Chronic organizing microangiopathy in a renal transplant recipient

Nephrol Dial Transplant (2005) 20: 1734–1737 doi:10.1093/ndt/gfh929 Advance Access publication 14 June 2005 Case Report Chronic organizing microangiopathy in a renal transplant recipient Christina M. Wyatt1, Steven Dikman2, Vinita Sehgal1,3, Barbara T. Murphy1,3, Jonathan S. Bromberg3, Scott Ames3 and Enver Akalin1,3 1 Keywords: humoral rejection; renal transplantation; thrombotic microangiopathy Introduction Thrombotic microangiopathy (TMA), not an uncommon but potentially serious complication of transplantation, occurs in 3–15% 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 haemolytic–uraemic 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 Correspondence and offprint requests to: Enver Akalin, MD, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1104, New York, NY 10029, USA. Email: 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 166–195 ng/ml), prednisone and mycophenolate ß The Author [2005]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: Division of Nephrology, 2Department of Pathology and 3Recanati-Miller Transplantation Institute, Mount Sinai School of Medicine, New York, NY, USA Post-transplant thrombotic microangiopathy Fig. 1. (A) Acute humoral rejection with acute glomerular microangiopathic changes consisting of segmental capillary dilatation and congestion, intracapillary thrombi, red blood cell fragments and loss of endothelial cells with reticulated eosinophilic material along the capillary walls. There is mild interstitial oedema accompanied by interstitial neutrophils. H&E stain, original magnification 200. (B) Acute humoral rejection. C4d is diffusely positive in interstitial capillaries. Immunoperoxidase method, original magnification 200. 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). The patient’s renal insufficiency (creatinine 2.4–2.6 mg/dl) persisted over the next Fig. 2. Glomerulus with the hilus and afferent arteriole narrowed by intimal fib (...truncated)