Dietary Inulin to Improve SARS-CoV-2 Vaccine Response in Kidney Transplant Recipients: The RIVASTIM-Inulin Randomised Controlled Trial.

Kidney transplant recipients are at an increased risk of hospitalisation and death from SARS-CoV-2 infection, and standard two-dose vaccination schedules are typically inadequate to generate protective immunity. Gut dysbiosis, which is common among kidney transplant recipients and known to effect systemic immunity, may be a contributing factor to a lack of vaccine immunogenicity in this at-risk cohort. The gut microbiota modulates vaccine responses, with the production of immunomodulatory short-chain fatty acids by bacteria such as Bifidobacterium associated with heightened vaccine responses in both observational and experimental studies. As SCFA-producing populations in the gut microbiota are enhanced by diets rich in non-digestible fibre, dietary supplementation with prebiotic fibre emerges as a potential adjuvant strategy to correct dysbiosis and improve vaccine-induced immunity. In a randomised, double-bind, placebo-controlled trial of 72 kidney transplant recipients, we found dietary supplementation with prebiotic inulin for 4 weeks before and after a third SARS-CoV2 mRNA vaccine to be feasible, tolerable, and safe. Inulin supplementation resulted in an increase in gut Bifidobacterium, as determined by 16S RNA sequencing, but did not increase in vitro neutralisation of live SARS-CoV-2 virus at 4 weeks following a third vaccination. Dietary fibre supplementation is a feasible strategy with the potential to enhance vaccine-induced immunity and warrants further investigation.

Prospective evaluation of a closed-incision negative pressure wound therapy system in kidney transplantation and its association with wound complications.

Introduction: Wound complications can cause considerable morbidity in kidney transplantation. Closed-incision negative pressure wound therapy (ciNPWT) systems have been efficacious in reducing wound complications across surgical specialties. The aims of this study were to evaluate the use of ciNPWT, Prevena™, in kidney transplant recipients and to determine any association with wound complications. Material and methods: A single-center, prospective observational cohort study was performed in 2018. A total of 30 consecutive kidney transplant recipients deemed at high risk for wound complications received ciNPWT, and the results were compared to those of a historical cohort of subjects who received conventional dressings. Analysis for recipients with obesity and propensity score matching were performed. Results: In total, 127 subjects were included in the analysis. Of these, 30 received a ciNPWT dressing and were compared with 97 subjects from a non-study historical control group who had conventional dressing. The overall wound complication rate was 21.3% (27/127). There was no reduction in the rate of wound complications with ciNPWT when compared with conventional dressing [23.3% (7/30) and 20.6% (20/97), respectively, p = 0.75]. In the obese subset (BMI ≥30 kg/m2), there was no significant reduction in wound complications [31.1% (5/16) and 36.8% (7/19), respectively, p = 0.73]. Propensity score matching yielded 26 matched pairs with equivalent rates of wound complications (23.1%, 6/26). Conclusion: This is the first reported cohort study evaluating the use of ciNPWT in kidney transplantation. While ciNPWT is safe and well tolerated, it is not associated with a statistically significant reduction in wound complications when compared to conventional dressing. The findings from this study will be used to inform future studies associated with ciNPWT in kidney transplantation.

ABO Incompatible Kidney Transplantation Without B-cell Depletion is Associated With Increased Early Acute Rejection: A Single-Center Australian Experience.

We performed a single-center retrospective cohort study of 66 consecutive ABO incompatible kidney transplants (ABOiKT) performed without B-cell depleting therapy. Outcomes were compared to an earlier era performed with rituximab (n = 18) and a contemporaneous cohort of ABO compatible live donor transplants (ABOcKT). Acute rejection within 3 months of transplant was significantly more common after rituximab-free ABOiKT compared to ABOiKT with rituximab (OR 8.8, p = 0.04) and ABOcKT (OR 2.9, p = 0.005) in adjusted analyses. Six recipients of rituximab-free ABOiKT experienced refractory antibody mediated rejection requiring splenectomy, and a further two incurred early graft loss with no such episodes amongst ABOiKT with rituximab or ABOcKT cohorts. Patient and graft survival were similar between groups over a median follow-up of 3.1 years. This observational evidence lends strong support to the continued inclusion of rituximab in desensitization protocols for ABOiKT.

Survival after kidney transplantation compared with ongoing dialysis for people over 70 years of age: A matched-pair analysis.

Kidney transplantation offers improved survival and quality of life compared to dialysis for most recipients; however, benefits for elderly patients (>70 years) remain uncertain. Using the Australia and New Zealand Dialysis and Transplant Registry (2009-2019), elderly transplant recipients were matched to a waitlisted dialysis patient by age, cause of end-stage kidney disease, and dialysis duration (paired controls). We censored dialysis patients at the time of transplant. Survival was compared using stratified Cox regression. Elderly transplant recipients (KTRs) (n = 465) were matched to waitlisted pairs. Transplant group mortality initially exceeded dialysis due to excess infection-related deaths (1.9 transplant versus 0.3 dialysis/100 patient-years, P = .03). Beyond month 9, a progressive survival benefit in favor of transplantation was apparent. Over a median follow-up of 1.7 years, mortality was 38% lower for KTRs (95% confidence interval 0.41-0.94, P = .02), and 5-year survival was 80% KTRs vs 53% dialysis (P < .001). Recipients of living and standard criteria donor kidneys acquired immediate survival advantage compared with dialysis, while recipients of expanded criteria donor's kidneys experienced elevated risk of death for the first 17 months. Compared with remaining on dialysis, elderly KTRs incur an increased risk of early posttransplant mortality but thereafter may anticipate progressively superior survival rates.

Obesity is Associated With Delayed Graft Function in Kidney Transplant Recipients: A Paired Kidney Analysis.

Obesity is increasingly prevalent among candidates for kidney transplantation. Existing studies have shown conflicting post-transplant outcomes for obese patients which may relate to confounding bias from donor-related characteristics that were unaccounted for. We used ANZDATA Registry data to compare graft and patient survival between obese (BMI >27.5 kg/m2 Asians; >30 kg/m2 non-Asians) and non-obese kidney transplant recipients, while controlling for donor characteristics by comparing recipients of paired kidneys. We selected transplant pairs (2000-2020) where a deceased donor supplied one kidney to an obese candidate and the other to a non-obese candidate. We compared the incidence of delayed graft function (DGF), graft failure and death by multivariable models. We identified 1,522 pairs. Obesity was associated with an increased risk of DGF (aRR = 1.26, 95% CI 1.11-1.44, p < 0.001). Obese recipients were more likely to experience death-censored graft failure (aHR = 1.25, 95% CI 1.05-1.49, p = 0.012), and more likely to die with function (aHR = 1.32, 95% CI 1.15-1.56, p = 0.001), versus non-obese recipients. Long-term patient survival was significantly worse in obese patients with 10- and 15-year survival of 71% and 56% compared to 77% and 63% in non-obese patients. Addressing obesity is an unmet clinical need in kidney transplantation.

Rapamycin and inulin for third-dose vaccine response stimulation (RIVASTIM): Inulin - study protocol for a pilot, multicentre, randomised, double-blinded, controlled trial of dietary inulin to improve SARS-CoV-2 vaccine response in kidney transplant recipients.

INTRODUCTION: Kidney transplant recipients (KTRs) are at an increased risk of hospitalisation and death from COVID-19. Vaccination against SARS-CoV-2 is our primary risk mitigation strategy, yet vaccine effectiveness in KTRs is suboptimal. Strategies to enhance vaccine efficacy are therefore required. Current evidence supports the role of the gut microbiota in shaping the immune response to vaccination. Gut dysbiosis is common in KTRs and is a potential contributor to impaired COVID-19 vaccine responses. We hypothesise that dietary fibre supplementation will attenuate gut dysbiosis and promote vaccine responsiveness in KTRs. METHODS AND ANALYSIS: Rapamycin and inulin for third-dose vaccine response stimulation-inulin is a multicentre, randomised, prospective, double-blinded, placebo-controlled pilot trial examining the effect of dietary inulin supplementation prior to a third dose of COVID-19 vaccine in KTRs who have failed to develop protective immunity following a 2-dose COVID-19 vaccine schedule. Participants will be randomised 1:1 to inulin (active) or maltodextrin (placebo control), administered as 20 g/day of powdered supplement dissolved in water, for 4 weeks prior to and following vaccination. The primary outcome is the proportion of participants in each trial arm that achieve in vitro neutralisation of live SARS-CoV-2 virus at 4 weeks following a third dose of COVID-19 vaccine. Secondary outcomes include the safety and tolerability of dietary inulin, the diversity and differential abundance of gut microbiota, and vaccine-specific immune cell populations and responses. ETHICS AND DISSEMINATION: Ethics approval was obtained from the Central Adelaide Local Health Network (CALHN) Human Research Ethics Committee (HREC) (approval number: 2021/HRE00354) and the Sydney Local Health District (SHLD) HREC (approval numbers: X21-0411 and 2021/STE04280). Results of this trial will be published following peer-review and presented at scientific meetings and congresses. TRIAL REGISTRATION NUMBER: ACTRN12621001465842.

Rapamycin and inulin for booster vaccine response stimulation (RIVASTIM)-rapamycin: study protocol for a randomised, controlled trial of immunosuppression modification with rapamycin to improve SARS-CoV-2 vaccine response in kidney transplant recipients.

Kidney transplant recipients are at an increased risk of severe COVID-19-associated hospitalisation and death. Vaccination has been a key public health strategy to reduce disease severity and infectivity, but the effectiveness of COVID vaccines is markedly reduced in kidney transplant recipients. Urgent strategies to enhance vaccine efficacy are needed. METHODS: RIVASTIM-rapamycin is a multicentre, randomised, controlled trial examining the effect of immunosuppression modification prior to a third dose of COVID-19 vaccine in kidney transplant recipients who have failed to develop protective immunity to a 2-dose COVID-19 vaccine schedule. Participants will be randomised 1:1 to either remain on standard of care immunosuppression with tacrolimus, mycophenolate, and prednisolone (control) or cease mycophenolate and commence sirolimus (intervention) for 4 weeks prior to and following vaccination. The primary outcome is the proportion of participants in each trial arm who develop protective serological neutralisation of live SARS-CoV-2 virus at 4-6 weeks following a third COVID-19 vaccination. Secondary outcomes include SARS-CoV-receptor binding domain IgG, vaccine-specific immune cell populations and responses, and the safety and tolerability of sirolimus switch. DISCUSSION: Immunosuppression modification strategies may improve immunological vaccine response. We hypothesise that substituting the mTOR inhibitor sirolimus for mycophenolate in a triple drug regimen will enhance humoral and cell-mediated responses to COVID vaccination for kidney transplant recipients. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry ACTRN12621001412820. Registered on 20 October 2021; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=382891&isReview=true.

The Utility of Pre- and Post-Transplant Oral Glucose Tolerance Tests: Identifying Kidney Transplant Recipients With or at Risk of New Onset Diabetes After Transplant.

Background: New onset diabetes after transplant (NODAT) is common in kidney transplant recipients (KTRs). Identifying patients at risk prior to transplant may enable strategies to mitigate NODAT, with a pre-transplant oral glucose tolerance test (OGTT) suggested by the KDIGO 2020 Guidelines for this purpose. Methods: We investigated the utility of pre- and post-transplant OGTTs to stratify risk and diagnose NODAT in a retrospective, single-centre cohort study of all non-diabetic KTRs transplanted between 2003 and 2018. Results: We identified 597 KTRs who performed a pre-transplant OGTT, of which 441 had their post-transplant glycaemic status determined by a clinical diagnosis of NODAT or OGTT. Pre-transplant dysglycaemia was identified in 28% of KTRs and was associated with increasing age (p < 0.001), BMI (p = 0.03), and peritoneal dialysis (p < 0.001). Post-transplant dysglycaemia was common with NODAT and impaired glucose tolerance (IGT) occurring in 143 (32%) and 121 (27%) patients, respectively. Pre-transplant IGT was strongly associated with NODAT development (OR 3.8, p < 0.001). Conclusion: A pre-transplant OGTT identified candidates at increased risk of post-transplant dysglycaemia and NODAT, as diagnosed by an OGTT. Robust prospective trials are needed to determine whether various interventions can reduce post-transplant risk for candidates with an abnormal pre-transplant OGTT.

Rapidly progressive crescentic diabetic nephropathy: two case reports.

Crescents are not a well recognised feature of diabetic nephropathy. We present two cases of patients presenting with a rapid decline in renal function and subacute onset of nephrotic syndrome. Glomerulonephritis screening was negative, and renal biopsy revealed non-necrotising cellular crescents and typical features of late-stage diabetic nephropathy. We review the literature for diabetic nephropathy with crescents and explore possible underlying mechanisms.

Staged versus concurrent native nephrectomy and renal transplantation in patients with autosomal dominant polycystic kidney disease: A systematic review.

BACKGROUND: Patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD) frequently undergo native nephrectomy before transplantation. The nephrectomy may be a staged procedure or undertaken simultaneously with transplantation. When performed simultaneously, the transplant procedure is more prolonged, involves a larger operative field and incision. There is also a concern of a greater risk of graft loss with simultaneous nephrectomy and transplantation. Moreover, staged surgery may allow nephrectomy to be performed before immunosuppression introduction via a smaller incision or involving a minimally invasive approach. However, staged nephrectomy may require a period of dialysis not otherwise necessary if a transplant and nephrectomy were simultaneous. Moreover, only a single procedure is needed, implying the avoidance of a prior nephrectomy and its attendant morbidity in a patient with chronic renal insufficiency. To account for these issues, this study aims to compare the cumulative morbidity of two-staged procedures versus a single simultaneous approach in term of morbidity and graft outcomes. OBJECTIVES: This study aims to systematically review the literature to determine whether a staged or simultaneous approach to native nephrectomy in ADPKD is the optimal approach in terms of morbidity and graft outcomes. METHODS: A literature search of MEDLINE and EMBASE was conducted to identify published systematic reviews, randomized control trials, case-controlled studies and case studies. Data comparing outcomes of staged and simultaneous nephrectomy for patients undergoing kidney transplantation was extracted and analyzed. The main outcomes analyzed were length of hospitalization, blood loss, operative time, other early postoperative complications and risk of graft thrombosis. Meta-analysis was conducted where appropriate. RESULTS: Seven retrospective cohort studies were included in the review. There was a total of 385 patients included in the analysis, of whom 273 patients underwent simultaneous native nephrectomy and kidney transplantation. Meta-analysis showed an increased cumulative operative time in staged procedures (RR 1.86；95% CI 0.43-3.29 p = 0.01) and increased risk of blood transfusions (RR 2.69; 95% CI 1.92-3.46 p < 0.00001). For the transplant procedure, there were no significant difference in the length of stay (RR 1.03; 95% CI -2.01-4.14 p = 0.52), major postoperative complications (RR 0.02; 95% CI -0.15-0.10 p = 0.74) and vascular thromboses (RR 1.42 95% CI 0.23-8.59 p = 0.7). CONCLUSION: The results suggest that staged nephrectomy followed by kidney transplantation is associated with a longer cumulative operative time and increased cumulative risk of blood transfusions. There is no evidence to suggest that performing a simultaneous nephrectomy and kidney transplant procedure increases the perioperative mortality rate, major postoperative complication rates or risk of vascular thrombosis.

Biomarkers as diagnostic tests for delayed graft function in kidney transplantation.

Delayed graft function (DGF) after kidney transplantation is associated with inferior outcomes and higher healthcare costs. DGF is currently defined as the requirement for dialysis within seven days post-transplant; however, this definition is subjective and nonspecific. Novel biomarkers have potential to improve objectivity and enable earlier diagnosis of DGF. We reviewed the literature to describe the range of novel biomarkers previously studied to predict DGF. We identified marked heterogeneity and low reporting quality of published studies. Among the novel biomarkers, serum NGAL had the greatest potential as a biomarker to predict DGF, but requires further assessment and validation through larger scale studies of diagnostic test performance. Given inadequacies in the dialysis-based definition, coupled with the high incidence and impact of DGF, such studies should be pursued.

Transplant-associated penile Kaposi sarcoma managed with single agent paclitaxel chemotherapy: a case report.

BACKGROUND: Kaposi's sarcoma is an uncommon complication in renal transplant patients, and typically presents with cutaneous lesions on the lower extremities. Penile involvement has been reported only rarely. Management of cutaneous-limited disease is primarily reduction of immunosuppression and conversion to an mTOR-inhibitor, whereas the treatment of disseminated disease in transplant patients is more variable. CASE PRESENTATION: A 75-year-old male, originally from Somalia, received a deceased-donor kidney transplant for diabetic and hypertensive nephropathy. Seven months post-transplant he presented with lower limb lesions, oedema and bilateral deep vein thromboses. He then developed a fast-growing painful lesion on his penile shaft. A biopsy of this lesion confirmed KS, and a PET scan demonstrated disseminated disease in the lower extremities, penis and thoracic lymph nodes. His tacrolimus was converted to sirolimus, and his other immunosuppression was reduced. He was treated with single agent paclitaxel chemotherapy in view of his rapidly progressing, widespread disease. The penile lesion completely resolved, and the lower extremity lesions regressed significantly. His kidney allograft function remained stable throughout treatment. CONCLUSION: This case illustrates a rare presentation of an uncommon post-transplant complication and highlights the need for a high index of suspicion of KS in transplant patients presenting with atypical cutaneous lesions. It serves to demonstrate that the use of single agent paclitaxel chemotherapy, switch to an mTORi and reduction in immunosuppression where possible produces excellent short-term outcomes, adding to the body of evidence for this management strategy in disseminated Kaposi's sarcoma.

Comparison of the effect of single vs dual antiplatelet agents on post-operative haemorrhage after renal transplantation: A systematic review and meta-analysis.

OBJECTIVES: A significant proportion of renal transplant patients have cardiovascular comorbidities for which they receive treatment with antiplatelet agents. The aim of this study was to systematically review the current literature reporting perioperative outcomes for patients receiving dual antiplatelet therapy compared to single antiplatelet therapy at the time of kidney transplantation with particular reference to the risks of postoperative haemorrhage. MATERIALS AND METHODS: Embase, Medline and Cochrane databases were utilized to identify articles reporting outcomes of renal transplant recipients on single antiplatelet therapy and dual antiplatelet therapy. These outcomes were compared using a random effects model meta-analysis where appropriate. RESULTS: Six articles were incorporated in the analysis, including 130 receiving dual antiplatelet therapy, and 781 in the single antiplatelet therapy group. There was a significantly higher risk of post-operative haemorrhagic events in the dual antiplatelet therapy group compared to the single antiplatelet therapy group (RR 1.58, 95% CI 1.19-2.09, p = 0.001). Post-operative cardiovascular event rates were similar between both groups in individual studies, although this could not be quantitatively analysed. CONCLUSIONS: The use of dual antiplatelet therapy was associated with a higher risk of post-operative haemorrhage compared to the use of single antiplatelet therapy without increased rates of surgical intervention. However, the use of dual antiplatelet therapy may provide protection from cardiovascular events in an inherently higher risk patient group.

Death after Kidney Transplantation: An Analysis by Era and Time Post-Transplant.

BACKGROUND: Mortality risk after kidney transplantation can vary significantly during the post-transplant course. A contemporary assessment of trends in all-cause and cause-specific mortality at different periods post-transplant is required to better inform patients, clinicians, researchers, and policy makers. METHODS: We included all first kidney-only transplant recipients from 1980 through 2018 from the Australia and New Zealand Dialysis and Transplant Registry. We compared adjusted death rates per 5-year intervals, using a piecewise exponential survival model, stratified by time post-transplant or time post-graft failure. RESULTS: Of 23,210 recipients, 4765 died with a functioning graft. Risk of death declined over successive eras, at all periods post-transplant. Reductions in early deaths were most marked; however, recipients ≥10 years post-transplant were 20% less likely to die in the current era compared with preceding eras (2015-2018 versus 2005-2009, adjusted hazard ratio, 0.80; 95% confidence interval, 0.69 to 0.90). In 2015-2018, cardiovascular disease was the most common cause of death, particularly in months 0-3 post-transplant (1.18 per 100 patient-years). Cancer deaths were rare early post-transplant, but frequent at later time points (0.93 per 100 patient-years ≥10 years post-transplant). Among 3657 patients with first graft loss, 2472 died and were not retransplanted. Death was common in the first year after graft failure, and the cause was most commonly cardiovascular (50%). CONCLUSIONS: Reductions in death early and late post-transplant over the past 40 years represent a major achievement. Reductions in cause-specific mortality at all time points post-transplant are also apparent. However, relatively greater reductions in cardiovascular death have increased the prominence of late cancer deaths.

Successful kidney transplantation in a patient with stable multiple myeloma.

Renal failure is a common feature of multiple myeloma affecting 20-55% of patients at the initial presentation and is being associated with a significant increase in morbidity and mortality. Renal transplantation for patients with multiple myeloma is rarely considered given the incurable nature of the disease, the risk of post-transplant disease progression and perceived high risk of infections. Here we report a 57-year-old man with end-stage renal failure attributed to presumed IgA nephropathy, with pre-existing stable multiple myeloma, who received a kidney transplant from a two haplotype-matched sibling. Transplantation has been successful and with excellent kidney function and stable multiple myeloma 6 years post-transplant. This case highlights the potential benefits of renal transplantation in highly selected patients with multiple myeloma.

Screening for Asymptomatic Coronary Artery Disease in Waitlisted Kidney Transplant Candidates: A Cost-Utility Analysis.

RATIONALE & OBJECTIVE: On account of the high prevalence of cardiovascular disease in patients with kidney failure, clinical practice guidelines recommend regular screening for asymptomatic coronary artery disease (CAD) in patients on the kidney transplant waitlist. To date, the cost-effectiveness of such screening has not been evaluated. A Canadian-Australasian randomized controlled trial of screening kidney transplant candidates for CAD (CARSK) is currently is being conducted to answer this question. We conducted a cost-utility analysis to determine, before completion of the trial, the cost-effectiveness of no further screening versus regular screening for asymptomatic CAD and to evaluate potential influential variables that may affect results of the economic evaluation. STUDY DESIGN: A modeled cost-utility analysis. SETTING & POPULATION: A theoretical cohort of adult Australian and New Zealand kidney transplant candidates on the waitlist. INTERVENTION: No further screening for asymptomatic CAD versus regular protocolized screening (annual or second yearly) for CAD after kidney transplant waitlisting. OUTCOMES: Incremental cost-effectiveness ratio, reported as cost per quality-adjusted life-year (QALY). MODEL, PERSPECTIVES, & TIMEFRAME: Markov microsimulation model, health system perspective and over a lifetime horizon. RESULTS: In the base case, the incremental cost-effectiveness ratio of no further screening was $11,122 per QALY gained when compared with regular screening. No further screening increased survival by 0.49 life-year or 0.35 QALY. One-way sensitivity analyses identified the costs of transplantation in the first year and CAD prevalence as the most influential variables. Probabilistic sensitivity analyses showed that 94% of the simulations were cost-effective below a willingness-to-pay threshold of $50,000 per QALY gained. LIMITATIONS: Rates of cardiovascular events in waitlisted candidates and transplant recipients are limited in the contemporary era. The results may not be generalizable to populations outside Australia and New Zealand. CONCLUSIONS: No further screening for CAD after waitlisting is likely to be cost-effective and may improve survival. Precision around CAD prevalence estimates and health care resource use will reduce existing uncertainty.

Canadian-Australasian Randomised trial of screening kidney transplant candidates for coronary artery disease-A trial protocol for the CARSK study.

Transplantation is the preferred treatment for patients with kidney failure, but the need exceeds the supply of transplantable kidneys, and patients routinely wait >5 years on dialysis for a transplant. Coronary artery disease (CAD) is common in kidney failure and can exclude patients from transplantation or result in death before or after transplantation. Screening asymptomatic patients for CAD using noninvasive tests prior to wait-listing and at regular intervals (ie, annually) after wait-listing until transplantation is the established standard of care and is justified by the need to avoid adverse patient outcomes and loss of organs. Patients with abnormal screening tests undergo coronary angiography, and those with critical stenoses are revascularized. Screening is potentially harmful because patients may be excluded or delayed from transplantation, and complications after revascularization are more frequent in this population. CARSK will test the hypothesis that eliminating screening tests for occult CAD after wait-listing is not inferior to regular screening for the prevention of major adverse cardiac events defined as the composite of cardiovascular death, nonfatal myocardial infarction, urgent revascularization, and hospitalization for unstable angina. Secondary outcomes include the transplant rate, safety measures, and the cost-effectiveness of screening. Enrolment of 3,306 patients over 3 years is required, with patients followed for up to 5 years during wait-listing and for 1 year after transplantation. By validating or refuting the use of screening tests during wait-listing, CARSK will ensure judicious use of health resources and optimal patient outcomes.

Everolimus and Long-term Clinical Outcomes in Kidney Transplant Recipients: A Registry-based 10-year Follow-up of 5 Randomized Trials.

BACKGROUND: Data regarding the long-term efficacy of everolimus-based immunosuppression for kidney transplantation are lacking. Existing randomized controlled trials are limited by short follow-up duration which limits capacity to assess impact on graft and patient survival. METHODS: We linked individual trial participants to the Australian and New Zealand Dialysis and Transplant Registry. Using a 1-step meta-analysis approach, we investigated the 10-year risk of graft loss, mortality and graft function in 349 participants from 5 randomized trials of everolimus-based immunosuppression. RESULTS: Two hundred forty-two patients randomized to everolimus and 107 control patients were followed for a median of 9 years (interquartile range, 7.1, 9.8 y). There were no significant differences in the risk of all-cause graft loss (adjusted hazard ratio [HR], 1.16; 95% confidence interval [CI], 0.69-1.94), mortality (adjusted HR, 1.51; 95% CI, 0.78-2.93) and death-censored graft loss in everolimus versus control (adjusted HR, 1.00; 95% CI, 0.50-2.01). For patients in the early initiation (de novo or <6-month conversion) everolimus trials (n = 279), decline in estimated glomerular filtration rate did not significantly differ with control (mean difference in the slope of estimated glomerular filtrate rate, 0.01 mL/min per 1.73 m [-0.06 to +0.09]). CONCLUSIONS: This registry-based analysis with long-term follow-up found no differences in graft and recipient survival or graft function for everolimus over current standard of care.

De novo or early conversion to everolimus and long-term cancer outcomes in kidney transplant recipients: A trial-based linkage study.

Choice of immunosuppression may modify the risk of cancer after kidney transplantation, however, long-term data are lacking. Using the Australian and New Zealand Dialysis and Transplant Registry, we compared the 9-year risk of incident cancer, non-melanoma skin cancer (NMSC), and death attributed to cancer among participants from Australia and New Zealand in four randomized-controlled trials which compared de novo or early switch to an everolimus-containing regimen with calcineurin-inhibitor-based triple therapy. An adjusted Cox-model with random effects was used to determine such risks. Two hundred seventy-nine patients (192 everolimus, 87 control) were followed for a median of 9 years (IQR 6.7, 11.2). Compared with control, everolimus use was not associated with a reduction in the risk of incident cancer, NMSC, or cancer-related death (unadjusted HR [95% CI] 0.86 [0.49-1.48], 0.58 [0.30-1.12], and 1.18 [0.32-4.38], respectively). Subgroup analyses showed a 56% reduction for NMSC in patients randomized to everolimus + reduced-dose calcineurin-inhibitor versus control (unadjusted HR 0.44 [0.21-0.92]), which remained significant after adjusting for age, gender and smoking (adjusted HR 0.45 [0.21-0.96]). Although de novo or early switch to everolimus did not alter the 9-year risk of incident cancer or cancer-related death, everolimus with reduced-dose calcineurin-inhibitor strategy may reduce the long-term risk of NMSC.