Paul D. Lawton

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

The publication of the Australasian Creatinine Consensus Working Groups 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 m2. Age‐related decision points for eGFR in adults are not recommended, as although an eGFR < 60 mL/min/1.73 m2 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.

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

High rates of albuminuria but not of low eGFR in Urban Indigenous Australians: the DRUID Study

BackgroundIndigenous 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.Methods860 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 m2). 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.ResultsA 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.ConclusionsGiven 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.

Does relative remoteness affect chronic disease outcomes? Geographic variation in chronic disease mortality in Australia, 2002–2006

Objective: To examine the variation of chronic disease mortality by remoteness areas of Australia, including states and territories.

Kidney transplant outcomes in the indigenous population in the northern territory of Australia

Background. Indigenous Australians develop end-stage renal disease (ESRD) at a significantly higher rate than nonindigenous Australians. Renal transplantation is the preferred treatment modality; however, they are underrepresented in the transplanted population. In addition, despite the morbidity and mortality gains demonstrated in other patient groups, it is unclear whether such an advantage is replicated for indigenous Australians. We have sought to identify some of the factors that lead to poorer outcomes within this group of recipients. Methods. We performed a retrospective analysis of a cohort of renal transplant recipients (indigenous and nonindigenous) from the Northern Territory of Australia. Results. Indigenous patients waited longer on dialysis, were more sensitized at the time of transplantation, and the number of human leukocyte antigen mismatches was greater. Overall renal allograft survival is poorer among indigenous Australians (HR 4.13, 2.0–8.5, P<0.0001) with the majority of grafts lost due to recipient death. The most common cause of death was septicemia. Graft loss due to any cause has not been influenced by the absence of full-time specialist staff at major treatment centers. Infection rates are greatly increased in indigenous patients (RR 4.1, 95% CI 3.5–4.7, P<0.0001), in addition to the incidence of rejection (RR 2.5 95% CI 1.8–3.5, P<0.001) and hospitalization (RR 3.9, 95% CI 3.2–4.9, P<0.0001). There is increased steroid exposure among indigenous recipients. Conclusions. Indigenous recipients of cadaveric kidney transplants have worse outcomes than nonindigenous recipients, mostly due to increased mortality and morbidity from infective causes.

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.

The relationship between number of primary health care visits and hospitalisations: evidence from linked clinic and hospital data for remote Indigenous Australians

BackgroundPrimary health care (PHC) is widely regarded as essential for preventing and treating ill health. However, the evidence on whether improved PHC reduces hospitalisations has been mixed. This study examines the relationship between PHC and hospital inpatient care in a population with high health need, high rates of hospitalisation and relatively poor PHC access.MethodsThe cross-sectional study used linked individual level PHC visit and hospitalisation data for 52 739 Indigenous residents from 54 remote communities in the Northern Territory of Australia between 1 July 2007 and 30 June 2011. The association between PHC visits and hospitalisations was modelled using simple and spline quadratic regression for key demographics and disease groups including potentially avoidable hospitalisations.ResultsAt the aggregate level, the average annual number of PHC visits per person had a U-shaped association with hospitalisations. For all conditions combined, there was an inverse association between PHC visits and hospitalisations for people with less than four clinic visits per year, but a positive association for those visiting the clinic four times or more. For patients with diabetes, ischaemic heart disease or renal disease, the minimum level of hospitalisation was found when there was 20–30 PHC visits a year, and for children with otitis media and dental conditions, 5–8 visits a year.ConclusionsThe results of this study demonstrate a U-shape relationship between PHC visits and hospitalisations. Under the conditions of remote Indigenous Australians, there may be an optimal level of PHC at which hospitalisations are at a minimum. The authors propose that the effectiveness of a health system may hinge on a refined balance, rather than a straight-line relationship between primary health care and tertiary care.

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.

Inflammation, high ferritin, and erythropoietin resistance in indigenous maintenance hemodialysis patients from the Top End of Northern Australia

Use of erythropoiesis‐stimulating agents (ESAs) has improved the management of anemia in patients on maintenance hemodialysis (MHD). Iron deficiency and inflammation cause ESAs resistance and are both common among indigenous people of Northern Australia. As part of quality assurance in our Renal Anaemia Management program, we observed that there was use of higher doses of ESAs and adjuvant iron therapy in our MHD patients. This study aimed to explore the relationship among iron studies, inflammation, ESA responsiveness, and ESAs and iron requirements in indigenous patients on MHD from the Top End of Northern Australia. We performed a retrospective cohort analysis of anemia management in a cohort of our patients on MHD. We extracted data for 178 indigenous and 19 non‐indigenous patients from 1 March 2009 to 28 February 2010 from the Renal Anaemia Management database, which collects data prospectively in MHD patients. Ninety‐nine percent of the whole sample had a ferritin level above the international guidelines threshold of >500 µg/L. Indigenous patients had higher ferritin (1534 ± 245.5 µg/L vs. 1013 ± 323.3 µg/L, P = 0.002). C‐reactive protein (CRP) was high in 56.9% of the total cohort. One hundred percent of those with normal CRP had high ferritin (>500 µg/L). C‐reactive protein was higher in indigenous than in non‐indigenous patients. Erythropoiesis‐stimulating agents hyporesponsiveness was higher in indigenous patients (P < 0.0001). There was no significant difference in ESAs hyporesponsiveness among different levels of CRP (P = 0.116), ferritin (P = 0.408), and transferrin saturation (P = 0.503). Indigenous patients required higher total iron dose (2820.30 [2000–4350] vs. 2336.12 [1912–2900], P = 0.02). There was no significant relationship between the high ferritin and CRP. In indigenous dialysis patients, iron therapy and ESAs use are higher. The high iron use is due to a lack of published evidence to guide the administration of iron in patients with high ferritin. The high ferritin and ESAs resistance could not be fully explained by inflammation and need further evaluation. Further studies are required to determine the safe use of iron and management of ESAs resistance in our hemodialysis population.