Renal thrombotic microangiopathy associated with chronic humoral graft versus host disease after hematopoietic stem cell transplantation

Abstract

Thrombotic microangiopathy (TMA) is a known complication of hematopoietic stem cell transplantation (HSCT). The pathogenesis of TMA is controversial but considered to involve various factors such as total body irradiation, use of calcineurin inhibitors for prophylaxis against graft versus host disease (GVHD), viral infection, and GVHD. Herein we describe a case with renal TMA after HSCT, which was probably associated with antibody-mediated endothelial cell injury from chronic GVHD (termed here 'chronic humoral GVHD'). A 49-year-old man presented two years after HSCT with renal dysfunction and proteinuria but without the clinical features of TMA. Histopathological examination of renal biopsy showed chronic glomerular endothelial cell injury with double contour of the glomerular basement membrane, microthrombi and the deposition of complement split product C4d along the glomerular capillaries. Renal tubulitis and peritubular capillaritis were also noted with a multilayered basement membrane and patchy C4d deposition on peritubular capillaries. These findings resemble those of chronic antibody-mediated rejection after kidney transplantation. Furthermore, C4d deposition suggests complement activation. Although circulating anti-blood type and anti-human leukocyte antigen antibodies were not detected, the renal TMA in this case was probably associated with chronic humoral GVHD.

Renal pathology in hematopoietic cell transplant recipients: a contemporary biopsy, nephrectomy, and autopsy series

“…Mii et al 23,49 surmised that this finding might provide evidence of antibodymediated pathology, based on analogy with antibody mediation rejection in solid organ transplantation. 49 Subsequently, Laskin et al 25 found arteriolar but not glomerular C4d staining to correlate with histologic thrombotic microangiopathy in patients with both allogeneic and autologous hematopoietic cell transplant. However, neither study included a nonhematopoietic cell transplant thrombotic microangiopathy control group.…”

“…In separate studies, Mii et al, 23,49 Laskin et al, 25 and Sakamoto et al 50 demonstrated C4d labeling in arterioles and glomeruli of biopsy and autopsy kidney specimens from patients with hematopoietic cell transplant and thrombotic microangiopathy. Mii et al 23,49 surmised that this finding might provide evidence of antibodymediated pathology, based on analogy with antibody mediation rejection in solid organ transplantation. 49 Subsequently, Laskin et al 25 found arteriolar but not glomerular C4d staining to correlate with histologic thrombotic microangiopathy in patients with both allogeneic and autologous hematopoietic cell transplant.…”

“…23,25,49 We used C4d as a surrogate marker of immune deposits and identified two hematopoietic cell transplant recipients with granular capillary loop deposition, consistent with occult membranous nephropathy. In separate studies, Mii et al, 23,49 Laskin et al, 25 and Sakamoto et al 50 demonstrated C4d labeling in arterioles and glomeruli of biopsy and autopsy kidney specimens from patients with hematopoietic cell transplant and thrombotic microangiopathy. Mii et al 23,49 surmised that this finding might provide evidence of antibodymediated pathology, based on analogy with antibody mediation rejection in solid organ transplantation.…”

Small vessels, big trouble in the kidneys and beyond: hematopoietic stem cell transplantation–associated thrombotic microangiopathy

“…50 Recently, the first case that documented TA-TMA secondary to Ab-mediated tissue injury showed by diffuse C4d deposition in the glomerular capillaries was published. 40 Because detection of C4d is a reliable marker of Ab deposition and complement activation, 49 the investigators concluded that this case of TA-TMA was probably mediated by a humoral immune response. However, no circulating anti-HLA Abs were detected.…”

“…35 Smaller studies have identified elevated levels of circulating cytokines, including IL-8, IL-12, and thrombomodulin, during TA-TMA. 21,40,41 The variable antigenicity of endothelial cells may explain why certain patient populations are more resistant to cytokine-induced vascular injury than others. 35 …”