Loss of renal function following bone marrow transplantation: an analysis of angiotensin converting enzyme D/I polymorphism and other clinical risk factors

Abstract

Summary:Chronic renal failure is an acknowledged late complication of BMT. It is related to the intensive chemotherapy, radiation and supporting medications. Polymorphism in the angiotensin converting enzyme (ACE) gene is associated with progression of nephropathy caused by diabetes and IgA nephropathy. We sought to determine whether ACE genotype and other clinical factors were associated with loss of renal function after BMT. We determined the genotype of 106 adult allogeneic BMT recipients, who received a similar preparative regimen, survived 1 year, and had assessment of renal function up to 3 years after BMT. We found that the distribution of genotypes was similar to the general population; 29%, 51%, and 20% for the DD, DI, and II genotypes, respectively. There was no statistical difference in patient survival between the three groups. Among all patients, the average creatinine clearance declined from 124 (95% CI 117, 131) to 89 (95% CI 78, 100) ml/min over the 36 months after BMT. Decline in renal function over time was less for patients with the DD compared to the II genotype (P = 0.040). Renal function in patients with the DD genotype was also better than those with the DI genotype, but this was of borderline statistical significance (P = 0.055). Renal shielding reduced decline in renal function compared to no shielding (P = 0.026). We conclude that the ACE genotype does not seem to influence survival, but the DD genotype may be protective against renal injury after BMT. Furthermore, we confirm that renal shielding during TBI reduces the renal injury after BMT. Bone Marrow Transplantation (2001) The late occurrence of chronic renal failure is a known complication of allogeneic bone marrow transplantation. 1 The combined effects of intensive radiation and chemotherapy are implicated in the pathogenesis of acute and chronic renal insufficiency. Factors contributing to acute renal failure include hypotension, sepsis and the administration of nephrotoxic medications such as aminoglycoside antibiotics, cyclosporine, tacrolimus and amphotericin. A distinct syndrome of chronic renal failure after BMT termed 'bone marrow transplant nephropathy' has been described that consists of azotemia, disproportionate anemia, and hypertension. 2,3 This syndrome is thought to be due to either microvascular or renal parenchymal damage from the preparative regimen and in its most severe form resembles hemolytic uremic syndrome (HUS).Studies using animal models of BMT nephropathy have shown that angiotensin converting enzyme (ACE) inhibitors can effectively prevent and treat the syndrome. 4,5 This finding implicates the renin-angiotensin axis in the pathogenesis of the disorder. ACE is responsible for the cleavage of angiotensin I to angiotensin II, which has potent effects on vascular tone, growth and repair. The ACE gene contains a polymorphism based on the presence or absence of a 287-base pair intron. 6 The presence of the intron has been termed the 'insertion' or 'I' allele, and the absence of the intron the 'deletion' or...

Chronic kidney disease in long-term survivors of hematopoietic cell transplant

“…35 Although cyclosporine has been associated with CKD in some studies of solid organ transplant, 36,37 a comprehensive study of approximately 69 000 patients receiving heart, lung, liver, intestine and combined heart-lung transplants, showed that cyclosporine use at initial hospitalization was associated with only a slightly increased risk of developing CKD after organ transplant (HR ¼ 1.24, 95% CI 1.17-1.30). 38 TBI is frequently suggested as a possible cause of CKD after HCT, 5,9,33,[39][40][41] although the data are not consistent. 6,8,34,42 CKD has been thought to be synonymous with radiation nephritis or hemolytic uremic syndrome secondary to either TBI or calcinuerin inhibitors.…”

Genomic screening and complications of hematopoietic stem cell transplantation: has the time come?

“…Selection bias was a concern in this study, because only a fraction of the eligible patients survived to participate, had adequate follow-up data, and conditioning was not standard. 74 Doses of TBI were higher than those used than at most centers, and the development of renal failure in patients who receive 12 Gy TBI or less, with or without renal shielding, may be less dependent on ACE genotype. Furthermore, ACE inhibitors are widely used to treat hypertension after HSCT, and this study did not control for the use of ACE inhibitors.…”

“…Juckett et al 74 106 ACE Single-center retrospective study in 1-year survivors of allo-HSCT whose renal function was followed for up to 3 years; rate of decline in creatinine clearance associated with ACE genotype on multivariable analysis despite no difference in survival across genotypes. Conditioning regimen was the same in all patients but not standard for most institutions; GVHD prophylaxis was T-depletion of graft and CSA; renal shielding changed twice during the course of the study; ACE inhibitor drug use was not analyzed and repair.…”

“…Angiotensin-converting enzyme (ACE) inhibitors have proven effective in preventing and treating this syndrome in animal models, and an association between decline of renal function in patients after HSCT and polymorphisms within the ACE gene has been reported. 74 The ACE gene encodes the enzyme responsible for cleaving angiotensin I to angiotensin II, which in turn has important effects on vascular tone, growth, and remodeling. A common polymorphism in the ACE gene, identified in 1990, is based on the insertion (I allele) or deletion (D allele) of a 287-base-pair intron.…”

Calcineurin Inhibitor Nephrotoxicity

“…However, in high-risk patients and pediatric kidney allograft recipients, a significant association between this ACE variant in recipients and renal allograft outcome was demonstrated (340,341). In nonrenal transplantation, this ACE variant has also been associated with renal dysfunction after bone marrow and heart transplantation (342,343).…”