Susan A. Mott

The early development of the kidney and implications for future health.

The kidney is a relative newcomer among the organ systems for which relevance of the developmental origins hypothesis has been explored. Nephrology is a young discipline, to which epidemiologic principles have only been recently applied, and although the availability of renal replacement therapy in westernized countries has created a large group of people with end stage renal disease who can be studied in retrospect, attention has only recently focused on the vastly greater numbers of people with earlier stages of chronic kidney disease, and their accentuated cardiovascular risk. Development of the human kidney is influenced by genetic and epigenetic factors, by maternal nutritional status, maternal stature and the intrauterine environment, the length of gestation, the neonatal course and by postnatal nutrition. Many factors that influence kidney development also influence other developing organ systems. This paper summarizes some of the current knowledge and the implications of kidney development for future health, much of which have also been described in other recent reviews.

Renal biopsy findings among Indigenous Australians: a nationwide review

Australias 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 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.

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.

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 (Nglom) and average glomerular volume (Vglom) 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 Vglom 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). Nglom 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 Vglom with hypertension (P < 0.001) and BMI (P < 0.001). In multivariate analysis, African American race was associated with increased Vglom (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 Vglom was linked most directly to hypertension without significant contributions from race. The hypertension-associated enlargement of Vglom 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 Vglom and arterial intimal thickening seemed to be related to the more frequent and more severe hypertension among African Americans.

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.

Relationships between birthweight and biomarkers of chronic disease in childhood: Aboriginal birth cohort study 1987-2001

Reports of relationships between lower birthweight and later chronic diseases are mainly from populations with low rates of low birthweight (LBW) and growth-restricted births. A prospective study of an Australian Aboriginal birth cohort with a mean birthweight of 3050 g (SD 630), 16% LBW and 28% fetal growth restriction was used to examine the relationships between birthweight and selected biomarkers of chronic adult disease. At a mean age of 11.4 years (range 8.9-14), the mean weight was 35.7 kg (SD 11.8) and the mean height was 143.8 cm (SD 10.6). Using the Centers for Disease Control and Prevention (CDC) 2000 growth references, weight and height-for-age z-scores were -0.8 (SD 1.4) and -0.5 (SD 1.07) respectively and using World Health Organisation criteria, 19% of children were classified as underweight (weight for age Z-score <2.0). The relationships between birthweight and blood pressure (n = 475), total cholesterol (n = 461), Apolipoprotein A-1 (n = 343), Apolipoprotein B (n = 390), respiratory function tests (n = 427), kidney size determined by ultrasound (n = 446), urinary albumin/creatinine ratio (n = 420) and fasting triglycerides (n = 281), insulin (n = 272) and glucose (n = 279) were examined using regression models adjusted for sex, gestational age, current age and puberty status. In this population with high rates of fetal growth restriction at birth and an excess of under-nutrition at age 11 years we found that birthweight had a negative relationship with child blood pressure only, while current child weight was positively related to blood pressure, total cholesterol, Apolipoprotein B, respiratory function tests, kidney size, and fasting triglycerides, insulin and glucose.

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.

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.

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.