Chronic organizing microangiopathy in a renal transplant recipient

Christina M. Wyatt 2 3 Steven Dikman 1 2 Vinita Sehgal 0 2 3 Barbara T. Murphy 0 2 3 Jonathan S. Bromberg 0 2 Scott Ames 0 2 Enver Akalin 0 2 3 0 Recanati-Miller Transplantation Institute, Mount Sinai School of Medicine , New York, NY, USA 1 Department of Pathology 2 Mount Sinai School of Medicine , One Gustave L. Levy Place, Box 1104, New York, NY 10029, USA 3 Division of Nephrology The Author [2005]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: Introduction Thrombotic microangiopathy (TMA), not an uncommon but potentially serious complication of transplantation, occurs in 315% of renal transplant recipients [1,2]. De novo post-transplant TMA is mostly due to calcineurin inhibitor toxicity. Histologically, TMA is characterized by glomerular endocapillary damage with subendothelial accumulation of amorphous material. Narrowing or occlusion of capillaries with intravascular fibrin thrombi and fragmented erythrocytes is common. Similar changes may involve arterioles and arteries. Post-transplant TMA can be isolated to the allograft or can present with clinical and laboratory evidence of systemic TMA, including fever, haemolytic anaemia and renal failure. Intravascular haemolysis leads to the presence of schistocytes on peripheral blood smear, increased lactate dehydrogenase (LDH), and decreased haptoglobin levels in the systemic form of post-transplant TMA, which is often referred to as haemolyticuraemic syndrome (HUS). Both localized and systemic TMA can present with acute renal failure, and both have been associated with decreased graft survival [1,2]. Here we use the descriptive term TMA to refer to both localized and systemic forms of post-transplant TMA, as well as to systemic forms of TMA in the general population, including HUS and thrombotic thrombocytopenic purpura (TTP). Recurrence of TMA following clinical resolution has been described in renal transplant recipients with pre-transplant TMA and in patients rechallenged with calcineurin inhibitors following an episode of calcineurin inhibitor-induced TMA [3]. The role of the initial endothelial insult in recurrent disease is unclear, and the significance of residual histological changes is not well described. Because the organizing phase of TMA may resemble chronic transplant glomerulopathy, it is unclear how often post-transplant TMA evolves into the fibrotic organizing phase. We present serial renal biopsies from a patient with acute humoral rejection and later development of malignant hypertension and systemic TMA, in whom intervening biopsies revealed fibrotic microvascular changes attributed to chronic organizing microangiopathy. Case A 46-year-old African-American female with end-stage renal disease attributed to hypertensive nephropathy underwent living-related donor renal transplantation from her 29-year-old daughter. The aetiology of native kidney disease was not confirmed by renal biopsy due to late referral; however, the patient had no proteinuria, haematuria or clinical manifestations of systemic illness prior to the initiation of dialysis. Initial complement-dependent cytotoxicity (CDC) T-cell cross-match was negative. CDC B-cell cross-match and flow cytometry T-cell and B-cell cross-match were positive, with a donor-specific anti-human leukocyte antigen (HLA) antibody (anti-A2) demonstrated by antigen-coated flow beads (Luminex). There were no pre-transplant anti-HLA class II antibodies. The addition of in vitro intravenous immunogloblulin (IVIG) into test wells completely abrogated the CDC and flow cytometry cross-match positivity. The patient received induction therapy with IVIG (100 mg/kg for 3 days) and thymoglobulin (1.5 mg/kg for 5 days), which has been shown to permit the successful transplantation of patients with positive CDC B-cell and flow cytometry cross-match [4]. Maintenance therapy included cyclosporin microemulsion, (trough 166195 ng/ml), prednisone and mycophenolate mofetil. The patient was discharged on post-operative day 4 with a creatinine of 1.2 mg/dl. On post-operative day 7, the patient was readmitted with oliguria and creatinine of 4.4 mg/dl in the setting of a low cyclosporin trough (106 ng/ml). Renal biopsy showed neutrophilic infiltrates in the interstitium and interstitial capillaries, as well as acute microangiopathic glomerular changes, including swelling of glomerular capillary endothelial cells, segmental capillary dilatation and congestion, intracapillary thrombi and red blood cell fragments (Figure 1A). The vascular pole of some glomeruli showed endothelial damage, but the afferent arterioles and arteries were unremarkable. There was no evidence of arteriolar muscle cell degeneration or adventitial hyaline nodules. Interstitial capillaries were strongly positive for C4d (Figure 1B). Repeat CDC T- and B-cell cross-match and donorspecific antibody (anti-A2) were positive. The clinical and biopsy findings indicated acute humoral rejection, and the patient was treated with IVIG, plasmapheresis, OKT3 and rituximab. Cyclosporin was changed to tacrolimus for maintenance therapy. Subsequent renal biopsies on post-operative days 21 and 31 showed resolution of the acute microangiopathic glomerular changes and neutrophilic infiltrates but persistence of a strong C4d reaction in interstitial capillaries. Both biopsies demonstrated marked fibrous narrowing of the hilum of multiple glomeruli, attributed to organizing microangiopathy (Figure 2). Several immediately adjacent afferent arterioles displayed mild fibrous intimal thickening, but the glomerular capillaries and other arterioles and arteries were unremarkable. Renal function gradually improved, reaching a new baseline creatinine of 1.7 mg/dl. Over the next 9 months, tacrolimus trough levels were maintained between 7 and 10 ng/ml, and blood pressure was well controlled on combination b-blocker and calcium channel blocker therapy. Renal function remained stable until 1 year post-transplant, when the creatinine rose to 2.6 mg/dl in the setting of cytomegalovirus (CMV) viraemia. Repeat CDC and flow cytometry cross-match was negative. Renal biopsy demonstrated mild interstitial fibrosis and tubular atrophy (Banff 97: ci1, ct1), with no evidence of acute rejection or active microangiopathy by light microscopy. Persistent fibrosis at the glomerular hilus represented chronic organizing microangiopathy. Light microscopy did not disclose glomerular capillary TMA changes; however, electron microscopy demonstrated scattered glomerular capillary subendothelial widening and mild organizing subendothelial damage. Interstitial capillaries were negative for C4d, and there was no histological or immunohistological evidence of CMV or polyoma virus infection. Arterioles contained focal hyalinization, including an area of adventitial hyalinization consistent with calcineurin inhibitor toxicity. Arteries were unremarkable (Banff 97: g0, i0, ah2, cg0, ci1, ct1, cv0). (...truncated)