Obesity and Cardiac Risk after Kidney Transplantation: Experience at One Center and Comprehensive Literature Review. Transplantation 2008; 86: 303–312 K. L. Lentine, L. A. Rocca-Rey, G. Bacchi, N. Wasi, L. Schmitz, P. R. Salvalaggio, K. C. Abbot, M. A. Schnitzler, L. Neri, and D. C. Brennan
Data from the Framingham Heart Study indicate that in a Caucasian population with normal body mass index (BMI), the long-term risk for becoming overweight or obese exceeds 50% and 25% respectively. In 2007, 25.6% of adults in the United States were reported to be obese.
Obesity, in the general population, is associated with an increased risk for cardiovascular disease, diabetes mellitus, hypertension, and hyperlipidemia. In dialysis patients, low BMI often reflects underlying comorbidities and malnutrition, and is a marker for increased mortality. In renal transplant recipients, obesity is a predictor for perioperative complications, delayed graft function, graft loss, and increased mortality. Death with a functioning allograft is the most common cause of renal allograft loss, and cardiovascular disease is the leading cause of death post-transplant.
The relationship between BMI and post-transplant cardiovascular events is not well described. In this article, Lentine et al. report the findings of a retrospective, single-center study that examined associations, in adult patients, between BMI at transplant and the incidence of congestive heart failure (CHF), atrial fibrillation (AF), and myocardial infarction (MI) post-transplant. BMI values were ranked into quartiles, and because of the small number of patients in subsamples, the first and second quartiles were compared with the third and fourth. The primary outcome was a composite of CHF, AF, and MI, and individual event types were considered as secondary outcomes. The authors also performed a comprehensive literature review to frame the results of their study in the context of current knowledge and to identify questions for future studies.
Findings.
BMI range in the 1102 patients who satisfied inclusion criteria was 14.8 to 46.9 kg/m2. Twenty-five percent were obese (BMI ≥30 kg/m2). After transplant, the 5-yr cumulative incidence of the composite cardiac outcome was 18.52%. The incidence increased significantly across BMI quartiles (rising from 8.67% in the lower to 29.35% in the higher quartiles), primarily as a result of increases in the incidence of AF and CHF. The cumulative incidence of MI did not differ by BMI quartiles. On multivariate adjustment for baseline factors, the relationship of BMI with the cardiac composite and AF were significant, and with CHF, nearly significant. In multivariable regression, in patients with pretransplant heart disease and nondiabetic ESRD, each 5-unit increase in BMI was significantly associated with increased risk of the cardiac composite.
Commentary.
The findings of this single-center study by Lentine et al. are consistent with previous reports that identify high BMI at time of transplant as a predictive factor for increased cardiac risk, especially AF and CHF. The authors comment that the absence of an association between BMI and MI may be a result of more intense scrutiny of obese patients with CKD before listing, or perhaps even a selection bias in organ allocation. They acknowledge that the retrospective design is a limitation of the study, as is the lack of documentation in their database of some cardiac risk factors. In a recent editorial, Schnitzler et al. (1) comment on the need for algorithms to treat pretransplant cardiovascular risk factors, and for prospective studies to evaluate the efficacy of these algorithms. The study also does not address the impact of post-transplant weight gain on cardiovascular risk, a continuing problem despite the increasing use of steroid minimization protocols. Patient education on healthy nutritional habits and regular exercise are interventions that are likely to play an important role in modification of risk factors for post-transplant cardiovascular disease.
Footnotes
Published online ahead of print. Publication date available at www.cjasn.org.
- Copyright © 2009 by the American Society of Nephrology
Pretransplant Serum Vitamin D Levels and Risk of Cancer after Renal Transplantation. Transplantation 2008; 85: 1755–1759 D. Ducloux, C. Courivaud, J. Bamoulid, A. Kazory, G. Dumoulin, and J. M. Chalopin
There is increasing evidence that vitamin D has important nonskeletal effects. Epidemiologic data show an inverse association between 25-hydroxy vitamin D3 (25-OH D3) levels and risk for colorectal, prostate, and breast cancer. In a randomized trial, in postmenopausal women, calcium supplementation alone or calcium plus vitamin D substantially reduced all-cancer risk (1).
Vitamin D insufficiency or deficiency is a common finding in patients with chronic kidney disease (CKD). In patients receiving maintenance hemodialysis, studies have demonstrated a survival advantage for patients who receive injectable vitamin D sterols over those who do not. In a recent study, more than 90% of renal transplant recipients were noted to have 25-OH D3 insufficiency or deficiency (2).
The incidence of malignancies considerably increases after organ transplantation. In addition to exposure to immunosuppressive agents and viral infections, low vitamin D levels, as in the general population, could be predictive of increased risk for cancer after transplantation. In this study, Ducloux et al. evaluated the predictive value of pre- and post-transplant serum levels of 25-OH-D3 for development of post-transplant malignancies in 363 consecutive deceased-donor renal transplant recipients. Patients received antibody induction, and maintenance regimens comprised a combination of prednisone, azathioprine or mycophenolate mofetil, and cyclosporine or tacrolimus. 25-OH-D3 levels were measured pretransplant and at 12 and 24 mo post-transplant. On the basis of pretransplant OH-D3 levels. patients were classified into three groups: vitamin D deficient (<10 ng/ml), insufficient (10 to 32 ng/ml), and sufficient (>32 ng/ml). All patients were followed for a minimum of 3 yr after transplantation, and follow-up was censored at 5 yr.
Findings.
The majority of patients (85%) were either vitamin D insufficient or deficient pretransplant. Mean OH-D3 levels were lower at 12 and 24 mo post-transplant. The incidence of cancer in the study population was 8.8%. A higher cancer rate was observed in patients with vitamin D deficiency (13.7%) when compared with patients with vitamin D insufficiency (7%) and vitamin D sufficiency (3.7%). In univariate analysis, age, pretransplant vitamin D levels, and 1-yr post-transplant vitamin D levels were factors associated with development of cancer. Cox regression analysis revealed that age and low 25-OH-D3 levels were risk factors. There was no significant difference in incidence of cancer among the immunosuppressive regimens and no particular relationship between vitamin D status and the type of malignancy.
Commentary.
This study by Ducloux et al. suggests that vitamin D status, as defined by pretransplant serum levels of 25-OH-D3, is an is an important determinant of cancer risk in renal transplant recipients. Patients with vitamin D deficiency had a fourfold increase in the risk of cancer when compared with those who had normal vitamin D levels. The most common malignancies were lymphoma and nonmelanoma skin cancer, which are the tumors whose incidence is markedly increased in solid organ transplant recipients. The authors point out the limitations of their study, bias that is inherent to retrospective studies, and that statistical association is not necessarily synonymous with a causal relationship. Epidemiologic studies in the general population indicate that individuals with low vitamin D levels may be at risk for various cancers, with the strongest evidence for colorectal cancer.
Low vitamin D levels are common in patients with CKD. Actinic precautions that transplant recipients are advised to adopt, to reduce risk for skin cancer, may contribute to persistence of vitamin D deficiency after transplantation. Transplant recipients have a higher incidence of tumors when compared with the general population. Prospective studies are needed to determine whether vitamin D supplementation, an inexpensive and safe intervention, decreases the incidence of cancer in renal transplant recipients.
Successful Treatment of BK Viremia Using Reduction in Immunosuppression Without Antiviral Therapy. Transplantation 2008; 85: 850–854 E. R. Saad, B. A. Bresnahan, E. P. Cohen, N. Lu, R. J. Orentas, B. Vasudev, and S. Hariharan
Transplant recipients are at increased risk for opportunistic infections. Over the past decade, polyoma virus infection, caused by BK virus (BKV) and less often by JC virus, has emerged as an important cause for renal allograft dysfunction and graft loss. The prevalence of BK virus-induced nephropathy (BKVN) has been estimated to be between 1% and 10%. Although there appears to be a correlation between the overall intensity of immunosuppression and risk for BKV infection, no one drug has been incriminated. Reduction in immunosuppression is the cornerstone of the management of BKV infection. In this communication, Saad et al. report their experience with management of 24 patients diagnosed with BK viremia during the process of evaluation of renal allograft dysfunction. Twenty patients received antibody induction, and the maintenance immunosuppressive regimen in all comprised prednisone; mycophenolate mofetil (MMF); and either tacrolimus, cyclosporine, or sirolimus. After the diagnosis of BK virus infection, the dose of MMF and calcineurin inhibitor (CNI) was approximately halved, and target levels for the CNI or sirolimus were reduced to 50% of previous levels. None of the patients received anti-viral agents. Renal function and plasma BK viral load were serially monitored. Patients with deteriorating renal function underwent a repeat biopsy, and those diagnosed with acute rejection were treated with pulse steroids. The mean follow-up period after diagnosis of BKV infection was 30.9 mo (range, 17 to 43 mo).
Findings.
Sixteen patients (66%) had histologic findings of BKVN, and all 24 had BK viremia detected by real-time PCR performed either at the time of or immediately after the renal biopsy. After reduction in immunosuppression, BK viral load decreased starting within 15 to 30 d, and viremia resolved in all of the patients after a mean of 5.8 mo (range, 1 to 9.5 mo). A significant correlation was noted between reduction in immunosuppression dose over time (as measured using a “cumulative immunosuppressive scale” for doses of MMF and tacrolimus) and decline in BK viral load. Renal function stabilized or improved in 17 patients (71%) and declined in the other seven, despite clearance of viremia. Three patients (13%) developed acute rejection that was successfully treated with pulse steroids. One patient had relapse of BKVN during pregnancy, leading to graft loss.
Commentary.
The management of BKV infection in renal transplant recipients is a vexing problem. The reported incidence of renal allograft loss in patients with established BKVN has ranged from 15% to 50%. Early detection of systemic infection, before the onset of renal dysfunction, may offer the best hope of preventing graft loss. Prospective studies have shown that detection of BK virus replication in the urine (finding of “decoy cells” or BK viruria) precedes BK viremia by a median of 4 wk and histologically confirmed BKVN by a median of 12 wk. This observation has led to the recommendation by an international panel (1) that all renal transplant recipients should be screened for evidence of BKV replication in the urine.
Brennan et al. have reported resolution of BK viremia in 95% of patients managed by preemptive reduction in immunosuppression, without risk of rejection or allograft dysfunction (2).
In patients with renal allograft dysfunction secondary to BKVN, in addition to reduction in immunosuppression, antiviral agents (leflunomide and cidofovir), intravenous Ig, and fluoroquinolones have been used. Saad et al. report that reduction of immunosuppression alone was sufficient to clear BK viremia in all of their patients. At a mean follow-up period of 30.9 mo, 71% had stable renal function.
In addition its retrospective nature, the lack of a control group and small sample size are limitations of the study. Larger prospective randomized trials may help define the optimal management of this important cause of renal allograft dysfunction and loss.
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