Viruses in Posttransplant Thrombotic Microangiopathy

We read the case reports recently published in Transplantation suggesting the causal association of cytomegalovirus (CMV) and hepatitis C viruses with thrombotic microangiopathy (TMA) (1,2) with great interest. The authors reported several individual cases of TMA that occurred in hepatitis C seropositive transplant recipients or during symptomatic CMV disease. The purpose of this communication is to state that our much larger experience does not support the association of TMA with either hepatitis C or symptomatic CMV infection. Between 1995 and 1999 we diagnosed TMA in 29 kidney transplant recipients of 629 renal and renal/pancreas transplants performed in our center for the same period. In all patients the diagnosis was established by kidney biopsy. None of the patients diagnosed with TMA had positive serology for hepatitis C. A total of 44 of these 629 transplant recipients were hepatitis C positive and none of them developed TMA. Twenty-six of 29 patients that developed TMA were seropositive for CMV at the time of kidney transplant. However, no clinical or laboratory evidence (including viral culture, serology, pp 65 antigenemia, or inclusion bodies on biopsy) of CMV disease was found in any of the patients diagnosed with TMA. Of the three patients that were seronegative at the time of transplant two remained negative and one converted without clinical or laboratory evidence of active CMV disease. In an additional patient, TMA was diagnosed in native kidney biopsy after lung transplant. Again no evidence of CMV disease or hepatitis C infection was found. CMV has been implicated in the pathogenesis of transplant glomerulopathy (3) and more recently in transplant renal artery stenosis (4) in the absence of conclusive evidence to support this suggestion. Similarly, we think that it is premature to associate TMA with hepatitis C infection or CMV disease based on isolated case reports. Our data do not allow us to comment on the possible association of TMA with parvovirus infection recently suggested (5). Thrombotic microangiopathy after kidney transplant is not a rare event. Its incidence ranged from 1–14% in published literature (6). The annual incidence of TMA in our center is around 5%. In our experience a typical clinical picture is not seen in as many as 50% of patients. As we reported recently (7) only 40% of patients with TMA had thrombocytopenia and/or signs of intravascular hemolysis and only 46% exhibited an increase in LDH. These observations are consistent with the data reported by Zarifian (6). The mechanisms involved in the pathogenesis of posttransplant TMA are not completely clear. Treatments with cyclosporine, tacrolimus, and OKT-3 antibodies resulted in TMA in both native and transplanted kidneys. Recently deficiency and/or inhibitor of the high molecular weight von Willebrand factor protease has been reported in nontransplant patients with TMA (8,9). It would be very interesting to test for the activity of this enzyme in transplant recipients. In conclusion, we were unable to find an association of TMA with hepatitis C or symptomatic CMV disease. Based on our experience with 29 patients diagnosed with TMA after kidney transplant we do not have any evidence to support the role of these viruses in the pathogenesis of posttransplant TMA. Fuad Afzal Milos N. Budisavljevic P. R. Rajagopalan Prabhakar K. Baliga