Allogeneic hematopoietic stem cell transplantation (ASCT) is a widely used procedure for the treatment of multiple hematological diseases.1 A complication of ASCT is graft-versus-host disease (GVHD), which can develop acutely during the first 100 days after ASCT (a-GVHD) or be a chronic complication (c-GVHD) when it occurs after this time period.2 c-GVHD is the most common late complication in patients with ASCT, present in 40–80% of transplant recipients, and is responsible for high morbidity and mortality3. The most common manifestations of c-GVHD are cutaneous and mucosal (lichen planus, scleroderma-like lesions, mucosal erosions with ulcerated lesions), gastrointestinal, and hepatic.1

The kidney may be affected during the course of ASCT as a consequence of drug toxicity linked to pre-transplant conditioning, sepsis, or toxicity from calcineurin inhibitors used to prevent GVHD.4 This involvement may be clinically expressed as acute kidney failure with an incidence of 50–75%,5 or as chronic kidney disease with reported incidence that ranges between 7% and 66% depending on the series.6 Glomerular involvement secondary to c-GVHD is a rare complication, with a prevalence of less than 2% in published series. The most frequent histopathological patterns are membranous nephropathy and minimal change disease, followed by much less frequent lesions such as focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis, IgA nephropathy, crescentic glomerulonephritis, and lupus nephritis-like glomerular lesions.7 The objective of this study is to describe the clinical and analytical characteristics of patients with c-GVHD who underwent renal biopsy due to manifestations of glomerular injury.

We present a group of patients with glomerular disease associated with chronic GVHD. In all cases, glomerular involvement occurred in patients with other manifestations of GVHD. The most frequent clinical presentation was NS in the context of MG and, less frequently, FSGS, consistent with other reports shown in Table 3. The finding of TMA, present in our group and also in other series (Table 3), may be a consequence of the immunological activity of GVHD or of treatment with calcineurin inhibitors used as prophylaxis. In our case (case 6), TMA appeared after the development of GVHD in a patient with multiple extrarenal manifestations of the disease, suggesting that it may be a direct consequence of the disease. In other series, the finding of TMA (Table 3) is primarily associated with the use of calcineurin inhibitors. One case of MG in our series (case 1) was tissue-positive for the phospholipase A2 receptor (immunohistochemistry) without detecting anti-phospholipase A2 receptor (Pla2r) antibodies in plasma. This situation, that has been described in isolated cases,8,9 may be explained in the context of GVHD by the production of donor-derived antibodies in response to allovariants of podocyte antigens (Plar2) from the recipient.10 Other podocyte antigens identified in MG from patients with GVHD were NELL-1 (neural epidermal growth factor-like protein 1),11 described in primary MG (without identified underlying disease), malignant diseases, drugs, autoimmune diseases, and solid organ and hematopoietic organ transplantation.12 In a recent report, Sethi et al. identified the procadherin FAT1 in 5 of 9 patients who developed MG in the context of GVHD.13 In most of our patients with MG, we did not study the antigen involved in basement membrane deposition. The increased use of laser microdissection and mass spectrophotometry may allow for greater understanding of the antigens involved in MG development in patients with GVHD. The treatments prescribed in our patients varied (Table 2), with a notable favorable response in those presenting with podocytopathies (MG/FSGS) compared to those with TMA or MPGN. In our series, three patients were treated with rituximab, achieving complete remission in a short period of time. In other series (Table 3), treatment with rituximab was associated with complete remission in a high number of cases, which may be explained by the involvement of B lymphocytes in the pathogenesis of GVHD, particularly in late stages (chronic GVHD).2,3 In our patients the prognosis of renal function was good; only one patient (case 6) with rapidly progressive renal failure and TMA lesions in the renal biopsy required chronic dialysis. The strength of this study is that it captures all patients with chronic GVHD biopsied in the country. Its weakness is the retrospective nature of the analysis, which can lead to the loss of relevant information.

Glomerular involvement secondary to chronic GVHD is rare. The most common histopathological pattern in renal biopsy is MG, followed by FSGS, MPGN, and TMA. Treatment based on corticosteroids combined with other immunosuppressants achieves adequate response rates. Rituximab appears to have a prominent place in the treatment of patients presenting with podocytopathy (MG, FSGS) in this context. The more extended use of mass spectrophotometry may allow identification of antigens associated with membrane deposits in those who develop MG in the context of GVHD secondary to ASCT.

This research has not received specific grants from public, commercial, or non-profit agencies.