Olwyn Johnston

Sirolimus Is Associated with New-Onset Diabetes in Kidney Transplant Recipients

New-onset diabetes (NOD) is associated with transplant failure. A few single-center studies have suggested that sirolimus is associated with NOD, but this is not well established. With the use of data from the United States Renal Data System, this study evaluated the association between sirolimus use at the time of transplantation and NOD among 20,124 adult recipients of a first kidney transplant without diabetes. Compared with patients treated with cyclosporine and either mycophenolate mofetil orazathioprine, sirolimus-treated patients were at increased risk for NOD, whether it was used in combination with cyclosporine (adjusted hazard ratio [HR] 1.61; 95% confidence interval [CI] 1.36 to 1.90),tacrolimus (adjusted HR 1.66; 95% CI 1.42 to 1.93), or an antimetabolite (mycophenolate mofetil orazathioprine; adjusted HR 1.36; 95% CI 1.09 to 1.69). Similar results were obtained in a subgroup analysis that included the 16,861 patients who did not have their immunosuppressive regimen changed throughout the first posttransplantation year. In conclusion, sirolimus is independently associated with NOD. Given the negative impact of NOD on posttransplantation outcomes, these findings should be confirmed in prospective studies or in meta-analyses of existing trials that involved sirolimus.

Impact of Acute Rejection and New-Onset Diabetes on Long-Term Transplant Graft and Patient Survival

BACKGROUND AND OBJECTIVES Development of new therapeutic strategies to improve long-term transplant outcomes requires improved understanding of the mechanisms by which these complications limit long-term transplant survival. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS The association of acute rejection and new-onset diabetes was determined in the first posttransplantation year with the outcomes of transplant failure from any cause, death-censored graft loss, and death with a functioning graft in 27,707 adult recipients of first kidney-only transplants, with graft survival of at least 1 yr, performed between 1995 and 2002 in the United States. RESULTS In multivariate analyses, patients who developed acute rejection or new-onset diabetes had a similar risk for transplant failure from any cause, but the mechanisms of transplant failure were different: Acute rejection was associated with death-censored graft loss but only weakly associated with death with a functioning graft. In contrast new-onset diabetes was not associated with death-censored graft loss but was associated with an increased risk for death with a functioning graft. CONCLUSIONS Acute rejection and new-onset diabetes have a similar impact on long-term transplant survival but lead to transplant failure through different mechanisms. The mechanisms by which new-onset diabetes leads to transplant failure should be prospectively studied. Targeted therapeutic strategies to minimize the impact of various early posttransplantation complications may lead to improved long-term outcomes.

Treatment of polyomavirus infection in kidney transplant recipients: a systematic review.

Background. Polyomavirus-associated nephropathy (PVAN) is an important cause of kidney graft loss but there is no consensus on its management. This study aimed to systematically document all published treatments for PVAN to determine the most effective therapy. Methods. A computerized search in MEDLINE, EMBASE, and Cochrane databases (1950–2008) was performed. References from review articles and published abstracts from the American Transplant Congress (2005–2008) were also included. Study selection criteria included (a) population: adult (>18 years) kidney-only, primary or repeat renal transplant recipients; (b) setting: polyoma viruria, viremia or biopsy-proven PVAN or both; and (c) treatment: immunosuppression reduction alone or with adjuvant agents. The primary outcome was graft failure rate, and secondary outcomes included acute rejection rate, elimination of viruria and viremia, graft function, patient survival, and adverse events. Results. Of 555 identified citations, 40 studies examining the effect of immunosuppression reduction alone or in combination with cidofovir, leflunomide, intravenous immunoglobulin, or ciprofloxacin were included for appraisal. Pooled results found a death-censored graft loss rate of 8/100 patient-years for immunosuppression reduction alone and 8 and 13/100 patient-years for the addition of cidofovir or leflunomide, respectively. Conclusions. There does not seem to be a graft survival benefit of adding cidofovir or leflunomide to immunosuppression reduction for the management of PVAN. However, the evidence base is poor and highlights the urgent need for adequately powered randomized trials to define the optimal treatment of this important condition.

Nephrectomy After Transplant Failure: Current Practice and Outcomes

The role of transplant nephrectomy after transplant failure is uncertain. We report the use and consequences of transplant nephrectomy among 19 107 transplant failure patients between 1995 and 2003 in the United States. Among 3707 patients with early transplant failure (graft survival <12 m), nephrectomy was performed in 56%, and was associated with an increased risk of death (HR 1.13, 95% CI 1.01–1.26). In contrast, among 15 400 patients with late transplant failure (graft survival ≥12 m), nephrectomy was performed in 27%, and was associated with a decreased risk of death (HR 0.89, 95% CI 0.83–0.95). In early transplant failure patients, nephrectomy was associated with a lower risk of repeat transplant failure (HR 0.72, 95% CI 0.56–0.94), while among late transplant failure patients; nephrectomy was associated with a higher risk of repeat transplant failure (HR 1.20, 95% CI 1.02–1.41). Definitive conclusions are not possible from this observational study. The role of nephrectomy in the management of dialysis treated transplant failure patients, and the implications of nephrectomy for repeat transplantation should be further studied in prospective studies.

The survival benefit of kidney transplantation in obese patients.

Obese patients have a decreased risk of death on dialysis but an increased risk of death after transplantation, and may derive a lower survival benefit from transplantation. Using data from the United States between 1995 and 2007 and multivariate non‐proportional hazards analyses we determined the relative risk of death in transplant recipients grouped by body mass index (BMI) compared to wait‐listed candidates with the same BMI (n = 208 498). One year after transplantation the survival benefit of transplantation varied by BMI: Standard criteria donor transplantation was associated with a 48% reduction in the risk of death in patients with BMI ≥ 40 kg/m2 but a ≥66% reduction in patients with BMI < 40 kg/m2. Living donor transplantation was associated with ≥66% reduction in the risk of death in all BMI groups. In sub‐group analyses, transplantation from any donor source was associated with a survival benefit in obese patients ≥50 years, and diabetic patients, but a survival benefit was not demonstrated in Black patients with BMI ≥ 40 kg/m2. Although most obese patients selected for transplantation derive a survival benefit, the benefit is lower when BMI is ≥40 kg/m2, and uncertain in Black patients with BMI ≥ 40 kg/m2.

Quantification of the Early Risk of Death in Elderly Kidney Transplant Recipients

To inform decision making regarding transplantation in patients ≥ 65 years, we quantified the early posttransplant risk of death by determining the time to equal risk and equal survival between transplant recipients and wait‐listed dialysis patients in the United States between 1995 and 2007 (total n = 25 468). Survival was determined using separate multivariate nonproportional hazards analyses in low‐, intermediate‐ and high‐risk cardiovascular risk patients. Compared to wait‐listed patients with similar cardiovascular risk, standard criteria (SCD) and expanded criteria (ECD) recipients had a higher risk of death in the perioperative and early‐posttransplant period. In contrast, low and intermediate risk living donor (LD) recipients had an immediate survival advantage compared to similar risk wait‐listed patients. In all risk groups, transplantation was associated with a long‐term survival advantage compared to dialysis, but there were marked differences in time to equal risk of death, and time to equal survival by donor type. For example, survival in high‐risk recipients of an LD, SCD and ECD transplant became equal to that in similar risk wait‐listed patients 130, 368 and 521 days after transplantation. Early posttransplant mortality risk is eliminated in low‐ and intermediate‐risk patients, and markedly reduced in high‐risk patients with LD transplantation.

The Effect of Race and Income on Living Kidney Donation in the United States

Studies of racial disparities in access to living donor kidney transplantation focus mainly on patient factors, whereas donor factors remain largely unexamined. Here, data from the US Census Bureau were combined with data on all African-American and white living kidney donors in the United States who were registered in the United Network for Organ Sharing (UNOS) between 1998 and 2010 (N=57,896) to examine the associations between living kidney donation (LKD) and donor median household income and race. The relative incidence of LKD was determined in zip code quintiles ranked by median household income after adjustment for age, sex, ESRD rate, and geography. The incidence of LKD was greater in higher-income quintiles in both African-American and white populations. Notably, the total incidence of LKD was higher in the African-American population than in the white population (incidence rate ratio [IRR], 1.20; 95% confidence interval [95% CI], 1.17 to 1.24]), but ratios varied by income. The incidence of LKD was lower in the African-American population than in the white population in the lowest income quintile (IRR, 0.84; 95% CI, 0.78 to 0.90), but higher in the African-American population in the three highest income quintiles, with IRRs of 1.31 (95% CI, 1.22 to 1.41) in Q3, 1.50 (95% CI, 1.39 to 1.62) in Q4, and 1.87 (95% CI, 1.73 to 2.02) in Q5. Thus, these data suggest that racial disparities in access to living donor transplantation are likely due to socioeconomic factors rather than cultural differences in the acceptance of LKD.

Screening for de novo anti-human leukocyte antigen antibodies in nonsensitized kidney transplant recipients does not predict acute rejection.

Background. The purpose of this study was to determine whether screening for anti-human leukocyte antigen (HLA) antibodies (Abs) could predict development of acute rejection (AR) before clinical evidence of kidney allograft dysfunction in nonsensitized recipients. Methods. Eighty-four non-HLA identical kidney transplant recipients were prospectively tested for anti-HLA Abs (FlowPRA analysis and anti-HLA Ab specificity determination) at 0, 10, 20, 30, 60, 90, 180 and 365 posttransplantation, and at the time of clinical suspicion of AR. Allograft biopsies were performed at the time of engraftment, 3 and 12 months posttransplantation, when patients developed new anti-HLA Abs, or when clinically indicated. Results. Among the 70 patients without preformed anti-HLA Abs, 11 developed de novo anti-HLA Abs (8 donor-specific Abs) at a median of 30 days (q1-q3=10–180 days) after transplantation. Patients with de novo anti-HLA Abs had a shorter time to AR than patients without de novo anti-HLA Abs, P=0.06. However, in all cases, de novo anti-HLA Abs developed concomitantly or after a clinically evident AR. Conclusions. Although de novo anti-HLA Abs were associated with AR, routine screening for anti-HLA Abs was not useful in identifying patients at risk for AR before clinical evidence of allograft dysfunction.

Prevention of Sepsis during the Transition to Dialysis May Improve the Survival of Transplant Failure Patients

Dialysis patients are at risk for sepsis, and the risk may be even higher among transplant failure patients because of previous or ongoing immunosuppression. The incidence and the consequences of sepsis as defined by International Classification of Diseases, Ninth Revision, Clinical Modification hospital discharge diagnoses codes were determined among 5117 patients who initiated dialysis after transplant failure between 1995 and 2004 in the United States. The overall sepsis rate was 11.8 per 100 patient years (95% confidence interval [CI] 11.5 to 12.1). Sepsis was highest in the first 6 mo after transplant failure (35.6 per 100 patient years [95% CI 29.4 to 43.0] between 0 to 3 mo after transplant failure; 19.7 per 100 patient years [95% CI 17.2 to 22.5] between 3 to 6 mo after transplant failure). In comparison, the sepsis rate among incident dialysis patients between 3 and 6 mo after dialysis initiation was 7.8 per 100 patient years (95% CI 7.3 to 8.3), whereas the sepsis rate among transplant recipients between 3 and 6 mo after transplantation was 5.4 per 100 patient years (95% CI 4.9 to 5.9). Patients who were > or =60 yr, obese patients, patients with diabetes, and patients with a history or peripheral vascular disease or congestive heart failure were at risk for sepsis. Transplant nephrectomy was not associated with septicemia. The role of continued immunosuppression and vascular access creation was not assessed and should be addressed in future studies. In a multivariate analysis, patients who were hospitalized for sepsis had an increased risk for death (hazard ratio 2.93; 95% CI 2.64 to 3.24; P < 0.001). Strategies to prevent sepsis during the transition from transplantation to dialysis may improve the survival of patients with allograft failure.

Income of living kidney donors and the income difference between living kidney donors and their recipients in the United States.

Disincentives for living kidney donation are common but are poorly understood. We studied 54 483 living donor kidney transplants in the United States between 2000 and 2009, limiting to those with valid zip code data to allow determination of median household income by linkage to the 2000 U.S. Census. We then determined the income and income difference of donors and recipients. The median household income in donors and recipients was