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NDT Advance Access originally published online on May 23, 2006
Nephrology Dialysis Transplantation 2006 21(9):2577-2582; doi:10.1093/ndt/gfl227
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© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Original Articles: Dialysis and Transplantation

Differences in decline in GFR with age between males and females. Reference data on clearances of inulin and PAH in potential kidney donors

Ulla B. Berg

Department of Pediatrics, Karolinska Institutet, Karolinska University Hospital Huddinge, S-14186 Stockholm, Sweden

Correspondence and offprint requests to: U. B. Berg, MD, PhD, Department of Pediatrics, Karolinska Institutet, Karolinska University Hospital Huddinge, S-14186 Stockholm, Sweden. Email: ulla.b.berg{at}karolinska.se



   Abstract
Top
 Abstract
Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. To ensure that potential kidney donors have no renal impairment, it is extremely important to have accurate methods for evaluating the glomerular filtration rate (GFR). The golden standard, clearance of inulin, has been used in the present study. The aim was to evaluate the effects of age and sex on renal function and present reference data.

Methods. A total of 122 potential kidney donors, 62 females, aged 21–67 years, were investigated with the GFR and effective renal plasma flow (ERPF) determined by clearances of inulin and para-amino hippurate.

Results. The mean ± SD GFR and ERPF were 105 ± 13 and 545 ± 108 ml/min/1.73 m2, respectively, and we found no difference between the males and females. When relating GFR and ERPF to age, however, a significant decline was found in GFR and ERPF in males, but not in females in the age range of 20–50 years. GFR fell by a mean of 8.7 ml/min/1.73 m2 and ERPF by 90 ml/min/1.73 m2 per decade in male donors.

Conclusion. With adequate methods for determining GFR and ERPF, a clear difference in the effect of age was seen between the sexes. Males showed a significant decrease between 20 and 50 years of age, which was not seen in females. Females seem to be protected in the pre-menopausal period probably by oestrogens. These results confirm clinically those found in rats.

Keywords: clearance of inulin; effective renal plasma flow; glomerular filtration rate; kidney donors; reference values; sex and age



   Introduction
Top
 Abstract
 Introduction
Subjects and methods
 Results
 Discussion
 References
 
The best measure of renal function is the glomerular filtration rate (GFR). The assessment of GFR is important for various reasons: the characterization of various renal diseases, evaluating the effect of different therapies, adjusting the doses of various drugs and ensuring that potential kidney donors have normal renal function. It is also important to use accurate methods for the determination of GFR and adequate reference values. Previous studies of renal function have shown conflicting results with regards to the effects of age and sex on renal function [1–5]. Moreover, various methods have been used to determine GFR. In our unit of paediatric nephrology, 70% of the paediatric kidney transplantations are done using living donors, mostly parents, but sometimes even grandparents. Most of the potential donors are investigated by means of accurate renal function tests—namely, by determining GFR and effective renal plasma flow (ERPF) by clearances of inulin and para-aminohippurate (PAH). They are examined before donation, around 3 months after and thereafter every other year at the same time as their kidney recipients [6]. We report here the investigations done before transplantation in order to give reference values for GFR and ERPF, and the effects of age and sex on these variables. Since most parents are quite young, we can evaluate only the influence of age between 20 and 50 years.



   Subjects and methods
Top
 Abstract
 Introduction
 Subjects and methods
Results
 Discussion
 References
 
A total of 122 potential kidney donors, 62 females, mainly parents of paediatric recipients in our unit, were investigated. Their ages varied between 21.5 and 67.1 (median 38.5) years, and no difference was found between males and females (median 38.7 and 38.8 years, respectively). Eighty-three (40 females) became living donors while 39 (22 females) were investigated as potential donors, but their spouses were chosen for donation. Table 1 gives some demographic data of the individuals. A total of 48 (25 females) donors were parents or relatives of children with hereditary diseases (familial juvenile nephronophthisis, autosomal recessive polycystic kidney disease, congenital nephrosis of the Finnish type, etc.), 37 (18 females) were relatives of children with malformations (dysplastic kidneys, urethral valves, etc.), 33 (16 females) were relatives of children with acquired diseases (mainly glomerulopathies) and four were unrelated kidney donors. The ages of the donors to children with hereditary diseases, malformations or acquired diseases were about the same (mean 37, 36 and 41 years, respectively). Renal function was evaluated with the GFR and ERPF assessed by the clearances of inulin (Inutest, 25%, Laevosan-Gesellschaft, Vienna, Austria) and PAH (amino-hippurate sodium, 20%, Merck Sharp & Dohme International, Merck & Co., Inc., Whitehouse Station, NJ, USA), respectively. A standard clearance technique was used [7]. After a prime dose of inulin 64 mg/kg body weight and PAH 9 mg/kg body weight, a continuous infusion of 1–2 mg/kg inulin and 0.15–0.30 mg/kg PAH per minute was given intravenously. Water diuresis was induced by an oral water intake of 20 ml/kg body weight during the first hour (maximum 1200 ml) and then 5 ml/kg body weight (maximum 300 ml) every 30 min. This enabled these persons to empty their bladders by spontaneous micturition every 30 min. After 1 h equilibration time, four urine samples were collected and, midway through each collection period, a blood sample was drawn. The clearance values shown are the mean values of the four clearance periods. For 2 years, no PAH was available on the market. Therefore, the number of persons investigated for ERPF and GFR sometimes differ. The filtration fraction (FF) is calculated as 100 x GFR/ERPF.


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  		Table 1. Demographic data of potential donors in regard gender and if becoming a living donor or not (spousal donation)

 
Blood and urine concentrations of inulin were determined by an enzymatic method [8] and that of PAH by Brun's [9] method. Body surface area (BSA) was calculated using Haycock et al.'s [10] method.

Blood pressure (BP) was measured in the right arm, after the patients had rested for 30 min, with an Omron digital blood pressure monitor (Model Hem-700C, Boehringer Mannheim, Scandinavia AB, Bromma, Sweden) and taken before the renal function test was started. The mean arterial blood pressure (MAP) was calculated as the diastolic BP plus one-third of the difference between the systolic and diastolic BPs.

The study was approved by the Ethics Committee of the Karolinska Institute.

Statistical analyses
The mean and SD are given for the normally distributed values. The Student's t-test was used for the normally distributed variables and the Mann–Whitney U-test for the not normally distributed data. In comparisons of potential donors of different age decades, one-way analysis of variance (ANOVA) was used, followed by post-hoc t-tests with the Bonferroni adjustment for the normally distributed variables. Univariate regression analyses were employed to evaluate the correlations between the age and different renal function variables. The differences in slope of renal function data vs age between sexes were analysed by multiple linear regression analyses with the independent variables sex, age and sex x age. The sex x age interaction refers to the statistical test of whether the slopes are parallel or not. P < 0.05 was regarded as significant. Multiple regression analyses were employed when different factors of importance for the renal haemodynamics should be analysed. We used the statistical program of Statistica 7.0.



   Results
Top
 Abstract
 Introduction
 Subjects and methods
 Results
Discussion
 References
 
The mean absolute and relative GFR for the entire group were 115 (20) ml/min and 105 (13) ml/min/1.73 m2 BSA, and the corresponding values for ERPF were 593 (138) ml/min and 545 (108) ml/min/1.73 m2, respectively. We found no differences in GFR or ERPF between relatives of children with hereditary diseases, malformations or acquired diseases (mean GFR 105, 108 and 104 ml/min/1.73 m2, and mean ERPF 551, 550 and 520 ml/min/1.73 m2, respectively). Table 2 shows the absolute (ml/min) and relative (ml/min/1.73 m2) GFR and ERPF values of male and female donors. The FF and BSA are also given. The absolute GFR and ERPF were significantly higher in males than in females, but when related to 1.73 m2 BSA, no differences between them were seen.


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  		Table 2. Renal haemodynamics of potential donors in regard to gender

 
When the ages of the donors were divided into 5-year age intervals, we found no significant differences between GFR of the donors aged 20 to <25 years and those aged 25 to <30 years, between those aged 30 to <35 and those aged 35 to <40 years, etc. We, therefore, divided the donors into 10-year age intervals, i.e., age decades. Table 3 shows the mean relative GFR, ERPF and FF in males and females divided into various age decades. The greatest difference with age was seen in ERPF. When comparing males and females in the various age decades, males showed significantly higher relative GFR and ERPF and significantly lower FF than females in the age range of 20 to <30 years, but no significant differences between the sexes were seen in the other age decades (Table 3).


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  		Table 3. Relative GFR, ERPF (ml/min/1.73 m2) and FF (%) of all potential donors in regard to sex and age decades

 
When relating the absolute (ml/min) and relative (ml/min/1.73 m2) GFR to age in all the donors, we found a significant drop (R = –0.205, n = 122, P = 0.02 and R = –0.312, P = 0.0003, respectively) with a mean decline of 4.8 ml/min and 5.1 ml/min/1.73 m2 per decade, respectively. A similar decline with age was seen in the absolute and relative ERPF (R = –0.295, n = 110, P = 0.002 and R = –0.401, P < 0.0001, respectively, with a mean fall of 48 ml/min and 50 ml/min/1.73 m2 per decade, respectively) and a significant increase in FF with age (R = 0.244, n = 110, P = 0.01). Figures 1(A and B) and 2(A and B) show the absolute and relative GFR in relation to age and sex, and Figures 3(A and B) and 4(A and B) show the absolute and relative ERPF in relation to age and sex. We found significant decreases in absolute and relative GFR in males with a mean fall in the absolute GFR of 8.1 ml/min per decade and in the relative GFR of 8.7 ml/min/1.73 m2 per decade. The significant decline in GFR with age persisted if the donor aged >60 years of age was excluded. No such decline in absolute (1.7 ml/min per decade) and relative GFR (1.4 ml/min/1.73 m2 per decade) was seen in females during the corresponding ages with or without the donors aged >60 years. A significant difference (P = 0.0074) was noted in the slope of the relative GFR vs age between males and females. Declines with age were also seen in the absolute (87 ml/min per decade) and relative ERPF (90 ml/min/1.73 m2 per decade) in males, but not in females (10 ml/min per decade and 13 ml/min/1.73 m2 per decade, respectively) (Figures 3 and 4), and there was a significant (P = 0.0008) difference in the slopes between the sexes. When calculating the regression with the interaction term (sex x age), we found that declines in GFR and ERPF were significant in males, but not in females. Similarly, the FF increased significantly with age in males, but not in females (Figure 5A and B).


Figure 1
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  		Fig. 1. A and B show the relationship between age and the absolute GFR (ml/min) of males and females. A nearly significant difference (P = 0.083) between the slopes was seen.

 

Figure 2
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  		Fig. 2. A and B show the relationship between age and the relative GFR (ml/min/1.73 m2 BSA) of males and females. The fall in GFR of 8.7 ml/min/1.73 m2 per decade in males differed significantly from that in females (1.4 ml/min/1.73 m2 per decade, P = 0.0074).

 

Figure 3
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  		Fig. 3. A and B show the relationship between age and the absolute ERPF (ml/min) of males and females. The fall in ERPF of 87 ml/min per decade in males differed significantly from that in females (11 ml/min per decade, P = 0.0039).

 

Figure 4
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  		Fig. 4. A and B show the relationship between age and the relative ERPF (ml/min/1.73 m2 BSA) of males and females. The fall in ERPF of 90 ml/min/1.73 m2 per decade in males differed significantly from that in females (13 ml/min/1.73 m2 per decade, P = 0.0008).

 

Figure 5
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  		Fig. 5. A and B show the relationship between age and the FF (%) of males and females.

 
In a multiple regression analyses with GFR or ERPF as dependent variables and age, BMI and MAP as independent variables, age was the only variable that turned out to be of significance and only for the male subjects.



   Discussion
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
References
 
Only a few studies have been published concerning the assessment of GFR and ERPF by clearances of inulin and PAH, which is the golden standard [1,11]. Several other GFR markers have been used such as radiolabelled substances of Cr ethylenediaminetetra-acetic acid (CrEDTA), Tc diethylenetriamine-penta-acetic acid (TcDTPA) and iothalamate. The effects of sex and age have also been discussed, and some authors state that GFR is about the same in males and females when GFR is related to 1.73 m2 BSA [1–5], which is in accordance with our results. As expected, however, absolute GFR was significantly higher in men than in women, which was due to the greater BSA in men [1,5]. Although there was no difference between the sexes in mean relative GFR or ERPF, we found considerable differences between males and females when the functional variables were related to age. In the present study, significant declines in absolute and relative GFR and ERPF with age were seen in males as early as 20 years, but not in females. This has not been reported before, but Wesson [11] described a delayed and slower fall in GFR with age in women. Barai et al. [12] investigated potential kidney donors in India and found that their GFR was much lower than that of a Western population, but when they analysed the relative GFR in various age groups, they found no significant difference in the 20–30 or 30–40 year age groups between males and females, but significantly higher GFR in females than in males aged 41–45 years, which suggests a slower or no progression in females with age—i.e. results which are in accordance with ours. Most authors have noted a decline in GFR with age, but the regression analyses included all patients without taking gender into account [1–3]. Using Cr EDTA, Grewal and Blake [5] found no significant decline in GFR with age up to 40 years. However, Rule et al. [4] reported a decline in absolute GFR in both males and females, and some have noted a slower decline in GFR before 40–50 years of age and a faster progression after this [2,11]. Since hardly any of our donors were over 50 years of age, we can only report the relationship between GFR and age 20–50 years—i.e. the pre-menopausal period in women. It seems likely that females are protected by oestrogens in the pre-menopausal period. In experimental studies of rats, females are protected from the age-dependent decline in GFR as compared with males [13]. The rate of progression of chronic renal disease is also faster in men than in pre-menopausal women [14] and this protection disappears after the menopause and can be restored by oestradiol replacement [15]. In a recent report by Baylis [16], a marked sexual dimorphism with respect to renal haemodynamics and structure is thought to protect females because of the beneficial effects of oestrogens and the damaging ones of androgens. Moreover, sexual dimorphism includes the nitric oxide (NO) system which enables pre-menopausal females to produce more NO than males [17]. The protective action of oestrogens has been ascribed to their direct anti-growth effects on the glomerular mesangial cells and inhibition of mesangial extracellular matrix accumulation—i.e. typical events in the development of glomerular sclerosis [18–20]. Oestrogens have been reported to stimulate the action of endothelial NO [21] and inhibit angiotensin II production [22] while testosterone has the opposite effect [21,23,24]. Another study compared the kidney function of healthy women taking various contraceptives with those not taking them; the authors found that in all groups taking contraceptives, endogenous creatinine clearance was significantly higher than in those not taking them [25].

Our mean GFR of 105 ml/min/1.73 m2 seems to be lower than that measured with the clearance of inulin [1,26] but does not differ from that reported with other GFR markers, such as iothalamate [4] and 51CrEDTA [5]. An explanation for the somewhat lower GFR in our donors may be the high hydration used in this study, which has been shown to reduce GFR [27]. Moreover, many of our potential donors are relatives of recipients and may therefore have a greater prevalence of subclinical renal disease. However, the GFR in relatives of children with hereditary diseases was about the same as in those of children with acquired diseases, and we found no sex or age differences between the donors of kidneys to recipients with hereditary diseases, malformations or acquired diseases.

In conclusion, we report reference data on GFR and ERPF in a group of potential donors 20–50 years of age. Males showed a significant decline in GFR and ERPF with age during this period while this was not seen in females, who are probably protected by oestrogens.



   Acknowledgments
 
This study was supported by grants from Karolinska Institutet and from the Swedish Medical Research Foundation (nr 6864).

Conflict of interest statement. None declared



   References
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 28. 1.06
Accepted in revised form: 30. 3.06


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