#3885 Kidney Transplantation in Early Pregnancy-Associated Atypical Hemolytic Uremic Syndrome

Abstract

Background and Aims Clinical differentiation of pregnancy-associated thrombotic microangiopathies is challenging and can occur in conjunction with or mimic conditions including hemolysis, elevated liver enzymes, low platelet count (HELLP) syndrome, pre-eclampsia (PET), thrombotic thrombocytopenia purpura (TTP) and atypical HUS (aHUS). aHUS that occurs during pregnancy classically presents in the third trimester. When kidney transplantation is performed in aHUS patients, disease recurrence is high and can be associated with transplant failure. Here, we report a unique case of aHUS that presented early during pregnancy where the patient subsequently underwent kidney transplantation. Method We present a case report. Ethics approval was obtained by the Queen's University Health Sciences and Affiliated Teaching Hospitals Research Ethics Board. Results A 30 year old G2P0A1 diabetic African American woman presents at 9 weeks gestation with new hypertension. At 18 weeks, she developed acute kidney injury and proteinuria. Further investigations revealed hemoglobin 68 g/L, platelets 120 x 109/L, increased LDH 588 U/L, undetectable haptoglobin and schistocytes on blood smear. Creatinine was 88 umol/L, increased from a baseline of 50 umol/L, and proteinuria greater than 1 g/day. Pre-eclampsia was ruled out as her presentation began at 9 weeks gestation, prior to placental implantation. Placental growth factor levels at 24 and 28 weeks remained >100 pg/mL. HELLP syndrome was excluded given the timing in pregnancy and normal liver enzymes. TTP was excluded with a normal ADAMTS13. Complement Factor H autoantibody was negative. Complement studies revealed grossly elevated soluble C5b-9 level (sC5b-9) of 1.05 (normal <0.3 mg/L). aHUS was diagnosed and she began treatment with eculizumab (ECU). Ex-vivo serum C5b-9 deposition on human microvascular endothelial cells was assessed and was severely abnormal pre-treatment with ECU (activated 223%, normal <150%), and normalized with ECU therapy (activated 123%, normal <150%). Genetic testing eventually revealed a Complement Factor I mutation, NM_000204.3:c.550G/A, p. Vall84Met reported as likely pathogenic and confirming primary aHUS. Due to worsening renal function, she delivered a healthy boy at 30 weeks gestation by Caesarean section. A renal biopsy performed 3 weeks post-partum demonstrated features of TMA, mainly chronic (i.e. treated) and severe diabetic nephropathy with advanced glomerular sclerosis. Six months post-partum, she required dialysis. She remained on ECU and had an unrelated living kidney transplantation 1.5 years later. Her kidney transplantation included basiliximab and methylprednisolone induction. Calcineurin inhibitors were prescribed in standard fashion. Given severity of original multiorgan aHUS and CFI mutation, she was treated with eculizumab 1200 mg the day prior to surgery and another 1200 mg on post operative day 1. Subsequently she was given eculizumab 900 mg weekly for 4 weeks then 1200 mg every 2 weeks. Eculizumab drug level for adequacy of complement blockade was measured on day 4 post transplant and was 279 (therapeutic >100 mcg/mL) and sC5b-9 was 1504 (normal < 244). Repeated ECU level pre 900 mg dose was 189 and sC5b-9 was 392. 6 months post transplant she has excellent graft function without proteinuria (urine ACR 2.2 mg/mmol) or evidence of aHUS recurrence. Conclusion aHUS, although described to occur late in pregnancy or post-partum, presented here during the first trimester. Thus, TMA in pregnancy is not always PET or HELLP. aHUS is a treatable condition in pregnancy, and should be considered as a possibility particularly for presentations occurring prior to 20 weeks gestation. Complement function studies may aid in aHUS diagnosis. Despite extra ECU dosing and therapeutic ECU levels for this patient post kidney transplantation, she had evidence of massive C5 release (grossly elevated sC5b-9 level). sC5b-9 measurement post transplantation may be useful to guide ECU dosing.

Complement Biosensors Identify a Classical Pathway Stimulus in Complement-Mediated Hemolytic Uremic Syndrome

“…S3). Furthermore, this exemplifies the important differences between fluid phase analysis and assays of membrane-directed activation 31,32 .…”