Scleroderma Renal Crisis: Presentation, Treatment, and Prognosis

ABSTRACT: Scleroderma is a rare, life-threatening autoimmune disorder that causes fibrotic changes in the skin and vasculature. Scleroderma renal crisis (SRC) is a potentially fatal complication of scleroderma, with a mortality rate near 10%. A majority of patients who develop SRC will have an established diagnosis of diffuse cutaneous systemic sclerosis (dcSSc) before progressing to SRC. However, in rare and extreme cases, patients develop evidence of hypertensive crisis, which may include irreversible acute kidney injury, as the initial presentation. If not managed appropriately, SRC will progress to irreversible end-organ damage and ultimately will lead to death. This article reviews the history, presentation, treatment, and prognosis of this complex disease.

KEYWORDS: Scleroderma, scleroderma renal crisis, hypertensive crisis, renal insufficiency

Scleroderma, also called systemic sclerosis (SSc), is a rare, life-threatening, heterogeneous, autoimmune, inflammatory connective tissue condition that causes fibrotic changes in the skin and vasculature, ultimately affecting the major organ systems.^1-7 It affects women 4 times as often as men, with an age of onset between 30 and 60 years of age.^2,5,6 While it is believed to be associated with both genetic and environmental factors, involving cellular and humoral immunity, the true etiology of SSc remains elusive.^2,4,6

SSc is classified as either limited cutaneous (lcSSc) or diffuse cutaneous (dcSSc), determined by the extent of cutaneous manifestations.^1,4-6 The magnitude of skin and organ involvement predicts the clinical course and ultimately the morbidity and mortality, with the most dismal prognosis associated with diffuse disease.^2,4 Cases of lcSSc generally are restricted to the peripheral aspects of the body, distal to the elbows and knees, and are characterized by sclerodactyly and acrosclerosis.^1,4-6 However, lcSSc also can include Raynaud disease, dysphagia, calcinosis cutis, and telangiectasia; although such cases are uncommon, lcSSc can progress insidiously to include pulmonary hypertension and biliary cirrhosis.⁴

Paradoxically, dcSSc involves the more proximal aspects of the extremities and the trunk, as well as the vital organs, including the cardiac, pulmonary, gastrointestinal, and renal systems.^1,4,5 Scleroderma renal crisis (SRC) is a life-threatening complication commonly associated with dcSSc. SRC is characterized by an accelerated phase of hypertension and acute renal failure and also is associated with a high mortality rate.^2,5 Although non-nephrotic proteinuria, mild elevation of serum creatinine, and hypertension develop in 50% of all patients with SSc, from 10% to 20% of patients will go on to develop renal crisis.^5,6 Further complicating this disease are reported cases of SRC in which the patient is normotensive at presentation.⁸

This article reviews the pathology and clinical presentation of SRC, exploring the risk factors and highlighting the clinical management, treatment, and prevention of SRC.

Pathology

Although the pathophysiology underlying SRC is not completely understood, it is accepted as being related to intimal thickening of the renal interlobular and arcuate arteries as a result of endothelial cell injury and abnormal oxidative stress, leading to fibroblast activity.^5,7 This process begins as a narrowing of arterial vessels, leading to decreased renal perfusion and progressing to hyperplasia of the juxtaglomerular apparatus and increased renin release, microangiopathic hemolytic anemia (MAHA), and high levels of soluble adhesion molecules (eg, vascular cell adhesion molecule 1, intracellular adhesion molecule 1, E-selectin, endothelin-1).^2,9 This historically has been evidenced by improvement in hypertension after nephrectomy.^2,5 Counterintuitively, hyperreninemia is not regarded as the primary trigger for SRC, with elevated renin levels being noted in patients without evidence of renal involvement.⁵

This is not to undermine the role of high renin levels in complicating the disease process, with elevated renin levels being demonstrated before and throughout the progression of the disease.⁵ This is explained as a progression to renal failure secondary to an episodic vasospasm of the renal cortical arterial system, which leads to cortical ischemia, in turn causing activation of the renin-angiotensin-aldosterone system (RAAS).⁵ A vicious cycle ultimately develops, which perpetuates intrarenal vasoconstriction and induction of renin-mediated hypertension.⁵ In the presence of malignant hypertension, MAHA has been established as an independent predictor of impending renal failure secondary to the fragmentation of erythrocytes passing through renal arterioles that have become narrowed by intravascular fibrin.⁵

Most research is aimed at explaining the pathogenesis of SRC presenting in classic hypertensive crisis. However, 11% of patients with renal crisis will be normotensive,⁸ making the understanding of the disease process even more ambiguous. It has been suggested that the RAAS may be less activated, leading to modest blood pressure (BP) elevation,² and that vascular insult and vasoconstriction are the culprits, rather than a renin-mediation etiology. Despite treatment with tension-lowering medications, poorer prognosis and higher mortality rates have been observed in patients with normotensive SRC compared with hypertensive patients. This observation may support a distinct mechanism that is non–renin-mediated.^10,11 Additional research is needed.

Clinical Presentation

Generally, a majority of patients present classically with hypertension and evidence of end-organ damage, with an average BP reported as 193/114 mm Hg.² The presentation of patients with SRC, as with many diseases, may include a variable history, physical examination, and diagnostic findings. Patients may report symptoms consistent with hypertensive retinopathy and/or encephalopathy, hematuria, abrupt oliguria/anuria, seizures, and even pulmonary edema.^2,5 This then rapidly progresses to oliguric renal failure, commonly in the absence of previous signs of renal disease.⁶

Microscopic urinalysis often reveals proteinuria, hematuria, and granular casts.² Biopsies of the kidney in patients with established SRC also have revealed mucin in the intertubular arteries, fibrinoid necrosis of arterioles, and evidence of upregulation of the endothelin-1 and endothelin-B receptors with immunohistochemical staining.² A biopsy however, is not necessary to make the diagnosis of renal crisis, but it may help to determine the underlying renal pathology in certain patients, such as normotensive patients with a history of SSc who present with declining renal function, oliguria, and azotemia.⁵

Risk Factors for SRC

Risk factors for renal crisis have been investigated in an attempt to predict which patients are threatened by the disease course, to project mitigation strategies, and to develop treatment regimens.⁵ Although these efforts have had minimal success, the salient risk factors that have been identified include the following: being black; having anemia; having diffuse and rapidly progressive skin disease and joint contractures; having new cardiac events or cardiac disease (including pericardial effusion); the recent use of high-dose corticosteroids; the presence of anti-RNA-polymerase antibodies (ARAs); new onset (within 4 years) of SSc; and, possibly, the use of cyclosporine.^2,5-12

What has not been established is whether these threatening factors are a reflection of disease severity or merely the developing pathogenesis of the existing disease state and its expected clinical course.² Although a complete discussion of the role of these risk factors in SRC is beyond the scope of this article, a review of the most important contributions of each risk factor to disease progression is presented.

Diffuse skin involvement. An estimated 66% of SSc patients develop SRC within 1 year of diagnosis, increasing to 86% at 4 years.² One study reported that SRC occurred within 7.5 months from the onset of the first non-Raynaud disease symptom.² Another study¹³ of 287 patients and 287 matched control subjects reported that certain findings associated with dcSSc, such as the presence of a palpable tendon friction rub, were associated with a 2-fold increase in in the risk of SRC. Consequently, the presence of dcSSc alone is by far the greatest predictor of disease severity and rate of progression, especially as it pertains to SRC.

Corticosteroid use. While not an ideal means of preventing disease progression, corticosteroids are useful in improving and controlling pain secondary to myalgia and arthralgia and therefore are a common and reasonable treatment option for the management of SSc.⁴ Nevertheless, corticosteroids often are provided only when more conservative therapy with nonsteroidal anti-inflammatory drugs has failed.⁶ An estimated 60% of patients with SRC have received corticosteroids prior to presentation.^2,14 This estimation is supported by an observational study¹² that found that a recent history of high-dose corticosteroid use (> 15 mg/d of prednisolone or equivalent) preceded the SRC diagnosis in most patients.

However, this association does not implicate corticosteroids directly as a cause of SRC, since the cause-and-effect of low-dose corticosteroid use and SRC has not been demonstrated adequately. Nevertheless, it is worth noting that a greater number of patients who started new low-dose corticosteroid regimens developed SRC compared with those who did not.¹² Even though corticosteroids should not necessarily be avoided in the treatment of patients with dcSSc, if they are used, they should be provided judiciously.^2,5,6

Cyclosporine use. Cyclosporine is a renal vasoconstrictor that can be used as adjuvant therapy for SSc with or without corticosteroids.¹⁵ Recently, its benefit has been clinically challenged, in large part because reports of benefits mostly have been anecdotal. Additionally, evidence from recent studies suggests that cyclosporine use actually may accelerate acute kidney injury and renal failure, which reportedly has occurred in nearly 40% of patients treated with cyclosporine as a component of the SSc regimen.¹⁵

The presence of autoantibodies. A dense fine speckled immunofluorescence pattern of antinuclear antibodies is detectable in 60% of patients with SRC, compared with only 12% in patients without the condition.² Studies have linked other autoantibodies with a high incidence of skin and renal disease—for example, SSc-specific ARA I and III, which are measurable in approximately 59% of patients with SRC.² Other markers include antifibrillarin/anti-U3-ribonucleoprotein antibodies, which also may identify patients at risk for developing manifestations of SSc, including SRC.¹⁶ In contrast, anticentromere antibodies and antitopoisomerase 1 antibodies have been shown to be less-reliable predictors of disease progression.^2,17

Clinical Management

A carefully taken history of patients with newly diagnosed SSc may enable early detection of SRC. Patients with dcSSc who are early in the disease course are at greatest risk for SRC, particularly if skin involvement is advancing rapidly. Therefore, close interval monitoring is vital during the first 4 to 5 years of clinical suspicion.²

Once the diagnosis has been confirmed, BP should be monitored monthly in the clinic, with daily self-monitoring if signs of hypertension are present. In patients without an existing diagnosis of hypertension and a BP less than 120/70 mm Hg, a persistent increase of 20 mm Hg in systolic BP and 10 mm Hg in diastolic BP should be managed.² In addition, patients with a history of existing hypertension with a sustained BP of more than 150/90 mm Hg warrant prompt evaluation and treatment.²

The progression of SSc, or even the development of SRC in the appropriate clinical setting, may be detected with assessment of serum creatinine and protein concentrations in the urine via protein-creatinine ratios, defined as new proteinuria greater than 500 mg/day.^18,19 According to Kingdon and colleagues,¹⁸ calculating the estimated glomerular filtration rate is best done using the Modification of Diet in Renal Disease formula, which can classify renal impairment.

Once the diagnosis of SRC has been made, tailored treatment should be initiated. SRC can progress to end-stage renal disease (ESRD) over a short time, usually 1 to 2 months, with death occurring within 1 year if left untreated.²⁰ The success of therapy is contingent on BP control, which is imperative prior to the onset of irreversible renal damage. Because SRC most commonly stems from the progression of an existing diffuse disease state, the treatment of both is required, although these treatments are not inherently identical.

Treatment

Angiotensin-converting enzyme inhibitors (ACEIs). The recommended first-line agents in the treatment of SRC are ACEIs, which provide a significant reduction (more than 60%) in mortality.^5,6,12 Some have argued that the effectiveness of treatment with ACEIs supports the role of the RAAS in SRC, although this is not fully supported by the available data.^5,6 Moreover, angiotensin receptor blockers (ARBs) have not been proven as effective as ACEIs, leading some to question the accepted pathogenesis of the disease and, therefore, the pharmacotherapeutic reasons for the effectiveness of ACEIs.⁵

Despite that the pathogenesis remains unclear, the success of ACEI therapy for SRC is well established, making them the standard of care (especially if provided when the serum creatinine level is <3 mg/dL). However, further studies are needed to support the current understanding of SRC, as well as the long-term effects of treatment on renal dynamics.^5,6 Furthermore, no proven benefit has been established for prophylactic intervention with ACEIs.⁵ On the contrary, the use of ACEIs and ARBs as prophylaxis actually is associated with poorer renal outcomes.^5,6

The most experience has been with captopril; although data are limited for other ACEIs such as enalapril or ramipril, these agents also may provide comparable benefit. Captopril has the primary advantages of a rapid onset of action (peak effect at 60-90 min) and a short duration of action, which allows for rapid dose titration compared with enalapril, which is not routinely used due to its longer duration of action (up to 36 h).^21,22

Throughout treatment, it is recommended that a methodical reduction in BP be pursued, because a precipitous decrease can reduce renal perfusion and increase the risk of acute tubular necrosis. The initial goal of therapy is to return the patient to baseline BP within 72 hours. Although hypertension usually is acute in SRC, rapid BP reduction to baseline does not bear the same risks as seen with rapid BP reduction in patients with long-standing hypertension; nevertheless, conventional practice standards are not to exceed a maximum BP reduction of 20 mm Hg per day.^2,23,24

Other BP-lowering agents. Dihydropyridine calcium channel blockers (CCBs) and prostacyclin analogues are appropriate for the treatment of vasospastic conditions such as Raynaud disease, which occurs in more than 90% of dcSSc patients.^4,6 The mainstay of CCB treatment, nifedipine, decreases calcium influx into smooth muscle, allowing for relaxation of the muscle lining of blood vessels.^4,6 The alternative, prostacyclin analogues, are potent vasodilators that reduce the permeability of the endothelium and inhibit vasoconstriction while reducing platelet aggregation and promoting endothelial cell lining.^4,6

These medications lead to a significant improvement in the reduction of distal small-vessel complications associated with the temporary ischemia caused by vasospasm, particularly in digits and earlobes, but this is not the limit of their systemic benefit.⁶ In addition to assisting in the reduction of the complications that can lead to digital ulcers, CCBs in particular have the added benefit of improving other symptoms associated with SSc, such reducing esophageal impairment by decreasing lower esophageal sphincter pressure.⁶ Despite these benefits, CCBs have not been shown to reduce the effects of or progression of renal disease.

Therapies for SSc without SRC. In the absence of SRC, treatment for SSc is based on the symptoms associated with the established disease process. Since the cause remains largely idiopathic, treatment regimens are aimed at improving peripheral circulation, preventing the synthesis and release of harmful cytokines, and inhibiting fibrosis. This is done using agents that are immunosuppressive, reduce collagen synthesis, or enhance collagenase production. For lcSSc, these agents include vitamin D analogues, UV-A phototherapy, corticosteroids, and methotrexate.⁴ The therapeutic options available for treatment of dcSSc include dihydropyridine CCBs and prostaglandins, immunosuppressants, and antifibrotic agents.^4-6 Patients whose SSc progresses to SRC should be receive other targeted hypertension therapy to prevent irreversible vascular injury, since the agents mentioned here have no therapeutic role in the acute management of SRC.

Immunosuppressants. Immunosuppressive agents used for the treatment of dcSSc have questionable benefits targeting the cellular and humoral immunity effect.^4,6 Among of the immunosuppressants with reportedly variable results are cyclosporine, azathioprine, and methotrexate.^4,6 These agents are commonly used in cases of pulmonary disease, particularly pulmonary fibrosis, which is a significant complication associated with dcSSc.^4,6 These are all established treatments for possible systemic progression of dcSSc; however, they have relative benefits and risks, each unique to a patient’s comorbidities and affected body systems.^4,6 Despite their commonplace use, none have been validated as effective in preventing the progression to renal insufficiency, or as treatment for SRC as monotherapy or adjuvant therapy.

Renal dialysis. Renal replacement remains in use as therapy, especially in the acute care setting with SRC-associated uremia despite treatment with ACEIs. However, the rate of survival on dialysis of patients with SRC is worse than those with other forms of ESRD. This observation was illustrated in a study²⁵ that included more than 364,000 patients in the United States Renal Data System with ESRD on maintenance dialysis, 820 of whom had SSc. The 2-year survival rate was lower in patients with SSc (49% vs 64% in all other patients).

Given the beneficial effects of ACEIs in SRC, it is important to continue ACEI therapy, even if in low doses, once the SRC diagnosis has been established. The goal remains maintenance of normal BP (ie, < 140/90 mm Hg); in dialysis-dependent patients, ACEIs may be continued as needed indefinitely for BP control if control of extracellular volume is insufficient.²⁵

Alternative therapies. Historically, treatment with the copper chelating agent d-penicillamine was believed to be clinically beneficial, but its use has been scrutinized in contemporary literature. Recent clinical trials have shown d-penicillamine to be associated with significant adverse effects with no appreciable reduction in morbidity or mortality.⁴ Intuitively, a patient would seem to benefit from the pharmacokinetic blocking of the aldehyde group in intermolecular and intramolecular cross-linkages in collagen. However, any benefit comes at a great cost, including bone marrow suppression, renal injury, gastrointestinal intolerance, and dermatologic complications such as pemphigus vulgaris.⁴ Therefore, its use is strongly discouraged.

Prevention

No preventive measures have been validated in the literature to support predictable, reliable improvement in outcomes. However, the treatment regimens discussed here have been useful in targeting symptoms, with a significant reduction in morbidity and mortality associated with this complicated condition. SRC is not easily prevented, but with prompt recognition, it can be treated effectively, even leading to the restoration of renal function.

The Take-Home Message

SRC is a rare, life-threatening complication that most commonly is associated with dcSSc. While advances in medicine have reduced the associated mortality, and many therapeutic options for the treatment of SSc are available, the therapy for SRC is more complex. Because the presentation of SRC is variable, with some patients being hypertensive and others being normotensive, and some with evidence of renal insufficiency, clinicians should be aware of patients’ full clinical history and the risk factors associated with SRC. Early diagnosis, consultation with appropriate subspecialists, and prompt initiation of therapy with ACEIs can slow progression of the disease course, improving overall morbidity and mortality. 

The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, or the United States Government.

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