Better kidney allograft survival despite higher-risk donor and recipient characteristics between 1995-2014.

BACKGROUND AND HYPOTHESIS: Advances in organ procurement, surgical techniques, immunosuppression regimens and prophylactic antibiotic therapies have dramatically improved short term kidney transplant graft failure. It is unclear how these interventions have affected longer term graft failure. It is hypothesised that graft failure has improved over the last 20 years. METHODS: Data on all first kidney transplants from 1995-2014 were extracted from the Australia and New Zealand Dialysis and Transplant Registry with follow-up as of 31 December, 2021. Primary exposure was transplant era, classified into 5-year intervals. Primary outcome was all-cause 5-year graft failure. Secondary outcomes included all-cause 10-year graft failure and cause-specific graft failure. Kaplan Meier curves and multivariable Cox Proportional Hazards Regression models were used to assess trends in all-cause graft failure. Fine-Gray subdistribution hazard models verified that changes in death rates were not biasing the Cox Proportional Hazards Regression models. Cumulative incidence functions were used to assess temporal trends in cause-specific graft failure. RESULTS: Across 10 871 kidney transplants, there was a shift towards transplanting more recipients aged over 45 years old, with more comorbidities, longer dialysis vintage, body mass index greater than 30 kg/m2 and greater human leukocyte antigen mismatches. Donor age has increased but no clear shift in donor source was observed. Compared to 1995-1999 (reference), the adjusted hazard ratio for 5-year graft failure was 0.78 (95% CI 0.67-0.91), 0.70 (95% CI 0.59-0.83) and 0.60 (95% CI 0.50-0.73) for 2000-2004, 2005-2009, and 2010-2014, respectively. Ten-year graft failure similarly reduced from 0.83 (95% CI 0.74-0.93) for 2000-04 to 0.78 (95% CI 0.68-0.89) for 2010-14, compared to 1995-99. CONCLUSION: Medium and long term all-cause graft failure has improved steadily since 1995-99. Significant reductions in graft failure due to rejection and vascular causes were observed at 5 years, and due to rejection, vascular causes, death and glomerular disease at 10 years.

People with genetic kidney diseases on kidney replacement therapy have different clinical outcomes compared to people with other kidney diseases.

Despite increasing awareness of genetic kidney disease prevalence, there is limited population-level information about long term outcomes of people with genetic kidney disease receiving kidney replacement therapy. This analysis included people who commenced kidney replacement therapy between 1989 and 2020 as recorded in the Australian and New Zealand Dialysis and Transplant registry. Genetic kidney diseases were subclassified as majority and minority monogenic. Non-genetic kidney diseases were included as the comparator group. Primary outcome measures were 10-year mortality and 10-year graft failure. Cox proportional hazard regression were used to calculate unadjusted and adjusted hazard ratios (AHRs) for primary outcomes. There were 59,231 people in the dialysis subgroup and 21,860 people in the transplant subgroup. People on dialysis with genetic kidney diseases had reduced 10-year mortality risk (majority monogenic AHR: 0.70, 95% CI 0.66-0.76; minority monogenic AHR 0.86, 95% CI 0.80-0.92). This reduced 10-year mortality risk continued after kidney transplantation (majority monogenic AHR: 0.82, 95% CI 0.71-0.93; minority monogenic AHR 0.80, 95% CI 0.68-0.95). Majority monogenic genetic kidney diseases were associated with reduced 10-year graft failure compared to minority monogenic genetic kidney diseases and other kidney diseases (majority monogenic AHR 0.69, 95% CI 0.59-0.79). This binational registry analysis identified that people with genetic kidney disease have different mortality and graft failure risks compared to people with other kidney diseases.

Determining priority indicators of utility for genomic testing in rare disease: A Delphi study.

PURPOSE: Determining the value of genomic tests in rare disease necessitates a broader conceptualization of genomic utility beyond diagnostic yield. Despite widespread discussion, consensus toward which aspects of value to consider is lacking. This study aimed to use expert opinion to identify and refine priority indicators of utility in rare disease genomic testing. METHODS: We used 2 survey rounds following Delphi methodology to obtain consensus on indicators of utility among experts involved in policy, clinical, research, and consumer advocacy leadership in Australia. We analyzed quantitative and qualitative data to identify, define, and determine priority indicators. RESULTS: Twenty-five experts completed round 1 and 18 completed both rounds. Twenty indicators reached consensus as a priority in value assessment, including those relating to prognostic information, timeliness of results, practical and health care outcomes, clinical accreditation, and diagnostic yield. Whereas indicators pertaining to discovery research, disutility, and factors secondary to primary reason for testing were considered less of a priority and were removed. CONCLUSION: This study obtained expert consensus on different utility indicators that are considered a priority in determining the value of genomic testing in rare disease in Australia. Indicators may inform a standardized approach to evidence generation and assessment to guide future research, decision making, and implementation efforts.

Characteristics and clinical outcomes of patients with kidney failure of unknown aetiology from ANZDATA registry.

INTRODUCTION: Kidney failure of unknown aetiology (uESKD) is also heavily location dependent varying between 27% in Egypt to 54% in Aguacalientes, Mexico. There is limited information about the characteristics of people with uESKD in Australia and New Zealand, as well as their clinical outcomes on kidney replacement therapy. METHODS: Data on people commencing kidney replacement therapy 1989-2021 were received from the Australia and New Zealand Dialysis and Transplant (ANZDATA) registry. Primary exposure was cause of kidney failure-uESKD or non-uESKD (known-ESKD). Primary outcome was mortality. Secondary outcome was kidney transplantation. Dialysis and transplant cohorts were analysed separately. Cox Proportional Hazards Regression models were used to evaluate correlations between cause of kidney failure and mortality risk. Subgroup analyses were completed to compare mortality risk in people with uESKD to those with diabetic nephropathy, autosomal dominant polycystic kidney disease (ADPKD), glomerular disease and other kidney diseases. RESULTS: This study included 60,448 people on dialysis and 20,859 transplant recipients. 1-year, 3-year and 5-year mortality rates in people with uESKD on dialysis were 31.6%, 58.7% and 77.2%, respectively. 1-year, 3-year and 5-year mortality rates in transplant recipients with uESKD were 2.8%, 13.8% and 24.0%, respectively. People with uESKD on dialysis had a higher mortality risk compared to those without uESKD on univariable and multivariable analyses (adjusted hazard ratio [AHR] 1.10, 95% CI 1.06-1.16, p<0.001). Transplant recipients with uESKD have a higher mortality risk compared to those without uESKD on univariable and multivariable analyses (AHR 1.17, 95% CI 1.01-1.35, p<0.05). People with uESKD had similar likelihood of kidney transplantation compared to people with known-ESKD. CONCLUSION: People with uESKD on kidney replacement therapy have higher mortality risk compared to people with other kidney diseases. Further studies are required to identify contributing factors to these findings.

Exploring the impact and utility of genomic sequencing in established CKD.

Clinical genetics is increasingly recognized as an important area within nephrology care. Clinicians require awareness of genetic kidney disease to recognize clinical phenotypes, consider use of genomics to aid diagnosis, and inform treatment decisions. Understanding the broad spectrum of clinical phenotypes and principles of genomic sequencing is becoming increasingly required in clinical nephrology, with nephrologists requiring education and support to achieve meaningful patient outcomes. Establishment of effective clinical resources, multi-disciplinary teams and education is important to increase application of genomics in clinical care, for the benefit of patients and their families. Novel applications of genomics in chronic kidney disease include pharmacogenomics and clinical translation of polygenic risk scores. This review explores established and emerging impacts and utility of genomics in kidney disease.

Attitudes and barriers towards deprescribing in older patients experiencing polypharmacy: a narrative review.

Polypharmacy, commonly defined as ≥5 medications, is a rising public health concern due to its many risks of harm. One commonly recommended strategy to address polypharmacy is medication reviews, with subsequent deprescription of inappropriate medications. In this review, we explore the intersection of older age, polypharmacy, and deprescribing in a contemporary context by appraising the published literature (2012-2022) to identify articles that included new primary data on deprescribing medications in patients aged ≥65 years currently taking ≥5 medications. We found 31 articles were found which describe the current perceptions of clinicians towards deprescribing, the identified barriers, key enabling factors, and future directions in approaching deprescribing. Currently, clinicians believe that deprescribing is a complex process, and despite the majority of clinicians reporting feeling comfortable in deprescribing, fewer engage with this process regularly. Common barriers cited include a lack of knowledge and training around the deprescribing process, a lack of time, a breakdown in communication, perceived 'abandonment of care', fear of adverse consequences, and resistance from patients and/or their carers. Common enabling factors of deprescribing include recognition of key opportunities to instigate this process, regular medication reviews, improving lines of communication, education of both patients and clinicians and a multidisciplinary approach towards patient care. Addressing polypharmacy requires a nuanced approach in a generally complex group of patients. Key strategies to reducing the risks of polypharmacy include education of patients and clinicians, in addition to improving communication between healthcare providers in a multidisciplinary approach.

Real world evaluation of kidney failure risk equations in predicting progression from chronic kidney disease to kidney failure in an Australian cohort.

BACKGROUND: Chronic kidney disease progression to kidney failure is diverse, and progression may be different according to genetic aspects and settings of care. We aimed to describe kidney failure risk equation prognostic accuracy in an Australian population. METHODS: A retrospective cohort study was undertaken in a public hospital community-based chronic kidney disease service in Brisbane, Australia, which included a cohort of 406 adult patients with chronic kidney disease Stages 3-4 followed up over 5 years (1/1/13-1/1/18). Risk of progression to kidney failure at baseline using Kidney Failure Risk Equation models with three (eGFR/age/sex), four (add urinary-ACR) and eight variables (add serum-albumin/phosphate/bicarbonate/calcium) at 5 and 2 years were compared to actual patient outcomes. RESULTS: Of 406 patients followed up over 5 years, 71 (17.5%) developed kidney failure, while 112 died before reaching kidney failure. The overall mean difference between observed and predicted risk was 0.51% (p = 0.659), 0.93% (p = 0.602), and - 0.03% (p = 0.967) for the three-, four- and eight-variable models, respectively. There was small improvement in the receiver operating characteristic-area under the curve from three-variable to four-variable models: 0.888 (95%CI = 0.819-0.957) versus 0.916 (95%CI = 0.847-0.985). The eight-variable model showed marginal receiver operating characteristic-area under the curve improvement: 0.916 (95%CI = 0.847-0.985) versus 0.922 (95%CI = 0.853-0.991). The results were similar in predicting 2 year risk of kidney failure. CONCLUSIONS: The kidney failure risk equation accurately predicted progression to kidney failure in an Australian chronic kidney disease population. Younger age, male sex, lower estimated glomerular filtration rate, higher albuminuria, diabetes mellitus, tobacco smoking and non-Caucasian ethnicity were associated with increased risk of kidney failure. Cause-specific cumulative incidence function for progression to kidney failure or death, stratified by chronic kidney disease stage, demonstrated differences within different chronic kidney disease stages, highlighting the interaction between comorbidity and outcome.

Monogenic and polygenic concepts in chronic kidney disease (CKD).

Kidney function is strongly influenced by genetic factors with both monogenic and polygenic factors contributing to kidney function. Monogenic disorders with primarily autosomal dominant inheritance patterns account for 10% of adult and 50% of paediatric kidney diseases. However, kidney function is also a complex trait with polygenic architecture, where genetic factors interact with environment and lifestyle factors. Family studies suggest that kidney function has significant heritability at 35-69%, capturing complexities of the genome with shared environmental factors. Genome-wide association studies estimate the single nucleotide polymorphism-based heritability of kidney function between 7.1 and 20.3%. These heritability estimates, measuring the extent to which genetic variation contributes to CKD risk, indicate a strong genetic contribution. Polygenic Risk Scores have recently been developed for chronic kidney disease and kidney function, and validated in large populations. Polygenic Risk Scores show correlation with kidney function but lack the specificity to predict individual-level changes in kidney function. Certain kidney diseases, such as membranous nephropathy and IgA nephropathy that have significant genetic components, may benefit most from polygenic risk scores for improved risk stratification. Genetic studies of kidney function also provide a potential avenue for the development of more targeted therapies and interventions. Understanding the development and validation of genomic scores is required to guide their implementation and identify the most appropriate potential implications in clinical practice. In this review, we provide an overview of the heritability of kidney function traits in population studies, explore both monogenic and polygenic concepts in kidney disease, with a focus on recently developed polygenic risk scores in kidney function and chronic kidney disease, and review specific diseases which are most amenable to incorporation of genomic scores.

Polypharmacy in older patients presenting to a tertiary regional health service: identifying correlations between demographics, presentations and length of stay.

This study aimed to describe hospital admissions in patients experiencing polypharmacy and evaluate the effects of demographic factors on length of stay (LOS) and polypharmacy. We found that increasing age is associated with increasing polypharmacy rates but decreasing LOS. Females were more likely to experience higher rates of polypharmacy, but males were more likely to have longer LOS. First Nations peoples had higher rates of polypharmacy and longer LOS. Future projects investigating deprescribing methods are critical.

Do educational interventions improve prescribing skills of medical students compared to no additional learning? A systematic review.

Research suggests that medical students are not confident and may be ill-prepared to prescribe competently. Therefore, changes to standard education may be required to fortify medical student prescribing skills, confidence, and competence. However, specific education to write a safe and legal prescription is generally lacking. Furthermore, the term prescribe and the skill thereof is not clearly defined. This review compares additional education for medical students to no identified additional education or another educational modality on the skill of prescription writing. Secondary aims include review of education modalities, prescribing skill assessments, educator professional background, and timing of education within the medical curriculum. This systematic review was conducted and reported using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Databases searched included: CINAHL, Cochrane Library, EMBASE, Emcare (Ovid), MEDLINE (Ovid), PubMed and Scopus. Search terms included: medical education, medical undergraduate, medical student, medical school, and prescriptions. The search was conducted in February 2023, and quantitative outcomes were reported. Of the 5197 citations identified, 12 met the inclusion criteria. Eleven studies reported significant improvements in prescribing skills of medical students after additional educational intervention(s). Various educational modalities were implemented, including case-based teaching (n=3), patient-based teaching (n=1), tutorial-based teaching (n=2), didactic teaching (n=1), and mixed methods (n=6). There were no commonalities in the professional background of the educator; however, five studies used faculty members. There was no consensus on the best assessment type and time to implement prescription writing education during medical training. There are a range of interventions to educate and assess prescribing competencies of medical students. Despite heterogenous study designs, there is evidence of the superiority of additional prescription writing education versus no identified additional education to develop prescription writing skills. The introduction of formal teaching and standardised assessment of prescribing skills for medical students is recommended.

High risk clear cell renal cell carcinoma microenvironments contain protumour immunophenotypes lacking specific immune checkpoints.

Perioperative immune checkpoint inhibitor (ICI) trials for intermediate high-risk clear cell renal cell carcinoma (ccRCC) have failed to consistently demonstrate improved patient outcomes. These unsuccessful ICI trials suggest that the tumour infiltrating immunophenotypes, termed here as the immune cell types, states and their spatial location within the tumour microenvironment (TME), were unfavourable for ICI treatment. Defining the tumour infiltrating immune cells may assist with the identification of predictive immunophenotypes within the TME that are favourable for ICI treatment. To define the immunophenotypes within the ccRCC TME, fresh para-tumour (pTME, n = 2), low-grade (LG, n = 4, G1-G2) and high-grade (HG, n = 4, G3-G4) tissue samples from six patients with ccRCC presenting at a tertiary referral hospital underwent spatial transcriptomics sequencing (ST-seq). Within the generated ST-seq datasets, immune cell types and states, termed here as exhausted/pro-tumour state or non-exhausted/anti-tumour state, were identified using multiple publicly available single-cell RNA and T-cell receptor sequencing datasets as references. HG TMEs revealed abundant exhausted/pro-tumour immune cells with no consistent increase in expression of PD-1, PD-L1 and CTLA4 checkpoints and angiogenic genes. Additional HG TME immunophenotype characteristics included: pro-tumour tissue-resident monocytes with consistently increased expression of HAVCR2 and LAG3 checkpoints; an exhausted CD8+ T cells sub-population with stem-like progenitor gene expression; and pro-tumour tumour-associated macrophages and monocytes within the recurrent TME with the expression of TREM2. Whilst limited by a modest sample size, this study represents the largest ST-seq dataset on human ccRCC. Our study reveals that high-risk ccRCC TMEs are infiltrated by exhausted/pro-tumour immunophenotypes lacking specific checkpoint gene expression confirming that HG ccRCC TME are immunogenic but not ICI favourable.

Identifying the barriers to kidney transplantation for patients in rural and remote areas: a scoping review.

BACKGROUND: Populations in rural and remote areas have higher rates of chronic kidney disease and kidney failure than those in urban or metropolitan areas, and mortality rates for chronic kidney disease are almost twice as high in remote areas compared to major cities. Despite this, patients residing in regional, rural, or remote areas are less likely to be wait-listed for or receive a kidney transplant. The objective of this scoping review is to identify specific barriers to kidney transplantation for adult patients residing in rural and remote areas from the perspectives of health professionals and patients/carers. METHODS: Studies were identified through database (MEDLINE, CINAHL, Emcare, Scopus) searches and assessed against inclusion criteria to determine eligibility. A descriptive content analysis was undertaken to identify and describe barriers as key themes. RESULTS: The 24 selected studies included both quantitative (n = 5) and qualitative (n = 19) methodologies. In studies conducted in health professional populations (n = 10) the most prevalent themes identified were perceived social and cultural issues (80%), burden of travel and distance from treatment (60%), and system-level factors as barriers (60%). In patient/carer populations (n = 14), the most prevalent themes were limited understanding of illness and treatment options (71%), dislocation from family and support network (71%), and physical and psychosocial effects of treatment (71%). CONCLUSIONS: Patients in regional, rural, and remote areas face many additional barriers to kidney transplantation, which are predominantly associated with the need to travel or relocate to access required medical testing and transplantation facilities.