Patients with cirrhosis have a 30-day readmission rate of over 30

There is little doubt that kidney transplantation is the most desirable treatment for patients requiring renal replacement therapy. It is also clear that the deceased donor pool is a limited and finite resource. Living kidney donation has the potential to impact overall numbers of patients receiving those organs and as well as opening a space on the deceased donor list. Another truism is that the clinical outcomes of living donor recipients are better than those receiving deceased donor kidneys, as a whole. The major tenet of living donation since its beginning has been the safety of the donor, both in the short and long terms. In the short term, efforts are directed to limit risks of anesthesia, operative techniques, and the postoperative recovery. Long-term considerations are concentrated on remaining renal function and maintenance of the same. Because of the successes of living donor kidney transplantation, programs have chosen to push the envelope increasing access to living donors. As living donor programs have matured, acceptance of nonrelated donors and even altruistic donors have become common. Living donor age has increased over time, and some programs have allowed individuals with mild, controlled hypertension to donate. In this issue, Hebert et al1 have studied the past use of living kidney donors with compromised glucose control. This article considers the impact of isolated impaired fasting glucose (IFG) in living donors without other identified comorbidities. They utilize data from 3 large living donor kidney centers and publicly available data from The Renal Lung Living Donor Evaluation study. These 3 centers contacted donors for follow-up data on the development of diabetes, hypertension, kidney disease, cardiovascular disease, cancer, or other health conditions. The study period spans from 1963 to 2007, and as a result of the changing guidelines for diabetes and IFG over this time period, allows for examination of long-term outcomes of patients selected for living donation which, by older criteria, were selected to donate with imperfect glucose control. They postulated that IFG would not subject these donors to a higher risk of future renal dysfunction, compared to those with normoglycemia. They conclude that living kidney donors with IFG “do well in the short- and intermediate-term and the risk of ESKD in those with fasting glucose >126 mg/dL at the time of donation is comparable to people with two kidneys.” They further state that they would propose that “potential kidney donors with impaired fasting glucose be considered for donation after they receive formal counseling” regarding their risks and need for compliance to guidelines for their future glucose management. This study suffers from many weaknesses of its design. It is predicated on a registry/survey database which relies on collection of remotely obtained data points. However, considering the length of the follow-up period of included patients it is remarkably complete with only 7% of 8922 donors excluded for a lack of glucose testing in follow-up. Several of the pieces of data are collected only at a single point in time. Years from donation to study closure is relatively short in the big picture, varying from a mean of 11.5–14.3 y. The graphic representation of the cumulative incidence of individual outcomes show diverging curves, with mortality, hypertension, diabetes, proteinuria, and lower GFR’s increasing over time when normal fasting sugars are compared to those with IFGs. Ideally, it would be desirable to have longer follow-up time periods in that diabetic renal disease may take longer to develop. This is clearly a selected population of healthy individuals chosen to donate. The comparator group of age-adjusted US population diabetes data provided by the CDC are probably a different population, in that the study population is clearly a selected group of healthy individuals chosen to donate who are provided with routine follow-up health care postdonation. While not the definitive trial that we seek, this adds important information to our repertoire. This is clearly the largest study addressing this question, considering the available number of patients to follow over time and that the study population includes individuals over nearly 50 y of living donation. Transplant teams make difficult decisions every day regarding the suitability of the patients they care for. None are more difficult than the safety of a potential donor who derives very little benefit from the procedure itself. This study provides even more information that allows the clinician to provide counseling to the potential donor as to the long-term risks of donating a kidney. It is probably even more important for an older donor, who is dedicated to donation, to further understand the risks as they have a more finite window for longevity. These data provide another tool that can guide our clinical decision making in this difficult environment. As importantly, the more information that we can provide our patients do help to empower them to make rational decisions. Routine utilization of donors with mild impaired glucose metabolism needs careful consideration and we should not simply sugar coat it. Knowledge is power. Information is liberating. Education is the premise of progress, in every society, in every family. —Kofi Annan Secretary General of the UN (1997–2006)

IntroductionDonation after cardiac death (DCD) has been leading the way to help bridge the growing gap between availability of donors and recipients on waitlist. With advances in technology and our understanding of DCD donation the safety profile is growing. It is becoming an increasing viable option even in marginal settings.DiscussionThe ethos surroundings DCD is still a matter of contention but there is support and collaboration from larger societies and establishments with development of standardizing protocols. Preparation is key. Experience of the procurement and transplanting surgeons are pivotal. There are multiple moving parts and for the success of a DCD program, dedication is needed from the donor hospitals, organ procurement organizations and the transplant centers. Previous practices based on anecdotal experiences are now either supported by or refuted by increasing evidence and data, based on the development of consensus-based guidelines with the end goal of having uniform outcomes. Normothermic regional and machine perfusion have expanded options in the DCD world, challenging the limits and expanding our paradigm. Recognition of the weaknesses and organ specific complications allow the clinician to make choices for optimal outcomes. These advancements have allowed outcomes to be optimized.ConclusionsExpanding the organ donor pool is one solution to increase the availability of organs for transplantation. Increasing the attention to and the use of DCD organs combined with machine and normothermic perfusion is a future strategy to obtain ongoing clinical success in organ transplantation and lower the waiting list mortality.

OBJECTIVES:Development of pharmaceutical agents in transplantation is currently limited by long waits for hard endpoints. We applied a validated integrative risk-prognostication system integrative Box (iBox) as a surrogate endpoint to the TRANSFORM Study, a large randomised controlled trial, to project individual patient long-term kidney allograft survival from 1 year to 11 years after randomisation. DESIGN:Post-hoc analysis of a randomised open-label controlled trial. SETTING:Multicentre study including 186 centres in 42 countries worldwide. PARTICIPANTS:2037 de novo kidney transplant recipients. INTERVENTION:Participants were randomised (1:1) to receive everolimus with reduced-exposure calcineurin inhibitor (EVR+rCNI) or mycophenolic acid with standard-exposure CNI (MPA+sCNI). PRIMARY OUTCOME MEASURE:The iBox scores were computed for each participant at 1 year after randomisation using functional, immunological and histological parameters. Individual long-term death-censored allograft survival over 4, 6 and 11 years after randomisation was projected with the iBox risk-prognostication system. RESULTS:Overall, 940 patients receiving EVR+rCNI and 932 receiving MPA+sCNI completed the 1-year visit. iBox scores generated at 1 year yielded graft survival prediction rates of 90.9% vs 92.1%, 87.9% vs 89.5%, and 80.0% vs 82.4% in the EVR+rCNI versus MPA+sCNI arms at 4, 6, and 11 years post-randomisation, respectively (all differences below the 10% non-inferiority margin defined by study protocol). Inclusion of immunological and histological Banff diagnoses parameters in iBox scores resulted in comparable and non-inferior predicted graft survival for both treatments. CONCLUSIONS:This proof-of-concept study provides the first application of a validated prognostication system as a surrogate endpoint in the field of transplantation. The iBox system, by projecting kidney allograft survival up to 11 years post-randomisation, confirms the non-inferiority of EVR+rCNI versus MPA+sCNI regimen. Given the current process engaged for surrogate endpoints qualification, this study illustrates the potential to fast track development of pharmaceutical agents. TRIAL REGISTRATION NUMBER:TRANSFORM trial: NCT01950819.iBox prognostication system: NCT03474003.

Background Hospital readmission (HR) after surgery is considered a quality metric. Methods Data on 2371 first-time adult kidney transplant (KT) recipients were collected to analyze the "early" (<= 30 days) and "late" (31-365 days) HR patterns after KT at a single center over a 12-year time span (2002-2013). Results 30-day, 90-day, and 1-year HR were 31%, 41%, and 53%, respectively. Risk factors for HR included age >50, female sex, black race, BMI >30, transplant LOS >5 days, and pre-transplant time on dialysis >765 days. Indications for early (n = 749) and late (n = 508) HR were similar. Early HR (OR: 3.80, P = .007) and black race (OR: 2.38, P = .009) were associated with higher odds of 1-year graft failure while frequency (1-2, 3-4, 5+) of HR (ORs: 4.68, 8.36, 9.44, P < .001) and age > 50 (OR: 2.11, P = .007) were associated with higher odds of 1-year mortality. Transplant LOS > 5 days increased both odds of 1-year graft failure (OR: 3.51, P = .001) and mortality (OR: 2.05, P = .006). One-year graft and recipient survival were 96.7% and 94.8%, respectively. Conclusions Hospital readmission was associated with reduced graft and patient survival; however, despite a relatively high and consistent HR rate after KT, overall 1-year graft and patient survival was high.

OBJECTIVES:In TRANSFORM, de novo kidney transplant recipients received either everolimus in combination with reduced-exposure calcineurin inhibitor (EVR+rCNI) at standard EVR pre-dose concentrations of 3-8 ng/mL or mycophenolic acid plus standard-exposure CNI (MPA+sCNI). The authors analyzed the incidence of wound healing adverse events (WHAEs) over the 2-year study period 15. METHODS:Patients were randomized to either EVR+rCNI or MPA+sCNI, both combined with induction therapy and steroids 19. RESULTS:The safety population consisted of 2,026 patients (EVR+rCNI: 1,014, MPA+sCNI: 1,012). The proportion of patients with at least 1 WHAE was comparable between EVR+rCNI and MPA+sCNI treatment groups [20.6% vs. 17.3%; risk ratio (RR): 1.19; 95% confidence interval (CI): 0.99, 1.43] at month 24. The numerical difference between EVR+rCNI and MPA+sCNI was mainly caused by an increased proportion of EVR patients with lymphocele and wound dehiscence [7.5% vs. 5.1% (RR: 1.46; 95% CI: 1.04, 2.05) and 3.9% vs. 1.8% (RR: 2.22; 95%CI: 1.28, 3.84), respectively] 20. CONCLUSION:The immediate introduction of EVR+rCNI after kidney transplantation was associated with an overall comparable incidence of WHAEs versus current standard-of-care over the 24-month study period. There was an increased relative risk of experiencing lymphocele and wound dehiscence but the absolute risks were rather low in both groups 21. CT.GOV IDENTIFIER:NCT01950819.

Since the inception of pancreas transplant as a treatment for type 1 diabetes mellitus, there has been considerable debate about the best way to manage exocrine secretions and monitor patients for graft rejection. For patients who undergo bladder exocrine drainage of a pancreatic allograft, a bladder-to-enteric drainage conversion can serve as a rescue procedure in case of anastomotic leaks or other complications. However, this procedure is associated with its own complications, including a rarely described entero vesical fistula. Here we report on a 45-year-old man who underwent a simultaneous kidney and pancreas transplant with bladder drainage to the latter. He developed a pancreatic allograft duodenal leak (duodenal-vesical anastomosis) requiring a bladder-to-enteric drainage conversion. The patient returned 2 weeks after discharge with an enterovesical fistula. He was treated nonsurgically with intravenous antibiotics, bowel rest, and parenteral nutrition, and the fistula successfully closed in approximately 2 weeks. Overall, enterovesical fistula formation is a rare but treatable complication that can occur after a bladder-to-enteric drainage conversion of a pancreatic transplant allograft. It can be managed nonsurgically, which is preferable in these immunocompromised patients.

Background. The safety profiles of standard therapy versus everolimus with reduced-exposure calcineurin inhibitor (CNI) therapy using contemporary protocols in de novo kidney transplant recipients have not been compared in detail. Methods. TRANSFORM was a randomized, international trial in which de novo kidney transplant patients were randomized to everolimus with reduced-exposure CNI (N = 1014) or mycophenolic acid (MPA) with standard-exposure CNI (N = 1012), both with induction and corticosteroids. Results. Within the safety population (everolimus 1014, MPA 1012), adverse events with a suspected relation to study drug occurred in 62.9% versus 59.2% of patients given everolimus or MPA, respectively (P = 0.085). Hyperlipidemia, interstitial lung disease, peripheral edema, proteinuria, stomatitis/mouth ulceration, thrombocytopenia, and wound healing complications were more frequent with everolimus, whereas diarrhea, nausea, vomiting, leukopenia, tremor, and insomnia were more frequent in the MPA group. The incidence of viral infections (17.2% versus 29.2%; P < 0.001), cytomegalovirus (CMV) infections (8.1% versus 20.1%; P < 0.001), CMV syndrome (13.6% versus 23.0%, P = 0.044), and BK virus (BKV) infections (4.3% versus 8.0%, P < 0.001) were less frequent with everolimus. CMV infection was less common with everolimus versus MPA after adjusting for prophylaxis therapy in the D+/R- subgroup (P < 0.001). Study drug was discontinued more frequently due to rejection or impaired healing with everolimus, and more often due to BKV infection or BKV nephropathy with MPA. Conclusions. De novo everolimus with reduced-exposure CNI yielded a comparable incidence, though a distinctly different pattern, of adverse events versus current standard of care. Both regimens are safe and effective, yet their distinct profiles may enable tailoring for individual kidney transplant recipients.

The mammalian target of rapamycin (mTOR) inhibitor, everolimus, in combination with reduced-exposure calcineurin inhibitor (CNI), has been demonstrated in clinical trials to have comparable efficacy in low-to-moderate immunological risk kidney transplant recipients to the Standard of Care, mycophenolic acid (MPA) in combination with standard-exposure CNI. Current treatment guidelines consider mTOR inhibitors to be a second-line therapy in the majority of cases; however, given that everolimus-based regimens are associated with a reduced rate of viral infections after transplantation, their wider use could have great benefits for kidney transplant patients. In this evidence-based practice guideline, we consider the de novo use of everolimus in kidney transplant recipients. The main outcomes of our consideration of the available evidence are that: 1. Everolimus, in combination with reduced-exposure CNI and low dose steroids, is a suitable regimen for the prophylaxis of kidney transplant rejection in the majority of low-to-moderate immunological risk adult patients, with individualized management; 2. Induction with either basiliximab or rabbit anti-thymocyte globulin is an effective therapy for kidney transplant recipients when initiating an everolimus-based, reduced-exposure CNI regimen; and 3. An individualized approach should be adopted when managing kidney transplant recipients on everolimus-based therapy.

TRANSFORM (TRANSplant eFficacy and safety Outcomes with an eveRolimus-based regiMen) was a 24-month, prospective, open-label trial in 2037 de novo renal transplant recipients randomized (1:1) within 24 hours of transplantation to receive everolimus (EVR) with reduced-exposure calcineurin inhibitor (EVR + rCNI) or mycophenolate with standard-exposure CNI. Consistent with previously reported 12-month findings, noninferiority of the EVR + rCNI regimen for the primary endpoint of treated biopsy-proven acute rejection (tBPAR) or estimated glomerular filtration rate (eGFR) <50 mL/min per 1.73 m2 was achieved at month 24 (47.9% vs 43.7%; difference = 4.2%; 95% confidence interval = -0.3, 8.7; P = .006). Mean eGFR was stable up to month 24 (52.6 vs 54.9 mL/min per 1.73 m2 ) in both arms. The incidence of de novo donor-specific antibodies (dnDSA) was lower in the EVR + rCNI arm (12.3% vs 17.6%) among on-treatment patients. Although discontinuation rates due to adverse events were higher with EVR + rCNI (27.2% vs 15.0%), rates of cytomegalovirus (2.8% vs 13.5%) and BK virus (5.8% vs 10.3%) infections were lower. Cytomegalovirus infection rates were significantly lower with EVR + rCNI even in the D+/R- high-risk group (P < .0001). In conclusion, the EVR + rCNI regimen offers comparable efficacy and graft function with low tBPAR and dnDSA rates and significantly lower incidence of viral infections relative to standard-of-care up to 24 months. Clinicaltrials.gov number: NCT01950819.

Introduction Anti-proliferative properties of mammalian target of rapamycin inhibitors (mTORi) may interfere with the wound healing process post-transplantation (Tx) and as such, some are hesitant to incorporate mTORi into immunosuppressive regimens immediately post-Tx. Several studies with everolimus (EVR) have shown comparable wound healing events (WHE) vs mycophenolic acid (MPA)-based regimen. Here, we evaluate the effect of EVR in combination with reduced-exposure calcineurin inhibitor (rCNI) vs MPA with standard-exposure CNI (sCNI) on WHE from the TRANSFORM study. Methods TRANSFORM (NCT01950819) is a 24-month (M), multicentre, open-label study in which de novo adult kidney transplant recipients were randomised within 24 hours of Tx to receive either EVR+rCNI (N=1022; EVR trough level [C0]: 3-8 ng/mL; tacrolimus [TAC] C0: 4-7, 2-5, and 2-4 ng/mL or cyclosporine [CsA] C0: 100-150, 50-100, and 25-50 ng/mL from Day 1(D1)-M2, M3-M6, and M7-M24, respectively) or MPA+sCNI (N=1015; MPA [1.44 g/day of enteric-coated mycophenolate sodium or 2 g/day of mycophenolate mofetil]; TAC C0: 8-12, 6-10, and 5-8 ng/mL or CsA C0: 200-300, 150-200, and 100-200 ng/mL from D1-M2, M3-M6, and M7-M24, respectively). All patients received basiliximab or rabbit antithymocyte globulin induction and steroids. The WHE by treatment groups at M12 are summarised here. Results Overall baseline characteristics, including mean body mass index (25.6 kg/m2 in both groups) and proportion of patients with diabetes (EVR+rCNI vs MPA+sCNI: 27.3% vs 26.5%), were comparable between the groups. Up to 86% of patients were within the target EVR C0 over M12. The overall incidence of WHE at M12 was comparable between the groups (EVR+rCNI vs MPA+sCNI: 39.0% vs 33.7%). Procedural pain, lymphocele, and incision site pain were the most commonly reported WHE in both the groups and were majorly of mild to moderate severity (Table). Patients in the EVR+rCNI vs MPA+sCNI group reported significantly, but slightly, higher incidence of wound dehiscence (3.8% vs 1.8%) and impaired healing (3.5% vs 0.8%). Impaired healing and lymphoceles were the most frequent adverse events leading to study drug discontinuation/dose adjustment/drug interruption in the EVR+rCNI group (Table). Conclusion The results from the TRANSFORM study show that in spite of EVR initiation within 24 hours of Tx, the increased risk of WHE was limited between the EVR+rCNI and MPA+sCNI groups.

Background Everolimus permits reduced calcineurin inhibitor (CNI) exposure, but the efficacy and safety outcomes of this treatment after kidney transplant require confirmation.Methods In a multicenter noninferiority trial, we randomized 2037 de novo kidney transplant recipients to receive, in combination with induction therapy and corticosteroids, everolimus with reduced-exposure CNI (everolimus arm) or mycophenolic acid (MPA) with standard-exposure CNI (MPA arm). The primary end point was treated biopsy-proven acute rejection or eGFR<50 ml/min per 1.73 m2 at post-transplant month 12 using a 10% noninferiority margin.Results In the intent-to-treat population (everolimus n=1022, MPA n=1015), the primary end point incidence was 48.2% (493) with everolimus and 45.1% (457) with MPA (difference 3.2%; 95% confidence interval, -1.3% to 7.6%). Similar between-treatment differences in incidence were observed in the subgroups of patients who received tacrolimus or cyclosporine. Treated biopsy-proven acute rejection, graft loss, or death at post-transplant month 12 occurred in 14.9% and 12.5% of patients treated with everolimus and MPA, respectively (difference 2.3%; 95% confidence interval, -1.7% to 6.4%). De novo donor-specific antibody incidence at 12 months and antibody-mediated rejection rate did not differ between arms. Cytomegalovirus (3.6% versus 13.3%) and BK virus infections (4.3% versus 8.0%) were less frequent in the everolimus arm than in the MPA arm. Overall, 23.0% and 11.9% of patients treated with everolimus and MPA, respectively, discontinued the study drug because of adverse events.Conclusions In kidney transplant recipients at mild-to-moderate immunologic risk, everolimus was noninferior to MPA for a binary composite end point assessing immunosuppressive efficacy and preservation of graft function.