H. Bloomfield

Post-streptococcal glomerulonephritis is a strong risk factor for chronic kidney disease in later life

Although unusual in western countries and in Australia in general, post-streptococcal glomerulonephritis (PSGN) is still common in Australian Aboriginal children living in remote communities. Here, we evaluated whether episodes of acute PSGN increased the risk for chronic kidney disease in later life in 1519 residents of a remote Aboriginal community (85% of those age eligible), with high rates of renal and cardiovascular disease, who participated in a health screen over a 3-year period. Of these, 200 had had at least one episode of PSGN, with 27 having had multiple episodes, usually in childhood. High levels of albuminuria (albumin/creatinine ratio) with increasing age were confirmed. All PSGN episodes were associated with group A streptococcal skin infections, often related to scabies. In both genders, aged 10-39 years at screening, about one in five had such a history. Among them, PSGN (5 years or more earlier) was significantly associated with higher levels of albuminuria than those without. In women, aged 30-39 years, a history of PSGN was associated with a significantly higher frequency of estimated glomerular filtration rates <60 ml/min. The adjusted odds ratios for an albumin/creatinine ratio over 34 g/mol (overt albuminuria) in males and females with a history of PSGN were 4.6 and 3.1, respectively, compared with those without a history. Thus, PSGN contributes to the very serious burden of chronic kidney disease in this community. Rigorous strategies to prevent scabies and Group A streptococcal infections will reduce this burden.

Chronic disease profiles in a high risk Aboriginal community over a 10-year interval

Aim: To identify whether the macrophage CSF-1 receptor promotes macrophage accumulation and the progression of nephropathy in type 2 diabetic mice. Background: Macrophages are the key inflammatory cells associated with the development and progression of diabetic nephropathy. CSF-1, which is up-regulated in diabetic kidneys, is required for the proliferation, differentiation and activation of monocyte-macrophages and exerts its effects through its receptor tyrosine kinase encoded by the c-fms proto-oncogene. Blockade of c-fms in acute renal disease has proved beneficial in an animal model of renal allograft rejection but the role of c-fms in diabetic nephropathy has not been examined. Methods: Obese, diabetic db/db BL/KS mice with established albuminuria were treated with intraperitoneal injections of neutralizing anti-c-fms mAb (AFS98, 50 mg/kg/twice weekly) or isotype matched control IgG (50 mg/kg/twice weekly) from 12 to 18 weeks of age. Results: Administration of AFS98 mAb did not affect obesity, hyperglycaemia, circulating monocyte levels or the established albuminuria of db/db mice. However, treatment with AFS98 suppressed renal inflammation by reducing kidney macrophages (accumulation, activation and proliferation), MCP-1 levels (mRNA and urine protein), kidney activation of proinflammatory pathways (JNK and ATF-2), and TNF-a mRNA. In addition, AFS98 treatment decreased tubular injury (apoptosis and hypertrophy), interstitial damage (cell proliferation and myofibroblast accrual) and renal fibrosis (TGF-b and collagen IV mRNA), indicating that c-fms antibody can also inhibit the damage caused by inflammation in diabetic kidneys. Conclusions: Treatment with a neutralizing c-fms antibody demonstrates that macrophage activation through the CSF-1 receptor induces renal inflammation and injury in type 2 diabetic mice, supporting the concept that macrophages promote diabetic nephropathy.

The Rise of Chronic Kidney Disease in Remote Living Aboriginal People in the Context of the Epidemiologic and Health Transition

Aim: To access the determinants of infra-renal aortic calcifi cation in patients with Chronic Kidney disease (CKD). Background: Infra-renal aortic calcification is associated with increased cardiovascular morbidity. Few studies have investigated this in CKD patients with most reports failing to use validated methods of quantifying calcification severity. Methods: We estimated infra-renal aortic calcification in 58 CKD patients (39 dialysis, 19 non dialysis) who had undergone abdominal aortic Computed Tomography. Infra-renal aortic calcification volume was estimated using a previously validated highly reproducible semi automated method. Clinical risk factors and co-morbidities (age, atherosclerotic risk factors, medications), serum creatinine, corrected serum calcium and phosphate concentrations were assessed. The association of these risk factors with aortic calcification was analyzed using both univariate and multivariate statistical tests. Results: In all 58 patients aortic calcification severity was strongly correlated with age (Spearman correlation coefficient (r) = 0.680, P < 0.001), but only weakly correlation with eGFR (r = 0.218, P = 0.103) and serum creatinine (r = −0.231, P = 0.084). Patients that required dialysis were much younger [n = 39, median age 58 years, IQR 49–67] than those not on dialysis [n = 19, median age 73 years IQR 66–78] and thus were analyzed separately. In patients receiving dialysis use of calcium based phosphate binders was associated with less calcification [median calcification volume 14 cm3, IQR 0–361, compared to 570 cm3, 2–2468, P = 0.022]. On regression analysis the only factors associated with aortic calcification were age (beta 0.482, P = 0.004) and corrected serum calcium concentrations (beta 0.368, P = 0.012). Conclusion: In this study the principle risk factor for aortic calcification was age. Serum calcium concentrations and use of calcium based phosphate binders may also influence calcification in patients on dialysis but larger studies are required to better assess this.

46 AMPLIFICATION OF ALBUMINURIA IN REMOTE-LIVING AUSTRALIAN ABORIGINAL ADULTS BY EARLY LIFE RISK FACTORS: THE MULTIDETERMINANT OR MULTIHIT MODEL OF RENAL DISEASE

Background: Albuminuria predicts renal failure in remote-living Aboriginal people. It increases sharply with age and over modest ranges of BMI, is higher in females, and is exacerbated by lower birthweight (Bwt) and childhood poststreptococcal glomerulonephritis (PSGN). We describe the effect of these early-life risk factors, singly and together, on urine ACR. Methods: Subjects were 800 members of one tribal group, ages 10-39 yr during community-wide health screens (>80% participation), with records reviewed for Bwt and histories of PSGN. Urine ACR was the outcome of interest. Results: 29% of females & 23% of males had Bwts <2.5 kg, while 24% & 22% had recorded “remote” episodes of PSGN (>3 years prior). Bwt (inversely), a PSGN history, BMI and age were all independently correlated with ACR in both sexes. ACR was lowest with Bwts above the group median (2.81 kg) and no PSGN history, inconsistently higher with either lower Bwts or past PSGN, and highest with both. ACR levels in relation to age and BMI were similarly ordered. Females showed these effects at a younger age, and were more sensitive than males to a single risk factor. ACR >3.4 (microalbuminuria threshold) was increased 1.9-fold and 2.7-fold in females with 1 and 2 risk factors, relative to those with none; rates were not higher in males with one risk factor, but were increased 3.7-fold with two risk factors. Discussion: Low Bwts and high rates of PSGN allow this demonstration of the “multideterminant” model of renal disease in relation to early life risk factors. Nephron deficiency established in early life, through underendowment (lower Bwts) or childhood loss (PSGN) probably propagates albuminuria with increasing age or BMI. Greater sensitivity in females is probably due to their lower nephron endowment, a feature of females generally, and exacerbated by their lower Bwts and slightly higher adult BMIs. Potential for primary prevention is excellent.

Medication use and chronic disease profiles in one high risk aboriginal community

Disease Jeff S Coombes, Amanda Crawford, Robert G Fassett, 3 Dale A Kunde, Iain K Robertson, Madeleine J Ball, Dominic P Geraghty School of Human Movement Studies, University of Queensland, Brisbane, Queensland, AUSTRALIA School of Human Life Sciences, University of Tasmania, Launceston, Tasmania, AUSTRALIA 3 Royal Brisbane and Womens Hospital, Brisbane, Queensland, AUSTRALIA Project funded by the Clifford Craig Medical Research Trust (C Prosser Green Endowment)

New onset albuminuria, hypertension and diabetes in a high risk aboriginal community over 10 years

Disease Jeff S Coombes, Amanda Crawford, Robert G Fassett, 3 Dale A Kunde, Iain K Robertson, Madeleine J Ball, Dominic P Geraghty School of Human Movement Studies, University of Queensland, Brisbane, Queensland, AUSTRALIA School of Human Life Sciences, University of Tasmania, Launceston, Tasmania, AUSTRALIA 3 Royal Brisbane and Womens Hospital, Brisbane, Queensland, AUSTRALIA Project funded by the Clifford Craig Medical Research Trust (C Prosser Green Endowment)

Birth weight and chronic disease profiles in a high risk Aboriginal community

Aim: To identify whether the macrophage CSF-1 receptor promotes macrophage accumulation and the progression of nephropathy in type 2 diabetic mice. Background: Macrophages are the key inflammatory cells associated with the development and progression of diabetic nephropathy. CSF-1, which is up-regulated in diabetic kidneys, is required for the proliferation, differentiation and activation of monocyte-macrophages and exerts its effects through its receptor tyrosine kinase encoded by the c-fms proto-oncogene. Blockade of c-fms in acute renal disease has proved beneficial in an animal model of renal allograft rejection but the role of c-fms in diabetic nephropathy has not been examined. Methods: Obese, diabetic db/db BL/KS mice with established albuminuria were treated with intraperitoneal injections of neutralizing anti-c-fms mAb (AFS98, 50 mg/kg/twice weekly) or isotype matched control IgG (50 mg/kg/twice weekly) from 12 to 18 weeks of age. Results: Administration of AFS98 mAb did not affect obesity, hyperglycaemia, circulating monocyte levels or the established albuminuria of db/db mice. However, treatment with AFS98 suppressed renal inflammation by reducing kidney macrophages (accumulation, activation and proliferation), MCP-1 levels (mRNA and urine protein), kidney activation of proinflammatory pathways (JNK and ATF-2), and TNF-a mRNA. In addition, AFS98 treatment decreased tubular injury (apoptosis and hypertrophy), interstitial damage (cell proliferation and myofibroblast accrual) and renal fibrosis (TGF-b and collagen IV mRNA), indicating that c-fms antibody can also inhibit the damage caused by inflammation in diabetic kidneys. Conclusions: Treatment with a neutralizing c-fms antibody demonstrates that macrophage activation through the CSF-1 receptor induces renal inflammation and injury in type 2 diabetic mice, supporting the concept that macrophages promote diabetic nephropathy.