Background A diminished number of nephrons has been proposedas one of the factors contributing to the development of primaryhypertension.
Methods To test this hypothesis, we used a three-dimensionalstereologic method to compare the number and volume of glomeruliin 10 middle-aged white patients (age range, 35 to 59 years)with a history of primary hypertension or left ventricular hypertrophy(or both) and renal arteriolar lesions with the number and volumein 10 normotensive subjects matched for sex, age, height, andweight. All 20 subjects had died in accidents.
Results Patients with hypertension had significantly fewer glomeruliper kidney than matched normotensive controls (median, 702,379vs. 1,429,200). Patients with hypertension also had a significantlygreater glomerular volume than did the controls (median, 6.50x10–3mm3 vs. 2.79x10–3 mm3; P<0.001) but very few obsolescentglomeruli.
Conclusions The data support the hypothesis that the numberof nephrons is reduced in white patients with primary hypertension.
Primary hypertension is very common, but its pathogenesis remainselusive. The cause is presumably heterogeneous, though severalobservations point to the kidney as involved in the genesisof primary hypertension. Cross-transplantation experiments1,2,3suggest that hypertension "travels with the kidney," in thathypertension will develop in the normotensive recipient of akidney genetically programmed for hypertension. Patients withrenal failure who receive renal allografts from donors who havea history of cerebral hemorrhage and thus, most likely, hypertensiontend to have higher blood-pressure values than recipients oftransplants from normotensive donors.4 Curtis et al.5 reportedthat patients who had dialysis-dependent renal failure as aresult of hypertension despite the absence of primary renaldisease became normotensive after receiving allografts fromnormotensive donors, provided the new kidneys functioned well.
It has been proposed that a low number of nephrons increasesthe risk of both hypertension and progressive renal disease.6This hypothesis was based on observations that rat strains witha high complement of nephrons were less susceptible to progressiverenal disease.7 Conversely, in animals and humans, a reductionin the number of nephrons is associated with hypertension andan increased risk of progressive renal disease.8 The predispositionof some racial and ethnic groups to hypertension and progressiverenal disease has been ascribed to renal problems. Indeed, enlargedglomeruli as surrogate markers for reduced numbers of nephronswere found in some members of these groups.9,10 We designedthe present study to test the hypothesis proposed by Brenneret al.11 that a reduced number of nephrons contributes to essentialhypertension in the general population. To this end, we useda three-dimensional stereologic technique to compare the numberand volume of glomeruli in 10 middle-aged patients with documentedhypertension who had died in accidents with the number and volumein 10 matched subjects without evidence of hypertension whohad also died in accidents.
Methods
Study Subjects
One kidney was obtained from each of 10 middle-aged white subjects(age range, 35 to 59 years) who had died in accidents, who metthe inclusion criteria, and who underwent autopsy at the Instituteof Pathology of Darmstadt in Darmstadt, Germany, and the Instituteof Pathology and Forensic Medicine, University of Heidelberg,Heidelberg, Germany. Inclusion criteria comprised death beforethe age of 60 years; concentric left ventricular hypertrophy,a medical history of primary hypertension, or both; and thecharacteristic arteriolar lesions of the kidney found in patientswith hypertension. Exclusion criteria were evidence of secondaryhypertension, diabetes, a history of alcohol or drug abuse,or evidence of renal disease on histologic examination of thekidney. Control subjects had also died accidentally, had noevidence of hypertension, and were closely matched to the patientswith respect to sex, age, height, and weight. Written or oralinformed consent was obtained from next of kin, the local authorities,and local ethics committees.
Tissue Sampling and Stereologic Methods
The number and volume of glomeruli were estimated with use ofa three-dimensional approach that represented a modificationof the "fractionator" method.12,13 The number and area of glomeruliwere counted in randomly selected portions of the right kidney.All subjects had two kidneys; in three subjects the left kidneywas obtained because the right kidney had been severely damagedduring the accident. Major autolysis was not present.
The kidney was carefully removed and weighed. After immersionand fixation in formaldehyde, the whole kidney was cut into2-mm slices in a cranial-to-caudal direction, and the medullawas removed from the cortical rim. The cortical rim was weighed,and the cortical density was quantitated with use of the volume-replacementmethod. All kidney slices were placed onto paper marked witha coordinate system. Fifteen tissue blocks (measuring 5 by 5by 2 mm) were randomly selected with the use of random numbers,according to the area weighted-sampling principle. The blockswere dehydrated and embedded in methacrylate, and the degreeof shrinkage was determined in fixed kidney blocks. Assumingisotropic conditions, shrinkage did not exceed 4 percent ofthe volume. The blocks were serially sectioned (3 µm)and stained with methylene blue. Every first and eighth sectionwas selected for stereologic analysis, which involved the useof two microscopes (microscope A, model BH2, Olympus Optical;microscope B, model B202, Olympus Optical), a video-camera module(model XZ711P, Sony), and a computer screen (Nokia). For eachpair of samples, the first section was the reference sectionand was examined with microscope A; the resulting image wasprojected onto the computer screen with use of the video camera.A system of coordinates divided the computer screen into 204squares. Each square represented an area of 6.4x10–3 mm2of the examined cortical area. The eighth section was examinedwith microscope B. To rule out the possibility that differencesin results between the two microscopes were due to the microscopesthemselves, the comparison and reference sections were exchangedin random samples and examined with microscope A and microscopeB, respectively. The maximal mean difference in qualifying glomeruliwas 5.23 percent. Several blocks from the remaining kidney tissuewere then embedded in paraffin, sectioned (4 µm), andstained with hematoxylin and eosin, periodic acid–Schiff,or silver stains.
To estimate the number of glomeruli and the average glomerularvolume per kidney, we determined the number of points on thegrid that touched the cortical area, including the glomerulararea; the number of points on the grid that touched the glomerulararea; and the number of glomeruli found in the reference section.Cortical areas with obvious technical artifacts were excluded.The sampling volume was calculated by multiplying total tissuearea (the number of points on the grid that touched the corticalarea x the grid area) by the thickness of the section (e.g.,3 µm x 8 sections = 24 µm). A correction for tissueshrinkage (x1.04) was made, and the resulting volume, multipliedby the specific weight of the fixed kidney, yielded the massof the portion of the cortex being examined (mexam cor). Theweight of the kidney under examination was divided by the weightof the total kidney cortex, yielding a ratio (mexam cor:mtotalcor). The number of glomeruli was then determined with the followingequation: number = 1 ÷ (mexam cor:mtotal cor) x Q–,where Q– is the number of glomeruli found in the referencesection but not in the comparison section.
The mean glomerular volume was estimated by calculating theratio between the portion of the cortical area represented byglomerular area and the numerical density of glomeruli in thecortex. The total glomerular volume per kidney was estimatedby multiplying the number of glomeruli by the mean glomerularvolume.
Validation of the Method
In order to validate the method, two kidneys were examined byone of the investigators as well as by a second person familiarwith the three-dimensional stereologic method. Both observerswere unaware of the subject's disease status. Intraobserverand interobserver error were 0.99 percent and 2.04 percent,respectively.
Histologic Examination of the Kidney
In addition to the stereologic analysis, all kidneys were examinedby light microscopy. In all patients with hypertension, thecharacteristic findings of medial and intimal thickening withintimal fibrosis of preglomerular arterioles and hyalinosisof afferent arterioles were detected. Such vascular lesionswere uniformly absent in the kidneys of normotensive controls.The changes associated with arteriolar lesions and thickeningof Bowman's capsule were judged on a four-point scale as absent(a score of 0), minor (a score of 1), moderate (a score of 2),or severe, with the entire Bowman's capsule thickened (a scoreof 3).
To exclude the possibility that the number of glomeruli in thekidneys of patients with hypertension was spuriously low becauseglomeruli had vanished, paraffin-embedded sections stained withperiodic acid–Schiff and silver stains were carefullyexamined for potential residues of glomeruli and the numberof heavily sclerosed or obliterated glomeruli per 100 glomeruliin the cortical rim was counted. Obsolescent or obliteratedglomeruli were defined as structures with heavily sclerosedor no discernible capillary tuft but thickening or visible remnantsof Bowman's capsule. The number of such glomeruli was quantitatedon sections stained with hematoxylin and eosin, but additionalsections were screened with the use of silver and periodic acid–Schiffstains. As an index of periglomerular inflammation, we quantitatedthe proportion of the area surrounding the glomerulus (as apercentage of the visual field) that was infiltrated by mononuclearcells.
Statistical Analysis
Results are expressed as medians and interquartile ranges. TheMann–Whitney test for paired differences was used.
Results
Characteristics of the Subjects
Patients with hypertension and control subjects were similarwith respect to mean age, height, body weight, and kidney weight(Table 1). The relative weight of the heart — the ratioof the weight of the heart to the body weight — was significantlyhigher in patients with hypertension than in controls (P<0.001).
The mean number of intact glomeruli was significantly lower— by 46.6 percent — in the kidneys of the patientswith hypertension than in the kidneys of control subjects (Figure 1A).There was no trend toward a difference in results betweenthe sexes (Table 2). The mean glomerular volume was significantlyhigher — by 133 percent — in the kidneys of patientswith hypertension than in the kidneys of matched controls (Figure 1B).This higher mean glomerular volume resulted in a slightlyhigher total glomerular volume per kidney in the patients withhypertension than in the matched controls (median, 4.56x103mm3 vs. 3.98x103 mm3), but the difference was not statisticallysignificant.
Figure 1. Number of Glomeruli per Kidney (Panel A) and Mean Glomerular Volume (Panel B) in 10 Patients with Hypertension and 10 Matched Normotensive Controls.
There were occasional obliterated glomeruli in a juxtamedullarlocation. The percentage of obliterated glomeruli was significantlyhigher in the patients with hypertension than in the matchedcontrols (median, 5.5 percent vs. 0.0 percent; P<0.001).This finding prompted us to validate the reliability of themethod of detecting obliterated glomeruli. To this end we examinedthe kidneys of two elderly women (ages, 89 and 90 years) whohad had severe hypertensive heart disease and nephrosclerosiswith renal scarring and who were not study subjects. The totalnumber of histologically detectable glomeruli (i.e., intactplus sclerosed glomeruli) was slightly below the range describedfor patients with hypertension (468,301 and 606,150, respectively),although 25 percent and 30 percent of the glomeruli, respectively,were completely sclerosed. The mean glomerular volume in thesetwo patients was 2.58 x 10–3 mm3 and 2.83 x 10–3mm3, respectively.
Morphologic Investigation of the Kidney
Arteriolosclerosis of afferent arterioles was consistently foundin all the patients with hypertension (Table 3 and Figure 2B)but was absent or marginal in the control group (Figure 2A).In addition, the score for the thickening of Bowman's capsulewas significantly higher in the patients with hypertension thanin the control group. The percentage of periglomerular interstitiumthat was infiltrated by mononuclear cells was also significantlyhigher in patients with hypertension than in normotensive controls.Periglomerular infiltration was seen in all the patients withhypertension (and affected up to 19 percent of the periglomerulararea) but was virtually absent in the controls.
Figure 2. Representative Light Micrographs of Renal Cortex from a Normotensive Control (Panel A) and a Patient with Hypertension (Panel B).
The patient with hypertension has larger glomeruli and typical arteriolar changes with hyalinosis (arrow and inset).
Discussion
Our findings, obtained in a consecutive series of subjects whodied in accidents, suggest that the number of glomeruli is lowerin the kidneys of patients with hypertension than in the kidneysof matched normotensive controls. Nyengaard and Bendtsen14 observedthat the number of glomeruli decreases with age owing to theaccelerated loss of glomeruli after the age of 60 years. Consequently,we excluded all subjects who were 60 or older. Variable numbersof glomeruli have been reported in the general population, rangingfrom 331,000 to 2 million glomeruli per kidney, with no differencebetween the sexes.15,16,17 In our opinion these differencesare largely explained by differences in the counting methodsused. The number of glomeruli in our control subjects was similarto the numbers obtained with the acid-maceration method (580,000to 2 million),16,18 which assesses the entire organ and takesinto account the differences in the density of glomeruli inthe various zones of the renal cortex.19
Recently, Bertram et al. reported preliminary findings on thenumber and volume of glomeruli in forensic-autopsy samples obtainedfrom subjects without kidney disease.20 They found a considerablevariation in the number of glomeruli, ranging from 210,332 to1,825,380. Using the fractionator technique, Gundersen et al.found lower numbers of glomeruli (331,000 to 1,424,000).13 Thedifference in numbers is unexplained, but we did not use theoriginal fractionator method. Differences in findings may inpart be explained by tissue shrinkage, which interferes withabsolute counts in the method we adopted. In the original fractionatormethod, a correction factor was used to account for the proportionof the sample fraction in which the counting of glomeruli wasnot performed. This correction was not necessary in our modification,since the fraction of the cortical rim examined was calculateddirectly from the volume of the sample examined and the densityof the cortical rim, but this approach introduced the potentialproblem of tissue shrinkage, as noted. With our modified three-dimensionalstereologic method, intraobserver and interobserver errors didnot exceed 0.99 percent and 2.04 percent, respectively.
Irrespective of the ongoing discussion concerning the optimalmethod of counting glomeruli, we would emphasize that in thepresent controlled study, the difference between the patientswith hypertension and the control subjects was so large andconsistent that it is highly unlikely that the result was dueto a methodologic artifact.
Of more concern is another potential problem — the lossof glomeruli in the kidneys of patients with hypertension. Usingperiodic acid–Schiff and silver stains to detect residualmaterial from Bowman's capsules, we observed only a small proportionof obsolescent glomeruli. As a further control, we specificallyexamined the kidneys of two elderly women with severe hypertension,which we expected to have a high proportion of obliterated glomeruli.We were satisfied that the number of intact plus obliteratedglomeruli was only slightly below the range expected for patientswith hypertension. This observation suggests that even severehypertension-induced renal damage does not cause the completedisappearance of glomeruli. It may be argued that shrunken glomerulimay not have been detected with our sampling technique and thatwe may thus have underestimated the number of glomeruli. Thesmallest glomerular diameter in the kidneys of the patientswith hypertension was 97.5 µm, and the distance betweentwo sampling planes with our technique was 24 µm, thusincreasing the likelihood that all glomeruli were detected.Although we cannot rule out the possibility that some glomerularloss may have gone undetected, we found no relation betweenthe number of glomeruli and age in our subjects.
The hypothesis that a reduced number of nephrons leads to primaryhypertension is given further support by observations that theglomerular volume serves as a surrogate for the number of glomeruliand is very high in members of racial and ethnic groups witha predilection for renal failure over time.9,10 In this context,it is of note that the numbers of glomeruli are also significantlylower in spontaneously hypertensive rats than in normotensivecontrols.21 Furthermore, Fassi et al. showed that the progressiverenal damage in the Milan Wistar rat is associated with an inborndeficit of nephrons.7
Whether the reduced number of nephrons is caused by geneticor environmental factors is unclear. Several studies suggestedthat changes in the intrauterine environment lead to retardedrenal growth before birth, low birth weight, and hypertensionduring adult life.22,23,24 A correlation between reduced birthweight and decreased formation of nephrons was recently foundin experiments in rats.25 In humans, an association has beenfound between low birth weight and reduced renal volume, possiblyindicating a reduced number of nephrons.26 All these data areconsistent with the concept that the number of nephrons, whichis determined during fetal development, is an important determinantof cardiovascular abnormalities during adult life. The presentdata, obtained at autopsy from white patients with primary hypertension,provide further evidence in support of this concept.
Supported by grants from the Medical Faculty of Heidelberg andthe Deutsche Forschungsgemeinschaft (SFB 423, project B 8).
We are indebted to R. Büchele and Prof. Dr. B. Krempienfor generous technical support and to Zlata Antoni, Gudrun Gorsberg,and Peter Rieger for technical assistance.
Source Information
From the Departments of Pathology (G.K.), Forensic Medicine (G.K., G.Z.), and Internal Medicine (E.R.), University of Heidelberg, Heidelberg; the Department of Pathology, City Hospital of Darmstadt, Darmstadt (G.M.); and the Department of Pathology, University of Erlangen-Nürnberg, Erlangen (K.A.) — all in Germany.
Address reprint requests to Dr. Amann at the Department of Pathology, University of Erlangen-Nürnberg, Krankenhausstr. 8-10, 91054 Erlangen, Germany, or at kerstin.amann{at}patho.imed.uni-erlangen.de.
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Nephron Number and Primary Hypertension
Johnson R. J., Rodríguez-Iturbe B., Herrera-Acosta J., O'Neill W. C., Querfeld U., Niaudet P., Amann K., Ritz E.
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291: F1104-F1107
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Fetita, L.-S., Sobngwi, E., Serradas, P., Calvo, F., Gautier, J.-F.
(2006). Consequences of Fetal Exposure to Maternal Diabetes in Offspring. J. Clin. Endocrinol. Metab.
91: 3718-3724
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Woods, L. L.
(2006). Maternal glucocorticoids and prenatal programming of hypertension. Am. J. Physiol. Regul. Integr. Comp. Physiol.
291: R1069-R1075
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Dziarmaga, A., Hueber, P.-A., Iglesias, D., Hache, N., Jeffs, A., Gendron, N., MacKenzie, A., Eccles, M., Goodyer, P.
(2006). Neuronal apoptosis inhibitory protein is expressed in developing kidney and is regulated by PAX2. Am. J. Physiol. Renal Physiol.
291: F913-F920
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Bursztyn, M., Gross, M.-L., Goltser-Dubner, T., Koleganova, N., Birman, T., Smith, Y., Ariel, I.
(2006). Adult Hypertension in Intrauterine Growth-Restricted Offspring of Hyperinsulinemic Rats: Evidence of Subtle Renal Damage. Hypertension
48: 717-723
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Messerli, F.H., Mancia, G., Conti, C.R., Hewkin, A.C., Kupfer, S., Champion, A., Kolloch, R., Benetos, A., Pepine, C.J., Nakagawa, K., Holla, V.R., Wei, Y., Wang, W.H., Gatica, A., Wei, S., Mei, S., Miller, C.M., Cha, D.R., Price, E. Jr., Zent, R., Pozzi, A., Breyer, M.D., Guan, Y., Falck, J.R., Waterman, M.R., Capdevila, J.H.
(2006). Lowering of Blood Pressure--The Lower, the Better?: Dogma Disputed: Can Aggressively Lowering Blood Pressure in Hypertensive Patients with Coronary Artery Disease Be Dangerous? Ann Intern Med 144: 884-893, 2006. J. Am. Soc. Nephrol.
17: 2345-2352
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Ritz, E.
(2006). Salt--friend or foe?. Nephrol Dial Transplant
21: 2052-2056
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Fagerudd, J., Forsblom, C., Pettersson-Fernholm, K., Saraheimo, M., Waden, J., Ronnback, M., Rosengard-Barlund, M., Bjorkesten, C.-G. a., Thorn, L., Wessman, M., Groop, P.-H., on behalf of the FinnDiane Study Group,
(2006). Low birth weight does not increase the risk of nephropathy in Finnish type 1 diabetic patients. Nephrol Dial Transplant
21: 2159-2165
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Amann, K., Wanner, C., Ritz, E.
(2006). Cross-Talk between the Kidney and the Cardiovascular System. J. Am. Soc. Nephrol.
17: 2112-2119
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Feig, D. I., Rodriguez-Iturbe, B., Nakagawa, T., Johnson, R. J.
(2006). Nephron Number, Uric Acid, and Renal Microvascular Disease in the Pathogenesis of Essential Hypertension. Hypertension
48: 25-26
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Dziarmaga, A., Eccles, M., Goodyer, P.
(2006). Suppression of Ureteric Bud Apoptosis Rescues Nephron Endowment and Adult Renal Function in Pax2 Mutant Mice. J. Am. Soc. Nephrol.
17: 1568-1575
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Brown, M. J
(2006). Hypertension and ethnic group.. BMJ
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Taylor, C M, Narchi, H
(2006). Risk of hypertension in children with multicystic dysplastic kidney.. Arch. Dis. Child.
91: 277-278
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Zandi-Nejad, K., Luyckx, V. A., Brenner, B. M.
(2006). Adult Hypertension and Kidney Disease: The Role of Fetal Programming. Hypertension
47: 502-508
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Narkiewicz, K.
(2006). Obesity and hypertension--the issue is more complex than we thought. Nephrol Dial Transplant
21: 264-267
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Brantsma, A. H., Bakker, S. J.L., de Zeeuw, D., de Jong, P. E., Gansevoort, R. T., for the PREVEND Study Group,
(2006). Urinary Albumin Excretion as a Predictor of the Development of Hypertension in the General Population. J. Am. Soc. Nephrol.
17: 331-335
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Hoy, W. E., Samuel, T., Hughson, M. D., Nicol, J. L., Bertram, J. F.
(2006). How Many Glomerular Profiles Must Be Measured to Obtain Reliable Estimates of Mean Glomerular Areas in Human Renal Biopsies?. J. Am. Soc. Nephrol.
17: 556-563
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Alexander, B. T.
(2006). Fetal programming of hypertension. Am. J. Physiol. Regul. Integr. Comp. Physiol.
290: R1-R10
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Hall, P. M.
(2006). Prevention of Progression in Diabetic Nephropathy. Diabetes Spectr.
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Strojek, K., Nicod, J., Ferrari, P., Grzeszczak, W., Gorska, J., Dick, B., Frey, F., Ritz, E.
(2005). Salt-sensitive blood pressure--an intermediate phenotype predisposing to diabetic nephropathy?. Nephrol Dial Transplant
20: 2113-2119
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CY, H., CE, M., J, D., AS, G., C, I., E, T., HC, C., M, L., S, R., ER, R., B, T., G, L., N, P., KL, G., Y, W., DA, K., B, J., D, H., P, B., V, P., N, R., C, F., I, R., M, C., M, R., E, d. H., H, B., SJ, B., M, Z., E, R., P, M., MA, S., J, M., H, K., S, S., CR, B., P, N., HP, H., BA, Y., J, Z., FJ, v. d. W.
(2005). Which Comes First--Renal Dysfunction or High Blood Pressure?: Elevated Blood Pressure and Risk of End-Stage Renal Disease in Subjects without Baseline Kidney Disease. Arch Intern Med 165: 923-928, 2005. J. Am. Soc. Nephrol.
16: 2817-2820
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Woods, L. L., Weeks, D. A.
(2005). Prenatal programming of adult blood pressure: role of maternal corticosteroids. Am. J. Physiol. Regul. Integr. Comp. Physiol.
289: R955-R962
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Schreuder, M. F., Nyengaard, J. R., Fodor, M., van Wijk, J. A.E., Delemarre-van de Waal, H. A.
(2005). Glomerular Number and Function Are Influenced by Spontaneous and Induced Low Birth Weight in Rats. J. Am. Soc. Nephrol.
16: 2913-2919
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Samuel, T., Hoy, W. E., Douglas-Denton, R., Hughson, M. D., Bertram, J. F.
(2005). Determinants of Glomerular Volume in Different Cortical Zones of the Human Kidney. J. Am. Soc. Nephrol.
16: 3102-3109
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Woods, L. L., Ingelfinger, J. R., Rasch, R.
(2005). Modest maternal protein restriction fails to program adult hypertension in female rats. Am. J. Physiol. Regul. Integr. Comp. Physiol.
289: R1131-R1136
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Barker, D. J.P., Bagby, S. P.
(2005). Developmental Antecedents of Cardiovascular Disease: A Historical Perspective. J. Am. Soc. Nephrol.
16: 2537-2544
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Hoy, W. E., Hughson, M. D., Bertram, J. F., Douglas-Denton, R., Amann, K.
(2005). Nephron Number, Hypertension, Renal Disease, and Renal Failure. J. Am. Soc. Nephrol.
16: 2557-2564
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McMullen, S., Langley-Evans, S. C., Johnson, R. J., Rodriguez-Iturbe, B., Nakagawa, T., Kang, D.-H., Feig, D. I., Herrera-Acosta, J.
(2005). Essential Hypertension: Defending the Contribution of a Congenital Nephron Deficit. Hypertension
46: e4-e5
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Safar, M. E., Boudier, H. S.
(2005). Vascular Development, Pulse Pressure, and the Mechanisms of Hypertension. Hypertension
46: 205-209
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Welham, S. J. M., Riley, P. R., Wade, A., Hubank, M., Woolf, A. S.
(2005). Maternal diet programs embryonic kidney gene expression. Physiol. Genomics
22: 48-56
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Crowley, S., Gurley, S., Oliverio, M., Pazmino, A., Griffiths, R, Flannery, P., Spurney, R., Kim, H-S, Smithies, O, Le, T., Coffman, T., Boucher, J, Masri, B, Daviaud, D, Gesta, S, Guigne, C, Mazzucotelli, A, Castan-Laurell, I, Tack, I, Knibiehler, B, Carpene, C, Audigier, Y, Saulnier-Blache, J., Valet, P, Engeli, S, Bohnke, J, Gorzelniak, K, Janke, J, Schling, P, Bader, M, Luft, F, Sharma, A.
(2005). Is the Kidney Always the Cause of Hypertension?: Distinct Roles for the Kidney and Systemic Tissues in Blood Pressure Regulation by the Renin-Angiotensin System. J Clin Invest 115: 1092-1099, 2005. J. Am. Soc. Nephrol.
16: 1525-1532
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Tse, H. K.W., Leung, M. B.W., Woolf, A. S., Menke, A. L., Hastie, N. D., Gosling, J. A., Pang, C.-P., Shum, A. S.W.
(2005). Implication of Wt1 in the Pathogenesis of Nephrogenic Failure in a Mouse Model of Retinoic Acid-Induced Caudal Regression Syndrome. Am. J. Pathol.
166: 1295-1307
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Sharma, K., Cook, A., Smith, M., Valancius, C., Inscho, E. W.
(2005). TGF-{beta} impairs renal autoregulation via generation of ROS. Am. J. Physiol. Renal Physiol.
288: F1069-F1077
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Hsu, C.-y., McCulloch, C. E., Darbinian, J., Go, A. S., Iribarren, C.
(2005). Elevated Blood Pressure and Risk of End-stage Renal Disease in Subjects Without Baseline Kidney Disease. Arch Intern Med
165: 923-928
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Wang, T. J., Evans, J. C., Meigs, J. B., Rifai, N., Fox, C. S., D'Agostino, R. B., Levy, D., Vasan, R. S.
(2005). Low-Grade Albuminuria and the Risks of Hypertension and Blood Pressure Progression. Circulation
111: 1370-1376
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Gross, M.-L., Amann, K., Ritz, E.
(2005). Nephron Number and Renal Risk in Hypertension and Diabetes. J. Am. Soc. Nephrol.
16: S27-S29
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Johnson, R. J., Rodriguez-Iturbe, B., Nakagawa, T., Kang, D.-H., Feig, D. I., Herrera-Acosta, J.
(2005). Subtle Renal Injury Is Likely a Common Mechanism for Salt-Sensitive Essential Hypertension. Hypertension
45: 326-330
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Painter, R. C., Roseboom, T. J., van Montfrans, G. A., Bossuyt, P. M.M., Krediet, R. T., Osmond, C., Barker, D. J.P., Bleker, O. P.
(2005). Microalbuminuria in Adults after Prenatal Exposure to the Dutch Famine. J. Am. Soc. Nephrol.
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Barker, D.J.P.
(2004). The Developmental Origins of Adult Disease. J. Am. Coll. Nutr.
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Tendron-Franzin, A., Gouyon, J.-B., Guignard, J.-P., Decramer, S., Justrabo, E., Gilbert, T., Salomon Semama, D.
(2004). Long-Term Effects of In Utero Exposure to Cyclosporin A on Renal Function in the Rabbit. J. Am. Soc. Nephrol.
15: 2687-2693
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Hovind, P., Tarnow, L., Rossing, P., Jensen, B. R., Graae, M., Torp, I., Binder, C., Parving, H.-H.
(2004). Predictors for the development of microalbuminuria and macroalbuminuria in patients with type 1 diabetes: inception cohort study. BMJ
328: 1105-
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Shah, M. M., Sampogna, R. V., Sakurai, H., Bush, K. T., Nigam, S. K.
(2004). Branching morphogenesis and kidney disease. Development
131: 1449-1462
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Ruilope, L. M.
(2004). New European guidelines for management of hypertension: what is relevant for the nephrologist. Nephrol Dial Transplant
19: 524-528
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Stallone, G., Di Paolo, S., Schena, A., Infante, B., Battaglia, M., Ditonno, P., Gesualdo, L., Grandaliano, G., Paolo Schena, F.
(2004). Addition of Sirolimus to Cyclosporine Delays the Recovery from Delayed Graft Function but Does not Affect 1-Year Graft Function. J. Am. Soc. Nephrol.
15: 228-233
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Moreno, C., Dumas, P., Kaldunski, M. L., Tonellato, P. J., Greene, A. S., Roman, R. J., Cheng, Q., Wang, Z., Jacob, H. J., Cowley, A. W. Jr
(2003). Genomic map of cardiovascular phenotypes of hypertension in female Dahl S rats. Physiol. Genomics
15: 243-257
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Franco, M. d. C. P., Nigro, D., Fortes, Z. B, Tostes, R. C.A, Carvalho, M. H. C, Lucas, S. R. R., Gomes, G. N., Coimbra, T. M., Gil, F. Z.
(2003). Intrauterine undernutrition--renal and vascular origin of hypertension. Cardiovasc Res
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Quigg, R. J.
(2003). Complement and the Kidney. J. Immunol.
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Fulladosa, X., Moreso, F., Narvaez, J. A., Grinyo, J. M., Seron, D.
(2003). Estimation of Total Glomerular Number in Stable Renal Transplants. J. Am. Soc. Nephrol.
14: 2662-2668
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Feig, D. I., Johnson, R. J.
(2003). Hyperuricemia in Childhood Primary Hypertension. Hypertension
42: 247-252
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Rostand, S. G.
(2003). Oligonephronia, primary hypertension and renal disease: 'is the child father to the man?'. Nephrol Dial Transplant
18: 1434-1438
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Rostand, S. G.
(2003). Oligonephronia, primary hypertension and renal disease: 'is the child father to the man?'. Nephrol Dial Transplant
18: 1434-1438
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Yu, H. T.
(2003). Progression of Chronic Renal Failure. Arch Intern Med
163: 1417-1429
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Johnson, R. J., Rodriguez-Iturbe, B., Herrera-Acosta, J., O'Neill, W. C., Querfeld, U., Niaudet, P., Amann, K., Ritz, E.
(2003). Nephron Number and Primary Hypertension. NEJM
348: 1717-1719
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Q–, where Q– is the number of glomeruli found in the reference section but not in the comparison section. 
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