S. Joseph Kim

Delayed Graft Function and the Risk for Death with a Functioning Graft

Delayed graft function (DGF) associates with an increased risk for graft failure, but its link with death with graft function (DWGF) is unknown. We used the US Renal Data System to assemble a cohort of all first, adult, deceased-donor kidney transplant recipients from January 1, 1998, through December 31, 2004. In total, 11,542 (23%) of 50,246 recipients required at least one dialysis session in the first week after transplantation. Compared with patients without DGF, patients with DGF were significantly more likely to die with a functioning graft (relative hazard 1.83 [95% confidence interval 1.73 to 1.93] and 1.53 [95% CI 1.45 to 1.63] for unadjusted and fully adjusted models, respectively). The risk for DWGF was slightly higher among women with DGF than among men. There was no significant heterogeneity among other subgroups, and the results were robust to sensitivity analyses. Acute rejection within the first year attenuated the DGF-DWGF association. Cardiovascular and infectious deaths were slightly more prevalent in the DGF group, but the relative hazards of cause-specific death were similar between DWGF and deaths during total follow-up. In summary, DGF associates with an increased risk for DWGF; the mechanisms underlying the negative impact of DGF require further study.

Reduced Incidence of New-Onset Diabetes Mellitus after Renal Transplantation with 3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase Inhibitors (Statins)

Statins have anti‐inflammatory effects, modify endothelial function and improve peripheral insulin resistance. We hypothesized that statins influence the development of new‐onset diabetes mellitus in renal transplant recipients. The records of all previously non‐diabetic adults who received an allograft in Toronto between January 1, 1999 and December 31, 2001 were reviewed with follow‐up through December 31, 2002. All patients receiving cyclosporine or tacrolimus, mycophenolate mofetil and prednisone were included. New‐onset diabetes was diagnosed by the Canadian Diabetic Association criteria: fasting plasma glucose ≥7.0 mmol/L or 2‐h postprandial glucose ≥11.1 mmol/L on more than two occasions. Statin use prior to diabetes development was recorded along with other variables. Cox proportional hazards models analyzing statin use as a time‐dependent covariate were performed. Three hundred fourteen recipients met study criteria, of whom 129 received statins. New‐onset diabetes incidence was 16% (n = 49). Statins (p = 0.0004, HR 0.238[0.109–0.524]) and ACE inhibitors/ARB (p = 0.01, HR 0.309[0.127–0.750]) were associated with decreased risk. Prednisone dose (p = 0.0001, HR 1.007[1.003–1.010] per 1 mg/d at 3 months), weight at transplant (p = 0.02, HR 1.022[1.003–1.042] per 1 kg), black ethnicity (p = 0.02, HR 1.230[1.023–1.480]) and age ≥45 years (p = 0.01, HR 2.226[1.162–4.261]) were associated with increased diabetes. Statin use is associated with reduced new‐onset diabetes development after renal transplantation.

Time-dependent variability in tacrolimus trough blood levels is a risk factor for late kidney transplant failure

Wide variations in tacrolimus levels have been identified as a risk factor for inferior kidney allograft survival but past studies have not properly accounted for the dynamic nature of drug exposure over time. Here we evaluated whether time-varying exposure to tacrolimus increases the risk of long-term adverse outcomes in a retrospective cohort study in adult kidney transplant recipients on tacrolimus-based immunosuppression. Time-dependent Cox proportional hazards models were used to examine the association between the standard deviation of tacrolimus levels (TacSD) starting at 1-year post-transplant and the composite end point of late allograft rejection, transplant glomerulopathy, or total graft loss (including death). Among 356 patients, there was a significant 27% increase in the adjusted hazard of the composite end point for every 1-unit increase in TacSD (hazard ratio 1.27 (95% confidence interval 1.03, 1.56)). There was also a graded increase in the relative hazard for the composite end point by TacSD threshold (hazard ratios 1.33, 1.50, 1.84, and 2.56 for TacSD 1.5, 2, 2.5, and 3, respectively). The results were similar for total graft loss and the composite end point excluding death. Thus, increased time-dependent TacSD may be an independent risk factor for adverse kidney transplant outcomes. TacSD may serve as a monitoring tool to identify high-risk patients. Whether interventions to decrease TacSD will improve outcomes requires further study.

Cancer Mortality Among Recipients of Solid-Organ Transplantation in Ontario, Canada

IMPORTANCE Solid-organ transplant recipients (SOTRs) are at greater risk of developing some cancers than the general population; however, because they are also at increased risk of mortality from noncancer causes, the effect of transplantation on cancer mortality is unclear. OBJECTIVE To describe cancer mortality in SOTRs and to assess whether SOTRs are at increased risk of cancer mortality compared with the general population. DESIGN, SETTING, AND PARTICIPANTS Population-based cohort study of patients who underwent solid-organ transplantation in Ontario, Canada, between 1991 and 2010 with 85 557 person-years of follow-up through December 31, 2011. Solid-organ transplantation was identified using the national transplant register and linked to the provincial cancer registry and administrative databases. The analysis was conducted between November 2013 and February 2015. EXPOSURE Solid-organ transplantation. MAIN OUTCOMES AND MEASURES Cancer mortality for SOTRs was compared with that of the general population using standardized mortality ratios (SMRs). Mortality and cause of death were ascertained by record linkage between the Canadian Organ Replacement Register, the Ontario Cancer Registry, and the Office of the Registrar General of Ontario death database. RESULTS A total of 11 061 SOTRs were identified, including 6516 kidney, 2606 liver, 929 heart, and 705 lung transplantations. Recipients had a median (interquartile range) age of 49 (37-58) years, and 4004 (36.2%) were women. Of 3068 deaths, 603 (20%) were cancer related. Cancer mortality in SOTRs was significantly elevated compared with the Ontario population (SMR, 2.84 [95% CI, 2.61-3.07]). The risk remained elevated when patients with pretransplant malignant neoplasms (n = 1124) were excluded (SMR, 1.93 [95% CI, 1.75-2.13]). The increased risk was observed irrespective of transplanted organ. The SMR for cancer death after solid-organ transplantation was higher in children (SMR, 84.61 [95% CI, 52.00-128.40]) and lower in patients older than 60 years (SMR, 1.88 [95% CI, 1.62-2.18]) but remained elevated compared with the general population at all ages. CONCLUSIONS AND RELEVANCE Cancer death rate in SOTRs was increased compared with that expected in the general population; cancer was the second leading cause of death in these patients. Advances in prevention, clinical surveillance, and cancer treatment modalities for SOTRs are needed to reduce the burden of cancer mortality in this population.

Levofloxacin for BK Virus Prophylaxis Following Kidney Transplantation A Randomized Clinical Trial

IMPORTANCE BK virus infection is a significant complication of modern immunosuppression used in kidney transplantation. Viral reactivation occurs first in the urine (BK viruria) and is associated with a high risk of transplant failure. There are currently no therapies to prevent or treat BK virus infection. Quinolone antibiotics have antiviral properties against BK virus but efficacy at preventing this infection has not been shown in prospective controlled studies. OBJECTIVE To determine if levofloxacin can prevent BK viruria in kidney transplant recipients. DESIGN, SETTING, AND PARTICIPANTS Double-blind, placebo-controlled randomized trial involving 154 patients who received a living or deceased donor kidney-only transplant in 7 Canadian transplant centers between December 2011 and June 2013. INTERVENTIONS Participants were randomly assigned to receive a 3-month course of levofloxacin (500 mg/d; n = 76) or placebo (n = 78) starting within 5 days after transplantation. MAIN OUTCOMES AND MEASURES The primary outcome was time to occurrence of BK viruria (detected using quantitative real-time polymerase chain reaction) within the first year after transplantation. Secondary outcomes included BK viremia, peak viral load, rejection, and patient and allograft survival. RESULTS The mean follow-up time was 46.5 weeks in the levofloxacin group and 46.3 weeks in the placebo group (27 patients had follow-up terminated before the end of the planned follow-up period or development of viruria because the trial was stopped early owing to lack of funding). BK viruria occurred in 22 patients (29%) in the levofloxacin group and in 26 patients (33.3%) in the placebo group (hazard ratio, 0.91; 95% CI, 0.51-1.63; P = .58). There was no significant difference between the 2 groups in regard to any of the secondary end points. There was an increased risk of resistant infection among isolates usually sensitive to quinolones in the levofloxacin group vs placebo (14/24 [58.3%] vs 15/45 [33.3%], respectively; risk ratio, 1.75; 95% CI, 1.01-2.98) as well as a nonsignificant increased risk of suspected tendinitis (6/76 [7.9%] vs 1/78 [1.3%]; risk ratio, 6.16; 95% CI, 0.76-49.95). CONCLUSIONS AND RELEVANCE Among kidney transplant recipients, a 3-month course of levofloxacin initiated early following transplantation did not prevent BK viruria. Levofloxacin was associated with an increased risk of adverse events such as bacterial resistance. These findings do not support the use of levofloxacin to prevent posttransplant BK virus infection. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01353339.

Delayed graft function and the risk of acute rejection in the modern era of kidney transplantation

Delayed graft function (DGF) is commonly considered a risk factor for acute rejection, although this finding has not been uniformly observed across all studies. The link between DGF and acute rejection may have changed over time due to advances in immunosuppression and medical management. Here we conducted a cohort study of 645 patients over 12 years to evaluate the association of DGF and biopsy-proven acute rejection (BPAR) in a modern cohort of kidney transplant recipients. DGF was defined as the need for at least one dialysis session in the first week after kidney transplantation. The 1-, 3-, and 5-year cumulative probabilities of BPAR were 16.0, 21.8, and 22.6% in the DGF group, significantly different from the 10.1, 12.4, and 15.7% in the non-DGF group. In multivariable Cox proportional hazards model, the adjusted relative hazard for BPAR in DGF (vs. no DGF) was 1.55 (95% confidence interval (CI): 1.03, 2.32). This association was generally robust to different definitions of DGF. The relative hazard was also similarly elevated for T-cell- or antibody-mediated BPAR (1.52 (0.92, 2.51) and 1.54 (0.85, 2.77), respectively). Finally, the association was consistent across clinically relevant subgroups. Thus DGF remains an important risk factor for BPAR in a contemporary cohort of kidney transplant recipients. Interventions to reduce the risk of DGF and/or its aftereffects remain of paramount importance to improve kidney transplant outcomes.

Informing the Debate: Rates of Kidney Transplantation in Nations With Presumed Consent

BACKGROUND The kidney is the most common transplanted organ, accounting for almost all living donor transplantations and most deceased donor organ transplantations. The organ shortage has caused policymakers in many nations to debate the merits of adopting presumed consent legislation as a way to increase donor organ donation from deceased donors. OBJECTIVE To compare characteristics and kidney transplantation rates for countries with presumed consent for deceased organ donation with countries with explicit consent. DESIGN A longitudinal study of international kidney transplantation from 1997 to 2007. SETTING 44 nations performing kidney transplantation. PATIENTS Recipients of deceased and living kidney donor transplants. MEASUREMENTS Rates of transplantation of kidneys from deceased and living donors. RESULTS National characteristics, such as population size, proportion of the population self-identified as Catholic, per capita gross domestic product, health expenditures, and physician density, varied widely for the 22 nations with presumed consent and the 22 nations with explicit consent. Deceased donor kidney transplantation rates were higher in nations with presumed consent (median, 22.6 transplantations per million population [pmp]; interquartile range [IQR], 9.3 to 33.8) versus nations with explicit consent (median, 13.9 transplantations pmp; IQR, 3.6 to 23.1). Living donor kidney transplantation rates were lower in nations with presumed consent (median, 2.4 transplantations pmp; IQR, 1.7 to 4.3) versus nations with explicit consent (median, 5.9 transplantations pmp; IQR, 2.3 to 12.2). The findings were consistent when nations were classified according to per capita gross domestic product, health expenditures, and physician density. LIMITATION As with any observational study, associations may not be causal. CONCLUSION Nations with presumed consent have higher rates of deceased donor kidney transplantation than nations with explicit consent. Any nation deciding to adopt presumed consent should carefully consider and reduce any negative effect on rates of living donation. PRIMARY FUNDING SOURCE Canadian Institutes of Health Research and Lawson Health Research Institute.

De Novo DQ Donor-Specific Antibodies Are Associated with Chronic Lung Allograft Dysfunction after Lung Transplantation

RATIONALE Despite increasing evidence about the role of donor-specific human leukocyte antigen (HLA) antibodies in transplant outcomes, the incidence and impact of de novo donor-specific antibodies (dnDSA) after lung transplantation remains unclear. OBJECTIVES To describe the incidence, characteristics, and impact of dnDSA after lung transplantation. METHODS We investigated a single-center cohort of 340 lung transplant recipients undergoing transplant during 2008 to 2011. All patients underwent HLA-antibody testing quarterly pretransplant and at regular intervals over the first 24 months after transplant. The patients received modified immunosuppression depending on their pretransplant sensitization status. Risk factors for dnDSA development, as well as the associations of dnDSA with patient survival and chronic lung allograft dysfunction (CLAD), were determined using multivariable analysis. MEASUREMENTS AND MAIN RESULTS The cumulative incidence of dnDSA was 47% at a median of 86 days (range, 44-185 d) after lung transplantation. Seventy-six percent of recipients with dnDSA had DQ-DSA. Male sex and the use of ex vivo lung perfusion were associated with an increased risk of dnDSA, whereas increased HLA-DQB1 matching was protective. DQ-dnDSA preceded or coincided with the diagnosis of CLAD in all cases. Developing dnDSA (vs. no dnDSA) was associated with a twofold increased risk of CLAD (hazard ratio, 2.04; 95% confidence interval, 1.13-3.69). This association appeared to be driven by the development of DQ-dnDSA. CONCLUSIONS dnDSA are common after lung transplantation, with the majority being DQ DSA. DQ-dnDSA are associated with an increased risk of CLAD. Strategies to prevent or treat DQ-dnDSA may improve outcomes for lung transplant recipients.

Individuals of Pacific Asian origin with IgA nephropathy have an increased risk of progression to end-stage renal disease.

IgA nephropathy (IgAN) accounts for a far higher proportion of end-stage renal disease (ESRD) in Asia compared with North America. It is not known whether this is entirely because of differences in disease prevalence or a higher risk of disease progression. The lack of a racially diverse population cohort followed longitudinally has previously precluded the ability to address this question. To determine whether Asians in North America with IgAN are at higher risk for ESRD, we analyzed a cohort of 202 patients of self-reported Pacific Asian origin and 467 of other origin from the Toronto GN Registry followed up for a median of 46.4 months. The primary outcome of ESRD (dialysis, transplantation, or eGFR below 15) was analyzed using Cox regression analysis. Baseline eGFR was 59.6 ml/min/1.73 m(2), and median proteinuria was 1.8 g/day. ESRD occurred in 213 patients. By univariable analysis, the risk of ESRD was similar between the two groups (hazard ratio 0.98, 95% CI 0.73, 1.31); however, after adjusting for age, gender, eGFR, medication use, blood pressure, and proteinuria, the risk of ESRD was significantly higher in Pacific Asian individuals (hazard ratio 1.56, 95% CI 1.10, 2.22). This was supported by a significant 1.62 ml/min/1.73 m(2)/year faster rate of eGFR decline (95% CI -3.19, -0.5) and an increased risk of a reduction in eGFR by half (hazard ratio 1.81, 95% CI 1.25, 2.62). Thus, in a large multiracial cohort of patients with IgAN, individuals of Pacific Asian origin have a higher risk of progression to ESRD.

Survival and Hospitalization for Intensive Home Hemodialysis Compared with Kidney Transplantation

Canadian patients receiving intensive home hemodialysis (IHHD; ≥16 hours per week) have survival comparable to that of deceased donor kidney transplant recipients in the United States, but a comparison with Canadian kidney transplant recipients has not been conducted. We conducted a retrospective cohort study of consecutive, adult IHHD patients and kidney transplant recipients between 2000 and 2011 at a large Canadian tertiary care center. The primary outcome was time-to-treatment failure or death for IHHD patients compared with expanded criteria, standard criteria, and living donor recipients, and secondary outcomes included hospitalization rate. Treatment failure was defined as a permanent switch to an alternative dialysis modality for IHHD patients, and graft failure for transplant recipients. The cohort comprised 173 IHHD patients and 202 expanded criteria, 642 standard criteria, and 673 living donor recipients. There were 285 events in the primary analysis. Transplant recipients had a reduced risk of treatment failure/death compared with IHHD patients, with relative hazards of 0.45 (95% confidence interval [95% CI], 0.31 to 0.67) for living donor recipients, 0.39 (95% CI, 0.26 to 0.59) for standard criteria donor recipients, and 0.42 (95% CI, 0.26 to 0.67) for expanded criteria donor recipients. IHHD patients had a lower hospitalization rate in the first year of treatment compared with standard criteria donor recipients and in the first 3 months of treatment compared with living donor and expanded criteria donor recipients. In this cohort, kidney transplantation was associated with superior treatment and patient survival, but higher early rates of hospitalization, compared with IHHD.