American Journal of Transplantation 2008; 8: 1878–1890
Wiley Periodicals Inc.
C 2008 The Authors
C 2008 The American Society of
Journal compilation Transplantation and the American Society of Transplant Surgeons
doi: 10.1111/j.1600-6143.2008.02339.x
Health Outcomes for Living Kidney Donors with
Isolated Medical Abnormalities: A Systematic Review
A. Younga,b , L. Storsleyc , A. X. Garga,b, ∗ ,
D. Treleavend , C. Y. Nguane , M. S. Cuerdena
and M. Karpinskic
For the Donor Nephrectomy Outcomes Research
(DONOR) Network
a
Division of Nephrology and
b
Department of Epidemiology and Biostatistics,
University of Western Ontario, London, ON, Canada
c
Department of Medicine, University of Manitoba,
Winnipeg, MB, Canada
d
Department of Medicine, McMaster University,
Hamilton, ON, Canada
e
Department of Urologic Sciences, University of British
Columbia, Vancouver, BC, Canada
Donor Nephrectomy Outcomes Research (DONOR)
Network Investigators: Neil Boudville, Laurence Chan,
Christine Dipchand, Mona Doshi, Liane Feldman, Amit
Garg, Colin Geddes, Eric Gibney, John Gill, Martin
Karpinski, Scott Klarenbach, Greg Knoll, Charmaine Lok,
Mauricio Monroy-Cuadros, Norman Muirhead,
Christopher Y. Nguan, Chirag Parikh, Emilio Poggio, G. V.
Ramesh Prasad, Leroy Storsley, Sudha Tata, Darin
Treleaven, Robert Yang, Ann Young
∗ Corresponding author: Amit X. Garg,
amit.garg@lhsc.on.ca
Individuals with isolated medical abnormalities (IMAs)
are undergoing living donor nephrectomy more frequently. Knowledge of health risks for these living
donors is important for donor selection, informed consent and follow-up. We systematically reviewed studies with ≥3 living kidney donors with preexisting IMAs,
including older age, obesity, hypertension, reduced
glomerular filtration rate (GFR), proteinuria, microscopic hematuria and nephrolithiasis. We abstracted
data on study and donor characteristics, perioperative
outcomes, longer term renal and blood pressure outcomes and mortality and compared them to those of
non-IMA donors.
We found 22 studies on older donors (n = 987), 10
on obese donors (n = 484), 6 on hypertensive donors
(n = 125), 4 on donors with nephrolithiasis (n = 32), 2
on donors with microscopic hematuria and one study
each on donors with proteinuria or reduced GFR. Perioperative outcomes for donors with and without
IMAs were similar. Few studies reported longer term
(≥1 year) rates of hypertension, proteinuria or renal
function. Studies were frequently retrospective and
without a comparison group. Given the variability
1878
among studies and their methodological limitations,
uncertainties remain regarding long-term medical outcomes for IMA donors. As transplant centers continue
to cautiously screen and counsel potential IMA donors,
rigorously conducted, longer term prospective cohort
studies are needed.
Key words: Hypertension, incremental risk, isolated
medical abnormality, kidney transplantation, living
donors, marginal donor
Received 5 March 2008, revised 9 May 2008 and accepted for publication 7 June 2008
Introduction
In recent years, living donor kidney transplantation rates
have increased greatly in response to the growing need
and longer waiting times for deceased donor transplantation. Increasingly, individuals who would have previously
been deemed unsuitable as living donors due to relative
medical contraindications are being considered. Described
variably as having ‘isolated medical abnormalities (IMAs)’
(1,2), ‘asymptomatic urinary abnormalities’ (3) or as ‘complex’, ‘marginal’ or ‘at incremental risk’ (4–6), these living donors have conditions such as older age, obesity,
hypertension, microscopic hematuria, proteinuria, reduced
glomerular filtration rate (GFR) or nephrolithiasis (7). They
may also have more than one abnormality. Some IMAs,
namely older age, hypertension and albuminuria, are established risk factors for long-term renal impairment and
cardiovascular disease (8–13).
Long-term outcomes in healthy living kidney donors are frequently reported and help guide donor selection and followup. Outcomes among individuals with preexisting IMA(s)
and a 50% reduction in renal mass via donor nephrectomy
are less well known. This review aims to comprehensively
assemble all relevant literature on outcomes of living kidney donors with IMAs. We examined short- and longer
term medical outcomes, study quality and consistency of
results. Herein, IMAs are defined as: (1) age: ≥60 years old,
(2) obesity: BMI ≥30 kg/m2 , (3) hypertension: BP >140/90
mmHg or on antihypertensive medication, (4) hematuria:
asymptomatic, microscopic, (5) proteinuria: ≥0.15 g/day,
(6) GFR: ≤80 mL/min, (7) nephrolithiasis: ≥1 calculi.
Living Kidney Donors with IMAs
Methods
Study selection
The conduct and reporting of this systematic review and meta-analysis
was guided by the Meta-analysis of Observational Studies in Epidemiology
consensus statement (14). Cohort studies published in any language as full
text or abstracts were relevant if they studied three or more living kidney
donors with IMAs and reported at least one perioperative and/or longer term
donor medical outcome. Results were considered longer term if donors
were followed for at least 1 year after donation. Recipient outcomes and
donor psychosocial or financial outcomes were not considered.
We compiled citations from MEDLINE (1950–Jan/2008), EMBASE (1980–
Jan/2008), CINAHL (1982–Jan/2008), BIOSIS Previews (1969–Jan/2008)
and Cochrane Library bibliographic data bases. The search strategy included
the terms living kidney donor combined with isolated medical abnormality,
marginal donor, incremental risk, hypertension, hematuria, proteinuria, renal function, renal calculi, obesity or older. Terms were truncated to capture
variations in terminology. Synonyms and related terms were also included.
Searches used keywords over subject headings. The search strategy was
pilot tested and modified to ensure that articles of known relevance were
identified. Reference lists of included studies, the Science Citation Index
and PubMed’s ‘see related articles’ were also searched. All citations were
downloaded into Reference Manager 11.0 (Thomson ISI Research-Soft,
Philadelphia, PA).
Three authors (AY/MK/LS) independently evaluated each citation. Unsuitable articles were excluded on the basis of title or abstract. Any potentially
relevant citations were retrieved in full text for a more detailed evaluation.
Following evaluation, disagreements on article eligibility were resolved by
consensus. When the same group of donors was described in multiple
publications, we cited the article with the most IMA donors.
Data abstraction
Two authors (AY/MK) independently reviewed and abstracted study characteristics and methodological quality, baseline donor characteristics, surgical
details and complications, pre- and postdonation blood pressure, proteinuria, hematuria, renal function and mortality. Another author (LS) independently confirmed the accuracy of all abstracted data. Disagreements on
abstracted data were resolved by consensus. Primary study authors were
contacted to clarify interpretations or to provide additional data. When a
study described more than one IMA, data on each IMA with three or more
living donors were abstracted independently. Quality appraisal of the studies was guided by Hayden et al. (15).
Statistical analysis
Interrater reliability was assessed using Fleiss’ generalized j, which describes the chance-corrected agreement among more than two raters
(16,17). Analysis was done using Nichols’ MKAPPASC.SPS macro (18) with
SPSS statistical software 15.0 (Chicago, IL).
Descriptive statistics (e.g. group means) were weighted by the number
of donors in each study group. Variance estimates for pre-post donation
changes in outcomes such as blood pressure were not reported; they were
2
2
calculated as r2 = rpre
+ rpost
− 2qrprerpost , where q represents the correlation between the pre- and postdonation values. We used a correlation
of 0.5 to impute the missing change variance estimates in the final metaanalysis (19). Sensitivity analyses were performed on the choice of correlation, and results were qualitatively similar.
For study-level meta-analysis, Cochran’s Q statistic was used to determine
the presence of between-study heterogeneity by summing the squared de-
American Journal of Transplantation 2008; 8: 1878–1890
viations of each study’s estimate from the meta-analytic estimate, weighting each study by the inverse variance of its effect estimator (20). The
statistic was compared to the v 2 distribution with k -1 degrees of freedom,
where k was the number of studies. The I2 statistic describes the percentage of total variation across studies that is due to heterogeneity rather than
chance; I2 values of 25%, 50% and 75% were indicative of low, moderate
and extreme heterogeneity, respectively (21). Results were mathematically
pooled when I2 was ≤50%, using a random effects method that accounts
for within- and between-study heterogeneity (22,23).
Renal function is usually assessed by creatinine clearance or GFR and is
often standardized to body surface area (BSA). In pooled estimates, we
described all estimates of renal function as GFR, reported in ml/min (per
1.73 m2 ).
Meta-analyses were conducted using Review Manager 4.2 (Cochrane Collaboration, Oxford, UK). Results were graphed in R 2.0.1 (R Foundation for
Statistical Computing, Vienna, Austria).
Results
Study selection
We screened 3510 citations, from which 90 full text articles were retrieved for detailed evaluation (Figure 1).
Forty-three articles met the criteria for review. Six were
subsequently excluded because they described the same
groups of donors (24–29). Thus, we identified 37 articles
with perioperative and/or longer term (≥ 1 year) medical
outcomes for three or more living kidney donors with preexisting IMAs (5,30–65). Chance-corrected agreement for
article eligibility between three independent reviewers was
substantial (j = 0.71) (66).
Description of included articles
The 37 studies were published between 1986 and 2007
and were all in English. Thirty were full text articles and
seven were conference abstracts (38,48,50,52,55,61,63).
Potentially relevant publications identified:
citations or abstracts screened for retrieval
(n = 3510)
Publications excluded on the basis
of title and abstract (n = 3420)
Full-text publications retrieved for
more detailed evaluation (n = 90)
Publications excluded with reasons (n = 53):
• No IMAs of interest reported (n = 8)
• Citation about living kidney recipients and
not donors (n = 14)
• Inclusion criteria not met (n = 19)
• No distinct analysis of IMA donors (n = 6)
• Duplicate citation or same donors
described in multiple publications (n = 6)
Publications included in the
review (n = 37)
Figure 1: Flow diagram outlining selection of studies of living
kidney donors with IMAs.
1879
Young et al.
The studies were from 13 countries: mostly North
America (46%: USA: 15 studies, Mexico: 2 studies), followed by Europe (38%: Germany: 3 studies; Greece,
Switzerland, Turkey: 2 studies each; Italy, Norway, Republic of Macedonia, Slovenia, Yugoslavia: 1 study each), then
Asia (16%: India, Japan: 3 studies each). We successfully
contacted 11 primary authors; 9 kindly supplied additional
data (33,34,36,38,47,49,51,54,55,57,60).
Some studies described more than one IMA, resulting in:
22 studies on older donors (5,30–50), 10 on obese donors
(49,51–59), 6 on hypertensive donors (5,38,41,48,49,60),
4 on donors with nephrolithiasis (5,63–65), 2 on donors
with microscopic hematuria (61,62) and one study each
on donors with proteinuria (38) or reduced GFR (38)
(Table 1). Only four studies reported the proportion of IMA
donors lost to follow-up; all exceeded 10% (range 10–60%)
(43,57,58,63). Donor outcomes assessed across studies of
living kidney donors with IMAs are summarized in Table 2.
Perioperative outcomes
Older and younger donors were compared on operative
time (32,36,46), surgical blood loss (32,36) and length of
hospital stay (32,36,46), with no significant differences
(Figure 2A). Similarly, obese and nonobese donors were
compared on operative time (51–54,56,58), blood loss
(51,52,54,56) and hospital stay (51–54,56,58) (Figure 2B).
Differences were statistically significant but clinically insignificant. Surgical complications (e.g. minor infections,
hemorrhage, pneumonia or pneumothorax) were not significantly higher for older or obese donors.
Older donors, longer term outcomes
Twenty-two articles reported on 987 older living kidney
donors (mean age: 66 years old; range: 60–85 at donation).
Older donors were most commonly defined as ≥60 years
(68% of studies) with other studies defining older as ≥61
(45), ≥65 (36,38,44,47) and ≥66 years (30,42). Six were
prospective cohort studies (35,38,45–47,49) and 16 were
retrospective cohort studies (5,30–34,36,37,39–44,48,50).
Sixteen studies had a comparison group of donors
<60 years old (weighted mean age at donation: 47 years).
Of these, six studies enrolled younger donors contemporaneously with older donors (35,38,45–47,49), while the rest
used historical controls. Loss to follow-up was reported in
only 1 of 22 studies.
Older donors were followed for a median of 1.8 years
(range from postop to 10 years). Fifteen of 22 studies had
mean follow-up periods of 1 year or longer after donation,
of which only 4 had mean follow-up periods of ≥5 years.
Long-term renal function was reported in 8 of 15 studies; 1
study each described postdonation GFR (44) and change in
GFR from 3 months to 1 year postdonation (41), 4 studies
described change in serum creatinine from predonation to
follow-up (37,40,43,49) and 3 studies described change in
GFR from predonation to follow-up (38,49,50). Long-term
1880
blood pressure and proteinuria changes were reported in
only 2 and 1 study, respectively.
Meta-analysis of four studies comparing 181 older donors
to 666 younger donors on change in serum creatinine
from predonation to follow-up is presented in Figure 3A
(37,40,43,49). Median follow-up was 2 years (range 1.0–
6.7 years). Results were too statistically heterogeneous to
mathematically pool (v 2 = 31.90, p < 0.00001, I2 = 91%).
One study reported that older donors had a 10 lmol/L
(0.1 mg/dL) significantly greater increase in serum creatinine after donation over the increase for younger donors
(49). Another study reported a 21 lmol/L (0.2 mg/dL) increase, but the confidence interval was wide and insignificant (40). Change in GFR from predonation to follow-up
was reported in three studies comparing 23 older donors
to 541 younger donors (38,49,50). GFR was assessed by
inulin or radioisotope (38,49) or not reported (50). There
was low-to-moderate statistical heterogeneity between
the three studies (v 2 = 3.20, p = 0.20, I2 = 38%) (Figure
3B). When results were mathematically pooled, the decrement in GFR after donation was significantly less for older
than younger donors (weighted mean difference: −6.38
mL/min (per 1.73 m2 ), 95% CI: −2.56 to −10.21). This
pooled estimate is driven by one study with results contrary to what is expected (49).
Long-term changes in blood pressure and proteinuria were
not well characterized for older donors. Rather than an
increase, one study reported a decrease in blood pressure for older donors compared to a small increase in
younger donors after 1 year (SBP: −4.3 vs. 1.2 mmHg;
DBP: −0.9 vs. 1.4 mmHg) (38). Another study reported
a minimal difference in mean arterial blood pressure
by age group after 6.7 years (49). One study reported
no increase in albumin:creatinine ratio for either donors
≥65 years or <65 years, 1 year after donation (38). There
were 27 deaths among older donors and 6 among younger
donors, all unrelated to nephrectomy.
Obese donors, longer term outcomes
Ten studies examined 484 obese living donors with a
mean BMI of 34.5 kg/m2 at donation (range: 32–39 kg/m2 ).
Eight studies (78%) used an obesity cutpoint of 30 kg/m2 ;
the other studies used definitions of BMI ≥31 (56) and
35 kg/m2 (51). Five studies prospectively followed a cohort
of obese living donors (49,53–55,59), four were retrospective cohort studies (51,56–58) and one collected retrospective and prospective data (52). All studies compared obese
donors to nonobese donors with BMI <30 kg/m2 (weighted
mean BMI 24.4 kg/m2 ). Only two studies reported loss to
follow-up rates (41% and 60%) (57,58).
The median follow-up time for obese donors was
2.4 months (range from postdonation hospital discharge
to 6.7 years). Long-term follow-up occurred in only 2 of 10
studies, with follow-up of 4.2 (59) and 6.7 years (49). Both
studies described long-term change in serum creatinine
American Journal of Transplantation 2008; 8: 1878–1890
Living Kidney Donors with IMAs
Table 1: Characteristics of studies examining outcomes of living kidney donors, stratified by type of donor IMA
Older donors
Source∗
Hayashi et al., (30)
Berardinelli et al., (31)
Jacobs et al., (32)
Haberal et al., (33)
Shimmura et al., (34)
Fauchald et al., (35)
Tsuchiya et al., (36)
Lezaic et al., (37)
Tsinalis et al., ‡ (38)
Kumar et al., (39)
Nyberg et al., (40)
Srivastava et al., (41)
Grekas et al., (42)
Kostakis et al., (43)
Hsu et al., (44)
Siebels et al., (45)
Kumar et al., (5)
Neipp et al., (46)
Ivanovski et al., (47)
Sahin et al., ‡ (48)
Gracida et al., (49)
Pabico et al., ‡ (50)
Primary
location
Ehime, Japan
Milan, Italy
Baltimore, USA
Ankara, Turkey
Tokyo, Japan
Oslo, Norway
Akita, Japan
Belgrade, Yugoslavia
Basel, Switzerland
Lucknow, India
Minneapolis, USA
Delhi, India
Thessaloniki, Greece
Athens, Greece
Baltimore, USA
Munich, Germany
Lucknow, India
Hannover, Germany
Skopje, Macedonia
Istanbul, Turkey
Mexico City, Mexico
Rochester, USA
Prospective IMA
Non-IMA
study
donors donor controls
No
No
No
No
No
Yes
No
No
Yes
No
No
No
No
No
No
Yes
No
Yes
Yes
No
Yes
No
41
39
42
34
241
70
14
50
13
21
5
46
25
161
6
19
82
35
28
20
6
4
None
193
42
None
518
165
48
99
75
25
10
None
35
174
None
141
None
158
50
None
422
14
Year(s) of
donation
1980–1993
1969–2002
1996–2002
1975–1989
1982–1995
1985–1988
1998–2004
1987–1992
1988–1998
1989–1993
1971–1995
1996–2004
1976–1985
1986–1996
1995–2001
1994–2001
1988–2001
1996–2005
1991–1999
1983–1999
1992–2001
1976
Older donor age,
Proportion lost
mean ± SD (range), y† to follow-up, %
71 ± . . . (66–80)
64 ± 4 (60–72)
65 ± 4 (. . .)
62 ± . . . (60–76)
64 ± 4 (60–78)
66 ± . . . (60–81)
69 ± 4 (65–77)
66 ± 4 (60–85)
69 ± 4 (65–80)
64 ± . . . (. . .)
69 ± 10 (62–87)
62 ± 3 (60–71)
. . . (66–76)
68 ± 6 (60–82)
69 ± 3 (65–74)
. . . (>61)
63 ± 3 (. . .)
65 ± 4 (. . .)
69 ± . . . (65–81)
. . . (>60)
62 ± . . . (. . .)
66 ± . . . (60–73)
...
...
...
...
...
...
...
...
...
...
...
...
...
24
...
...
...
...
...
...
...
...
Obese donors
Source∗
Jacobs et al., (51)
Chavin et al.,‡ (52)
Chow et al., (53)
Mateo et al., (54)
Bachmann et al., ‡ (55)
Kuo et al., (56)
Rea et al., (57)
Heimbach et al., (58)
Espinoza et al., (59)
Gracida et al., (49)
Primary
location
Baltimore, USA
Charleston, USA
Rochester, USA
Los Angeles, USA
Basel, Switzerland
Washington, USA
Rochester, USA
Minnesota, USA
Mexico City, Mexico
Mexico City, Mexico
Prospective
study
IMA
donors
Non-IMA
donor controls
Year(s) of
donation
IMA donor BMI,
mean ± SD
(range), kg/m2 †
Proportion
lost to
follow-up, %
No
...
Yes
Yes
Yes
No
No
No
Yes
Yes
41
23
34
12
23
12
49
172
37
81
41
64
75
35
180
28
41
381
537
422
1996–1999
1998–2001
1999–2000
1999–2002
...
1998–1999
2000–2003
1999–2003
1992–1999
1992–2001
39 ± 4
34 ± 1
34 ± 4
32 ± 2
. . . (>30)
34 ± 4
38 ± 5
34 ± 3
33 ± 2
33 ± . . .
...
...
...
...
...
...
60
41
...
...
Hypertensive donors
Source∗
Primary
location
Prospective
study
IMA
donors
Non-IMA
donor
controls
Year(s) of
donation
Textor et al., (60)
Rochester, USA
Yes
24
124
2001–2002
Tsinalis et al., ‡ (38)
Basel, Switzerland
Yes
46
75
1988–1998
Srivastava et al., (41)
Delhi, India
No
18
None
1996–2004
Kumar et al., (5)
Lucknow, India
No
12
None
1988–2001
Sahin et al., ‡ (48)
Gracida et al., (49)
Istanbul, Turkey
Mexico City, Mexico
No
Yes
9
16
None
422
1983–1999
1992–2001
Definition of
hypertensive
donor
BP > 140/90 by RN
or > 135/85 by
ABPM
BP > 150/90 or
antiHTN meds
HTN controlled by a
single med
HTN controlled by a
single med
...
HTN controlled by
diet or a single
med
Proportion
lost to
follow-up, %
...
...
...
...
...
...
Continued.
American Journal of Transplantation 2008; 8: 1878–1890
1881
Young et al.
Table 1: Continued
Reduced glomerular filtration rate (GFR)
Source∗
Primary
location
Prospective
study
IMA
donors
Non-IMA donor
controls
Year(s) of
donation
Definition of
IMA
Proportion lost
to follow-up, %
Tsinalis et al.,‡ (38)
Basel,
Switzerland
Yes
16
75
1988–1998
GFR < 70 mL/min
by inulin
clearance
...
Tsinalis et al.,‡ (38)
Basel,
Switzerland
Yes
8
Proteinuria
75
1988–1998
Alb/Cr > 10
mg/mmol OR
Pro/Cr > 0.02
g/mmol
...
Reinhardt et al.,‡ (61)
Goettingen,
Germany
Ljubljana,
Slovenia
Yes
...
Yes
3
None
Presence of
microhematuria
IgA nephropathy
confirmed by
biopsy
Strang et al.,‡ (63)
Birmingham,
USA
Yes
9
Renal calculi
None
2005–2006
10
Martin et al.,(64)
Indianapolis,
USA
Yes
5
None
2003–2005
Rashid et al., (65)
Ann Arbor, USA
Yes
10
None
1996–2000
Kumar et al., (5)
Lucknow, India
No
8
None
1988–2001
Computed
tomographic (CT)
positive
screening
Computed
tomographic (CT)
positive
screening
Incidental, unilateral
renal lithiasis
Stone = < 1 cm
Koselj et al., (62)
Microscopic hematuria
5
None
...
...
...
...
...
...
Alb/Cr = albumin to creatinine ratio; ABPM = ambulatory blood pressure monitoring; BP = blood pressure; Pro/Cr = protein to creatinine
ratio; RN = registered nurse.
†Age and BMI are reported at the time of donation.
Ellipses (. . .) indicate not reported.
∗ Studies are arranged by the average number of years after donation.
‡Published as an abstract from a conference proceeding.
and GFR (assessed using inulin or radioisotopes) from predonation to follow-up. Missing and nonimputable variance
estimates precluded pooling of results. The two studies
had conflicting results for the change in serum creatinine:
one reported a 17 lmol/L greater increase in obese donors
(59), while the other reported a 5 lmol/L greater increase
in nonobese donors (49). The studies also had conflicting reports on change in GFR after donation: one reported
no substantive difference between obese and nonobese
donors (−40 vs. −38 mL/min (per 1.73 m2 )) (59), while the
other described a 10 mL/min (per 1.73 m2 ) greater decrement in GFR for nonobese donors over the decrement
seen in obese donors (49). One study also reported an
increase of 4.6 mmHg for obese donors and 3 mmHg for
nonobese donors in mean arterial pressure (no variance estimates reported) (49). Neither study reported proteinuria
as an outcome. There were no deaths reported among
obese donors.
Hypertensive donors, longer term outcomes
Six studies described 125 hypertensive donors (5,38,41,
48,49,60). Definitions for hypertension varied substantially,
1882
from blood pressure cutpoints of 135/85 to 150/90 mmHg
to controlled blood pressure on a single antihypertensive
agent or combinations thereof. Some studies did not provide a definition (48,49). Only one study reported measurement of blood pressure by health professionals (60); others
did not specify how blood pressure was measured. Half
of the studies were prospective cohort studies (38,49,60)
with normotensive donors enrolled contemporaneously.
The remaining used a retrospective design with no control group (5,41,48). None of the studies reported loss to
follow-up.
Follow-up ranged from 10 months to 6.7 years (median:
2.6 years). Five of six studies had mean follow-up periods
of 1 year or more, of which two had mean follow-up periods
≥5 years. One long-term study only described the change
in GFR from 3 months postdonation to 1-year follow-up in
hypertensive donors (41). Of the remaining long-term studies, two assessed renal function. One found that hypertensive donors experienced a 14 lmol/L greater increase
in serum creatinine over that of normotensive donors
6.7 years after donation. Two studies compared 62
American Journal of Transplantation 2008; 8: 1878–1890
Living Kidney Donors with IMAs
Figure 2: (A) Meta-analyses
of perioperative outcomes for
older donors. (B) Meta-analyses
of perioperative outcomes for
obese donors.
American Journal of Transplantation 2008; 8: 1878–1890
1883
Young et al.
A
Increase in serum creatinine (μmol/L)*
Source
Lezaic et al., 1996
Nyberg et al., 1997
Kostakis et al., 1997
Gracida et al., 2003
Length of
follow-up
(years)
1.0 (…)
1.8 (0.1-4.0)
2.1 (…)
6.7 (0.5-9.5)
IMA donors
N
Mean (SD)
9 (4)
50
58 (18)
4
19 (8)
121
28 (5)
6
Non-IMA donors Older donor increase in serum creatinine
N
Mean (SD)
mean difference (umol/L) 95% CI
11 (7)
-2 (-3,0)
99
37 (24)
21 (-1,44)
11
2 (-1,4)
134 17 (9)
10 (6,14)
422 19 (6)
-25
Increase in serum creatinine
less for older donors
B
0
25
50
Increase in serum creatinine
greater for older donors
Decrement in GFR (mL/min (per 1.73 m2))*
Source
Tsinalis et al., 1999
Gracida et al., 2003
Pabico et al., 1986
Pooled estimate
Length of
follow-up
(years)
1.0 (…)
6.7 (0.5-9.5)
10.0 (…)
Older donor decrement in GFR mean
IMA donors
Non-IMA donors
N Mean (SD) N Mean (SD)
13 33 (18)
105 34 (16)
30 (5)
6
422 38 (12)
47 (14)
4
14 43 (21)
23
541
Test for overall effect: Z = 3.27 (P = 0.001)
0 (-11,10)
-8 (-12,-4)
4 (-14,22)
-6 (-10,-3)
-25
0
Decrement in GFR
less for older donors
25
Decrement in GFR
greater for older donors
Note: Graphed results are the difference between IMA and non-IMA donors on the change in outcome from before donation to
after donation.
† See Table 1 for mean donor age
(…) indicates missing value
* Results were not pooled for I > 50%
hypertensive donors to 527 normotensive donors on
change in inulin or radioisotope GFR (38,49). The results were conflicted, substantially heterogeneous and not
pooled (v 2 = 12.12, p = 0.0005, I2 = 92%) (Figure 4).
urine albumin. Another study reported on 10 living donors
with reduced GFR; however, we believed the defined predonation GFR of ≤ 45 mL/min was a reporting error (5).
Attempts to contact the authors for clarification were unsuccessful; thus, we excluded these 10 donors.
Change in blood pressure after donation was quantified
in one study. Blood pressure did not increase 1 year after donation; rather systolic and diastolic blood pressures
reportedly decreased by 5 mmHg and 6 mmHg more,
respectively, in hypertensive than normotensive donors
(38). One study assessed change in mean arterial blood
pressure after donation, which also decreased more often in hypertensive donors (49). One year after donation, neither hypertensive nor normotensive donors experienced an increase in albumin:creatinine ratio (38). There
were two cases of donor mortality, both unrelated to
nephrectomy.
Two studies considered donors with preexisting microscopic hematuria (61,62). One had 5 donors from Alport
syndrome families. After a mean follow-up of 4.7 years,
2 developed new onset hypertension, 3 had proteinuria
and 3 had creatinine clearances ranging from 31 to 52 mL/
min (61). The other study followed 3 donors with biopsyconfirmed IgA nephropathy. After 7 years, 2 had normal
renal function, urinalysis and blood pressure and one had
a GFR < 15 mL/min per 1.73 m2 (62).
One study considered donors with proteinuria, defined as
a urine albumin:creatinine ratio > 10 mg/mmol or urine
protein:creatinine ratio > 20 mg/mmol (38). After 1 year,
donors with proteinuria maintained blood pressures below 140/90 mmHg (38) and albumin excretion decreased.
Postdonation GFR assessed using inulin was no different
between donors with and without preexisting proteinuria.
Donors with other IMAs
One abstract considered 16 donors with reduced GFR, defined as ≤70 mL/min (38). Eight years after donation, the
donor with the lowest predonation GFR (60 mL/min assessed using inulin) had stable renal function and normal
A
Figure
3: Meta-analyses
of long-term medical outcomes for older donors.
Decrement in GFR (mL/min (per 1.73 m2))*
Source
Tsinalis et al., 1999
Gracida et al., 2003
Length of
follow-up
(years)
1.0 (…)
6.7 (0.5-9.5)
IMA donors
N Mean (SD)
46 38 (17)
16 29 (8)
Non-IMA donors
N Mean (SD)
105 34 (16)
422 38 (12)
Hypertensive donor decrement in GFR
4 (-1,10)
-8 (-12,-4)
-15
Decrement in GFR less
for hypertensive donors
0
15
Decrement in GFR greater
for hypertensive donors
Note: Graphed results are the difference between IMA and non-IMA donors on the change in outcome from before donation to
after donation.
† See Table 1 for definitions of hypertensive donor in each study
(…) indicates missing value
* Results were not pooled for I > 50%
1884
Figure 4: Meta-analyses of
long-term medical outcomes
for hypertensive donors.
American Journal of Transplantation 2008; 8: 1878–1890
Living Kidney Donors with IMAs
Table 2: Donor outcomes assessed across studies of living kidney donors with IMAs (stratified by type of IMA)
Perioperative
Source∗
Hayashi et al., 1995
Berardinelli et al., 2003
Jacobs et al., 2004
Haberal et al., 1991
Shimmura et al., 1999
Fauchald et al., 1991
Tsuchiya et al., 2006
Lezaic et al., 1996
Tsinalis et al., 1999
Kumar et al., 1994
Nyberg et al., 1997
Srivastava et al., 2005
Grekas et al., 1989
Kostakis et al., 1997
Hsu et al., 2002
Siebels et al., 2003
Kumar et al., 2003
Neipp et al., 2006
Ivanovski et al., 2001
Sahin et al., 2000
Gracida et al., 2003
Pabico et al., 1986
Jacobs et al., 2000
Chavin et al., 2002
Chow et al., 2002
Mateo et al., 2003
Bachmann et al., 2005
Kuo et al., 2000
Rea et al., 2006
Heimbach et al., 2005
Espinoza et al., 2006
Gracida et al., 2003
Surgical
details
Complications
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
Textor et al., 2004
Tsinalis et al., 1999
Srivastava et al., 2005
Kumar et al., 2003
Sahin et al., 2000
Gracida et al., 2003
Tsinalis et al., 1999
Kumar et al., 2003
Tsinalis et al., 1999
Reinhardt et al., 2007
Koselj et al., 1997
Strang et al., 2007
Martin et al., 2007
Rashid et al., 2004
Kumar et al., 2003
Kumar et al., 2003
Longer term
Years after
donation (range)
Blood
pressure
Older donors
Until postop
Until d/c
Until d/c
. . . (0.1–3.6)
. . . (1—13.8)
0.3 (. . .)
0.5 (. . .)
1 (. . .)
1 (. . .)
1.8 (. . .)
1.8 (0.1–4)
1.8 (0.5—4.2)
2 (. . .)
2.1 (. . .)
2.1 (0.3–4.5)
3.2 (0.04–5.2)
3.3 (0.3–7.4)
4.3 (0.1–9.1)
5 (. . .)
5.3 (1.8–7.4)
6.7 (0.5–9.5)
10 (. . .)
Obese donors
Until d/c
Until d/c
Until d/c
Until d/c
5 days
0.4 (. . .)
0.9 (0.1–2.7)
0.9 (0.1–4.1)
4.2 (. . .)
6.7 (0.5–9.5)
Hypertensive donors
0.8 (0.4–1.2)
1 (. . .)
1.8 (0.5–4.2)
3.3 (0.3–7.4)
5.3 (1.8–7.4)
6.7 (0.5–9.5)
Proteinuria
Renal
function
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
Reduced renal function
√
1 (. . .)
3.3 (0.3–7.4)
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
Mortality
√
√
√
√
√
√
Proteinuria
√
√
√
1 (. . .)
Microscopic hematuria
√
√
√
4.7 (1–12)
√
7 (. . .)
Renal calculi
0.9 (. . .)
1.9 (. . .)
3 (. . .)
3.3 (0.3–7.4)
Studies assessed development of new renal calculi
3.3 (0.3–7.4)
and stone-related complications after donation
d/c = discharge; postop = postoperatively.
American Journal of Transplantation 2008; 8: 1878–1890
1885
1886
IMA
100 (12)
Tsinalis et al., 1999
102 (16)
102 (16)
To convert serum creatinine from lmol/L to g/dL, divide by 88.4.
† Reported as creatinine clearance (mL/min), an estimate of GFR.
‡ Assessment of CrCl and GFR are described in the ‘Results’ section.
62 (5)
80 (. . .)
88 (. . .)
100 (22)
102 (16)
116 (. . .)
118 (16)
116 (. . .)
112 (14)
112 (. . .)
94 (20)
102 (19)
108 (. . .)
103 (18)
111 (41)†
116 (. . .)
128 (22)†
102 (16)
91 (20)†
79 (15)†
100 (36)†
NonIMA
101 (16)
122 (39)†
101 (. . .)
103 (14)†
Tsinalis et al., 1999
95 (10)
96 (9)
Textor et al., 2004
Tsinalis et al., 1999
Gracida et al., 2003
80 (9)
75 (19)
80 (9)
106 (18)
93 (15)
80 (9)
80 (. . .)
80 (4)
89 (27)
88 (18)
88 (8)
95 (13)
71 (9)
80 (. . .)
80 (. . .)
88 (27)
72 (16)
84 (. . .)
86 (21)
44 (. . .)
87 (20)†
67 (9)†
80 (15)
90 (3)
107 (19)†
IMA
GFR (mL/min
(per 1.73 m2 ))‡
80 (18)
NonIMA
Jacobs et al., 2000
Mateo et al., 2003
Kuo et al., 2000
Rea et al., 2006
Heimbach et al., 2005
Espinoza et al., 2006
Gracida et al., 2003
Hayashi et al., 1995
64 (. . .)
Jacobs et al., 2004
80 (18)
Haberal et al., 1991
Shimmura et al., 1999 81 (15)
Tsuchiya et al., 2006
Lezaic et al., 1996
95 (3)
Tsinalis et al., 1999
Kumar et al., 1994
106 (18)
Nyberg et al., 1997
84 (15)
Kostakis et al., 1997
88 (. . .)
Hsu et al., 2002
Gracida et al., 2003
87 (. . .)
Pabico et al., 1986
Source∗
Serum Creatinine
(lmol/L)
Before donation
IMA
Obese donors
Until d/c
Until d/c
115 (20)
0.4 (. . .)
124 (18)
0.9 (0.1–2.7)
115 (18)
0.9 (0.1–4.1)
126 (21)
4.2 (. . .)
115 (27)
6.7 (0.5–9.5)
94 (. . .)
Hypertensive donors
0.8 (0.4–1.2)
133 (17)
1 (. . .)
6.7 (0.5–9.5)
121 (. . .)
Reduced renal function
1 (. . .)
Proteinuria
1 (. . .)
98 (. . .)
124 (11)
102 (21)
115 (18)
124 (18)
120 (. . .)
106 (18)
98 (. . .)
98 (. . .)
109 (27)
101 (. . .)
105 (20)
88 (17.7)
100 (8)
124 (27)
NonIMA
65 (9)
52 (11)
61 (22)
64 (14)
78 (. . .)
72 (10)
84 (. . .)
107 (6)†
72 (15)
71 (. . .)
56 (14)†
53 (10)
58 (12)†
IMA
68 (15)
68 (15)
68 (11)
68 (15)
79 (. . .)
80 (16)
79 (. . .)
118 (4)†
65 (12)
79 (. . .)
85 (19)†
68 (15)
64 (16)†
NonIMA
GFR (mL/min
(per 1.73 m2 ))
After donation
Serum Creatinine
(lmol/L)
Older donors
Until postop
97 (. . .)
Until d/c
124 (27)
. . . (0.1–3.6)
97 (9)
. . . (1–13.8)
108 (21)
0.5 (. . .)
93 (17.7)
1 (. . .)
104 (4)
1 (. . .)
1.8 (. . .)
1.8 (0.1–4)
133 (19)
2.1 (. . .)
107 (. . .)
2.1 (0.3–4.5)
109 (36)
6.7 (0.5–9.5)
115 (. . .)
10 (. . .)
Years after
donation (range)
Table 3: Studies of living kidney donors with IMAs that assessed GFR after donation
33 (9)
37 (15)
26 (24)
35 (18)
27 (15)
31 (19)
44 (23)
14 (. . .)
28 (5)
49 (18)
19 (8)
9 (4)
27 (19)
33 (. . .)
44 (23)
IMA
19 (6)
29 (11)
27 (20)
35 (15)
18 (18)
27 (17)
27 (15)
19 (. . .)
19 (6)
37 (24)
17 (9)
10 (7)
25 (18)
44 (23)
NonIMA
Serum Creatinine
(lmol/L)
−38 (16)
−38 (16)
−38 (. . .)
−32 (19)
−34 (16)
−38 (16)
−34 (16)
−34 (16)
−40 (12)
−28 (. . .)
−33 (21)
−38 (17)
−29 (11)
−10 (10)
−35 (11)
−38 (12)
−43 (21)†
−34 (16)
−27 (18)†
NonIMA
−29 (16)
−30 (5)
−47 (14)†
−33 (18)
−29 (18)†
IMA
GFR (mL/min
(per 1.73 m2 ))
Change
Young et al.
American Journal of Transplantation 2008; 8: 1878–1890
Living Kidney Donors with IMAs
Four studies examined 32 donors with renal calculi at the
time of nephrectomy (5,63–65). Stone size ranged from
1 mm to 8 mm. One study reported that after 2 years,
1 donor experienced anuria from a stone in the lower
ureter; after emergency stenting, the stone was removed
via ureteroscopy (5). The other studies reported no recurrence of stone disease or stone-related complications
(mean follow-up: 2.3 years).
Discussion
We comprehensively reviewed the literature on outcomes
of living kidney donors with IMAs. Reassuringly, perioperative outcomes such as surgical time, blood loss and
length of hospital stay were similar for donors with and
without IMAs. Few studies adequately examined intermediate or long-term medical outcomes of principal interest
to donors, recipients and transplant professionals. For this
reason and the methodological limitations therein, the risks
of this form of transplantation remain uncertain.
Strengths and limitations of the review
To our knowledge, this is the first comprehensive review
of this topic. We believe our search strategy was robust
and identified all relevant articles. Using multiple reviewers minimized potential selection biases and ensured accuracy of the abstracted data. We successfully contacted
primary authors to clarify interpretations of study results
and to obtain additional data. For some outcomes, we justified mathematically pooling results, mindful of the small
number of studies (65).
The most significant limitation of any review is the quality
of the primary studies. There are very few studies documenting important health outcomes among living kidney
donors with IMAs. Across all IMAs groups, longer term
assessments (≥1 year) of blood pressure, proteinuria and
renal function were reported in only 3, 2 and 10 studies, respectively. Only 17 of the 37 studies had prospective data
collection. Only one prospective study reported the loss
to follow-up (10%) and 3 retrospective studies reported
loss to follow-up of 24–60%, raising concerns about the
representativeness of the results. Study size was also frequently small; for the prospective studies, only 3 followed
≥30 donors. Some studies reported differential lengths of
follow-up between IMA and non-IMA donors. Overall, the
ability of these studies to identify significant differences
in long-term medical risks, should they in truth exist, is
limited.
Variable definitions of IMA donors confounded the comparison of studies. Some studies were excluded because IMA
definitions did not meet our criteria for review. For example, some studies defined ‘older’ as ≥55 years of age and
included donors over 60. Without data on each patient, our
review excluded some eligible older donors. Furthermore,
some donors may have had more than one IMA (e.g. hyAmerican Journal of Transplantation 2008; 8: 1878–1890
pertensive, older donors). While we stratified results by
IMA, overlaps of conditions were often unclear, leading to
potential misclassification. It is possible that risk outcomes
attributable to any IMA may be confounded by other health
conditions or other IMAs.
Last, we cannot exclude the possibility of a publication
bias from the underreporting of adverse outcomes for IMA
donors. While there are methods to assess such bias, such
as Egger’s test for funnel plot asymmetry (67), too few
studies precluded such proper assessments.
IMA donors in perspective
Long-term follow-up studies in living kidney donation suggest that the risks for a healthy donor are low. Although
donors may be more likely to develop hypertension and
proteinuria (68,69), they do not appear to be at increased
risk of accelerated loss of renal function, kidney failure
or cardiovascular disease (70–72). Many of these studies
are small, retrospective, have limited long-term follow-up
(∼10 years), considerable losses or unsuitable controls
(73–75). Notwithstanding these methodological concerns
and uncertainties, living donation is a globally accepted
practice.
The Amsterdam Forum report contains recommendations
for an international standard of care in an effort to ‘define
and affirm the responsibility of the transplant community
for the live kidney donor ’ (7). The guidelines suggest that
potential IMA donors should generally be precluded from
donation due to substantial uncertainty for the long-term
risks of nephrectomy compared to donors in good general
health. Donors with IMAs are, however, being accepted
with increasing frequency. Analysis of the OPTN/UNOS
data base found that of 9319 kidney donations from July
2004 to December 2005, 2143 (23%) of donors were over
65 years of age or had hypertension, obesity or proteinuria
(76). Furthermore, a survey of transplant programs in the
USA indicates that they are more willing to accept older or
hypertensive donors than a decade ago (77).
The overall growth of living donation and the acceptance
of more IMA donors may be driven by the success of the
procedure, accumulation of long-term experience in nonIMA donors, a perpetual shortage of deceased donor organs and a greater emphasis on donor autonomy among
transplant teams. The living donor population may also
be changing over time; baseline prevalence of IMAs may
be increasing or donors may be more determined to donate
than ever before. Within reasonable limits, donors have the
right to accept personal risk when making an informed decision with their recipients. In the absence of reliable data,
transplant teams must still provide responsible counsel as
more individuals with IMAs come forward for assessment.
For readers, we efficiently summarized all available literature on outcomes among living kidney donors with IMAs.
1887
Young et al.
Unfortunately, the existing literature does little to inform
clinical practice or guide informed consent procedures.
Better data and further studies are needed to make definitive conclusions. Until then, potential donors with IMAs
are either excluded from donation, or physicians must extrapolate the risks and uncertainties using population data.
One approach, advocated by Steiner, considers the prevalence of an IMA (e.g. hypertension) in the general population and the reported incidence of kidney failure associated with the IMA to approximate the risk of renal disease
for IMA donors (78). One must be mindful that this approach does not consider the role of a donor nephrectomy
in risk (if any) and is not possible for IMAs without robust
population data (e.g. borderline GFR). Moreover, this approach cannot be used to estimate many other relevant
donor outcomes such as severity of hypertension or cardiovascular risk. Hopefully, the few existing studies of IMA
donors designed to assess longer term outcomes will report follow-up data in the future (38,60). Recent efforts to
develop living donor registries may also aid in assessing
the long-term risks for IMA donors.
Well-designed prospective cohort studies in living kidney
donation have been called for, including further studies of
IMA donors. In designing such studies, we highlight several methodological considerations. To increase generalizability and facilitate recruitment, future studies should be
multicentre efforts with standardized definitions for IMAs.
In addition to IMAs, other risk factors for adverse donor
outcomes should be considered, including family history
of renal failure and hypertension and race (79–81). General
population controls with IMAs would likely be unsuitable
appreciating that they are not evaluated to the same degree that IMA donors are. Thus, healthy donor controls
would need to be considered. Assessment of blood pressure, renal outcomes and other clinically significant outcomes would need to be standardized and rigorously performed over the long term. Finally, for donors with multiple
IMAs, analytic methods would need to be used to minimize
confounding on the incremental effect of any given IMA on
long-term outcomes. Future studies considering these issues would ultimately address the effect of expanding the
living donor pool with IMA donors and translate to better
centre policy. As transplant centers continue to cautiously
screen and counsel potential IMA donors, we strongly advocate for the initiation and concurrent data collection from
such rigorously designed studies.
Acknowledgments
We thank Ms. Heather Thiessen-Philbrook, MMath for her statistical advice. We also thank the 11 primary authors of the included studies who
generously confirmed and provided information for this review.
This review was supported by the Multi Organ Transplant Program of the
London Health Sciences Centre, London, Ontario, Canada. Ms. Ann Young
was supported by a Canada Graduate Scholarship from the Canadian In-
1888
stitutes of Health Research, a Schulich Graduate Scholarship from the University of Western Ontario and a research award from the Lawson Health
Research Institute. Dr. Amit Garg was supported by a Clinician Scientist
Award from the Canadian Institutes of Health Research.
Conflict of Interest: None declared.
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