Hung-Tien Kuo

Associations of Pretransplant Diabetes Mellitus, New-Onset Diabetes After Transplant, and Acute Rejection With Transplant Outcomes: An Analysis of the Organ Procurement and Transplant Network/United Network for Organ Sharing (OPTN/UNOS) Database

BACKGROUND Diabetes and acute rejection are major contributors to morbidity and mortality in kidney transplant recipients. Immunosuppressive medications decrease acute rejection, but increase the frequency of new-onset diabetes after transplant. Our objective was to investigate the joint associations of diabetes (pretransplant diabetes and new-onset diabetes after transplant) and acute rejection with transplant outcomes in a recent transplant cohort. STUDY DESIGN Historical cohort study. SETTING & PARTICIPANTS 37,448 recipients (age ≥ 18 years; 2004-2007) surviving with a functioning transplant for longer than 1 year were identified in the Organ Procurement and Transplant Network/United Network for Organ Sharing (OPTN/UNOS) database as of May 22, 2009. PREDICTORS Recipients were stratified into 6 mutually exclusive groups according to status of diabetes and acute rejection at 1 year: group 1, neither (reference; n = 20,964); group 2, new-onset diabetes alone (n = 2,140); group 3, pretransplant diabetes alone (n = 10,730); group 4, acute rejection alone (n = 2,282); group 5, new-onset diabetes and acute rejection (n = 361); and group 6, pretransplant diabetes and acute rejection (n = 1,061). Analyses were adjusted for other recipient, donor, and transplant characteristics. OUTCOMES MEASUREMENTS: Multivariate Cox regression analysis of time to transplant failure (overall and death censored) and mortality (all-cause and cardiovascular). RESULTS Median follow-up after 1 year was 548 days (25th-75th percentiles, 334-752 days). During this time, there were 3,047 outcomes of overall transplant failure. New-onset diabetes alone (group 2) was not associated significantly with any study outcomes. Groups 3-6 were associated with higher overall transplant failure risk. However, only groups 4-6 were associated with higher death-censored transplant failure risk. Group 3, 4, and 6 were associated with higher all-cause mortality risk, whereas only groups 3 and 6 were associated with higher cardiovascular mortality risk. LIMITATIONS Potential information bias with exposure, covariable, or outcome misclassification; relatively short follow-up. CONCLUSIONS Pretransplant diabetes is the major predictor of all-cause and cardiovascular mortality, and acute rejection during the first year is the major predictor of death-censored transplant failure in kidney recipients surviving with a functioning transplant for at least 1 year. The influence of new-onset diabetes on long-term outcomes needs further observation.

Obesity Was Associated With Inferior Outcomes in Simultaneous Pancreas Kidney Transplant

Background. In kidney transplant, obesity was reported to be associated with increased posttransplant complications and worse survival outcomes. The impact of obesity in simultaneous pancreas-kidney (SPK) transplant is less known. Methods. Using Organ Procurement Transplantation Network/United Network for Organ Sharing data as of August 2008, we included all adults (>18 years) type 1 diabetic SPK recipients between years 2000 and 2007 with a pretransplant body mass index (BMI) of 18.5 to 40 kg/m2. The cohort was divided in three groups: normal (BMI 18.5–24.9 kg/m2, reference group), overweight (BMI 25–29.9 kg/m2), and obese (BMI 30–40 kg/m2). Covariate-adjusted relative risk of a combination of posttransplant complications and patient, pancreas and kidney allograft outcomes were evaluated. Results. Of 5725 recipients, 56%, 33%, and 11% were in normal, overweight, and obese groups, respectively. Overweight and obese recipients were older, had a higher percent of coronary artery disease, and private health insurance coverage. Overall posttransplant complications were higher in obese group (35.7% vs. 28.6%) when compared with normal BMI group. They were mainly due to increased delayed kidney graft function (11.8% vs. 7.4%), 1-year kidney acute rejection (17.0% vs. 12.1%), and pancreas graft thrombosis (2.6% vs. 1.3%). After adjusting for possible confounders, the odds ratios for overall transplant complications were 1.03 (95% confidence interval [CI]: 0.90–1.17) for overweight and 1.38 (95% CI: 1.15–1.68) for obese. Obesity, but not overweight, was associated with patient death (hazard ratio [HR]: 1.35; 95% CI: 1.00–1.81), pancreas graft loss (HR: 1.41; 95% CI: 1.17–1.69), and kidney graft loss (HR: 1.33; 95% CI: 1.05–1.67) at 3 years. The higher rates of death and graft failure in the first 30 days posttransplant mostly accounted for the 3-year survival differences. Conclusion. Obesity in SPK recipients was associated with increased risk of posttransplant complications, pancreas and kidney graft loss, and patient death.

Association of Fluid Overload with Cardiovascular Morbidity and All-Cause Mortality in Stages 4 and 5 CKD

BACKGROUND AND OBJECTIVES Fluid overload is a common characteristic associated with renal progression in CKD. Additionally, fluid overload is an independent predictor of all-cause or cardiovascular mortality in patients on dialysis, but its influence on patients not on dialysis is uncertain. The aim of the study was to assess the relationship between the severity of fluid status and clinical outcomes in an advanced CKD cohort. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS In total, 478 predialysis patients with stages 4 and 5 CKD in the integrated CKD care program were enrolled from January of 2011 to December of 2011 and followed-up until August of 2013. The clinical outcomes included cardiovascular morbidity and all-cause mortality. The relative hydration status (overhydration/extracellular water) was used as the presentation of the severity of fluid status and measured using a body composition monitor. Overhydration/extracellular water >7% was defined as fluid overload. RESULTS Over a median follow-up period of 23.2 (12.6-26.4) months, 66 (13.8%) patients reached all-cause mortality or cardiovascular morbidity. The adjusted hazard ratio of the combined outcome of all-cause mortality or cardiovascular morbidity for every 1% higher overhydration/extracellular water was 1.08 (95% confidence interval, 1.04 to 1.12; P<0.001). The adjusted overhydration/extracellular water for the combined outcome of all-cause mortality or cardiovascular morbidity in participants with overhydration/extracellular water ≥7% compared with those with overhydration/extracellular water <7% was 1.93 (95% confidence interval, 1.01 to 3.69; P=0.04). In subgroup analysis, higher overhydration/extracellular water was consistently associated with increased risk for the combined outcome independent of diabetes, cardiovascular disease, and serum albumin. There was no significant interaction between all subgroups. CONCLUSIONS These findings suggest that fluid overload is an independent risk factor of the combined outcome of all-cause mortality or cardiovascular morbidity in patients with advanced CKD.

Intermediate-term outcomes associated with kidney transplantation in recipients 80 years and older: an analysis of the OPTN/UNOS database.

Background. An increasing number of patients 80 years and older have received a kidney transplant in the United States, but their outcomes are not well described. Using Organ Procurement and Transplantation Network/United Network of Organ Sharing data, outcomes of recipients 80 years and older were evaluated. Methods. Thirty-one thousand one hundred seventy-nine elderly recipients defined by age 60 years and older receiving kidney transplants from 2000 to 2008 were stratified: ages 60 to 69 years (n=24,877), 70 to 79 years (n=6,103), and 80 years and older (n=199). Cox regression models were used to compare patient, graft, and death-censored graft survival. Results. The majority of recipients 80 years and older was male (82.9%), white (87.9%), and less likely to have diabetes or coronary artery disease. More expanded criteria donor (ECD) but fewer living donor transplants were performed among 80 years and older compared with those younger than 80 years. Perioperative mortality, defined as death within 30 days posttransplant, was rare (60–69 years: 1.4%; 70–79 years: 1.5%; and ≥80 years: 2.5%) but tended to be higher among those 80 years and older compared with recipients 60 to 69 years (hazard ratio [HR] 1.67; 95% confidence interval [CI] 0.69–4.05). At 2 years, survival was lower for 80 years and older (73%; HR 2.42; 95% CI 1.91–3.06) and 70 to 79 years (86%; HR: 1.42; 95% CI: 1.34–1.51) compared with recipients 60 to 69 years (89%). There was a greater risk of graft loss among recipients 80 years and older compared with those 60 to 69 years (HR 1.78; 95% CI 1.42–2.23); however, no difference in death-censored graft survival was observed (0.89; 0.57–1.39). Among recipients 80 years and older, no difference in survival was observed between standard criteria donor and ECD recipients. Conclusion. Although perioperative mortality was uncommon among elderly recipients (1.5%), a trend toward higher perioperative mortality was observed in recipients 80 years and older. There was no difference in survival among standard criteria donor and ECD recipients.

Outcomes of Simultaneous Pancreas-Kidney Transplantation in Type 2 Diabetic Recipients

BACKGROUND AND OBJECTIVES Type 2 diabetic patients with end-stage renal disease may receive a simultaneous pancreas-kidney (SPK) transplant. However, outcomes are not well described. Risks for death and graft failure were examined in SPK type 2 diabetic recipients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Using the United Network for Organ Sharing database, outcomes of SPK transplants were compared between type 2 and type 1 diabetic recipients. All primary SPK adult recipients transplanted between 2000 and 2007 (n=6756) were stratified according to end-stage pancreas disease diagnosis (type 1: n=6141, type 2: n=582). Posttransplant complications and risks for death and kidney/pancreas graft failure were compared. RESULTS Of the 6756 SPK transplants, 8.6% were performed in recipients with a type 2 diabetes diagnosis. Rates of delayed kidney graft function and primary kidney nonfunction were higher in the type 2 diabetics. Five-year overall and death-censored kidney graft survival were inferior in type 2 diabetics. After adjustment for other risk factors, including recipient (age, race, body weight, dialysis time, and cardiovascular comorbidities), donor, and transplant immune characteristics, type 2 diabetes was not associated with increased risk for death or kidney or pancreas failure when compared with type 1 diabetic recipients. CONCLUSIONS After adjustment for other risk factors, SPK recipients with type 2 diabetes diagnosis were not at increased risk for death, kidney failure, or pancreas failure when compared with recipients with type 1 diabetes.

Induction Immunosuppressive Therapy in the Elderly Kidney Transplant Recipient in the United States

BACKGROUND AND OBJECTIVES The choice of induction agent in the elderly kidney transplant recipient is unclear. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS The risks of rejection at 1 year, functional graft loss, and death by induction agent (IL2 receptor antibodies [IL2RA], alemtuzumab, and rabbit antithymocyte globulin [rATG]) were compared among five groups of elderly (≥60 years) deceased-donor kidney transplant recipients on the basis of recipient risk and donor risk using United Network of Organ Sharing data from 2003 to 2008. RESULTS In high-risk recipients with high-risk donors there was a higher risk of rejection and functional graft loss with IL2RA versus rATG. Among low-risk recipients with low-risk donors there was no difference in outcomes between IL2RA and rATG. In the two groups in which donor or recipient was high risk, there was a higher risk of rejection but not functional graft loss with IL2RA. Among low-risk recipients with high-risk donors, there was a trend toward a higher risk of death with IL2RA. CONCLUSIONS rATG may be preferable in high-risk recipients with high-risk donors and possibly low-risk recipients with high-risk donors. In the remaining groups, although rATG is associated with a lower risk of acute rejection, long-term outcomes do not appear to differ. Prospective comparison of these agents in an elderly cohort is warranted to compare the efficacy and adverse consequences of these agents to refine the use of induction immunosuppressive therapy in the elderly population.

Risk Factors for Development of New-Onset Diabetes Mellitus in Adult Heart Transplant Recipients

Background. The objectives of this study are to examine the incidence of new-onset diabetes mellitus (NODM) and to identify its risk factors in adult heart recipients using the Organ Procurement and Transplant Network/United Network of Organ Sharing database. Methods. Between July 2004 and December 2007, 4972 adults (aged 18 years or older) received their first heart transplant alone, and had at least one follow-up report of posttransplant diabetic status. Among these, 3763 recipients were identified as not having diabetes mellitus pretransplant. Risk factors for NODM were examined using multivariate Cox regression analysis using the time to NODM diagnosis as a time-varying endpoint. Results. NODM was reported in 1075 (28.6%) of the 3763 recipients without pretransplant diabetes (median follow-up time, 713 days). Independent risk factors for development of NODM included older age (hazard ratio=1.20 for age ≥50 years vs. <50, P=0. 01), non-white race (0.70 for white vs. non-white, P<0.0001), higher body mass index (BMI) (1.55 for BMI ≥25 vs. <25, P<0.0001), ischemic heart disease (1.24, P<0.0001), recipient cytomegalovirus positivity (1.16, P=0.003), tobacco use (1.16, P=0.02), tacrolimus use at discharge (1.85 for tacrolimus vs. cyclosporine use, P<0.0001), and use of steroids at discharge (2.59 for steroid use vs. none, P=0.008). Conclusions. NODM is common and occurs in more than a quarter of heart recipients during the median follow-up period of 2 years. Risk factors for NODM after heart transplant are similar to those reported in other solid organ transplants. Some of these factors, such as BMI and immunosuppressive regimen, are potentially modifiable.

Increased glomerular and extracellular malondialdehyde levels in patients and rats with focal segmental glomerulosclerosis

Background  Evidence suggests an increase in oxidative stress in patients with chronic kidney disease, as glomerulosclerosis is the prerequisite for chronic kidney disease; whether the oxidative stress already exists early on is not known.

Risk Factors for Development of New-onset Diabetes Mellitus in Pediatric Renal Transplant Recipients: An Analysis of the Optn/unos Database

Background. The objective of this study was to identify the risk factors for new-onset diabetes mellitus (NODM) after kidney transplant in pediatric renal transplant recipients using Organ Procurement Transplant Network/United Network of Organ Sharing database. Methods. A total of 2726 nondiabetic primary kidney transplant recipients (age 2-20 years, transplanted between July 2004 and December 2007) in the Organ Procurement Transplant Network/United Network of Organ Sharing database as of August 2008 with at least one follow-up report were included. We examined the risk factors for NODM using multivariate Cox regression analysis using the time to NODM reported as a time-varying endpoint. In recipients with functional graft at 1 year after transplant, the graft survivals during subsequent 24 months were compared according to the presence of NODM within first year of transplant. Results. NODM was reported in 4.6% (median follow-up time: 693 days). Independent risk factors for NODM included increased age (>10 years vs. <10 years, hazard ratio [HR]=2.143, P=0.015), abnormal body mass index percentile (<5% or >85% vs. 5%-85%, HR=1.697, P=0.01), and steroid use at discharge (yes vs. no, HR=3.573, P=0.03). Living donor transplant was associated with a decreased risk of NODM (living vs. deceased, HR=0.629, P=0.05). NODM within first year of transplant was not associated with inferior graft survival during subsequent 24 months. Discussion. Some of the identified risk factors for NODM are potentially modifiable, including abnormal body mass index percentile and the use of steroid. Prospective clinical trials are needed to assess whether modifying these risk factors will prevent NODM.

Outcomes of preemptive kidney with or without subsequent pancreas transplant compared with preemptive simultaneous pancreas/kidney transplantation.

Background. Prior studies have indicated that type 1 diabetic (T1DM) recipients of a simultaneous pancreas-kidney (SPK) transplant have greater short-term mortality compared with living donor kidney (LDK) transplantation. Whether this association remains and how outcomes compare to deceased donor kidney (DDK) transplantation in the preemptive setting are unknown. Methods. Using data on recipients transplanted between 2000 and 2010 from the Organ Procurement and Transplantation Network/United Network of Organ Sharing, patient and graft survival (calculated from the time of kidney transplant) of pancreas after preemptive LDK (PALK, n=389), preemptive LDK not receiving a pancreas transplant (LDK/noP, n=289), preemptive DDK (n=112), and preemptive SPK transplantations (n=1402) were compared. Results. At 6 years, patient survival was excellent (PALK=89.4%, LDK/noP=84.9%, DDK=81.2%, and SPK=91.1%) and not different between PALK, LDK/noP, and SPK (P value vs. PALK: LDK/noP=0.08; SPK=0.85) but was lower with preemptive DDK versus preemptive PALK (P=0.03). When both LDK groups were considered together, there was higher mortality in the first 180 days after transplant with preemptive DDK (3.7% vs. 1.1%; P=0.03) and similar mortality with preemptive SPK (2.3%; P=0.07). After multivariate adjustment, there was a trend toward increased risk of death with preemptive DDK compared with preemptive PALK (hazard ratio: 1.91; 95% confidence interval: 0.95–3.84). Conclusions. Patient survival associated with preemptive transplantation among T1DM recipients was excellent at 6 years, with the greatest survival favoring PALK, LDK/noP, and SPK rather than DDK. In contrast with prior studies reporting greater short-term mortality with SPK among the general T1DM population, short-term mortality after preemptive transplant is similar between LDK and SPK.