Original Clinical Science

Compensatory Hypertrophy of the Remaining

Kidney in Medically Complex Living Kidney
Donors Over the Long Term
Timucin Taner,1 Corey W. Iqbal,2 Stephen C. Textor,1 Mark D. Stegall,1 and Michael B. Ishitani1

Background. The criteria for living kidney donation are changing, resulting in increased numbers of individuals with risk factors
Downloaded from https://journals.lww.com/transplantjournal by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3FJPxKcC74DHhTa4p4Aa1SCg1cSEZy/N/0kY/+mTPv9k= on 10/01/2020

being accepted as donors. The long-term function and volume changes in the remaining kidney of these medically complex do-
nors remain largely unknown. Methods. Living kidney donors with three separate risk factors (older age, obesity, or hyperten-
sion) were reevaluated 5 years after donation. The function and volume of the remaining kidney were assessed and compared
to those of standard donors. Results. The body size correlated significantly with the kidney size and glomerular filtration rate
(GFR) at the time of donation. Five years after donation, the remaining kidney size increased by a mean of 29.3%, and the GFR
by 35.6%. The increase in GFR was uniform. In univariate analysis, neither the changes in the size nor the changes in the
1GFR were found to be associated with the risk factors. Conclusion. Medically complex living donors demonstrate similar
compensatory increase in function and volume of the remaining kidney compared to standard donors, 5 years after donation.

(Transplantation 2015;99: 555–559)

B ecause the kidney transplant recipient waiting list con-

tinues 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 hy-
pertension. As a result, the criteria for donor eligibility at many
transplant centers have changed in recent years. Thus, the liv-
ing donor demographics are strikingly different in the current
era than those reported in the earlier days of kidney transplan-
tation. In fact, a quarter of living donors are “medically com-
plex” 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 func-
tional 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, sug-
gesting an impaired functional compensation in these higher
Received 10 April 2014. Revision requested 22 April 2014.
Accepted 5 June 2014.
1
William J. von Liebig Transplantation Center, Mayo Clinic, Rochester, MN.
2
Children’s Mercy Hospital and Clinic, Kansas City, MO.
The authors declare no funding or conflicts of interest.
T.T., C.W.I., and M.B.I. participated in research design, writing of the article, and data
analysis. S.C.T. and M.D.S. participated in research design and writing of the article.
Correspondence: Timucin Taner, MD, PhD, Mayo Clinic, 200 First Street SW, Roch-
ester, MN 55905. (taner.timucin@mayo.edu)
Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
ISSN: 0041-1337/15/9903-555
DOI: 10.1097/TP.0000000000000356
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 hy-
pertrophy 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 differ-
ent risk factors at the time of donation on the remaining kid-
ney in the long term. In line with this, we report the impact of
older age, obesity, and hypertension on the compensatory re-
sponse of the remaining kidney regarding both parenchymal
volume and function 5 years after donation.
RESULTS
Donor Characteristics
A total of 46 living kidney donors were enrolled in and
have completed this prospective study. Of these, 16 were stan-
dard 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 medica-
tion 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, respec-
tively, and there was no significant intergroup difference. The

Transplantation ■ March 2015 ■ Volume 99 ■ Number 3 www.transplantjournal.com 555

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556 Transplantation ■ March 2015 ■ Volume 99 ■ Number 3 www.transplantjournal.com

TABLE 1.
Donor characteristics at the time of donation (A) and follow-up (B)

Standard (n=16) Older (n=10) Obese (n=11) Hypertensive (n=9) Pa

A
Age, yr 42.4 ± 5.9 61.3 ± 6.1 42.1 ± 10.2 53.3 ± 9.1 <0.001
Sex (M:F) 5:11 3:7 4:7 3:6
Race (white:non-white) 15:1 9:1 11:0 9:0
Donated kidney (left:right) 13:3 7:4 9:2 7:2
Weight, kg 65.4 ± 5.3 75.5 ± 19.1 114.9 ± 9.7 80.9 ± 13.6 <0.001
BMI, kg/m2 22.6 ± 1.2 27.3 ± 4.8 38.1 ± 2.2 27.2 ± 4.5 <0.001
Serum creatinine, mg/dL 1.0 ± 0.04 1.1 ± 0.05 1.1 ± 0.05 1.0 ± 0.05 NS
GFR, mL/m2/min 99 ± 4.4 92 ± 5.5 101 ± 4.9 97 ± 5.5 NS
Blood pressure, mm Hg
Systolic 123 ± 7 129 ± 14 131 ± 11 153 ± 12 <0.001
Diastolic 71 ± 8 73 ± 10 81 ± 10 86 ± 8 0.001
Proteinuria, mg/dL 3.2 ± 1.9 3.4 ± 1.8 3.8 ± 1.8 3.2 ± 2 NS
B
Time since donation, mean, yr (range) 5.6 (4.9-6.6) 6 (4.9-7.1) 5.7 (5.2-6.5) 6 (5.2-6.9) NS
Weight, kg 65.8 ± 7.5 76 ± 19.3 109.3 ± 23.4 84.7 ± 12.6 <0.001
BMI, kg/m2 22.7 ± 1.6 27.6 ± 5.2 35.8 ± 6.3 28.4 ± 4.3 <0.001
Serum creatinine, mg/dL 1.2 ± 0.06 1.2 ± 0.07 1.1 ± 0.07 1.0 ± 0.07 NS
GFR, mL/m2/min 65 ± 3.7 62 ± 4.5 73 ± 4.3 66 ± 4.7 NS
Blood pressure, mm Hg
Systolic 115 ± 7 124 ± 11 128 ± 15 143 ± 20 <0.001
Diastolic 70±5 77 ± 4 81 ± 11 81 ± 7 0.001
Proteinuria, mg/dL 3.4 ± 2.1 3.4 ± 1.7 3.8 ± 2.6 3.8 ± 1.9 NS
Microalbuminuria, mg/24 hr 1.3 ± 3.4 2.4 ± 8.6 4.9 ± 8.5 1.3 ± 1.9 NS
a
ANOVA is used to test differences between groups.
Values represent mean ± SD for continuous variables.
SD, standard deviation; ANOVA, analysis of variance, GFR, glomerular filtration rate; BMI, body mass index; NS, not significant.

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 co-
efficient 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 dona-
tion. 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 dem-
onstrated any significant changes.
Donor Characteristics at Follow-Up
After an average of 5.8 years after donation, the character-
istic significant intergroup differences were noted to have
remained the same (Table 1B). The weight and BMI of all do-
nors, 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 FIGURE 1. Correlation of kidney volume to body weight (A) and
66 (±4.7) mL/m2 per min in standard, older, obese, and GFR (B). Each filled circle represents a single donor.

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

© 2014 Wolters Kluwer
FIGURE 2. Changes in remaining kidney volume between the
time of donation and follow-up. Each filled circle represents a sin-
gle donor. The donors with two (older age and hypertension)* and all
three** risk factors.
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 kid-
ney 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 in-
crease 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).
DISCUSSION
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 hypertro-
phy of the remaining kidney and the concomitant increase
in GFR more than 5 years after donation and assessed the im-
pact 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, re-
gardless of the underlying risk factors.
In healthy individuals, uninephrectomy induces an in-
crease in renal plasma flow in the remaining kidney.6 This in-
crease directly correlates with a rise in glomerular plasma
TABLE 2.
Volume changes in remaining kidney
Standard (n=16)
3
Kidney volume, cm
At donation 118.4±18.4
At follow-up 154.6±32.5
Change in kidney volume, cm3 36.3±19.9
Change in kidney volume, % 30.3±16.6
Change in GFR, mL/m2/min 34±4.6
Change in GFR, % 33.5±19.9
a
ANOVA is used to test differences between groups.
Values represent mean±SD for continuous variables.
SD, standard deviation; ANOVA, analysis of variance, GFR, glomerular filtration rate; NS, not significant.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Taner et al 557
flow, resulting in an increased GFR of each nephron. These
changes, when consistently present, lead to glomerular hy-
pertrophy 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 hyperin-
filtration occurs also in older donors, albeit more modestly
than in younger donors.9
Because the kidney donors undergo a very stringent selec-
tion 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 at-
rophy, 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 car-
cinoma, the estimated GFR at 1 year was found to be mark-
edly 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 in-
creases this risk by 19%.11 In the largest retrospective analy-
sis 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 micro-
vascular 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 do-
nors, 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 signif-
icantly lower postdonation resting,14 as well as dopamine-
induced GFR,3 compared to standard donors. However,
Older (n=10) Obese (n=11) Hypertensive (n=9) Pa
112.8±25.4 157.8±18 125.4±16.9 <0.001
154.8±32.5 198.3±18.6 153.6±21.2 <0.001
39.2±25.8 40.5±21.9 28.2±17.3 NS
36±25.4 26.7±15.1 23.2±15.4 NS
32±5.7 28±5.1 30±5.7 NS
32.5±23.4 33.5±21.1 37.3±12.3 NS
558 Transplantation ■ March 2015 ■ Volume 99 ■ Number 3
TABLE 3.
Impact of common donor risk factors on GFR and volume changes in remaining kidney
Compensatory hypertrophy
R 2
Age, >55 0.07
Obesity
BMI>35 kg/m2 0.002
Weight, per kg 0.006
Hypertension 0.037
Pearson’s correlation is used.
GFR, glomerular filtration rate; BMI, body mass index; NS, not significant.
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 de-
crease 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 do-
nors,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 previ-
ously 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 dona-
tion, potentially masking significantly different GFR of kid-
neys in a single individual.
In summary, our results show that compensatory hyper-
trophy 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
Patients
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 tomogra-
phy 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 hyper-
tension) were randomly selected from Mayo Clinic Trans-
plant Center database and contacted with the invitation to
participate in the study. All randomly selected donors were
recruited and consented successfully. The GFR was calcu-
lated using the 125I-iothalamate clearance, and adjusted for
body surface area (mL/1.73 m2/min). Predonation, both
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
www.transplantjournal.com
Compensatory increase in GFR
P R2
P
NS 0.004 NS
NS 0.001 NS
NS 0 NS
NS 0.005 NS
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 accord-
ing 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.
Statistical Analyses
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.
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