Risk of kidney disease following a pregnancy complicated by diabetes: a longitudinal, population-based data-linkage study among Aboriginal women in the Northern Territory, Australia.

AIMS/HYPOTHESIS: The aim of this work was to investigate the risk of developing chronic kidney disease (CKD) or end-stage kidney disease (ESKD) following a pregnancy complicated by gestational diabetes mellitus (GDM) or pre-existing diabetes among Aboriginal women in the Northern Territory (NT), Australia. METHODS: We undertook a longitudinal study of linked healthcare datasets. All Aboriginal women who gave birth between 2000 and 2016 were eligible for inclusion. Diabetes status in the index pregnancy was as recorded in the NT Perinatal Data Collection. Outcomes included any stage of CKD and ESKD as defined by ICD-10 coding in the NT Hospital Inpatient Activity dataset between 2000 and 2018. Risk was compared using Cox proportional hazards regression. RESULTS: Among 10,508 Aboriginal women, the mean age was 23.1 (SD 6.1) years; 731 (7.0%) had GDM and 239 (2.3%) had pre-existing diabetes in pregnancy. Median follow-up was 12.1 years. Compared with women with no diabetes during pregnancy, women with GDM had increased risk of CKD (9.2% vs 2.2%, adjusted HR 5.2 [95% CI 3.9, 7.1]) and ESKD (2.4% vs 0.4%, adjusted HR 10.8 [95% CI 5.6, 20.8]). Among women with pre-existing diabetes in pregnancy, 29.1% developed CKD (adjusted HR 10.9 [95% CI 7.7, 15.4]) and 9.9% developed ESKD (adjusted HR 28.0 [95% CI 13.4, 58.6]). CONCLUSIONS/INTERPRETATION: Aboriginal women in the NT with GDM or pre-existing diabetes during pregnancy are at high risk of developing CKD and ESKD. Pregnancy presents an important opportunity to identify kidney disease risk. Strategies to prevent kidney disease and address the social determinants of health are needed.

Retrospective case-control study exploring pretransplant predictors for loss of kidney transplant function or death among indigenous kidney transplant recipients.

BACKGROUND: The factors affecting the outcomes among Indigenous kidney transplant recipients is not fully understood. We conducted a retrospective case control study to identify risk factors beyond those explained by the ANZDATA registry. AIM: To identify the risk factors for loss of kidney transplant function or death among Indigenous kidney transplant recipients. METHODS: Cases were defined as all Indigenous Australian kidney transplant recipients from 1 January 2005 to 31 December 2015 from the major hospitals in the Northern Territory (NT) and South Australia (SA) who experienced graft loss (including patient death) up to 2-years post-transplant. Controls (matched 4:1) were defined as all indigenous kidney transplant recipients during the same period with functioning transplants at 2-years post-transplant operation. Matching was done on gender and diabetes status. Regression analysis adjusted for age was used for comparing cases and controls. RESULTS: There were 17 cases and 68 matched controls. Among cases, the odds ratio for more than one hospital admission episode (compared with ≤1 episode) in the 2-year pretransplant period was 6.2 (95% confidence interval, 1.2-32.5). However, there were no significant differences in the frequency of comorbidities at renal replacement therapy start, cardiovascular intervention pretransplant, pretransplant infection screening, age and gender of the donors, frequency of admission episodes where an infection was documented, the total length of inpatient stay or admission to intensive care unit during pretransplant hospital admission between cases and controls. CONCLUSION: Early graft loss was associated with a higher frequency of hospital admissions in the 2-years pretransplant period. In contrast, other measured factors in the pretransplant period did not predict these adverse outcomes.

Disparity of access to kidney transplantation by Indigenous and non-Indigenous Australians.

OBJECTIVE: To compare the likelihood of Indigenous and non-Indigenous Australians being placed on the waiting list for transplantation of a kidney from a deceased donor; to compare the subsequent likelihood of transplantation. DESIGN, SETTING AND PARTICIPANTS: Observational cohort study; analysis of data from the Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry for patients aged 18-60 years at the start of renal replacement therapy, who commenced renal replacement therapy in Australia between 28 June 2006 and 31 December 2016. MAIN OUTCOME MEASURES: Time to wait-listing; time to kidney transplantation after wait-listing. RESULTS: 10 839 patients met the inclusion criteria, of whom 2039 (19%) were Indigenous Australians; 217 Indigenous and 3829 non-Indigenous patients were active on the waiting list at least once during the study period. The hazard ratio (HR) for wait-listing (Indigenous v non-Indigenous patients, adjusted for patient- and disease-related factors) in the first year of renal replacement therapy varied with age and remoteness (range, 0.11 [95% CI, 0.07-0.15] to 0.36 [95% CI, 0.16-0.56]); in subsequent years the adjusted HR was 0.90 (95% CI, 0.50-1.6). The adjusted HR for transplantation during the first year of wait-listing did not differ significantly from 1.0; for subsequent years of wait-listing, however, the adjusted HR was 0.40 (95% CI, 0.29-0.55). CONCLUSION: Disparities between Indigenous and non-Indigenous patients with end-stage kidney disease in access to kidney transplantation are not explained by patient- or disease-related factors. Changes in policy and practice are needed to reduce these differences.

Contribution of cardiometabolic risk factors to estimated glomerular filtration rate decline in Indigenous Australians with and without albuminuria - the eGFR Follow-up Study.

AIM: We assessed associations between cardiometabolic risk factors and estimated glomerular filtration rate (eGFR) decline according to baseline albuminuria to identify potential treatment targets in Indigenous Australians. METHODS: The eGFR Follow-up Study is a longitudinal cohort of 520 Indigenous Australians. Linear regression was used to estimate associations between baseline cardiometabolic risk factors and annual Chronic Kidney Disease Epidemiology Collaboration eGFR change (mL/min per 1.73m2 /year), among those classified with baseline normoalbuminuria (urine albumin-to-creatinine ratio (uACR) <3 mg/mmol; n = 297), microalbuminuria (uACR 3-30 mg/mmol; n = 114) and macroalbuminuria (uACR ≥30 mg/mmol; n = 109). RESULTS: After a median of 3 years follow-up, progressive declines of the age- and sex-adjusted mean eGFR were observed across albuminuria categories (-2.0 [-2.6 to -1.4], -2.5 [-3.7 to -1.3] and -6.3 [-7.8 to -4.9] mL/min per 1.72m2 /year). Although a borderline association was observed between greater baseline haemoglobin A1c and eGFR decline in those with macroalbuminuria (P = 0.059), relationships were not significant in those with microalbuminuria (P = 0.187) or normoalbuminuria (P = 0.23). Greater baseline blood pressure, C-reactive protein, waist-to-hip ratio and lower high-density lipoprotein cholesterol showed non-significant trends with greater eGFR decline in the presence of albuminuria. CONCLUSION: Over a 3 year period, marked eGFR decline was observed with greater baseline albuminuria. Cardiometabolic risk factors were not strong predictors for eGFR decline in Indigenous Australians without albuminuria. Longer follow-up may elucidate the role of these predictors and other mechanisms in chronic kidney disease progression in this population.

Resting heart rate, physiological stress and disadvantage in Aboriginal and Torres Strait Islander Australians: analysis from a cross-sectional study.

BACKGROUND: Lower socioeconomic status has been linked to long-term stress, which can manifest in individuals as physiological stress. The aim was to explore the relationship between low socioeconomic status and physiological stress in Aboriginal and Torres Strait Islander Australians. METHODS: Using data from the eGFR Study (a cross-sectional study of 634 Indigenous Australians in urban and remote areas of northern and central Australia), we examined associations between resting heart rate and demographic, socioeconomic, and biomedical factors. An elevated resting heart rate has been proposed as a measure of sustained stress activation and was used as a marker of physiological stress. Relationships were assessed between heart rate and the above variables using univariate and multiple regression analyses. RESULTS: We reported a mean resting heart rate of 74 beats/min in the cohort (mean age 45 years). On multiple regression analysis, higher heart rate was found to be independently associated with Aboriginal ethnicity, being a current smoker, having only primary level schooling, higher HbA1c and higher diastolic blood pressure (model R(2) 0.25). CONCLUSIONS: Elevated resting heart rate was associated with lower socioeconomic status and poorer health profile in Aboriginal and Torres Strait Islander Australians. Higher resting heart rate may be an indicator of stress and disadvantage in this population at high risk of chronic diseases.

Hyperfiltration in Indigenous Australians with and without diabetes.

BACKGROUND: Hyperfiltration (HF) has been linked to the development of diabetic kidney disease (DKD), but the causative or predictive role of HF in the pathogenesis of DKD still remains unclear. To date, there have been no studies of HF in Indigenous Australians, a population with high rates of both diabetes and end-stage kidney disease. We aimed to compare the characteristics and frequency of HF in Indigenous Australians with and without type 2 diabetes. METHODS: Indigenous Australian participants, recruited across five pre-defined strata of health, diabetes status and kidney function, had a reference glomerular filtration rate (GFR) measured using plasma disappearance of iohexol [measured GFR(mGFR)] over 4 h. HF was defined in various ways: (i) mGFR > 144 mL/min/1.73 m(2), which is mGFR > 1.96 × SD above the mean of the mGFR in non-diabetic participants with normal albuminuria and normal renal function (mGFR > 90 mL/min/1.73 m(2)); (ii) age-corrected mGFR (>144 mL/min/1.73 m(2)) to account for the effect of ageing on GFR in subjects over 40 years of age with cut-off 1 mL/min/1.73 m(2) lower for every year; (iii) mGFR > 144 mL/min, without correction for body surface area or age, as well as (iv) mGFR > 125 mL/min/1.73 m(2), without adjustment for age. RESULTS: A total of 383 Indigenous participants, 125 with and 258 without diabetes, with mGFR > 90 mL/min/1.73 m(2) were studied. The proportion of participants with HF was 7% using mGFR > 144 mL/min/1.73 m(2), 11% using the age-adjusted definition, 19% using mGFR > 144 mL/min and 27% using mGFR > 125 mL/min/1.73 m(2). Diabetes was more common in participants with HF (40-74%) compared with normofiltering participants (28-31%), regardless of the definition of HF. CONCLUSIONS: HF exists in Indigenous Australians with and without diabetes. A greater proportion of participants had diabetes in HF group compared with normofiltration group. Long-term follow-up of this cohort is necessary to determine if HF plays a role in the development of DKD and non-DKD.

Survival of Indigenous Australians receiving renal replacement therapy: closing the gap?

OBJECTIVES: To compare mortality rates for Indigenous and non-Indigenous Australians commencing renal replacement therapy (RRT) over time and by categories of remoteness of place of residence. DESIGN, SETTING AND PARTICIPANTS: An observational cohort study of Australia and New Zealand Dialysis and Transplant Registry (ANZDATA) data on Indigenous and non-Indigenous Australians registered with ANZDATA who commenced RRT from 1 January 1995 to 31 December 2009 and were followed until 31 December 2011. MAIN OUTCOME MEASURES: Five-year all-cause mortality for Indigenous and non-Indigenous patients in three cohorts (1995-1999, 2000-2004 and 2005-2009) and five remoteness (of place of residence) categories. RESULTS: Indigenous patients were younger, more likely to have diabetes, be referred late and be from a more remote area than non-Indigenous patients. Age and comorbid conditions increased with successive cohorts for both groups. Unadjusted analysis (using the log-rank test) showed an increased risk of death for Indigenous patients in the 1995-1999 (P = 0.02) and 2000-2004 (P = 0.03) cohorts, but not for the 2005-2009 cohort (P = 0.7). However, a Cox proportional hazards model adjusted for covariates (age, sex, late referral and comorbid conditions [diabetes, coronary artery disease, peripheral vascular disease, cerebrovascular disease, lung disease], and body mass index < 18.5 kg/m(2) and > 30 kg/m(2)) showed the following Indigenous:non-Indigenous hazard ratios (with 95% CIs) for major capital cities: 1995-1999, 1.47 (1.21-1.79); 2000-2004, 1.35 (1.12-1.63); and 2005-2009, 1.37 (1.14-1.66). CONCLUSIONS: Although unadjusted analysis suggests that the survival gap between Indigenous and non-Indigenous patients receiving RRT has closed, there remains a significant disparity in survival after adjusting for the variables considered in our study.

Chronic kidney disease in the Top End of the Northern Territory of Australia, 2002-2011: a retrospective cohort study using existing laboratory data.

BACKGROUND: The Northern Territory of Australia has a very high incidence of treated end-stage kidney disease (ESKD), largely confined to Indigenous Australians living in remote, under-resourced areas. Surveillance of chronic kidney disease (CKD) is still in its infancy in Australia. We estimate the prevalence and rate of progression of measured CKD across a region using inexpensive readily available laboratory information. METHODS: Using a retrospective de-identified extraction of all records with a serum creatinine or urinary albumin-to-creatinine ratio from the single largest ambulatory pathology provider to the Top End of the Northern Territory of Australia between 1st February 2002 and 31st December 2011, the yearly total and age-specific prevalence of measured microalbuminuria, overt albuminuria and estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m(2), and the prevalence of progressive CKD, were calculated. RESULTS: There was a steady increase in the proportion tested across all health districts in the region, more prominent in non-urban districts. In 2009, the regional adult prevalence of measured microalbuminuria and overt albuminuria was as high as 8.1 %, overt albuminuria alone up to 3.0 % and eGFR < 60 up to 2.3 %. Rates of progressive disease were extremely high, particularly for those with albuminuria (53.1-100 % for those with urinary albumin-creatinine ratio > 300 mg/mmol). CONCLUSIONS: The rates of testing, particularly in districts of high measured prevalence of markers of CKD, are encouraging. However, extremely high rates of progressive CKD are troubling. Further describing the outcomes of CKD in this population would require analysis of linked datasets.

Engagement and partnership with consumers and communities in the co-design and conduct of Research: Lessons from the INtravenous iron polymaltose for First Nations Australian patients with high FERRitin levels on haemodialysis (INFERR) clinical trial.

BACKGROUND: Engagement and partnership with consumers and communities throughout research processes produces high quality research meeting community needs and promoting translation of research into improved policy and practice. Partnership is critical in research involving Aboriginal and/or Torres Strait Islander people (First Nations Peoples) to ensure cultural safety. We present lessons from the design, implementation and progress of the National Health and Medical Research Council funded INtravenous iron polymaltose for First Nations Australian patients with high FERRitin levels on hemodialysis (INFERR) clinical trial. MAIN BODY: The trial was designed to understand the benefits and harms of iron therapy in First Nations Australians on haemodialysis with anaemia and hyperferritinaemia. The lack of evidence for treatment was discussed with patients who were potential participants. A key element ensuring safe conduct of the INFERR trial was the establishment of the Indigenous Reference Groups (IRGs) comprising of dialysis patients based in the Top End of Australia and Central Australia. Two IRGs were needed based on advice from First Nations communities and researchers/academics on the project regarding local cultural differences and approaches to trial conduct. The IRGs underpin culturally safe trial conduct by providing input into study materials and translating study findings into effective messages and policies for First Nations dialysis patients. Throughout the trial conduct, the IRGs' role has developed to provide key mechanisms for advice and guidance regarding research conduct both in this study and more broadly. Support provided to the IRGs by trial First Nations Research Officers and independent First Nations researchers/academics who simplify research concepts is critical. The IRGs have developed feedback documents and processes to participants, stakeholders, and the renal units. They guarantee culturally safe advice for embedding findings from the trial into clinical practice guidelines ensuring evidence-based approaches in managing anaemia in haemodialysis patients with hyperferritinaemia. CONCLUSION: Active consumer and community partnership is critical in research conduct to ensure research impact. Strong partnership with consumers in the INFERR clinical trial has demonstrated that First Nations Consumers will engage in research they understand, that addresses health priorities for them and where they feel respected, listened to, and empowered to achieve change.

In this paper, we present the importance of actively involving consumers in the planning, implementation and conduct of research using the example of a clinical trial among Aboriginal and/or Torres Strait Australians (First Nations Australians) who have kidney disease and are currently receiving haemodialysis. The study assesses how safe and effective it is for people on dialysis to receive iron given through the vein during dialysis when they have anaemia and high levels of a blood test called ferritin, a test used routinely to measure iron levels. Two consumer reference groups of First Nations patients on dialysis, one based in the Top End of Australia and the other based in Central Australia, are supported by First Nations Research Officers and Research Academics to make sure that the research is performed in a way that involves, respects and values First Nations participation, culture, and knowledge. Active consumer and community partnership in this study has supported robust research governance processes which we believe are crucial for knowledge translation to have a positive impact for patients.

Chronic kidney disease and automatic reporting of estimated glomerular filtration rate: new developments and revised recommendations.

The publication of the Australasian Creatinine Consensus Working Group's position statements in 2005 and 2007 resulted in automatic reporting of estimated glomerular filtration rate (eGFR) with requests for serum creatinine concentration in adults, facilitated the unification of units of measurement for creatinine and eGFR, and promoted the standardisation of assays. New advancements and continuing debate led the Australasian Creatinine Consensus Working Group to reconvene in 2010. The working group recommends that the method of calculating eGFR should be changed to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula, and that all laboratories should report eGFR values as a precise figure to at least 90 mL/min/1.73 m(2). Age-related decision points for eGFR in adults are not recommended, as although an eGFR < 60 mL/min/1.73 m(2) is very common in older people, it is nevertheless predictive of significantly increased risks of adverse clinical outcomes, and should not be considered a normal part of ageing.If using eGFR for drug dosing, body size should be considered, in addition to referring to the approved product information. For drugs with a narrow therapeutic index, therapeutic drug monitoring or a valid marker of drug effect should be used to individualise dosing. The CKD-EPI formula has been validated as a tool to estimate GFR in some populations of non-European ancestry living in Western countries. Pending publication of validation studies, the working group also recommends that Australasian laboratories continue to automatically report eGFR in Aboriginal and Torres Strait Islander peoples. The working group concluded that routine calculation of eGFR is not recommended in children and youth, or in pregnant women. Serum creatinine concentration (preferably using an enzymatic assay for paediatric patients) should remain as the standard test for kidney function in these populations.

Plasma cell infiltrates and renal allograft outcomes in indigenous and non-indigenous people of the Northern Territory of Australia.

INTRODUCTION: Plasma cell-rich rejection is a distinct histological phenomenon associated with poor renal allograft outcomes. Aboriginal and Torres Straight Islander (ATSI) transplant recipients have poorer allograft survival and higher rates of acute rejection. We sought to determine whether a higher incidence of plasma cell-rich infiltrates (PCIR) could account for poorer survival. METHODS: Renal transplant biopsies performed in recipients from the Northern Territory of Australia between 1985 and 2007 were reviewed and correlated with outcome. Biopsies were designated PCIR positive when plasma cells constituted >10% of the interstitial infiltrate. RESULTS: Four hundred and seventy-seven biopsies from 177 recipients (108 ATSI) were performed. Median graft survival was shorter for recipients with PCIR: 4.0 years (interquartile range 2.18-6.41) versus 5.4 years (2.0-9.99) (P = 0.013). ATSI recipients had higher rates of plasma cell-rich rejection (RR 1.76, 95% CI 1.43-2.17, P < 0.0001), which occurred earlier (251 vs 869 days, P = 0.03) compared with non-indigenous recipients. On multivariate analysis, PCIR did not independently influence allograft survival. There was a correlation between PCIR and panel reactive antibody peak >20% (RR 1.29, 95% CI 1.03-1.56, P = 0.025), ≥5 human leukocyte antigen mismatches (RR 1.91, 1.41-2.58, p < 0.0001), increasing post-transplant infection rate (>10 infections RR 5.11, 1.69-15.5, P = 0.004), and subsequent death from septicaemia (RR 1.6, 1.17-2.18, P = 0.003). CONCLUSION: PCIR is associated with infection and markers of chronic immunological stimulation but does not independently contribute to inferior renal allograft outcomes, even in ATSI recipients.

High rates of albuminuria but not of low eGFR in urban indigenous Australians: the DRUID study.

BACKGROUND: Indigenous Australians have an incidence of end stage kidney disease 8-10 times higher than non-Indigenous Australians. The majority of research studies concerning Indigenous Australians have been performed in rural or remote regions, whilst the majority of Indigenous Australians actually live in urban settings. We studied prevalence and factors associated with markers of kidney disease in an urban Indigenous Australian cohort, and compared results with those for the general Australian population. METHODS: 860 Indigenous adult participants of the Darwin Region Urban Indigenous Diabetes (DRUID) Study were assessed for albuminuria (urine albumin-creatinine ratio≥2.5 mg/mmol males, ≥3.5 mg/mmol females) and low eGFR (estimated glomular filtration rate < 60 mls/min/1.73 m(2)). Associations between risk factors and kidney disease markers were explored. Comparison was made with the AusDiab cohort (n = 8,936 aged 25-64 years), representative of the general Australian adult population. RESULTS: A high prevalence of albuminuria (14.8%) was found in DRUID, whilst prevalence of low eGFR was 2.4%. Older age, higher HbA1c, hypertension, higher C-reactive protein and current smoking were independently associated with albuminuria on multiple regression. Low eGFR was independently associated with older age, hypertension, albuminuria and higher triglycerides. Compared to AusDiab participants, DRUID participants had a 3-fold higher adjusted risk of albuminuria but not of low eGFR. CONCLUSIONS: Given the significant excess of ESKD observed in Indigenous versus non-Indigenous Australians, these findings could suggest either: albuminuria may be a better prognostic marker of kidney disease than low eGFR; that eGFR equations may be inaccurate in the Indigenous population; a less marked differential between Indigenous and non-Indigenous Australians for ESKD rates in urban compared to remote regions; or that differences in the pathophysiology of chronic kidney disease exist between Indigenous and non-Indigenous populations.

Narrative Review of Hyperferritinemia, Iron Deficiency, and the Challenges of Managing Anemia in Aboriginal and Torres Strait Islander Australians With CKD.

Aboriginal and Torres Strait Islander Australians (Indigenous Australians) suffer some of the highest rates of chronic kidney disease (CKD) in the world. Among Indigenous Australians in remote areas of the Northern Territory, prevalence rates for renal replacement therapy (RRT) are up to 30 times higher than national prevalence. Anemia among patients with CKD is a common complication. Iron deficiency is one of the major causes. Iron deficiency is also one of the key causes of poor response to the mainstay of anemia therapy with erythropoiesis-stimulating agents (ESAs). Therefore, the effective management of anemia in people with CKD is largely dependent on effective identification and correction of iron deficiency. The current identification of iron deficiency in routine clinical practice is dependent on 2 surrogate markers of iron status: serum ferritin concentration and transferrin saturation (TSAT). However, questions exist regarding the use of serum ferritin concentration in people with CKD because it is an acute-phase reactant that can be raised in the context of acute and chronic inflammation. Serum ferritin concentration among Indigenous Australians receiving RRT is often markedly elevated and falls outside reference ranges within most national and international guidelines for iron therapy for people with CKD. This review explores published data on the challenges of managing anemia in Indigenous people with CKD and the need for future research on the efficacy and safety of treatment of anemia of CKD in patients with high ferritin and evidence iron deficiency.

INFERR-Iron infusion in haemodialysis study: INtravenous iron polymaltose for First Nations Australian patients with high FERRitin levels on haemodialysis-a protocol for a prospective open-label blinded endpoint randomised controlled trial.

BACKGROUND: The effectiveness of erythropoiesis-stimulating agents, which are the main stay of managing anaemia of chronic kidney disease (CKD), is largely dependent on adequate body iron stores. The iron stores are determined by the levels of serum ferritin concentration and transferrin saturation. These two surrogate markers of iron stores are used to guide iron replacement therapy. Most Aboriginal and/or Torres Islander Australians of the Northern Territory (herein respectfully referred to as First Nations Australians) with end-stage kidney disease have ferritin levels higher than current guideline recommendations for iron therapy. There is no clear evidence to guide safe and effective treatment with iron in these patients. We aim to assess the impact of intravenous iron treatment on all-cause death and hospitalisation with a principal diagnosis of all-cause infection in First Nations patients on haemodialysis with anaemia, high ferritin levels and low transferrin saturation METHODS: In a prospective open-label blinded endpoint randomised controlled trial, a total of 576 participants on maintenance haemodialysis with high ferritin (> 700 µg/L and ≤ 2000 µg/L) and low transferrin saturation (< 40%) from all the 7 renal units across the Northern Territory of Australia will be randomised 1:1 to receive intravenous iron polymaltose 400 mg once monthly (200 mg during 2 consecutive haemodialysis sessions) (Arm A) or no IV iron treatment (standard treatment) (Arm B). Rescue therapy will be administered when the ferritin levels fall below 700 µg/L or when clinically indicated. The primary outcome will be the differences between the two study arms in the risk of hospitalisation with all-cause infection or death. An economic analysis and several secondary and tertiary outcomes analyses will also be performed. DISCUSSION: The INFERR clinical trial will address significant uncertainty on the safety and efficacy of iron therapy in First Nations Australians with CKD with hyperferritinaemia and evidence of iron deficiency. This will hopefully lead to the development of evidence-based guidelines. It will also provide the opportunity to explore the causes of hyperferritinaemia in First Nations Australians from the Northern Territory. TRIAL REGISTRATION: This trial is registered with The Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12620000705987 . Registered 29 June 2020.

Study Protocol--accurate assessment of kidney function in Indigenous Australians: aims and methods of the eGFR study.

BACKGROUND: There is an overwhelming burden of cardiovascular disease, type 2 diabetes and chronic kidney disease among Indigenous Australians. In this high risk population, it is vital that we are able to measure accurately kidney function. Glomerular filtration rate is the best overall marker of kidney function. However, differences in body build and body composition between Indigenous and non-Indigenous Australians suggest that creatinine-based estimates of glomerular filtration rate derived for European populations may not be appropriate for Indigenous Australians. The burden of kidney disease is borne disproportionately by Indigenous Australians in central and northern Australia, and there is significant heterogeneity in body build and composition within and amongst these groups. This heterogeneity might differentially affect the accuracy of estimation of glomerular filtration rate between different Indigenous groups. By assessing kidney function in Indigenous Australians from Northern Queensland, Northern Territory and Western Australia, we aim to determine a validated and practical measure of glomerular filtration rate suitable for use in all Indigenous Australians. METHODS/DESIGN: A cross-sectional study of Indigenous Australian adults (target n = 600, 50% male) across 4 sites: Top End, Northern Territory; Central Australia; Far North Queensland and Western Australia. The reference measure of glomerular filtration rate was the plasma disappearance rate of iohexol over 4 hours. We will compare the accuracy of the following glomerular filtration rate measures with the reference measure: Modification of Diet in Renal Disease 4-variable formula, Chronic Kidney Disease Epidemiology Collaboration equation, Cockcroft-Gault formula and cystatin C- derived estimates. Detailed assessment of body build and composition was performed using anthropometric measurements, skinfold thicknesses, bioelectrical impedance and a sub-study used dual-energy X-ray absorptiometry. A questionnaire was performed for socio-economic status and medical history. DISCUSSION: We have successfully managed several operational challenges within this multi-centre complex clinical research project performed across remote North, Western and Central Australia. It seems unlikely that a single correction factor (similar to that for African-Americans) to the equation for estimated glomerular filtration rate will prove appropriate or practical for Indigenous Australians. However, it may be that a modification of the equation in Indigenous Australians would be to include a measure of fat-free mass.