Birthweight and the Prevalence, Progression, and Incidence of CKD in a Multideterminant Model in a High-Risk Australian Aboriginal Community.

INTRODUCTION: We have previously showed that albuminuria was associated with low birthweight in young adults in a remote Australian Aboriginal community that has high rates of kidney disease. Here we describe the association of birthweight with incidence and progression of kidney disease over time. METHODS: Among 695 members of an Aboriginal community with recorded birthweights, urine albumin creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR) were measured at ages 5 to 40 years, and follow-up values were measured or imputed again a median of 11.6 years later. Prevalence of markers on each occasion and change over time were evaluated in the context of birthweights and other potentially significant factors. RESULTS: On the second screen, ACR was inversely and significantly correlated with birthweight and eGFR was directly correlated with birthweight. Increases in ACR and in proportions of persons who developed new-onset (incident) albuminuria between screens were higher in those of lower birthweights (<2.5 kg). Proportions of persons who lost ≥20% of their baseline eGFR were higher in the lower birthweight groups. Lower birthweights also amplified elevations of ACR associated with other risk factors, specifically higher body mass indexes (BMIs) and a prior history of poststreptococcal glomerulonephritis (PSGN). At both screens, progressively higher levels of ACR beyond the mid-microalbuminuria range were correlated with lower levels of eGFR. CONCLUSIONS: Lower birthweight contributes to an excess of kidney disease and its progression in this population. Because an excess of low birthweight and episodes of PSGN are eminently preventable, substantial containment of kidney disease is feasible.

An update on chronic kidney disease in Aboriginal Australians.

We provide a brief update on some aspects of chronic kidney disease (CKD) in Indigenous Australians, with CKD referring to all stages of pre-terminal kidney disease, as well as to end-stage kidney failure (ESKF), whether or not a person receives renal replacement therapy (RRT). Recently recorded rates of ESKF and RRT were 6- and 8-fold those recoded for non-Indigenous Australians with age adjustment, while non-dialysis CKD hospitalizations and CKD-attributed deaths were 8-fold and 3-fold higher. The median age of Indigenous people who developed ESKF was ~ 30 years less than for non-Indigenous people, and 84% of them received RTT, while only half of non-Indigenous people with ESKF did so. However, the nationwide average Indigenous incidence rate of RRT appears to have stabilized. The 2012 Australian Health Survey showed elevated levels of CKD markers in Indigenous people at the community level. For all CKD parameters, rates among Indigenous people were strikingly correlated with increasing remoteness of residence and socioeconomic disadvantage, and there was a female predominance in remote areas. The burden of renal disease in Australian Indigenous people is seriously understated by Global Burden of Disease Mortality methodology, because it employs underlying cause of death only, and because deaths of people on RRT are frequently attributed to non-renal causes. These data give a much-expanded view of CKD in Aboriginal people. Methodologic approaches must be remedied for a full appreciation of the burden, costs, and outcomes of the disease, to direct appropriate policy development.

Heavy metal imaging in fibrotic human kidney tissue using the synchrotron X-ray fluorescence microprobe.

Abnormally high exposure to heavy metals and their accumulation in some tissues are recognized as causes of many acute and chronic human diseases. Because of the roles many metals have in normal human physiology, proving cause and effect between exposure to heavy metals and pathogenesis of disease is problematic. Therefore, many illnesses that develop through occupational and environmental exposure are not considered directly related to heavy metal toxicity. The high sensitivity and spatial resolution of elements using the synchrotron X-ray fluorescence microprobe (XFM) may give a robust means to investigate spatial distribution of heavy metals in correlation with specific pathologies. For example, proven presence of different heavy metals may correlate spatially with kidney fibrosis, suggesting a mechanistic link between heavy metal-induced fibrosis and chronic kidney disease. One specific example that may benefit from such an analysis relates to a cluster of people with chronic kidney disease of unknown cause (CKDu), in a significant proportion of the population of the North Central Province of Sri Lanka. Here, it was postulated that heavy metal exposure, in particular of cadmium, in foods and agriculture may be one cause of end-stage kidney disease and premature death of patients with CKDu. Synchrotron methods had not been applied previously to this particular problem. This manuscript provides a brief review of the literature and reports some pilot data from an investigation of localization of kidney fibrosis in CKDu with selected heavy metals including cadmium.

A randomised controlled trial of potential for pharmacologic prevention of new-onset albuminuria, hypertension and diabetes in a remote Aboriginal Australian community, 2008-2013.

INTRODUCTION: We conducted a double-blind randomised controlled trial in a remote-living Australian Aboriginal group at high risk for chronic disease to assess whether pharmacological treatment with angiotensin converting enzyme inhibitor (ACEi) could delay the onset of albuminuria, hypertension or diabetes in people currently free of those conditions. METHODS: Eligibility criteria in 2008 were age ≥18yr, blood pressure ≤140/90 mm/Hg, urinary albumin creatinine ratio (ACR) < 3.4 mg/mmol, normal levels of glycosylated haemoglobin, and, in females, infertility. A 2011 amendment allowed enrolment of fertile females using long-term contraception. "Treatment" was the ACEi perindopril arginine, or placebo, and participant events were ACR ≥3.4 mg/mmol and/or blood pressure >140/90 mm Hg and/or haemoglobin A1c >6.5%, and/or cardiovascular events. Results were analysed in 125 randomised participants who commenced treatment. RESULTS: Recruitment was low, especially of women, and dropout rates high: there were finally 60 and 65 people in the ACEi and placebo groups respectively. In females, there were no events among 10 in the ACEi group, versus 5 events among 17 in the placebo group, and longitudinal ACR, HbA1c and blood pressure levels supported probable benefit of ACEi. There was no benefit of ACEi in males, but a probable benefit on diabetes/hypertension events. With the genders combined, there was probable reduction of diabetes (zero vs 4 events, p = 0.068), and of diabetes or hypertension (zero vs 5 events, p = 0.037). DISCUSSION: In this high-risk population, ACEi probably delays development of albuminuria, diabetes and hypertension in females, and of non-ACR events overall. Repeat investigation with a larger sample size is warranted.

APOL1 Risk Variants Independently Associated With Early Cardiovascular Disease Death.

INTRODUCTION: The relationship of APOL1 renal risk variants to cardiovascular disease (CVD) is controversial and was the subject of this investigation. METHODS: Age, cause of death, and nephrosclerosis (the latter defined by glomerulosclerosis) were analyzed in the autopsies of 162 African Americans and 136 whites genotyped for APOL1 risk alleles. RESULTS: Sudden deaths represented >75% of CVD autopsies for both races and all-risk genotypes. The average ages of CVD deaths for African Americans with 1 and 2 APOL1 risk alleles were, respectively, 7.0 years (P = 0.02) and 12.2 years (P < 0.01) younger than African Americans with 0 risk alleles and 8.7 years (P = 0.01) and 13.9 years (P = 0.01) younger than whites. Age differences were not significant between African Americans and whites with 0 risk alleles (P = 0.61). The younger CVD deaths of African Americans were associated with less severe glomerulosclerosis with 2 (P = 0.01), although not 1 (P = 0.09), compared with 0 APOL1 risk alleles. Cardiomyopathy was found in 23% of African Americans with 1 and 2 risk alleles and significantly contributed to the lower age (P = 0.01). For non-CVD deaths, age differences were not seen by race (P = 0.28) or among African Americans by risk allele status (P = 0.38). CONCLUSION: Carriage of 1 or 2 APOL1 risk alleles in African Americans was associated with earlier age deaths due to coronary artery disease and cardiomyopathy. For 2 risk alleles, the early age was independent of nephrosclerosis.

APOL1 Risk Alleles are Associated with More Severe Arteriosclerosis in Renal Resistance Vessels with Aging and Hypertension.

The increased risk of end-stage kidney disease (ESKD) among hypertensive African Americans is partly related to APOL1 allele variants. Hypertension-associated arterionephrosclerosis consists of arteriosclerosis, glomerulosclerosis, and cortical fibrosis. The initial glomerulosclerosis, attributed to preglomerular arteriosclerosis and ischemia, consists of focal global glomerulosclerosis (FGGS), but in biopsy studies, focal segmental glomerulosclerosis (FSGS) is found with progression to ESKD, particularly in African Americans. This is a study of arterionephrosclerosis in successfully APOL1 genotyped autopsy kidney tissue of 159 African Americans (61 no risk alleles, 68 one risk allele, 30 two risk alleles) and 135 whites aged 18-89 years from a general population with no clinical renal disease. Glomerulosclerosis was nearly exclusively FGGS with only three subjects having FSGS-like lesions that were unrelated to APOL1 risk status. For both races, in multivariable analysis, the dependent variables of arteriosclerosis, glomerulosclerosis, and cortical fibrosis were all significantly related to the independent variables of older age (P < 0.001) and hypertension (P < 0.001). A relationship between APOL1 genotype and arteriosclerosis was apparent only after 35 years of age when, for any level of elevated blood pressure, more severe arteriosclerosis was found in the interlobular arteries of 14 subjects with two APOL1 risk alleles when compared to African Americans with none (n = 37, P = 0.02) or one risk alleles (n = 35, P = 0.02). With the limitation of the small number of subjects contributing to the positive results, the findings imply that APOL1 risk alleles recessively augment small vessel arteriosclerosis in conjunction with age and hypertension. FSGS was not a significant finding, indicating that in the early stages of arterionephrosclerosis, the primary pathologic influence of APOL1 genotype is vascular rather than glomerular.

An expanded nationwide view of chronic kidney disease in Aboriginal Australians.

We summarize new knowledge that has accrued in recent years on chronic kidney disease (CKD) in Indigenous Australians. CKD refers to all stages of preterminal kidney disease, including end-stage kidney failure (ESKF), whether or not a person receives renal replacement therapy (RRT). Recently recorded rates of ESKF, RRT, non-dialysis CKD hospitalizations and CKD attributed deaths were, respectively, more than sixfold, eightfold, eightfold and threefold those of non-Indigenous Australians, with age adjustment, although all except the RRT rates are still under-enumerated. However, the nationwide average Indigenous incidence rate of RRT appears to have stabilized. The median age of Indigenous people with ESKF was about 30 years less than for non-Indigenous people, and 84% of them received RTT, while only half of non-Indigenous people with ESKF did so. The first-ever (2012) nationwide health survey data showed elevated levels of CKD markers in Indigenous people at the community level. For all CKD parameters, rates among Indigenous people themselves were strikingly correlated with increasing remoteness of residence and socio-economic disadvantage, and there was a female predominance in remote areas. The burden of renal disease in Australian Indigenous people is seriously understated by Global Burden of Disease Mortality methodology, because it employs underlying cause of death only, and because deaths of people on RRT are frequently attributed to non-renal causes. These data give a much expanded view of CKD in Aboriginal people. Methodologic approaches must be remedied for a full appreciation of the burden, costs and outcomes of the disease, to direct appropriate policy development.

APOL1 Risk Alleles Are Associated with Exaggerated Age-Related Changes in Glomerular Number and Volume in African-American Adults: An Autopsy Study.

APOL1 genetic variants contribute to kidney disease in African Americans. We assessed correlations between APOL1 profiles and renal histological features in subjects without renal disease. Glomerular number (N glom) and mean glomerular volume (V glom) were measured by the dissector/fractionator method in kidneys of African-American and non-African-American adults without renal disease, undergoing autopsies in Jackson, Mississippi. APOL1 risk alleles were genotyped and the kidney findings were evaluated in the context of those profiles. The proportions of African Americans with none, one, and two APOL1 risk alleles were 38%, 43%, and 19%, respectively; 38% of African Americans had G1 allele variants and 31% of African Americans had G2 allele variants. Only APOL1-positive African Americans had significant reductions in N glom and increases in V glom with increasing age. Regression analysis predicted an annual average loss of 8834 (P=0.03, sex adjusted) glomeruli per single kidney over the first 38 years of adult life in African Americans with two risk alleles. Body mass index above the group medians, but below the obesity definition of ≥ 30 kg/m(2), enhanced the expression of age-related changes in N glom in African Americans with either one or two APOL1 risk alleles. These findings indicate that APOL1 risk alleles are associated with exaggerated age-related nephron loss, probably decaying from a larger pool of smaller glomeruli in early adult life, along with enlargement of the remaining glomeruli. These phenomena might mark mechanisms of accentuated susceptibility to kidney disease in APOL1-positive African Americans.

Paediatric end-stage renal disease in a tertiary hospital in South West Nigeria.

BACKGROUND: Children and adolescents with end-stage renal disease (ESRD) in sub-Saharan Africa may have the worst outcomes globally. Barriers to management include late presentation, poor socioeconomic conditions, absence of medical insurance, limited diagnostic facilities and non-availability of chronic renal replacement therapy (RRT). Our study was to determine the incidence, aetiology, management and outcomes of paediatric ESRD in a tertiary hospital in Nigeria. METHODS: A retrospective case review of paediatric ESRD at the University College Hospital Ibadan, Nigeria, over 8 years, from January 2005 to December 2012. RESULTS: 53 patients (56.6% male), median age 11 (inter quartile range 8.5-12) years were studied. Mean annual incidence of ESRD in Ibadan for children aged 14 years and below was 4 per million age related population (PMARP) while for those aged 5-14 years it was 6.0 PMARP. Glomerulonephritis was the cause in 41 (77.4%) patients amongst whom, 29 had chronic glomerulonephritis and 12 had nephrotic syndrome. Congenital anomalies of the kidneys and urinary tract (CAKUT) accounted for 11 (21.2%) cases, posterior urethral valves being the most common. Acute haemodialysis, acute peritoneal dialysis or a combination of these were performed in 33 (62.3%), 6 (11.3%) and 4 (7.5%) patients respectively. Median survival was 47 days and in-hospital mortality was 59%. CONCLUSIONS: Incidence of paediatric ESRD in Ibadan is higher than previous reports from sub-Saharan Africa. Glomerulonephritis, and then CAKUT are the most common causes. Mortality is high, primarily due to lack of resources. Preventive nephrology and chronic RRT programmes are urgently needed.

Hypertension, glomerular hypertrophy and nephrosclerosis: the effect of race.

BACKGROUND: African Americans have more severe hypertensive nephrosclerosis than white Americans, possibly at similar levels of blood pressure. Glomerular volume is increased in African Americans relative to whites, but it is uncertain how this relates to nephrosclerosis and whether it contributes to or compensates for glomerulosclerosis. METHODS: Stereological disector/fractionator estimates of glomerular number (N(glom)) and average glomerular volume (V(glom)) were obtained on autopsy kidneys of 171 African Americans and 131 whites. Eighty-eight African Americans and 49 whites were identified as hypertensive. Nephrosclerosis was measured morphometrically as the percentage of glomerulosclerosis, proportion of cortical fibrosis and interlobular artery intimal thickness, and analyzed with V(glom) by age, race, gender, body mass index (BMI) and blood pressure. RESULTS: African Americans were more frequently hypertensive (58.5%) than whites (35.8%) and when hypertensive had higher levels of blood pressure (P = 0.02). N(glom) was significantly lower in hypertensive compared with non-hypertensive subjects among white women (P = 0.02) but not white males (P = 0.34) or African American females (P = 0.10) or males (P = 0.41). For each race and gender, glomerulosclerosis, cortical fibrosis and arterial intimal thickening were statistically correlated with age (P < 0.001) and hypertension (P < 0.001) and increased V(glom) with hypertension (P < 0.001) and BMI (P < 0.001). In multivariate analysis, African American race was associated with increased V(glom) (P = 0.01) and arterial intimal thickening (P < 0.01), while interactions between race and blood pressure indicated that the severity of nephrosclerosis including increased V(glom) was linked most directly to hypertension without significant contributions from race. The hypertension-associated enlargement of V(glom) was present with mild degrees of glomerulosclerosis and changed little as the severity of glomerulosclerosis increased. CONCLUSIONS: Glomerular hypertrophy was identified as an integral feature of hypertensive nephropathy and appeared to precede rather than compensate for glomerulosclerosis. An effect of race on V(glom) and arterial intimal thickening seemed to be related to the more frequent and more severe hypertension among African Americans.

Birthweight and fasting glucose and insulin levels: results from the Aboriginal Birth Cohort Study.

OBJECTIVE: To examine the relationships between birthweight, current size, and fasting glucose and fasting insulin levels in Aboriginal adolescents. DESIGN, PARTICIPANTS AND SETTING: Longitudinal prospective study of a Northern Territory Aboriginal birth cohort of 686 Aboriginal babies born at the Royal Darwin Hospital between January 1987 and March 1990, and followed up between December 2006 and January 2008 in over 40 NT locations. MAIN OUTCOME MEASURES: Fasting insulin and glucose levels, adjusted for gestational age, sex and contemporary age. RESULTS: Among the 134 participants with complete data, those with fetal growth restriction (FGR) or low birthweight (LBW) at birth were not overweight at 18 2013s. In these circumstances, birthweight showed a significant positively directed association with fasting glucose levels (P = 0.002). Current weight showed a significant and positively directed association with both fasting insulin (P < 0.001) and fasting glucose levels (P = 0.001), and current height showed a significant and positively directed association with insulin levels (P = 0.006). CONCLUSIONS: Birthweight was only positively associated with fasting glucose levels, with no association with fasting insulin levels. The high-risk combination for type 2 diabetes of LBW or FGR with later overweight or obesity was rare in this adolescent Aboriginal population.

Renal biopsy findings among Indigenous Australians: a nationwide review.

Australia's Indigenous people have high rates of chronic kidney disease and kidney failure. To define renal disease among these people, we reviewed 643 renal biopsies on Indigenous people across Australia, and compared them with 249 biopsies of non-Indigenous patients. The intent was to reach a consensus on pathological findings and terminology, quantify glomerular size, and establish and compare regional biopsy profiles. The relative population-adjusted biopsy frequencies were 16.9, 6.6, and 1, respectively, for Aboriginal people living remotely/very remotely, for Torres Strait Islander people, and for non-remote-living Aboriginal people. Indigenous people more often had heavy proteinuria and renal failure at biopsy. No single condition defined the Indigenous biopsies and, where biopsy rates were high, all common conditions were in absolute excess. Indigenous people were more often diabetic than non-Indigenous people, but diabetic changes were still present in fewer than half their biopsies. Their biopsies also had higher rates of segmental sclerosis, post-infectious glomerulonephritis, and mixed morphologies. Among the great excess of biopsies in remote/very remote Aborigines, females predominated, with younger age at biopsy and larger mean glomerular volumes. Glomerulomegaly characterized biopsies with mesangiopathic changes only, with IgA deposition, or with diabetic change, and with focal segmental glomerulosclerosis (FSGS). This review reveals great variations in biopsy rates and findings among Indigenous Australians, and findings refute the prevailing dogma that most indigenous renal disease is due to diabetes. Glomerulomegaly in remote/very remote Aboriginal people is probably due to nephron deficiency, in part related to low birth weight, and probably contributes to the increased susceptibility to kidney disease and the predisposition to FSGS.

Distribution of volumes of individual glomeruli in kidneys at autopsy: association with physical and clinical characteristics and with ethnic group.

We have demonstrated considerable variability in the volumes of different glomeruli in given individuals (individual glomerular volume: IGV) in a stereologic study of kidneys at forensic autopsy performed to investigate sudden or unexpected death in people without manifest kidney disease. We review some important associations of IGV by subject characteristics and by ethnic groups. IGVs were measured by the Cavalieri method in 30 glomeruli in each of 111 adult males who belonged to 4 ethnic groups, i.e. US Whites, African-Americans, Africans from Senegal, and Australian Aborigines. Correlations of pooled IGV values with certain subject characteristics were evaluated in the US Whites. Pooled IGV data were compared in subjects across the 4 ethnic groups. In US Whites, mean IGV and its variance were greater with higher age, lower nephron number, lower birth weight, and with gross obesity, hypertension and cardiovascular death. In comparisons by ethnic group, mean IGV and IGV ranges were higher in African-Americans and Australian Aborigines than in US Whites and African Senegalese subjects. We conclude that glomerular enlargement with volume heterogeneity marks more advanced age, relative nephron deficiency, lower birth weight, obesity, hypertension, and advanced cardiovascular disease. The findings in African-Americans and Australian Aborigines suggest that larger IGVs and volume heterogeneity might mark populations with accentuated susceptibility to hypertension and kidney disease, but the data need to be further examined in the context of the determining characteristics defined in the US Whites.

CKD in Aboriginal Australians.

Chronic kidney disease (CKD) is one component of a spectrum of chronic disease in Aboriginal Australians. CKD is marked by albuminuria, which predicts renal failure and nonrenal natural death. Rates vary greatly by community and region and are much higher in remote areas. This reflects the heterogeneous characteristics and circumstances of Aboriginal people. CKD is multideterminant, and early-life influences (notably low birth weight), infections (including poststreptococcal glomerulonephritis), metabolic/hemodynamic parameters, and epigenetic/genetic factors probably contribute. CKD is associated intimately with cardiovascular risk. Albuminuria progresses over time, with a high incidence of new onset of pathologic levels of albuminuria in all age groups. All the usual morphologic findings are found in renal biopsy specimens. However, glomerular enlargement is notable in individuals from remote regions, but not those living closer to population centers. Glomerulomegaly probably represents compensatory hypertrophy caused by low nephron number, which probably underlies the accentuated susceptibility to renal disease. In the last decade, health care services have been transformed to accommodate systematic chronic disease surveillance and management. After a relentless increase for 3 decades, rates of Aboriginal people starting renal replacement therapy, as well as chronic disease deaths, appear to be stabilizing in some regions. Official endorsement of these system changes, plus ongoing reductions in the incidence of low birth weight and infections, hold promise for continued better outcomes.

Status of chronic kidney disease prevention programs: International Federation of Kidney Foundation Members 2005/2007.

The International Federation of Kidney Foundations surveyed its members on chronic kidney disease 'prevention' programs in their regions and countries in 2005 and 2007. A profile was developed, representing 28 countries (56% response). Some form of screening activity was reported in 24 of the 28 countries (85.7%). Two countries (7%) had, or anticipated development of, legislated national screening. Programs were conducted by kidney foundations or research groups, and were variously population based, focused on high risk groups or opportunistic. Tests in 63% of responding programs included weight, height, blood pressure, blood glucose, dipstick urinalysis and serum creatinine. Several programs used the USA's Kidney Early Evaluation Program's and International Society of Nephrology's templates. World Kidney Day activities contributed significantly. Stated needs were for more government recognition, firm policies and approaches, and critically, resources. Repeat responders reported progress in 2007, particularly in government interest and education delivery. Despite difficulties, programs are developing in many regions. Most need more resources and some members need substantial and sustained assistance.