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

Abstract

Thrombotic microangiopathy (TMA) is a major complication after hematopoietic stem cell transplantation (HSCT). In this study, we examined the clinical and pathologic features of 2 patients and 5 autopsy cases with HSCT-associated renal TMA to clarify the association between graft-versus-host disease (GVHD) and renal TMA. The median interval between HSCT and renal biopsy or autopsy was 7 months (range 3-42 months). Clinically, acute and chronic GVHD occurred in 7 and 4 patients, respectively. Clinical evidence for TMA was detected in 2 patients, while chronic kidney disease developed in all patients. The main histopathological findings were diffuse endothelial injury in glomeruli, peritubular capillaries (PTCs), and small arteries. In addition, all cases showed glomerulitis, renal tubulitis, and peritubular capillaritis with infiltration of CD3+ T cells and TIA-1+ cytotoxic cells, suggesting that GVHD occurred during the development of TMA. Diffuse and patchy C4d deposition was noted in glomerular capillaries and PTCs, respectively, in 2 biopsy and 2 autopsy cases, suggesting the involvement of antibody-mediated renal endothelial injury in more than 50% of renal TMA cases. In conclusion, the kidney is a potential target of chronic GVHD that may induce the development of HSCT-associated TMA. Importantly, some cases are associated with chronic humoral GVHD.

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

“…23,38,40 In their study of 26 autopsy cases, El-Seisi et al 38 noted substantial interstitial fibrosis, as we found in our group, but they also found tubulitis of unspecified degree in 67% of autopsied hematopoietic cell transplant patients, although they did not find an association of tubulitis with clinical GVHD. In a study of seven hematopoietic cell transplant patients with thrombotic microangiopathy, Mii et al 23 noted mild or moderate interstitial inflammation in all patients (two biopsy, five autopsy).…”

“…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.…”

“…8,[10][11][12][13][14][15][16][17][18] These include membranous nephropathy, minimal change disease, and focal segmental glomerulosclerosis. In addition, acute and chronic thrombotic microangiopathy, or 'transplant-associated thrombotic microangiopathy,' has been shown to occur commonly in hematopoietic cell transplant recipients, 8,14,[17][18][19][20][21][22][23][24][25] with smaller reported numbers of membranoproliferative glomerulonephritis, proliferative glomerulonephritis, ANCA-associated glomerulonephritis, and IgA nephropathy. 8,18,[26][27][28][29][30][31][32][33][34][35][36][37] In studies also examining nonglomerular pathology, kidney specimens also show concomitant tubulointerstitial and vascular changes in hematopoietic cell transplant patients.…”

Graft versus host disease-dependent renal dysfunction after hematopoietic stem cell transplantation

“…According to kidney histological findings, glomeruli accompanied with diffuse double contour in glomerular basement membrane, thickening of vascular intima, and substantial width of subendothelial widening was observed. Moreover, C4d staining was detected in a part of glomerular capillaries and peritubular capillaries, which coincides with the symptoms of GVHD [8]. We speculated that TMA was improved by increase of tacrolimus with improvement of GVHD.…”