Living kidney donors undergo unilateral nephrectomy without medical benefit. The procedure is considered acceptably safe (1–9), which is a paradigm based predominantly on retrospective, cross-sectional studies prone to selection and information bias (10). Subtle evolution of cardiovascular risk factors such as blood pressure (BP) elevation and hypertension (11), decline in kidney function and chronic renal insufficiency (12), and de novo proteinuria (12) may therefore be undetected. There is also concern about circadian BP rhythm disturbance, which may occur with kidney function loss less than required for hypertension (13), and likewise, there is also concern about development of the metabolic syndrome (14).
The purpose of this prospective, observational study was to describe changes in BP, renal function, and urinary protein excretion to 6 months postdonation. In addition, we describe the short-term natural history of additional markers of cardiovascular risk including the body mass index (BMI), the fasting lipid profile, and glucose metabolism in a prospectively assembled cohort of living kidney donors.
METHODS
Our hospital performs approximately 100 renal transplants annually, of which one half are derived from living donors. Presurgical evaluation includes excluding hypertension by office BP measurement (>140/90 mm Hg) and 24-hr ambulatory BP (ABP) monitoring (>135/85 mm Hg); renal insufficiency: estimated glomerular filtration rate (eGFR) (<70 mL/min/1.73 m2); proteinuria (>300 mg/24 hr); diabetes (fasting blood glucose≥7.0 mmol/L and/or 2-hr blood glucose≥11.1 mmol/L on 75 g oral glucose tolerance testing); and morbid obesity (BMI>40 kg/m2). Nephrolithiasis and surgical contraindications are excluded through abdominal computerized tomography. Standard postdonation evaluation includes an office visit 3 months postdonation, during which a sphygmomanometer-measured BP is obtained, renal function is estimated by the abbreviated Modification of Diet in Renal Disease (MDRD) equation (15), and a random urine sample is evaluated for proteinuria. All potential donors receiving prior approval to donate by an independent team were approached for participation.
Donors providing informed consent were asked to repeat all testing at 6 months postdonation except radiographic imaging. Twenty-four hour ABP measurements were performed using a calibrated DynaPulse 5000A monitor. Self-reported awake and sleep defined waking (daytime) and sleep (nighttime) periods. Systolic (SBP) and diastolic blood pressure measurements were recorded every 60 min. Nocturnal nondipping was defined as nighttime-to-daytime SBP ratio more than or equal to 0.9. An additional BP measurement by American Heart Association guidelines was obtained at the time of 24-hr ABP measurement both pre- and postdonation; this “office” BP value was used for data analysis.
Renal function was estimated by serum creatinine; creatinine clearance (CCr) from the Cockcroft-Gault equation (16) and 24-hr urine collection; and eGFR calculation using the abbreviated MDRD equation (15). All donors also provided a 24-hr urine collection for protein excretion, 75 g oral glucose tolerance testing, and fasting lipid profiles at 6 months.
A priori analyses performed included (1) whole population comparisons between their predonation values and 6 month postdonation values for all parameters; (2) comparisons between these two points in time separately for donors classified as dippers or nondippers based on their predonation 24-hr ABP profile; and (3) comparisons between dippers and nondippers both predonation ABP measurement-based and at 6 months based on their 6 month postdonation profile.
Pre-to-postdonation comparisons were made by paired or unpaired Student’s t test, Wilcoxon rank sum test, or chi-square analysis. Bivariate comparisons were made using Pearson’s correlation coefficient. A two-tailed P value less than 0.05 was considered statistically significant. SAS version 9.2 (Cary, NC) was the statistical software package used. The study was approved by Research Ethics Boards at both St. Michael’s Hospital and the University of Toronto.
RESULTS
Between October 1, 2004 and April 30, 2007 there were 129 live donor renal transplants performed (70 biologically related, 56 emotionally related, 2 paired exchange, and 1 anonymous nondirected). Sixty-nine (53%) patients provided initial consent. Reasons for nonconsent included unwillingness to travel or provide other follow-up testing (31) foreign residence (9), or competing protocols (9). Eleven donors did not provide specific reasons for nonconsent. Fifty-eight of 69 (84%) consented donors completed their testing at 6 months (maximum time permitted was 8 months) postdonation, whereas 11 were lost to follow-up. Demographic characteristics are provided in Table 1. Of the 11 donors lost to follow-up, 7 were men, 5 white, and age was 34.7±9 (24–54) with no significant differences from consenting donors.
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TABLE 1: Demographic characteristics of study population
Changes in BP, renal function, urine protein excretion, BMI, glucose, and lipid levels from predonation to 6 months postdonation are summarized in Table 2. At their predonation baseline, there were 39 dippers and 19 nondippers. The night-day SBP ratio was 0.83±0.05 (0.72–0.89) in the dippers and 0.95±0.04 (0.90–1.02) in the nondippers (P<0.0001). There were no statistically significant demographic or clinical differences between predonation dippers and nondippers. At 6 months, the night-day SBP ratio difference was no longer significant: 0.86±0.10 (0.68–1.30) in predonation dippers and 0.88±0.08 (0.73–1.09) in predonation nondippers (P=0.46).
TABLE 2: Characteristics of donors (N=58) completing predonation and 6-mo postdonation evaluation
At 6 months, there were 46 dippers and 12 nondippers. Twelve of 19 nondippers at baseline became dippers, whereas 6 of 39 baseline dippers became nondippers (P=0.26). Again, apart from the defined night-day SBP ratio, there were no differences between donors classified on the basis of their 6-month dipping status. Predonation BP did not correlate with renal function (P=0.92) or protein excretion (P=0.79), nor did postdonation BP (P=0.12, P=0.62, respectively). There were no differences between converters between dipper and nondipper status and nonconverters. No donors received antihypertensives.
Change in renal function as assessed by the Cockcroft-Gault equation is summarized in Table 2. Similar results were seen with the MDRD-equation estimated GFR and 24-hr urine collection (Table 2). Percentage decline in renal function is shown in Figure 1. There was no difference in 24-hr urine creatinine content from pre- to postdonation (11.4±4 vs. 10.3±3 mmol/L, P=0.27). Most donors were in the range of more than 90 or 60–89 mL/min/1.73 m2. Although a small number reached stage III chronic kidney disease (CKD) (eGFR 30–59 mL/min/1.73 m2) postdonation, none reached stage IV. A post hoc subanalysis comparing patients reaching stage III CKD with those in stages I or II at 6 months revealed no significant differences other than higher systolic BP (123±13.1 (117–129) vs. 113±14.5 mm Hg (106–121), P=0.048). No differences in renal function or protein excretion were noted between dippers and nondippers.
FIGURE 1.:
Percent change in renal function from predonation to 6 months postdonation as estimated by three different methods.
The 6-month eGFR did not correlate with 24-hr SBP (P=0.42), night-day SBP ratio (P=0.22), or 24-hr urine protein (P=0.76). There was no correlation between night-day SBP ratio change and change in eGFR (correlation coefficient: −0.17, P=0.22), 24-hr urine CCr (−0.04, P=0.77), or protein excretion (−0.22, P=0.23).
There was no change in BMI, blood glucose, fasting lipids, or hemoglobin. Triglycerides were, however, higher at 6 months postdonation. No differences were noted between dipper and nondipper subgroups.
DISCUSSION
This prospective 6-month study in kidney donors provides reassurance of the short-term safety of unilateral nephrectomy. Blood pressure was unchanged and there was no night-day SBP ratio or nondipping increase. Nondipping was not associated with any added risk. There was no metabolic change except in triglycerides.
A previous study of 15 donors performed between 2 weeks and 3 months postdonation demonstrated an unchanged night-day mean arterial pressure ratio. However, change in ratio correlated with decrease in CCr (13). We were unable to corroborate this; a possible explanation is the longer interval between the two ABP measurements and use of outpatient readings. A substantial loss of renal function not typically seen in donors may be required before appearance of an elevated BP (17). However, an abnormal circadian BP rhythm is associated with acceleration of progression of nephropathy (18) and several end-organ effects (19). The prospective demonstration of no unfavorable circadian rhythm change in this study provides further donor reassurance. In a study of 148 predominantly white donors, 24 of whom were hypertensive predonation, ABP was not higher at 6 to 12 months (20). Our study confirms this finding and extends it to an ethnically diverse population.
The study is limited by lack of a gold standard for renal function measurement, which was not used to avoid precipitous reduction in recruitment rate. It is important to point out that some donors had postdonation CCr as low as 40 and eGFR as low as 35 mL/min/1.73 m2 placing them in stage III CKD (Table 2, Fig. 1). All such identified donors were referred to their predonation nephrologist. We also intend to follow these patients in subsequent years. Addition of a nonnephrectomized control group will also strengthen conclusions regarding postdonation outcomes (21).
There is concern that renal mass loss can lead to glucose intolerance. In 28 rats subjected to unilateral nephrectomy, glucose intolerance was noted (22). Others demonstrated increases in body weight and triglycerides (23) and metabolic syndrome (14). This study provides reassurance that traditional markers of cardiovascular risk are not increased in living donors in the short term. An increase in triglyceride levels was noted but firm conclusions cannot be made because of the multiple comparisons made which could produce chance results.
In summary, living kidney donation is not associated with short-term increases in BP, protein excretion, or metabolic risk. We suggest further observation for individuals with lower GFR for possible increased cardiovascular risk factors.
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