Introduction

The denomination of scleroderma renal crisis (SRC) was proposed in 1952 by Moore and Seehan [1]; they first described the typical histopathological lesion. SRC is an infrequent complication of systemic sclerosis (SSc) that presents as new onset accelerated phase hypertension and/or rapidly deteriorating renal function, frequently accompanied by signs of microangiopathic hemolysis [2]. Although the pathology is now well described, the pathogenesis remains poorly understood. Prior to the late 1970s, SRC had an almost uniformly fatal course [3]. Since the introduction of angiotensin-converting enzyme inhibitors (ACEi), survival has dramatically improved and the 1-year mortality rate associated with SRC decreased from 76% to less than 15% [4]. However, despite aggressive antihypertensive therapy, 5-year survival of patients who developed a SRC is only 65% [5–8]. In addition, exposure to certain drugs, particularly glucocorticoids, has been pointed out as a potential precipitating factor for SRC [9].

Pathophysiology

The pathogenesis of SRC is incompletely understood [10]. The typical arterial “onion bulb” lesion observed in SRC is the consequence of a proliferation of the vascular intima, which leads to a narrowing of the vessel lumen and reduced blood flow [11]. Other mechanisms such as vascular hyperreactivity can take place, since Cannon et al. reported a “renal Raynaud’s phenomenon”, responsible for a decreased renal perfusion [12], and since Traub et al. [3] reported an increased frequency of SRC during winter.

The cortical blood flow was found to be significantly decreased in patients experiencing SRC or progressive renal failure whereas SSc patients without renal involvement showed normal renal blood flow [12]. However, Doppler ultrasonography and renal perfusion scintigraphy failed to identify patients at risk for developing SRC [13, 14].

Activation of the renin–angiotensin–aldosterone system appears to play an important role in the pathophysiology of SRC. There is evidence for a juxtaglomerular apparatus hyperplasia, and blood pressure can usually be controlled with high-dose ACEi [15]. However, unfortunately, an elevated plasma renin level does not predict the development of SRC [16, 17]. Since vascular changes and hyperreninemia may be present in asymptomatic SSc patients, additional factors are probably involved in triggering SRC. A number of factors responsible for a reduction of renal blood flow such as sepsis, dehydratation, cardiac arrhythmia, congestive heart failure, and nephrotoxic drugs such as nonsteroidal anti-inflammatory drugs (NSAIDs) [17] may trigger SRC. In addition, the role of pregnancy per se is debated [18, 19].

A number of substances (e.g., cocaine) [20] and drugs, including cyclosporin [21] and corticosteroids (CS) [5, 7, 9, 22], have been implicated as precipitants of SRC. In a case-controlled study, in the 6 months prior to SRC onset or to the first visit, medium to high-dose CS (≥15 mg/day prednisone) were administered significantly more frequently in SRC patients (36%) than in controls (12%; OR 4.37) [22]. We recently reported in a cohort of 50 SSc patients who suffered SRC that 60% of them had been exposed to CS prior to SRC [7]. The odds ratios for developing SRC associated with CS exposure during the preceding 3- or 1-month periods were 24.1 (95% CI, 3.0–193.8) and 17.4 (95% CI, 2.1–144.0), respectively. In addition, Helfrich et al. have observed an association of high-dose (>30 mg/day) corticosteroid therapy with normotensive SRC [9]. However, corticosteroid are often prescribed in patients with early diffuse SSc who are at high risk of developing SRC and confounding variables cannot be definitively ruled out. Nevertheless, based on the current literature, which documents a dose/risk relationship for GC and SRC, we strongly suggest to avoid any medium- to long-term use of glucocorticoids in SSc.

The mechanism by which corticosteroids may trigger SRC has not been elucidated so far. Endothelin-1 (ET-1) might be involved, since increased circulating levels of ET-1 were documented in SSc patients with SRC, as well as in those with pulmonary arterial hypertension [23, 24]. In agreement are immunohistological findings of Kobayashi et al. who documented the expression of ET-1 and type B receptor of ET-1 in kidney biopsies of two patients who died of SRC [24]. Interestingly, in corticosteroid-induced osteonecrosis, the expression of type A receptor of ET-1 in bone tissue was increased as compared to bone tissues from patients who experienced osteonecrosis due to other causes [25]. However, whether the same pathophysiological mechanism comes into play in kidney vessels of SSc patients remains to be demonstrated.

Prevalence

The prevalence of SSc is still poorly documented, with disparity between states and countries [26]. It ranges between 200 and 260 cases/million persons in the USA and in Australia [27, 28], 20 and 50 cases/million in Asia [29], and 100 and 200 cases/million in Europe [30, 31].

SRC occurs roughly in 4–6% [32, 33] of SSc patients, predominantly in those presenting with diffuse SSc [17, 32]. Historically, SRC occurred in up to 25% of SSc patients, whereas in a recent work from the EULAR Scleroderma Trials And Research (EUSTAR) group data base, it is reported to have decreased to less than 5% of these patients [32] and less than 2% in patients with limited cutaneous SSc, possibly due to the prescription of ACEi [2, 17, 32].

Clinical features

The main clinical features of patients experiencing SRC in published cohorts are listed Table 1. On average, 90% of patients experiencing SRC present with a blood pressure over 150/90 mmHg. Clinical signs of SRC are mainly those of malignant hypertension with hypertensive encephalopathy, congestive heart failure, and arrythmia. Hypertensive encephalopathy is characterized by acute or subacute onset of lethargy, fatigue, confusion, headaches, visual disturbances (including blindness), and seizures [34]. Some of these signs are nonspecific and must be interpreted in the clinical context of patients at risk. If inadequately treated, hypertensive encephalopathy may lead to cerebral hemorrhage, particularly in the presence of thrombotic microangiopathy, and result in coma and death. Of note, seizures, either focal or generalized, may be the first manifestation of SRC. Another clinical scenario is rapidly progressive dyspnea due to congestive heart failure which is related to hypertension or diastolic left ventricular dysfunction in the context of oliguria. Several patients may present large pericardial effusion. Finally, pulmonary hemorrhage has been life-threatening in some cases [9].

Table 1 Main clinical and biological manifestations of scleroderma renal crisis
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Normotensive scleroderma renal crisis

In 10% of the cases, SRC occurs in the absence of hypertension [7, 35]. Patients developing normotensive SRC are often exposed to corticosteroids, present with thrombotic microangiopathy in two thirds of the cases and their prognosis is worse than in the presence of hypertension [7, 9]. Distinguishing SRC associated autoimmune thrombotic thrombocytopenic purpura from other causes of thrombotic microangiopathy may be difficult but is mandatory since treatments differ. However, with the availability of accurate assays for ADAMTS-13 activity, these distinctions should now be made more clearly [36].

Scleroderma renal crisis sine scleroderma

SRC can occur in patients who have no evidence of skin sclerosis [37, 38]. Clinical features, useful in identifying these patients, include disease duration of less than 1 year, recent onset of Raynaud’s phenomenon, acute onset of fatigue, weight loss, polyarthritis, swollen hands and lower legs, carpal tunnel syndrome, and tendon friction rubs. Usually, after a few months of evolution, patients develop skin thickening that progresses to a diffuse form of SSc.

Differential diagnosis

In case of acute renal failure in a patient with SSc, a number of differential diagnoses should be considered. Renal arterial stenosis can present with malignant hypertension. Hypovolemia can mimick SRC. It may be provoked by dehydratation, third space sequestration in case of gut involvement and intestinal paresis, by diuretics, NSAIDs, cardiac failure, and/or arrhythmia. However, SRC can also occur surrepedently in this setting. Crescentic glomerulonephritis associated with anti-neutrophil cytoplasm antibodies with anti-myeloperoxidase specificity have been described as a cause of renal insufficiency in SSc patients [39, 40]. However, malignant hypertension and thrombotic microangiopathy are lacking in these situations. There is evidence of microscopic hematuria and the diagnosis is finally confirmed by renal biopsy. Renal toxicity of d-penicillamine is well documented, responsible for proteinuria and membranous nephropathy. Proteinuria in the nephrotic range can be due toxicity of NSAID. Finally, in a prospective observational study, Steen et al. observed that only 5% of 675 patients with diffuse SSc presented unexplained renal abnormalities over a mean of 12.5 years [40].

Laboratory findings

Serum creatinine can be markedly increased at presentation. Even after control of blood pressure, it can increase during several additional days. Urinalysis frequently shows mild proteinuria (0.5 to 2.5 g/l). Microscopic hematuria, often detected by dipstick, correspond to hemoglobinuria in most of the cases.

Thrombotic microangiopathy, defined by hemolytic anemia and thrombocytopenia, occurs in 43% of patients with SRC. Thrombocytopenia is usually moderate, over 50,000/mm³ in most of the cases, and frequently returns to normal range after control of blood pressure.

Anti nuclear antibodies (abs) are common. Of note, anti-topoisomerase abs which are found in 30% of patients with diffuse SSc, are not predictive of the occurrence of this manifestation. However, anti-RNA polymerase III abs which have been detected almost exclusively in diffuse SSc identify patients at risk. Thirty-three percent of these patients will develop SRC [41]. Anti-RNA polymerase III abs are particularly useful in patient who have no skin involvement, notably in very early diffuse SSc. It is remarkable, that patients with anti-centromere abs have very rarely been reported to experience SRC.

Renal pathology

Renal biopsy is not necessary to confirm the diagnosis of SRC in classical forms. However, a number of research groups are performing systematic renal biopsy in order to better evaluate the prognosis of SRC [8]. In atypical clinical presentation, renal biopsy is mandatory to confirm the diagnosis of SRC. In all cases, renal biopsy will be performed after control of blood pressure. In case of severe thrombocytopenia, renal biopsy can be performed through jugular vein catheterism.

In severe SRC, vascular occlusion and tissue ischemia may lead to grossly visible renal infarcts and subcapsular hemorrhages [42]. Characteristic changes in the arteries and arterioles are the pathologic hallmarks of SRC. Larger arteries appear normal or may reveal nonspecific changes, whereas small arteries and arterioles, especially in the interlobular and arcuate arteries, undergo severe changes. The characteristic pathologic lesion is mucoid intimal thickening with concentrically arranged myointimal cellular proliferation without inflammatory cells, otherwise known as the onion skin lesion (Figs. 1 and 2). The mucinous intimal change mostly consists of glycoprotein and mucopolysaccharides. Fibrinoid necrosis may be present in arterial walls without others signs of vasculitis (Fig. 3). Fibrin deposits may also be found in the thickened intima. These vascular changes lead to narrowing and occlusion of the vessel lumen [43]. Notably, in contrast to lesions encountered in malignant hypertension occurring in the absence of SSc, in renal biopsies from patients developing SRC, the media of interlobular arteries is often thinned and surrounded by peri-adventitial and adventitial fibrosis (Fig. 2). In addition, glomerular and tubular changes are frequently found, as a consequence of ischemia (Fig. 2). Glomerular changes may vary considerably. Some glomeruli may have subnormal aspect, other can be ischemic, but one sees a thickening of capillary walls with a double contour aspect with silver or PAS staining, accumulation of glomerular intracapillary eosinophilic material corresponding to fibrin thrombi, lesions observed in thrombotic microangiopathy (Figs. 4 and 5). Mesangiolysis may also be present. The juxtaglomerular apparatus is prominent, especially in those cases with severe occlusive arterial and arteriolar lesions.

Fig. 1
figure 1

Masson green light trichrome: chronic injury in an interlobular artery with mucoid changes and endothélial prolifération. Magnification ×250

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Fig. 2
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Jones staining: interlobular artery with mucoid changes and concentric intimal fibroplasia with so-called onion skinning changes, enlargement of the vascular diameter, perivascular fibrosis, and ischemic glomerulus. Magnification ×250

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Fig. 3
figure 3

Masson green light trichrome. Focal necrosis of the vascular wall with fibrin deposit. And mucoid obstruction of an artériole. Magnification ×400

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Fig. 4
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Masson green light trichrome: glomerulus with thrombotic microangiopathy (fibrin in capillary lumens, preglomerular artérioles with thrombosis). Magnification ×100

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Fig. 5
figure 5

Jones staining: extensive réduplication of glomerular bassement membrane and mesangiolysis. Magnification ×400

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Juxtaglomerular hyperplasia may be documented, that is the consequence of the hyperrenemia that can be encountered during SRC. Immunoglobulin and complement deposits may be detected in small arteries. However, it is important to keep in mind that many of these pathologic changes can also be observed in SSc patients who do not develop SRC or in patients experiencing malignant hypertension in the absence of SSc.

Predictive factors

Steen et al. and others [17, 44] identified a number of risk factors that predictive of SRC (Table 2) including SSc duration of <4 years, diffuse and rapidly progressive skin thickening, new anemia, new cardiac events (e.g., pericardial effusion or congestive heart failure), presence of anti-RNA polymerase III antibody, and the use of corticosteroids therapy at a prednisone dose >15–20 mg/day. Patients presenting with these characteristics should be followed very closely and monitor their blood pressure themselves in at least weekly intervals.

Table 2 Risks factors of scleroderma renal crisis (from [2])
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A past history of hypertension, urinary abnormalities, increased serum creatinine, anti-topoisomerase 1, or anti-centromere abs and pathologic abnormalities in renal blood vessels preceding the onset of SRC have not been shown to be associated with an increased occurrence of SRC.

Prognosis

The prognosis of SRC in large series of the literature is detailed in Table 3. Prior to the 1970s and advent of ACEi, SRC almost always resulted in renal failure and death, usually within months. The use of ACEi dramatically improved the prognosis of SRC. Steen et al. identified risk factors that were associated with a bad outcome: male gender, older age, presence of congestive heart failure, serum creatinin greater than 3 mg/dl at the initiation of treatment, and a time period of more than 3 days to control blood pressure [4, 45].

Table 3 Prognosis of scleroderma renal crisis
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In the largest prospective observational cohort study to date, Steen et al. reported a good outcome in 60% of the patients. More than half of those who required dialysis were able to discontinue it within 2 years, and the mortality rate was 15% at 1 year [4]. In two recent English and French studies published [8, 46], the mortality rate at 5 years was between 30% and 40%, corresponding to data from a North American multicenter randomized trial comparing high- versus low-dose d-penicillamine with a 50% mortality report [5] and from the South Australian Scleroderma Register with a 30% mortality rate despite aggressive antihypertensive treatment [6].

Treatment

Prompt recognition of SRC and initiation of ACEi therapy offer the best outcome [4]. ACEi must be continued even if there is a deterioration in renal function. The goal of the treatment is to obtain control of blood pressure as soon as possible. Angiotensin receptor blockers offer a theoretical benefit, but—in contrast to ACEi—clinical experience with these agents has been variable [47].

Continuous low doses of prostacyclin are used by several groups [33], however, without strong beneficial evidence. Very recently, endothelin receptor blockers have been added to ACEi. However, evidence from clinical trials regarding a better outcome is lacking. In case of failure to normalize blood pressure with a maximal dose of ACEi, additional antihypertensive therapy is mandatory with combinations of calcium blockers, nitrates, or other vasodilators agent [33]. Since relative hypovolemia is frequent is SRC, there are concerns about the use of diuretics or labetalol. Plasma exchanges or immunosuppressive drugs exert no proven beneficial effect in the treatment of SRC. Corticosteroids are contra-indicated in SRC.

Requirement for dialysis is needed in up to half of the patients. It may be temporarily, with 50% of the patients being weaned from dialysis within 2 years after the onset of SRC [45].

The final decision of transplantation should not be made before 2 years after the onset of SRC. In a series of 260 SSc patients who underwent renal transplantation in the USA, the 5-year graft survival rate was 56.7% [48]. In this study, the risk of recurrence of SRC was increased in patients who presented early renal insufficiency following the onset of SRC. Recurrent SRC in the allograft may be predicted by the above mentioned risk factors [48].

The use of prophylactic ACEi remains a matter of debate since some SSc patients developed SRC while taking these agents [7, 33, 49].

Conclusion

SRC is nowadays a rare complication of SSc but remains severe. Prompt recognition and initiation of ACEi therapy offer the best opportunity for a good outcome. Nevertheless, the 5 years mortality remains unacceptable and additional therapies are needed to improve the prognosis of SRC. Meanwhile physicians should avoid use of glucocorticoids, nephrotoxic drugs, and intravascular hypovolemia.