Case 5 -

Thrombotic Microangiopathy (TMA) Marcello Franco Escola Paulisto Medicina Sao Paulo, Brazil

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Click here to download handout in 1-up pdf format for the current section Click here to download handout in 6-up pdf format for the current section I. Clinical summary: A 65 y/o woman was submitted to a renal transplantation, receiving a cadaveric kidney (65 y/o man who died of intraparenchymatous cerebral hematoma,with a final creatinine level of 1.3). She developed DGF and a Tx bx at Day 8 revealed features consistent with severe acute vascular rejection (Banff 2009: Type III). As the patient was old, presented several co-morbid conditions, as hypertension and obesity, the clinical option was not to treat the acute rejection and to proceed with the graft excision, 6 days later. The histopathology of the graft showed features of severe acute vascular rejection (Type III), glomeruli with mesangiolysis and vascular features consistent with TMA associated with the rejection. C4d in both specimens were positive, by immunohistochemistry. Case 5 - Figure 1 Case 5 - Figure 2 Case 5 - Figure 3 Case 5 - Figure 4 Case 5 - Figure 5 Case 5 - Figure 6 II. Comments: In this case, the presence of necrotizing arteritis in the biopsy at Day 8 post-implantation raised the diagnosis of acute vascular rejection, Banff 2009 Type III. The patient was not treated and submitted to a resection of the renal graft. The explant as described above revealed lesions consistent the severe vascular rejection associated with histological evidence of Thrombotic Microangiopathy (TMA) and Hemolytic Uremic Syndrome (HUS). It is always important to keep in mind the problem related with the sample problem while dealing with a biopsy, which may not show all the lesions in the graft due to the focality of the changes. Morphologically, there is overlapping between the vascular lesions of acute severe vascular rejection and TMA/HUS. TMA after kidney transplatation may be: i) A De Novo event, triggered by immunosuppression drugs or by an acute humoral mediated rejection or ii) A recurrent TMA, common in patients with atypical HUS (a-HUS). These patients frequently (60%) present a genetic or acquired defect in the complement system, such as in the central complement inhibitor factor H or in the membrane co-factor protein (MCP). The majority of renal transplant patients develop systemic TMA with manifest hemolysis and thrombocytopenia, whereas a subset has TMA localized only to the graft (38%). TMAs manifest as a spectrum of related disorders such as Thrombocytopenic purpura (TTP) and HUS. Genetic mutations are associated with both disorders: in TTP, the ADAMTS13 gene, the vWF cleaning protease is affected, and in HUS several complement genes are mutated. In addition, autoimmune forms exist for both disorders. In patients with a-HUS, renal transplantation usually fails due to recurrent HUS. In this situation, combined liver-kidney transplantation has been suggested to correct the underlying genetic defect. In addition, newer agents, such as complement inhibitors, may open a new era in the treatment of HUS. It is important to stress that while TMA is a frequent cause of renal graft dysfuntion, mostly associated with the use of the microemulsion form of CsA, systemic signs of the dysfunction are rare, undescoring the importance of the graft biopsy in making the diagnosis. In summary, the present case demonstrates the difficult differential diagnosis of the necrotizing vascular lesions in renal graft biopsies. This differential includes: Acute vascular rejection, Hemolytic uremic syndrome and Microangiopathy, or even the association of these entities in the graft. References: Noris M & Remuzzi G. Thrombotic microangiopathy after kidney transplantation. Amer J Tx 10: 1517-23, 2010. Sanchez-Corral P. Advances in understanding the aetiology of atypical HUS. Brit. J; Hemat. 150: 529-42, 2010. Ponticelli C & Banfi G. Thrombotic microangiopathy after kidney transplantation. A review. Transp. Intern. 19: 789-94, 2006. Schwimmer J. et al. De novo TMA in renal transplant patients: a comparison of HUS with localized renal TAM. Amer. J. Kidney Dis. 41: 471-9, 2003. Zipfel PF. et al. TMA: new insights and new challenges. Curr. Opin. Nephrol. Hypertens. 19: 372-8, 2010. Kavangh D. & Goodship T. Hemolytic uraemic syndrome. Nephrom. Clin. Pract. 118: 37-42, 2011. Zarafian A. et al. Cyclosporine-associated thrombotic microangiopathy in renal allografts. Kidney Intern. 55: 2457-66, 1999. Nast C. TMA in renal transplantation. Presented in the First International Renal Pathology Conference, in La Coruña, Spain, 2010. Jumani A. et al. Causes of acute TMA in patients receiving kidney transplantation. Exp. Clin. Transplant. 2: 268-72, 2004. Zuber J. et al. New insights into postrenal transplant HUS. Nat, Ver. Nephrol. 7: 23-35, 2011.