Back to the Basics of SARS-CoV-2 Biochemistry: Microvascular Occlusive Glycan Bindings Govern Its Morbidities and Inform Therapeutic Responses.

Consistent with the biochemistry of coronaviruses as well established over decades, SARS-CoV-2 makes its initial attachment to host cells through the binding of its spike protein (SP) to sialylated glycans (containing the monosaccharide sialic acid) on the cell surface. The virus can then slide over and enter via ACE2. SARS-CoV-2 SP attaches particularly tightly to the trillions of red blood cells (RBCs), platelets and endothelial cells in the human body, each cell very densely coated with sialic acid surface molecules but having no ACE2 or minimal ACE2. These interlaced attachments trigger the blood cell aggregation, microvascular occlusion and vascular damage that underlie the hypoxia, blood clotting and related morbidities of severe COVID-19. Notably, the two human betacoronaviruses that express a sialic acid-cleaving enzyme are benign, while the other three-SARS, SARS-CoV-2 and MERS-are virulent. RBC aggregation experimentally induced in several animal species using an injected polysaccharide caused most of the same morbidities of severe COVID-19. This glycan biochemistry is key to disentangling controversies that have arisen over the efficacy of certain generic COVID-19 treatment agents and the safety of SP-based COVID-19 vaccines. More broadly, disregard for the active physiological role of RBCs yields unreliable or erroneous reporting of pharmacokinetic parameters as routinely obtained for most drugs and other bioactive agents using detection in plasma, with whole-blood levels being up to 30-fold higher. Appreciation of the active role of RBCs can elucidate the microvascular underpinnings of other health conditions, including cardiovascular disease, and therapeutic opportunities to address them.

Oligonephronia: another piece in the CKDu jigsaw?

Rates of chronic kidney disease of unknown etiology are high in Aguascalientes, Mexico. Kidneys of adolescents are small by ultrasonography, compatible with oligonephronia, whereas proteinuria and higher estimated glomerular filtration rates and blood pressures among those with relatively higher kidney volumes probably flag relatively greater degrees of compensatory hypertrophy. Glomerulomegaly and podocytopathy, and later segmental glomerulosclerosis in biopsies, suggest a cascade driven by nephron deficiency. Better measures of glomerular number and volume should improve understanding, facilitate risk assessment, and guide interventions.

Novel genetic markers for chronic kidney disease in a geographically isolated population of Indigenous Australians: Individual and multiple phenotype genome-wide association study.

BACKGROUND: Chronic kidney disease (CKD) is highly prevalent among Indigenous Australians, especially those in remote regions. The Tiwi population has been isolated from mainland Australia for millennia and exhibits unique genetic characteristics that distinguish them from other Indigenous and non-Indigenous populations. Notably, the rate of end-stage renal disease is up to 20 times greater in this population compared to non-Indigenous populations. Despite the identification of numerous genetic loci associated with kidney disease through GWAS, the Indigenous population such as Tiwi remains severely underrepresented and the increased prevalence of CKD in this population may be due to unique disease-causing alleles/genes. METHODS: We used albumin-to-creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR) to estimate the prevalence of kidney disease in the Tiwi population (N = 492) in comparison to the UK Biobank (UKBB) (N = 134,724) database. We then performed an exploratory factor analysis to identify correlations among 10 CKD-related phenotypes and identify new multi-phenotype factors. We subsequently conducted a genome-wide association study (GWAS) on all single and multiple phenotype factors using mixed linear regression models, adjusted for age, sex, population stratification, and genetic relatedness between individuals. RESULTS: Based on ACR, 20.3% of the population was at severely increased risk of CKD progression and showed elevated levels of ACR compared to the UKBB population independent of HbA1c. A GWAS of ACR revealed novel association loci in the genes MEG3 (chr14:100812018:T:A), RAB36 (rs11704318), and TIAM2 (rs9689640). Additionally, multiple phenotypes GWAS of ACR, eGFR, urine albumin, and serum creatinine identified a novel variant that mapped to the gene MEIS2 (chr15:37218869:A:G). Most of the identified variants were found to be either absent or rare in the UKBB population. CONCLUSIONS: Our study highlights the Tiwi population's predisposition towards elevated ACR, and the collection of novel genetic variants associated with kidney function. These associations may prove valuable in the early diagnosis and treatment of renal disease in this underrepresented population. Additionally, further research is needed to comprehensively validate the functions of the identified variants/genes.

Regional Variation in Hemoglobin Distribution Among Individuals With CKD: the ISN International Network of CKD Cohorts.

Introduction: Despite recognized geographic and sex-based differences in hemoglobin in the general population, these factors are typically ignored in patients with chronic kidney disease (CKD) in whom a single therapeutic range for hemoglobin is recommended. We sought to compare the distribution of hemoglobin across international nondialysis CKD populations and evaluate predictors of hemoglobin. Methods: In this cross-sectional study, hemoglobin distribution was evaluated in each cohort overall and stratified by sex and estimated glomerular filtration rate (eGFR). Relationships between candidate predictors and hemoglobin were assessed from linear regression models in each cohort. Estimates were subsequently pooled in a random effects model. Results: A total of 58,613 participants from 21 adult cohorts (median eGFR range of 17-49 ml/min) and 3 pediatric cohorts (median eGFR range of 26-45 ml/min) were included with broad geographic representation. Hemoglobin values varied substantially among the cohorts, overall and within eGFR categories, with particularly low mean hemoglobin observed in women from Asian and African cohorts. Across the eGFR range, women had a lower hemoglobin compared to men, even at an eGFR of 15 ml/min (mean difference 5.3 g/l, 95% confidence interval [CI] 3.7-6.9). Lower eGFR, female sex, older age, lower body mass index, and diabetic kidney disease were all independent predictors of a lower hemoglobin value; however, this only explained a minority of variance (R2 7%-44% across cohorts). Conclusion: There are substantial regional differences in hemoglobin distribution among individuals with CKD, and the majority of variance is unexplained by demographics, eGFR, or comorbidities. These findings call for a renewed interest in improving our understanding of hemoglobin determinants in specific CKD populations.

Hospitalizations Among Adults With CKD in Public Renal Specialty Practices: A Retrospective Study From Queensland, Australia.

Rationale & Objective: Little is known about hospital admissions in nondialysis patients with chronic kidney disease (CKD) before death or starting kidney replacement therapy (KRT). Study Design: Retrospective observational cohort study. Setting & Participants: Hospitalizations among 7,201 patients with CKD from 10 public renal clinics in Queensland (QLD), enrolled in the CKD.QLD registry starting in May 2011, were followed for 25,496.34 person-years until they started receiving KRT or died, or until June 30, 2018. Predictors: Demographic and clinical characteristics of patients with CKD. Outcomes: Hospital admissions. Analytical Approach: We evaluated the association of demographic and clinical features with hospitalizations, length of hospital stay, and cost. Results: Approximately 81.5% of the patients were admitted at least once, with 42,283 admissions, costing Australian dollars (AUD) 231 million. The average number of admissions per person-year was 1.7, and the cost was AUD 9,060, 10 times and 2 times their Australian averages, respectively. Single (1-day) admissions constituted 59.2% of all the hospital episodes, led by neoplasms (largely chemotherapy), anemia, CKD-related conditions and eye conditions (largely cataract extractions), but only 14.8% of the total costs. Approximately 41% of admissions were >1-day admissions, constituting 85.2% of the total costs, with cardiovascular conditions, respiratory conditions, CKD-related conditions, and injuries, fractures, or poisoning being the dominant causes. Readmission within 30 days of discharge constituted >42% of the admissions and 46.8% costs. Admissions not directly related to CKD constituted 90% of the admissions and costs. More than 40% of the admissions and costs were through the emergency department. Approximately 19% of the hospitalized patients and 27% of the admissions did not have kidney disease mentioned as either principal or associate causes. Limitations: Variable follow-up times because of different dates of consent. Conclusions: The hospital burden of patients with CKD is mainly driven by complex multiday admissions and readmissions involving comorbid conditions, which may not be directly related to their CKD. Strategies to prevent these complex admissions and readmissions should minimize hospital costs and outcomes. Plain-Language Summary: We analyzed primary causes, types, and costs of hospitalizations among 7,201 patients with chronic kidney disease (CKD) from renal speciality clinics across Queensland, Australia, over an average follow-up of 3.54 years. The average annual cost per person was $9,060, and was the highest in those with more advanced CKD, higher age, and with diabetes. More than 85% of costs were driven by more complex hospitalizations with longer length of stay. Cardiovascular disease was the single largest contributor for hospitalizations, length of hospital stay, and total costs. Readmission within 30 days of discharge, particularly for the same disorder, and multiday admissions should be the main targets for mitigation of hospital costs in this population.

The Diagnostic Performance of a Clinical Diagnosis of Diabetic Kidney Disease.

BACKGROUND: Diabetic kidney disease (DKD), a common cause of CKD and kidney failure, is usually diagnosed clinically. However, there is little evidence comparing the performance of a clinical diagnosis to biopsy-proven diagnosis. PURPOSE OF THE STUDY: Diagnostic performance of a clinical diagnosis was determined in a group of patients with diabetes and chronic kidney disease who underwent kidney biopsy after an initial clinical diagnosis. METHODS: A data analysis of 54 patients who were part of a study cohort for a prospective analysis of cardiovascular and kidney outcomes and who had undergone kidney biopsy after an initial clinical diagnosis of DKD or non-DKD (NDKD) at enrolment was used. We determined the sensitivity, specificity, and positive and negative predictive values of a clinical diagnosis of DKD. RESULTS: A total of 37 of 43 patients clinically diagnosed with DKD also had biopsy-proven DKD, whilst only 1 of 11 patients who had clinically diagnosed NDKD had biopsy-proven DKD. Sensitivity was 97.4%, specificity was 62.5%, positive predictive value 86%, and negative predictive value 90.9%. Comparable values were obtained when analysis was restricted to those with primary rather than secondary diagnosis of DKD or when restricted to those with only DKD found at biopsy. CONCLUSION: A clinical diagnosis of DKD has high sensitivity and is unlikely to overlook cases but may lead to overdiagnosis.

When Characteristics of Clinical Trials Require Per-Protocol as Well as Intention-to-Treat Outcomes to Draw Reliable Conclusions: Three Examples.

Under exceptional circumstances, including high rates of protocol non-compliance, per-protocol (PP) analysis can better indicate the real-world benefits of a medical intervention than intention-to-treat (ITT) analysis. Exemplifying this, the first randomized clinical trial (RCT) considered found that colonoscopy screenings were marginally beneficial, based upon ITT analysis, with only 42% of the intervention group actually undergoing the procedure. However, the study authors themselves concluded that the medical efficacy of that screening was a 50% reduction in colorectal cancer deaths among that 42% PP group. The second RCT found a ten-fold reduction in mortality for a COVID-19 treatment drug vs. placebo by PP analysis, but only a minor benefit by ITT analysis. The third RCT, conducted as an arm of the same platform trial as the second RCT, tested another COVID-19 treatment drug and reported no significant benefit by ITT analysis. Inconsistencies and irregularities in the reporting of protocol compliance for this study required consideration of PP outcomes for deaths and hospitalizations, yet the study coauthors refused to disclose them, instead directing inquiring scientists to a data repository which never held the study's data. These three RCTs illustrate conditions under which PP outcomes may differ significantly from ITT outcomes and the need for data transparency when these reported or indicated discrepancies arise.

The pharmacogenomic landscape of an Indigenous Australian population.

Background: Population genomic studies of individuals of Indigenous ancestry have been extremely limited comprising <0.5% of participants in international genetic databases and genome-wide association studies, contributing to a "genomic gap" that limits their access to personalised medicine. While Indigenous Australians face a high burden of chronic disease and associated medication exposure, corresponding genomic and drug safety datasets are sorely lacking. Methods: To address this, we conducted a pharmacogenomic study of almost 500 individuals from a founder Indigenous Tiwi population. Whole genome sequencing was performed using short-read Illumina Novaseq6000 technology. We characterised the pharmacogenomics (PGx) landscape of this population by analysing sequencing results and associated pharmacological treatment data. Results: We observed that every individual in the cohort carry at least one actionable genotype and 77% of them carry at least three clinically actionable genotypes across 19 pharmacogenes. Overall, 41% of the Tiwi cohort were predicted to exhibit impaired CYP2D6 metabolism, with this frequency being much higher than that for other global populations. Over half of the population predicted an impaired CYP2C9, CYP2C19, and CYP2B6 metabolism with implications for the processing of commonly used analgesics, statins, anticoagulants, antiretrovirals, antidepressants, and antipsychotics. Moreover, we identified 31 potentially actionable novel variants within Very Important Pharmacogenes (VIPs), five of which were common among the Tiwi. We further detected important clinical implications for the drugs involved with cancer pharmacogenomics such as thiopurines and tamoxifen, immunosuppressants like tacrolimus and certain antivirals used in the hepatitis C treatment due to potential differences in their metabolic processing. Conclusion: The pharmacogenomic profiles generated in our study demonstrate the utility of pre-emptive PGx testing and have the potential to help guide the development and application of precision therapeutic strategies tailored to Tiwi Indigenous patients. Our research provides valuable insights on pre-emptive PGx testing and the feasibility of its use in ancestrally diverse populations, emphasizing the need for increased diversity and inclusivity in PGx investigations.

The Impact of Anaemia on Outcomes, Admissions, and Costs in Patients with Chronic Kidney Disease in Two Public Nephrology Practices in Queensland: A CKD.QLD Registry Study.

Aim: Anaemia among patients with chronic kidney disease (CKD) leads to poor overall outcomes. This study explores anaemia and its impact on nondialysis CKD (NDD-CKD) patients. Methods: 2,303 adults with CKD from two CKD.QLD Registry sites were characterised at consent and followed until start of kidney replacement therapy (KRT), death, or censor date. Mean follow-up was 3.9 (SD 2.1) years. Analysis explored the impact of anaemia on death, KRT start, cardiovascular events (CVE), admissions, and costs in these NDD-CKD patients. Results: At consent, 45.6% patients were anaemic. Males were more often anaemic (53.6%) than females, and anaemia was significantly more common over the age of 65 years. The prevalence of anaemia was highest among CKD patients with diabetic nephropathy (27.4%) and renovascular disease (29.2%) and lowest in patients with genetic renal disease (3.3%). Patients with admissions for gastrointestinal bleeding had more severe anaemia, but accounted for only the minority of cases overall. Administration of ESAs, iron infusions, and blood transfusions were all correlated with more severe degrees of anaemia. The number of hospital admissions, length of stay, and hospital costs were all strikingly higher with more severe degrees of anaemia. Adjusted hazard ratios (CI 95%) of patients with moderate and severe anaemia vs. no anaemia for subsequent CVE, KRT, and death without KRT were 1.7 (1.4-2.0), 2.0 (1.4-2.9), and 1.8 (1.5-2.3), respectively. Conclusion: Anaemia is associated with higher rates of CVE, progression to KRT and death in NDD- CKD patients, and with greater hospital utilisation and costs. Preventing and treating anaemia should improve clinical and economic outcomes.

Chronic kidney disease in public renal practices in Queensland, Australia, 2011-2018.

AIM: To describe adults with (non-dialysis) chronic kidney disease (CKD) in nine public renal practice sites in the Australian state of Queensland. METHODS: 7,060 persons were recruited to a CKD Registry in May 2011 and until start of kidney replacement therapy (KRT), death without KRT or June 2018, for a median period of 3.4 years. RESULTS: The cohort comprised 7,060 persons, 52% males, with a median age of 68 yr; 85% had CKD stages 3A to 5, 45.4% were diabetic, 24.6% had diabetic nephropathy, and 51.7% were obese. Younger persons mostly had glomerulonephritis or genetic renal disease, while older persons mostly had diabetic nephropathy, renovascular disease and multiple diagnoses. Proportions of specific renal diagnoses varied >2-fold across sites. Over the first year, eGFR fell in 24% but was stable or improved in 76%. Over follow up, 10% started KRT, at a median age of 62 yr, most with CKD stages 4 and 5 at consent, while 18.8% died without KRT, at a median age of 80 yr. Indigenous people were younger at consent and more often had diabetes and diabetic kidney disease and had higher incidence rates of KRT. CONCLUSION: The spectrum of characteristics in CKD patients in renal practices is much broader than represented by the minority who ultimately start KRT. Variation in CKD by causes, age, site and Indigenous status, the prevalence of obesity, relative stability of kidney function in many persons over the short term, and differences between those who KRT and die without KRT are all important to explore.

Targeted biomarkers of progression in chronic kidney disease.

BACKGROUND: Chronic kidney disease (CKD) is an increasingly significant health issue worldwide. Early stages of CKD can be asymptomatic and disease trajectory difficult to predict. Not every-one with CKD progresses to kidney failure, where kidney replacement therapy is the only life-sustaining therapy. Predicting which patients will progress to kidney failure would allow better use of targeted treatments and more effective allocation of health resources. Current diagnostic tests to identify patients with progressive disease perform poorly but there is a suite of new and emerging predictive biomarkers with great clinical promise. METHODS: This narrative review describes new and emerging biomarkers of pathophysiologic processes of CKD development and progression, accessible in blood or urine liquid biopsies. Biomarkers were selected based on their reported pathobiological functions in kidney injury, inflammation, oxidative stress, repair and fibrosis. Biomarker function and evidence of involvement in CKD development and progression are reported. CONCLUSION: Many biomarkers reviewed here have received little attention to date, perhaps because of conflicting conclusions of their utility in CKD. The functional roles of the selected biomarkers in the underlying pathobiology of progression of CKD are a powerful rationale for advancing and validating these molecules as prognosticators and predictors of CKD trajectory.

The prevalence of Fabry disease in a statewide chronic kidney disease cohort - Outcomes of the aCQuiRE (Ckd.Qld fabRy Epidemiology) study.

BACKGROUND: Prevalence of Fabry disease amongst Chronic Kidney Disease (CKD) patients on haemodialysis has been shown to be approximately 0.2%. METHODS: We undertook a cross-sectional study employing a cascade screening strategy for Fabry Disease amongst 3000 adult, male and female patients affected by CKD stage 1-5D/T at public, specialty renal practices within participating Queensland Hospital and Health Services from October 2017 to August 2019. A multi-tiered FD screening strategy, utilising a combination of dried blood spot (DBS) enzymatic testing, and if low, then lyso-GB3 testing and DNA sequencing, was used. RESULTS: Mean (SD) age was 64.0 (15.8) years (n = 2992), and 57.9% were male. Eight participants withrew out of the 3000 who consented. Of 2992 screened, 6 (0.20%) received a diagnosis of FD, 2902 (96.99%) did not have FD, and 84 (2.81%) received inconclusive results. Of the patients diagnosed with FD, mean age was 48.5 years; 5 were male (0.29%) and 1 was female (0.08%); 4 were on kidney replacement therapy (2 dialysis and 2 transplant); 3 were new diagnoses. CONCLUSIONS: Estimated overall FD prevalence was 0.20%. Screening of the broader CKD population may be beneficial in identifying cases of FD. TRIAL REGISTRATION: The aCQuiRE Study has been prospectively registered with the Queensland Health Database of Research Activity (DORA, https://dora.health.qld.gov.au ) as pj09946 (Registered 3rd July 2017).

The genomic landscape of blood groups in Indigenous Australians in remote communities.

BACKGROUND: Red blood cell (RBC) membrane-associated blood group systems are clinically significant. Alloimmunisation is a persistent risk associated with blood transfusion owing to the antigen polymorphisms among these RBC-associated blood groups. Next-generation sequencing (NGS) offers an opportunity to characterize the blood group variant profile of a given individual. Australia comprises a large multiethnic population where most blood donors are Caucasian and blood group variants remain poorly studied among Indigenous Australians. In this study, we focused on the Tiwi Islanders, who have lived in relative isolation for thousands of years. METHODS AND MATERIALS: We predicted the blood group phenotype profiles in the Tiwi (457) and 1000 Genomes Phase 3 (1KGP3-2504) cohort individuals using RBCeq (https://www.rbceq.org/). The predicted phenotype prevalence was compared with the previous literature report. RESULTS: We report, for the first time, comprehensive blood group profiles corresponding to the 35 known blood group systems among the Indigenous Tiwi islander population and identify possible novel antigen variants therein. Our results demonstrate that the genetic makeup of the Tiwi participants is distinct from that of other populations, with a low prevalence of LU (Au[a-b+]) and ABO (A2) and D+C+c+E+e- phenotype, an absence of Diego blood group variants, and a unique RHD (DIII type4) variant. CONCLUSION: Our results may contribute to the development of a database of predicted phenotype donors among the Tiwi population and aid in improving transfusion safety for the ~2800 Tiwi people and the ~800,000 other Indigenous Australians throughout the nation.

Promoting Plant-Based Therapies for Chronic Kidney Disease.

Chronic kidney disease (CKD) is debilitating, increasing in incidence worldwide, and a financial and social burden on health systems. Kidney failure, the final stage of CKD, is life-threatening if untreated with kidney replacement therapies. Current therapies using commercially-available drugs, such as angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers and calcium channel blockers, generally only delay the progression of CKD. This review article focuses on effective alternative therapies to improve the prevention and treatment of CKD, using plants or plant extracts. Three mechanistic processes that are well-documented in CKD pathogenesis are inflammation, fibrosis, and oxidative stress. Many plants and their extracts are already known to ameliorate kidney dysfunction through antioxidant action, with subsequent benefits on inflammation and fibrosis. In vitro and in vivo experiments using plant-based therapies for pre-clinical research demonstrate some robust therapeutic benefits. In the CKD clinic, combination treatments of plant extracts with conventional therapies that are seen as relatively successful currently may confer additive or synergistic renoprotective effects. Therefore, the aim of recent research is to identify, rigorously test pre-clinically and clinically, and avoid any toxic outcomes to obtain optimal therapeutic benefit from medicinal plants. This review may prove to be a filtering tool to researchers into complementary and alternative medicines to find out the current trends of using plant-based therapies for the treatment of kidney diseases, including CKD.

Adenine overload induces ferroptosis in human primary proximal tubular epithelial cells.

The pathogenesis of crystal nephropathy involves deposition of intratubular crystals, tubular obstruction and cell death. The deposition of 8-dihydroxyadenine (DHA) crystals within kidney tubules, for instance, is caused by a hereditary deficiency of adenine phosphoribosyl transferase in humans or adenine overload in preclinical models. However, the downstream pathobiological patterns of tubular cell attrition in adenine/DHA-induced nephropathy remain poorly understood. In this study, we investigated: (i) the modes of adenine-induced tubular cell death in an experimental rat model and in human primary proximal tubular epithelial cells (PTEC); and (ii) the therapeutic effect of the flavonoid baicalein as a novel cell death inhibitor. In a rat model of adenine diet-induced crystal nephropathy, significantly elevated levels of tubular iron deposition and lipid peroxidation (4-hydroxynonenal; 4-HNE) were detected. This phenotype is indicative of ferroptosis, a novel form of regulated necrosis. In cultures of human primary PTEC, adenine overload-induced significantly increased mitochondrial superoxide levels, mitochondrial depolarisation, DNA damage and necrotic cell death compared with untreated PTEC. Molecular interrogation of adenine-stimulated PTEC revealed a significant reduction in the lipid repair enzyme glutathione peroxidase 4 (GPX4) and the significant increase in 4-HNE compared with untreated PTEC, supporting the concept of ferroptotic cell death. Moreover, baicalein treatment inhibited ferroptosis in adenine-stimulated PTEC by selectively modulating the mitochondrial antioxidant enzyme superoxide dismutase 2 (SOD2) and thus, suppressing mitochondrial superoxide production and DNA damage. These data identify ferroptosis as the primary pattern of PTEC necrosis in adenine-induced nephropathy and establish baicalein as a potential therapeutic tool for the clinical management of ferroptosis-associated crystal nephropathies (e.g., DHA nephropathy, oxalate nephropathy).

Kidney failure, CKD progression and mortality after nephrectomy.

PURPOSE: This study tested the hypothesis that progression of chronic kidney disease (CKD) is less aggressive in patients whose primary cause of CKD was nephrectomy, compared with non-surgical causes. METHODS: A sample of 5983 patients from five specialist nephrology practices was ascertained from the Queensland CKD Registry. Rates of kidney failure/death were compared on primary aetiology of CKD using multivariable Cox proportional hazards models. CKD progression was compared using multivariable linear and logistic regression analyses. RESULTS: Of 235 patients with an acquired single kidney as their primary cause of CKD, 24 (10%) and 38 (17%) developed kidney failure or died at median [IQR] follow-up times of 12.9 [2.5-31.0] and 33.6 [18.0-57.9] months after recruitment. Among patients with an eGFR < 45 mL/min per 1.73m2 at recruitment, patients with diabetic nephropathy and PCKD had the highest rates (per 1000 person-years) of kidney failure (107.8, 95% CI 71.0-163.8; 75.5, 95% CI 65.6-87.1); whereas, patients with glomerulonephritis and an acquired single kidney had lower rates (52.9, 95% CI 38.8-72.1; 34.6, 95% CI 20.5-58.4, respectively). Among patients with an eGFR ≥ 45 mL/min per 1.73m2, those with diabetic nephropathy had the highest rates of kidney failure (16.6, 95% CI 92.5-117.3); whereas, those with glomerulonephritis, PCKD and acquired single kidney had a lower risk (11.3, 95% CI 7.1-17.9; 11.7, 95% CI 3.8-36.2; 10.7, 95% CI 4.0-28.4, respectively). CONCLUSION: Patients who developed CKD after nephrectomy had similar rates of adverse events to most other causes of CKD, except for diabetic nephropathy which was consistently associated with worse outcomes. While CKD after nephrectomy is not the most aggressive cause of kidney disease, it is by no means benign, and is associated with a tangible risk of kidney failure and death, which is comparable to other major causes of CKD.

Determining the association between the type of intervention for ischaemic heart disease and mortality and morbidity in patients with chronic kidney disease.

BACKGROUND: Association between chronic kidney disease (CKD) and ischaemic heart disease (IHD) is well known. Clinically, because of the use of intra-arterial contrast, coronary angiograms are sometimes not performed to avoid further deterioration in kidney function among CKD patients. AIMS: To identify whether intervention for non-ST elevation myocardial infarction (NSTEMI) is associated with increased mortality or further renal deterioration. METHODS: A retrospective observational cohort study involving 144 patients with a diagnosis of IHD in the CKD.QLD registry from May 2011 to August 2017, with a minimum of 2-years follow up, was undertaken. Patients were divided into two groups based on whether they obtained an interventional or medical management for NSTEMI. RESULTS: Fifty-nine patients had medically managed and 85 patients had intervention for IHD. Patients in the medically managed group were observed to be significantly older (median: 78 vs 69 years; P < 0.05) with worse baseline renal function (median: 31 vs 36 mL/min/1.73 m2 ; P <0.05) and higher serum urate level (median: 0.5 vs 0.4 mmol/L; P = 0.2). The interventional group had lower prevalence of diabetes, dyslipidaemia, cerebrovascular disease and peripheral vascular disease. Although this was not significant, Kaplan-Meier analysis revealed a significant decrease in mean survival of medically managed group compared with the interventional group. Furthermore, post adjustment for age and above comorbidities, the medically managed group and higher age were associated with significantly higher mortality. However, the patients in the medically managed and interventional groups had no significant difference in delta estimated glomerular filtration rate. CONCLUSIONS: In this observational study, intervention for IHD was associated with increased survival with no change in renal disease progression in comparison with medically managed patients.

Pharmacogenomic analysis of a genetically distinct Indigenous population.

Indigenous Australians face a disproportionately severe burden of chronic disease relative to other Australians, with elevated rates of morbidity and mortality. While genomics technologies are slowly gaining momentum in personalised treatments for many, a lack of pharmacogenomic research in Indigenous peoples could delay adoption. Appropriately implementing pharmacogenomics in clinical care necessitates an understanding of the frequencies of pharmacologically relevant genetic variants within Indigenous populations. We analysed whole-genome sequence data from 187 individuals from the Tiwi Islands and characterised the pharmacogenomic landscape of this population. Specifically, we compared variant profiles and allelic distributions of previously described pharmacologically significant genes and variants with other population groups. We identified 22 translationally relevant pharmacogenomic variants and 18 clinically actionable guidelines with implications for drug dosing and treatment of conditions including heart disease, diabetes and cancer. We specifically observed increased poor and intermediate metabolizer phenotypes in the CYP2C9 (PM:19%, IM:44%) and CYP2C19 (PM:18%, IM:44%) genes.