Sitagliptin Versus Placebo to Reduce the Incidence and Severity of Posttransplant Diabetes Mellitus After Kidney Transplantation-A Single-center, Randomized, Double-blind Controlled Trial.

BACKGROUND: Postkidney transplant diabetes mellitus (PTDM) affects cardiovascular, allograft, and recipient health. We tested whether early intervention with sitagliptin for hyperglycemia (blood glucose >200 mg/dL) within the first week of transplant and discontinued at 3 mo could prevent development of PTDM in patients without preexisting diabetes. METHODS: The primary efficacy objective was to improve 2-h oral glucose tolerance test (OGTT) by > 20 mg/dL at 3 mo posttransplant. The secondary efficacy objective was to prevent new onset PTDM, defined as a normal OGTT at 3 mo. RESULTS: Sixty-one patients consented, and 50 patients were analyzed. The 3-mo 2-h OGTT (end of treatment) was 141.00 ± 62.44 mg/dL in the sitagliptin arm and 165.22 ± 72.03 mg/dL ( P = 0.218) in the placebo arm. The 6-mo 2-h OGTT (end of follow-up) was 174.38 ± 77.93 mg/dL in the sitagliptin arm and 171.86 ± 83.69 ng/dL ( P = 0.918) in the placebo arm. Mean intrapatient difference between 3- and 6-mo 2-h OGTT in the 3-mo period off study drug was 27.56 + 52.74 mg/dL in the sitagliptin arm and -0.14 + 45.80 mg/dL in the placebo arm ( P = 0.0692). At 3 mo, 61.54% of sitagliptin and 43.48% of placebo patients had a normal 2-h OGTT ( P = 0.2062), with the absolute risk reduction 18.06%. There were no differences in HbA1c at 3 or 6 mo between sitagliptin and placebo groups. Participants tolerated sitagliptin well. CONCLUSIONS: Although this study did not show a significant difference between groups, it can inform future studies in the use of sitagliptin in the very early posttransplant period.

Impact of antimetabolite discontinuation following cytomegalovirus or BK polyoma virus infection in kidney transplant recipients.

BACKGROUND: Cytomegalovirus (CMV) and BK polyoma virus (BKV) infection following kidney transplantation have been associated with allograft dysfunction and allograft loss. Reduction in immunosuppression is a mainstay of management yet has been associated with increased risk of rejection. According to international consensus guidelines, one approach to management of these viral infections is to discontinue the antimetabolite. Little is known surrounding long-term outcomes in these patients, and it remains unclear if consideration should be given to resuming the antimetabolite as variable re-escalation strategies have been reported. The objective was to describe episodes of rejection and identify risk factors for rejection following antimetabolite withdrawal after CMV or BKV DNAemia in kidney transplant recipients. METHODS: This single-center, retrospective review evaluated adult kidney transplant recipients with a serum CMV or BKV DNA PCR ≥500 copies/ml who underwent antimetabolite discontinuation. The primary outcome assessed was the incidence of biopsy-proven acute rejection (BPAR). RESULTS: One hundred fifty-nine patients were included. Overall, 14 patients (8.8%) experienced BPAR at a median of 1.6 years after antimetabolite discontinuation. Compared to CMV, discontinuation after BKV DNAemia was associated with a higher incidence of BPAR. Characteristics observed more frequently in patients with BPAR included younger age, female sex, higher initial viral load, and development of de novo donor-specific antibody (DSA). CONCLUSION: These findings suggest that antimetabolite discontinuation after CMV or BKV DNAemia in kidney transplant recipients is a reasonable and safe approach. Further prospective studies investigating optimal immunosuppression management following CMV or BKV DNAemia in kidney transplant recipients are warranted.

Clinical Experience with Extended-Release Tacrolimus in Older Adult Kidney Transplant Recipients: A Retrospective Cohort Study.

BACKGROUND: Extended-release tacrolimus (LCP-Tac) prescribing information states that there is insufficient data in older adult patients from which to make recommendations on use in this population. This study sought to provide information on de novo use of LCP-Tac in the older adult kidney transplant population. METHODS: This single-center retrospective study had two distinct objectives; to determine if weight-based doses of LCP-Tac differ based on recipient age and to compare safety and efficacy between LCP-Tac and immediate-release tacrolimus (IR-Tac) in older adult transplant recipients. Data was obtained through electronic chart review up to 2 years after transplant with censoring for graft loss and death. RESULTS: Weight-based doses were compared between patients aged ≥ 65 years (n = 84), 36-64 years (n = 64), and ≤35 years (n = 44). LCP-Tac weight-based doses were lower at all time points in patients ≥ 65 years of age. Both age and race significantly impacted required dose on linear regression. The doses required to achieve therapeutic tacrolimus troughs were significantly lower in all age groups compared with the current FDA de novo dosing recommendation. In the older adult population, graft outcomes and infectious and metabolic complications were compared between recipients of LCP-Tac (n = 84) and IR-Tac (n = 42). Within this cohort, there were no differences between LCP-Tac and IR-Tac on graft function, rejection, graft loss, death, cytomegalovirus viremia, BK viremia, hypertension, diabetes, alopecia, or tremor up to 2 years after transplant. CONCLUSIONS: Older adult recipients required significantly lower LCP-Tac doses compared with younger recipients and with the FDA-labeled starting dose. There were no differences in graft outcomes or adverse effects in older adult patients who received LCP-Tac versus IR-Tac.

Choice of Acid Suppressant Therapy and Long-Term Graft Outcomes After Kidney Transplantation.

STUDY OBJECTIVE: The purpose of this study was to comprehensively evaluate the long-term adverse effects of proton pump inhibitors (PPIs) compared with histamine-2 receptor antagonists (H2RAs) in kidney transplant recipients. METHODS: This retrospective cohort compared 582 patients treated with PPI with 705 patients treated with H2RA and evaluated adverse effects throughout their course of acid suppressant therapy to a maximum of nine years posttransplant. The primary outcome of interest was renal function at 1 year posttransplant; secondary outcomes included renal function at 30 days, 3, 5, and 9 years posttransplant as well as rejection, electrolyte and laboratory abnormalities, osteoporosis, pneumonia, and Clostridium difficile infections. RESULTS: Renal function did not significantly differ at any timepoint posttransplant. Rejection rates and Clostridium difficile infections were similar between groups; osteoporosis and pneumonia rates were numerically higher in the PPI treated arm but did not reach statistical significance. Proton pump inhibitor (PPI) treated patients were more likely to experience hypomagnesemia requiring supplementation. High dose PPI treated patients had significantly higher rates of pneumonia and osteoporosis compared with H2RA treated patients. Patients were maintained on PPI therapy for an average of 5 years and H2RA therapy for 3 years posttransplant, the majority without a clear indication for therapy. CONCLUSIONS: There was no difference in renal function, rejection, or graft loss between PPI and H2RA treated patients. The majority of patients were maintained on PPI therapy for several years posttransplant without a clear indication; critical evaluation of ongoing need for acid suppressant therapy in the posttransplant course should be an area of future focus.

Tacrolimus Concentration-to-Dose Ratios in Kidney Transplant Recipients and Relationship to Clinical Outcomes.

INTRODUCTION: One factor impacting tacrolimus interpatient variability is the presence of CYP3A5 polymorphisms. Low tacrolimus concentration-to-dose ratios (CDRs), or rapid metabolizers (RMs), have been associated with poor graft function outcomes and higher biopsy-proven acute rejection (BPAR) rates in a predominantly white population. Pretransplant CYP genotyping is not routinely conducted, and therefore only a small number of studies have assessed the use of tacrolimus CDRs as a surrogate for metabolism. We explored differences in outcomes between patients with low tacrolimus CDRs and high tacrolimus CDRs (i.e., nonrapid metabolizers [NRMs]) in a diverse patient population. OBJECTIVE: To determine the relationship between tacrolimus CDRs and graft and patient outcomes in kidney transplant recipients at a large transplant center between 2006 and 2016. METHODS: Inclusion criteria consisted of adult kidney transplant recipients who received rabbit antithymocyte globulin induction followed by a maintenance regimen of tacrolimus, mycophenolate, and prednisone. The primary end point was BPAR at 1 year. Secondary end points included graft survival, patient survival, and toxicities. Determination of clusters was conducted using the two-step cluster analysis with a defined two-cluster distribution. Kaplan-Meier survival curves were created using the log-rank test. RESULTS: The NRM cluster consisted of 322 patients with a mean CDR of 2.91 ng/ml/mg. The RM cluster consisted of 932 patients with a mean CDR of 1.14 ng/ml/mg. The BPAR at 1 year posttransplant was 3.7% in the NRM cluster and 3.6% in the RM cluster (p=0.95). Death at 5 years was higher in the NRM group compared with the RM group for unknown reasons (p=0.03). Differences in the incidence of posttransplant toxicities were not statistically significant at any time point, except for increased rates of cutaneous cancer at 5 years and cardiovascular disease overall in the NRM group. CONCLUSION: Tailoring tacrolimus therapy early posttransplant based on CDR is not supported by the findings in this study.

Influence of pretransplant midodrine use on outcomes after kidney transplantation.

Evaluation of potential kidney transplant recipients is important to identify and treat conditions that may influence graft or patient survival after transplantation. We performed a single-center, observational cohort study to determine whether pretransplant midodrine use influences outcomes after kidney transplantation. We analyzed graft and patient outcomes for adult patients who underwent a kidney-only transplantation at Barnes-Jewish Hospital from January 1999 to December 2015. We quantified adjusted associations of pretransplant midodrine use with post-transplant complications by multivariable Cox regression. Among the 2621 kidney transplant recipients analyzed, 37 (1.4%) were taking midodrine immediately prior to transplantation. Midodrine users were more commonly older (56.5 vs 50.4 years) and obese (67.6% vs 33.6%). Midodrine users were also more likely to be on hemodialysis (86.5% vs 59.2%), to have a longer duration of dialysis dependence (646 months vs 577 months), and to have higher levels of sensitization (peak panel reactive antibody >20%, 32.4% vs 15.8%) compared to nonusers. Pretransplant midodrine users had significantly higher rates of delayed graft function (DGF) (32.4% vs 6.7%, P < 0.001). No difference in the incidence of DGF was observed based on the midodrine dosing regimen. After multivariable adjustment for recipient and donor characteristics, pretransplant midodrine use was independently associated with graft failure at 1 year (adjusted hazard ratio, 5.11; 95% confidence interval, 2.09-12.49).

Effects of recurrent urinary tract infections on graft and patient outcomes after kidney transplantation.

BACKGROUND: Urinary tract infections (UTIs) are common following kidney transplantation (KT); however, the influence of recurrent post-KT UTI (R-UTI) is not well-characterized. METHODS: We compared graft outcomes, patient outcomes and multidrug-resistance rates between patients with no UTI, nonrecurrent UTI (NR-UTI) (urine sample containing >105 bacterial colony-forming units/mL) and R-UTI (≥2 UTIs in any 6-month period or ≥3 UTIs in any 12-month period) post-KT in a retrospective cohort study (1999-2014) at Barnes-Jewish Hospital (St Louis, MO). All adult KT recipients were included and those experiencing mortality within 30 days of KT were excluded. RESULTS: Of 2469 recipients included, 1835 (74.3%) had no UTI, 465 (18.8%) had NR-UTI and 169 (6.8%) had R-UTI. R-UTI was associated with poorer graft survival compared with NR-UTI [hazard ratio (HR) 1.45; 95% confidence interval (CI) 1.23-1.83; P < 0.001) and no UTI (HR 2.11; 95% CI 2.02-3.80; P < 0.001). This relationship persisted after adjusting for confounding factors in Cox regression (HR 2.01; 95% CI 1.53-2.66; P < 0.001). There was no difference in patient survival between no UTI and NR-UTI (HR 1.21; 95% CI 0.91-1.63; P = 0.181); however, R-UTI was associated with poorer patient survival compared with nonrecurrent cases (HR 1.87; 95% CI 1.21-2.89; P = 0.005). R-UTI were more likely to be caused by multidrug-resistant Gram-negative organisms (risk ratio 1.49; 95% CI 1.31-1.70; P < 0.001). CONCLUSIONS: R-UTIs were associated with poorer graft and patient outcomes, as well as increased multidrug-resistance compared with nonrecurrent cases.

Assessment of bleeding events associated with short-duration therapeutic enoxaparin use in the morbidly obese.

BACKGROUND: Enoxaparin dosing for patients with morbid obesity is uncertain, and therefore, an elevated incidence of bleeding may exist in this group. OBJECTIVE: To determine if increased bleeding events occur in patients with morbid obesity (body mass index ≥ 40 kg/m(2)) compared with lower-weight patients with treatment doses of enoxaparin. METHODS: Patients at a single, academic medical center receiving enoxaparin for at least 24 hours from July to December 2009 were retrospectively evaluated. Patients with morbid obesity were randomly selected among the total cohort and were matched with lower-weight controls (1:2 ratio) based on the presence of renal dysfunction (serum creatinine >1.4 mg/dL). Bleeding events, defined on the basis of laboratory changes, administration of blood products, or clinical data, occurring up to 24 hours after enoxaparin administration were evaluated. Independent risk factors for bleeding were assessed via multivariate analysis. RESULTS: The maximum single dose administered throughout the study was 150 mg, and the largest patient enrolled weighed 175 kg. Final enoxaparin doses in morbidly obese (0.98 mg/kg) patients were lower compared with that in controls (1.04 mg/kg, P < .01). The proportion of patients with bleeding events was 29% in the morbidly obese and 23.5% in the control group (P = .30). Enoxaparin doses <0.9 mg/kg (adjusted odds ratio [AOR] = 2.35; 95% CI = 1.01-5.47; P = .04), durations of therapy beyond 48 hours (AOR = 2.42; 95% CI = 1.35-4.33; P < .01), and female gender (AOR = 2.05; 95% CI = 1.12-3.73; P = .02) were associated with bleeding, whereas warfarin use (AOR = 0.46; 95% CI = 0.26-0.81; P < .01) was associated with fewer bleeding events. CONCLUSIONS: Results suggest that dosing enoxaparin in morbidly obese patients (up to 175 kg in weight) with doses capped at 150 mg was not associated with increased bleeding incidence.