa) for 24 months. ¹⁹ There was no difference between active drug and placebo for renal outcomes as assessed by creatinine.

Side effects to captopril have been reported. The most common has been skin rash and dysgeusia. ¹⁷ Also, hepatotoxicity has been reported. ²⁰ Thus, there might be an interest in the use of a drug that also acts on the renin‐angiotensin‐aldosterone system, such as an angiotensin receptor blocker (ARB), for SRC. SRC is essentially a form of bilateral intrarenal renal artery stenosis. Use of an ACE inhibitor or ARB may improve renal function due to a change in afferent arteriolar resistance and a reduction in glomerular capillary pressure. There are only a few case reports on the use of ARBs, and the results are mixed. ²¹ , ²² One case report ²² describes blood pressure control with an ACE inhibitor and failure of control with losartan. The other case report ²¹ describes blood pressure control and reversal of renal failure with losartan.

Studies that preceded the use of captopril for SRC showed that almost all patients with renal disease died within 1 year. Now the rate of renal failure is reduced. However 20%–50% of patients with SRC progress despite an ACE. The ARBs are a class of medication that affect the renin‐angiotensin‐aldosterone system, are quite well tolerated, and are proven to be nephroprotective in type 2 diabetics with proteinuria.

It should be noted that the data presented are a composite of case reports and consecutive patients and are for the most part uncontrolled and unblinded. Randomized double‐blind trials could be constructed to compare ARBs with ACE inhibitors (given along with other agents to reduce blood pressure). Prevention trials should be designed to ascertain whether ARBs or ACE inhibitors could prevent SRC.