Clinical Nephrology, Vol. 80 – No. 4/2013 (293-297) Differentiating scleroderma renal crisis from other causes of thrombotic microangiopathy in a postpartum patient Neph Education Muaz Abudiab1, Megan L. Krause1, Mary E. Fidler2, Karl A. Nath3 and 3 ©2013 Dustri-Verlag Dr. K. Feistle Suzanne M. Norby ISSN 0301-0430 DOI 10.5414/CN107465 1Department of Internal Medicine, 2Department of Laboratory Medicine and e-pub: May 14, 2012 Pathology, and 3Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA Key words Abstract. Thrombotic thrombocytopenic of large von Willebrand factor multimers in thrombotic microangio­ purpura (TTP), hemolytic uremic syndrome idiopathic TTP was ascribed to deficiency of pathy – scleroderma – (HUS), and scleroderma renal crisis (SRC) the von Willebrand factor-cleaving protease postpartum – mixed all present with features of thrombotic mi- (ADAMTS13) enzyme [3]. Hemolytic ure- connective tissue croangiopathy. Distinguishing among these disease entities is critical, however, as treatments mic syndrome (HUS) is most often associated differ and may be mutually exclusive. We with infection by Escherichia coli 0157:H7, describe the case of a 25-year-old woman which produces a verotoxin that mediates en- with an undefined mixed connective tissue dothelial damage. Increasingly, atypical forms disease who presented 6 weeks post-partum of HUS (aHUS) are recognized to result from with fever, transient aphasia, thrombocyto- penia, hemolytic anemia, and acute kidney disorders of complement regulation, includ- injury eventually requiring initiation of he- ing antibodies to or mutations in the genes modialysis. Renal biopsy revealed thrombot- encoding complement factors B, H, and I as ic microangiopathy. Renal function did not well as cell surface marker CD46, comple- improve despite immediate initiation of plas- ment component 3 (C3), and thrombomodu- ma exchange, and an angiotensin-converting lin [4]. Pathological specimens from target or- enzyme (ACE) inhibitor was initiated fol- lowing discontinuation of plasma exchange. gans (kidneys, cerebral vasculature, and skin) At last follow up, she remained dialysis de- reveal thrombotic microangiopathy (TMA). pendent. Due to the myriad causes of throm- This finding is seen in a number of process- botic microangiopathy and potential for di- es, including malignant hypertension, tumor agnostic uncertainty, the patient’s response cell embolism, paroxysmal nocturnal hemo- to therapy should be closely monitored and used to guide modification of therapy. globinuria, humoral rejection in transplanted organs, antiphospholipid antibody syndrome, postpartum state, drug-mediated endothelial damage, and scleroderma renal crisis (SRC) Introduction [5]. SRC results in new onset of significant systemic hypertension and renal dysfunction Thrombotic microangiopathies are a di- [6]. Early treatment with angiotensin-con- verse group of disorders that clinically present verting enzyme (ACE) inhibitors has reduced in a similar manner. Thrombotic thrombocyto- 12-month mortality of SRC to less than 15% Received penic purpura (TTP), first described in 1924, [7]. Distinguishing other causes of TMA from September 21, 2011; is a rare but potentially lethal condition [1]. SRC can be difficult. However, simultaneous accepted in revised form The diagnosis is made clinically and is classi- therapy with plasma exchange and an ACE February 6, 2012 cally characterized by a pentad of thrombocy- inhibitor is contraindicated due to the poten- Correspondence to topenia, microangiopathic hemolytic anemia, tial for developing a bradykinin-mediated Muaz M. Abudiab, MD transient neurological symptoms, renal dys- reaction resulting in severe hypotension [8]. Mayo Clinic, 200 First function, and fever. Although the introduc- Existing literature discussing the diagnostic Street SW, Rochester, tion of therapeutic plasma exchange in the difficulty in differentiating other causes of MN 55905, USA Abudiab.Muaz@ 1970’s has improved survival rates, mortality TMA, such as post-partum TTP, from SRC is mayo.edu remains 10 – 20% [2]. In 1998, the presence scarce [9]. Herein, we report the 6th case of Abudiab, Krause, Fidler et al. 294 scleroderma renal crisis (with overlap features of TTP) in mixed connective tissue disease (MCTD) [10, 11, 12, 13, 14], but only the sec- ond in the postpartum period. Case report A 25-year-old woman with mixed con- nective tissue disease (MCTD) presented to another institution 6 weeks post-partum with low-grade fever, generalized malaise, nausea, and dyspnea on exertion. Two tran- Figure 1. Laboratory data during clinical course. sient episodes of aphasia with bilateral low- er facial weakness were also reported. She had recently been restarted on prednisone 40 mg daily after developing dyspnea and pleuritis, thought to be an exacerbation of MCTD, which was characterized by positive antinuclear antibodies, anti-Smith antibody, and anti-ribonucleoprotein antibody. Anti- topoisomerase antibodies (anti-Scl-70) and anti-centromere antibodies were negative. Upon presentation, she had uncontrolled hypertension, periorbital edema, and livedo reticularis. On admission to our institution, she was noted to have non-oliguric acute kid- ney injury with serum creatinine 4.3 mg/dl, nephrotic range proteinuria, normocytic ane- mia with hemoglobin 10.4 g/dl, and throm- bocytopenia with a platelet count of 63 × 109/l. As illustrated in Figure 1, the anemia Figure 2. Masson’s trichrome stain (× 40) show­ ing glomerulus with segmental thrombosis and me­ and thrombocytopenia were progressive, and sangiolysis. lactate dehydrogenase (LDH) was elevated. Haptoglobin level was low at 23 mg/dl. Complement levels were normal. Rare schis- tocytes were seen on peripheral blood smear, consistent with hemolysis. A renal biopsy was performed, revealing active and chronic thrombotic microangiopathy (Figure 2) by light microscopy processed urgently. In view of recent neurologic symptoms, acute kidney injury, thrombocytopenia, microangiopathic hemolytic anemia, and history of low grade fever, a presumptive diagnosis of TTP was made. Plasma exchange was initiated emer- gently, and prednisone was increased to 80 mg daily with subsequent improvement in platelet count and LDH. In addition, hemo- dialysis was initiated for worsening kidney injury. After four sessions of plasma exchange, Figure 3. Jones’ methenamine silver stain (× 40) showing renal artery with prominent myxoid intimal however, LDH began to rise despite nor- thickening malization of haptoglobin and resolution of Scleroderma renal crisis vs. other causes of thrombotic microangiopathy 295 Table 1. Comparison of common clinical characteristics of causes of peripartum TMA [17, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34]. TTP “Typical” Atypical HUS Pre­eclampsia HELLP SRC APS HUS Clinical Fever, HTN, Abdominal None or HTN, nausea, Abdominal Dyspnea, HTN, arterial and presentation neurologic pain, bloody non-specific vomiting, pain, altered venous symptoms, diarrhea due prodrome with abnormal headache, mentation, HTN thromboses, fetal bleeding, to verotoxin­ malaise, fatigue, vision malaise, demise purpuric rash production; upper respiratory nausea, neurologic symptoms vomiting, symptoms HTN possible Typical MAHA, MAHA, MAHA, Proteinuria, MAHA, MAHA, MAHA, laboratory ↓platelets, ↓platelets, ↓platelets, hyperuricemia ↑AST, AKI, ↓platelets, findings AKI, AKI, AKI, ↓platelets proteinuria, AKI, proteinuria, proteinuria, proteinuria, proteinuria, hematuria hematuria, hematuria hematuria hematuria, antiphospholipid ↓complement antibodies Other Low level of Stool Abnormalities of MAHA, AKI, AKI Autoantibodies Autoantibodies possible ADAMTS13 culture complement regu­ and ↑AST may suggestive of suggestive of laboratory positive for latory proteins occur in scleroderma SLE findings verotoxin­ (Factors B, H, severe producing and I, MCP, C3, pre­eclampsia E. coli thrombomodulin) Occurrence Rare; Rare; Rare; post­partum > 20 weeks > 20 weeks Unclear; > 24 1/3 of cases and timing generally < post­partum gestation; gestation; weeks reported during related to 23 – 26 occasionally occasionally gestation when pregnancy or pregnancy weeks postpartum postpartum observed postpartum gestation period Treatment Plasma Supportive Plasma ex­ Anti­HTN Delivery ACE­inhibitor Anticoagulation, exchange, change, therapy; when therapy plasma steroids, eculizumab severe, exchange rituximab magnesium sulfate and delivery Renal ESRD is rare CKD in ESRD in Low risk of ESRD is rare ESRD in 20% ESRD is rare prognosis (0 – 6%) 5 – 25% 20 – 60% ESRD (~ 8%) (0 – 2%) treated with (few case ACE­inhibitor reports) TMA = thrombotic microangiopathy; TTP = thrombotic thrombocytopenic purpura; HUS = hemolytic uremic syndrome; SRC = sclero­ derma renal crisis; APS = antiphospholipid antibody syndrome; HELLP = hemolysis, elevated liver enzymes, low platelets; HTN = hypertension; MAHA = microangiopathic hemolytic anemia; AKI = acute kidney injury; AST = aspartate aminotransferase; ADAMTS = a disintegrin­like and metalloprotease with thrombospondin type 1 motif; MCP = membrane cofactor protein; SLE = systemic lupus erythematosus; ACE = angiotensin converting enzyme; ESRD = end­stage renal disease; CKD = chronic kidney disease. schistocytes on peripheral smear (Figure 1). Discussion The ADAMTS13 level, sent prior to initia- tion of plasma exchange, returned as normal. This case illustrates the diagnostic dif- As the patient’s course evolved, the concern ficulty in differentiating