Balanced crystalloid solution versus saline in deceased donor kidney transplantation (BEST-Fluids): a pragmatic, double-blind, randomised, controlled trial.

BACKGROUND: Delayed graft function (DGF) is a major adverse complication of deceased donor kidney transplantation. Intravenous fluids are routinely given to patients receiving a transplant to maintain intravascular volume and optimise graft function. Saline (0·9% sodium chloride) is widely used but might increase the risk of DGF due to its high chloride content. We aimed to test our hypothesis that using a balanced low-chloride crystalloid solution (Plasma-Lyte 148) instead of saline would reduce the incidence of DGF. METHODS: BEST-Fluids was a pragmatic, registry-embedded, multicentre, double-blind, randomised, controlled trial at 16 hospitals in Australia and New Zealand. Adults and children of any age receiving a deceased donor kidney transplant were eligible; those receiving a multi-organ transplant or weighing less than 20 kg were excluded. Participants were randomly assigned (1:1) using an adaptive minimisation algorithm to intravenous balanced crystalloid solution (Plasma-Lyte 148) or saline during surgery and up until 48 h after transplantation. Trial fluids were supplied in identical bags and clinicians determined the fluid volume, rate, and time of discontinuation. The primary outcome was DGF, defined as receiving dialysis within 7 days after transplantation. All participants who consented and received a transplant were included in the intention-to-treat analysis of the primary outcome. Safety was analysed in all randomly assigned eligible participants who commenced surgery and received trial fluids, whether or not they received a transplant. This study is registered with Australian New Zealand Clinical Trials Registry, (ACTRN12617000358347), and ClinicalTrials.gov (NCT03829488). FINDINGS: Between Jan 26, 2018, and Aug 10, 2020, 808 participants were randomly assigned to balanced crystalloid (n=404) or saline (n=404) and received a transplant (512 [63%] were male and 296 [37%] were female). One participant in the saline group withdrew before 7 days and was excluded, leaving 404 participants in the balanced crystalloid group and 403 in the saline group that were included in the primary analysis. DGF occurred in 121 (30%) of 404 participants in the balanced crystalloid group versus 160 (40%) of 403 in the saline group (adjusted relative risk 0·74 [95% CI 0·66 to 0·84; p<0·0001]; adjusted risk difference 10·1% [95% CI 3·5 to 16·6]). In the safety analysis, numbers of investigator-reported serious adverse events were similar in both groups, being reported in three (<1%) of 406 participants in the balanced crystalloid group versus five (1%) of 409 participants in the saline group (adjusted risk difference -0·5%, 95% CI -1·8 to 0·9; p=0·48). INTERPRETATION: Among patients receiving a deceased donor kidney transplant, intravenous fluid therapy with balanced crystalloid solution reduced the incidence of DGF compared with saline. Balanced crystalloid solution should be the standard-of-care intravenous fluid used in deceased donor kidney transplantation. FUNDING: Medical Research Future Fund and National Health and Medical Research Council (Australia), Health Research Council (New Zealand), Royal Australasian College of Physicians, and Baxter.

A multinational cohort study uncovered sex differences in excess mortality after kidney transplant.

Worldwide and at all ages, males have a higher mortality risk than females. This mortality bias should be preserved in kidney transplant recipients unless there are sex differences in the effects of transplantation. Here we compared the excess risk of mortality (risk above the general population) in female versus male recipients of all ages recorded in three large transplant databases. This included first deceased donor kidney transplant recipients and accounted for the modifying effects of donor sex and recipient age. After harmonization of variables across cohorts, relative survival models were fitted in each cohort separately and results were combined using individual patient data meta-analysis among 466,892 individuals (1988-2019). When the donor was male, female recipients 0-12 years (Relative Excess Risk 1.54, 95% Confidence Interval 1.20-1.99), 13-24 years (1.17, 1.01-1.34), 25-44 years (1.11, 1.05-1.18) and 60 years and older (1.05, 1.02-1.08) showed higher excess mortality risks than male recipients of the same age. When the donor was female, the Relative Excess Risk for those over 12 years were similar to those when the donor was male. There is a higher excess mortality risk in female than male recipients with differences larger at younger than older ages and only statistically significant when the donor was male. While these findings may be partly explained by the known sex differences in graft loss risks, sex differences in the risks of death with graft function may also contribute. Thus, higher risks in females than males suggest that management needs to be modified to optimize transplant outcomes among females.

Sex Disparity in Cause-Specific and All-Cause Mortality Among Incident Dialysis Patients.

RATIONALE & OBJECTIVE: Early mortality rates of female patients receiving dialysis have been, at times, observed to be higher than rates among male patients. The differences in cause-specific mortality between male and female incident dialysis patients with kidney failure are not well understood and were the focus of this study. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Incident patients who had initiated dialysis in Australia and New Zealand in 1998-2018. EXPOSURE: Sex. OUTCOMES: Cause-specific and all-cause mortality while receiving dialysis, censored for kidney transplant. ANALYTICAL APPROACH: Adjusted cause-specific proportional hazards models, focusing on the first 5 years following initiation of dialysis. RESULTS: Among 53,414 patients (20,876 [39%] female) followed for a median period of 2.8 (IQR, 1.3-5.2) years, 27,137 (51%) died, with the predominant cause of death attributed to cardiovascular disease (18%), followed by dialysis withdrawal (16%). Compared with male patients, female patients were more likely to die in the first 5 years after dialysis initiation (adjusted hazard ratio [AHR], 1.08 [95% CI, 1.05-1.11]). Even though female patients experienced a lower risk of cardiovascular disease-related mortality (AHR, 0.93 [95% CI, 0.89-0.98]) than male patients, they experienced a greater risk of infection-related (AHR, 1.20 [95% CI, 1.10-1.32]) and dialysis withdrawal-related (AHR, 1.19 [95% CI, 1.13-1.26]) mortality. LIMITATIONS: Possibility of residual and unmeasured confounders. CONCLUSIONS: Compared with male patients, female patients had a higher risk of all-cause mortality in the first 5 years after dialysis initiation, a difference driven by higher rates of mortality from infections and dialysis withdrawals. These findings may inform the study of sex differences in mortality in other geographic settings.

Cigarette smoking and adverse health outcomes in patients treated with maintenance dialysis.

BACKGROUND: The association of smoking with new-onset cardiovascular disease, chronic lung disease, malignancy and mortality in dialysis is well-known. The smoking prevalence and its association with clinical outcome was assessed. METHODS: Multicentre cohort study using 'ANZDATA' Registry, 57 838 adults who commenced dialysis (>3 months) between 1990 and 2016 were included. Patients' demographics, initial dialysis modality, presence of comorbidities and smoking history are predictors. The primary outcome was all-cause mortality. Secondary outcomes were smoking prevalence, cause-specific mortality, non-skin cancers, cardiovascular and chronic lung diseases. RESULTS: Of the 57 838 patients, 56 512 (mean age of 58.9 ± 15.1 years, 40.1% female, 43% diabetic), had data on smoking history with 13.6% current, 40.7% former and 45.6% never smokers. Former and current smokers had 10% (HR 1.10; 95% CI: 1.08, 1.13) and 22%(HR 1.22; 95% CI: 1.18, 1.26) higher risk of all-cause mortality. They were 13% (HR 1.13; 95% CI: 1.09, 1.18) and 23% (HR 1.23; 95% CI: 1.17, 1.29) for CVD mortality. Smoking was associated with higher mortality from respiratory failure (HR 1.59; 95% CI: 1.13, 2.23, p = .073 and HR 1.33; 95% CI: 1.01, 1.74, p = .042) for current and former smokers. Current and former smokers had higher risk for non-skin cancer (HR 1.30; 95% CI: 1.19, 1.42 and HR 1.24; 95% CI: 1.17, 1.32). Smoking was associated with a higher rate of death from cancer (HR 1.26; 95% CI 1.19-1.33) and chronic lung disease (HR 1.48; 95% CI 1.15-1.92). Former and current smokers had a higher adjusted risk for de novo vascular disease (PVD, CVD), CAD (adjusted RR 1.1; 95% Cl: 1.09-1.12). CONCLUSIONS: In dialysis patients, smoking was associated with higher rates of all-cause mortality, cardiovascular mortality, respiratory failure, chronic lung disease and malignancy along with higher risks of non-skin cancers, de novo vascular disease and chronic lung disease.

Invasive Management and Outcomes in Acute Coronary Syndromes and Chronic Kidney Disease (ANZACS-QI 70).

AIMS: Guidelines recommend management with an invasive coronary angiogram in acute coronary syndromes (ACS), but most studies excluded patients with advanced chronic kidney disease (CKD). Our aims were to describe, in a comprehensive ACS cohort, the incidence of CKD, coronary angiography utilisation and outcomes, according to CKD stage. METHODS: National datasets were used to identify hospitalised ACS patients (2013 to 2018) in the Northern region of New Zealand. CKD stage was obtained from a linked laboratory dataset. Outcomes included all-cause and cause-specific mortality, and non-fatal myocardial infarction, heart failure and stroke. RESULTS: Thirty-eight percent (38%) of the 23,432 ACS patients had CKD stage 3 or higher: 2,403 (10%) had stages 4/5 CKD. Overall 61% received coronary angiography. Compared with normal renal function the adjusted rate of coronary angiography was lower in CKD stage 3b (RR 0.75, 95% confidence intervals [CIs] 0.69, 0.82) and stages 4/5 without dialysis (RR 0.41, 95% CIs 0.36, 0.46), but similar for those on dialysis (RR 0.89, 95% CIs 0.77, 1.02). All-cause mortality (mean follow-up 3.2 years) increased with CKD stage from 8% (normal kidney function) to 69% (stages 4/5 CKD without dialysis). Compared with coronary angiography, the adjusted all-cause and CVD mortality risks were higher in those without coronary angiography, except for those on dialysis, where these risks converged. CONCLUSIONS: Invasive management fell below an eGFR of 45 mL/min (≤ stage 3b), and nearly half of all deaths occurred in these patients. Clinical trials are needed to assess the role of invasive management in ACS and advanced CKD.

Interactions Between Donor Age and 12-Month Estimated Glomerular Filtration Rate on Allograft and Patient Outcomes After Kidney Transplantation.

Reduced estimated glomerular filtration rate (eGFR) at 12-months after kidney transplantation is associated with increased risk of allograft loss, but it is uncertain whether donor age and types modify this relationship. Using Australia and New Zealand registry data, multivariable Cox proportional modelling was used to examine the interactive effects between donor age, types and 12-month eGFR on overall allograft loss. We included 11,095 recipients (4,423 received live-donors). Recipients with lowest 12-month eGFR (<30 ml/min/1.73 m2) experienced the greatest risk of allograft loss, with adjusted HR [95% CI) of 2.65 [2.38-2.95] compared to eGFR of 30-60 ml/min/1.73 m2; whereas the adjusted HR for highest eGFR (>60 ml/min/1.73 m2) was 0.67 [0.62-0.74]. The association of 12-month eGFR and allograft loss was modified by donor age (but not donor types) where a higher risk of allograft loss in recipients with lower compared with higher 12-month eGFR being most pronounced in the younger donor age groups (p < 0.01). Recipients with eGFR <30 ml/min/1.73 m2 12-months after transplantation experienced ≥2.5-fold increased risk of overall allograft loss compared to those with eGFR of >60 ml/min/1.73 m2, and the magnitude of the increased risk is most marked among recipients with younger donors. Careful deliberation of other factors including donor age when considering eGFR as a surrogate for clinical endpoints is warranted.

Socio-economic disparity, access to care and patient-relevant outcomes after kidney allograft failure.

Social disparity is a major impediment to optimal health outcomes after kidney transplantation. In this study, we aimed to define the association between socio-economic status (SES) disparities and patient-relevant outcomes after kidney allograft failure. Using data from the Australia and New Zealand Dialysis and Transplant registry, we included patients with failed first-kidney allografts in Australia between 2005 and 2017. The association between residential postcode-derived SES in quintiles (quintile 1-most disadvantaged areas, quintile 5-most advantaged areas) with uptake of home dialysis (peritoneal or home haemodialysis) within the first 12-months post-allograft failure, repeat transplantation and death on dialysis were examined using competing-risk analysis. Of 2175 patients who had experienced first allograft failure, 417(19%) and 505(23%) patients were of SES quintiles 1 and 5, respectively. Compared to patients of quintile 5, quintile 1 patients were less likely to receive repeat transplants (adjusted subdistributional hazard ratio [SHR] 0.70,95%CI 0.55-0.89) and were more likely to die on dialysis (1.37 [1.04-1.81]), but there was no association with the uptake of home dialysis (1.02 [0.77-1.35]). Low SES may have a negative effect on outcomes post-allograft failure and further research is required into how best to mitigate this. However, small-scale variation within SES cannot be accounted for in this study.

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.

Impact of chronic kidney disease on mortality and cardiovascular outcomes after acute coronary syndrome: A nationwide data linkage study (ANZACS-QI 44).

AIMS: Chronic kidney disease (CKD) is associated with an increased risk of cardiovascular disease (CVD). We examined the characteristics, management and outcomes of patients with CKD in the All New Zealand Acute Coronary Syndrome Quality Improvement (ANZACS-QI) national registry. METHODS: The cohort comprised New Zealand (NZ) patients with an acute coronary syndrome undergoing coronary angiography between January 2013 and December 2016. Patients were categorized according to their stage of CKD. Outcomes included all-cause and cause-specific mortality and hospitalization with myocardial infarction (MI), stroke and major bleeding. RESULTS: Of the 20 604 patients, 20.3% had normal renal function, with 53.3%, 23.3%, 1.7% and 1.4% having CKD stages 2, 3, 4 and 5 CKD, respectively. Patients with severe CKD were more likely to be Maori or Pacific and live in an area with greater socioeconomic deprivation. Death, recurrent MI or stroke, and major bleeding all increased incrementally with each worsening stage of CKD severity. Compared with those with normal renal function, patients with stage 5 CKD had a much higher all-cause (hazard ratio [HR] 16.41, 95% CI 13.06-20.61), cardiovascular (HR 16.38, 95% CI 12.17-22.04) and non-cardiovascular mortality (HR 13.66 9, 95% CI.56-19.51). In addition, patients with stage 5 CKD were at a higher risk of recurrent MI or stroke (HR 4.73, 95% CI 3.86-5.80) and bleeding (HR 5.84, 95% CI 4.39-7.76). CONCLUSION: CKD was associated with increased mortality and a high incidence of morbidity in patients undergoing coronary angiography in New Zealand. Initiatives to understand and improve outcomes in this group of patients are urgently needed.

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.

Association of prevalent vascular disease with allograft failure and mortality in live-donor kidney transplant recipients - a retrospective cohort study.

Limited data exist regarding the impact of prevalent vascular disease after live-donor kidney transplantation. We aimed to determine the associations between the number of prevalent vascular diseases, allograft, and patient outcomes following live-donor transplantation. This cohort study used data from the Australia and New Zealand Dialysis and Transplant Registry. Rates between recipients of live-donor kidney transplants ± prevalent vascular disease prior to transplantation were calculated. The associations between vascular disease, allograft failure, and all-cause mortality were assessed using Cox regression modeling. Kaplan-Meier proportions were used to calculate all-cause mortality and death with a function graft stratified by vascular disease burden. Of 4742 live-donor recipients, 428 (9%) and 84 (2%) had prevalent vascular disease at 1 and ≥2 sites, respectively. Compared to recipients without vascular disease, the respective adjusted hazard ratios (95% confidence intervals) for patients with vascular disease at 1 and ≥2 sites were 1.78 (1.41-2.25) and 3.02 (2.03-4.50) for all-cause mortality; and 1.54 (1.26-1.88) and 2.28 (1.54-3.38) for allograft failure. All-cause mortality in recipients with vascular disease at 0, 1 and ≥2 sites was 0.028 (0.025, 0.031), 0.090 (0.073, 0.106) and 0.247 (0.196, 0.282) over the first 5-year post-transplant. There was an incremental association between the number of prevalent vascular disease sites and risk of allograft failure and all-cause mortality in live-donor kidney transplant recipients.

Transplantation and diabetes (Transdiab): a pilot randomised controlled trial of metformin in impaired glucose tolerance after kidney transplantation.

BACKGROUND: Post transplantation diabetes mellitus (PTDM) is a common and serious complication after renal transplantation with significant morbidity and mortality. Metformin has proven benefits in the general population and might be advantageous in the prevention and management of PTDM. METHODS: Transplantation and Diabetes (Transdiab) is a single-centre, unblinded, pilot randomised controlled trial assessing the feasibility, tolerability and efficacy of metformin after renal transplantation in patients with impaired glucose tolerance (IGT). Participants had an oral glucose tolerance test (OGTT) in the 4-12 weeks post-transplantation; those with IGT were randomised to standard care or standard care and metformin 500 mg twice daily and followed up for 12 months. RESULTS: Seventy eight patients had an OGTT over 24 months, 25 of them had IGT, of those, 19 patients were randomised, giving a feasibility of recruitment of 24.4%. Ten patients were randomised to metformin and 9 patients to standard care. Tolerability and efficacy was similar between the 2 groups with no serious adverse events. There was no difference in secondary outcomes relating to the metabolic profile. CONCLUSIONS: The use of metformin post renal transplantation appeared feasible and safe. Larger randomised controlled trials (RCTs) are needed to establish and confirm the efficacy and safety of metformin post renal transplantation. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12614001171606 . Date of registration 7/11/2014.

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.

Insulin and glucose-lowering agents for treating people with diabetes and chronic kidney disease.

BACKGROUND: Diabetes is the commonest cause of chronic kidney disease (CKD). Both conditions commonly co-exist. Glucometabolic changes and concurrent dialysis in diabetes and CKD make glucose-lowering challenging, increasing the risk of hypoglycaemia. Glucose-lowering agents have been mainly studied in people with near-normal kidney function. It is important to characterise existing knowledge of glucose-lowering agents in CKD to guide treatment. OBJECTIVES: To examine the efficacy and safety of insulin and other pharmacological interventions for lowering glucose levels in people with diabetes and CKD. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 12 February 2018 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: All randomised controlled trials (RCTs) and quasi-RCTs looking at head-to-head comparisons of active regimens of glucose-lowering therapy or active regimen compared with placebo/standard care in people with diabetes and CKD (estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2) were eligible. DATA COLLECTION AND ANALYSIS: Four authors independently assessed study eligibility, risk of bias, and quality of data and performed data extraction. Continuous outcomes were expressed as post-treatment mean differences (MD). Adverse events were expressed as post-treatment absolute risk differences (RD). Dichotomous clinical outcomes were presented as risk ratios (RR) with 95% confidence intervals (CI). MAIN RESULTS: Forty-four studies (128 records, 13,036 participants) were included. Nine studies compared sodium glucose co-transporter-2 (SGLT2) inhibitors to placebo; 13 studies compared dipeptidyl peptidase-4 (DPP-4) inhibitors to placebo; 2 studies compared glucagon-like peptide-1 (GLP-1) agonists to placebo; 8 studies compared glitazones to no glitazone treatment; 1 study compared glinide to no glinide treatment; and 4 studies compared different types, doses or modes of administration of insulin. In addition, 2 studies compared sitagliptin to glipizide; and 1 study compared each of sitagliptin to insulin, glitazars to pioglitazone, vildagliptin to sitagliptin, linagliptin to voglibose, and albiglutide to sitagliptin. Most studies had a high risk of bias due to funding and attrition bias, and an unclear risk of detection bias.Compared to placebo, SGLT2 inhibitors probably reduce HbA1c (7 studies, 1092 participants: MD -0.29%, -0.38 to -0.19 (-3.2 mmol/mol, -4.2 to -2.2); I2 = 0%), fasting blood glucose (FBG) (5 studies, 855 participants: MD -0.48 mmol/L, -0.78 to -0.19; I2 = 0%), systolic blood pressure (BP) (7 studies, 1198 participants: MD -4.68 mmHg, -6.69 to -2.68; I2 = 40%), diastolic BP (6 studies, 1142 participants: MD -1.72 mmHg, -2.77 to -0.66; I2 = 0%), heart failure (3 studies, 2519 participants: RR 0.59, 0.41 to 0.87; I2 = 0%), and hyperkalaemia (4 studies, 2788 participants: RR 0.58, 0.42 to 0.81; I2 = 0%); but probably increase genital infections (7 studies, 3086 participants: RR 2.50, 1.52 to 4.11; I2 = 0%), and creatinine (4 studies, 848 participants: MD 3.82 µmol/L, 1.45 to 6.19; I2 = 16%) (all effects of moderate certainty evidence). SGLT2 inhibitors may reduce weight (5 studies, 1029 participants: MD -1.41 kg, -1.8 to -1.02; I2 = 28%) and albuminuria (MD -8.14 mg/mmol creatinine, -14.51 to -1.77; I2 = 11%; low certainty evidence). SGLT2 inhibitors may have little or no effect on the risk of cardiovascular death, hypoglycaemia, acute kidney injury (AKI), and urinary tract infection (low certainty evidence). It is uncertain whether SGLT2 inhibitors have any effect on death, end-stage kidney disease (ESKD), hypovolaemia, fractures, diabetic ketoacidosis, or discontinuation due to adverse effects (very low certainty evidence).Compared to placebo, DPP-4 inhibitors may reduce HbA1c (7 studies, 867 participants: MD -0.62%, -0.85 to -0.39 (-6.8 mmol/mol, -9.3 to -4.3); I2 = 59%) but may have little or no effect on FBG (low certainty evidence). DPP-4 inhibitors probably have little or no effect on cardiovascular death (2 studies, 5897 participants: RR 0.93, 0.77 to 1.11; I2 = 0%) and weight (2 studies, 210 participants: MD 0.16 kg, -0.58 to 0.90; I2 = 29%; moderate certainty evidence). Compared to placebo, DPP-4 inhibitors may have little or no effect on heart failure, upper respiratory tract infections, and liver impairment (low certainty evidence). Compared to placebo, it is uncertain whether DPP-4 inhibitors have any effect on eGFR, hypoglycaemia, pancreatitis, pancreatic cancer, or discontinuation due to adverse effects (very low certainty evidence).Compared to placebo, GLP-1 agonists probably reduce HbA1c (7 studies, 867 participants: MD -0.53%, -1.01 to -0.06 (-5.8 mmol/mol, -11.0 to -0.7); I2 = 41%; moderate certainty evidence) and may reduce weight (low certainty evidence). GLP-1 agonists may have little or no effect on eGFR, hypoglycaemia, or discontinuation due to adverse effects (low certainty evidence). It is uncertain whether GLP-1 agonists reduce FBG, increase gastrointestinal symptoms, or affect the risk of pancreatitis (very low certainty evidence).Compared to placebo, it is uncertain whether glitazones have any effect on HbA1c, FBG, death, weight, and risk of hypoglycaemia (very low certainty evidence).Compared to glipizide, sitagliptin probably reduces hypoglycaemia (2 studies, 551 participants: RR 0.40, 0.23 to 0.69; I2 = 0%; moderate certainty evidence). Compared to glipizide, sitagliptin may have had little or no effect on HbA1c, FBG, weight, and eGFR (low certainty evidence). Compared to glipizide, it is uncertain if sitagliptin has any effect on death or discontinuation due to adverse effects (very low certainty).For types, dosages or modes of administration of insulin and other head-to-head comparisons only individual studies were available so no conclusions could be made. AUTHORS' CONCLUSIONS: Evidence concerning the efficacy and safety of glucose-lowering agents in diabetes and CKD is limited. SGLT2 inhibitors and GLP-1 agonists are probably efficacious for glucose-lowering and DPP-4 inhibitors may be efficacious for glucose-lowering. Additionally, SGLT2 inhibitors probably reduce BP, heart failure, and hyperkalaemia but increase genital infections, and slightly increase creatinine. The safety profile for GLP-1 agonists is uncertain. No further conclusions could be made for the other classes of glucose-lowering agents including insulin. More high quality studies are required to help guide therapeutic choice for glucose-lowering in diabetes and CKD.

The risk of cancer in kidney transplant recipients may be reduced in those maintained on everolimus and reduced cyclosporine.

Kidney transplant recipients are at a high risk of developing cancers after transplantation. Switching from calcineurin inhibitors to sirolimus has been shown to prevent secondary nonmelanoma skin cancer but whether everolimus with reduced exposure to calcineurin inhibitors has similar anti-cancer effects remains unknown. Therefore, we compared the risk of incident cancer over seven years of follow-up among kidney transplant recipients randomized to everolimus plus reduced exposure cyclosporine versus mycophenolate sodium and standard exposure cyclosporine. Using the Australian and New Zealand Dialysis and Transplant Registry (ANZDATA), we assessed the seven-year risk of incident cancer and other graft outcomes among a subgroup of recipients who had participated in the A2309 study using adjusted Cox proportional hazard models. Of 95 recipients, 66 were randomized to everolimus (1.5 mg or 3 mg) with reduced cyclosporine and 29 received mycophenolate sodium and standard exposure cyclosporine. Compared to mycophenolate sodium and standard exposure cyclosporine, everolimus treatment was associated with unadjusted hazard ratios of 0.28 (95% confidence interval 0.11-0.74), 0.39 (0.16-0.98) and 0.41 (0.23-0.71), respectively for nonmelanoma skin cancer, non-skin cancers and any cancers. Interestingly, the adjusted hazard ratios were 0.34 (0.13-0.91), 0.35 (0.09-1.25) and 0.32 (0.15-0.71), respectively. There was no association between treatment groups and rejection, graft loss or death. Compared to standard-exposure cyclosporine, everolimus with reduced exposure to cyclosporine may be associated with a reduced risk of cancer, particularly for non-melanoma skin cancer. Thus, if confirmed in larger patient cohorts, de novo use of everolimus with reduced exposure to calcineurin inhibitors may enable a reduction in cancer burden after transplantation.

Cytomegalovirus and cancer after kidney transplantation: Role of the human leukocyte antigen system?

BACKGROUND: The role of cytomegalovirus (CMV) in cancer development after transplantation remains uncertain. We aimed to determine the association between donor and recipient CMV serological status and the risk of cancer development after kidney transplantation. METHODS: Using data from the Australian and New Zealand Dialysis and Transplant (ANZDATA) Registry, we assessed the association between CMV donor/recipient (D/R) serological status and the risk of solid organ cancers in primary adult deceased-donor kidney transplant patients between 1990 and 2012. RESULTS: Of 8140 recipients, a total of 895 (11%) recipients developed incident cancers during a follow-up time of 51 555 person-years. Human leukocyte antigen (HLA) mismatches was an effect modifier between CMV serological status and cancer (P=.03 for interaction). In recipients who have received 0-2 HLA-ABDR mismatched kidneys, the adjusted hazard ratios for cancer incidence among those with CMV D-/R-, CMV D-/R+, and CMV D+/R- were 0.47 (95% confidence interval [CI]: 0.24-0.91), 1.42 (95% CI: 0.97-2.07), and 1.02 (95% CI: 0.67-1.57), respectively compared with the reference of CMV D+/R+. A similar association was not observed in those with >2 HLA-ABDR mismatches. CONCLUSION: CMV D-/R- status was associated with a reduced risk of cancer in kidney transplant recipients who have received well-matched renal allografts, suggesting a potential role of HLA matching in cancer development.

Carvedilol and Cardiac Biomarkers in Dialysis Patients: Secondary Analysis of a Randomized Controlled Trial.

BACKGROUND/AIMS: Cardiac biomarkers are associated with cardiac abnormalities and adverse outcomes in dialysis patients. Our aim was to report the effect of the beta-blocker carvedilol on cardiac biomarkers in adult dialysis patients. METHODS: The Beta-Blocker to Lower Cardiovascular Dialysis Events Feasibility Study was a randomized controlled trial comparing carvedilol to placebo. Serum and plasma were collected before the run-in, then 6 and 12 months post-randomization to measure B-type Natriuretic Peptide (BNP), N-terminal BNP (NT-ProBNP), high-sensitivity cardiac troponins I (hs-TnI) and T (hs-TnT), and galectin-3. Left ventricular global longitudinal strain (GLS) was measured by echocardiography at baseline. RESULTS: Seventy-two participants were recruited of whom 49 completed the run-in and were randomized to carvedilol (n=26) or placebo (n=23). Baseline echocardiography demonstrated median (inter-quartile range) GLS of -14.27% (-16.63 to -11.93). NTproBNP and hs-TnT correlated with GLS (Spearman's rho=0.34 [p=0.018] and rho=0.28 [p=0.049], respectively). Median change scores from baseline to 12 months did not differ significantly between participants with complete biomarker data randomized to carvedilol (n=15) or placebo (n=16) for any biomarkers. CONCLUSIONS: NT-proBNP and hs-TnT were associated with GLS. However, changes in levels of the biomarkers from baseline to 12 months were not different between groups randomized to carvedilol and placebo.

Glucose-lowering agents for treating pre-existing and new-onset diabetes in kidney transplant recipients.

BACKGROUND: Kidney transplantation is the preferred form of kidney replacement therapy for patients with end-stage kidney disease (ESKD) and is often complicated by worsening or new-onset diabetes. Management of hyperglycaemia is important to reduce post-transplant and diabetes-related complications. The safety and efficacy of glucose-lowering agents after kidney transplantation is largely unknown. OBJECTIVES: To evaluate the efficacy and safety of pharmacological interventions for lowering glucose levels in patients who have undergone kidney transplantation and have diabetes. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Specialised Register to 15 April 2016 through contact with the Information Specialist using search terms relevant to this review. Studies contained in the Specialised Register are identified through search strategies specifically designed for CENTRAL, MEDLINE, and EMBASE; handsearching conference proceedings; and searching the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: All randomised controlled trials (RCTs), quasi-RCTs and cross-over studies examining head-to-head comparisons of active regimens of glucose-lowering therapy or active regimen compared with placebo/standard care in patients who have received a kidney transplant and have diabetes were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two authors independently assessed study eligibility and quality and performed data extraction. Continuous outcomes were expressed as post-treatment mean differences (MD) or standardised mean difference (SMD). Adverse events were expressed as post-treatment absolute risk differences (RD). Dichotomous clinical outcomes were presented as risk ratios (RR) with 95% confidence intervals (CI). MAIN RESULTS: We included seven studies that involved a total of 399 kidney transplant recipients. All included studies had observed heterogeneity in the patient population, interventions and measured outcomes or missing data (which was unavailable despite correspondence with authors). Many studies had incompletely reported methodology preventing meta-analysis and leading to low confidence in treatment estimates.Three studies with 241 kidney transplant recipients examined the use of more intensive compared to less intensive insulin therapy in kidney transplant recipients with pre-existing type 1 or 2 diabetes. Evidence for the effects of more intensive compared to less intensive insulin therapy on transplant graft survival, HbA1c, fasting blood glucose, all cause mortality and adverse effects including hypoglycaemia was of very low quality. More intensive versus less intensive insulin therapy resulted in no difference in transplant or graft survival over three to five years in one study while another study showed that more intensive versus less intensive insulin therapy resulted in more rejection events over the three year follow-up (11 events in total; 9 in the more intensive group, P = 0.01). One study showed that more intensive insulin therapy resulted in a lower mean HbA1c (10 ± 0.8% versus 13 ± 0.9%) and lower fasting blood glucose (7.22 ± 0.5 mmol/L versus 13.44 ± 1.22 mmol/L) at 13 months compared with standard insulin therapy. Another study showed no difference between more intensive compared to less intensive insulin therapy on all-cause mortality over a five year follow-up period. All studies showed either an increased frequency of hypoglycaemia or severe hypoglycaemia episodes.Three studies with a total of 115 transplant recipients examined the use of DPP4 inhibitors for new-onset diabetes after transplantation. Evidence for the treatment effect of DPP4 inhibitors on transplant or graft survival, HbA1c and fasting blood glucose levels, all cause mortality, and adverse events including hypoglycaemia was of low quality. One study comparing vildagliptin to placebo and another comparing sitagliptin to placebo showed no difference in transplant or graft survival over two to four months of follow-up. One study comparing vildagliptin to placebo showed no significant change in estimated glomerular filtration rate from baseline (1.9 ± 10.3 mL/min/1.73 m2, P = 0.48 and 2.1 ± 6.1 mL/min/1.73 m2, P = 0.22) and no deaths, in either treatment group over three months of follow-up. One study comparing vildagliptin to placebo showed a lower HbA1c level (mean ± SD) (6.3 ± 0.5% versus versus 6.7 ± 0.6%, P = 0.03) and trend towards a greater lowering of fasting blood glucose (-0.91 ± -0.92 mmol/L versus vs -0.19 ± 1.16 mmol/L, P = 0.08) with vildagliptin. One study comparing sitagliptin to insulin glargine showed an equivalent lowering of HbA1c (-0.6 ± 0.5% versus -0.6 ± 0.6%, P = NS) and fasting blood glucose (4.92 ± 1.42 versus 4.76 ± 1.09 mmol/L, P = NS) with sitagliptin. For the outcome of hypoglycaemia, one study comparing vildagliptin to placebo reported no episodes of hypoglycaemia, one study comparing sitagliptin to insulin glargine reported fewer episodes of hypoglycaemia with sitagliptin (3/28 patients; 10.7% versus 5/28; 17.9%) and one cross-over study of sitagliptin and placebo reported two episodes of asymptomatic moderate hypoglycaemia (2 to 3.9 mmol/L) when sitagliptin was administered with glipizide. All three studies reported no drug interactions between DPP4 inhibitors and the immunosuppressive agents taken.Evidence for the treatment effect of pioglitazone for treating pre-existing diabetes was of low quality. One study with 62 transplant recipients compared the use of pioglitazone with insulin to insulin alone for treating pre-existing diabetes. Pioglitazone resulted in a lower HbA1c level (mean ± SD) (-1.21 ± 1.2 versus 0.39 ± 1%, P < 0.001) but had no effects on fasting blood glucose (6.58 ± 2.71 versus 7.28 ± 2.78 mmol/L, P = 0.14 ), and change in creatinine (3.54 ± 15.03 versus 10.61 ± 18.56 mmol/L, P = 0.53) and minimal adverse effects (no episodes of hypoglycaemia, three dropped out due to mild to moderate lower extremity oedema, cyclosporin levels were not affected). AUTHORS' CONCLUSIONS: Evidence concerning the efficacy and safety of glucose-lowering agents for treating pre-existing and new-onset diabetes in kidney transplant recipients is limited. Existing studies examine more intensive versus less intensive insulin therapy, and the use of DPP4 inhibitors and pioglitazone. The safety and efficacy of more intensive compared to less intensive insulin therapy is very uncertain and the safety and efficacy of DPP4 inhibitors and pioglitazone is uncertain, due to data being limited and of poor quality. Additional RCTs are required to clarify the safety and efficacy of current glucose-lowering agents for kidney transplant recipients with diabetes.

Communicating projected survival with treatments for chronic kidney disease: patient comprehension and perspectives on visual aids.

BACKGROUND: Mortality in end stage renal disease (ESRD) is higher than many malignancies. There is no data about the optimal way to present information about projected survival to patients with ESRD. In other areas, graphs have been shown to be more easily understood than narrative. We examined patient comprehension and perspectives on graphs in communicating projected survival in chronic kidney disease (CKD). METHODS: One hundred seventy-seven patients with CKD were shown 4 different graphs presenting post transplantation survival data. Patients were asked to interpret a Kaplan Meier curve, pie chart, histogram and pictograph and answer a multi-choice question to determine understanding. RESULTS: We measured interpretation, usefulness and preference for the graphs. Most patients correctly interpreted the graphs. There was asignificant difference in the percentage of correct answers when comparing different graph types (p = 0.0439). The pictograph was correctly interpreted by 81% of participants, the histogram by 79%, pie chart by 77% and Kaplan Meier by 69%. Correct interpretation of the histogram was associated with educational level (p = 0.008) and inversely associated with age > 65 (p = 0.008). Of those who interpreted all four graphs correctly, there was an association with employment (p = 0.001) and New Zealand European ethnicity (p = 0.002). 87% of patients found the graphs useful. The pie chart was the most preferred graph (p 0.002). The readability of the graphs may have been improved with an alternative colour choice, especially in the setting of visual impairment. CONCLUSION: Visual aids, can be beneficial adjuncts to discussing survival in CKD.

The ß-Blocker to Lower Cardiovascular Dialysis Events (BLOCADE) Feasibility Study: A Randomized Controlled Trial.

BACKGROUND: ß-Blocking agents reduce cardiovascular mortality in patients with heart disease, but their potential benefit in dialysis patients is unclear. We aimed to determine the feasibility of a randomized controlled trial (RCT). STUDY DESIGN: Pilot RCT. SETTING & PARTICIPANTS: Patients who received dialysis for 3 or more months and were 50 years or older (or ≥18 years with diabetes or cardiovascular disease) were recruited from 11 sites in Australia and New Zealand. We aimed to recruit 150 participants. INTERVENTION: After a 6-week run-in with the ß-blocker carvedilol, we randomly assigned participants to treatment with carvedilol or placebo for 12 months. OUTCOMES & MEASUREMENTS: The prespecified primary outcome was the proportion of participants who tolerated carvedilol, 6.25mg, twice daily during the run-in period. After randomization, we report participant withdrawal and the incidence of intradialytic hypotension (IDH). RESULTS: Of 1,443 patients screened, 354 were eligible, 91 consented, and 72 entered the run-in stage. 49 of 72 run-in participants (68%; 95% CI, 57%-79%) achieved the primary outcome. 5 of the 23 withdrawals from run-in were attributable to bradycardia or hypotension. After randomization, 10 of 26 allocated to carvedilol and 4 of 23 allocated to placebo withdrew. 4 participants randomly assigned to carvedilol withdrew because of bradycardia or hypotension. Overall, there were 4 IDH events per 100 hemodialysis sessions; in participants allocated to carvedilol versus placebo, respectively, there were 7 versus 2 IDH events per 100 hemodialysis sessions (P=0.1) in the 2 weeks immediately following a dose increase and 4 versus 3 IDH events per 100 hemodialysis sessions after no dose increase (P=0.7). LIMITATIONS: Unable to recruit planned sample size. CONCLUSIONS: Recruiting patients receiving dialysis to an RCT of ß-blocker versus placebo will prove challenging. Possible solutions include international collaboration and exploring novel trial designs such as a registry-based RCT.