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NDT Advance Access published online on February 28, 2008
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn039
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© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


Renal pathology, glomerular number and volume in a West African urban community

Bridgette J. McNamara1, Boucar Diouf2, Michael D. Hughson3, Rebecca N. Douglas-Denton1, Wendy E. Hoy4 and John F. Bertram1

1 Department of Anatomy and Developmental Biology, Monash University, Melbourne, Australia 2 Hôpital Aristide Le Dantec, Dakar, Senegal 3 University of Mississippi Medical Center, Jackson, Mississippi, USA 4 Centre for Chronic Disease, University of Queensland, Brisbane, Australia

Correspondence and offprint requests to: John F. Bertram, Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, 3800. Australia. Tel: +61-3-99052751; Fax: +61-3-99052462; E-mail: john.bertram{at}med.monash.edu.au



   Abstract
Top
 Abstract
Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Low glomerular number and large glomerular volume are hypothesized to be risk factors for hypertensive renal disease in adult life. Reports of human glomerular number are based on studies from developed nations and have found single kidney mean values of ~900 000 per kidney with a roughly 8-fold range matched by a similar range in glomerular volume. Glomerular number and volume have never been investigated in people from a developing country.

Methods. This study analysed the pathology of 81 autopsy kidneys from Dakar, Senegal, and determined total glomerular number and mean glomerular volume in 28 of these kidneys using the physical disector/fractionator method.

Results. Total glomerular number ranged 2.6-fold from 536 171 to 1 394 010, with a mean of 925 485 nephrons. The mean glomerular volume was 5.74 µm3 x 106 with a 2.5-fold variation that was strongly and inversely correlated with total glomerular number. Glomerular number was inversely correlated with age, and age-associated increases in arteriosclerosis, cortical fibrosis and glomerulosclerosis were observed. Arteriolar nephrosclerosis was observed in 34% of adults. Mean glomerular number in this Dakar population was similar to that previously reported for people from developed nations, while the range of glomerular number and mean glomerular volume was much narrower.

Conclusions. The frequency of arteriolar nephrosclerosis in these Senegalese adults was high (34%), suggesting that hypertensive kidney disease could contribute to a large burden of future chronic kidney disease in this population. Unusually low glomerular number or large glomerular volume do not appear to provide a basis for this potential burden of kidney disease.

Keywords: arteriosclerosis; developing world; glomerular volume; nephron number; renal pathology; Senegal; stereology



   Introduction
Top
 Abstract
 Introduction
Subjects and methods
 Results
 Discussion
 References
 
The global burden of hypertensive and diabetic chronic kidney disease is reaching epidemic proportions. The problem is compounded by rising rates of obesity, higher life expectancies and ageing populations and looms largest in resource-poor developing countries where the greatest increases in disease burden are expected. In developing countries, such as in regions of Africa, the prevalence of diabetes is anticipated to increase by 170% by 2025 [1].

Reliable statistics on the incidence of chronic disease in developing African nations are scarce. In countries such as Senegal, West Africa, where there are three nephrologists for a population of 11 million, it is difficult to know the extent of chronic kidney disease and the extent to which endemic infections, diabetes and hypertension contribute to this disease.

Total glomerular (nephron) number is a proposed determinant within the multifactorial aetiology of hypertension. Individuals with low glomerular number are suggested to be at increased risk of hypertension and progressive kidney disease in a later stage of life [2–4]. Estimates of total glomerular number in Danes [5], Germans [3], African Americans, white Americans, Australian Aborigines, Australian whites [6,7] and the French [8] have demonstrated an average of ~900 000 and an <8-fold range, with estimates ranging from just above 200 000 to nearly 2 million glomeruli per kidney.

The above studies have also described large ranges in glomerular size in normal human kidneys. For example, a 5.2-fold range in mean glomerular volume (3.29– 16.99 µm3 x 106) has been observed in autopsy kidneys from American adults with a number of kidneys having very large glomeruli [7]. Glomerular hypertrophy, while beneficial in maintaining filtration, may pose a risk in the longer term, as enlarged glomeruli are thought to be more susceptible to sclerosis [9–11]. Glomerulomegaly has been reported as a frequent occurrence in renal biopsies in communities with elevated rates of end-stage renal disease (ESRD) including native Americans [12] and Australian Aborigines [11,13].

Here we report findings from the first investigation of glomerular number and volume in a developing country or in an African population. Associations between total glomerular number, mean glomerular volume, age, gender and body size for 28 subjects from Dakar (Senegal) are investigated to determine whether low glomerular number and large glomerular volume could contribute to an increased risk of chronic hypertensive kidney disease within this population. We also evaluated kidney pathology in 81 subjects to determine whether there is any indigenous kidney disease that may be increasing rates of hypertension on a secondary basis.



   Subjects and methods
Top
 Abstract
 Introduction
 Subjects and methods
Results
 Discussion
 References
 
Kidneys were collected and weighed from people coming to coronial autopsy at Hôpital Aristide Le Dantec in Dakar (Senegal) from 2003 to 2005. The right kidney from each subject was perfusion-fixed in 10% formalin and was sent whole to Monash University, Melbourne, Australia for analysis. Kidney collection and analysis was carried out with permission of next of kin and in accordance with the standards of the Standing Committee on Ethics in Research Involving Humans (SCERH) at Monash University (project approval numbers 2002/204 and 2006/753).

Pathological assessment was performed on kidneys from the first 81 subjects to be received and processed: 62 adults (>18 years) and 19 children. The sample predominantly represents Africans from an urban setting; 78 of the 81 subjects were born and resided in Dakar. The other three subjects were a 15-year-old male from Matam, and a 12-year-old girl and a 28-year-old male from Gambia. Unexpected trauma (including road accident, violence or drowning) was the main cause of death (60%), followed by cardiovascular and cerebrovascular events (19%) and other non-renal illnesses (infections, cancer and pneumonia) (19%). Two of the 21 adult females died of complications in childbirth.

A smaller sample was taken from the larger group of 81 for stereological analysis. Two males and two females from seven age categories (0–9, 10–19, ..., >60 years) were selected. Only subjects whose left and right kidneys were of approximately equal weight and without macroscopic congenital deformities were included in the study. In the 50- to 59-year-old age category, only one female subject fulfilled these criteria, so an additional female from the 40- to 49-year-old age range was examined. The cause of death in this smaller sample was predominantly unexpected trauma (75%), and no subjects died of cardiovascular causes (refer to Table 1).


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  		Table 1 Physical characteristics and stereological estimates of total glomerular number and mean glomerular volume in the 28 subjects from Dakar (Senegal) who were investigated

 
The selected kidneys were sampled systematically for stereology. The samples were embedded in glycolmethacrylate and sectioned at 20 µm. The physical disector/fractionator combination was used for unbiased stereological estimation of total glomerular, and thereby nephron, number. In accordance with the disector technique, systematically sampled section pairs were used to count glomeruli. The fundamental principle of the technique is to count particles, in this case glomeruli, at a unique point, for example when a glomerulus first appears or disappears in serial sections. By counting glomeruli at a unique point, assumptions and biases involving size, shape and orientation of the glomerulus are not required. Glomeruli were counted in a known fraction of the kidney and basic calculations were used to calculate the total number in the whole kidney. Mean glomerular volume (Vglom) estimates were obtained by dividing the volume density of glomeruli in the kidney (VVglom,kid) (derived from point counting with a grid) by the numerical density of glomeruli in the kidney (NVglom,kid). These unbiased methods have been previously described in detail [6,14].

Renal pathology was analysed in a representative block from the mid-hilar portion of the kidney. Four-micrometre paraffin sections were stained with periodic-acid Schiff (PAS) for the analysis of glomerulosclerosis, arteriosclerosis and arteriolar hyalinosis, and with Masson's Trichrome for the estimation of cortical fibrosis. Glomerulosclerosis was assessed in 100 consecutive glomeruli at 400x magnification, and was expressed as the percentage of glomeruli sclerosed. Similarly, arteriolar hyalinosis is the fraction of afferent arterioles hyalinized, assessed in 100 vessels at 400x magnification. To assess arteriosclerosis of renal vessels, photomicrographs captured at 200x magnification using a Leica DC 200 camera on an Olympus AX70 light microscope were analysed using Image Pro Plus 4.5 software (Media Cybernetics Inc., Silver Spring, USA). The ratio of intimal thickening of the vessel wall to the outer diameter of the vessel was calculated [15,16]. Compliance arteries were defined as vessels with a diameter >250 µm and ≤500 µm and resistance arteries where the vessel diameter was between 90 and 250 µm. All vessels present in the tissue wedge with a diameter between 90 and 500 µm were measured and an average ratio was recorded for compliance and resistance arteries. Cortical fibrosis, expressed as the fraction of cortex that is fibrotic, was assessed on 10–15 photomicrographs of the section using a 1.7-cm grid to point-count the areas of fibrosis and the area of cortex.

Statistical analysis
Analysis of data was performed using STATA statistical package, Version 8 (College Station, TX, USA). Pearson's product moment correlation and linear regression were used to analyse relationships between parametric variables. Spearman's rho correlation (r) was used for non-parametric data. Student t-tests were used to compare two groups where the data were normally distributed and the Mann–Whitney test was used in cases of non-normal distribution. In all tests, P < 0.05 was considered significant. Analysis involving measures of mean glomerular volume was conducted in adult subjects alone because of the dramatic changes in volume during childhood growth.



   Results
Top
 Abstract
 Introduction
 Subjects and methods
 Results
Discussion
 References
 
This report describes renal pathology findings in 81 Senegalese Africans from Dakar: 62 adults and 19 children. Physical characteristics of the subjects, aged from 2 to 76 years, are presented in Table 2. Senegalese adults had an average height of 167.1 cm, average weight of 71.3 kg and average kidney weight of 138.6 g. We also report stereological estimates of total glomerular number and mean glomerular volume in 28 Senegalese Africans ranging in age from 5 to 70 years: 14 males and 14 females. The mean and range of physical characteristics in this smaller sample are very similar to the larger sample (Table 3). A summary of stereological data from the 28 subjects is presented in Table 4 and individual values and the cause of death for each subject are shown in Table 1.


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  		Table 2 Physical characteristics of the 81 subjects from Dakar (Senegal) in whom renal pathology was assessed

 

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  		Table 3 Physical characteristics of the 28 subjects whose kidneys were used for the stereological estimation of total glomerular number and mean glomerular volume

 

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  		Table 4 Summary of stereological estimates from autopsy kidneys of the 28 subjects from Dakar (Senegal)

 
Kidney weight and body size
Kidney weight increased rapidly during childhood and adolescence, and appeared to decrease in late adulthood after the age of ~60 years (Figure 1A). Similarly, body weight increased during childhood and adolescence to reach a stable level during early adulthood. Unlike kidney weight, body weight did not decline in late adulthood (Figure 1B). The 2.7-fold range in adult kidney weight was larger than the variation in body weight. This was particularly evident in young adults aged 18–35 years of age, where body weight had a limited range but kidney weight showed the largest variation. Kidney weight was directly correlated with body surface area (BSA) when all subjects, including children, were analysed (r = 0.63, P < 0.0001) (Figure 1C), but there was no significant correlation in adults alone (r = 0.15, P = 0.25).


Figure 1
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  		Fig. 1 (a) Relationship between right kidney weight and age. (b) Relationship between body weight and age. (c) Relationship between right kidney weight and body surface area (BSA) (m2). n = 81 subjects in all figures. Individual values are shown together with line of best fit and 95% confidence intervals (shaded area).

 
Total glomerular number: range, age and gender
Total glomerular number per kidney in the 28 Senegalese Africans ranged 2.6-fold, from 536 171 to 1 394 010, with a mean of 925 485 glomeruli (Table 4). Females had 17% fewer glomeruli than males (adjusted for age, n = 28, P = 0.02). Adults had significantly fewer glomeruli than children (P = 0.038), and there was a strong inverse correlation between glomerular number and age (r = –0.52, P = 0.005) (Figure 2). Total glomerular number was not correlated with adult kidney weight, body weight or adult height.


Figure 2
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  		Fig. 2 The effect of age on total glomerular number. Individual values are shown together with line of best fit and 95% confidence intervals (shaded area). There is a significant inverse relationship between glomerular number and age (n = 28, r2 = 0.27, P = 0.005). The relationship is not quite significant (r2 = 0.16, P = 0.08) in adults alone (likely due to small sample size).

 
Glomerular volume
The mean glomerular volume in adults ranged 2.5-fold, from 3.06 to 7.54 µm3 x 106, with a mean of 5.74 µm3 x 106 (Table 4). Mean glomerular volume was similar in men and women (P = 0.68). There was a strong direct correlation between mean glomerular volume and BSA when all subjects were analysed (r = 0.79, P < 0.0001), but the relationship was not significant in adults alone (r = 0.35, P = 0.13). Mean glomerular volume in adults was inversely correlated with total glomerular number (n = 20, r = –0.61, P = 0.005), indicating that subjects with fewer nephrons tended to have larger glomeruli (Figure 3). The total glomerular volume (the total volume of all glomeruli in the kidney) in adults ranged from 3.15 to 7.09 cm3, with a mean value of 4.88 cm3 (Table 4). Total glomerular volume did not differ significantly by gender (P = 0.57).


Figure 3
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  		Fig. 3 Inverse relationship between total glomerular number and mean glomerular volume in adults (n = 20, r2 = 0.38 P = 0.005). Individual values are shown together with line of best fit and 95% confidence intervals (shaded area).

 
Renal pathology
Kidney pathology was observed in 30 of the 81 kidneys. Representative photomicrographs of the renal histopathology are shown in Figure 4. Arteriolar nephrosclerosis was the most common pathology observed (Figure 4A). This pathology that ranged from mild to severe was observed in 21 (34%) of the 62 adults. The number of cases was similar in men and women. The 21 subjects with arteriolar nephrosclerosis were significantly older than the other subjects (54.2 ± 13.1 years and 32.1 ± 12.2 years; P < 0.0001). Cardiovascular disease accounted for cause of death in 29% (n = 6) of these 21 subjects; one subject died of non-renal related illness while the remainder died from unexpected trauma (67%, n = 14). Overall in the 62 adults, the prevalence of arteriolar nephrosclerosis in the 12 subjects dying from cardiovascular disease (50%) was higher than that in the remaining 50 who died from other causes (30%). Subjects dying of cardiovascular disease were also significantly older (P = 0.02) and had increased glomerulosclerosis (P = 0.002), cortical fibrosis (P = 0.04) and arteriosclerosis (P = 0.03) compared to subjects dying of other causes. Apart from arteriolar nephrosclerosis, pathology native to the kidney was not common. Two cases revealed a chronic interstitial nephritis and one case a focal crescentic glomerulonephritis. There was one case of focal segmental glomerulosclerosis involving 2 of 88 glomeruli (Figure 4B). The case also demonstrated acute renal tubular necrosis with the deposition of a large amount of black pigment that may indicate a malarial infection.


Figure 4
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  		Fig. 4 Photomicrographs of renal pathology in subjects from Dakar (Senegal) in sections stained with PAS (a and b) or Masson's Trichrome (c and d). (a) Arteriosclerosis (intimal thickening of the vessel wall). (b) Focal segmental glomerulosclerosis; arrow indicates the sclerosed region. (c) Sickle cell disease or trait. (d) Glomerular capillary thrombosis (likely dissiminated intravascular coagulation). Scale bars = 50 µm.

 
Unrelated to a native kidney disease were two subjects with diffuse intravascular sickling that could be the result of either sickle cell disease or trait (Figure 4C). The absence of any chronic renal damage suggested sickle cell trait. Glomerular capillary thrombosis (Figure 4D) consistent with disseminated intravascular coagulation (DIC) was observed in a 37-year-old female road accident victim who suffered multiple fractures, peritoneal bleeding and a post-trauma abortion.

Renal pathology in children
Kidneys of the 19 children displayed very little pathology. Congenital glomerulosclerosis was observed in three of the six children aged 5 years or less. In one male and two females, sclerosis affected 5.3 to 9.7% of glomeruli. This congenital glomerulosclerosis was not accompanied by cortical fibrosis or tubular atrophy.

Arteriosclerosis, cortical fibrosis, glomerulosclerosis and arteriolar hyalinosis
The frequency of arteriolar nephrosclerosis increased with age and the trends were the same in males and females. Arteriosclerosis of compliance (Spearman's rho (r) = 0.79, P < 0.0001) (Figure 5A) and resistance (r = 0.67, P < 0.0001) arteries, as well as arteriolar hyalinosis (r = 0.51, P < 0.0001) and glomerular obsolescence (r = 0.55, P < 0.0001) increased significantly with age (Figure 5B). The percentage of glomerular obsolescence ranged from 0 to 16%, with a geometic mean of 1.7% and an extremely right-skewed distribution.


Figure 5
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  		Fig. 5 (a) Relationship between arteriosclerosis of compliance arteries and age (n = 81, r = 0.79, P < 0.0001). (b) Relationship between age and glomerulosclerosis (r = 0.55 and P < 0.0001). Individual values are shown together with line of best fit and 95% confidence intervals (shaded area) for all ages in (a) and for subjects aged over 5 years in (b).

 
The fraction of cortex affected by cortical fibrosis also increased with age (r = 0.63, P < 0.0001), and was tightly correlated with glomerular obsolescence (r = 0.68, P < 0.0001) (Figure 6) and arteriosclerosis of renal arteries (compliance: r = 0.77, P < 0.0001; resistance: r = 0.76, P < 0.0001).


Figure 6
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  		Fig. 6 Relationship between percentage of glomerulosclerosis and cortical fibrosis in adult subjects (n = 62, r = 0.68, P < 0.0001). Individual values are shown together with line of best fit and 95% confidence intervals (shaded area) for subjects aged over 5 years.

 
In the sample of 20 adults in whom glomerular number and volume were estimated there were no significant correlations between total glomerular number or mean glomerular volume and the extent of arteriosclerosis, glomerulosclerosis, cortical fibrosis or arteriolar hyalinosis.



   Discussion
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
References
 
This analysis of kidneys from this West African urban community extends the knowledge of human glomerular number and volume into a developing African population and has demonstrated (1) a 2.6-fold range of glomerular number, (2) a 2.5-fold variation inmean glomerular volume, (3) inverse correlations between age and glomerular number and (4) a high prevalence of arteriolar nephrosclerosis. The mean number of 925 485 ± 225 427 glomeruli for all subjects was similar to the values reported for African Americans, white Americans and white Australians (Table 5).


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  		Table 5 Comparison of estimates of total glomerular number (mean and range) in eight human populations

 
Estimates of an individual's glomerular number at the time of death are a result of (1) glomerular endowment (the number of glomeruli an individual was born with) and (2) glomerular loss occurring with ageing, that is primarily the result of glomerular obsolescence and loss due to arteriosclerosis. In humans, nephron formation is complete at term birth, with no new glomeruli formed after this time [17], and in humans birth weight has been directly correlated with nephron number with an increase of 200 000 to 300 000 glomeruli for every 1 kg increase in birth weight [15]. In addition to genetic influences, an individual's glomerular endowment may be affected by their prenatal environment. Adverse events during pregnancy, including maternal malnutrition [18–20], maternal undernutrition [21,22] and maternal stress (glucocorticoid exposure) [23–25] have been shown to affect kidney development in a number of experimental animal models and to result in a reduction in glomerular endowment.

The nationwide incidence of low birth weight in Senegal (18%) is much higher than in developed countries such as the United States (8%) and Australia (7%) [26]. Based on these national statistics and considering the correlation between birth weight and nephron number, we initially hypothesized that there would be a lower glomerular number in this Senegalese sample than in the other groups that we have studied. However, this was not the case, and estimates of glomerular number were similar to those in developed countries as reported by us and others (see Table 5).

It may be notable that our sample consisted predominantly of people who were born and lived in urban Dakar, where living and nutritional conditions are better than those in remote regions of Senegal. Statistics that are specific to the city of Dakar are scarce; however, one 6-month study conducted in two main maternity hospitals in Dakar in 1995 reported a 10.7% rate of low birth weight, which is closer to that seen in the developed world [27]. Another study based in Dakar in 2001 investigated the rate of low birth weight in babies born to mothers under the age of 20 (10% of all births) and found that 23% of babies in this subgroup had a low birth weight [28]. Despite the high rate of low birth weight in babies born to teenage mothers, maternal health during pregnancy has been reported to be an important priority in Dakar. Pregnant women, breast-feeding mothers and young children were spared reductions in meal quality and frequency when these measures were required in households to cope with insufficient resources [29].

The 2.5-fold range in mean glomerular volume and the mean value of 5.74 µm3 x 106 are similar to the values reported by Nyengaard and Bendtsen (1992) in Danes [5], but are considerably <7–8 µm3 x 106 mean volumes found in Americans and Australians [6,7]. We did not find excessively high mean glomerular volumes like those observed in Australians and Americans (up to 16.99 µm3 x 106) in the Dakar sample. This might be attributed to the narrower range of body sizes in the Dakar community compared with the two previously mentioned populations. Mean glomerular volume has a fairly strong direct relationship with BSA and BMI [4]. Few of the 20 adults in this Dakar sample were obese, and there was only a 1.3-fold range in BSA compared to the African American study in which more than half of the adult population was obese and in which many were severely obese [4].

The kidney pathology observed in this Senegalese urban community was similar to that described for more developed nations [4,6]. Glomerular obsolescence, cortical fibrosis and arteriosclerosis increased with age, and after the age of 30 years kidneys of most Senegalese Africans showed varying degrees of arteriolar nephrosclerosis. The study of the kidney pathology also showed that arteriolar nephrosclerosis was primary and not secondary to a native kidney disease.

Arteriolar nephrosclerosis consisting of arteriosclerosis of the intra-renal renal arteries, interstitial fibrosis and tubular atrophy, and global glomerulosclerosis recognized as glomerular obsolescence, represents the pathology of benign nephrosclerosis that is strongly linked to hypertension. However, it commonly occurs in ageing individuals who never had elevated blood pressure. The common denominator seems to be arteriosclerotic vascular disease, and some observers suggest that the renal arteriolosclerosis precedes and is the cause of hypertension [30–32,16]. There was an unfortunate lack of clinical blood pressures with which to investigate the relationship between blood pressure and the severity of arteriolar nephrosclerosis.

The observation of arteriolar nephrosclerosis in over one-third of the adults suggests that the prevalence of hypertension and/or arteriosclerotic vascular disease in the Dakar city population is considerable. This is reflected in a 1992 report which found that 10.6% of Dakar residents 15 years or older were hypertensive and that the prevalence in those >55 years was between 40% and 54.8% [33].

In summary, this study found that low glomerular number and unusually large glomerular volume are not the characteristic of the kidneys of Senegalese Africans from Dakar city. Body size and glomerular volumes in these Dakar residents have not yet reached the excessively large levels found in Americans and Australians, but hypertension and arteriosclerosis associated kidney disease appear to be widespread.



   Acknowledgments
 
The authors would like to acknowledge Ian Boundy, Sue Connell and Julie Hickey for their assistance preparing the tissue samples for histological examination. PhD scholarship funding for B. McNamara was provided by an Australian Postgraduate Award (APA) and a Faculty of Medicine Dean's Excellence Award. Partial support was provided by grants from the National Institutes of Health NIH 1 RO1 DK065970-01 and NIH Center of Excellence in Minority Health 5P20M00534-02.

Conflict of interest statement. The authors have nothing to declare.



   References
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 5.10.07
Accepted in revised form: 21. 1.08


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 Nephrol Dial TransplantHome page
B. J. McNamara, B. Diouf, M. D. Hughson, W. E. Hoy, and J. F. Bertram
Associations between age, body size and nephron number with individual glomerular volumes in urban West African males
Nephrol. Dial. Transplant., May 1, 2009; 24(5): 1500 - 1506.
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