Patients with Transplantation-Associated Thrombotic Microangiopathy Demonstrate Elevated Levels of Ba Protein That Correlate with Renal Function

Abstract

Introduction Transplantation-associated thrombotic microangiopathy (TA-TMA) is a complication of hematopoietic stem cell transplant (HSCT) characterized by hemolytic anemia, thrombocytopenia, and microvascular thrombosis that leads to multiple end-organ injury. The kidney is most uniformly affected. The disease is challenging, as it is difficult to diagnose, the pathogenesis is poorly understood, and therapies are limited, resulting in long-term complications and mortality as high as 80%. TA-TMA has been associated with genetic abnormalities in the alternative complement pathway (AP), part of the innate immune system (Fig. 1). In this study, we hypothesized that TA-TMA patients would demonstrate markers of AP activation. We aimed to measure the AP activation products C3a, C5a, and Ba in HSCT patients with TA-TMA in order to assess if the degree of AP activation correlated with renal function in these individuals. Methods Allogeneic HSCT patients with elevated lactate dehydrogenase and renal dysfunction (doubling of creatinine, proteinuria, and/or hypertension) were eligible for enrollment. Plasma samples were collected for measurement of C3a, C5a, and Ba at enrollment and intervals up to 6 months. Estimated glomerular filtration rate (eGFR), an assessment of renal function, was calculated by the Schwartz equation. 17 patients met eligibility criteria and were enrolled over a 2.5-year period. 10 of these met full criteria for TA-TMA based on our institutional guidelines, and 7 recovered without developing TA-TMA and served as controls. Results Ba levels were higher in TA-TMA patients compared to control patients at enrollment (P=0.001, Fig. 2 and Table 1) and remained higher throughout study duration. eGFR levels were lower in TA-TMA patients at enrollment (P=0.016), and remained lower throughout the study (Fig. 2). There were no differences in C3a or C5a between patient populations at enrollment (Table 1) or at any interval. In patients with more than one measurement, eGFR decreased as Ba levels increased over time. Among the 10 TA-TMA patients, 6 were treated with therapeutic plasma exchange (TPE) plus the complement C5 inhibitor, eculizumab, 2 were treated with TPE alone, 1 was treated with eculizumab alone, and 1 did not receive any treatment prior to a rapid decompensation and death. 1/7 (14%) control patients died, and 7/10 (70%) TA-TMA patients died. Conclusions In comparison to controls, TA-TMA patients demonstrated higher Ba levels at enrollment and throughout study, consistent with AP activation. Ba protein, therefore, may serve as a beneficial diagnostic marker for TA-TMA. Furthermore, renal function was worse in the TA-TMA group compared to the control group throughout study, and Ba levels inversely correlated with eGFR. Components generated early during AP activation, therefore, may be directly involved in the pathogenesis of renal endothelial injury in TA-TMA.