Characteristics and Outcomes of Renal Transplant Recipients with Hemolytic Uremic Syndrome in the United States.

Hemolytic uremic syndrome (HUS) is a rare disorder, classically characterized by thrombocytopenia, microangiopathic hemolytic anemia, and renal failure. The HUS may be due to either hereditary or acquired conditions.1 The renal failure component is thought to be secondary to occlusion of vessel lumina with platelet-rich thrombi, endothelial swelling and detachment, and subendothelial fibrin-like protein deposition in the glomerular arterioles (thrombotic microangiopathy [TMA]).2 Ninety percent of HUS cases are seen during childhood (median age, 2 years) and is mostly caused by Shiga toxin producing bacteria (mostly Escherichia coli, O157:H7, Shigella dysenteriae type 1, or pneumococcal infection), also called ST-HUS.3,4 Shiga toxin binds to globotriaosyleceramide (Gb3) on endothelial cells, mesangial cells, and podocytes that result in cell apoptosis through ribosomal inactivation and thrombosis via inducing secretion of endothelial von Willebrand factor.5,6 Children with ST-HUS frequently require acute dialysis support but rarely progress to end-stage renal disease (ESRD) (rate approximately 3%) or die (mortality rate nearly 3%).7,8 The ST-HUS rarely recurs after transplantation (less than 1%).9 Non–ST-HUS is used to describe as atypical HUS (aHUS). There has been significant advancement in the understanding of pathogenesis of aHUS with the recognition of underlying genetic mutations that result in uncontrolled complement activation by the alternative complement pathway. Hereditary complement-mediated HUS, which accounts for up to 70% of the aHUS cases, is associated with either a loss-of-function mutation in a regulatory gene (complement factor H [CFH], complement factor I [CFI], membrane cofactor protein [MCP or CD46], C3 convertase [C3bBb], or thrombomodulin [THBD]) or a gain-of-function mutation in an effector gene (complement factor B [CFB] or complement 3 [C3]).10-12 Moreover, a functional deficiency in CFH due to antibody against CFH, associated with homozygous CFHR1-CFHR3 deletion, has been identified as cause of HUS that compose of 10% of complement-mediated HUS cases.13-15 However, incomplete penetrance, with approximately 50% of these mutation carriers developing HUS, indicates that additional genetic mutations or environmental complement amplifying events (drugs, infections, surgery, and pregnancy) are often necessary for disease manifestation.16,17 Atypical HUS is a severe disease that is associated with a 10% to 15% mortality during first clinical presentation and up to 50% of cases will progress to ESRD within the first year.2 Atypical HUS recurs after renal transplantation in approximately 20% to 80% of patients, mainly within first 1 to 3 months.18-20 Recurrent aHUS accounts for 60% to 100% allograft failures depending on underlying genetic mutation.21,22 Renal transplantation has distinctive features that may trigger HUS in genetically susceptible recipients. These include donor kidney injury due to brain death with autonomic storm and procurement injury, warm-cold ischemia, ischemia-reperfusion injury, acute rejection, medications (calcineurin inhibitors [CNI], cyclosporine and tacrolimus; mechanistic target of rapamycin inhibitors, sirolimus and everolimus), induction agents (alemtuzumab), and severe hypertension. To date, there are limited data on outcomes after renal transplant in pediatric (age younger than 18 years) and adult HUS cases in the United States.23,24 In this study, we used the Organ Procurement and Transplantation Network/United Network for Organ Sharing (OPTN/UNOS) data to examine the impact of HUS and its posttransplant recurrence on outcomes in the period from 1987 to 2013. Pediatric and adult patients with ESRD-HUS were analyzed, and their results were compared with a propensity score (PS)–matched control group with alternative primary renal disease.