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.

Impact of metformin on malignancy in solid organ transplantation.

Malignancy after solid organ transplant is a common occurrence that is associated with increased morbidity and mortality. Literature in the general diabetic population has identified possible antineoplastic properties of metformin. This retrospective study aims to determine if metformin results in a malignancy risk reduction in a cohort of diabetic kidney, liver, and heart transplant recipients. The population included transplant recipients without use of metformin at any time point (DMO arm, n = 147) and those with use of metformin (DMM arm, n = 172); the two arms were matched based on organ type and transplant date prior to application of exclusion criteria. Recipients with prior malignancy, malignancy before diabetes diagnosis, and metformin duration <30 days were excluded. The primary endpoint of malignancy first occurrence post-transplant was not found to be statistically significant at 1, 5, 10, and 15 years. In the subgroup of heart transplant recipients, there was a significant reduction in malignancy at 15 years post-transplant. Older age and Caucasian race were identified as significant risk factors for malignancy, while never smoker was a protective factor. Metformin use in this solid organ transplant cohort was not found to significantly reduce malignancy risk compared to use of other anti-diabetic agents.

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).

Evaluation of Flexible Tacrolimus Drug Concentration Monitoring Approach in Patients Receiving Extended-Release Once-Daily Tacrolimus Tablets.

The majority of United States kidney transplant patients are treated with tacrolimus, a drug effective in preventing graft rejection, but with a narrow therapeutic range, necessitating close monitoring to avoid increased risks of transplant rejection or toxicity if the tacrolimus concentration is too low or too high, respectively. The trough drug concentration tests are time sensitive; patients treated on a twice-daily basis have blood draws exactly 12 hours after their previous dose. The schedule's rigidity causes problems for both patients and health care providers. Novel once-daily tacrolimus formulations such as LCPT (an extended-release tablet by Veloxis Pharmaceuticals, Inc., Cary, North Carolina) have allowed for blood draws on a once-daily basis; however, even that schedule can be restrictive. Results from tests taken either before or after that 24-hour target time may be discarded, or worse, may lead to inappropriate dose changes. Data from ASTCOFF, a phase 3B pharmacokinetic clinical trial (NCT02339246), demonstrated that the unique pharmacokinetic curve of LCPT may allow for a therapeutic monitoring window that extends for 3 hours before or after the 24-hour monitoring target. Furthermore, important tools to help clinicians interpret these levels, such as formulas to estimate the 24-hour trough level if an alternative monitoring time is used, were constructed from these data. These study results give treating clinicians access to data that allow them to safely use and monitor LCPT in their patients and expand the body of evidence surrounding differentiation and practical application of the novel LCPT tacrolimus formulation.

Prospective Evaluation of Pasireotide in Patients Undergoing Pancreaticoduodenectomy: The Washington University Experience.

BACKGROUND: Pasireotide is a newer generation somatostatin analogue that led to a significant reduction in pancreatic fistula after pancreatectomy in a single-center randomized controlled trial. We sought to determine if pasireotide reduces the incidence of pancreatic fistula and other complications after pancreaticoduodenectomy at our high volume center. STUDY DESIGN: All patients undergoing pancreaticoduodenectomy between April 2011 and January 2017 were prospectively followed, and their complications were graded using the Modified Accordion Grading System (MAGS) in our institutional complications database. For 18 months, 5 pancreatic surgeons used pasireotide routinely in patients undergoing pancreaticoduodenectomy. Patients receiving pasireotide were then propensity score-matched to patients who did not receive pasireotide, and their outcomes were compared. RESULTS: There were 459 patients who underwent pancreaticoduodenectomy, and 127 patients (28%) received pasireotide. Patients who received pasireotide were significantly more likely to have dilated pancreatic ducts and have a drain left at the time of surgery. Patients who received pasireotide had no difference in pancreatic fistula, overall complications, 90-day readmission, or 90-day mortality. However, patients who received pasireotide had a significantly reduced rate of postoperative bleeding/anemia (8.7% vs 16.9%, p = 0.03). Among 112 propensity score-matched pairs, patients who received pasireotide did not have significantly different rates of pancreatic fistula, and the rates of severe (MAGS grades 3 to 6) pancreatic fistula were identical between the 2 groups (7.1% vs 7.1%, p = 1.00). Matched patients who received pasireotide had significantly decreased postoperative bleeding/anemia (9.8% vs 19.6%, p = 0.04). CONCLUSIONS: Pasireotide did not reduce the incidence or severity of pancreatic fistulas after pancreaticoduodenectomy, but was associated with a decrease in postoperative bleeding/anemia. A multicenter randomized trial is needed to accurately define the role of pasireotide in the postoperative management of pancreaticoduodenectomy patients.

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.

The Privilege of Induction Avoidance and Calcineurin Inhibitors Withdrawal in 2 Haplotype HLA Matched White Kidney Transplantation.

BACKGROUND: White recipients of 2-haplotype HLA-matched living kidney transplants are perceived to be of low immunologic risk. Little is known about the safety of induction avoidance and calcineurin inhibitor withdrawal in these patients. METHODS: We reviewed our experience at a single center and compared it to Organ Procurement and Transplantation Network (OPTN) registry data and only included 2-haplotype HLA-matched white living kidney transplants recipients between 2000 and 2013. RESULTS: There were 56 recipients in a single center (where no induction was given) and 2976 recipients in the OPTN. Among the OPTN recipients, 1285 received no induction, 903 basiliximab, 608 thymoglobulin, and 180 alemtuzumab. First-year acute rejection rates were similar after induction-free transplantation among the center and induced groups nationally. Compared with induction-free transplantation in the national data, there was no decrease in graft failure risk over 13 years with use of basiliximab (adjusted hazard ratio [aHR], 0.86; confidence interval [CI], 0.68-1.08), Thymoglobulin (aHR, 0.92; CI, 0.7-1.21) or alemtuzumab (aHR, 1.18; CI, 0.72-1.93). Among induction-free recipients at the center, calcineurin inhibitor withdrawal at 1 year (n = 27) did not significantly impact graft failure risk (HR,1.62; CI, 0.38-6.89). CONCLUSIONS: This study may serve as a foundation for further studies to provide personalized, tailored, immunosuppression for this very low-risk population of kidney transplant patients.

Transplant Center Volume and the Risk of Pancreas Allograft Failure.

BACKGROUND: Successful pancreas transplantation requires surgical expertise and multidisciplinary medical management. The impact of transplant center volume on pancreas allograft survival remains unclear. METHODS: We examined Organ Procurement and Transplantation Network data on 11 568 simultaneous pancreas-kidney (SPK) and 4308 solitary pancreas (pancreas transplant alone and pancreas after kidney) transplants between 2000 and 2013. RESULTS: Average annual transplant center volume was categorized by tertiles into low, medium, and high volume, respectively, as follows: 1 to 6 (n = 3861), 7 to 13 (n = 3891), and 14 to 34 (n = 3888) for SPK, and 1 to 3 (n = 1417), 4 to 10 (n = 1518), and 11 to 33 (n = 1377) for solitary pancreas transplants. Favorable donor characteristics were seen in low-volume centers. For SPK transplantation, low (adjusted hazard ration [aHR], 1.55, 95% confidence interval [CI], 1.34-1.8) and medium (aHR, 1.24; 95% CI, 1.07-1.44) center volumes were associated with a higher risk of early pancreas graft failure at 3 months. The increased risk associated with low center volume extended to 1, 5, and 10 years. For solitary pancreas transplants, low, but not medium, center volume was associated with a higher risk of early pancreas graft failure at 3 months (aHR, 1.56; 95% CI, 1.232-1.976), and this risk persisted over 10 years. Patients transplanted at high-volume centers had better pancreas survival rates across all categories of the Pancreas Donor Risk Index. CONCLUSION: On average, low center volume were associated with higher risk for pancreas failure. Future studies should seek to identify care processes that support optimal outcomes after pancreas transplantation irrespective of center volume.

Polyomavirus Reactivation and Immune Responses to Kidney-Specific Self-Antigens in Transplantation.

Humoral immune responses against donor antigens are important determinants of long-term transplant outcomes. Reactivation of the polyomavirus BK has been associated with de novo antibodies against mismatched donor HLA antigens in kidney transplantation. The effect of polyomavirus reactivation (BK viremia or JC viruria) on antibodies to kidney-specific self-antigens is unknown. We previously reported excellent 5-year outcomes after minimization of immunosuppression for BK viremia and after no intervention for JC viruria. Here, we report the 10-year results of this trial (n=193) along with a nested case-control study (n=40) to explore associations between polyomavirus reactivation and immune responses to the self-antigens fibronectin (FN) and collagen type-IV (Col-IV). Consistent with 5-year findings, subjects taking tacrolimus, compared with those taking cyclosporin, had less acute rejection (11% versus 22%, P=0.05) and graft loss (9% versus 22%, P=0.01) along with better transplant function (eGFR 65±19 versus 50±24 ml/min per 1.73 m2, P<0.001) at 10 years. Subjects undergoing immunosuppression reduction for BK viremia had 10-year outcomes similar to those without viremia. In the case-control study, antibodies to FN/Col-IV were more prevalent during year 1 in subjects with polyomavirus reactivation than in those without reactivation (48% versus 11%, P=0.04). Subjects with antibodies to FN/Col-IV had more acute rejection than did those without these antibodies (38% versus 8%, P=0.02). These data demonstrate the long-term safety and effectiveness of minimizing immunosuppression to treat BK viremia. Furthermore, these results indicate that polyomavirus reactivation associates with immune responses to kidney-specific self-antigens that may increase the risk for acute rejection through unclear mechanisms.

Ureteral stent placement and immediate graft function are associated with increased risk of BK viremia in the first year after kidney transplantation.

Ureteral stent (UrSt) placement has been shown to be a significant independent risk factor for BK viruria, viremia, and BK virus nephropathy. We assessed whether this observation could be validated at our high volume kidney transplant center that has had a strong historical focus on BK virus nephropathy detection. We performed a retrospective case-control study of adults receiving a kidney-only transplant and followed for 1 year between 2004 and 2011 with uniform immunosuppression and use of blood BK virus PCR screening protocol. Among 1147 patients, 443 (38.6%) received a UrSt and 17.2% with a UrSt had BK viremia versus 13.5% without stent (odds ratio 1.33; 95% CI: 1.00-1.78). We confirmed a previously reported association between immediate graft function (IGF) and higher rate of BK viremia (15.7% vs. 5.9% in patients without IGF). On multivariable competing risks Cox regression in patients with IGF, UrSt (adjusted hazard ratio [aHR] 1.35; 95% CI: 1.04-1.75) and African American race (aHR 1.47; 95% CI: 1.04-2.09) significantly increased the risk for BK viremia. In the largest sample size to date, we confirmed that UrSt placement during kidney transplant surgery is a risk factor for BK viremia within the first year post-transplant and that IGF is associated with BK viremia.

Single-dose rituximab for recurrent glomerulonephritis post-renal transplant.

BACKGROUND/AIMS: Post-renal transplant recurrent glomerulonephritis (GN) contributes to allograft loss. Rituximab treatment has been used in a multidose strategy with variable efficacy and toxicity. We investigated a novel single-dose approach. METHODS: A single center, retrospective, cohort study was conducted between January 1998 and April 2012 among renal allograft recipients with recurrent GN treated with rituximab (cases) or without (controls). The primary outcome was complete response (CR, urine protein/creatinine ratio (UP/C) <0.3). Secondary outcomes included partial response (PR >50% reduction in UP/C), response relapse, treatment-response by GN type, acute rejection incidence, time to graft loss, and infection incidence. RESULTS: The median dose of rituximab was 200 mg per patient. Of 20 rituximab cases and 13 controls, CR was achieved in eight (40%) versus four (31%), respectively (p = 0.72). Three subjects in each group achieved PR (p = 0.66). Response relapse was similar between the two groups (p = 0.47). Significantly more subjects with recurrent membranous nephropathy (MN) achieved CR with rituximab treatment (p = 0.029). Acute rejection was lower in the rituximab group versus controls (n = 0 vs. 4; p = 0.046). The mean time to graft loss was much later in the rituximab group (35 months, (95% CI 33-37)) versus controls (29 months, (95% CI 24-35)) at 36 months (p = 0.04). There was no infection increase in rituximab-treated subjects (p = 0.16). CONCLUSION: Single-dose rituximab for treatment of recurrent GN was associated with less subsequent rejection and longer time to graft loss without increased infection, but was no more effective than regimens not using rituximab at 36-months except those with recurrent membranous GN.

Renal transplantation in the setting of early steroid withdrawal: a comparison of rabbit antithymocyte globulin induction dosing in two eras.

BACKGROUND: Modern immunosuppression and rabbit antithymocyte globulin (rATG) have facilitated the success of early steroid withdrawal (ESW) protocols. Little data exist on optimal rATG dosing in ESW protocols. METHODS: Rejection at 12 months in era 1 (four doses of rATG, 1.25 mg/kg) vs. era 2 (three doses of rATG, 1.25 mg/kg) was the primary endpoint. Secondary endpoints included patient and graft survival, renal function and infectious complications. Factors associated with rejection at 1 year were identified. RESULTS: 199 patients received rATG induction and ESW: 102 in era 1 and 97 in era 2. Compared to era 1, era 2 was not associated with worse outcomes, including rejection, renal function, infection or graft survival. Rejection at 1 year and uncensored graft survival differed between the dosing groups. Rejection rates were significantly higher in the <4 mg/kg group compared to the 4-5.9-mg/kg and the ≥6-mg/kg groups, whereas uncensored graft survival was the lowest in the ≥6-mg/kg group. Factors associated with rejection at 12 months included: rATG dose received of 4-5.9 versus <4 mg/kg (OR 0.20, 95% CI 0.036-0.85, p = 0.026); recipient age (per year, OR 0.94, 95% CI 0.89-1.0, p = 0.038); panel reactive antibody 10-79.9 versus <10% (OR 5.4, 95% CI 1.2-25, p = 0.030) and rATG dose held (OR 4.0, 95% CI 1.0-15, p = 0.049). CONCLUSIONS: A comparison of rATG dosing based on era did not result in a significant difference in rejection, renal function, infection or graft survival. However, when evaluating the study population based on actual dose received there were notable differences in both rejection rates and uncensored graft survival.

Timing of sirolimus conversion influences recovery of renal function in liver transplant recipients.

The long-term use of calcineurin inhibitors (CNI) leads to renal dysfunction in many liver transplant (LT) recipients. The purpose of this analysis is to evaluate renal function in patients converted from CNI to sirolimus (SRL). From May 2002-November 2006, 137 LT were performed in 125 patients, 72 of which were converted to SRL. Evaluation of SRL conversion was stratified by early conversion (<90 d from LT) (EC) vs. late conversion (LC). Renal function was evaluated using the six-point modification of diet in renal disease formula (estimated glomerular filtration rate [eGFR]). Forty-two patients on SRL and 40 on CNI had at least three months of follow-up and are included in the eGFR evaluation. At all time points after conversion, the EC group demonstrated a significantly higher mean eGFR than those in the LC group. A significant improvement in eGFR was seen within the EC group when comparing eGFR at time of conversion to eGFR at three, six, nine, and 12 months after conversion and last follow-up. The only improvement in the LC group was from conversion to the three-month time point. We conclude that EC to SRL results in a profound improvement in eGFR that begins at three months and is sustained beyond one yr.