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Background Proteinuria is well recognised as a marker of chronic kidney disease (CKD), as a risk factor for progression of CKD among those with known CKD, and as a risk factor for cardiovascular events and death among both the general and CKD populations. Which measure of proteinuria is most predictive of renal events remains uncertain. Methods We conducted a prospective study with 144 proteinuric CKD and kidney transplant recipients attending an outpatient clinic of a tertiary care hospital in Australia. We concurrently collected morning spot urine protein-to-creatinine ratio (UPCR), albumin-to-creatinine ratio (UACR) and 24-h urinary protein excretion (24-UPE) from each participant at baseline. The primary outcome was a composite of death, ESKD or > 30% decline in eGFR over 5-years. Secondary outcomes were each component of the composite outcome. For each proteinuria measure, we performed a Cox Proportional Hazards model and calculated the Harrell’s C-statistic and Akaike’s Information Criterion (AIC). Results After a mean follow-up of 5 years (range 4.4–6), 85 (59%) patients met the primary composite outcome including 23 deaths (16%). The multivariable analysis showed strong evidence of an association between each log-transformed proteinuria measurement and the primary composite outcome. [Log-UPCR 1.31 (95% CI 1.18–1.63), log-UACR 1.27 (1.11–1.45) and log-24-UPE 1.43 (1.20–1.71)]. The C-Statistic were similar for all three measures of proteinuria [UPCR: 0.74 (95% CI: 0.69–0.80), UACR: 0.75 (0.69–0.81), 24-UPE: 0.75 (0.69–0.81)] as were the models’ AIC (671, 668 and 665 respectively). For secondary outcomes, no proteinuria measure was significantly associated with death alone ([log-UPCR = 1.18 (0.96–1.84), log-UACR = 1.19 (1.00–1.55), log-24-UPE = 1.19 (0.83–1.71)], whilst UACR and 24-UPE demonstrated marginally better association with ESKD and > 30% decline in eGFR respectively. [For ESKD, adj log-UACR HR = 1.33 (1.07–1.66). For > 30% decline in eGFR, log-24-UPE adj HR = 1.54 (1.13–2.09)]. Conclusion In patients with stable, non-nephrotic CKD, all three measures of proteinuria were similarly predictive of hard clinical endpoints, defined as a composite of death, ESKD and > 30% decline in eGFR. However, which measure best predicted the outcomes individually is less certain.

IntroductionKidney 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 analysisRapamycin 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 disseminationEthics 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 numberACTRN12621001465842.

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

IntroductionKidney transplantation remains the best treatment for end-stage kidney disease, however the requirement for indefinite immunosuppression increases the risk of cardiovascular disease, cancer and infection, leading to a reduction in long-term patient and graft survival. The gut microbiome is a critical determinant of health and modulates host immunity and metabolism through a number of recognised pathways, including through the production of immunomodulatory short-chain fatty acids (SCFA). Dietary supplementation with non-digestible fibre can augment the microbial production of SCFA and lead to favourable immune and metabolic outcomes, although this has yet to be shown in human kidney transplant recipients.Methods and analysisDietary inulin for gut health in solid-organ transplantation (DIGEST) is a single-centre, unblinded, pilot parallel-arm randomised controlled trial designed to assess the feasibility and adherence of dietary inulin, a naturally occurring dietary fibre, in the early post-transplant period in kidney transplant recipients. Participants will be randomised at day 28 post-transplant to a 4-week period of dietary inulin (10–20 g/day) in addition to standard care, or standard care alone, and followed-up until week 12 post-transplant.The primary outcomes of the study are: (i) the feasibility of participant recruitment, randomisation and retention; (ii) adherence to the intervention (inulin) and (iii) the tolerability of inulin determined by changes in gastrointestinal symptoms as scored on the Gastrointestinal Symptom Rating Scale.Secondary outcomes include: (1) glycaemic variability determined by continuous glucose monitoring; (2) abundance of SCFA-producing microbiota, as determined by 16s rRNA sequencing of the faecal metagenome; (3) serum SCFA concentrations; (4) peripheral blood immune cell populations; (5) recipient inflammatory and metabolic profiles and (6) the incidence of biopsy-proven acute rejection and kidney function determined by estimated glomerular filtration rate.Ethics and disseminationAll study visits, clinical and laboratory assessments will be integrated into usual post-transplant care, creating no additional healthcare encounters or procedures. The risks associated with this study are minor. Inulin has been shown to be well tolerated across a variety of cohorts, with the occurrence of short-term adverse gastrointestinal symptoms self-limiting. However, with gastrointestinal adverse events common following kidney transplantation, the tolerability of inulin in this cohort remains unknown. The results of DIGEST will be published in peer-reviewed journals and presented at academic conferences. This study has been approved by the Sydney Local Health District’s Ethics Committee (Royal Prince Alfred Hospital Zone).Trial registration numberACTRN12620000623998.

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.

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.

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/m 2 Asians; >30 kg/m 2 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.

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.

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.