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DOI: 10.5152/eurjrheum.2020.20048 Invited Review

Scleroderma renal crisis: Case reports and update on critical issues Elisabetta Zanatta1 , Veronica Codullo2 , Yannick Allanore3 Abstract

To date, 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 (ACE) inhibitors and —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 , systemic arterial hyperten- sion, 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 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 units. While describing these patients’ risk factors, clinical presentation, and , we aim to discuss the state of the art in SRC and highlight critical issues. Keywords: Systemic sclerosis, scleroderma renal crisis, microangiopathy, predictors, therapy

ORCID iDs of the authors: Introduction E.Z. 0000-0002-4845-5413; V.C. 0000-0003-2557-8514; Owing to decreased frequency (1, 2) and substantial improvement in survival over time (after the in- Y.A. 0000-0002-6149-0002. troduction of angiotensin-converting enzyme [ACE] inhibitors) (3), scleroderma renal crisis (SRC) is no longer the leading cause of associated with systemic sclerosis (SSc) (4, 5). Nevertheless, the prog- Cite this article as: Zanatta E, Codullo V, Allanore Y. Scleroderma renal crisis: Case nosis remains poor in patients with SSc experiencing SRC, and dialysis is required in about 50% of cases reports and update on critical issues. with a considerably high mortality rate (6, 7). Here, we discuss three emblematic patients recently fol- Eur J Rheumatol November 19, 2020; 10.5152/eurjrheum.2020.20048 [Epub lowed in our tertiary referral to highlight the importance of early diagnosis, discuss predictive Ahead of Print]. factors, and introduce therapeutic strategies that might result in a more benign disease course in the 1 Division of Rheumatology, Department near future. Demographic and clinical data, treatment, and outcome of each patient are summarized of , University of Padova, Padova, Italy in Table 1. 2 Unit of Rheumatology, IRCCS Foundation Policlinico San Matteo, Pavia, Italy All patients gave written informed consent for their anonymized medical information to appear in publica- 3 Department of Rheumatology, Paris Descartes University Cochin , tions and educational material. Paris, France Address for Correspondence: Yannick Allanore; Department of Case discussion Rheumatology, Paris Descartes University Cochin Hospital, Paris, France Case 1 E-mail: [email protected] A 40-year-old Caucasian female was diagnosed in 2012 with the diffuse cutaneous form of systemic sclero- Submitted: April 02, 2020 sis (dcSSc), with anti-topoisomerase I (anti-SCl70) positivity and . Accepted: July 12, 2020 Available Online Date: November 19, 2020 Copyright@Author(s) - Available online at A mild interstitial disease (ILD) was detected in 2017 and following a lung (late 2018), www.eurjrheumatol.org. lung progressed radiologically and functionally, which prompted a switch from methotrexate Content of this journal is licensed under a Creative to mycophenolate mofetil, plus a cycle of intravenous (IV) in March 2019. Meanwhile, a trans- Commons Attribution-NonCommercial 4.0 International License. thoracic 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). Zanatta et al. Update on scleroderma renal crisis Eur J Rheumatol 2020

The patient’s past included tion progressively worsened (sCr peaked at 396 no longer possible. The patient died sudden- arterial hypertension treated with calcium μmol/L and BUN 48 mmol/L) ​​requiring hemo- ly 8 months later, probably due to malignant channel blockers (since 2011) and left breast dialysis (3 sessions overall). Concurrently, signs arrhythmia. adenocarcinoma human epidermal growth of microangiopathy recovered. factor 2 (HER2) positivity (2013) treat- Case 3 ed with mastectomy, hormone therapy, and She was discharged with sCr 249 μmol/L and A 71-year-old Caucasian female was diagnosed and for bone and liver therapy with (5 mg daily). Six months in June 2018 with , PM-Scl100 metastases. A magnetic resonance imaging later, she had sCr 128 μmol/L (estimated glo- positive with dcSSc, telangiectasia, and myosi- (MRI) in May 2019 also revealed brain metas- merular filtration rate [EGFR] 43 mL/min/mq), tis (creatine phosphokinase [CPK] up to 2500 tases treated with radiotherapy plus two ste- requiring low-dose furosemide (40 mg/daily), UI/L with evidence of muscle at MRI). roid —methylprednisolone 120 mg/day also indicated for a concomitant mild right Although high-sensitive troponin levels were in early May and medium-dose ventricular elevated pressure due to PH. elevated, cardiac MRI and positron emission continued orally. During an outpatient visit in tomography showed no signs of active myo- late May, she complained of mild asthenia; her Case 2 carditis with evidence of previous lower apical blood pressure was 150/90 mm Hg; and blood A 61-year-old Caucasian male, with no sig- ischemia. Pulmonary function tests revealed tests revealed a minimal increase in serum cre- nificant prior , was hospitalized in a significant reduction of diffusing capacity atinine (sCr, 95 μmol/L), with a mildly reduced March 2016 for melena and . Gastros- for carbon monoxide (DLCO) (37%) with pre- platelet count (92,000/µl). In early June, the copy with histologic examination revealed a served lung volumes but no radiological signs patient reported a worsening of asthenia and stenosing and bleeding mass at the antrum of ILD or PH. After excluding any paraneoplas- dyspnea, and blood tests showed evidence and body of the stomach (adenocarcinoma), tic etiology, the patient was treated with IV of acute renal failure (sCr 245 μmol/L, blood whereupon the patient underwent a total pulses of methylprednisolone (1 g×3) in late urea nitrogen [BUN] 36.1 mmol/L), and signs gastrectomy and until August July, followed by oral prednisone (15 mg/daily) of peripheral microangiopathy consisting of 2016. A routine in December 2016 and methotrexate, resulting in a progressive anemia (hemoglobin [Hb] 8.8 g/dL), a further revealed sCr 184 μmol/L, which nearly dou- normalization of myocytolysis indices. Starting deterioration of (68.000/ bled in January 2017 (311 μmol/L, eGFR 18 mid-November 2018, she complained of mild µl), decreased haptoglobin with increased mL/min/mq) with concomitant anemia (Hb asthenia and blood tests showed a slight but lactate dehydrogenase (LDH) levels (<0.10 g/ 9.9 g/dL). Evidence of mild leg edema and steady increase of sCr (100 μmol/L; normal dL and 985 UI/L, respectively), and presence blood pressure of 160/85 mmHg prompted values ≤80 μmol/L vs. 59 μmol/L in June, 71 of blood schistocytes (5.5%). Direct Coombs an urgent referral. At this time, μmol/L in July and 90 μmol/L in September). In and antineutrophilic cytoplasmic the patient also reported experiencing asthe- mid-December, she presented with high blood (ANCA) were negative. A disintegrin-like and nia and hand during the past pressure (170/100 mmHg), oliguria (sCr in- metalloproteinase with thrombospondin type 2 months. In late February, he was rushed creased to 357 μmol/L with BUN 29.5 mmol/L), 1 motif 13 (ADAMTS 13) activity was normal, to the hospital for a rapid worsening of dys- and early signs of microangiopathy (thrombo- and ADAMTS13 inhibitor was negative. At the pnea, with evidence of respiratory and heart cytopenia, undetectable haptoglobin, and in- time of admission, the patient presented with failure, and blood pressure 170/100 mm Hg. creased LDH). At the time of admission to the systemic arterial hypertension (190/110 mm Blood tests showed sCr 650 μmol/L with BUN Nephrology Unit, the patient clinically present- Hg) with preserved , and a diagnosis of 38 mmol/L and anemia (Hb 8.8 g/dL). Signs ed fluid retention with signs of heart failure hypertensive SRC was established. She initial- of microangiopathy also appeared 1 week lat- requiring high-dose IV diuretics and ACE inhib- ly received IV urapidil, followed by ramipril (5 er: mild thrombocytopenia (101,000/µl) with itors under suspicion of SRC, first captopril later mg/twice daily) + amlodipine (Table 1). In the undetectable haptoglobin and increased replaced by ramipril. However, arterial blood 10 days following the SRC onset, kidney func- LDH 390 U/L; blood schistocytes were absent. pressure control was only achieved by adding A transthoracic echocardiography showed a urapidil, rilmenidine, and amlodipine. Renal Main Points pericardial effusion and PH, while chest X-rays ultrasound and MRI were substantially normal, revealed a bilateral pleural effusion partially while a kidney biopsy revealed glomerular le- • Scleroderma renal crisis (SRC) remains today a life-threatening complication of responsive to high-dose diuretics. sions suggestive of SRC with thrombotic mi- systemic sclerosis (SSc). croangiopathy and evidence of diffuse intersti- A rheumatology assessment showed diffuse tial fibrosis (75% of the cortical surface) (Figure The exact role of steroids in triggering • thickening (modified Rodnan Skin Score, 1). Despite signs of improving peripheral mi- SRC warrants further investigations. mRSS 35) with melanoderma, telangiectasia on croangiopathy, renal function progressively • Angiotensin-converting enzyme (ACE) the face and flexion contractures of the fingers, worsened after a month (sCr up to 707 μmol/L inhibitors and prompt achievement of and a positive anti-RNA-polymerase III anti- and BUN 35 mmol/L), requiring hemodialysis. blood pressure control remain the cor- body test. Thus, a diagnosis of dcSSc compli- At present, the patient is undergoing dialysis nerstone in the management of SRC. cated by SRC with mild microangiopathy was three times a week and is on a low-dose ACE • The identification of patients in whom established and treated with ramipril (5 mg/ inhibitor and is being evaluated for inclusion thrombotic microangiopathy (TMA) twice daily). Plasma exchange (PEx) was initi- on the kidney transplantation list. is the main mechanism of SRC is par- ated following a previously reported treatment amount to block microangiopathy as protocol (8). Nevertheless, renal function wors- Clinical and research consequences soon as possible. ened (max values ​​sCr 755 μmol/L and BUN In two out of three patients (1 and 3), the ad- 50.5 mmol/L) requiring hemodialysis. Unfortu- ministration of IV steroid pulses followed by In severe SSc-TMA cases, plasma ex- • nately, despite PEx and long-term therapy with oral medium-dose prednisone preceded the change may be taken into consideration. ACE inhibitors, discontinuation of dialysis was SRC onset. The use of corticosteroids (especial- Eur J Rheumatol 2020 Zanatta et al. Update on scleroderma renal crisis

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 6 months (likely few months) Cutaneous form dcSSc dcSSc dcSSc specificity Anti-topoisomerase I Anti-RNApolymerase III PM-Scl100 Other risk factors for SRC Steroids, large joint contractures, low DLCO, suspected SSc Steroids, low DLCO, suspected heart enlargement, PH, low DLCO cardiomyopathy 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 Labetalol, amlodipine - Labetalol, rilmenidine to achieve pressure control 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.

the association was not confirmed after adjust- a b ing 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 prac- tice to avoid high-dose , if not strictly necessary in SSc.

Our two cases aggregate several recognized risk factors for SRC (12, 15): dcSSc subset, c d large joint contractures, heart enlargement, low DLCO, PH (case 1); dcSS, SSc duration <4 years, low DLCO, possible cardiomyopathy from microcirculatory damage (case 3). How- ever, 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 ste- roids. We believe further studies should be conducted in the modern era to clarify the role Figure 1. a-d. Kidney biopsy of a 71-year-old Caucasian female affected with scleroderma renal of steroids in triggering SRC. However, so far, crisis (case 3): interstitial fibrosis (a), double contour of the glomerular basement membrane the current European League Against Rheuma- (b), fibrosis and intimal proliferation with obliteration of the arteriolar lumen (c, d). Masson’s tri- tism (EULAR) recommendations (16) state that chrome stain, original magnification ×50 (a), ×400 (b-d). “Several retrospective studies suggest that glu- ly prednisone >15 mg per day) has been iden- tribution of steroids may be overestimated and cocorticoids are associated with a higher risk of tified as a risk factor for SRC, mostly from stud- a bias of indication may apply (the risk relates SRC. Blood pressure and renal function should be carefully monitored in patients with SSc ies conducted during the 20th century (9, 10). to the patient phenotype that requires the use treated with glucocorticoids” with a strength of Furthermore, a more recent report found an as- of corticosteroids) (12). In this regard, two re- recommendation C. sociation between exposure to prednisone at cent studies (13, 14) found that while SSc pa- the SRC onset and increased risk of death (11). tients with SRC were more frequently treated In the past years, there has been a growing in- One of the main issues is that the precise con- with corticosteroids than those without SRC, terest about the role of previous exposure to Zanatta et al. Update on scleroderma renal crisis Eur J Rheumatol 2020

ACE inhibitors in increasing the SRC risk. Re- DLCO (case 3)—and cardiac involvement (like- ACE inhibitors alone. It is worth noting that cently, this association has been reported by ly present in all three cases) (20). malignant hypertension is also a well-known a study from the European Scleroderma Trials cause of microangiopathy, and thus achieving and Research group (EUSTAR) database (14). By Another intriguing point highlighted by our adequate blood pressure control may have contrast, Gordon et al. (17) did not find a sig- cases 1 and 2, which also emerged from the played an important role in resolving microan- nificant association after adjusting for - analysis of Gordon et al. (20), is that the con- giopathy in this case. By contrast, PEx did not uria, which was not considered in the EUSTAR comitant presence of malignancy may consti- yield any benefit on renal function for patient study. This may explain, at least partially, why tute another important precipitating factor for 2 whose clinical presentation was more similar some studies (11, 18) reported a worse out- SRC. to that of nd-SRC, with clear serum markers of come (i.e., permanent dialysis and/or death) in peripheral microangiopathy appearing later. patients previously exposed to ACE inhibitors: SRC generally occurs early during the course of Given the presence of typical signs of SSc-TMA these drugs might not only mask hypertension SSc (in 75% of cases within 4 years of disease at renal biopsy—even though with concom- causing a delayed SRC diagnosis (as already onset (15)), but it may also be present in pa- itant diffuse fibrosis—it cannot be excluded hypothesized) but they may also constitute a tients without a previous diagnosis of SSc, as that patient 3 could have benefited from PEx passive marker of renal damage and others risk seen in patient 2. Similar to previous reports and/or eculizumab. factors for SRC. In fact, different from previous (26), the initial symptom in all our patients reports in the literature (15, 19), more recent was an unspecific but very marked new-on- It has been also postulated (28) that steroids findings suggest that the presence of chronic set asthenia, which can therefore constitute may participate in producing a hypercoagu- kidney disease (CKD) (20) along with a history an alarm bell for SRC in at-risk SSc patients. A lable state and thus exacerbate the microan- of systemic hypertension and evidence of pro- few days before SRC onset, patient 1 showed giopathy, suggesting that SSc-TMA could help teinuria (13, 20) might all be predictors of SRC. a mild reduction platelet count (92,000/mmc), explain the worse prognosis in normotensive Because Black SSc patients seem to be more suggesting thrombocytopenia as an early sign renal crisis—previously linked to the use of ste- likely to develop proteinuria (21), it is important of SRC with microangiopathy. roids (9, 31). Despite none of our patients had a that these data are confirmed in two separate normotensive SRC, those previously undergo- large SSc cohorts including different ethnicities In the past years, there has been a growing ing steroid treatment (case 1 and 3), actually (13, 20). Thus, it has been postulated that pro- interest in studying the signs of microangiop- had clearer signs of TMA. teinuria may arise from an underlying systemic athy in SRC—detectable in about 40 to 50% vascular (e.g., evolving scleroderma of patients (27)—as it relates to the potential Although helpful in some patients and very renal involvement), and this seems plausible pathogenetic mechanisms, the classification of intriguing from a speculative standpoint, it is given that proteinuria has been recognized as the renal crisis itself, the clinical presentation, worth noting that a clear distinction between a predictor of 5-year mortality (22). However, it and therapeutic options. Yamashita et al. (28) SSc-TMA and nd-SRC cannot be applied in sev- is worth noting that systemic arterial hyperten- have recently proposed the identification of eral real-life SRC cases, often characterized by a sion may result in chronic kidney vasculopathy a SSc-associated thrombotic microangiopa- mixed presentation. with proteinuria in some cases, therefore the thy (SSc-TMA) as a distinct pathophysiological possibility of a multifactorial damage prior to and clinical entity form a narrowly defined SRC The use of ACE inhibitors and rapid achieve- SRC (i.e., both SSc and non-SSc related) should (nd-SRC). The authors posit that, SSc-TMA pa- ment of blood pressure control should re- be taken into account. Despite having no pre- tients present initially with thrombocytopenia, main the cornerstones of the management of vious systemic hypertension, patient 3 exhib- followed by elevated blood pressure and wors- patients with SRC. As was the case in patient ited a slight but steady increase in sCr levels ening of renal function; by contrast, nd-SRC 3, captopril might be preferred in the early about 6 months before SRC onset, suggesting seems to be characterized by markedly ele- phases due to its short half-life, later replaced a possible non-acute, SSc-related renal vascu- vated blood pressure and worsening of renal by enalapril or ramipril to avoid the former’s lopathy, which could also explain the presence function first, followed by mild thrombocyto- (, cytopenia, and risk of hypo- of diffuse fibrosis on kidney biopsy. Moreover, penia. tension) (32, 33). The addition of several other patient 1 had been suffering from systemic ar- anti-hypertensive drugs in patient 3 was nec- terial hypertension for several years although From a pathophysiological standpoint, SSc- essary to normalize blood pressure and rapidly no proteinuria had been previously reported. TMA during SRC is believed to share some improve ongoing renal ischemia. In this regard, similarities with atypical hemolytic uremic syn- calcium channel blockers may be considered With regard to autoantibody profiles, all recent drome (aHUS), thus the complement pathway first, followed by centrally acting alpha-block- studies have unambiguously highlighted an- might play an important role (29). In line with ers and diuretics, bearing in mind that diuretics ti-RNA-polymerase III positivity (patient 2) as a this and different from what is proposed for may further stimulate renin release (though key marker of high-risk SRC (23, 24), whereas nd-SRC (i.e., conventional ACE inhibitor), ther- they may also be indispensable to force the there are conflicting data pertaining to an- apy with PEx is suggested in SSc-TMA, with the diuresis in some cases) and alpha-blockers ti-SCl70 (case 1), with some studies reporting possibility of considering the monoclonal anti- carry an increased risk of (29). its association with SRC (11, 20) and others not body against C5 eculizumab (Alexion Pharma; Conversely, beta-blockers should be avoided (13). New Haven, USA) in few selected non-respon- altogether due to their well-known vasospastic sive patients (28-30). effects on the microcirculation. Among other manifestations recently con- firmed as risk factors for SRC are the presence Patient 1, in particular, exhibited a clinical and About new therapeutic options (34), recent of a pulmonary vasculopathy—clinically evi- serological presentation of SRC similar to SSc- reports have shown some benefits with eculi- dent PH (case 1 and similar to a previously re- TMA as hypothesized by Yamashita et al. (28). zumab, especially in cases with a predominant ported SRC case (25)) or subclinical as impaired However, her kidney function improved with SSc-TMA presentation as mentioned earlier (26, Eur J Rheumatol 2020 Zanatta et al. Update on scleroderma renal crisis

35, 36). Eculizumab is a recombinant human- opsy performed within 1 month from SRC on- agement. Joint Bone Spine 2019; 87: 293-9. ized that binds to the set (43), that is when the hemodynamic state [Crossref] complement component C5, preventing the of the patient is more unstable. This must be 6. Penn H, Howie AJ, Kingdon EJ, Bunn CC, Strat- generation of C5a and C5b-9 and thus lysis and clearly taken into account because the main ton RJ, Black CM, et al. Scleroderma renal crisis: Patient characteristics and long-term out- endothelial damage. The main limitations of side effects of ERAs are fluid retention and comes. QJM 2007; 100: 485-94. the use of eculizumab are an increased risk of systemic hypotension, which may precipitate [Crossref] 7. Teixeira L, Mouthon L, Mahr A, Berezné A, Agard (especially Neisseria and meningo- renal perfusion (42). C, Mehrenberger M, et al. Mortality and risk fac- coccal infections) and its prohibitive cost (it is tors of scleroderma renal crisis: A French retro- among the most expensive drugs in the world) Finally, as in patient 3, kidney transplantation spective study of 50 patients. Ann Rheum Dis (37, 38). On the other hand, the challenge to should be delayed at least 18 to 24 months af- 2008; 67: 110-6. [Crossref] determine the optimal therapeutic window ter dialysis initiation, because it has been shown 8. Cozzi F, Marson P, Cardarelli S, Favaro M, Tison and identify the patients who would most ben- that up to 50% of patients with end-stage renal T, Tonello M, et al. Prognosis of scleroderma efit from it. With regard to the last point, kidney disease due to SRC recover from dialysis after a renal crisis: A long-term observational study. biopsies can detect deposits of C1q, C3b, C4d, mean period of 8 to 11 months (6, 46). Trans- Nephrol Dial Transplant 2012; 27: 4398-403. and C5b-9 in the endothelium of renal arteri- planted SSc patients exhibited a good survival [Crossref] 9. Helfrich DJ, Banner B, Steen VD, Medsger TA. oles and glomeruli (35, 39). In previous studies rate (82.5% at 5 years in data collected between Normotensive renal failure in systemic sclerosis. (8), and as seen in patient 2, PEx appears to re- 1987 and 2018) with a very low recurrence rate Arthritis Rheum 1989; 32: 1128-34. [Crossref] solve the signs of peripheral microangiopathy (1.9 to 5% in the literature) (47). 10. Steen VD, Medsger TA. Case-control study of quite rapidly but seems not to have substantial corticosteroids and other drugs that either effect on kidney function in some cases. Fur- Conclusion precipitate or protect from the development of thermore, a delicate hemodynamic balance In conclusion, our cases highlight emblematic scleroderma renal crisis. Arthritis Rheum 1998; and the use of ACE inhibitors complicate PEx; issues in the clinical presentation and man- 41: 1613-9. [Crossref] thus, it is not universally indicated. agement of patients with SRC. Despite recent 11. Hudson M, Baron M, Tatibouet S, Furst DE, Khan- advances, SRC endures as one of the most dif- na D, Hummers L, et al. Exposure to ACE inhibi- About other possible treatments for SRC— ficult complications to predict and manage in tors prior to the onset of scleroderma renal cri- sis-results from the international scleroderma with or without microangiopathy—endothe- patients with SSc. Further studies are urgently renal crisis survey. Semin Arthritis Rheum 2014; lin receptors antagonists (ERAs) have been needed to ascertain the efficacy of emerging 43: 666-72. [Crossref] considered in recent years (40). Endothelin 1 such as eculizumab and ERAs. 12. DeMarco PJ, Weisman MH, Seibold JR, Furst (ET-1) is strongly involved in renal cell injury, DE, Wong WK, Hurwitz EL, et al. Predictors and , and fibrosis leading to CKD (41, Peer-review: Externally peer-reviewed. outcomes of scleroderma renal crisis: The high- 42). Moreover, ET-1 has been found to be over- dose versus low-dose D-penicillamine in early expressed in kidney biopsies of SRC patients, Author Contributions: Conception - E.Z., V.C., Y.A.; Su- diffuse systemic sclerosis trial. Arthritis Rheum pervision - E.Z., V.C.; Resources - E.Z., V.C., Y.A.; Writing even more so when compared to patients with 2002; 46: 2983-9. [Crossref] Manuscript - E.Z., V.C., Y.A. other nephropathies (43). ERAs have shown 13. Moinzadeh P, Kuhr K, Siegert E, Blank N, Sunder- good efficacy in few case reports (44) and in koetter C, Henes J, et al. Scleroderma renal crisis: Acknowledgments: For the images of the kidney bi- Risk factors for an increasingly rare organ com- a British pilot study (BIRD-1) (40), in which the opsy, the authors want to thank Camille Cohen (Ne- plication. J Rheumatol 2020; 47: 241-8. [Cross- dual ERAs bosentan (62.5 mg/twice daily, for 1 phrology Unit) and Marion Rabant (Pathology Unit), ref] month; then 125 mg/twice daily for 5 months) Necker Hospital, Paris. 14. Bütikofer L, Varisco PA, Distler O, Kowal-Bielec- was added to ACE inhibitors within 6 weeks of ka O, Allanore Y, Riemekasten G, et al. ACE in- SRC onset. Compared to patients treated with Conflict of Interest: The authors have no conflict of hibitors in SSc patients display a risk factor for ACE inhibitors alone, patients treated with interest to declare. scleroderma renal crisis-a EUSTAR analysis. Ar- bosentan trended toward a better renal func- thritis Res Ther 2020; 22: 59. 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