Nephrectomy Elicits Impact of Age and BMI on Renal Hemodynamics: Lower Postdonation Reserve Capacity in Older or Overweight Kidney Donors

Abstract

Renal functional reserve could be relevant for the maintenance of renal function after kidney donation. Low-dose dopamine induces renal vasodilation with a rise in glomerular filtration rate (GFR) in healthy subjects and is thought to be a reflection of reserve capacity (RC). Older age and higher body mass index (BMI) may be associated with reduced RC. We therefore investigated RC in 178 consecutive living kidney donors (39% males, age 48 ± 11 years, BMI 25.5 ± 4.1). RC was determined as the rise in GFR (¹²⁵I-iothalamate), 4 months before and 2 months after donor nephrectomy. Before donor nephrectomy, GFR was 114 ± 20 mL/min, with a reduction to 72 ± 12 mL/min after donor nephrectomy. The dopamine-induced rise in GFR of 11 ± 10% was reduced to 5 ± 7% after donor nephrectomy (p < 0.001). Before donor nephrectomy, older age and higher BMI did not affect reserve capacity. After donor nephrectomy, the response of GFR to dopamine independently and negatively correlated with older age and higher BMI. Moreover, postdonation reserve capacity was absent in obese donors. The presence of overweight had more impact on loss of RC in younger donors. In conclusion, donor nephrectomy unmasked an age- and overweight-induced loss of reserve capacity. Younger donors with obesity should be carefully monitored.

Introduction

The kidney has a substantial functional reserve capacity (RC) that is assumed to be relevant for the preservation of renal function after loss of functional renal mass, for instance after living kidney donation. Renal RC can be estimated from the renal hemodynamic response to intravenous administration of low-dose dopamine, an amino acid solution or an oral protein load (1–3). Dopamine induces vasodilation of predominantly the postglomerular arteriole. The rise in glomerular filtration rate (GFR) is allowed by concomitant dilation of the afferent arteriole, thus leading to a rise in glomerular perfusion and filtration. The resulting increase in GFR is considered to be a reflection of renal RC (4).

Older age, by loss of nephrons and/or renal arteriosclerosis, has been associated with reduced renal RC (5–7). In the presence of hypertension, obese patients were also reported to have reduced renal RC, compared to lean hypertensive subjects (8), possibly due to hyperfiltration. In chronic renal disease, RC has been reported to be decreased, possibly due to hyperfiltration in the remaining nephrons (4). However, data are not consistent, which may be due to relatively small study populations and differences in patient selection (9,10). In a large series of 125 prospective living kidney donors (mean age 49 ± 11 years; mean BMI 25 ± 4 kg/m²), we did not find renal RC to be reduced in older or more overweight donors during predonation screening, presumably because kidney donors represent a healthy subset of the population. However, older age and higher BMI were independently associated with a larger decrease in renal function early after donation, suggesting impairment in renal adaptive capacity. This had not been detected from the renal hemodynamic responses to dopamine and amino acids prior to donation (11).

Effects of age and overweight on renal risk after living kidney donation are of clinical relevance, as—due to persistent donor shortage—older and/or overweight subjects are increasingly accepted for kidney donation. This implies that the long-term renal risk profile for the current donor population may not be similar to that of the former, healthier, donor population (12).

After kidney donation, renal hemodynamic RC is decreased (13–15), most likely resulting from a state of renal vasodilatation that occurs in the remaining kidney as part of the compensatory response (13). It is unknown whether renal RC after kidney donation is affected by risk factors for renal function loss, such as older age and higher body mass index (BMI).

Based on the above studies, we hypothesized that the decrease in renal RC after kidney donation would be larger in older and in overweight subjects. To test this hypothesis, we analyzed data on renal reserve before and early after donation in 178 living kidney donors and analyzed for the impact of age and BMI.

Methods

Subjects

The study population consisted of 178 consecutive living kidney donors (age 48 ± 11 years, 39% males, mean BMI 25.5 ± 4.1 kg/m²) who underwent the screening protocol with subsequent donation in the University Medical Center Groningen between 1984 and 2005. With regards to age, 95 donors were younger than 50 years, 35 donors were in the range of 50–55 years, 24 donors in the range of 56–60, 13 in the range of 61–65, 8 in the range of 66–70 and 3 donors in the range of 71–75 years. All donors were normotensive or with well-regulated blood pressure by maximum of one antihypertensive drug (eight subjects), they did not have a history of diabetes, kidney disease or cardiovascular events. Potential donors with latent diabetes, identified by abnormal oral glucose tolerance test, were excluded from donation. Physical examination did not reveal abnormal findings. In our center, GFR and its RC are routinely measured as part of the living donation protocol. As described below, GFR was measured as the clearance of ¹²⁵I-iothalamate, first without stimulation, and directly hereafter during stimulation by low-dose dopamine. Measurements were performed 4 months before and 2 months after kidney donation. All donors consented with the use of their clinical data for study purposes.

Renal hemodynamic measurements

GFR was measured by combined constant infusion of radiolabeled tracers ¹²⁵I-iothalamate and ¹³¹I-hippurate, the donors being in a quiet room, in the semisupine position. After drawing a blank blood sample, a priming solution containing 0.04 mL/kg body weight of the infusion solution (0.04 MBq of ¹²⁵I-iothalamate and 0.03 MBq of ¹³¹I-hippurate) plus an extra of 0.6 MBq of ¹²⁵I-iothalamate was given at 08:00 hours, followed by infusion at 12 mL/h. In order to attain stable plasma concentrations of both tracers, a 2-h stabilization period followed, after which baseline measurements started at 10:00 hours. The clearances were calculated as (U × V)/P and (I × V)/P, respectively. U × V represents the urinary excretion of the tracer, I × V represents the infusion rate of the tracer and P represents the tracer value in plasma at the end of each clearance period. This method corrects for incomplete bladder emptying and dead space, by multiplying the urinary clearance of ¹²⁵I-iothalamate with the ratio of the plasma and urinary clearance of ¹³¹I-hippurate. The day-to-day variability for GFR is 2.5% (16).

To obtain RC, the above-described baseline procedure was extended for 2 h. During this period, dopamine was infused at a rate of 1.5 μg/kg/min. GFR during these 2 h was compared with baseline GFR and expressed both as the absolute change in GFR in milliliter per minute and as the percentage change. A clinically relevant adequate reserve response was defined as a rise in GFR to dopamine that exceeded the 2.5% variability of the GFR assay. Therefore a cutoff of 2 mL/min was applied for postdonation renal reserve.

BMI was calculated as (body weight/length²) and divided into classes as follows: normal weight: BMI <25 kg/m² (87 donors), overweight: BMI 25–29.9 kg/m² (70 donors) obesity: BMI ≥30 kg/m² (21 donors).

Statistical analysis

Data are presented as mean ± standard deviation unless stated otherwise. GFR data are presented as absolute values (mL/min) as well as indexed to height (mL/min/m) for analyses with break-up by BMI class and indexed for BSA for analyses with break-up by tertiles of age. Whereas usually GFR is indexed to BSA, the close association between BSA and BMI has been recognized to introduce bias in analyses of the impact of BMI on renal function (17,18). Therefore, indexing to height has been recommended.

Renal RC was analyzed as the percentage change in GFR and as the absolute change in GFR induced by dopamine infusion. Associations were analyzed by univariate analysis (Pearson). In addition, multilinear regression analysis was applied with age and BMI as independent variables entered into the regression equation and renal hemodynamic parameters (proportional rise in GFR) as dependent variables. The influence of donor age on renal function and reserve was assessed by age as a continuous variable and by tertiles of age. Differences in RC between BMI classes were analyzed by analysis of variance (ANOVA) followed by post hoc analysis (LSD) to account for multiple comparisons. Furthermore, we applied ANOVA and post hoc analyses to RC in the different tertiles of age. The above-mentioned cutoff of 2 mL/min change in GFR in response to dopamine was adapted in logistic regression and ROC analyses to predict adequate RC from either age or BMI. To account for possible interaction between BMI and age, the interaction term was calculated as BMI × age and analyzed as a continuous variable. Finally, ANOVA and general linear modeling were applied to the combination of BMI and age. Statistical analyses were performed by using the SPSS version 14.0 software (SPSS Inc., Chicago, IL). A p-value <0.05 was considered statistically significant.

Results

Characteristics: renal function and renal reserve

Thirty-nine percent of donors were male. The mean donor age was 48 ± 11 years and mean BMI was 25.5 ± 4.1 kg/m². Before kidney donation, baseline GFR was 114 ± 20 mL/min, with a reduction to 64 ± 7% of predonation values after donation (p < 0.001). Before donation, infusion of low-dose dopamine (GFR_dopa) significantly increased GFR to 126 ± 24 mL/min, p < 0.001 versus baseline. After donation, infusion of low-dose dopamine induced an increase in GFR from 72 ± 12 mL/min to 76 ± 13 mL/min (p < 0.001 vs. postdonation baseline values). Postdonation renal reserve was significantly reduced compared to predonation renal reserve (p < 0.001).

The population characteristics are given in Table 1 for break up by BMI class. Of the whole population, more than half were either overweight (BMI 25–30; 70/178) or obese (BMI >30; 21/178). Predonation uncorrected GFR was highest in the higher BMI classes, albeit only of borderline statistical significance. There were no differences in predonation RC between the different classes of BMI. Remarkably, postdonation RC was significantly different between the different BMI classes, with a lower RC in overweight and obese subjects, both when expressed as mL/min and as percentage change, shown in the upper panel of Figure 1. In obese subjects, the response to dopamine did no longer reach statistical significance, indicating lack of postdonation RC.

Table 1.  Descriptive statistics before and after living kidney donation for different classes of body mass index

	Normal (n = 87)	Overweight (n = 70)	Obese (n = 21)	p-Value (ANOVA)
Data are provided as mean ± standard deviation; normal weight: BMI <25, overweight: BMI 25–29.9, obese: BMI ≥30. ANOVA was used to test the differences between the weight classes. Creatinine converted from mg/dL into μmol/L: ^1 before donation, normal weight 83 ± 11 μmol/L; overweight 86 ± 13 μmol/L; obese 80 ± 11 μmol/L; ^2 after donation, normal weight 111 ± 17 μmol/L; overweight 120 ± 19 μmol/L; obese donors 115 ± 20 μmol/L. *Dopamine-stimulated GFR values compared to baseline values: p < 0.001, before as well as after donation (paired t-tests). To prevent introduction of bias by body weight, GFR was corrected for height. BMI = body mass index; GFRdopa= GFR after infusion of low-dose dopamine; GFR = glomerular filtration rate; ANOVA = analysis of variance.
Before donation
Age (years)	46 ± 11	49 ± 11	52 ± 8	0.07
Body mass index (kg/m^2)	22.4 ± 1.7	27.0 ± 1.4	33.5 ± 3.7	by default
Percentage male donors	34%	47%	33%	NS
GFR baseline (mL/min)	111 ± 15	117 ± 23	119 ± 24	0.07
GFRdopa (mL/min)	122 ± 19*	129 ± 28*	132 ± 27*	0.10
Absolute change in GFR to dopamine	11.7 ± 9.9	12.4 ± 13.7	12.6 ± 12.8	NS
Percentage change in GFR to dopamine	10.6 ± 8.7	10.8 ± 10.4	11.1 ± 11.9	NS
GFR normalized for height (mL/min/m)	64 ± 8	68 ± 11	70 ± 13	0.01
GFRdopa normalized for height (mL/min/m)	71 ± 10*	74 ± 14*	78 ± 15*	0.03
Serum creatinine (mg/dL)^1	0.9 ± 0.1	1.0 ± 0.1	0.9 ± 0.1	NS
After donation
GFR baseline (mL/min)	70 ± 11	74 ± 13	74 ± 11	0.10
GFR on dopamine (mL/min)	75 ± 14*	77 ± 13*	76 ± 12	NS
Absolute change in GFR to dopamine	4.9 ± 6.1	3.4 ± 4.1	0.9 ± 4.0	0.005
Percentage change in GFR to dopamine	6.7 ± 8.4	4.8 ± 5.5	1.3 ± 5.5	0.006
GFR normalized for height (mL/min/m)	41 ± 6	42 ± 6	45 ± 6	0.01
GFRdopa normalized for height (mL/min/m)	43 ± 8*	44 ± 7*	45 ± 6	NS
Serum creatinine (mg/dL)^2	1.3 ± 0.2	1.4 ± 0.2	1.3 ± 0.2	<0.01

Figure 1. BMI and age-related differences in renal reserve capacity. Renal reserve capacity is expressed as the percentage rise in GFR after infusion of low-dose dopamine. There were no statistically significant differences in predonation reserve capacity between the groups of BMI or age (all ANOVA p > 0.10). After donation, reserve capacity was lower in donors with higher BMI and older age: (A) postdonation reserve capacity differed between BMI class: p = 0.005 (ANOVA). Post hoc analyses: overweight versus normal weight p = 0.086; overweight versus obese, p = 0.046 and obese versus normal weight, p = 0.002. Normal weight: n = 87; overweight: n = 70; obese: n = 21. (B) Postdonation reserve capacity differed between tertiles of age at donation: p = 0.006 (ANOVA). Post hoc analyses: oldest versus middle tertile, p = 0.036 and oldest versus youngest tertile, p = 0.002. BMI, body mass index; GFR, glomerular filtration rate.

Table 2 shows population characteristics for breakup by tertiles of age. As anticipated, both absolute GFR and BSA-corrected GFR were significantly lower in older subjects, before and after donation. Before donation, RC was not different for the age groups. After donation, however, RC was significantly lower in the older age groups, both when expressed as mL/min change and as percentage change, which is shown in the lower panel of Figure 1. Yet, even in the oldest age category, there was still a significant postdonation response to dopamine.

Table 2.  Descriptive statistics before and after living kidney donation for tertiles of age

	1st tertile (n = 62)	2nd tertile (n = 59)	3rd tertile (n = 57)	p-Value (ANOVA)
Data are provided as mean ± standard deviation unless stated otherwise. ANOVA was used to test the differences between the tertiles. Creatinine converted from mg/dL into μmol/L: ^1before donation, first tertile 84 ± 9 μmol/L; second tertile 83 ± 11 μmol/L; third tertile 84 ± 15 μmol/L; ^2after donation, first tertile 112 ± 16 μmol/L; second tertile 114 ± 16 μmol/L; third tertile 119 ± 23 μmol/L. Dopamine-stimulated GFR values compared to baseline values:*p < 0.001, before as well as after donation, ^#p<0.01 (paired t-tests). GFR, glomerular filtration rate; ANOVA, analysis of variance.
Before donation
Age (years, range)	21–45	46–53	54–75	By default
Body mass index (kg/m^2)	24.3 ± 4.3	25.8 ± 3.9	26.5 ± 4.0	0.01
Percentage male donors	40%	37%	40%	NS
GFR baseline (mL/min)	123 ± 19	113 ± 19	105 ± 17	<0.001
GFRdopa (mL/min)	135 ± 23*	127 ± 23*	116 ± 22*	<0.001
Absolute change in GFR to dopamine	11.8 ± 11.9	14.1 ± 10.2	10.4 ± 12.9	NS
Percentage change in GFR to dopamine	9.6 ± 8.9	12.6 ± 8.9	10.1 ± 11.2	NS
GFR normalized for BSA (mL/min/1.73 m^2)	113 ± 14	104 ± 14	96 ± 14	<0.001
GFRdopa normalized for BSA (mL/min/1.73 m^2)	124 ± 17*	116 ± 17*	105 ± 18*	<0.001
Serum creatinine (mg/dL)^1	0.9 ± 0.1	0.9 ± 0.1	1.0 ± 0.2	NS
After donation
GFR (mL/min)	77 ± 10	72 ± 12	66 ± 10	<0.001
GFRdopa (mL/min)	83 ± 11*	77 ± 13*	68 ± 11*	<0.001
Absolute change in GFR to dopamine	5.3 ± 5.5	4.4 ± 5.5	1.8 ± 4.2	0.001
Percentage change in GFR to dopamine	7.1 ± 7.3	6.1 ± 7.2	2.8 ± 6.1	0.002
GFR normalized for BSA (mL/min/1.73 m^2)	71 ± 9	67 ± 8	60 ± 8	<0.001
GFRdopa normalized for BSA (mL/min/1.73 m^2)	76 ± 11*	71 ± 11*	62 ± 8^#	<0.001
Serum creatinine (mg/dL)^2	1.3 ± 0.2	1.3 ± 0.2	1.3 ± 0.3	0.09

Determinants of renal reserve: univariate analysis

To exclude a possible confounding effect of the categorization of BMI and age, respectively, we also analyzed BMI and age as continuous variables in determining renal reserve. Scatter plots for the relation between the response of GFR to dopamine and BMI and age, respectively, are shown in Figure 2. The left panels show data before donation and the right panels show data after donation. Before donation, the renal responses to dopamine did not correlate to BMI or to age. After donation, however, the change in GFR to dopamine correlated negatively with BMI and age, both when expressed as a percentage (for BMI: R =−0.26, for age R =−0.28; both p < 0.001) and when expressed as mL/min (for BMI: R =−0.28, for age R =−0.33; both p < 0.001). To analyze whether these results were driven by the few donors with very high BMI, we repeated the univariate analyses after exclusion of donor with obesity (BMI>30) or overt obesity (BMI>35). The negative association between BMI and postdonation renal reserve persisted on either analysis (R =−0.19 with p ≤ 0.01 and R =−0.27 with p ≤ 0.001 respectively), indicating that the results were not controlled by outliers.

Figure 2. Renal reserve capacity in relation to BMI and age before and after kidney donation. Renal reserve capacity is expressed as delta GFR (absolute change in GFR after constant infusion of low-dose dopamine). Lines represent regression with 95% confidence interval of the mean. Before donation, renal reserve did not correlate to age or BMI. After donation, higher BMI (R =−0.28; p ≤ 0.001) and older age (R =−0.33; p ≤ 0.001) were negatively associated with renal reserve.

Combined effect of BMI and age on postdonation renal reserve

Older age and higher BMI are usually associated with one another so it is relevant to investigate both their independent and their combined effects. As anticipated, in our population, age positively correlated to BMI (R = 0.19, p = 0.01). To test whether the effects of BMI and age on postdonation RC were independent, first, we performed partial univariate correlation analyses. In these analyses, BMI—when corrected for age—and age—when corrected for BMI—were still negatively and significantly associated with RC (p = 0.001 and p = 0.008, respectively). Second, on multivariate analysis both age (p = 0.001) and BMI (p = 0.003) were independent negative predictors of the overall GFR response to dopamine (R² of 0.13; p < 0.001).

General linear modeling was performed to substantiate and visualize the presence of interaction between BMI and age for postdonation reserve. In this model, we found a significant interaction between BMI and age (R²= 0.17, p < 0.001), with BMI in classes and age in tertiles (in line with the data presentation in Tables 1 and 2). The top panel of Figure 3 shows the effect of overweight or obesity on renal RC by age group (with, for graphical clarity, data provided by cutoff at median age, ANOVA p = 0.002). There was a statistically significant difference in RC between younger and older donors with normal weight (post hoc p = 0.005). However, when overweight or obesity was present, there was no longer a difference between younger and older donors (p = 0.116 and p = 0.594, respectively).

Figure 3. Interaction between age and BMI in influencing functional reserve of GFR and the donation-induced decrease in reserve capacity. The donation-induced decrease in reserve capacity is plotted for age below (open circles) or above (black squares) the median of 49 years and different classes of BMI. Upper panel: reserve capacity expressed as renal response to dopamine in terms of a percentage. Lower panel: change in reserve capacity obtained as postdonation RC minus predonation RC. Younger donors (<49) with normal weight (BMI < 25) had a statistical significant smaller decrease in reserve capacity compared to older donors with normal weight (p = 0.005; post hoc analysis). However, when overweight (BMI 25–30) or obesity (BMI ≥30) was present, there was no longer a difference between younger or older donors. Furthermore, for younger donors, loss of renal reserve was profound when obesity was present (p = 0.023, obese vs. normal weight donors with age below the median; post hoc analysis). For older donors, body mass index did not influence the degree of loss of renal reserve.

Determinants of the postdonation decrease in RC

As shown in Tables 1 and 2, RC was significantly reduced after donation. To identify the determinants of the decrease in RC, we performed both univariate and multivariate analyses on the decrease in renal reserve, obtained as predonation RC minus postdonation RC (mL/min). On univariate analysis, both BMI (R =−0.22, p = 0.003) and age (R =−0.20, p = 0.006) were negatively correlated to the change in renal RC. Univariate, the interaction term BMI × age correlated to the decrease in RC (R = 0.26, p = 0.001). Multivariate regression analysis showed both factors to be independent determinants of the decrease in reserve capacity. On general linear modeling—entering BMI in classes and age in tertiles—the interaction term was a significant independent variable in predicting postdonation renal RC (R²= 0.14), with a p-value of 0.002, as illustrated in the lower panel of Figure 3, which shows by a break-up by median age for graphical clarity that BMI has considerable impact on the decline in RC in younger, but not older, donors: the nephrectomy-induced loss of renal reserve was most severe for young donors with obesity.

Prediction of adequate renal response to dopamine

A threshold of 2 mL/min was applied to define adequate renal response. Before donation, renal response to dopamine was below this cutoff for 20 donors. Predonation, logistic regression analysis for prediction of inadequate reserve provided a model of borderline significance only (Nagelkerke R²= 0.05; p = 0.08), in which only age was a statistically significant contributor (p < 0.05). After donation, renal response of 74 donors remained below 2 mL/min. The predicted potential for this inadequate response increased; Nagelkerke R²= 0.14 (p <0.01) and both BMI (p = 0.012) and age (p = 0.011) contributed to the model. Figure 4 shows prediction of postdonation renal response to dopamine by BMI and age as ROC curve. The areas under the curve (AUC) were significantly different from the reference line for both age and BMI. However, the strength in predicting an adequate reserve response by either variable was rather modest with AUC = 0.63 ± 0.04 for age and AUC = 0.64 ± 0.04 for BMI.

Figure 4. ROC curve for postdonation renal reserve predicted by age and BMI. The presence of postdonation renal reserve was defined at a threshold of 2 mL/min increase in GFR compared to baseline. Seventy-four donors did not reach this threshold after donation. Both BMI and age were independent predictors of adequate renal response on logistic regression analysis. The AUCs are significantly higher than the reference line, for age p = 0.003 and for BMI p = 0.001. Abbreviations: AUC = area under the curve; BMI = body mass index.

Analysis of donors with hypertension

Eight donors were using antihypertensive drugs (50% male), three of whom used ACEi or ARB. The mean age was 56 ± 5 years (range 48–63), versus 48 ± 11 years in the normotensive group (borderline statistical significance of p = 0.06). The mean BMI was 28 ± 3 kg/m² (range 24–31) versus 25 ± 4 kg/m² in the normotensive group (p = 0.15). GFR before and after donor nephrectomy was similar between normotensive and hypertensive donors. Renal RC was also similar in both groups, before and after donation.

Discussion

This study, the largest so far on renal RC before and after living kidney donation, shows that after kidney donation older age and higher BMI were independently associated with a lower RC. Quantitatively, the predictive value of either age or BMI for the amount of RC was limited, however. We can assume that several other—yet undefined—factors play a role in the renal response to dopamine. Still, it is remarkable that prior to donation, there was no relationship between age or BMI on the one hand and renal RC on the other. Donor nephrectomy seemed to unmask an age- and overweight-related loss of renal reserve.

Renal RC after kidney donation has been studied in several prior, smaller studies (13–15,19,20). All studies document the presence of RC after donation. Comparable to our results, renal RC tested with dopamine was found to be almost halved in kidney donors (13,14,19). This has been interpreted as a reflection of compensatory hyperperfusion and hyperfiltration of the remaining kidney. There is sparse data to suggest an association between impairment of RC and the risk for renal function loss. In diabetic patients, loss of renal reserve was found to accompany or precede microalbuminuria and glomerular lesions, well before the presence of overt diabetic nephropathy (21–23). In our study, renal reserve after donation was negatively affected by age and BMI. Moreover, postdonation RC was completely annihilated in obese donors. It should be mentioned that the postdonation differences in renal reserve observed here are quantitatively subtle. Based on our current data, it is not warranted to conclude on their clinical significance. However, previous studies have shown that even subtle changes in renal hemodynamics, be it in GFR or filtration fraction, can have prognostic impact for long-term renal function (24,25). Long-term follow-up, therefore, is warranted to investigate whether the BMI- or age-related impairment or the absence of renal reserve after donor nephrectomy is prognostic for an increased risk for renal function loss.

Currently, there is no validated reference value for an adequate renal hemodynamic RC, neither in subjects with two kidneys nor in subjects with a single kidney. From a clinical point of view, the most relevant definition would perhaps be the amount of renal reserve that allows the maintenance of long-term renal function despite uninephrectomy. We cannot ascertain such a cutoff from our current data. However, our data provide a basis to establish the prognostic value of specific cutoffs for RC in the future, as we provide the largest series on postdonation RC so far and follow-up studies are ongoing.

Prior studies have reported a decrease in RC in older subjects, albeit not invariably so (5,9,10). In our large population, we did not detect an effect of age on RC prior to kidney donation. This may be due to the fact that kidney donors represent an above-average healthy subset of the population, in whom GFR was also relatively well preserved with age, albeit lower than in younger subjects. Remarkably, donor nephrectomy elicited an age-related effect on renal RC. Effects of age on renal reserve have been attributed to impaired vasodilator response due to arteriosclerosis in the kidney's interlobular and arcuate arteries (7). Apparently, in our older subjects, the condition of the renal vasculature allowed for an appropriate response to dopamine before donation. After donation, due to compensatory vasodilation elicited by the nephrectomy, further vasodilation capacity may have been limited as a possible mechanism underlying the effect of age on renal reserve.

As to the effect of BMI, one prior study documented a reduced RC in obese hypertensives compared to lean hypertensives (8). Our study is the first to document an adverse effect of BMI on RC in normotensive subjects. Again, this effect was not present before donation, but was elicited by donor nephrectomy. In our study, with a small number of hypertensive subjects, the decrease in renal reserve could not be attributed to hypertension, but the power to detect such an effect was obviously low. Higher BMI was associated with higher baseline GFR, which may be a reflection of hyperfiltration due to weight excess, thus compromising renal reserve. Nevertheless, it is remarkable that before donation apparently the higher baseline GFR in the same subjects did not result in a detectably lower RC. It would be logical to assume that the reduction in renal mass calls on the renal reserve to maintain overall GFR, that weight-excess-associated hyperfiltration calls on renal reserve by a similar mechanism and that their combination thus resulted in the observed decrease in renal RC.

Previously, we found both higher BMI and age to be associated with the magnitude of renal function loss after kidney donation (11). Our current data demonstrate that these same factors are associated with reduced postdonation renal RC. Since higher BMI has in particular been associated with higher risk for renal damage after nephrectomy (26), our findings of a reduced postdonation renal reserve in kidney donors with higher BMI may be of clinical relevance. The higher baseline GFR in these donors may explain loss of postdonation adequate RC due to weight-excess-related hyperfiltration. In this respect, it is relevant to note that weight loss has been shown to correct obesity-induced hyperfiltration (28), so a potentially favorable intervention is available.

Hypertension, diabetes, proteinuria and/or hyperlipidemia are assumed to play a role in the development of renal damage with obesity (27). Yet, living kidney donors are selected for good health, and these comorbidities were therefore absent in our population. The changes in RC that we observed after donation are therefore related to the weight excess as such and not to comorbidities. The prognostic and pathophysiological impact of loss of RC relative to comorbid conditions remains to be established in long-term studies.

Remarkably, we observed that the presence of overweight had more impact on loss of RC in younger donors. Younger donors with overweight or obesity displayed a loss of renal reserve that was similar to the loss of reserve of older donors, in whom it occurred irrespective of BMI. Moreover, in obese donors, the capacity to increase GFR to low-dose dopamine was annihilated after donation. Our current study design, with only a brief duration of follow-up after donation, does not allow us to substantiate the clinical significance of this finding. Furthermore, long-term effects of lack of renal reserve in combination with comorbidities remain speculative. The prognostic impact of lack of renal reserve remains to be substantiated by long-term follow-up data. Theoretically, the absence of RC might be an unfavorable prognostic sign, indicating glomerular hyperfiltration, which could be harmful in the long run.

Our study has several limitations. First, we have only one time point after donation, which was on a relatively short-term. Moreover, it is uncertain how long-term adaptive responses could further modulate RC and it is unknown whether overweight or older donors adapt to nephrectomy over a different time frame. Second, our study was performed in a predominantly Caucasian population, which limits the generalizability of our data. There is some evidence that ethnic factors are relevant to renal RC and its association with renal damage (23). Third, the response to dopamine may not represent the maximal vasodilator response of the kidney and thus provide an incomplete assessment of renal hemodynamic reserve. Additional protein loading may provide a more complete reflection of hemodynamic reserve, but even a maximum hemodynamic response may still not be a true reflection of the adaptive capacity of the kidney. Renal adaptation after contra-lateral nephrectomy not only comprises more than just vasodilation but also includes tubular adaptation and renal growth. In line, as noted above, the clinical and prognostic impact of renal reserve, and changes in renal reserve, have not convincingly been established. Accordingly, the use of dopamine response as a tool to predict the long-term renal outcome is in itself still under investigation. Long-term follow-up studies are therefore needed to establish the clinical impact of our findings.

In conclusion, weight excess and older age are associated with impairment of postdonation renal RC. We emphasize the need for donor follow-up especially when obesity is involved in younger donors, since these donors are potentially exposed to an increased renal risk for a long period of time. Though a potential benefit from weight loss, low protein diet and/or ACE inhibition remains to be investigated, weight loss should be emphasized in donors with excess body weight.

Acknowledgments

The authors would like to thank Roelie Karsten and Marian Vroom for their technical assistance.

Conflict of Interest Statement

The authors do not have any commercial associations that might pose a conflict of interest in connection with the submitted manuscript.