Scleroderma renal crisis: Case reports and update on critical issues

Abstract

To date, scleroderma renal crisis (SRC) remains a life-threatening complication in patients affected by systemic sclerosis (SSc), with high morbidity and mortality. In the last few years, some studies have tried to more precisely identify predictors of SRC and clarify the role of previous drug exposure—in particular, angiotensin-converting enzyme (ACE) inhibitors and corticosteroids—in patients with SSc presenting other well-known risk factors for SRC. Different from the findings of previous reports, more recent findings suggest that the presence of chronic kidney disease, systemic arterial hypertension, and proteinuria might all be predictors of SRC. Moreover, because about 40 to 50% of SRC cases can present signs of microangiopathy, a recent study has proposed SSc thrombotic microangiopathy (SSc-TMA) as a clinically and pathophysiologically different entity from narrowly defined SRC. Even though such clear distinction may not always be applicable/feasible in clinical practice, it highlights that complement pathway dysregulation may play a key pathogenetic role in SRC presenting as TMA. Thus, plasma exchange may be considered in severe refractory cases. Nevertheless, ACE inhibitors and prompt achievement of blood pressure control (to rapidly improve ongoing renal ischemia) remain to date the cornerstone of SRC treatment. Here, we report the cases of three SSc patients with SRC followed at our rheumatology units. While describing these patients’ risk factors, clinical presentation, and therapy, we aim to discuss the state of the art in SRC and highlight critical issues.

Introduction

Owing to decreased frequency (1, 2) and substantial improvement in survival over time (after the introduction of angiotensin-converting enzyme [ACE] inhibitors) (3), scleroderma renal crisis (SRC) is no longer the leading cause of death associated with systemic sclerosis (SSc) (4, 5). Nevertheless, the prognosis remains poor in patients with SSc experiencing SRC, and dialysis is required in about 50% of cases with a considerably high mortality rate (6, 7). Here, we discuss three emblematic patients recently followed in our tertiary referral hospitals to highlight the importance of early diagnosis, discuss predictive factors, and introduce therapeutic strategies that might result in a more benign disease course in the near future. Demographic and clinical data, treatment, and outcome of each patient are summarized in Table 1.

Table 1.

Demographic, clinical, and laboratory characteristics, and SRC course in the three patients.

	Case 1	Case 2	Case 3
Age at SRC onset, yrs	47	62	71
DD at SRC onset	Seven years	SSc not diagnosed yet (likely few months)	6 months
Cutaneous form	dcSSc	dcSSc	dcSSc
Autoantibody specificity	Anti-topoisomerase I	Anti-RNApolymerase III	PM-Scl100
Other risk factors for SRC	Steroids, large joint contractures, heart enlargement, PH, low DLCO	low DLCO, suspected SSc cardiomyopathy	Steroids, low DLCO, suspected SSc cardiomyopathy
Signs of microangiopathy	Yes	Yes (1 week after SRC onset)	Yes
Presence of schistocytes	Yes (5.5%)	No	N/A
Maximun sCr level	396 μmol/L	755 μmol/L	707 μmol/L
Treatment for SRC	Ramipril	Ramiril, PEx	Captopril, ramipril
Treatment other than ACEi to achieve pressure control	Labetalol, amlodipine	-	Labetalol, rilmenidine and amlodipine
Dialysis	Yes (temporarily)	Yes (permanent)	Yes (permanent)
Outcome	sCr 128 μmol/L	Death (after 8 months)	Check list for kidney transplantation

ACEi: angiotensin-converting enzyme (ACE) inhibitors; DD: disease duration; dcSSc: diffuse cutaneous systemic sclerosis; DLCO: diffusing capacity of lung for carbon monoxide; PEx: plasma exchange; PH: pulmonary hypertension; sCr: serum creatinine; SRC: scleroderma renal crisis.

All patients gave written informed consent for their anonymized medical information to appear in publications and educational material.

Case discussion

Case 1

A 40-year-old Caucasian female was diagnosed in 2012 with the diffuse cutaneous form of systemic sclerosis (dcSSc), with anti-topoisomerase I (anti-SCl70) positivity and arthritis.

A mild interstitial lung disease (ILD) was detected in 2017 and following a lung infection (late 2018), lung fibrosis progressed radiologically and functionally, which prompted a switch from methotrexate to mycophenolate mofetil, plus a cycle of intravenous (IV) rituximab in March 2019. Meanwhile, a transthoracic echocardiography revealed pulmonary hypertension (PH), confirmed as precapillary at right heart catheterization, and the patient was then diagnosed to have group III pulmonary hypertension (PH-ILD).

The patient’s past medical history included arterial hypertension treated with calcium channel blockers (since 2011) and left breast adenocarcinoma human epidermal growth factor receptor 2 (HER2) positivity (2013) treated with mastectomy, hormone therapy, and docetaxel and trastuzumab for bone and liver metastases. A magnetic resonance imaging (MRI) in May 2019 also revealed brain metastases treated with radiotherapy plus two steroid pulses—methylprednisolone 120 mg/day in early May and medium-dose prednisone continued orally. During an outpatient visit in late May, she complained of mild asthenia; her blood pressure was 150/90 mm Hg; and blood tests revealed a minimal increase in serum creatinine (sCr, 95 μmol/L), with a mildly reduced platelet count (92,000/μl). In early June, the patient reported a worsening of asthenia and dyspnea, and blood tests showed evidence of acute renal failure (sCr 245 μmol/L, blood urea nitrogen [BUN] 36.1 mmol/L), and signs of peripheral microangiopathy consisting of anemia (hemoglobin [Hb] 8.8 g/dL), a further deterioration of thrombocytopenia (68.000/μl), decreased haptoglobin with increased lactate dehydrogenase (LDH) levels (<0.10 g/dL and 985 UI/L, respectively), and presence of blood schistocytes (5.5%). Direct Coombs and antineutrophilic cytoplasmic antibody (ANCA) were negative. A disintegrin-like and metalloproteinase with thrombospondin type 1 motif 13 (ADAMTS 13) activity was normal, and ADAMTS13 inhibitor was negative. At the time of admission, the patient presented with systemic arterial hypertension (190/110 mm Hg) with preserved diuresis, and a diagnosis of hypertensive SRC was established. She initially received IV urapidil, followed by ramipril (5 mg/twice daily) + amlodipine (Table 1). In the 10 days following the SRC onset, kidney function progressively worsened (sCr peaked at 396 μmol/L and BUN 48 mmol/L) requiring hemodialysis (3 sessions overall). Concurrently, signs of microangiopathy recovered.

She was discharged with sCr 249 μmol/L and therapy with ramipril (5 mg daily). Six months later, she had sCr 128 μmol/L (estimated glomerular filtration rate [EGFR] 43 mL/min/mq), requiring low-dose furosemide (40 mg/daily), also indicated for a concomitant mild right ventricular elevated pressure due to PH.

Case 2

A 61-year-old Caucasian male, with no significant prior diseases, was hospitalized in March 2016 for melena and anemia. Gastroscopy with histologic examination revealed a stenosing and bleeding mass at the antrum and body of the stomach (adenocarcinoma), whereupon the patient underwent a total gastrectomy and chemotherapy until August 2016. A routine blood test in December 2016 revealed sCr 184 μmol/L, which nearly doubled in January 2017 (311 μmol/L, eGFR 18 mL/min/mq) with concomitant anemia (Hb 9.9 g/dL). Evidence of mild leg edema and blood pressure of 160/85 mmHg prompted an urgent nephrology referral. At this time, the patient also reported experiencing asthenia and hand acrocyanosis during the past 2 months. In late February, he was rushed to the hospital for a rapid worsening of dyspnea, with evidence of respiratory and heart failure, and blood pressure 170/100 mm Hg. Blood tests showed sCr 650 μmol/L with BUN 38 mmol/L and anemia (Hb 8.8 g/dL). Signs of microangiopathy also appeared 1 week later: mild thrombocytopenia (101,000/μl) with undetectable haptoglobin and increased LDH 390 U/L; blood schistocytes were absent. A transthoracic echocardiography showed a pericardial effusion and PH, while chest X-rays revealed a bilateral pleural effusion partially responsive to high-dose diuretics.

A rheumatology assessment showed diffuse skin thickening (modified Rodnan Skin Score, mRSS 35) with melanoderma, telangiectasia on the face and flexion contractures of the fingers, and a positive anti-RNA-polymerase III antibody test. Thus, a diagnosis of dcSSc complicated by SRC with mild microangiopathy was established and treated with ramipril (5 mg/twice daily). Plasma exchange (PEx) was initiated following a previously reported treatment protocol (8). Nevertheless, renal function worsened (max values sCr 755 μmol/L and BUN 50.5 mmol/L) requiring hemodialysis. Unfortunately, despite PEx and long-term therapy with ACE inhibitors, discontinuation of dialysis was no longer possible. The patient died suddenly 8 months later, probably due to malignant arrhythmia.

Case 3

A 71-year-old Caucasian female was diagnosed in June 2018 with scleromyositis, PM-Scl100 positive with dcSSc, telangiectasia, and myositis (creatine phosphokinase [CPK] up to 2500 UI/L with evidence of muscle edema at MRI). Although high-sensitive troponin levels were elevated, cardiac MRI and positron emission tomography showed no signs of active myocarditis with evidence of previous lower apical ischemia. Pulmonary function tests revealed a significant reduction of diffusing capacity for carbon monoxide (DLCO) (37%) with preserved lung volumes but no radiological signs of ILD or PH. After excluding any paraneoplastic etiology, the patient was treated with IV pulses of methylprednisolone (1 g×3) in late July, followed by oral prednisone (15 mg/daily) and methotrexate, resulting in a progressive normalization of myocytolysis indices. Starting mid-November 2018, she complained of mild asthenia and blood tests showed a slight but steady increase of sCr (100 μmol/L; normal values ≤80 μmol/L vs. 59 μmol/L in June, 71 μmol/L in July and 90 μmol/L in September). In mid-December, she presented with high blood pressure (170/100 mmHg), oliguria (sCr increased to 357 μmol/L with BUN 29.5 mmol/L), and early signs of microangiopathy (thrombocytopenia, undetectable haptoglobin, and increased LDH). At the time of admission to the Nephrology Unit, the patient clinically presented fluid retention with signs of heart failure requiring high-dose IV diuretics and ACE inhibitors under suspicion of SRC, first captopril later replaced by ramipril. However, arterial blood pressure control was only achieved by adding urapidil, rilmenidine, and amlodipine. Renal ultrasound and MRI were substantially normal, while a kidney biopsy revealed glomerular lesions suggestive of SRC with thrombotic microangiopathy and evidence of diffuse interstitial fibrosis (75% of the cortical surface) (Figure 1). Despite signs of improving peripheral microangiopathy, renal function progressively worsened after a month (sCr up to 707 μmol/L and BUN 35 mmol/L), requiring hemodialysis. At present, the patient is undergoing dialysis three times a week and is on a low-dose ACE inhibitor and is being evaluated for inclusion on the kidney transplantation list.

Figure 1. a–d.

Kidney biopsy of a 71-year-old Caucasian female affected with scleroderma renal crisis (case 3): interstitial fibrosis (a), double contour of the glomerular basement membrane (b), fibrosis and intimal proliferation with obliteration of the arteriolar lumen (c, d). Masson’s trichrome stain, original magnification ×50 (a), ×400 (b–d).

Clinical and research consequences

In two out of three patients (1 and 3), the administration of IV steroid pulses followed by oral medium-dose prednisone preceded the SRC onset. The use of corticosteroids (especially prednisone >15 mg per day) has been identified as a risk factor for SRC, mostly from studies conducted during the 20^th century (9, 10). Furthermore, a more recent report found an association between exposure to prednisone at the SRC onset and increased risk of death (11). One of the main issues is that the precise contribution of steroids may be overestimated and a bias of indication may apply (the risk relates to the patient phenotype that requires the use of corticosteroids) (12). In this regard, two recent studies (13, 14) found that while SSc patients with SRC were more frequently treated with corticosteroids than those without SRC, the association was not confirmed after adjusting for some well-known renal crisis risk factors (e.g., mRSS, PH, erythrocyte sedimentation rate elevation, and low DLCO) (13). Furthermore, Bütikofer et al. (14) highlighted that a dose >15 mg of prednisone equivalents is rarely used in big cohorts, demonstrating the general practice to avoid high-dose glucocorticoids, if not strictly necessary in SSc.

Our two cases aggregate several recognized risk factors for SRC (12, 15): dcSSc subset, large joint contractures, heart enlargement, low DLCO, PH (case 1); dcSS, SSc duration <4 years, low DLCO, possible cardiomyopathy from microcirculatory damage (case 3). However, especially in case 1, the timeline between the initiation of steroid therapy and SRC onset in a patient with not recent onset SSc would appear to suggest a predominant role for steroids. We believe further studies should be conducted in the modern era to clarify the role of steroids in triggering SRC. However, so far, the current European League Against Rheumatism (EULAR) recommendations (16) state that “Several retrospective studies suggest that glucocorticoids are associated with a higher risk of SRC. Blood pressure and renal function should be carefully monitored in patients with SSc treated with glucocorticoids” with a strength of recommendation C.

In the past years, there has been a growing interest about the role of previous exposure to ACE inhibitors in increasing the SRC risk. Recently, this association has been reported by a study from the European Scleroderma Trials and Research group (EUSTAR) database (14). By contrast, Gordon et al. (17) did not find a significant association after adjusting for proteinuria, which was not considered in the EUSTAR study. This may explain, at least partially, why some studies (11, 18) reported a worse outcome (i.e., permanent dialysis and/or death) in patients previously exposed to ACE inhibitors: these drugs might not only mask hypertension causing a delayed SRC diagnosis (as already hypothesized) but they may also constitute a passive marker of renal damage and others risk factors for SRC. In fact, different from previous reports in the literature (15, 19), more recent findings suggest that the presence of chronic kidney disease (CKD) (20) along with a history of systemic hypertension and evidence of proteinuria (13, 20) might all be predictors of SRC. Because Black SSc patients seem to be more likely to develop proteinuria (21), it is important that these data are confirmed in two separate large SSc cohorts including different ethnicities (13, 20). Thus, it has been postulated that proteinuria may arise from an underlying systemic vascular pathology (e.g., evolving scleroderma renal involvement), and this seems plausible given that proteinuria has been recognized as a predictor of 5-year mortality (22). However, it is worth noting that systemic arterial hypertension may result in chronic kidney vasculopathy with proteinuria in some cases, therefore the possibility of a multifactorial damage prior to SRC (i.e., both SSc and non-SSc related) should be taken into account. Despite having no previous systemic hypertension, patient 3 exhibited a slight but steady increase in sCr levels about 6 months before SRC onset, suggesting a possible non-acute, SSc-related renal vasculopathy, which could also explain the presence of diffuse fibrosis on kidney biopsy. Moreover, patient 1 had been suffering from systemic arterial hypertension for several years although no proteinuria had been previously reported.

With regard to autoantibody profiles, all recent studies have unambiguously highlighted anti-RNA-polymerase III positivity (patient 2) as a key marker of high-risk SRC (23, 24), whereas there are conflicting data pertaining to anti-SCl70 (case 1), with some studies reporting its association with SRC (11, 20) and others not (13).

Among other manifestations recently confirmed as risk factors for SRC are the presence of a pulmonary vasculopathy—clinically evident PH (case 1 and similar to a previously reported SRC case (25)) or subclinical as impaired DLCO (case 3)—and cardiac involvement (likely present in all three cases) (20).

Another intriguing point highlighted by our cases 1 and 2, which also emerged from the analysis of Gordon et al. (20), is that the concomitant presence of malignancy may constitute another important precipitating factor for SRC.

SRC generally occurs early during the course of SSc (in 75% of cases within 4 years of disease onset (15)), but it may also be present in patients without a previous diagnosis of SSc, as seen in patient 2. Similar to previous reports (26), the initial symptom in all our patients was an unspecific but very marked new-onset asthenia, which can therefore constitute an alarm bell for SRC in at-risk SSc patients. A few days before SRC onset, patient 1 showed a mild reduction platelet count (92,000/mmc), suggesting thrombocytopenia as an early sign of SRC with microangiopathy.

In the past years, there has been a growing interest in studying the signs of microangiopathy in SRC—detectable in about 40 to 50% of patients (27)—as it relates to the potential pathogenetic mechanisms, the classification of the renal crisis itself, the clinical presentation, and therapeutic options. Yamashita et al. (28) have recently proposed the identification of a SSc-associated thrombotic microangiopathy (SSc-TMA) as a distinct pathophysiological and clinical entity form a narrowly defined SRC (nd-SRC). The authors posit that, SSc-TMA patients present initially with thrombocytopenia, followed by elevated blood pressure and worsening of renal function; by contrast, nd-SRC seems to be characterized by markedly elevated blood pressure and worsening of renal function first, followed by mild thrombocytopenia.

From a pathophysiological standpoint, SSc-TMA during SRC is believed to share some similarities with atypical hemolytic uremic syndrome (aHUS), thus the complement pathway might play an important role (29). In line with this and different from what is proposed for nd-SRC (i.e., conventional ACE inhibitor), therapy with PEx is suggested in SSc-TMA, with the possibility of considering the monoclonal antibody against C5 eculizumab (Alexion Pharma; New Haven, USA) in few selected non-responsive patients (28–30).

Patient 1, in particular, exhibited a clinical and serological presentation of SRC similar to SSc-TMA as hypothesized by Yamashita et al. (28). However, her kidney function improved with ACE inhibitors alone. It is worth noting that malignant hypertension is also a well-known cause of microangiopathy, and thus achieving adequate blood pressure control may have played an important role in resolving microangiopathy in this case. By contrast, PEx did not yield any benefit on renal function for patient 2 whose clinical presentation was more similar to that of nd-SRC, with clear serum markers of peripheral microangiopathy appearing later. Given the presence of typical signs of SSc-TMA at renal biopsy—even though with concomitant diffuse fibrosis—it cannot be excluded that patient 3 could have benefited from PEx and/or eculizumab.

It has been also postulated (28) that steroids may participate in producing a hypercoagulable state and thus exacerbate the microangiopathy, suggesting that SSc-TMA could help explain the worse prognosis in normotensive renal crisis—previously linked to the use of steroids (9, 31). Despite none of our patients had a normotensive SRC, those previously undergoing steroid treatment (case 1 and 3), actually had clearer signs of TMA.

Although helpful in some patients and very intriguing from a speculative standpoint, it is worth noting that a clear distinction between SSc-TMA and nd-SRC cannot be applied in several real-life SRC cases, often characterized by a mixed presentation.

The use of ACE inhibitors and rapid achievement of blood pressure control should remain the cornerstones of the management of patients with SRC. As was the case in patient 3, captopril might be preferred in the early phases due to its short half-life, later replaced by enalapril or ramipril to avoid the former’s side effects (rash, cytopenia, and risk of hypotension) (32, 33). The addition of several other anti-hypertensive drugs in patient 3 was necessary to normalize blood pressure and rapidly improve ongoing renal ischemia. In this regard, calcium channel blockers may be considered first, followed by centrally acting alpha-blockers and diuretics, bearing in mind that diuretics may further stimulate renin release (though they may also be indispensable to force the diuresis in some cases) and alpha-blockers carry an increased risk of hypotension (29). Conversely, beta-blockers should be avoided altogether due to their well-known vasospastic effects on the microcirculation.

About new therapeutic options (34), recent reports have shown some benefits with eculizumab, especially in cases with a predominant SSc-TMA presentation as mentioned earlier (26, 35, 36). Eculizumab is a recombinant humanized monoclonal antibody that binds to the complement component C5, preventing the generation of C5a and C5b-9 and thus lysis and endothelial damage. The main limitations of the use of eculizumab are an increased risk of infections (especially Neisseria and meningococcal infections) and its prohibitive cost (it is among the most expensive drugs in the world) (37, 38). On the other hand, the challenge to determine the optimal therapeutic window and identify the patients who would most benefit from it. With regard to the last point, kidney biopsies can detect deposits of C1q, C3b, C4d, and C5b-9 in the endothelium of renal arterioles and glomeruli (35, 39). In previous studies (8), and as seen in patient 2, PEx appears to resolve the signs of peripheral microangiopathy quite rapidly but seems not to have substantial effect on kidney function in some cases. Furthermore, a delicate hemodynamic balance and the use of ACE inhibitors complicate PEx; thus, it is not universally indicated.

About other possible treatments for SRC—with or without microangiopathy—endothelin receptors antagonists (ERAs) have been considered in recent years (40). Endothelin 1 (ET-1) is strongly involved in renal cell injury, inflammation, and fibrosis leading to CKD (41, 42). Moreover, ET-1 has been found to be over-expressed in kidney biopsies of SRC patients, even more so when compared to patients with other nephropathies (43). ERAs have shown good efficacy in few case reports (44) and in a British pilot study (BIRD-1) (40), in which the dual ERAs bosentan (62.5 mg/twice daily, for 1 month; then 125 mg/twice daily for 5 months) was added to ACE inhibitors within 6 weeks of SRC onset. Compared to patients treated with ACE inhibitors alone, patients treated with bosentan trended toward a better renal function with a reduced frequency of dialysis— though not statistically significant. The authors abstained from drawing definitive conclusions given the small number of patients (six) taking bosentan.

More recently, encouraging results have been reported from a randomized control trial (ZEBRA-1) evaluating the efficacy of the highly selective ERA zibotentan in SRC (45). Over a treatment period of 26 weeks, zibotentan (10 mg/day) was associated with improved eGFR at 52 weeks versus placebo.

The main limitations as it relates to the use of ERAs lie in the ability to accurately identify patients who would benefit the most and the optimal time to initiate the treatment. In fact, ET-1 has been found increased only in kidney biopsy performed within 1 month from SRC onset (43), that is when the hemodynamic state of the patient is more unstable. This must be clearly taken into account because the main side effects of ERAs are fluid retention and systemic hypotension, which may precipitate renal perfusion (42).

Finally, as in patient 3, kidney transplantation should be delayed at least 18 to 24 months after dialysis initiation, because it has been shown that up to 50% of patients with end-stage renal disease due to SRC recover from dialysis after a mean period of 8 to 11 months (6, 46). Transplanted SSc patients exhibited a good survival rate (82.5% at 5 years in data collected between 1987 and 2018) with a very low recurrence rate (1.9 to 5% in the literature) (47).

Conclusion

In conclusion, our cases highlight emblematic issues in the clinical presentation and management of patients with SRC. Despite recent advances, SRC endures as one of the most difficult complications to predict and manage in patients with SSc. Further studies are urgently needed to ascertain the efficacy of emerging therapies such as eculizumab and ERAs.

Main Points.

• Scleroderma renal crisis (SRC) remains today a life-threatening complication of systemic sclerosis (SSc).

• The exact role of steroids in triggering SRC warrants further investigations.

• Angiotensin-converting enzyme (ACE) inhibitors and prompt achievement of blood pressure control remain the cornerstone in the management of SRC.

• The identification of patients in whom thrombotic microangiopathy (TMA) is the main mechanism of SRC is paramount to block microangiopathy as soon as possible.

• In severe SSc-TMA cases, plasma exchange may be taken into consideration.