The influence of birthweight, past poststreptococcal glomerulonephritis and current body mass index on levels of albuminuria in young adults: the multideterminant model of renal disease in a remote Australian Aboriginal population with high rates of renal disease and renal failure.

BACKGROUND: Australian Aborigines in remote areas have very high rates of kidney disease, which is marked by albuminuria. We describe a 'multihit' model of albuminuria in young adults in one remote Aboriginal community. METHODS: Urinary albumin/creatinine ratios (ACRs) were measured in 655 subjects aged 15-39 years and evaluated in the context of birthweights, a history of 'remote' poststreptococcal glomerulonephritis (PSGN; ≥5 years earlier) and current body mass index (BMI). Birthweight had been <2.5 kg (low birthweight, LBW) in 25.4% of subjects and 22.8% had a remote history of PSGN. RESULTS: ACR levels rose with age. It exceeded the microalbuminuria threshold in 33.6% of subjects overall (25% of males and 45% of females). In multivariate models, birthweight (inversely), remote PSGN and current BMI were all independent predictors of ACR levels. The effects of birthweight and PSGN and their combination were expressed through amplification of ACR levels in relation to age and around the group median BMI of 20.8 kg/m(2). In people with BMI <20.8 (57.8% of all males and 40.3% of the females), LBW and PSGN alone had minimal effects on ACR, but in combination they strikingly amplified ACR in relation to age. Those with BMI ≥20.8 (which included 42.2% of the males and 59.7% of the females) had higher ACR levels, and both LBW and a PSGN history, separately and in combination, were associated with striking further amplification of ACR in the context of age. CONCLUSION: Much of the great excess of disease in this population is explained by high rates of the early life risk factors, LBW and PSGN. Their effects are expressed through amplification of ACR in the context of increasing age and are further moderated by levels of current body size. Both early life risk factors are potentially modifiable.

The multideterminant model of renal disease in a remote Australian Aboriginal population in the context of early life risk factors: lower birth weight, childhood post-streptococcal glomerulonephritis, and current body mass index influence levels of albuminuria in young Aboriginal adults.

BACKGROUND: Australian Aborigines in remote areas have very high rates of kidney disease, which is marked by albuminuria. We describe a "multihit" model of albuminuria in young adults in one remote Aboriginal community. METHODS: Urinary albumin/creatinine ratios (ACR) were measured in all subjects who volunteered to participate in a community-wide health screen. Subjects for this study were young adults who had birth weights recorded and whose medical records were inspected for a history of post-streptococcal glomerulonephritis (PSGN). Urine ACR levels were evaluated in the context of birth weights, PSGN history and current BMI. RESULTS: 580 subjects (335 males and 245 females) who were aged 18 - 39 years at time of screening and qualified for inclusion. 26% of subjects had birth weights of < 2.5 kg, and the median birth weight was 2.8 kg. 23% of subjects had a remote history of PSGN, all 3 or more years earlier. Median BMI for the group was 21 kg/m2. Urine ACR levels exceeded the microalbuminuria threshold of 3.4 g/mol in 35.5% of subjects. Birth weight (inversely), remote PSGN, and current BMI were all independent predictors of ACR levels. Median levels of ACR were lowest in those with birth weights ≥ 2.5 kg, and no history of PSGN, intermediate in those with either birth weights < 2.5 kg or a history of PSGN, and highest in those with both low birth weights and a PSGN history. ACR levels were higher in those with BMIs above the median values, most notably in those with lower birth weights or a PSGN history or both. INTERPRETATION: Much of the great excess of disease in this population is explained by high rates of the early life risk factors, low birth weight and PSGN. Their effects are expressed through amplification of ACR in the context of increasing age, and are further moderated by levels of current body size. Both early life risk factors are potentially modifiable.

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.

Nephrocalcinosis (enamel renal syndrome) caused by autosomal recessive FAM20A mutations.

BACKGROUND/AIMS: Calcium homeostasis requires regulated cellular and interstitial systems interacting to modulate the activity and movement of this ion. Disruption of these systems in the kidney results in nephrocalcinosis and nephrolithiasis, important medical problems whose pathogenesis is incompletely understood. METHODS: We investigated 25 patients from 16 families with unexplained nephrocalcinosis and characteristic dental defects (amelogenesis imperfecta, gingival hyperplasia, impaired tooth eruption). To identify the causative gene, we performed genome-wide linkage analysis, exome capture, next-generation sequencing, and Sanger sequencing. RESULTS: All patients had bi-allelic FAM20A mutations segregating with the disease; 20 different mutations were identified. CONCLUSIONS: This autosomal recessive disorder, also known as enamel renal syndrome, of FAM20A causes nephrocalcinosis and amelogenesis imperfecta. We speculate that all individuals with biallelic FAM20A mutations will eventually show nephrocalcinosis.