Human nephron number: implications for health and disease

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.

Weight for Gestational Age as a Baseline Predictor of Kidney Function in Adulthood

The role of the kidney in the pathogenesis of hypertension has long been established, although recent studies challenge renal hegemony and suggest an important role for vascular cells as well (1,2). In recent years, the formulation has expanded and now includes the concept that chronic hypertension and kidney disease are also related to events that occur during the prenatal period and usually result in low birth weight (LBW). A recent overview considered the role of fetal programming in the development of adult kidney disease and hypertension (3). The aim of this review is to present further evidence to support an association between LBW and the increased prevalence of hypertension as well as progression toward chronic kidney disease (CKD) in adult life. Various potential mechanisms for this association are discussed, specifically the low nephron number (LNN) hypothesis and related cellular and molecular mechanisms that have been proposed. LBW infants are defined as infants who weigh ≤2500 g at birth. Infants who are delivered before 37 wk from the first day of the last menstrual period are termed preterm. The LBW infant population can be divided into preterm, appropriate for gestational age (AGA), or small for gestational age (SGA). The predominant cause of LBW infants in the United States is preterm birth, whereas in developing countries, the cause is often intrauterine growth restriction (IUGR). During the year 2004, 8.1% of births in the United States were LBW, and more than half of these were preterm. During the past two decades, there has been an increase in the prevalence of LBW as higher risk pregnancies progress to term and postnatal survival improves (4) (Figure 1). Figure 1. Percentage of infants who were born preterm and percentage who were born with low birth weight (LBW; defined in text): United States, 1990, 1995, 2000, …

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). 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. 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. 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.

Is there an association between level of adult blood pressure and nephron number or renal filtration surface area?

Recent studies have reported that total nephron number varies widely in human kidneys and some racial groups with low nephron number have a higher incidence of hypertension and kidney disease. Importantly, nephrogenesis normally reaches completion at about 34-36 weeks gestation, with no new nephrons formed for the lifetime in humans after this time. Although the loss of glomeruli varies among individuals due to aging, blood pressure, or additional inducers of kidney injury, much of the variation in nephron number is nowadays thought to be present at birth. According to the hyperfiltration hypothesis, this subsequent nephron loss results in compensatory hyperfiltration and/or hypertension of remaining glomeruli, thereby contributing to increased susceptibility to systemic hypertension. However, recent studies have suggested that the association between a low nephron number and systemic hypertension is not a universal finding. In most studies to date, nephron counts were performed on kidneys obtained at autopsy. Several recent studies have attempted to estimate nephron number in living human subjects, but further work is required to obtain accurate and precise estimates of nephron number using these noninvasive methods. Longitudinal studies in living humans have the potential to reveal associations between nephron number and hypertension/renal pathology.

Low Birth Weight and Kidney Function: Is There a Relationship and Is it Determined by the Intrauterine Environment?

A novel genetic model to explore the Brenner hypothesis: Linking nephron endowment and number with hypertension

The relationship between low birth weight (LBW) and subsequent increased risk of hypertension and renal disease in humans is now well established. The initial hypothesis suggested that an adverse intrauterine environment, reflected by LBW, would impact renal development, resulting in a low nephron number and predisposition to hypertension and renal disease. Studies in various populations have shown a direct correlation between birth weight and nephron number, and in infants, nephron numbers are reduced in those of LBW. Among Caucasian and Australian Aboriginal adults, lower nephron numbers are associated with higher blood pressure, whereas higher nephron numbers appear to protect against hypertension. LBW is currently the best clinical surrogate for low nephron number and has been independently associated with higher blood pressure from infancy through to adulthood in many populations, as well as an increased risk of proteinuria, reduced glomerular filtration rate, chronic kidney disease, and end-stage renal disease in later life. The pathophysiology is analogous to that in other chronic kidney diseases where surviving nephrons are subject to hyperfiltration early on, resulting in glomerular hypertrophy, proteinuria, and eventually, especially in the setting of other renal disease risk factors, glomerulosclerosis, and loss of renal function. Mean nephron number varies by up to 13-fold in certain populations, however, therefore nephron number is unlikely the sole developmentally programmed risk factor for renal disease in later life, but may be a first ‘hit’ impacting an individual’s susceptibility to or resistance to superimposed renal injury. Augmentation of nephron number perinatally has only been addressed in experimental settings. In humans, therefore optimization of nephron number is likely best achieved through good perinatal care and adequate postnatal nutrition. Cardiovascular disease and diabetes are also developmentally programmed and therefore likely coexist in subjects with LBW and low nephron numbers. Awareness of an individual’s birth weight should serve to highlight the possibility of low nephron number and potential risk for future hypertension and renal disease, which may be attenuated by optimization of early nutrition, lifestyle choices, and management of other risk factors for renal disease.

The relationship between low birth weight (LBW), being born small for gestational age (SGA) or preterm and subsequent increased risk of hypertension and renal disease in humans is now well established. The initial hypothesis suggested that an adverse intrauterine environment, reflected by LBW, would impact renal development, resulting in a low nephron number and predisposition to hypertension and renal disease. Studies in various populations have shown a direct correlation between birth weight and gestational age and nephron number, and in infants, nephron numbers are reduced in those of LBW or born preterm. Among Caucasian and Australian Aboriginal adults, lower nephron numbers are associated with higher blood pressure, whereas higher nephron numbers appear to protect against hypertension. LBW, SGA, and preterm birth are currently the best clinical surrogates for low nephron number and have been independently associated with higher blood pressure from infancy through to adulthood in many populations, as well as an increased risk of proteinuria, reduced glomerular filtration rate, chronic kidney disease, and end-stage renal disease in later life. The proposed pathophysiology is analogous to that in other chronic kidney diseases where surviving nephrons are subject to hyperfiltration early on, resulting in glomerular hypertrophy, proteinuria, and eventually, especially in the setting of other renal disease risk factors, glomerulosclerosis, and loss of renal function. Mean nephron number varies by up to 13-fold in certain populations, however, therefore nephron number is unlikely the sole developmentally programmed risk factor for renal disease in later life, but may be a first ‘hit’ impacting an individual’s susceptibility to or resistance to superimposed renal injury. Augmentation of nephron number perinatally has only been addressed in experimental settings. In humans, optimization of nephron number is likely best achieved through good perinatal care and adequate postnatal nutrition. Cardiovascular disease and diabetes are also developmentally programmed and therefore likely coexist in subjects with LBW, SGA, or born preterm, and low nephron numbers. Awareness of an individual’s birth weight and gestational age should serve to highlight the possibility of low nephron number and potential risk for future hypertension and renal disease, which may be attenuated by optimization of early nutrition, lifestyle choices, and management of other risk factors for renal disease.

Glomerular hypertrophy has been described in several populations at high risk of chronic kidney disease. Total nephron (and thereby glomerular) number (N(glom)) varies widely in normal adult human kidneys and is generally inversely correlated with mean glomerular volume (V(glom)). However, little is known about the range of individual glomerular volumes (IV(glom)) within single human kidneys and the association with N(glom). The aim of the present study was to estimate IV(glom) in Caucasian and African Americans and identify any associations between heterogeneity in IV(glom) and nephron number. Using unbiased stereological techniques, IV(glom) was determined for 30 glomeruli in each of 24 adult male kidneys from Jackson, MS, USA (12 Caucasian and 12 African American). Half of each group had 'high' N(glom) (>1.2 million nephrons per kidney) and the other half had 'low' N(glom) (<600 000). Caucasians with high N(glom) had a relatively homogeneous distribution of IV(glom) as well as a relatively low mean value, while those with low N(glom) had much greater heterogeneity of IV(glom), as well as a larger IV(glom) (P < 0.0001) compared with those with high N(glom). This disparity was not apparent in African Americans, however, where subjects with both high and low N(glom) showed substantial heterogeneity in IV(glom) and larger mean values (P = 0.95). High N(glom) appeared to protect against glomerular enlargement and volume heterogeneity in Caucasians. However, substantial variation in IV(glom) and net enlargement in glomerular size in African Americans with high nephron numbers suggest that additional forces, independent of low N(glom), are driving glomerular enlargement and heterogeneity.

Food intake and the kidney: The right amounts at the right times

Nephron endowment refers to the total number of nephrons an individual is born with, as nephrogenesis in humans is completed by 36 weeks of gestation and no new nephrons are formed post-birth. Nephron number refers to the total number of nephrons measured at any point in time post-birth. Both genetic and environmental factors influence both nephron endowment and number. Understanding how specific genes or factors influence the process of nephrogenesis and nephron loss or demise is important as individuals with lower nephron endowment or number are thought to be at a higher risk of developing renal or cardiovascular disease. Understanding how environmental exposures over the course of a person's lifetime affects nephron number will also be vital in determining future disease risk. Thus, the ability to assess whole kidney nephron number quickly and reliably is a basic experimental requirement to better understand mechanisms that contribute to or promote nephrogenesis or nephron loss. Here, we describe the acid maceration method for the estimation of whole kidney nephron number based on the procedure described by Damadian, Shawayri, and Bricker, with slight modifications. The acid maceration method provides fast and reliable estimates of nephron number (as assessed by counting glomeruli) that are within 5% of those determined using more advanced, albeit expensive, methods such as magnetic resonance imaging. Moreover, the acid maceration method is an excellent high-throughput method to assess nephron number in large numbers of samples or experimental conditions.

reply: In aging male Wistar rats, renal injury develops spontaneously ([2][1]). It is gratifying that Dr. Schreuder is intrigued by our recent finding of a protective effect of early postnatal protein restriction (i.e., during lactation) on the spontaneous development of renal injury in male Wistar

Congenital Oligonephropathy and the Etiology of Adult Hypertension and Progressive Renal Injury