Graft-versus-host disease of the kidney after rapid tapering of cyclosporin following reduced intensity hematopoietic stem cell transplantation

Acute renal failure is a common problem after allogeneic hematopoietic stem cell transplantation (allo-SCT) and many factors contribute to its development.1 Graft-versus-host disease (GVHD) rarely involves the kidney and most physicians believe that the kidney is not target of acute GVHD. However, several case reports have been published concerning chronic GVHD of the kidney and resulting nephrotic syndrome.2, 3 We describe a patient who developed renal failure attributable to acute GVHD after rapid tapering of cyclosporin following reduced intensity stem cell transplantation (RIST). A detailed description of his clinical courses provides important information on renal involvement of acute GVHD.

A 60-year-old man underwent RIST for acute myeloid leukemia, from an HLA-identical sister. Induction chemotherapy with cytarabine and idarubicin failed. Pretransplant evaluation showed normal renal function. Preparative regimen comprised fludarabine 30 mg/m2 for 6 days and busulfan 4 mg/kg for 2 days. GVHD prophylaxis was cyclosporin 3 mg/kg, which was tapered rapidly from day 30 to day 45 to augment a graft-versus-leukemia effect. He achieved neutrophil engraftment on day 10. Regimen-related toxicities were minimal. His clinical course was uneventful until day 54, when he developed watery diarrhea. Blanching erythema appeared on day 60. Grade III acute GVHD was diagnosed based on histopathological examination, and cyclosporin was re-instated. Corticosteroids were avoided while GVHD was tolerable. His gastrointestinal GVHD worsened, and we initiated prednisolone 1.0 mg/kg on day 71. He responded to the immunosuppression, and the prednisolone and cyclosporin were tapered off by day 137. The creatinine clearance gradually decreased. Fractional excretion of sodium (FENa) was 2.3% on day 138. No hematuria, proteinuria or casts were detected on urinalysis. Renal ischemia had not occurred during his clinical course. Watery diarrhea started on day 150, but while the symptoms of gastrointestinal GVHD were mild, corticosteroids were withheld. When corticosteroids 0.5 mg/kg were resumed on day 178, the watery diarrhea immediately resolved. We tapered the corticosteroid off by day 209 but after discontinuation of corticosteroid, the watery diarrhea reappeared, and the renal dysfunction gradually worsened. His diarrhea was mild, and treated with supportive measures. Histopathological examination of the kidney on day 251 revealed tubulitis with tubular epithelial vacuolization (Figure 1). Glomerular change was minimal. Hemodialysis was initiated on day 270 for renal failure. We continued supportive treatment for the gastrointestinal GVHD. He died of septic shock on day 295.

Figure 1
figure1

Pathology of the kidney (HE staining). (a) Histopathological examination of the kidney revealed tubulitis with massive infiltration of mononuclear cells. Glomerular change was minimal. (b) Tubular epithelial vacuolization.

The following suggest that the renal dysfunction was most likely due to acute GVHD. First, the renal dysfunction followed GVHD and improved with corticosteroid. Second, FENa was elevated when the renal dysfunction developed, supporting the concept that the renal dysfunction was not secondary to circulatory failure and that the kidney was primarily damaged. Third, the patient had received only one course of chemotherapy and had normal renal function at RIST, so the possibility that an underlying renal dysfunction was aggravated is unlikely. Finally, the duration of cyclosporin and antibiotic administration was short, and their potential for causing renal toxicity was minimized. The histopathological findings suggesting nephrotoxicity of calcineurin inhibitors such as increasing arteriolar hyalinosis, small-vessel narrowing, and progressive ischemic glomerulosclerosis were absent in the present patient.4 Although the possibility cannot be excluded that renal toxicity from medications given during the peritransplant period aggravated an underlying renal dysfunction, it is unlikely to have been the primary cause. While conditioning regimen-related toxicities mostly develop within 28 days of transplantation,5 our patient developed renal dysfunction more than 100 days after transplantation.

Renal biopsy revealed tubulitis. The pathological diagnosis of tubular involvement is consistent with the clinical course and changes in FENa. Seshi et al reported tubulitis in 17 of 26 patients who underwent allo-SCT and autopsy. The high incidence of tubulitis suggests an association between allo-SCT and tubulitis since the pathological diagnosis of tubulitis is rare. Although they found no significant association between GVHD and tubulitis, and discussed the issue that tubulitis is not a manifestation of renal GVHD, the small sample size obscured any significance, as indicated. The clinical course of the present patient supports an association between GVHD and tubulitis, requiring further investigation.

Most physicians believe that the kidney is rarely involved in GVHD; however, in vivo imaging of mice with GVHD showed that several nonclassical organs are massively infiltrated by cytotoxic T-cell (CTL) during GVHD, including the brain, kidneys, and connective tissues.6 Infiltration of CTL into the kidney explains the high response rates following RIST for metastatic renal cell carcinoma (RCC),7 which derives from the proximal renal tubules. While tumor-specific antigens and minor histocompatibility antigens targeted by CTL have been cloned in allo-SCT for RCC,8 the mechanism of the graft-versus-tumor effects remains unknown. Response is closely related to GVHD in allo-SCT for RCC,7 and the sensitivity of RCC to alloimmunity can be explained by the hypothesis that the minor histocompatibility antigens expressed on proximal renal tubules are the target of alloimmunity and that RCC arising from the proximal renal tubules also expresses the antigen.

Renal tubules, especially proximal renal tubules, are the target organ of rejection after renal transplantation.9, 10 Since recipients are often transplanted from HLA-mismatched and/or cadaver donors, renal tubular dysfunction after renal transplantation occurs more commonly than after allo-SCT. Proximal renal tubules can also be the target of alloimmunity. In contrast, renal tubular dysfunction after allo-SCT from an HLA-matched donor may be mild and underdiagnosed. In the present patient, the rapid tapering of cyclosporin may have contributed to the clinical manifestation of renal tubular dysfunction. This patient might also have had age-related renal dysfunction, his renal function being more susceptible to insults including GVHD. Alternatively, differences in the pathogenesis of acute GVHD between conventional myeloablative allo-SCT and RIST11, 12 might have contributed to the development of renal tubulitis in this patient.

The clinical course of this patient suggested that acute GVHD may lead to renal dysfunction and that the target tissue is the renal tubules. This hypothesis needs further evaluation by prospective studies and basic investigation of the underlying mechanism.

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Acknowledgements

We thank Dr Yugo Shibagaki (Tokyo University) and Dr Takanori Teshima (Kyusyu University).

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Homma, C., Kami, M., Masuo, S. et al. Graft-versus-host disease of the kidney after rapid tapering of cyclosporin following reduced intensity hematopoietic stem cell transplantation. Bone Marrow Transplant 35, 929–930 (2005) doi:10.1038/sj.bmt.1704896

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