Changes in Blood Pressure and Arterial Hemodynamics following Living Kidney Donation

Visual Abstract

Abstract

Background and objectives

The Effect of a Reduction in GFR after Nephrectomy on Arterial Stiffness and Central Hemodynamics (EARNEST) study was a multicenter, prospective, controlled study designed to investigate the associations of an isolated reduction in kidney function on BP and arterial hemodynamics.

Design, setting, participants, & measurements

Prospective living kidney donors and healthy controls who fulfilled criteria for donation were recruited from centers with expertise in vascular research. Participants underwent office and ambulatory BP measurement, assessment of arterial stiffness, and biochemical tests at baseline and 12 months.

Results

A total of 469 participants were recruited, and 306 (168 donors and 138 controls) were followed up at 12 months. In the donor group, mean eGFR was 27 ml/min per 1.73 m² lower than baseline at 12 months. Compared with baseline, at 12 months the mean within-group difference in ambulatory day systolic BP in donors was 0.1 mm Hg (95% confidence interval, −1.7 to 1.9) and 0.6 mm Hg (95% confidence interval, −0.7 to 2.0) in controls. The between-group difference was −0.5 mm Hg (95% confidence interval, −2.8 to 1.7; P=0.62). The mean within-group difference in pulse wave velocity in donors was 0.3 m/s (95% confidence interval, 0.1 to 0.4) and 0.2 m/s (95% confidence interval, −0.0 to 0.4) in controls. The between-group difference was 0.1 m/s (95% confidence interval, −0.2 to 0.3; P=0.49).

Conclusions

Changes in ambulatory peripheral BP and pulse wave velocity in kidney donors at 12 months after nephrectomy were small and not different from controls.

Clinical Trial registry name and registration number

NCT01769924 (https://clinicaltrials.gov/ct2/show/NCT01769924).

Introduction

CKD is a major risk factor for cardiovascular disease; there is a graded association, independent of multiple cardiovascular risk factors, between GFR and cardiovascular risk (1). In early stage CKD, mortality from cardiovascular events is more likely than the need for KRT (2). Hypertension, increased arterial stiffness, chronic inflammation, and uremic toxins are thought to be key mediators of the higher cardiovascular risk (3). In patients with ESKD, increased arterial stiffness as measured by pulse wave velocity is an independent predictor of mortality (4). Increased arterial stiffness is also highly prevalent in the earlier stages of CKD (5). It is not clear whether increased BP and arterial stiffness in CKD are direct consequences of the reduced GFR or result from multiple comorbid conditions that tend to accompany CKD.

Living kidney donors provide an opportunity to prospectively examine the cardiovascular consequences of a reduction in kidney function without the confounding effects of comorbid disease. In the long term, kidney donors lose approximately 30% of their baseline GFR and, consequently, >65% have a GFR consistent with stages 2 and 3 CKD (6). They also have similar biochemical abnormalities to patients with CKD (7). Although the risk of ESKD after nephrectomy is higher compared with controls, absolute risk over a 15-year period remains low (8,9). To date, however, most studies of kidney donors have not shown a higher cardiovascular risk or mortality (10,11). Only one study has shown higher cardiovascular mortality compared with controls, which occurred later over a 10-year follow-up period (8). The aim of this study was to determine the effect of the reduction in kidney function that occurs after kidney donation on arterial stiffness and BP in a sample large enough to detect small differences.

Materials and Methods

Study Design

The EARNEST (Effect of A Reduction in GFR after NEphrectomy on arterial STiffness and central hemodynamics) study was a prospective, multicenter cohort study in the United Kingdom. We aimed to recruit 440 controls and 440 donors over a 2-year period from seven centers recognized for performing high numbers of living kidney transplants within the United Kingdom. Recruitment began in April 2012; the last follow-up patient was studied in May 2016. Recruitment was terminated in May 2015 on pragmatic and financial grounds. This was principally due to unanticipated large numbers of recruited participants dropping out at follow-up.

Study Population

The inclusion and exclusion criteria for donors and controls were in accordance with national guidelines disseminated by the Joint Working Party of the British Transplantation Society and the Renal Association for living kidney donors (12). Both donors and controls had to be deemed fit to donate a kidney.

Most healthy controls were individuals undergoing workup for donation but who were ultimately unable to donate due to factors such as immunologic mismatch or recipient illness. Alternatively, donor-related family members or volunteers donating blood at local blood donation centers were recruited.

Study Protocol

All participants were investigated at baseline (<6 weeks before nephrectomy for prospective living kidney donors) and at 12 months. A full illustrated and detailed protocol has previously been published, with a summary presented below (13).

Blood Pressure Measurement.

Office BP was measured three times, from the nondominant arm after 5 minutes of rest, using a validated automated device. BP was taken in both a sitting and supine position. Participants underwent 24-hour ambulatory BP monitoring using the Mobil-O-Graph NG (IEM, Stolberg, Germany) (14). BP recordings were taken every 30 minutes between the hours of 08:00 am to 22:00 pm, and every 60 minutes between 22:01 pm and 07:59 am (15,16).

Pulse Wave Velocity.

Pulse wave velocity was measured using the SphygmoCor (Atcor Medical, Sydney, Australia) by trained personnel after asking the participant to lie supine for 15 minutes. Repeated uniform pressure waveforms were acquired from both the carotid and femoral artery using a high fidelity micromanometer (SPC-301; Millar Instruments, Houston, TX) (17). A three-lead electrocardiogram was used to determine the time between the R wave and the foot of the pulse at each respective site as previously described (18). Arterial path distance was inferred using the distance from the sternal notch to the femoral pulse subtracted by the distance between the sternal notch and the carotid pulse (19).

Pulse Wave Analysis.

Using the SphygmoCor device, arterial pressure waveforms were obtained, from which central waveforms can be calculated. Central BP and augmentation index (AIx) were calculated using transfer functions as previously described (15,20). AIx is the augmentation pressure from the aortic waveform expressed as a percentage of pulse pressure (Figure 1).

Figure 1.

A typical example of an aortic pulse pressure waveform. The maximum pressure is systolic and the minimum pressure is diastolic. The first peak, the forward wave, indicates ejected blood from the heart. The second peak, the reflected wave, is that returned from peripheral vasculature. The difference between the two is augmentation pressure. Augmentation index is augmentation pressure expressed as a percentage of pulse pressure (43). Because augmentation index is influenced by timing of the reflected wave, augmentation index is corrected for a heart rate of 75 beats per minute (43). Reprinted from ref. 43, which is available under the terms of the Creative Commons Attribution License.

Assessment of GFR.

GFR was determined in all participants using standardized creatinine assays and the CKD Epidemiology Collaboration Creatinine Equation 2009 (21,22). A subset of living kidney donors underwent isotopic GFR measurement using clearance of chromium-51–EDTA at both baseline and follow-up (23,24).

Blood and Urine.

Biochemistry measurements included serum creatinine, calcium, albumin, phosphate, uric acid, and urinary albumin-creatinine ratio.

Primary Outcomes

The primary outcomes were (1) mean change in ambulatory systolic BP and (2) mean change in pulse wave velocity.

Statement of Ethics

Ethical approval for the main study was obtained in February 2013 from the South Cambridge Regional Ethics Committee (Integrated Research Application System reference 118797, Research Ethics Committee approval number 13/EE/0015). The EARNEST substudy (CRIB-DONOR) commenced in 2011, and ethical approval was obtained from the West Midlands Research Ethics Committee. All participants underwent informed consent in keeping with the principles set out by the Declaration of Helsinki.

Power Calculations and Sample Size

Using data from previous studies, the SD of the within-patient changes was assumed to be 10 mm Hg for BP and 1.0 m/s for pulse wave velocity (17,25). A sample size of 800 participants (400 subjects per group) was planned to provide 80% power to detect a difference of 2.2 mm Hg in systolic pressure or 0.22 m/s in pulse wave velocity using a two-sided t test at the 2.5% significance level. Values for a sample size of 400 participants (200 subjects per group) have 92% power to detect a difference of 4 mm Hg for systolic BP and 0.4 m/s for pulse wave velocity, allowing for 15% loss to follow-up at a significance level of 5%.

Statistical Analyses

Statistical analysis was performed using Stata statistical software (release 15; StataCorp LCC, College Station, TX). Continuous variables at baseline and 12 months were compared using independent samples t tests. Categoric variables were compared using chi-squared tests. A paired-samples t test was used to determine the mean change and 95% confidence interval (95% CI) between baseline and follow-up in each group (within-group change). Change from baseline to 12 months was calculated for both donors and controls. An independent samples t test was used to determine the mean change and 95% confidence interval between within-group change in donors and within-group change in controls (between-group change). Carotid-femoral pulse wave velocity was adjusted for average mean arterial pressure and average supine heart rate using unstandardized residuals calculated from a linear regression model. In supplementary analyses, we used multivariable linear regression to account for factors that may have confounded the relationship between kidney donation and change in pulse wave velocity (age, sex, and smoking status). A P value of <0.05 was considered significant, and no adjustments were made for multiple comparisons. Data presented include subjects who returned for follow-up. We dealt with missing data by performing a complete case analysis. Further subanalysis of those who remained in the study compared with those who were lost to follow-up is detailed in Supplemental Tables 1–3.

Results

Follow-Up and Events

A total of 469 participants were recruited; 20 were excluded because they lacked the minimal dataset required for analysis, and two were found to be ineligible after the initial visit (Figure 2). Recruitment was terminated at 3 years despite the lower-than-planned sample size due to financial constraints. Of the remaining 447 participants, there were 201 controls and 246 donors. Of these, a total of 38 controls and 46 donors were patients who originally consented into the CRIB-DONOR substudy; these participants reconsented to allow their data to be included (26). A total of 141 participants were unable to attend follow-up at 12 months, leaving 168 donors and 138 controls with complete paired data who were included in the final analysis. The most common reasons for lack of study completion by participants were change of address or difficulty attending clinic visits due to travel distance, work, and childcare commitments.

Figure 2.

Participants recruited into the EARNEST study. *Following eligibility assessment, there were 22 patients who consented to take part but were ultimately excluded from the study. After baseline blood tests, two “healthy controls” did not meet criteria due to incidental findings: one was diagnosed with diabetes and one had an insufficient kidney function. Consequently, neither met living kidney donation criteria. A further 20 patients consented to take part and withdrew before completing baseline assessment. This was usually because of competing appointments during living kidney donor workup.

For comparison between patients who were lost to follow-up and those who continued in the study, see Supplemental Table 1. Minimal differences were observed in those who did not return for follow-up at 12 months. Participants who continued in the study had a marginally lower eGFR and were more likely to be taking antihypertensive medications.

In addition, a further 49 donors and 27 controls who returned for follow-up had incomplete ambulatory BP recordings.

Patient Characteristics

The demographics of living kidney donors and healthy controls who attended for both baseline and 12-month follow-up visits were comparable with the exception of tobacco use (Table 1). Baseline hemodynamic and biochemical characteristics are shown in Tables 2 and 3. There were no significant differences between donors and controls in any of the baseline hemodynamic values and no clinically significant differences in biochemical values. At follow-up, there were six living kidney donors whose eGFR fell into stage 3b CKD and one whose eGFR fell into stage 4 CKD according to the Kidney Disease Improving Global Outcome guidelines.

Table 1.

Baseline characteristics of participants in the EARNEST study who completed both baseline and 12-month evaluations

Characteristics	Controls (n=138)	Donors (n=168)
Sex (male)a	57 (41)	78 (46)
Age (yr)a	49±14	51±12
Race
White	127 (92)	158 (94)
Nonwhite	8 (6)	9 (5)
Unknown	3 (2)	1 (1)
History of hypertension	9 (7)	17 (10)
Antihypertensive usagea	9 (7)	18 (11)
ACE/ARB usage	4 (3)	5 (3)
Calcium channel blocker usage	4 (3)	6 (4)
Current or previous smokera	38 (28)	74 (44)
eGFR, categories (ml/min per 1.73 m2)
<80	25 (18)	38 (23)
80 to <90	23 (17)	39 (23)
>90	88 (65)	91 (54)
Normalized isotopic GFR (ml/min per 1.73 m2)a	89±13	89±12

Categoric variables are presented as n (%) and continuous data are represented as mean±SD. EARNEST, Effect of a Reduction in GFR after Nephrectomy on Arterial Stiffness and Central Hemodynamics; ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker.

^aFor these categories (sex, age, antihypertensive usage, and current or previous smoker), there were n=168 donors and n=137 controls due to an incomplete dataset for one healthy control. For isotopic GFR, results from controls were part of the CRIB-DONOR substudy and included n=90 donors and n=22 controls.

Table 2.

Changes in hemodynamic and arterial parameters over 12 months

Variables	Patient Group (n)	Single Time Point		Change
		Baseline	12 mo	Within Groupa	Between Groupb	P Valuec
Weight (kg)
Donors	168	75.4±13.5	77.1±14.7	1.7 (0.4 to 3.0)	1.5 (−0.12 to 3.0)	0.07
Controls	136	74.7±13.9	74.9±13.8	0.2 (−0.4 to 0.8)
BMI (kg/m2)
Donors	168	26.2±3.3	26.8±4.6	0.6 (0.1 to 1.2)	0.5 (−0.1 to 1.1)	0.09
Controls	136	26.0±4.0	26.2±4.0	0.1 (−0.1 to 0.3)
Seated office systolic BP (mm Hg)
Donors	168	125±14	127±12	1.8 (−0.0 to 3.6)	2.8 (0.3 to 5.4)	0.03
Controls	135	125±17	124±17	−1.0 (−2.8 to 0.7)
Seated office diastolic BP (mm Hg)
Donors	168	78±9	80±8	1.7 (0.4 to 2.9)	1.0 (−0.74 to 2.9)	0.25
Controls	135	77±10	78±9	0.7 (−0.8 to 1.9)
Ambulatory day systolic BP (mm Hg)
Donors	119	124±10	124±10	0.1 (−1.7 to 1.9)	−0.5 (−2.8 to 1.7)	0.62
Controls	111	122±10	123±12	0.6 (−0.7 to 2.0)
Ambulatory day diastolic BP (mm Hg)
Donors	119	79±8	79±8	0.2 (−0.9 to 1.4)	−0.6 (−2.1 to 0.9)	0.40
Controls	111	77±8	78±9	0.9 (0.0 to 1.7)
Ambulatory day HR (bpm)
Donors	65	73±9	74±10	1.5 (−0.9 to 3.9)	2.8 (0.1 to 5.5)	0.04
Controls	82	72±9	71±10	−1.3 (−2.8 to 0.2)
Ambulatory night systolic BP (mm Hg)
Donors	111	111±11	112±11	0.9 (−1.1 to 3.0)	1.5 (−1.2 to 4.3)	0.27
Controls	105	110±10	110±12	−0.6 (−2.5 to 1.3)
Ambulatory night diastolic BP (mm Hg)
Donors	111	67±9	69±9	1.4 (−0.2 to 3.0)	1.1 (−0.9 to 3.3)	0.27
Controls	105	66±8	66±9	0.3 (−1.2 to 1.7)
Central systolic BP (mm Hg)
Donors	105	113±14	115±14	2.1 (−0.2 to 4.4)	3.3 (0.3 to 6.3)	0.03
Controls	108	111±17	109±17	−1.2 (−3.1 to 0.7)
Central diastolic BP (mm Hg)
Donors	105	77±9	78±10	1.3 (−0.7 to 3.2)	1.5 (−0.9 to 4.0)	0.22
Controls	108	75±10	75±10	−0.3 (−1.9 to 1.1)
Augmentation index, corrected for HR (%)
Donors	104	22.1±12.0	25.6±12.2	3.4 (1.5 to 5.3)	1.6 (−1.0 to 4.2)	0.23
Controls	108	20.4±12.5	22.3±12.0	1.8 (−0.0 to 3.6)
Adjusted carotid-femoral pulse wave velocity (m/s)
Donors	168	7.0±1.3	7.3±1.4	0.3 (0.1 to 0.4)	0.1 (−0.2 to 0.3)	0.49
Controls	138	7.0±1.4	7.2±1.4	0.2 (−0.0 to 0.4)

Data are displayed as mean±SD or mean (95% confidence intervals). BMI, body mass index; HR, Heart rate; BPM, Beats per minute.

^aWithin-group change refers to change in values between baseline and follow-up in each group, i.e., mean weight in donors for baseline was 75.4 kg and at follow-up was 77.1 kg, giving a within-group change of 1.7 kg. The 95% confidence interval was estimated using paired sample t tests.

^bBetween-group change refers to the difference between donors and controls within-group change i.e., for weight, within-group change for donors is 1.7 kg and 0.2 kg for controls, giving a between-group change of 1.5 kg. The 95% confidence interval was estimated using independent samples t tests.

^cComparison between controls and donors was made for within-group change (i.e., mean change in weight in donors [1.7 kg] versus mean change in weight in controls [0.2 kg]) using independent samples t tests.

Table 3.

Changes in biochemical parameters over 12 months

Variables	Patient Group (n)	Single Time Point		Change
		Baseline	12 mo	Within Groupa	Between Groupb	P Valuec
Sodium (meq/L)
Donors	167	140±2	140±2	−0.3 (−0.7 to 0.0)	−0.1 (−0.6 to 0.4)	0.59
Controls	137	141±2	140±2	−0.2 (−0.5 to 0.2)
Potassium (meq/L)
Donors	167	4.3±0.3	4.4±0.4	0.1 (0.0 to 0.2)	0.1 (0.0 to 0.2)	0.02
Controls	134	4.2±0.3	4.2±0.3	−0.0 (−0.1 to 0.1)
Urea (mg/dl)
Donors	167	31±8	38±10	8.4 (7.2 to 9.6)	7.2 (5.4 to 9.0)	<0.001
Controls	136	30±8	31±8	1.0 (0.03 to 2.4)
Creatinine (mg/dl)
Donors	168	0.8±0.2	1.2±0.2	0.3 (0.3 to 0.4)	0.3 (0.3 to 0.4)	<0.001
Controls	136	0.8±0.2	0.8±0.2	−0.02 (−0.03 to 0.009)
eGFR (ml/min per 1.73 m2)
Donors	168	91±15	64±14	−27 (−29 to −26)	−29 (−32 to −26)	<0.001
Controls	136	94±16	96±17	2 (−0.4 to 3.8)
Albumin (g/dl)
Donors	145	4.27±0.39	4.22±0.43	−0.04 (−0.10 to 0.01)	−0.07 (−0.15 to −0.0)	0.04
Controls	135	4.16±0.44	4.19±0.48	0.03 (−0.01 to 0.08)
Corrected calcium (mg/dl)
Donors	148	9.2±0.4	9.2±0.4	0.0 (−0.0 to 0.0)	−0.0 (−0.0 to 0.0)	0.28
Controls	136	9.2±0.4	9.2±0.4	0.0 (−0.0 to 0.0)
Phosphate (mg/dl)
Donors	130	3.4±0.6	3.1±0.6	−0.3 (−0.3 to −0.3)	−0.31 (−0.31 to −0.1)	<0.001
Controls	121	3.4±0.6	3.4±0.6	0.0 (−0.0 to 0.3)
Magnesium (mg/dl)
Donors	77	2.2±1.7	2.2±0.2	0.0 (−0.0 to 0.0)	−0.0 (−0.0 to 0.0)	0.94
Controls	85	2.2±1.7	2.2±0.2	0.0 (−0.0 to 0.0)
Uric acid (mg/dl)
Donors	93	5.0±1.2	5.9±1.3	0.9 (0.69 to 1.0)	0.9 (0.7 to 1.0)	<0.001
Controls	95	4.8±1.1	4.8±1.1	−0.0 (−0.6 to 0.1)
Urine albumin-creatinine ratio (mg/g)
Donors	66	24.6±41.2	23.1±39.8	−1.5 (−9.7 to 7.1)	−1.5 (−9.7 to 12.4)	0.80
Controls	69	20.1±32.7	17.1±32.0	−3.0 (−11.5 to 5.3)

Data are displayed as mean±SD or mean (95% confidence intervals).

^aWithin-group change refers to change in values between baseline and follow-up in each group, i.e., mean potassium in donors for baseline was 4.3 meq/L and at follow-up was 4.4 meq/L, giving a within-group change of 0.1 meq/L. The 95% confidence interval was estimated using paired sample t tests.

^bBetween-group change refers to the difference between donors and controls within-group change, i.e., for potassium, within-group change for donors is 0.1 meq/L and 0.0 meq/L for controls, giving a between-group change of 0.1 meq/L. The 95% confidence interval was estimated using independent samples t tests.

^cComparison between controls and donors was made for within-group change (i.e., mean change in potassium in donors [0.1 meq/L] versus mean change in weight in controls [0.0 meq/L]) using independent samples t tests.

Patient demographics and hemodynamic and biochemical characteristics at baseline for all those recruited (n=447) are shown in Supplemental Tables 2 and 3. Donors had a higher mean age than controls (51 years versus 47 years; P=0.003) and were more likely to have a history of previous smoking (46% versus 33%; P=0.007).

Comparison of Hemodynamic Variables in Living Kidney Donors and Controls

Arterial hemodynamic parameters at baseline and 12 months are given in Table 2. There were no significant differences between donors and controls in ambulatory BPs at 12 months. The changes in office systolic BP from baseline to 12 months in donors and controls were small. The mean change seen in donors (+1.8 mm Hg) was, however, different to that in controls; controls had a mean reduction of −1 mm Hg (difference of 2.8 mm Hg; 95% CI, 0.3 to 5.4; P=0.03). Using current American Heart Association ambulatory BP criteria, 13 (9%) in the control group and 15 (9%) in the donor group developed hypertension over the 12-month period with no significant difference between the two groups (P=0.18) (27). The mean change in ambulatory heart rate was significantly greater in donors compared with controls at 12 months (difference of 2.8 bpm; 95% CI, 0.1 to 5.5; P=0.04).

Adjusted pulse wave velocity was not significantly different at 12 months, nor was there any difference in changes from baseline. Our supplementary analyses showed no association between kidney donation and change in pulse wave velocity when accounting for factors that may influence this relationship (Supplemental Table 4). Change in central diastolic BP and AIx adjusted for heart rate were not significantly different in donors compared with controls. When considering changes from baseline, only central systolic BP changes were significantly greater in donors than controls (difference of 3.3 mm Hg; 95% CI, 0.3 to 6.3; P=0.03).

Comparison of Biochemistry in Living Kidney Donors and Controls

Results are shown in Table 3. At 12 months, eGFR fell by a mean of 27 ml/min per 1.73 m² in donors but was unchanged in controls. Although isotopic GFR measurement was part of the protocol for donation, in practice, few subjects consented to a 12-month isotopic GFR due to concerns about the duration of the test and exposure to ionizing radiation. The mean change from baseline for phosphate in donors was significantly lower compared with controls (difference, −0.31 mg/dl; 95% CI, −0.31 to −0.1; P≤0.001. In contrast, a significant increase in uric acid was seen in donors compared with controls (difference, 0.9 mg/dl; 95% CI, 0.7 to 1.0; P≤0.001).

Discussion

This prospective study of ambulatory BP monitoring and arterial hemodynamics in kidney donors provides important findings. There was no difference in ambulatory BP in donors compared with controls at 12 months after nephrectomy. Pulse wave velocity also did not differ in these groups. Central systolic BP increased slightly more in donors than controls and was higher in the donor group at 12 months. These results suggest the risk of a significant rise in BP at 12 months in kidney donors is small. This is in keeping with findings from the smaller CRIB-DONOR substudy but is surprising in view of the high prevalence of hypertension in patients with CKD and similar levels of GFR (26). Our data suggest a simple loss of nephron numbers does not invariably result in an elevated BP and that other aspects of CKD such as inflammation and nephron dysfunction may be required for this key pathophysiologic mediator to occur.

Previous data have been contradictory. In a 2006 meta-analysis of 48 studies of office BP in kidney donors, including a total of 5145 patients, there was an increase in systolic BP of 6 mm Hg (95% CI, 2 to 11) and an increase in diastolic pressure of 4 mm Hg (95% CI, 1 to 7) in donors at 5 years (28). More recently, however, Kasiske et al. (29) found no significant difference in >300 participants between kidney donors and controls in office BP at any time point up to 36 months. There was also no difference in ambulatory BP in 135 donors and 126 controls at 36 months (29). Taken together, our data and the study of Kasiske et al. (29) suggest the risk of a clinically important change in BP in the short term after kidney donation is low. Longer-term data are of course required.

Despite the absence of change in peripheral pressure, the mean change in central systolic pressure was greater in donors at 12 months compared with controls (+2.1 versus −1.2 mm Hg; P=0.03). Although this small difference may be a chance result due to multiple comparisons, it may be important because central BP is better related to left ventricular mass, carotid intimal thickness, and cardiovascular events than peripheral pressure (30,31). The small increase in AIx was not accompanied by a similar rise in pulse wave velocity. Discrepancies between changes in AIx and pulse wave velocity have been found by other observers in a number of situations and remain incompletely explained (32). Any increase in AIx suggests an increase in wave reflection, which might explain the increase in central BP. Because pulse wave velocity was unchanged, it is possible that this increased reflection occurred due to changes in peripheral, rather than central, arterial stiffness. We speculate this occurred as a consequence of ligation of one of the renal arteries causing amplification of the reflection site without a corresponding change in pulse wave velocity, although to date this has no supportive animal or human evidence. Previous studies examining arterial stiffness in kidney donors have been small and uncontrolled. De-Seigneux et al. (33) studied 21 patients before and 1 year after nephrectomy and found no change in AIx or pulse wave velocity. Similarly, Fesler et al. (34) found no change in pulse wave velocity at 12 months postnephrectomy in 45 donors. A cross-sectional study of 101 living kidney donors, however, found that pulse wave velocity was 10% higher than in control patients (35). We cannot exclude a small effect on pulse wave velocity because the study was not powered to detect a difference of <0.4 m/s.

Most of the biochemical changes after donation are in accord with previous studies (26,29). Our finding of lower phosphate levels in donors is perhaps surprising in view of the kidney excretion of phosphate but is consistent with a large prospective study of bone metabolism in kidney donors (36). We speculate this is a result of an increase in fibroblast growth factor 23, which has a pivotal role in phosphate homeostasis and has been associated with left ventricular hypertrophy (37,38).

In summary, this is a large, controlled, longitudinal, prospective study of hemodynamics in living kidney donors. This study indicates there is no change in ambulatory BP or arterial stiffness at 12 months postnephrectomy despite changes in biochemistry. This has important implications for the future of living kidney donors but also provides valuable insight into the pathophysiology of hypertension and myocardial disease in CKD, suggesting that an increase in BP is not an inevitable consequence of a reduced GFR.

Limitations

We did not reach the planned sample size, and a substantial proportion of participants did not return for follow-up at 1 year, which limited the study power and introduced the potential for selection bias. Barriers to studies of living kidney donors have been reported by others (39). They are often geographically remote from the transplant center (in contrast to the recipient) and are usually in full-time work after donation. Barriers to ambulatory BP monitoring in this study were in keeping with those previously observed, where one in five patients describe 24-hour monitoring as uncomfortable and nearly 70% are woken from sleep (40,41).

However, these limitations do not affect the internal validity of our results. There were only minor differences between participants who did and did not return for follow-up, so our results should be generalizable to the wider pool of potential kidney donors. Although not statistically different, the healthy controls were on average 2 years younger, more likely to be male, and more likely to have a history of hypertension. There was a greater rate of smoking among donors, which could be due in part to social deprivation based on geographic area or reflect health-promoting behavior in healthy controls. In addition, the large number of parameters measured beyond the prespecified primary end points mean there are issues of multiple testing necessitating caution in interpreting results because some differences may have arisen by chance.

Lack of ethnic diversity has been a notable problem in living kidney donor research (7). Over 90% of our cohort was White, and this does reflect the vast racial disparity currently facing transplantation (42). We recognize that although our data at 12 months are reassuring, longer-term and more diverse studies are required, particularly in light of literature showing higher cardiovascular risk in the long term (8).

Disclosures

P.B. Mark reports receiving personal fees from AstraZeneca, Bristol Myers Squibb, Janssen, Novartis, and Pfizer; grants from Boehringer Ingelheim; and personal fees and nonfinancial support from Napp, Pharmacosmos, and Vifor, all outside the submitted work. All remaining authors have nothing to disclose.

Funding

This study was funded by British Heart Foundation grant PG/12/35/29403. D. Banerjee reports receiving grants from AstraZeneca, British Heart Foundation, and Wellcome, during the conduct of the study. A.M. Price is supported by a British Heart Foundation clinical training fellowship, number FS/16/73/32314. L.A. Tomlinson is funded by a Wellcome Trust intermediate clinical fellowship, number 101143/Z/13/Z.

Supplemental Material

This article contains the following supplemental material online at http://cjasn.asnjournals.org/lookup/suppl/doi:10.2215/CJN.15651219/-/DCSupplemental.

Supplemental Table 1. Baseline characteristics of patients who were lost to follow-up compared with those who continued the study.

Supplemental Table 2. Baseline patient demographics of the whole cohort recruited.

Supplemental Table 3. Baseline biochemical and hemodynamic characteristics of the whole cohort recruited.

Supplemental Table 4. Linear regression model: Association between 12-month change in adjusted pulse wave velocity and kidney donation, age, sex, and smoking status.