Wendy E. Hoy

Effect of fetal and child health on kidney development and long-term risk of hypertension and kidney disease

Developmental programming of non-communicable diseases is now an established paradigm. With respect to hypertension and chronic kidney disease, adverse events experienced in utero can affect development of the fetal kidney and reduce final nephron number. Low birthweight and prematurity are the most consistent clinical surrogates for a low nephron number and are associated with increased risk of hypertension, proteinuria, and kidney disease in later life. Rapid weight gain in childhood or adolescence further compounds these risks. Low birthweight, prematurity, and rapid childhood weight gain should alert clinicians to an individuals lifelong risk of hypertension and kidney disease, prompting education to minimise additional risk factors and ensuring follow-up. Birthweight and prematurity are affected substantially by maternal nutrition and health during pregnancy. Optimisation of maternal health and early childhood nutrition could, therefore, attenuate this programming cycle and reduce the global burden of hypertension and kidney disease in the future.

Biomarkers in chronic kidney disease: a review

Chronic kidney disease (CKD) is a major public health problem. The classification of CKD by KDOQI and KDIGO and the routine eGFR reporting have resulted in increased identification of CKD. It is important to be able to identify those at high risk of CKD progression and its associated cardiovascular disease (CVD). Proteinuria is the most sensitive marker of CKD progression in clinical practice, especially when combined with eGFR, but these have limitations. Hence, early, more sensitive, biomarkers are required. Recently, promising biomarkers have been identified for CKD progression and its associated CVD morbidity and mortality. These may be more sensitive biomarkers of kidney function, the underlying pathophysiological processes, and/or cardiovascular risk. Although there are some common pathways to CKD progression, there are many primary causes, each with its own specific pathophysiological mechanism. Hence, a panel measuring multiple biomarkers including disease-specific biomarkers may be required. Large, longitudinal observational studies are needed to validate candidate biomarkers in a broad range of populations prior to implementation into routine CKD management. Recent renal biomarkers discovered include neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, and liver-type fatty acid-binding protein. Although none are ready for use in clinical practice, it is timely to review the role of such biomarkers in predicting CKD progression and/or CVD risk in CKD.

Nephron Number, Hypertension, Renal Disease, and Renal Failure

Essential hypertension is one of the most common diseases in the Western world, affecting about 26.4% of the adult population, and it is increasing (1). Its causes are heterogeneous and include genetic and environmental factors (2), but several observations point to an important role of the kidney in its genesis (3). In addition to variations in tubular transport mechanisms that could, for example, affect salt handling, structural characteristics of the kidney might also contribute to hypertension. The burden of chronic kidney disease is also increasing worldwide, due to population growth, increasing longevity, and changing risk factors. Although single-cause models of disease are still widely promoted, multideterminant or multihit models that can accommodate multiple risk factors in an individual or in a population are probably more applicable (4,5). In such a framework, nephron endowment is one potential determinant of disease susceptibility. Some time ago, Brenner and colleagues (6,7) proposed that lower nephron numbers predispose both to essential hypertension and to renal disease. They also proposed that hypertension and progressive renal insufficiency might be initiated and accelerated by glomerular hypertrophy and intraglomerular hypertension that develops as nephron number is reduced (8). In this review, we summarize data from recent studies that shed more light on these hypotheses. The data supply a new twist to possible mechanisms of the Barker hypothesis, which proposes that intrauterine growth retardation predisposes to chronic disease in later life (9). The review describes how nephron number is estimated and its range and some determinants and morphologic correlates. It then considers possible causes of low nephron numbers. Finally, associations of hypertension and renal disease with reduced nephron numbers are considered, and some potential clinical implications are discussed.

Accelerated Maturation and Abnormal Morphology in the Preterm Neonatal Kidney

Nephrogenesis is ongoing at the time of birth for the majority of preterm infants, but whether postnatal renal development follows a similar trajectory to normal in utero growth is unknown. Here, we examined tissue collected at autopsy from 28 kidneys from preterm neonates, whose postnatal survival ranged from 2 to 68 days, including 6 that had restricted intrauterine growth. In addition, we examined kidneys from 32 still-born gestational controls. We assessed the width of the nephrogenic zone, number of glomerular generations, cross-sectional area of the renal corpuscle, and glomerular maturity and morphology. Renal maturation accelerated after preterm birth, with an increased number of glomerular generations and a decreased width of the nephrogenic zone in the kidneys of preterm neonates. Of particular concern, compared with gestational controls, preterm kidneys had a greater percentage of morphologically abnormal glomeruli and a significantly larger cross-sectional area of the renal corpuscle, suggestive of renal hyperfiltration. These observations suggest that the preterm kidney may have fewer functional nephrons, thereby increasing vulnerability to impaired renal function in both the early postnatal period and later in life.

Nephron number, glomerular volume, renal disease and hypertension

Purpose of reviewTo discuss studies evaluating associations of glomerular number (Nglom) and glomerular volume with hypertension and kidney disease. Important findingsThe association of low Nglom with hypertension and renal insufficiency was described in the 1930s. Many investigators have noted loss of glomeruli with age, with most disappearing entirely, and have proposed that hypertension follows. In a recent German study, hypertensive patients had fewer glomeruli and larger mean glomerular volumes than nonhypertensive people. Among the 10-fold range of Nglom in our multiracial autopsy series, the lowest were in Australian Aborigines, who have the highest rates of renal failure. Nglom fell with age. There was a five-fold range in mean glomerular volume and considerable heterogeneity in individual glomerular volumes within a patient. Larger mean glomerular volume and greater individual glomerular volume heterogeneity correlated with lower Nglom, larger body size, hypertension, and black race. Hypertension increased with age and was marked by glomerular enlargement, intimal thickening and higher rates of glomerulosclerosis. In whites and Aborigines, but not in US blacks, lower Nglom was associated with hypertension, while robust numbers were highly protective. SummaryHigher mean glomerular volume and individual glomerular volume heterogeneity mark glomerular stress. Low Nglom is an important determinant of hypertension and renal disease. Many ‘missing’ nephrons have probably been lost during life, leaving little trace. Additional factors contribute to high rates of hypertension in blacks.

Waist circumference, body mass index, hip circumference and waist-to-hip ratio as predictors of cardiovascular disease in Aboriginal people.

Objective: To investigate waist circumference (WC), waist–hip ratio, hip circumference and body mass index (BMI) as risk factors for cardiovascular disease in Aboriginal Australians.Methods: This cohort study included 836 adults aged 20–74 y in a remote Aboriginal community. WC, waist–hip ratio, hip circumference and BMI were obtained from a screening program. The participants were followed for up to 10 y for cardiovascular events. A Cox regression model was used to calculate the rate ratio (RR) and 95% confidence interval (CI) for the first-ever cardiovascular event (fatal and nonfatal).Results: RRs for the first-ever cardiovascular event were 1.31 (95% CI: 1.11, 1.54), 1.29 (95% CI: 1.09,1.53), 1.28 (95% CI: 1.08, 1.52) and 1.10 (95% CI: 0.93, 1.30) per standard deviation increase in WC, BMI, hip circumference and waist–hip ratio, respectively, after adjustment for diabetes mellitus, total cholesterol, systolic blood pressure and smoking status. WC, BMI and hip circumference were significantly associated with cardiovascular risk, independent of other cardiovascular risk factors. Dividing each of the four parameters into quartiles, WC had the highest likelihood statistics (12.76) followed by BMI (11.45), hip circumference (10.57) and waist–hip ratio (3.15) for predicting first CV events.Conclusion: WC, BMI and hip circumference are associated with cardiovascular outcome, independent of traditional risk factors. However, WC appears to be a better predictor for cardiovascular risk than other parameters. Waist–hip ratio is not as useful as other measurements.Sponsorship: This research was funded by the National Health & Medical Research Council of Australia (193316).

A Common RET Variant Is Associated with Reduced Newborn Kidney Size and Function

Congenital nephron number varies five-fold among normal humans, and individuals at the lower end of this range may have an increased lifetime risk for essential hypertension or renal insufficiency; however, the mechanisms that determine nephron number are unknown. This study tested the hypothesis that common hypomorphic variants of the RET gene, which encodes a tyrosine kinase receptor critical for renal branching morphogenesis, might account for subtle renal hypoplasia in some normal newborns. A common single-nucleotide polymorphism (rs1800860 G/A) was identified within an exonic splicing enhancer in exon 7. The adenosine variant at mRNA position 1476 reduced affinity for spliceosome proteins, enhanced the likelihood of aberrant mRNA splicing, and diminished the level of functional transcript in human cells. In vivo, normal white newborns with an rs1800860(1476A) allele had kidney volumes 10% smaller and cord blood cystatin C levels 9% higher than those with the rs1800860(1476G) allele. These findings suggest that the RET(1476A) allele, in combination with other common polymorphic developmental genes, may account for subtle renal hypoplasia in a significant proportion of the white population. Whether this gene variant affects clinical outcomes requires further study.

A health profile of adults in a Northern Territory Aboriginal community, with an emphasis on preventable morbidities

Abstract: We conducted a brief health survey of adults in an isolated Northern Territory Aboriginal community, whose standardised mortality rates are the second highest in Australia. The screen revealed high rates of smoking and excessive drinking, of preventable infections and their sequelae, and of hypertension, insulin resistance, diabetes and renal disease. The infectious morbidities were more pronounced and the life–style morbidities almost entirely new since a health screen in 1957. Most morbidities were strongly associated with identifiable risk factors, such as overweight, smoking, excessive drinking, skin sores and scabies, all of which which are amenable to modification. Problems with food supply and pricing, poor food choices and diversion of money to cigarettes, beer and gambling all contributed to poor nutrition. Low birthweight probably compounds the risk for serious adult disease associated with these environmental influences. This profile highlights the failure of current systems to deal with health needs. Improvements in infrastructure, education and employment, and reinvigoration of preventive and primary health care programs, assumption of responsibility for health by the community and by individuals themselves, and better management of existing morbidities are essential to rectifying this shameful situation.

Exploring the Pathways Leading from Disadvantage to End-Stage Renal Disease for Indigenous Australians

Indigenous Australians are disadvantaged, relative to other Australians, over a range of socio-economic and health measures. The age- and sex-adjusted incidence of end-stage renal disease (ESRD)--the irreversible preterminal phase of chronic renal failure--is almost nine times higher amongst Indigenous than it is amongst non-indigenous Australians. A striking gradient exists from urban to remote regions, where the standardised ESRD incidence is from 20 to more than 30 times the national incidence. We discuss the profound impact of renal disease on Indigenous Australians and their communities. We explore the linkages between disadvantage, often accompanied by geographic isolation, and both the initiation of renal disease, and its progression to ESRD. Purported explanations for the excess burden of renal disease in indigenous populations can be categorised as: primary renal disease explanations;genetic explanations;early development explanations; and socio-economic explanations. We discuss the strengths and weaknesses of these explanations and suggest a new hypothesis which integrates the existing evidence. We use this hypothesis to illuminate the pathways between disadvantage and the human biological processes which culminate in ESRD, and to propose prevention strategies across the life-course of Indigenous Australians to reduce their ESRD risk. Our hypothesis is likely to be relevant to an understanding of patterns of renal disease in other high-risk populations, particularly indigenous people in the developed world and people in developing countries. Furthermore, analogous pathways might be relevant to other chronic diseases, such as diabetes and cardiovascular disease. If we are able to confirm the various pathways from disadvantage to human biology, we will be better placed to advocate evidence-based interventions, both within and beyond the scope of the health-care system, to address the excess burden of renal and other chronic diseases among affected populations.

Associations of Glomerular Number and Birth Weight With Clinicopathological Features of African Americans and Whites

BACKGROUND Hypertension and its cardiovascular complications affect African Americans more severely than whites, a disparity variously ascribed to low birth weight, low glomerular number, an exaggerated arteriolonephrosclerotic blood pressure response, and inflammation-induced oxidative stress. STUDY DESIGN Case series. SETTING AND PARTICIPANTS Autopsy kidneys of 107 African Americans and 87 whites aged 18 to 65 years at a single medical center between 1998 and 2005. Excluded were persons with known premorbid kidney disease; pathological findings of severe arterioarteriolonephrosclerosis, nodular and diffuse diabetic glomerulosclerosis, or nonischemic cardiomyopathy. PREDICTORS & OUTCOMES Associations of: (1) race, age, sex, birth weight, obesity, and glomerular number (predictors) with hypertension and death from coronary artery (CAD) and cerebrovascular disease (CVD; outcomes); and (2) age, blood pressure, and race (predictors) with arteriolonephrosclerotic changes, including chronic tubulointerstitial inflammation (outcomes). MEASUREMENTS Hypertension ascertained from chart review and heart weight. Cause of death determined from chart review and autopsy findings. Birth weight obtained from birth records (115 persons). Total glomerular number (N(glom)) estimated by using the dissector/fractionator technique. Arteriolosclerosis, glomerulosclerosis, cortical fibrosis, and chronic inflammation by using CD68 density were measured morphometrically. RESULTS 59 African Americans (55%) and 32 whites (37%) were classified as hypertensive. CAD and CVD were the cause of death in 64 (33%) and 18 persons (9%), respectively. By using multiple linear regression, birth weight (P < 0.001) and sex (P < 0.01), but not race (P = 0.3) or age (P = 0.2), predicted N(glom) (P < 0.001; adjusted r(2) = 0.176). Hypertension was associated with African American race (P = 0.04), older age (P < 0.001), and male sex (P = 0.01), but not with N(glom) (P = 0.9), body mass index (P = 0.9), or birth weight (P = 0.4). Hypertension was the only significant factor associated with CAD and CVD (P < 0.001 for both). Interactions of age and blood pressure with race showed that although African Americans had more severe hypertension (P < 0.001) and arteriolosclerosis (P = 0.01) at a younger age than whites, there were no significant racial differences in degrees of arteriolosclerosis, glomerulosclerosis, cortical fibrosis, or CD68 density for any level of increased blood pressure. LIMITATIONS The study is observational and descriptive. CONCLUSIONS The more severe hypertension found in African Americans could not be attributed to racial differences in N(glom) or birth weight. CAD and CVD death and increased arteriolonephrosclerosis, including CD68 density, were determined by using blood pressure without a significant interacting contribution from race.