Jaquelyne T. Hughes

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

BackgroundThere 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/DesignA 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.DiscussionWe 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.

Accurate assessment of kidney function in indigenous Australians: the estimated GFR study.

Study equation (8.9 [95% CI, 7.9-11.1] mL/min/1.73 m 2 less than mGFR) than with the CKD-EPI equation (3.8 [95% CI, 2.5-5.6] mL/min/1.73 m 2 less than mGFR). Stratified by mGFR group (Table S1), bias was greatest in indigenous participants with mGFR 90 mL/min/1.73 m 2 when the MDRD Study equation was used, but improved with use of the CKD-EPI equation (without the correction factor). The accuracy of eGFR was not significantly different between the 2 equations. Thus, the magnitude of bias using the MDRD Study equation in indigenous participants was similar with or without use of theAfrican American correction factor; however, the direction of bias differed (GFR was overestimated with the correction factor and underestimated without it). For the CKD-EPI equation, bias and accuracy were improved significantly by omitting the correction factor. WithomissionoftheAfricanAmericancorrectionfactor,eGFRCKDEPI provided a reasonably unbiased and accurate estimate of GFR, whereas the MDRD Study equation significantly underestimated GFRinIndigenousAustralians(comparedwithnonindigenousAustralians). This may relate to inherent limitations of the MDRD Study equation rather than body build or other differences in Indigenous Australians.The CKD-EPI equation has been shown to perform better at higher mGFRs (approximately 60 mL/min/1.73 m 2 ), and the MDRD Study performs better at lower GFRs. 9 The mean mGFR of the Indigenous Australian cohort (93 mL/min/1.73 m 2 ) was closer to that of the CKD-EPI than the MDRD development cohort, and this

Adiponectin is present in the urine in its native conformation, and specifically reduces the secretion of MCP‐1 by proximal tubular cells

Aim:  To determine whether adiponectin detected in urine is present in its native form and if adiponectin receptors (AdipoR) present and functional in proximal tubular (HK‐2) cells.

Performance of formulas for estimating glomerular filtration rate in Indigenous Australians with and without Type 2 diabetes: the eGFR Study

It has been proposed that the Chronic Kidney Disease Epidemiology Collaboration formula estimates glomerular filtration rate more accurately than the Modification of Diet in Renal Disease formula. With the very high incidence of diabetes and end‐stage kidney disease in Indigenous Australians, accurate estimation of glomerular filtration rate is vital in early detection of kidney disease. We aimed to assess the performance of the Chronic Kidney Disease Epidemiology Collaboration, Modification of Diet in Renal Disease and Cockcroft–Gault formulas in Indigenous Australians with and without diabetes.

Development of a single-frequency bioimpedance prediction equation for fat-free mass in an adult Indigenous Australian population

Background/Objectives:To describe the development of a single-frequency bioimpedance prediction equation for fat-free mass (FFM) suitable for adult Aboriginal and Torres Strait Islander peoples with and without diabetes or indicators of chronic kidney disease (CKD).Subjects/Methods:FFM was measured by whole-body dual-energy X-ray absorptiometry in 147 adult Indigenous Australians. Height, weight, body circumference and resistance were also measured. Adults with and without diabetes and indicators of CKD were examined. A random split sample with internal cross-validation approach was used to predict and subsequently validate FFM using resistance, height, weight, age and gender against measured FFM.Results:Among 147 adults with a median body mass index of 31 kg/m2, the final model of FFM was FFM (kg)=0.432 (height, cm2/resistance, ohm)−0.086 (age, years)+0.269 (weight, kg)−6.422 (if female)+16.429. Adjusted R2 was 0.94 and the root mean square error was 3.33 kg. The concordance was high (rc=0.97) between measured and predicted FFM across a wide range of FFM (31–85 kg).Conclusions:In the context of the high burden of diabetes and CKD among adult Indigenous Australians, this new equation for FFM was both accurate and precise and based on easily acquired variables (height, weight, age, gender and resistance) among a heterogeneous adult cohort.

Increased bone mineral density in Aboriginal and Torres Strait Islander Australians: Impact of body composition differences

Bone mineral density (BMD) has been reported to be both higher and lower in Indigenous women from different populations. Body composition data have been reported for Indigenous Australians, but there are few published BMD data in this population. We assessed BMD in 161 Indigenous Australians, identified as Aboriginal (n=70), Torres Strait Islander (n=68) or both (n=23). BMD measurements were made on Norland-XR46 (n=107) and Hologic (n=90) dual-energy X-ray absorptiometry (DXA) machines. Norland BMD and body composition measurements in these individuals, and also in 36 Caucasian Australians, were converted to equivalent Hologic BMD (BMD(H)) and body composition measurements for comparison. Femoral neck (FN) and lumbar spine Z-scores were high in Indigenous participants (mean FN Z-score: Indigenous men +0.98, p<0.0001 vs. mean zero; Indigenous women +0.82, p<0.0001 vs. mean zero). FN BMD(H) was higher in Aboriginal and/or Torres Strait Islander than Caucasian participants, after adjusting for age, gender, diabetes and height and remained higher in men after addition of lean mass to the model. We conclude that FN BMD is higher in Aboriginal and/or Torres Strait Islander Australians than Caucasian Australian reference ranges and these differences still remained significant in men after adjustment for lean mass. It remains to be seen whether these BMD differences translate to differences in fracture rates.

Progression of Kidney Disease in Indigenous Australians: The eGFR Follow-up Study

BACKGROUND AND OBJECTIVES Indigenous Australians experience a heavy burden of CKD. To address this burden, the eGFR Follow-Up Study recruited and followed an Indigenous Australian cohort from regions of Australia with the greatest ESRD burden. We sought to better understand factors contributing to the progression of kidney disease. Specific objectives were to assess rates of progression of eGFR in Indigenous Australians with and without CKD and identify factors associated with a decline in eGFR. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This observational longitudinal study of Indigenous Australian adults was conducted in >20 sites. The baseline cohort was recruited from community and primary care clinic sites across five strata of health, diabetes status, and kidney function. Participants were then invited to follow up at 2-4 years; if unavailable, vital status, progression to RRT, and serum creatinine were obtained from medical records. Primary outcomes were annual eGFR change and combined renal outcome (first of ≥30% eGFR decline with follow-up eGFR<60 ml/min per 1.73 m(2), progression to RRT, or renal death). RESULTS Participants (n=550) were followed for a median of 3.0 years. Baseline and follow-up eGFR (geometric mean [95% confidence interval], 83.9 (80.7 to 87.3) and 70.1 (65.9 to 74.5) ml/min per 1.73 m(2), respectively. Overall mean annual eGFR change was -3.1 (-3.6 to -2.5) ml/min per 1.73 m(2). Stratified by baseline eGFR (≥90, 60-89, <60 ml/min per 1.73 m(2)), annual eGFR changes were -3.0 (-3.6 to -2.4), -1.9 (-3.3 to -0.5), and -5.0 (-6.5 to -3.6) ml/min per 1.73 m(2). Across baseline eGFR categories, annual eGFR decline was greatest among adults with baseline albumin-to-creatinine ratio (ACR) >265 mg/g (30 mg/mmol). Baseline determinants of the combined renal outcome (experienced by 66 participants) were higher urine ACR, diabetes, lower measured GFR, and higher C-reactive protein. CONCLUSIONS The observed eGFR decline was three times higher than described in nonindigenous populations. ACR was confirmed as a powerful predictor for eGFR decline across diverse geographic regions.

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.

Comparison of creatinine and cystatin C based eGFR in the estimation of glomerular filtration rate in Indigenous Australians: The eGFR Study

BACKGROUND The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation that combines creatinine and cystatin C is superior to equations that include either measure alone in estimating glomerular filtration rate (GFR). However, whether cystatin C can provide any additional benefits in estimating GFR for Indigenous Australians, a population at high risk of end-stage kidney disease (ESKD) is unknown. METHODS Using a cross-sectional analysis from the eGFR Study of 654 Indigenous Australians at high risk of ESKD, eGFR was calculated using the CKD-EPI equations for serum creatinine (eGFRcr), cystatin C (eGFRcysC) and combined creatinine and cystatin C (eGFRcysC+cr). Reference GFR (mGFR) was determined using a non-isotopic iohexol plasma disappearance technique over 4h. Performance of each equation to mGFR was assessed by calculating bias, % bias, precision and accuracy for the total population, and according to age, sex, kidney disease, diabetes, obesity and c-reactive protein. RESULTS Data were available for 542 participants (38% men, mean [sd] age 45 [14] years). Bias was significantly greater for eGFRcysC (15.0mL/min/1.73m2; 95% CI 13.3-16.4, p<0.001) and eGFRcysC+cr (10.3; 8.8-11.5, p<0.001) compared to eGFRcr (5.4; 3.0-7.2). Accuracy was lower for eGFRcysC (80.3%; 76.7-83.5, p<0.001) but not for eGFRcysC+cr (91.9; 89.3-94.0, p=0.29) compared to eGFRcr (90.0; 87.2-92.4). Precision was comparable for all equations. The performance of eGFRcysC deteriorated across increasing levels of c-reactive protein. CONCLUSION Cystatin C based eGFR equations may not perform well in populations with high levels of chronic inflammation. CKD-EPI eGFR based on serum creatinine remains the preferred equation in Indigenous Australians.

Cross-sectional associations of albuminuria among Aboriginal and Torres Strait Islander adults: the eGFR Study

To describe the detailed associations of albuminuria among a contemporary cohort of Aboriginal and Torres Strait Islander people to inform strategies for chronic kidney disease prevention and management.