Renal Thrombotic Microangiopathy after Hematopoietic Cell Transplant: Role of GVHD in Pathogenesis

Background and objectives: Thrombotic microangiopathy (TMA) is a known complication of hematopoietic cell transplantation (HCT). The etiology and diagnosis of TMA in this patient population is often difficult because thrombocytopenia, microangiopathic hemolytic anemia, and kidney injury occur frequently in HCT recipients, and are the result of a variety of insults.Design, setting, participants & measurements: The authors reviewed renal pathology and clinical data from HCT patients to determine the prevalence of TMA and to identify correlative factors for developing TMA in the kidney. Kidney tissue was evaluated from 314 consecutive autopsies on patients who died after their first HCT (received between 1992 and 1999). Renal pathology was classified into three groups: (1) no renal thrombus (65%), (2) TMA (20%), and (3) isolated thrombosis (15%). Logistic regression models estimated the associations between each histologic category and clinical parameters: donor and recipient gender, patient age, human leukocyte antigen (HLA) matching of the donor and recipient, total body irradiation (TBI), acute graft versus host disease (GVHD), acute kidney injury, medications, and viral infections.Results: In a multivariate analysis, TMA correlated with acute GVHD grades II to IV, followed by female recipient/male donor, TBI > 1200 cGy, and adenovirus infection. Grades II to IV acute GVHD and female gender were associated with isolated renal thrombus.Conclusions: TMA in HCT recipients is associated with acute GVHD grades II to IV, recipient/donor mismatch, TBI > 1200 cGy, and adenovirus infection.Thrombotic microangiopathy (TMA) encompasses a spectrum of clinical diseases characterized by systemic or intrarenal platelet aggregation, thrombocytopenia, and microvascular fragmentation of erythrocytes, resulting in ischemic organ injury. Endothelial damage is thought to represent the inciting factor in TMA syndromes (1). Once the endothelium is damaged, loss of endothelial resistance to thrombus formation, leukocyte adhesion, and increased vascular sheer stress ensues and may augment and perpetuate the injury (2). Although abnormalities in von Willebrand factor and complement pathways have also been associated with inherited and recurrent forms of TMA (2), they have not been found in patients who developed TMA after hematopoietic cell transplant (HCT) (3).The incidence of TMA syndromes in the setting of HCT ranges between 2% and 21% (4–6). Renal biopsy specimens are difficult to obtain immediately after HCT, and therefore much of the literature on TMA has relied on clinical and laboratory features alone. However, it is difficult to establish the diagnosis of TMA in HCT patients by clinical and laboratory features alone because anemia, thrombocytopenia, and elevations in lactate dehydrogenase (LDH) and creatinine occur frequently because of delayed engraftment, infections, medications, or graft versus host disease (GVHD). Clinical manifestations of TMA range from a fulminant presentation associated with severe acute renal failure and death to a more common, indolent course resulting in the eventual development of chronic kidney disease. In many cases, elevations in serum creatinine may not occur until late in the disease process despite endothelial injury in the kidney, and therefore the diagnosis may be delayed or missed. We hypothesize that renal endothelial injury, consistent with TMA, exists in the absence of a clinical diagnosis of TMA and that this early injury may set the stage for progression to chronic kidney disease. In this study, we examined the renal pathology and clinical data from HCT patients to more accurately identify the prevalence of and risk factors for the development of TMA in the kidney.