It has been proposed that "nephron underdosing," i.e., a lownumber of nephrons at the time of birth, is linked to essentialhypertension and a greater propensity to develop progressiveloss of renal function after renal injury. This hypothesis wasconfirmed recently by examining the number of glomeruli in patientswith essential hypertension. The mechanisms through which alow number of nephrons causes hypertension have not been clarified,but it is likely that functional changes in postglomerular segmentsof the nephron, e.g., handling of sodium, play an importantrole. Neonatal uninephrectomy increases BP, renders BP saltsensitive, and renders the kidney more susceptible to damage.Apart from genetic factors, fetal/maternal malnutrition duringpregnancy seems to play an important role in the pathogenesisof nephron underdosing. Furthermore, intrauterine programmingduring organogenesis, e.g., by hyperglycemia, seems to be important:In animal experiments, offspring of either hyperglycemic ordiabetic mothers have fewer nephrons.
More than a decade ago, Brenner (1) proposed the hypothesisthat a low number of glomeruli at birth ("nephron underdosing")causes hypertension and after injury renders the kidney moresusceptible to renal damage and progressive loss of renal function.This hypothesis was tested recently by comparing the kidneysof 10 matched control subjects with those of 10 white victimsof accidents who had a history of hypertension and left ventricularhypertrophy. Stereologic analysis documented that in hypertensiveindividuals, the number of glomeruli was diminished and (presumablyas a compensatory effort to minimize the deviation of filtrationsurface) the volume of glomeruli was increased (2). Althoughit is currently unclear to what extent the findings in thissmall sample can be extrapolated to essential hypertension ingeneral, the observation is of considerable interest becauseit opens new perspectives.
First, genes that operate in organogenesis (e.g., PAX, WT1)may be involved in the genesis of hypertension. In this context,it is of interest that a structural abnormality (brachydactyly)has been shown in a genetic form of hypertension closely resemblingessential hypertension (3); furthermore, rarefaction of skincapillaries has been documented both in patients with essentialhypertension (4) and even in offspring of patients with essentialhypertension (5). Second, numerous findings point to a roleof intrauterine factors in the development of "nephron underdosing,"so to some extent, essential hypertension may also be the consequenceof intrauterine problems.
It has been argued that it is unlikely that nephron underdosingcauses hypertension because uninephrectomy for live kidney donationis not associated with hypertension in the donor (6). This objectioncertainly does not disprove the hypothesis of Brenner (1). First,long-term follow-up of live kidney donor showed that some hypertensionmay be seen (7,8). Furthermore, experimental data indicate thatneonatal and adult nephrectomy differ with respect to effectson BP (9), potentially suggesting that the hypertensinogeniceffect is demonstrable only during a sensitive phase.
It is perhaps also a simplifying assumption that the low glomerularnumber per se accounts for the increase in BP. Such an explanationis not satisfactory, because rough estimates of the total filteringsurface indicate that glomerular enlargement almost completelycompensates for the low number of glomeruli, thus ensuring analmost normal filtration surface. Preliminary experimental dataalso suggest that it is potentially not a low glomerular numberper se but associated developmentally programmed changes inthe function, particularly sodium reabsorption of postglomerularnephron segments that are involved in the genesis of hypertension(10).
Potential Causes of Nephron Underdosing: Maternal/Fetal Malnutrition
There is ample evidence that essential hypertension is to alarge extent explained by genetic factors. In this context,it is also of interest that nephron numbers are low in hypertension-pronerat strains such as hypertension prone Milan rats and spontaneouslyhypertensive rats (11).
Environmental factors that operate during the intrauterine phase,particularly during organogenesis, seem to play an additionalrole (12,13). Such factors include the action of toxins suchas gentamycin, cyclosporin A, vitamin A/retinoid deficiency,and smoking. Of particular interest in the context of the presentcommunication are findings indicating that intrauterine malnutritionbecause of placental dysfunction or poor maternal health aswell as hyperglycemia/diabetes cause lower numbers of nephrons(14).
Manalich et al. (15) examined 35 neonates and counted the glomeruliin coronal sections of the renal cortex. They found fewer andbigger nephrons in the kidney of newborns with low birth weight.They also found an almost four-fold increase in glomerular volumein newborns with low birth weight. The correlation between birthweight and glomerular number was very tight (r = 0.87). In arecent autopsy study on adults, Hughson et al. (16) found alinear relationship between glomerular number and birth weightas well. Again, a strong inverse relation was noted betweenglomerular number and glomerular volume.
Although the relation between low birth weight and glomerularnumbers has been well documented (15,16), its relation to hypertension(and high cardiovascular risk profile) in adults, that had beenproposed by Barker et al. (17), has not been confirmed consistently.Nevertheless, in the study by Hardy et al. (18) on 3634 individualswho were born in 1946, those with a birth weight >4000 ghad at 53 yr a mean systolic pressure of 136.5 mmHg, whereasthose with a birth weight <2500 g had a systolic pressureof 143 mmHg.
In experimental animals, streptozotocin-induced diabetes causesa highly significant reduction of glomerular numbers in theoffspring of diabetic mothers (13,19). Insulin plays an importantrole in glomerulogenesis as suggested by the observation thatreduced bioavailability of IGF, e.g., by overexpression of IGFbinding proteins or conditional transgene expression of IGFbpin pups, led to lower nephron numbers. Furthermore, in cultureexperiments, addition of IGF2 or IGF2-receptor sense or antisenseoligonucleotides stimulated and inhibited in vitro nephrogenesis,respectively (19,20). In a rat strain with inborn reductionof nephron numbers, the MWF strain, the nephron number was lessby 31% compared with Wistar rats, and this was associated withdiminished IGF2-receptor expression, underlining the importantrole of IGF in nephrogenesis.
Nephron Underdosing and Propensity to Glomerular Injury
It has been proposed that fewer numbers of glomeruli lead toa higher single nephron GFR so that eventually such hyperfilteringglomeruli develop focal glomerulosclerosis spontaneously andparticularly after injury (21,22). This concept is supportedby the results of animal experiments. Neonatal uninephrectomyin Sprague-Dawley rats caused an increase in glomerular volume,development of salt-sensitive hypertension, proteinuria, andglomerular scarring (9). The concept is also plausible in viewof the fact that postmitotic podocytes are the main, althoughnot only, target cells of glomerular injury. In large glomeruli,each podocyte has to cover an ever-enlarging domain so thatthe podocyte eventually covers an excessively large domain.The podocyte is no longer able to prevent the sequence of denudationof the basal membrane, synechy formation by fusion of the basalmembrane with the parietal Bowman capsule, and eventually glomerulosclerosis.This postulate would also be in line with observations of Milleret al. (22) that uninephrectomy caused relatively more albuminuriaand glomerulosclerosis in uninephrectomized compared with sham-operatedrats when both groups received an infusion of angiotensin II.
In a number of minorities, e.g., Australian aborigines (23),Pima Indians (24), and blacks (although the last has remainedcontroversial [16,25]), larger glomeruli have been found. Thisfinding was interpreted as an indication of reduced nephronnumbers and linked to the high predisposition to salt-sensitivehypertension in these minorities. There may be an analogy toanimal experiments in which neonatal uninephrectomy renderedBP more salt sensitive (9).
Both experimental and clinical observations indicate that lownephron numbers are a risk factor for hypertension and cardiovasculardisease. Recently, some potentially remediable factors thatoperate during the intrauterine period and determine pathologyin adult life have been identified and will hopefully lead ultimatelyto rational strategies of intervention.
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Abstract
Introduction
