Because the kidney transplant recipient waiting list continues to grow, the demand for living kidney donation is increasing. At the same time, population demographics are changing, such that today in the United States, a third of the population has metabolic syndrome, and an even bigger percentage is estimated to have at least one of the risk factors for the metabolic syndrome, namely, obesity and hypertension. As a result, the criteria for donor eligibility at many transplant centers have changed in recent years. Thus, the living donor demographics are strikingly different in the current era than those reported in the earlier days of kidney transplantation. In fact, a quarter of living donors are “medically complex” with hypertension and obesity.1 Similarly, donors older than 50 years now constitute one quarter of living donors.2
Several recent studies have questioned whether the functional capacity of the remaining kidney in medically complex living kidney donors is as robust as in standard living donors. For example, two months after donation, dopamine-induced rise in glomerular filtration rate (GFR) was found to be less in obese and older individuals than in standard donors, suggesting an impaired functional compensation in these higher risk donors.3 In another study, older age and higher body mass index (BMI) at the time of donation were associated with a GFR below 60 mL/m2 per min during follow-up.4 These results raise the question of whether these risk factors alter the underlying physiology related to compensatory hypertrophy in the setting of reduced nephron mass, and the overall long-term safety of kidney donation by older, obese, or hypertensive individuals.
We have previously reported our approach to expanded criteria living donors.5 Our goal is to continually assess the safety of kidney donation and to identify the impact of different risk factors at the time of donation on the remaining kidney in the long term. In line with this, we report the impact of older age, obesity, and hypertension on the compensatory response of the remaining kidney regarding both parenchymal volume and function 5 years after donation.
A total of 46 living kidney donors were enrolled in and have completed this prospective study. Of these, 16 were standard donors with no known risk factors, 10 were older donors (age>55 years at donation), 11 were obese (BMI>35 kg/m2 at donation), and 9 were hypertensive (BP>140/90 mm Hg on multiple occasions, or on a single antihypertensive medication at donation). The mean age at the time of donation was 48.3 years (±11.2), with the older group averaging a higher age of 61.3 years (±6.1) (Table 1A). One donor showed two (older age and hypertension), and one showed all three risk factors. Most of the donors were white. The average serum creatinine and corrected iothalamate clearance (GFR) were 1.0 (±0.05) mg/dL and 97 (±15.8) mL/m2 per min, respectively, and there was no significant intergroup difference. The average for each risk-associated factor (i.e., age in the older group, weight and BMI in the obese group, and blood pressure in the hypertensive group) was higher in the corresponding group, with minimal intergroup variability among the others.
Kidney Volume at the Time of Donation
The average volumes of the contralateral kidney at the time of donation were 118.4 (±18.4), 112.8 (±25.4), 157.8 (±18), and 125.4 (±16.9) cm3 in standard, older, obese, and hypertensive donors, respectively. The total kidney volume correlated with the body weight (Pearson’s correlation coefficient R2=0.54, P<0.001) (Figure 1A). In contrast, age (R2=0.02, P=0.4) and hypertension (R2=0.04, P=0.2) were not associated with the kidney volume at the time of donation. The kidney volume also correlated with the GFR (R2=0.5, P<0.001) (Figure 1B). Except for one older donor with moderate atherosclerotic changes (cv score of 2, Banff 2007 classification), none of the implantation biopsies demonstrated any significant changes.
Donor Characteristics at Follow-Up
After an average of 5.8 years after donation, the characteristic significant intergroup differences were noted to have remained the same (Table 1B). The weight and BMI of all donors, on average, did not change significantly during the follow-up. The obese group continued to weigh significantly more. The blood pressure in the hypertensive donors was lower, although this difference was not statistically significant. The average GFR were 65 (±3.7), 62 (±4.5), 73 (±4.3), and 66 (±4.7) mL/m2 per min in standard, older, obese, and hypertensive donors, respectively, and these were not statistically different. Kidney donation did not cause late proteinuria or microalbuminuria in any donors.
Volume Change and the Function of the Remaining Kidney
Regardless of preexisting risk factors, the remaining kidney volume and function increased at follow-up in all donors (Figure 2). The mean percent increase in size was 29.3% (±18) and was similar in all groups (Table 2). The average increase in GFR, compared to predonation GFR (calculated by dividing the total GFR by two), was 35.6% (±19.1) and not significantly different between groups. In univariate analyses, age, BMI, body weight, and hypertension did not have any influence on the compensatory hypertrophy or increase in GFR more than 5 years after donation (Table 3).
Living kidney donor selection criteria are changing as the waiting list for deceased donor kidney transplant continues to grow. In most transplant programs, select individuals with various risk factors are now routinely accepted as donors. We have previously published our criteria for high-risk donors. In a small cohort, we evaluated the compensatory hypertrophy of the remaining kidney and the concomitant increase in GFR more than 5 years after donation and assessed the impact of common risk factors on these parameters. Our results show that the compensatory hypertrophy and accompanying increase in GFR occurs in all carefully selected donors, regardless of the underlying risk factors.
In healthy individuals, uninephrectomy induces an increase in renal plasma flow in the remaining kidney.6 This increase directly correlates with a rise in glomerular plasma flow, resulting in an increased GFR of each nephron. These changes, when consistently present, lead to glomerular hypertrophy and increased filtration surface area, also known as the adaptive hypertrophic response, resulting in growth of the remaining kidney.7 A compensatory increase in the GFR in the remaining kidney up to 70%8 has been reported in young donors with no risk factors. This adaptive hyperinfiltration occurs also in older donors, albeit more modestly than in younger donors.9
Because the kidney donors undergo a very stringent selection process, our results are not completely unexpected. However, they highlight the importance of selection criteria because the prevalence of risk factors increase in the general population. It is well documented that the incidence of chronic kidney disease is significantly higher in people with metabolic syndrome.10,11 Two components of the metabolic syndrome, hypertension and obesity, independently, have been found to be associated with increased risk of developing chronic kidney disease in nondiabetic individuals by an odds ratio of 3 and 2, respectively.10 The prevalence of tubular atrophy, glomerulosclerosis, interstitial fibrosis, and arterial sclerosis is significantly higher in people with metabolic risk factors compared to healthy individuals.12 Likewise, among patients who underwent a uninephrectomy for renal cell carcinoma, the estimated GFR at 1 year was found to be markedly lower in those with metabolic syndrome.12 According to a large meta-analysis, hypertension confers a 61% higher risk of developing chronic kidney disease, whereas obesity increases this risk by 19%.11 In the largest retrospective analysis of living donors reported to date, older age and higher BMI at the time of donation were associated with a GFR below 60 mL/m2 per min.4 The findings of these large population-based studies are likely secondary to the inability of the remaining glomeruli to undergo the changes observed in healthy individuals, presumably secondary to the microvascular disease associated with metabolic syndrome. During the selection process of a potential living donor, theoretically, this risk factor is minimized. As such, in carefully selected donors, the function of the remaining kidney in hypertensive donors was recently reported to be comparable to that of normotensive donors,13 similar to our findings.
In the current study, both the volume and the GFR of the remaining kidney increased over time, regardless of the risk factors. This is in contrast to the findings by Rook et al., who demonstrated that older and obese donors had a significantly lower postdonation resting,14 as well as dopamine-induced GFR,3 compared to standard donors. However, the follow-up in their study was only 2 months, thus it is possible that the compensatory mechanisms may be slower in these at risk groups. Aging, in fact, is associated with a decrease in both the number (e.g., increased glomerulosclerosis) and size of glomeruli, collectively called glomerulopenia; resulting in a decreased GFR.15-17 Although the GFR in older donors can be significantly lower than that of younger donors,17 no persistent decline in the remaining kidney function has been observed in donors older than 50 years,18 and the cortical size of the remaining kidney increased similarly in older donors at 6 months.17 Our results confirm these previously published results, and to our knowledge, the current study is the only one with more than 5-year follow-up.
The main limitations of this study are that it represents the experience of a single-center with a small sample size of donors with potential geographical and racial bias. The follow-up data were obtained prospectively with a visit to our center, and the sample size was limited by the available funding, thus the study was designed to provide only enough power for a proof of concept. In addition, because it is not a part of our living donor evaluation, no attempt was made to measure GFR individually for each kidney before donation, potentially masking significantly different GFR of kidneys in a single individual.
In summary, our results show that compensatory hypertrophy and increase in GFR occur in the remaining kidney of medically complex living donors at a comparable rate to those of standard donors. These findings provide reassurance for carefully selected medically complex living donors.
MATERIALS AND METHODS
This study was approved by the Mayo Clinic Institutional Review Board. Between July 2000 and April 2003, a total of 506 donor nephrectomies were done in our center. Because the follow-up included a medical examination, laboratory work-up and a repeat noncontrast computerized tomography imaging; because of limited institutional funding, only donors who lived within a 100-mile radius were included in the study. 81 such donors were identified. Among these, based on the group criteria, a total of 46 donors without (standard) or with risk factors (older age, obesity, or hypertension) were randomly selected from Mayo Clinic Transplant Center database and contacted with the invitation to participate in the study. All randomly selected donors were recruited and consented successfully. The GFR was calculated using the 125I-iothalamate clearance, and adjusted for body surface area (mL/1.73 m2/min). Predonation, both kidneys were assumed to contribute to GFR equally, thus the GFR of the donated kidney was calculated by dividing the total GFR by 2. Implantation biopsies were obtained after vascular anastomosis and reperfusion. All biopsies were assessed by dedicated renal pathologists and scored according to Banff 2007 classification.
Measurement of Kidney Volume
Kidney volumes were calculated as described previously.19,20 Briefly, computerized tomography images at 1-mm intervals were reconstructed and displayed in multiplanar reformations (Siemens Medical Solutions, Forchheim, Germany). The length, width, and thickness of the kidney were used to estimate the total volume, using the “prolate ellipsoid” method. Both the cortical volume and the total kidney volume have been reported to correlate well with kidney function.21 Thus, total volume was measured and reported in the current study.
Categorical variables were analyzed by Fisher’s exact test. Continuous variables were analyzed using student t test, or analysis of variance. The strength of the relationship between variables was measured using Pearson coefficient. The results are expressed as mean±standard deviation. P less than 0.05 was considered statistically significant.
1. Reese PP, Feldman HI, McBride MA, et al. Substantial variation in the acceptance of medically complex live kidney donors across US renal transplant centers. Am J Transplant
2008; 8: 2062.
2. OPTN/SRTR 2011 Annual Data Report, 2012.
3. Rook M, Bosma RJ, van Son WJ, et al. Nephrectomy elicits impact of age and BMI on renal hemodynamics: lower postdonation reserve capacity in older or overweight kidney donors. Am J Transplant
2008; 8: 2077.
4. Ibrahim HN, Foley R, Tan L, et al. Long-term consequences of kidney donation. N Engl J Med
2009; 360: 459.
5. Textor S, Taler S. Expanding criteria for living kidney donors: what are the limits? Transplant Rev (Orlando)
2008; 22: 187.
6. Mueller TF, Luyckx VA. The natural history of residual renal function in transplant donors. J Am Soc Nephrol
2012; 23: 1462.
7. Jeon HG, Lee SR, Joo DJ, et al. Predictors of kidney volume change and delayed kidney function recovery after donor nephrectomy. J Urol
2010; 184: 1057.
8. Krohn AG, Ogden DA, Holmes JH. Renal function in 29 healthy adults before and after nephrectomy. JAMA
1966; 196: 322.
9. Velosa JA, Offord KP, Schroeder DR. Effect of age, sex, and glomerular filtration rate on renal function outcome of living kidney donors. Transplantation
1995; 60: 1618.
10. Chen J, Muntner P, Hamm LL, et al. The metabolic syndrome and chronic kidney disease in U.S. adults. Ann Intern Med
2004; 140: 167.
11. Thomas G, Sehgal AR, Kashyap SR, et al. Metabolic syndrome and kidney disease: a systematic review and meta-analysis. Clin J Am Soc Nephrol
2011; 6: 2364.
12. Alexander MP, Patel TV, Farag YM, et al. Kidney pathological changes in metabolic syndrome: a cross-sectional study. Am J Kidney Dis
2009; 53: 751.
13. Tent H, Sanders JS, Rook M, et al. Effects of preexistent hypertension on blood pressure and residual renal function after donor nephrectomy. Transplantation
2012; 93: 412.
14. Rook M, Hofker HS, van Son WJ, et al. Predictive capacity of pre-donation GFR and renal reserve capacity for donor renal function after living kidney donation. Am J Transplant
2006; 6: 1653.
15. Nyengaard JR, Bendtsen TF. Glomerular number and size in relation to age, kidney weight, and body surface in normal man. Anat Rec
1992; 232: 194.
16. Rule AD, Amer H, Cornell LD, et al. The association between age and nephrosclerosis on renal biopsy among healthy adults. Ann Intern Med
2010; 152: 561.
17. Tan JC, Busque S, Workeneh B, et al. Effects of aging on glomerular function and number in living kidney donors. Kidney Int
2010; 78: 686.
18. Balachandran VP, Aull MJ, Charlton M, et al. Kidneys from older living donors provide excellent intermediate-term outcomes after transplantation. Transplantation
2012; 94: 499.
19. Janoff DM, Davol P, Hazzard J, et al. Computerized tomography with 3-dimensional reconstruction for the evaluation of renal size and arterial anatomy in the living kidney donor. J Urol
2004; 171: 27.
20. Poggio ED, Hila S, Stephany B, et al. Donor kidney volume and outcomes following live donor kidney transplantation. Am J Transplant
2006; 6: 616.
21. Yano M, Lin MF, Hoffman KA, et al. Renal measurements on CT angiograms: correlation with graft function at living donor renal transplantation. Radiology
2012; 265: 151.