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

OBJECTIVE: 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. METHODS: A cross-sectional analysis of Indigenous participants of the eGFR Study. MEASURES: Clinical, biochemical and anthropometric measures were collected (including body-circumferences, blood pressure (BP); triglycerides, HbA1c, liver function tests, creatinine; urine- microscopic-haem, albumin: creatinine ratio (ACR), prescriptions- angiotensin converting enzyme inhibitor or angiotensin receptor II antagonist (ACEI/ARB). Albuminuria and diabetes were defined by an ACR>3.0 mg/mmol, and HbA1c≥48 mmol/mol or prior history respectively. Waist: hip ratio (WHR), and estimated glomerular filtration rate (eGFR) were calculated. ACR was non-normally distributed; a logarithmic transformation was applied (in base 2), with each unit increase in log2-albuminuria representing a doubling of ACR. RESULTS: 591 participants were assessed (71% Aboriginal, 61.6% female, mean age 45.1 years, BMI 30.2 kg/m2 , WHR 0.94, eGFR 99.2 ml/min/1.73m2 ). The overall prevalence of albuminuria, diabetes, microscopic-haem and ACEI/ARB use was 41.5%, 41.5%, 17.8% and 34.7% respectively; 69.3% of adults with albuminuria and diabetes received an ACEI/ARB. Using multivariable linear regression modelling, the potentially modifiable factors independently associated with log2-albuminuria were microscopic-haem, diabetes, WHR, systolic BP, alkaline phosphatase (all positive) and eGFR (inverse). CONCLUSION: Albuminuria is associated with diabetes, central obesity and haematuria. High ACEI/ARB prescribing for adults with diabetes and albuminuria was observed. Further understanding of the links between fat deposition, haematuria and albuminuria is required.

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

AIMS: 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. METHODS: Indigenous Australians with (n = 224) or without (n = 340) Type 2 diabetes had a reference glomerular filtration rate measure using plasma disappearance of iohexol (measured glomerular filtration rate) over 4 h. Serum creatinine was measured by an enzymatic method. Performance was assessed by bias (measured glomerular filtration rate - estimated glomerular filtration rate) and accuracy (percentage of estimated glomerular filtration rate within 30% of measured glomerular filtration rate). RESULTS: The median measured glomerular filtration rate (interquartile range) in participants with or without diabetes was 97 (68-119) and 108 (90-122) ml min(-1)  1.73 m(-2) , respectively. The Chronic Kidney Disease Epidemiology Collaboration formula had smaller bias and greater accuracy than the Modification of Diet in Renal Disease and Cockcroft-Gault formulas overall, for participants both with and without diabetes. However, for estimated glomerular filtration rate > 90 ml min(-1)  1.73 m(-2) , the Chronic Kidney Disease Epidemiology Collaboration formula had greater bias in participants with diabetes, underestimating measured glomerular filtration rate by 7.4 vs. 1.0 ml min(-1)  1.73 m(-2) in those without diabetes. The Chronic Kidney Disease Epidemiology Collaboration formula was less accurate across the whole range of estimated glomerular filtration rates in participants with vs. those without diabetes (87.1% vs. 93.3%). CONCLUSIONS: The Chronic Kidney Disease Epidemiology Collaboration formula outperforms the Modification of Diet in Renal Disease and Cockcroft-Gault formulas overall in Indigenous Australians with and without diabetes. However, the Chronic Kidney Disease Epidemiology Collaboration formula has greater bias in people with diabetes compared with those without diabetes, especially in those with normal renal function.

Distribution of volumes of individual glomeruli in kidneys at autopsy: association with age, nephron number, birth weight and body mass index.

BACKGROUND: Glomerular hypertrophy occurs in a number of normal and pathological states. Glomerular volume in kidneys at autopsy is usually indirectly derived from estimates of total glomerular mass and nephron number, and provides only a single value per kidney, with no indication of the range of volumes of glomeruli within the kidney of any given subject. We review findings of the distribution of volumes of different glomeruli within subjects without kidney disease, and their correlations with age, nephron number, birth weight and body mass index (BMI). METHODS: The study describes findings from autopsy kidneys of selected adult white males from the Southeast USA who had unexpected deaths, and who did not have renal scarring or renal disease. Total glomerular (nephron) number and total glomerular volume were estimated using the disector/fractionator combination, and mean glomerular volume (Vglom) was derived. The volumes of 30 individual glomeruli (IGV) in each subject were determined using the disector/Cavalieri method. IGV values were compared by categories of age, nephron number, birth weight and BMI. RESULTS: There was substantial variation in IGV within subjects. Older age, lower nephron number, lower birth weight and gross obesity were associated with higher mean IGV and with greater IGV heterogeneity. High Vglom and high IGVs were associated with more glomerulosclerosis. However, amongst the generally modest numbers of sclerosed glomeruli, the pattern was uniformly of ischemic collapse of the glomerular tuft. There was no detectable focal segmental glomerular tuft injury. DISCUSSION: In this series of people without overt renal disease, greater age, nephron deficit, lower birth weight and obesity were marked by glomerular enlargement and greater glomerular volume heterogeneity within individuals.

Recent patterns in chronic disease mortality in remote living Indigenous Australians.

BACKGROUND: Despite the well-recognised Indigenous-non-Indigenous health disparity, some reports suggest improvements in Indigenous mortality. Our aim was to quantify Indigenous mortality in Outer Regional (OR), Remote (R), and Very Remote (VR) areas in New South Wales, Queensland, South Australia, Western Australia, and the Northern Territory and changes in mortality from 1998 to 2005. METHODS: We calculated rates, standardized mortality ratios (SMRs) and percentage change in annual rates of Indigenous cardiovascular, diabetes and renal mortality mentioned anywhere on the death certificate by using ICD-10 codes and the 2001 total Australian population as the reference population. RESULTS: In 1998-2001, Indigenous SMRs for all-cause mortality were 241%, 421% and 220% in OR, R and VR, respectively. In 2001-03, corresponding SMRs were 202%, 331% and 176%. Percentage changes (95% confidence interval) in annual all-cause mortality were -3.0% (-5.3%, -0.7%) in OR, -4.2% (-7.4%, -0.9%) in R and -0.5 (-9.1%, -0.7%) in VR. In 2002-2005, compared with 1998-2001, changes in the number of Indigenous deaths were -147, -195, and -197 in OR, R and VR, respectively. Similar patterns and trends were observed for cardiovascular mortality. CONCLUSIONS: Mortality was elevated about 2-fold in OR, 4-fold in R and 2-fold in VR areas. The downward trend in mortality regardless of remoteness of residence was partly attributable to a decrease in the absolute number of deaths. These patterns were observed for each of the states/territories individually.

Bilirubin concentration is positively associated with haemoglobin concentration and inversely associated with albumin to creatinine ratio among Indigenous Australians: eGFR Study.

Low serum bilirubin concentrations are reported to be strongly associated with cardio-metabolic disease, but this relationship has not been reported among Indigenous Australian people who are known to be at high risk for diabetes and chronic kidney disease (CKD). HYPOTHESIS: serum bilirubin will be negatively associated with markers of chronic disease, including CKD and anaemia among Indigenous Australians. METHOD: A cross-sectional analysis of 594 adult Aboriginal and Torres Strait Islander (TSI) people in good health or with diabetes and markers of CKD. Measures included urine albumin: creatinine ratio (ACR), estimated glomerular filtration rate (eGFR), haemoglobin (Hb) and glycated haemoglobin (HbA1c). Diabetes was defined by medical history, medications or HbA1c≥6.5% or ≥48mmol/mol. Anaemia was defined as Hb<130g/L or <120g/L in males and females respectively. A multivariate regression analysis examining factors independently associated with log-bilirubin was performed. RESULTS: Participants mean (SD) age was 45.1 (14.5) years, and included 62.5% females, 71.7% Aboriginal, 41.1% with diabetes, 16.7% with anaemia, 41% with ACR>3mg/mmol and 18.2% with eGFR<60mL/min/1.73m2. Median bilirubin concentration was lower in females than males (6 v 8µmol/L, p<0.001) and in Aboriginal than TSI participants (6 v 9.5µmol/L, p<0.001). Six factors explained 35% of the variance of log-bilirubin; Hb and cholesterol (both positively related) and ACR, triglycerides, Aboriginal ethnicity and female gender (all inversely related). CONCLUSION: Serum bilirubin concentrations were positively associated with Hb and total cholesterol, and inversely associated with ACR. Further research to determine reasons explaining lower bilirubin concentrations among Aboriginal compared with TSI participants are needed.

Associations of serum adiponectin with markers of cardio-metabolic disease risk in Indigenous Australian adults with good health, diabetes and chronic kidney disease.

The higher serum adiponectin concentrations observed in females are often attributed to differences in adiposity or sex hormones. There is little data describing adiponectin in Indigenous Australians, and no studies examining its association with cardio-metabolic disease risk markers and chronic kidney disease (CKD). AIM: To describe the relationship of serum adiponectin with cardio-metabolic disease risk markers and kidney function in a community-based sample of Indigenous Australian adults, with particular reference to sex-specific differences. METHODS: A cross-sectional analysis of a community-based volunteer sample of 548 Indigenous Australian adults (62% female), stratified into five cardio-metabolic risk groups ranging from good health (strata-1) to high cardio-metabolic risk and low measured glomerular filtration rate (mGFR, <60ml/min/1.73m2) (strata-5). We examined serum adiponectin concentrations with cardio-metabolic risk markers, albuminuria and mGFR. RESULTS: Indigenous Australian females had a lower than expected adiponectin concentration (3.5µg/ml), which was higher than males in strata 1-4 (as in other populations), but not in strata-5 (mGFR<60, p=0.19), and higher leptin: adiponectin ratio than other populations (7.8ng/µg - strata-1, healthy females; 12.2ng/µg - strata-3, females with diabetes and mGFR≥90). Female-gender, HDL-cholesterol (positive), mGFR and waist: hip ratio (WHR) (inverse) were independently associated with log-adiponectin when mGFR≥60; when mGFR<60, female-gender was associated with 0.27 units lower log-adiponectin. CONCLUSION: Female-gender was not associated with higher adiponectin concentrations in Indigenous Australians with mGFR<60ml/min/1.73m2. High WHR was frequent in both genders, and inversely associated with adiponectin. Longitudinal studies are needed to examine relationships of serum adiponectin, obesity and cardiovascular disease events in Indigenous Australians.

Alcohol abuse-related mesangial glomerulonephritis: immunoelectron microscopy.

Immunoelectron microscopy, using post-embedding immunohistochemistry with colloidal gold, was performed on renal samples from forensic autopsies. We confirmed that electron-dense deposits seen in alcohol abuse-related mesangial nephritis correspond to immunoglobulins, as has been shown previously by others in idiopathic cases. We investigated seven control samples and 13 specimens from individuals with evidence of alcohol abuse, six of whom had mesangial nephritis with IgA deposition. We found concentration of the gold particles over large electron-dense deposits in four of six cases of mesangial nephritis, confirming that they correspond to the IgA shown by immunofluorescence. Furthermore, a similar concentration of gold particles was not observed in control cases or in alcoholics without mesangial glomerulonephritis (4/6 vs 0/14; p = 0.005). IgM, seen as small aggregates, was confirmed in only two of six of the same cases. This is the first time that immunoelectron microscopy is performed on tissues obtained post mortem.

Glomerular size and glomerulosclerosis in Australian aborigines.

We have previously described the prevalence of glomerulomegaly in biopsy specimens from Australian Aborigines with renal disease, a phenomenon documented in a number of other indigenous populations. Many of the biopsy specimens showed variable degrees of focal and segmental glomerulosclerosis (FSGS). Correlations between glomerular size and FSGS have been described in various animal models, as well as studies of humans. The aim of this study is to determine whether a relation exists between glomerular volume and severity of FSGS in biopsy specimens from Australian Aboriginals in the Northern Territory and Aboriginal inhabitants of the Tiwi Islands (Bathurst Island and Melville Island, Northern Territory, Australia). Consecutive clinical biopsy specimens were obtained from 78 non-Tiwi and 72 Tiwi Aboriginals. Glomerular volume was estimated using the stereological method of Weibel and Gomez. FSGS was graded from 0 to 4; 0 indicates no sclerosis and 4 indicates severe sclerosis. A biphasic relationship between glomerular size and severity of FSGS was identified. As the severity of FSGS increased from grade 0 to grade 3, glomerular size also increased. For both populations studied, glomeruli scored as grades 1, 2, and 3 were approximately 50% (P< 0.001), 65% (P< 0.001), and 100% (P< 0.001) larger than normal glomeruli, respectively. However, in glomeruli with grade 4 FSGS, glomerular size decreased to the size of normal glomeruli. These results show a biphasic relationship between severity of FSGS and glomerular size in Australian Aborigines.

Waist circumference, body mass index, hip circumference and waist-to-hip ratio as predictors of cardiovascular disease in Aboriginal people.

OBJECTIVE: To investigate waist circumference (WC), waist-hip ratio, hip circumference and body mass index (BMI) as risk factors for cardiovascular disease in Aboriginal Australians. METHODS: This cohort study included 836 adults aged 20-74 y in a remote Aboriginal community. WC, waist-hip ratio, hip circumference and BMI were obtained from a screening program. The participants were followed for up to 10 y for cardiovascular events. A Cox regression model was used to calculate the rate ratio (RR) and 95% confidence interval (CI) for the first-ever cardiovascular event (fatal and nonfatal). RESULTS: RRs for the first-ever cardiovascular event were 1.31 (95% CI: 1.11, 1.54), 1.29 (95% CI: 1.09,1.53), 1.28 (95% CI: 1.08, 1.52) and 1.10 (95% CI: 0.93, 1.30) per standard deviation increase in WC, BMI, hip circumference and waist-hip ratio, respectively, after adjustment for diabetes mellitus, total cholesterol, systolic blood pressure and smoking status. WC, BMI and hip circumference were significantly associated with cardiovascular risk, independent of other cardiovascular risk factors. Dividing each of the four parameters into quartiles, WC had the highest likelihood statistics (12.76) followed by BMI (11.45), hip circumference (10.57) and waist-hip ratio (3.15) for predicting first CV events. CONCLUSION: WC, BMI and hip circumference are associated with cardiovascular outcome, independent of traditional risk factors. However, WC appears to be a better predictor for cardiovascular risk than other parameters. Waist-hip ratio is not as useful as other measurements.

The influence of glucocorticoid dose on protein catabolism after renal transplantation.

Protein catabolic rate (PCR) and protein balance were measured daily by computerized mass balance studies in 20 subjects during hospitalization after renal transplantation. All hospital courses were uncomplicated. Ten subjects received approximately 1 mg/kg/day prednisone, and ten subjects received 3-5 mg/kg/day prednisone on day 1 with a tapering dose to approximately 1 mg/kg/day by discharge. In both groups, PCR rose during the first 3-4 postoperative days then stabilized at an accelerated level. PCR was significantly greater in the higher prednisone group. Despite encouragement most subjects ate less protein than prescribed, and most were in negative protein balance. Mean daily and net protein deficits were more severe in the higher prednisone group. Higher protein intakes improved protein balance. The protein catabolic effects of the two regimens have been defined and a dose dependency demonstrated. In any therapeutic situation the use of the minimum effective dose of steroids seem advised, and high protein intake should be encouraged to improve protein balance. Some steroid morbidity might thus be avoided.

Low incidence of glomerulosclerosis in normal kidneys.

Forty normal kidneys were selected from a series of 146 renal samples obtained at forensic autopsies of American Indians and whites. Glomeruli were counted and the percentage of globally sclerosed, obsolescent glomeruli was calculated for each case. The mean for sclerotic glomeruli was less than 3% in any age group younger than 56 years. This finding is in agreement with the results of similar studies, but substantially lower than the figures quoted in textbooks. Analysis of the combination of our data with studies performed by other authors shows that the 90th percentile of glomerular sclerosis can be calculated for any age by subtracting 10 from half the patient's age. No ethnic- or sex-related differences were seen in any age group.

Pathologic findings in mesangiopathic glomerulonephritis in Navajo Indians.

Immune complex-associated mesangiopathic glomerulonephritis was found in 64% of renal biopsies performed on Navajos over a 16-year period. It is characterized by mild mesangial expansion and predominant immunoglobulin (Ig) A and/or IgM deposits. Statistical analysis shows that glomerular deposits of IgG and C3, glomerular sclerosis, interstitial fibrosis, interstitial inflammation, and tubular atrophy are associated with renal insufficiency at the time of biopsy, and can be integrated into a pathologic index that has a high correlative value. Mesangiopathic glomerulonephritis is probably responsible for the high rates of non-diabetic end-stage renal disease seen in Navajo Indians.

Mesangiopathic glomerulonephritis in Zuni (New Mexico) Indians.

Zuni is a Pueblo Indian village having more than a sixfold greater incidence of nondiabetic end-stage renal disease than the rest of the United States. Renal biopsy specimens from 44 patients with nondiabetic renal disease were subdivided into two groups. In group 1, 21 patients with asymptomatic microscopic hematuria revealed a mild mesangiopathic glomerulonephritis in 18 cases. The predominantly staining immunoglobulin was IgM in ten specimens and IgA in eight specimens. In group 2, 23 patients with symptomatic renal disease presented with nephrotic range proteinuria (11), renal insufficiency (eight), and hypertension (four). A mesangiopathic glomerulonephritis was diagnosed in 16 cases, and in 11 was IgA predominant. Three cases of membranoproliferative glomerulonephritis occurred in group 2. Five cases revealed focal glomerulosclerosis without immune deposits (three in group 1 and two in group 2). More than half (57%) of the patients undergoing biopsy were related. Cases of symptomatic nondiabetic renal disease showed a significant tendency to cluster among the members of four families, suggesting a hereditary influence in the pathogenesis of immune-mediated glomerulonephritis in the Zuni.

A health profile of adults in a Northern Territory aboriginal community, with an emphasis on preventable morbidities.

We conducted a brief health survey of adults in an isolated Northern Territory Aboriginal community, whose standardised mortality rates are the second highest in Australia. The screen revealed high rates of smoking and excessive drinking, of preventable infections and their sequelae, and of hypertension, insulin resistance, diabetes and renal disease. The infectious morbidities were more pronounced and the life-style morbidities almost entirely new since a health screen in 1957. Most morbidities were strongly associated with identifiable risk factors, such as overweight, smoking, excessive drinking, skin sores and scabies, all of which which are amenable to modification. Problems with food supply and pricing, poor food choices and diversion of money to cigarettes, beer and gambling all contributed to poor nutrition. Low birthweight probably compounds the risk for serious adult disease associated with these environmental influences. This profile highlights the failure of current systems to deal with health needs. Improvements in infrastructure, education and employment, and reinvigoration of preventive and primary health care programs, assumption of responsibility for health by the community and by individuals themselves, and better management of existing morbidities are essential to rectifying this shameful situation.