Use of eculizumab in pregnancy-associated atypical hemolytic uremic syndrome

Introduction

Pregnancy-associated atypical hemolytic uremic syndrome (p-aHUS) is a rare disorder characterized by hemolysis, thrombocytopenia and ischemic end-organ damage in the form of acute kidney injury [1]. A rapid diagnosis is critical but challenging as the features of p-aHUS can mimic other postpartum complications. A disintegrin and metalloproteinase with thrombospondin type 1 motif 13 (ADAMTS13) assay is instrumental in differentiating atypical HUS (aHUS) from thrombotic thrombocytopenic purpura (TTP). Early initiation of eculizumab, a terminal complement inhibitor, has been associated with a rapid recovery of acute kidney injury in cases of aHUS. We present an unusual case of a 37-year-old primigravida who developed p-aHUS in the setting of hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome, ultimately successfully treated with eculizumab. She received a total of six doses of eculizumab and remained in remission at 12 months postpartum.

Case presentation

The patient is a 37-year-old primigravida with an unremarkable medical history and prenatal course who presented in active labor at term. She underwent an uncomplicated vaginal delivery with an estimated blood loss of 200 mL. She delivered a healthy baby girl with a weight of 2620 g and APGAR scores of 9 and 9 at 1 and 5 min, respectively. Her blood pressures were normal intrapartum.

One hour post-delivery, the patient reported a sudden-onset severe headache and 10/10 right upper quadrant pain. She was found to have severe range blood pressures to a maximum of 192/85. She received incrementally higher doses of intravenous (IV) labetalol hydrochloride and hydralazine for blood pressure control. Magnesium for seizure prophylaxis was initiated for pre-eclampsia with severe features. The patient’s right upper quadrant pain continued to worsen, and due to concerns of HELLP syndrome and possible liver capsule compromise, an abdominal ultrasound of the liver was performed, revealing unremarkable hepatic anatomy. A urine protein-to-creatinine ratio returned elevated at 2.1 (normal reference range <0.3). (For additional laboratory values see Figure 1.)

Figure 1:

Summary of the laboratory values.

On postpartum day (PPD) #1, the patient was noted to have severe jaundice. Acute fatty liver of pregnancy was considered, as total bilirubin was elevated at 2.6 mg/dL (44.5 μmol/L) (normal reference range 0.1–1.2 mg/dL); however, glucose and fibrinogen were within the normal range. Our primary suspicion was HELLP syndrome as aspartate aminotransferase (AST) returned to 41.8 μkat/L (2145 U/L) (normal reference range 0–45 U/L) and lactate dehydrogenase (LDH) was (41.8 μkat/L) (>2500 U/L) (reference range <260 U/L). She intermittently required 3 L of oxygen; a lung exam was consistent with pulmonary edema. Creatinine had jumped to 0.019 g/L (1.9 mg/dL) (normal reference range 0.6–1.1 mg/dL). To bolster her dramatically dropping platelets which had reached a nadir of 22 K/μL (22,000 U/L) (normal reference range >150,000 U/L), she was started on a 48-h course of IV dexamethasone. Her blood pressures responded to oral labetalol 200 mg twice daily; however, her subsequent laboratory results continued to worsen.

On PPD #2, her creatinine climbed to 0.032 g/L (3.2 mg/dL) and AST remained elevated at 19 μkat/L (1139 U/L). Haptoglobin was <6 and a peripheral smear showed schistocytes, consistent with hemolysis. Our differential diagnoses broadened to include thrombotic thrombocytopenic purpura (TTP) and HUS. With nephrology recommendation, the patient underwent total plasma exchange (TPE) on PPD #3 and #4. Despite rising creatinine, her urine output remained excellent and she remained free of electrolyte abnormalities. Her complement levels were low: C3 was 0.58 g/L (58 mg/dL) (normal reference range 79–152 mg/dL) and C4 was 0.15 g/L (15 mg/dL) (normal reference range 16–38 mg/dL).

Although the patient’s platelet counts, liver function tests, and LDH were improving, her creatinine continued to rise. Thus, on PPD #5, treatment with eculizumab 900 mg IV was initiated for working diagnosis of p-aHUS. In preparation, she was vaccinated against meningococcus and placed on ciprofloxacin prophylaxis. Creatinine peaked at 0.057 g/L (5.7 mg/dL) on PPD #6. ADAMTS13 activity eventually resulted as normal at 51%, supporting a diagnosis of p-aHUS. On PPD #11, she received a second dose of eculizumab. On PPD #14, creatinine remained improved and she was discharged home.

As an outpatient, she received eculizumab biweekly until PPD #46. As she was no longer postpartum and all sequelae of HELLP syndrome had resolved, treatment was discontinued after six total doses. At 2, 6 and 12 months postpartum, her creatinine remained at baseline (0.007 g/L). She ultimately pursued complement gene mutation testing which was negative.

Discussion

p-aHUS arises from an uncontrolled alternative complement pathway activation leading to diffuse endothelial damage. The formation of the resulting fibrin and platelet microthrombi in the vasculature leads to hemolysis, thrombocytopenia and ischemic end-organ damage in the form of acute kidney injury [2], [3], [4], [5]. Triggers for hyperactivation of the complement pathway include infection, inflammation, malignancy, endothelium-affecting drugs and maternal-fetal hemorrhage [5]. New evidence suggests that excessive complement activation in aHUS may be due to mutations in the complement genes that control activation or regulation of the alternative complement pathway, including complement factor H (CFH), membrane cofactor protein (CD46, previously known as MCP), complement factor I (CFI), complement factor B (CFB) and complement component 3 (C3). Most p-aHUS cases occur in the postpartum period [3], [7], though antepartum cases have been reported in the literature. Outcomes of untreated aHUS are poor: up to 50% of patients with aHUS progress to end-stage renal disease within a year and 25% die during the acute phase [4], [6].

Rapid diagnosis of p-aHUS is critical but challenging in the postpartum period as its features are similar to those of other diseases. Thrombocytopenia, microangiopathic hemolytic anemia and acute renal failure are also seen in TTP, HELLP syndrome and acute fatty liver of pregnancy. However, pathophysiology and therefore treatment of these entities is markedly different. TTP is caused by inherited or acquired defective ADAMTS13, an enzyme that cleaves von Willebrand factor into smaller multimers. Increased circulating von Willebrand factor induces adhesion and aggregation of platelets in the systemic and renal microcirculation, leading to microangiopathic hemolytic anemia, thrombosis and end-organ damage. In patients with acquired TTP, plasma ADAMTS13 activity is markedly reduced (<10%). Thus, an ADAMTS13 assay is instrumental in differentiating TTP and p-aHUS. TTP is managed with serial TPE; patients suspected of having p-aHUS should be started on TPE while workup is continued [2], [5], [6]. Approximately 80% of patients with aHUS may have a laboratory response to TPE, but unlike with TTP, renal dysfunction and the risk of death persists. Poor renal response to TPE should increase clinical suspicion for aHUS.

Differentiation between p-aHUS and HELLP syndrome is particularly difficult. Recent evidence suggests that several of the gene mutations associated with aHUS have also been found to be associated with the development of HELLP syndrome, thereby implicating complement hyperactivation as its pathogenesis [8], [9], [10]. As described previously, HELLP syndrome is a triad of microangiopathic hemolytic anemia, thrombocytopenia and elevated liver function tests. Approximately 3–15% of HELLP cases also have concomitant renal injury with elevated blood urea nitrogen and serum creatinine, overlapping with p-aHUS. However, in p-aHUS, the degree of renal injury is usually severe, and liver enzyme elevations are uncommon, although they may be present [9]. HELLP syndrome is typically diagnosed in the third trimester and improves after delivery of the fetus, with excellent prognosis for complete recovery.

Better understanding of the pathophysiology of aHUS has yielded a new therapy. Eculizumab, a humanized monoclonal antibody, binds to complement component C5, preventing its cleavage to C5a and C5b and ultimately inhibiting the formation of the terminal component of the complement cascade [3]. First approved for treatment of another complement-mediated disease, paroxysmal nocturnal hematuria, eculizumab received Food and Drug Administration (FDA) approval for the treatment of aHUS in 2011. However, knowledge regarding the initiation of dosing, monitoring, and length of treatment for p-aHUS is limited. The literature in pediatric and transplant patients support the initiation of eculizumab within 24 hours if p-aHUS is suspected [3], [5], [11], [12].

Little is known regarding the dosing, monitoring and length of treatment of p-aHUS. Loirat and Fremeaux-Bacchi [4] originally suggested a 4-week regimen of 900 mg IV eculizumab weekly, followed by 1200 mg every 2 weeks indefinitely. Given the enormous cost of eculizumab, the decision to continue life-long treatment cannot be made lightly. Discontinuation of therapy once in remission is controversial; case reports describe duration of treatment ranging from 26 to 114 weeks and also suggest that resumption of eculizumab in case of relapse is effective [11], [12]. Genetic testing may guide the duration of treatment; for example, factor H mutation is associated with high relapse rates and children with aHUS and CFI and CD46 mutations appear to have a lower risk of relapse [4]. However, only 30% of aHUS patients have identifiable mutations.

Most p-aHUS cases receive eculizumab in the postpartum period [3], [7], though antepartum treatment of women with pre-existing aHUS has also been reported. In one case series of three pregnant women with pre-existing aHUS, antepartum treatment with eculizumab did not prevent development of preeclampsia or HELLP syndrome, necessitating delivery in the early third trimester [13]. In another case report, antepartum treatment with eculizumab in the setting of HELLP syndrome successfully prolonged pregnancy from 26 weeks to 29 weeks [14]. These cases highlight the importance of further research in complement dysregulation and use of eculizumab in pregnancy and the postpartum period.