DOES NEPHRON NUMBER MATTER IN THE DEVELOPMENT OF KIDNEY DISEASE? The total number of nephrons in normal human kidneys varies over a 10-fold range. This variation in total nephron number leads us to question whether low nephron number increases the risk of renal disease in adulthood. This review considers the available evidence in humans linking low nephron number/reduced nephron endowment and the susceptibility to renal disease. Total nephron number in humans has been directly correlated with birth weight and inversely correlated with age, mean glomerular volume, and hypertension. Low nephron number may be the result of suboptimal nephrogenesis during kidney development and/or loss of nephrons once nephrogenesis has been completed. Low nephron number is frequently, but not always, associated with hypertrophy of remaining glomeruli. This compensatory hypertrophy has also been associated with a greater susceptibility for kidney disease. Three human studies have reported reduced nephron number in subjects with a history of hypertension. This correlation has been ob- served in White Europeans, White Americans (but not African Americans) and Australian Aborigines. Studies in additional populations are required, as well as a greater understand- ing of the fetal environmental and genetic determinants of low nephron number. (Ethn Dis. 2006;16[suppl 2]:S2-40–S2-45) Key Words: Human Nephron Number, Hy- pertension, Birth Weight Rebecca N. Douglas-Denton, BABScHons; Bridgette J. McNamara, BABScHons; Wendy E. Hoy, FRACP; Michael D. Hughson, MD; John F. Bertram, PhD INTRODUCTION The incidence of chronic renal disease, like several other chronic dis- eases, is increasing worldwide. Certain populations appear particularly suscep- tible, including African Americans and Australian Aborigines. The incidence of end stage renal disease (ESRD) in Australian Aborigines is on average 20 times greater than that in White Australians, and in some remote com- munities the incidence is up to 60 times greater. 1 African Americans have 5 times the incidence of ESRD than White Americans. 2 The underlying mechanisms for this increased suscepti- bility are not known, although socio- economic, environmental, and genetic factors are all believed to play a role. An increasing number of studies have focused on the fetal origins of adult diseases, the so-called Barker hypothesis. 3 Adverse events/conditions in utero may cause changes in de- velopment that lead to increased sus- ceptibility to hypertension and cardio- vascular disease in adult life. Numerous animal studies have shown that a pre- natal insult or suboptimal intrauterine conditions compromise organ develop- ment. In most cases the brain is spared at the cost of other organs, particularly the kidney. Reduced nephron number has been demonstrated in many animal models, including models of protein restriction, glucocorticoid exposure, vi- tamin A deficiency, exposure to certain antibiotics, and uterine artery ligation. 4–8 In humans, nephrogenesis is complete before birth. Thus, any deficit in nephron number when birth occurs at term, cannot be compensated by amplified nephrogenesis after birth. In populations where living standards are low or the health of pregnant women is overlooked and birth weights are fre- quently low, fetal kidney development is likely compromised and nephron num- ber is likely to be permanently reduced. In 1988, Brenner and colleagues proposed that individuals with reduced nephron endowment (low nephron number) would be at higher risk for developing hypertension later in life. 9 To date, little research has been con- ducted on the effect of a subopti- mal intrauterine environment on the risk of developing renal disease in adulthood. HUMAN NEPHRON NUMBER In humans, nephrogenesis begins at around 9 weeks of gestation and ceases at 36 weeks gestation, after which time no new nephrons are formed. 10 Unlike several other species, nephrogenesis in humans cannot continue after birth. It has long been accepted that the human kidney contains, on average, one million nephrons. Nephron number in human kidneys has now been studied by several research groups with state-of-the-art, unbiased stereological methods. All studies have reported a previously un- appreciated wide range in human neph- ron number. In their landmark 1992 study, Jens Nyengaard and Thomas Bendtsen studied 37 normal Danish kidneys obtained at autopsy and found a four-fold range in nephron number (331,000 to 1,424,000). 11 Since then, our group has shown an eight-fold range in nephron number in 78 kidneys from Black and White Americans and Aboriginal and White Australians. 12 In 2003, Keller et al. analyzed 20 human kidneys obtained at autopsy in Ger- From the Department of Anatomy and Cell Biology, Monash University, Mel- bourne, Australia (RND-D, BJM, JFB); Cen- tre for Chronic Disease, University of Queensland, Australia (WEH); and Depart- ment of Pathology, University of Mississippi, Jackson, Mississippi, USA (MDH). Address correspondence and reprint requests to John F. Bertram, PhD; De- partment of Anatomy and Cell Biology; School of Biomedical Sciences; PO Box 13C, Monash University; Clayton, Victoria, 3800; Australia; 03-9905-2751; 03-9905- 2766; john.bertram@med.monash.edu.au S2-40 Ethnicity & Disease, Volume 16, Spring 2006