Podocyte number and glomerulosclerosis indices are associated with the response to therapy for primary focal segmental glomerulosclerosis.

Corticosteroid therapy, often in combination with inhibition of the renin-angiotensin system, is first-line therapy for primary focal and segmental glomerulosclerosis (FSGS) with nephrotic-range proteinuria. However, the response to treatment is variable, and therefore new approaches to indicate the response to therapy are required. Podocyte depletion is a hallmark of early FSGS, and here we investigated whether podocyte number, density and/or size in diagnostic biopsies and/or the degree of glomerulosclerosis could indicate the clinical response to first-line therapy. In this retrospective single center cohort study, 19 participants (13 responders, 6 non-responders) were included. Biopsies obtained at diagnosis were prepared for analysis of podocyte number, density and size using design-based stereology. Renal function and proteinuria were assessed 6 months after therapy commenced. Responders and non-responders had similar levels of proteinuria at the time of biopsy and similar kidney function. Patients who did not respond to treatment at 6 months had a significantly higher percentage of glomeruli with global sclerosis than responders (p < 0.05) and glomerulosclerotic index (p < 0.05). Podocyte number per glomerulus in responders was 279 (203-507; median, IQR), 50% greater than that of non-responders (186, 118-310; p < 0.05). These findings suggest that primary FSGS patients with higher podocyte number per glomerulus and less advanced glomerulosclerosis are more likely to respond to first-line therapy at 6 months. A podocyte number less than approximately 216 per glomerulus, a GSI greater than 1 and percentage global sclerosis greater than approximately 20% are associated with a lack of response to therapy. Larger, prospective studies are warranted to confirm whether these parameters may help inform therapeutic decision making at the time of diagnosis of primary FSGS.

Creatinine-Based Definition of Kidney Disease in the Charlson Comorbidity Index May Underestimate Prognosis in Males Compared to an Estimated Glomerular Filtration Rate Definition.

(1) Background: The Charlson comorbidity index allocates two points for chronic kidney disease (CKD) if serum creatinine is above 3.0 mg/dL (270 µmol/L). However, contemporary CKD staging is based on the estimated glomerular filtration rate (eGFR) derived from population-based equations. The aim of this study was to determine the correlation between eGFR and the creatinine threshold of the Charlson comorbidity index for defining CKD. (2) Methods: We conducted a cross-sectional study of 664 patients with established CKD attending general nephrology clinics over 6 months. Dialysis patients and kidney transplant recipients were excluded. (3) Results: The median age was 68 years, and 58% of the participants were male. By modeling with fractional polynomial regression, we estimated that a creatinine of 270 µmol/L corresponded with an eGFR of 14.8 mL/min/1.73 m2 for females and 19.4 mL/min/m2 for males. We also estimated that an eGFR of 15 mL/min/1.73 m2 (threshold which defines Stage 5 CKD) corresponded to a serum creatinine of 275 µmol/L for females and 342 µmol/L for males. After applying these sex-specific creatinine thresholds, 39% of males and 3% of females in our CKD study population who scored points for CKD in the Charlson comorbidity index had not yet reached Stage 5 CKD. (4) Conclusions: There is a significant difference in the creatinine threshold to define Stage 5 CKD between males and females, with a bias for greater allocation of Charlson index points for CKD to males despite similar eGFR levels between the sexes. Further research could examine if replacing creatinine with eGFR improves the performance of the Charlson comorbidity index as a prognostic tool.

Drivers of arthropod biodiversity in an urban ecosystem.

Our world is becoming increasingly urbanized with a growing human population concentrated around cities. The expansion of urban areas has important consequences for biodiversity, yet the abiotic drivers of biodiversity in urban ecosystems have not been well characterized for the most diverse group of animals on the planet, arthropods. Given their great diversity, comparatively small home ranges, and ability to disperse, arthropods make an excellent model for studying which factors can most accurately predict urban biodiversity. We assessed the effects of (i) topography (distance to natural areas and to ocean) (ii) abiotic factors (mean annual temperature and diurnal range), and (iii) anthropogenic drivers (land value and amount of impervious surface) on the occurrence of six arthropod groups represented in Malaise trap collections run by the BioSCAN project across the Greater Los Angeles Area. We found striking heterogeneity in responses to all factors both within and between taxonomic groups. Diurnal temperature range had a consistently negative effect on occupancy but this effect was only significant in Phoridae. Anthropogenic drivers had mixed though mostly insignificant effects, as some groups and species were most diverse in highly urbanized areas, while other groups showed suppressed diversity. Only Phoridae was significantly affected by land value, where most species were more likely to occur in areas with lower land value. Los Angeles can support high regional arthropod diversity, but spatial community composition is highly dependent on the taxonomic group.

Patient Survival With Extended Home Hemodialysis Compared to In-Center Conventional Hemodialysis.

Introduction: More frequent and/or longer hemodialysis (HD) has been associated with improvements in numerous clinical outcomes in patients on dialysis. Home HD (HHD), which allows more frequent and/or longer dialysis with lower cost and flexibility in treatment planning, is not widely used worldwide. Although, retrospective studies have indicated better survival with HHD, this issue remains controversial. In this multicenter study, we compared thrice-weekly extended HHD with in-center conventional HD (ICHD) in a large patient population with a long-term follow-up. Methods: We matched 349 patients starting HHD between 2010 and 2014 with 1047 concurrent patients on ICHD by using propensity scores. Patients were followed-up with from their respective baseline until September 30, 2018. The primary outcome was overall survival. Secondary outcomes were technique survival; hospitalization; and changes in clinical, laboratory, and medication parameters. Results: The mean duration of dialysis session was 418 ± 54 minutes in HHD and 242 ± 10 minutes in patients on ICHD. All-cause mortality rate was 3.76 and 6.27 per 100 patient-years in the HHD and the ICHD groups, respectively. In the intention-to-treat analysis, HHD was associated with a 40% lower risk for all-cause mortality than ICHD (hazard ratio [HR] = 0.60; 95% confidence interval [CI] 0.45 to 0.80; P < 0.001). In HHD, the 5-year technical survival was 86.5%. HHD treatment provided better phosphate and blood pressure (BP) control, improvements in nutrition and inflammation, and reduction in hospitalization days and medication requirement. Conclusion: These results indicate that extended HHD is associated with higher survival and better outcomes compared to ICHD.

A Novel RUNX1 Genetic Variant Identified in a Young Male with Severe Osteoporosis.

This case describes a young man with an unusual cause of severe osteoporosis and markedly deranged bone microarchitecture resulting in multiple fractures. A potentially pathogenic germline variant in the runt-related transcription factor 1 (RUNX1) gene was discovered by a focused 51-gene myeloid malignancy panel during investigation for his unexplained normochromic normocytic anemia. Further bone-specific genetic testing and a pedigree analysis were declined by the patient. Recent experimental evidence demonstrates that RUNX1 plays a key role in the regulation of osteogenesis and bone homeostasis during skeletal development, mediated by the bone morphogenic protein and Wnt signaling pathways. Therefore, rarer causes of osteoporosis, including those affecting bone formation, should be considered in young patients with multiple unexpected minimal trauma fractures. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

A codesigned integrated kidney and diabetes model of care improves patient activation among patients from culturally and linguistically diverse backgrounds.

BACKGROUND: Little is known about the relationship between patients' cultural and linguistic backgrounds and patient activation, especially in people with diabetes and chronic kidney disease (CKD). We examined the association between culturally and linguistically diverse (CALD) background and patient activation and evaluated the impact of a codesigned integrated kidney and diabetes model of care on patient activation by CALD status in people with diabetes and CKD. METHODS: This longitudinal study recruited adults with diabetes and CKD (Stage 3a or worse) who attended a new diabetes and kidney disease service at a tertiary hospital. All completed the patient activation measure at baseline and after 12 months and had demographic and clinical data collected. Patients from CALD backgrounds included individuals who spoke a language other than English at home, while those from non-CALD backgrounds spoke English only as their primary language. Paired t-tests compared baseline and 12-month patient activation scores by CALD status. RESULTS: Patients from CALD backgrounds had lower activation scores (52.1 ± 17.6) compared to those from non-CALD backgrounds (58.5 ± 14.6) at baseline. Within-group comparisons showed that patient activation scores for patients from CALD backgrounds significantly improved by 7 points from baseline to 12 months follow-up (52.1 ± 17.6-59.4 ± 14.7), and no significant change was observed for those from non-CALD backgrounds (58.5 ± 14.6-58.8 ± 13.6). CONCLUSIONS: Among patients with diabetes and CKD, those from CALD backgrounds report worse activation scores. Interventions that support people from CALD backgrounds with comorbid diabetes and CKD, such as the integrated kidney and diabetes model of care, may address racial and ethnic disparities that exist in patient activation and thus improve clinical outcomes. PATIENT OR PUBLIC CONTRIBUTION: Patients, caregivers and national consumer advocacy organisations (Diabetes Australia and Kidney Health Australia) codesigned a new model of care in partnership with healthcare professionals and researchers. The development of the model of care was informed by focus groups of patients and healthcare professionals and semi-structured interviews of caregivers and healthcare professionals. Patients and caregivers also provided a rigorous evaluation of the new model of care, highlighting its strengths and weaknesses.

A new species of Mycomya Rondani, 1856 (Diptera: Mycetophilidae) common to southeast Australia, Tasmania, and New Zealand.

Mycomya quadrimaculata sp. nov. is described from specimens collected in southeast Australia, Tasmania, and New Zealand. A key and type photographs of known Australian and New Zealand Mycomya species are provided. The relative abundance, observed distribution, and morphological affinities of the new species suggests that it is adventive and a recent introduction to New Zealand. Wing characters indicate that the new species is most closely aligned with a subgroup of the Australian Mycomya fauna.

Genomic testing for suspected monogenic kidney disease in children and adults: A health economic evaluation.

PURPOSE: To assess the relative cost-effectiveness of genomic testing compared with standard non-genomic diagnostic investigations in patients with suspected monogenic kidney disease from an Australian health care system perspective. METHODS: Diagnostic and clinical information was used from a national cohort of 349 participants. Simulation modelling captured diagnostic, health, and economic outcomes during a time horizon from clinical presentation until 3 months post-test results based on the outcome of cost per additional diagnosis and lifetime horizon based on cost per quality-adjusted life-year (QALY) gained. RESULTS: Genomic testing was Australian dollars (AU$) 1600 more costly per patient and led to an additional 27 diagnoses out of a 100 individuals tested, resulting in an incremental cost-effectiveness ratio of AU$5991 per additional diagnosis. Using a lifetime horizon, genomic testing resulted in an additional cost of AU$438 and 0.04 QALYs gained per individual compared with standard diagnostic investigations, corresponding to an incremental cost-effectiveness ratio of AU$10,823 per QALY gained. Sub-group analyses identified that the results were largely driven by the cost-effectiveness in glomerular diseases. CONCLUSION: Based on established or expected thresholds of cost-effectiveness, our evidence suggests that genomic testing is very likely to be cost saving for individuals with suspected glomerular diseases, whereas no evidence of cost-effectiveness was found for non-glomerular diseases.

In situ single-crystal synchrotron X-ray diffraction studies of biologically active gases in metal-organic frameworks.

Metal-organic frameworks (MOFs) are well known for their ability to adsorb various gases. The use of MOFs for the storage and release of biologically active gases, particularly nitric oxide (NO) and carbon monoxide (CO), has been a subject of interest. To elucidate the binding mechanisms and geometry of these gases, an in situ single crystal X-ray diffraction (scXRD) study using synchrotron radiation at Diamond Light Source has been performed on a set of MOFs that display promising gas adsorption properties. NO and CO, were introduced into activated Ni-CPO-27 and the related Co-4,6-dihydroxyisophthalate (Co-4,6-dhip). Both MOFs show strong binding affinity towards CO and NO, however CO suffers more from competitive co-adsorption of water. Additionally, we show that morphology can play an important role in the ease of dehydration for these two systems.

Australian Workshops on Patients' Perspectives on Hemodialysis and Incremental Start.

Introduction: Most patients with kidney failure commence and continue hemodialysis (HD) thrice weekly. Incremental initiation (defined as HD less than thrice weekly) is increasingly considered to be safe and less burdensome, but little is known about patients' perspectives. We aimed to describe patients' priorities and concerns regarding incremental HD. Methods: Patients currently, previously, or soon to be receiving HD in Australia participated in two 90-minute online workshops to discuss views about HD focusing on incremental start and priorities for trial outcomes. Transcripts were analyzed using thematic analysis. Outcomes were ranked on the basis of the sum of participants' priority scores (i.e., single allocation of 3 points for most important, 2 for second, and 1 for third most important outcome). Results: All 26 participants (1 caregiver and 25 patients) preferred an incremental HD approach. The top prioritized outcomes were quality of life (QOL) (56 points), residual kidney function (RKF) (27 points), and mortality (16 points). The following 4 themes underpinning outcome priorities, experience, and safety concerns were identified: (i) unpreparedness and pressure to adapt, (ii) disruption to daily living, (iii) threats to safety, and (iv) hope and future planning. Conclusion: Patients with kidney failure preferred an incremental start to HD to minimize disruption to daily living and reduce the negative impacts on their education, ability to work, and family life. QOL was the most critically important outcome, followed by RKF and survival.

National health policies and strategies for addressing chronic kidney disease: Data from the International Society of Nephrology Global Kidney Health Atlas.

National strategies for addressing chronic kidney disease (CKD) are crucial to improving kidney health. We sought to describe country-level variations in non-communicable disease (NCD) strategies and CKD-specific policies across different regions and income levels worldwide. The International Society of Nephrology Global Kidney Health Atlas (GKHA) was a multinational cross-sectional survey conducted between July and October 2018. Responses from key opinion leaders in each country regarding national NCD strategies, the presence and scope of CKD-specific policies, and government recognition of CKD as a health priority were described overall and according to region and income level. 160 countries participated in the GKHA survey, comprising 97.8% of the world's population. Seventy-four (47%) countries had an established national NCD strategy, and 53 (34%) countries reported the existence of CKD-specific policies, with substantial variation across regions and income levels. Where CKD-specific policies existed, non-dialysis CKD care was variably addressed. 79 (51%) countries identified government recognition of CKD as a health priority. Low- and low-middle income countries were less likely to have strategies and policies for addressing CKD and have governments which recognise it as a health priority. The existence of CKD-specific policies, and a national NCD strategy more broadly, varied substantially across different regions around the world but was overall suboptimal, with major discrepancies between the burden of CKD in many countries and governmental recognition of CKD as a health priority. Greater recognition of CKD within national health policy is critical to improving kidney healthcare globally.

When details matter: Integrative revision of Holarctic Coelophthinia Edwards (Diptera, Mycetophilidae), including mapping of its mitogenome, leads to the description of four new pseudocryptic species.

Background: The small genus Coelophthinia Edwards, 1941 of the subfamily Gnoristinae (Diptera, Mycetophilidae) is so far known to harbour four species from the Palaearctic, Nearctic and Neotropical Regions. Extensive DNA barcoding of fungus gnats of the family Mycetophilidae through the International Barcode of Life project (iBOL) have initiated integrative studies resulting in taxonomic upgrades and a better understanding of many species and their delimitation. The opportunity was also taken to describe the mitogenome of a member of Coelophthinia for the first time. New information: The integrative studies give evidence for splitting the European species C.thoracica Edwards, 1941 into three different species. Four new species are described from the USA, Japan and the Nordic Region in Europe, Coelophthiniacirra Kerr sp. n., Coelophthiniaitoae Kurina sp. n., Coelophthinialata Kjaerandsen sp. n. and Coelophthinialoraasi Kjaerandsen sp. n., raising the number of Holarctic species from two to six. The mitogenome of Coelophthinialoraasi sp. n. is described and analysed.

Oral Anticoagulant Use in Patients With Atrial Fibrillation and Chronic Kidney Disease: A Review of the Evidence With Recommendations for Australian Clinical Practice.

Chronic kidney disease is common in patients with atrial fibrillation (AF) and is associated with heightened risks of stroke/systemic embolisation and bleeding. In this review we outline the evidence for AF stroke prevention in kidney disease, identify current knowledge gaps, and give recommendations for anticoagulation at various stages of chronic kidney disease. Overall, anticoagulation is underused. Warfarin use becomes increasingly difficult with advancing kidney disease, with difficulty maintaining international normalised ratio (INR) in therapeutic range, increased risk of intracranial and fatal bleeding compared to non-vitamin K oral anticoagulants (NOACs), and high rates of discontinuation. Similarly, the direct thrombin inhibitor dabigatran is not recommended as it is predominantly renally excreted with consequent increased plasma levels and bleeding risk with advanced kidney disease. The Factor Xa inhibitors apixaban and rivaroxaban have less renal excretion (25-35%), modest increases in plasma levels with advancing kidney disease, and are the preferred first line choice for anticoagulation in moderate kidney disease based on strong evidence from randomised clinical trials (RCTs). In severe kidney disease there is a paucity of RCT data, but extrapolation of the pharmacokinetic and RCT data for moderate kidney disease, and observational studies, support the considered use of dose-adjusted Factor Xa inhibitors unless the bleeding risk is prohibitive. In Australia, apixaban is approved for creatinine clearance down to 25 mL/min, and rivaroxaban down to 15 mL/min. For end-stage kidney disease warfarin is the only agent approved, but we recommend against anticoagulation (except in selected cases) due to high bleeding risk, multiple co-morbidities, and questionable benefit.

Theory Designed Strategies to Support Implementation of Genomics in Nephrology.

(1) Background: Genomic testing is increasingly utilized as a clinical tool; however, its integration into nephrology remains limited. The purpose of this study was to identify barriers and prioritize interventions for the widespread implementation of genomics in nephrology. (2) Methods: Qualitative, semi-structured interviews were conducted with 25 Australian adult nephrologists to determine their perspectives on interventions and models of care to support implementation of genomics in nephrology. Interviews were guided by a validated theoretical framework for the implementation of genomic medicine-the Consolidated Framework of Implementation Research (CFIR). (3) Results: Nephrologists were from 18 hospitals, with 7 having a dedicated multidisciplinary kidney genetics service. Most practiced in the public healthcare system (n = 24), a large number were early-career (n = 13), and few had genomics experience (n = 4). The top three preferred interventions were increased funding, access to genomics champions, and education and training. Where interventions to barriers were not reported, we used the CFIR/Expert Recommendations for Implementing Change matching tool to generate theory-informed approaches. The preferred model of service delivery was a multidisciplinary kidney genetics clinic. (4) Conclusions: This study identified surmountable barriers and practical interventions for the implementation of genomics in nephrology, with multidisciplinary kidney genetics clinics identified as the preferred model of care. The integration of genomics education into nephrology training, secure funding for testing, and counselling along with the identification of genomics champions should be pursued by health services more broadly.

Divergent Evolutionary Pathways of Myxoma Virus in Australia: Virulence Phenotypes in Susceptible and Partially Resistant Rabbits Indicate Possible Selection for Transmissibility.

To characterize the ongoing evolution of myxoma virus in Australian rabbits, we used experimental infections of laboratory rabbits to determine the virulence and disease phenotypes of recent virus isolates. The viruses, collected between 2012 and 2015, fell into three lineages, one of which, lineage c, experienced a punctuated increase in evolutionary rate. All viruses were capable of causing acute death with aspects of neutropenic septicemia, characterized by minimal signs of myxomatosis, the occurrence of pulmonary edema and bacteria invasions throughout internal organs, but with no inflammatory response. For the viruses of highest virulence all rabbits usually died at this point. In more attenuated viruses, some rabbits died acutely, while others developed an amyxomatous phenotype. Rabbits that survived for longer periods developed greatly swollen cutaneous tissues with very high virus titers. This was particularly true of lineage c viruses. Unexpectedly, we identified a line of laboratory rabbits with some innate resistance to myxomatosis and used these in direct comparisons with the fully susceptible rabbit line. Importantly, the same disease phenotype occurred in both susceptible and resistant rabbits, although virulence was shifted toward more attenuated grades in resistant animals. We propose that selection against inflammation at cutaneous sites prolongs virus replication and enhances transmission, leading to the amyxomatous phenotype. In some virus backgrounds this creates an immunosuppressive state that predisposes to high virulence and acute death. The alterations in disease pathogenesis, particularly the overwhelming bacterial invasions that characterize the modern viruses, suggest that their virulence grades are not directly comparable with earlier studies. IMPORTANCE The evolution of the myxoma virus (MYXV) following its release as a biological control for European rabbits in Australia is the textbook example of the coevolution of virus virulence and host resistance. However, most of our knowledge of MYXV evolution only covers the first few decades of its spread in Australia and often with little direct connection between how changes in virus phenotype relate to those in the underlying virus genotype. By conducting detailed experimental infections of recent isolates of MYXV in different lines of laboratory rabbits, we examined the ongoing evolution of MYXV disease phenotypes. Our results reveal a wide range of phenotypes, including an amyxomatous type, as well as the impact of invasive bacteria, that in part depended on the level of rabbit host resistance. These results provide a unique insight into the complex virus and host factors that combine to shape disease phenotype and viral evolution.

A comparison of arteriovenous fistula failure between Malaysian and Australian and New Zealand participants enrolled in the FAVOURED trial.

AIM: To describe and compare de novo arteriovenous fistula (AVF) failure rates between Australia and New Zealand (ANZ), and Malaysia. BACKGROUND: AVFs are preferred for haemodialysis access but are limited by high rates of early failure. METHODS: A post hoc analysis of 353 participants from ANZ and Malaysia included in the FAVOURED randomised-controlled trial undergoing de novo AVF surgery was performed. Composite AVF failure (thrombosis, abandonment, cannulation failure) and its individual components were compared between ANZ (n = 209) and Malaysian (n = 144) participants using logistic regression adjusted for patient- and potentially modifiable clinical factors. RESULTS: Participants' mean age was 55 ± 14.3 years and 64% were male. Compared with ANZ participants, Malaysian participants were younger with lower body mass index, higher prevalence of diabetes mellitus and lower prevalence of cardiovascular disease. AVF failure was less frequent in the Malaysian cohort (38% vs 54%; adjusted odds ratio (OR) 0.53, 95% confidence interval (CI) 0.31-0.93). This difference was driven by lower odds of cannulation failure (29% vs 47%, OR 0.45, 95% CI 0.25-0.80), while the odds of AVF thrombosis (17% vs 20%, OR 1.24, 95% CI 0.62-2.48) and abandonment (25% vs 23%, OR 1.17, 95% CI 0.62-2.16) were similar. CONCLUSIONS: The risk of AVF failure was significantly lower in Malaysia compared to ANZ and driven by a lower risk of cannulation failure. Differences in practice patterns, including patient selection, surgical techniques, anaesthesia or cannulation techniques may account for regional outcome differences and warrant further investigation.

A Novel Approach to Enhance the Regenerative Potential of Circulating Endothelial Progenitor Cells in Patients with End-Stage Kidney Disease.

Circulating bone marrow-derived endothelial progenitor cells (EPCs) facilitate vascular repair in several organs including the kidney but are progressively diminished in end-stage kidney disease (ESKD) patients, which correlates with cardiovascular outcomes and related mortality. We thus determined if enhancing the tissue-reparative effects of human bone marrow-derived mesenchymal stromal cells (BM-MSCs) with the vasculogenic effects of recombinant human relaxin (RLX) could promote EPC proliferation and function. CD34+ EPCs were isolated from the blood of healthy and ESKD patients, cultured until late EPCs had formed, then stimulated with BM-MSC-derived condition media (CM; 25%), RLX (1 or 10 ng/mL), or both treatments combined. Whilst RLX alone stimulated EPC proliferation, capillary tube formation and wound healing in vitro, these measures were more rapidly and markedly enhanced by the combined effects of BM-MSC-derived CM and RLX in EPCs derived from both healthy and ESKD patients. These findings have important clinical implications, having identified a novel combination therapy that can restore and enhance EPC number and function in ESKD patients.