Objectives: Our goal was to determine the short-term effects of donor nephrectomy on the cardiovascular system and to gain a better understanding of the recently recognized long-term increased risk of end-stage renal disease and cardiovascular mortality.

Materials and Methods: Living kidney donors who underwent donor nephrectomy between January 2010 and January 2015 at the Hacettepe University Transplantation Unit were retrospectively screened. Echocardiographic parameters, kidney volumes, and renal functions before nephrectomy were compared with measurements after nephrectomy. Flow-mediated dilatation values of living kidney donors were compared with healthy individuals.

Results: The study included 73 female and 31 male living kidney donors with a mean age of 46.1 ± 10.8 years. In the comparative analysis of donors versus 35 healthy individuals, the changes in flow-mediated dilatation were 12.3 ± 5.7% and 15.4 ± 6.3%, respectively (P = .016). In the comparative analysis of preoperative versus the last visit transthoracic echocardiographic results, left ventricular end-systolic and end-diastolic diameters decreased and left ventricular posterior wall thickness and septum thickness increased (P = .025, P = .002, P = .026, and P = .019, respectively).

Conclusions: Nephrectomy may cause several hemodynamic changes in living kidney donors, which may exacerbate cardiovascular risks in this population.

Key words : Flow-mediated dilatation, Living kidney donors, Renal transplantation

Introduction

Renal transplant is the best renal replacement therapy for patients with end-stage renal disease (ESRD). The scarcity of deceased renal donors and the better graft survival after living-donor kidney transplant have increased the value of living kidney donations. Living kidney donor (LKD) candidates are extensively evaluated to ensure that there will be adequate renal function in the remaining solitary kidney after nephrectomy with a minimal risk of short- and long-term mortality and morbidity.

Previous studies have suggested that there is no increase in cardiovascular and all-cause mortality in donors compared with healthy subjects with similar demographic characteristics.^1,2 However, kidney donors are a highly selected population, and their control groups in studies should be composed of those who are healthy enough to be donors. A recent study with an ideal control group revealed that kidney donors had a 1.4-fold increased risk of cardiovascular morbidity and a 1.3-fold increased risk of mortality compared with individuals who would have been eligible for donation.³ The mechanisms underlying increased cardiovascular risk have not yet been clearly identified.

Donor nephrectomy also results in increased renal blood flow and intraglomerular pressure in the remaining kidney. Changes in release of some cytokines and adhesion molecules due to hyper­filtration may cause an expansion of the mesangial matrix, glomerulosclerosis, and an increase in macrophage infiltration and collagen type IV.^4,5 Glomerulosclerosis and vasoconstriction of the efferent artery due to decreased release of vasodilator nitric oxide may activate the local renin-angiotensin system. Local hypoxia may occur as a result of the efferent arterial vasoconstriction and give rise to apoptosis and transformation to myofibroblasts in the tubular epithelium. This process may then result in extracellular matrix expansion and interstitial fibrosis.^6,7 A study assessing hyperfiltration and compensatory hypertrophy after donor nephrectomy reported a decreased response to vasodilator cytokines and an increase in peripheral vascular resistance.⁸

The aim of the present study was to evaluate the effects of nephrectomy on cardiovascular system in LKDs to gain a better understanding of the recently recognized long-term increased risk of ESRD and cardiovascular mortality.

Materials and Methods

Between January 2010 and January 2015, 163 LKDs who had undergone donor nephrectomy at the Hacettepe University Transplantation Unit were retrospectively screened. Donors who were pregnant, had a history of postnephrectomy pregnancy, or were followed up for less than 1 year after nephrectomy were excluded from the study. After application of the exclusion criteria, 104 LKD were included in the study. The procedures in this study were performed in accordance with the Helsinki Declaration of 1975.

Body mass indexes (BMI), comorbidity data, complete blood count measurements, serum bio­chemistry, lipid profiles, proteinuria, and creatinine levels in spot urine were obtained. The Chronic Kidney Disease Epidemiology Collaboration formula was used to determine the estimated glomerular filtration rate (eGFR). The spot urine protein-to-crea­tinine ratio (mg/g) was used to assess proteinuria.

Brachial artery flow-mediated dilatation (FMD) measurements had been made in 60 LKDs on their last visit. Unfortunately, there was a lack of preoperative values of FMD to compare; therefore, the values at the last visit were compared with measurements in 35 healthy volunteers who were similar to the LKD group with regard to age, sex, serum lipid levels, comorbidity, and kidney function. Transthoracic echocardiography tests were conducted in 75 LKDs on their last visit and compared with preoperative echocardiographic examinations for each LKD. These examinations were performed by an experienced cardiologist via 2-dimensional gray scale and color Doppler transthoracic echocardiography to evaluate left ventricular function and aortic diameter, with FMD measured using a 10-MHz vascular ultraso­nographic probe and completed vascular imaging obtained using a Vingmed Vivid 5 (General Electric Medical, Waukesha, WI, USA). Flow-mediated dilatation was measured in the LKDs and in the control group after no intake of caffeine-containing beverages and/or medications for at least 12 hours before measurement. After 15 minutes of rest, the long axis of the brachial artery was identified 2 to 5 cm superior to the antecubital fossa and marked. For this technique, the right arm remains in the same position during the measurement, and each measurement is made at the same place. Brachial artery diameter was measured at baseline and 5 minutes after reactive hyperemia in the diastolic phase. The percentage of FMD change was assessed with the following formula: 100 × (reactive hyperemia diameter – baseline diameter)/baseline diameter.

Kidney ultrasonographic examinations for the 75 LKDs were conducted by an experienced radiologist with an ultrasonography device (General Electric Medical), which measured the size of the remaining kidney in each patient. Volume change was assessed by comparing the preoperative renal volume that had been obtained via contrast-enhanced computed tomography versus the renal ultrasonographic images obtained at last visit. Volume calculations were performed using the following modified ellipsoid formula: length × width × anteroposterior widest diameter × π/6.

Statistical analysis was performed using SPSS Statistical Analysis Software version 21.0 for Mac OS (SPSS, Chicago, IL, USA). Pearson chi-square and Fisher exact tests were used to analyze categorical variables. We used t tests to compare the means of parametric variables and Mann-Whitney U tests to compare the means of nonparametric variables. A binary logistic regression analysis was performed, and a backward stepwise model was generated to perform multivariate analysis of the parameters identified as significant in the univariate analysis.

P < .05 was considered statistically significant. The confidence interval used in this analysis was set at 95%.

Results

The study included 73 female and 31 male LKDs with a mean age of 46.1 ± 10.8 years. The mean follow-up period after nephrectomy was 40.8 ± 15.5 months. Of the LKDs, 8.6% (9/104) had preoperative hypertension that had been under control with lifestyle modifications and/or a single antihypertensive drug; however, prevalence of hypertension increased, although statistically insignificantly, to 15.3% on last visit (16/104 patients; P = .137) (Table 1). Comorbid diseases were present in 18.2% (19/104) of the LKDs. The mean preoperative and last visit BMI measure­ments were 27.7 ± 7.7 and 29.1 ± 4.4 kg/m2, respectively (P = .141).

The mean preoperative eGFR level was 102.2 ± 15.2 mL/min/1.73 m², whereas the eGFR values on postoperative day 2, at the 1st postoperative month, at the 6th postoperative month, at the 12th postoperative month, and at last visit were 66.4 ± 16.4, 71 ± 16.2, 70.9 ± 15.3, 73.8 ± 17.7, and 80.8 ± 16.7 mL/min/1.73 m2, respectively. When the postoperative eGFR levels of LKDs were compared with their corresponding preoperative levels, we observed a decrease from postoperative month 1 to postoperative month 12. Although no significant difference was shown between month 1 eGFR and month 12 eGFR (P = .65), there was a significant increase in the last visit eGFR compared with eGFR at month 12 (P = .001; Figure 1).

The mean protein-to-creatinine ratio significantly increased from a baseline value of 70 ± 50 mg/g/day to 160 ± 160 mg/g/day at the last visit (P = .001). Spot urine protein-to-creatinine ratio was significantly affected by the ratio of kidney volume to BMI (P = .01). A higher protein-to-creatinine ratio was seen in LKDs who had a greater ratio of renal volume to BMI.

The mean low-density lipoprotein cholesterol level increased to 143.7 ± 26.8 mg/dL from 123.6 ± 29.2 after nephrectomy (P = .001). Similarly, there was an increase in the mean triglyceride level from 113.7 ± 80.5 to 160.9 ± 79.5 mg/dL (P = .009). However, there was no significant difference between pre­operative and postoperative high-density lipoprotein levels (48.2 ± 12.6 and 48.0 ± 12.5 mg/dL, respectively, P = .715).

The mean volume of the nondonated kidney was 72.6 ± 11.8 cm3 preoperatively, which increased to 90.5 ± 14.1 cm3 with a change of 24 ± 20% during the follow-up period (P = .001). Factors affecting the increase in renal volume were the ratios of renal volume to BMI and renal volume to body surface area. Both were found to be statistically significant in the univariate and multivariate analyses (P = .001 and P = .001, respectively). Age (P = .65), donor sex (P = .47), and presence of hypertension (P = .77) were not significantly associated with change in kidney volume. Preoperative and last visit morbidity, renal volume, and serum and urine parameters for LKDs in our study are presented in Table 1.

The mean preoperative left ventricular end-diastolic diameter was 4.68 ± 0.37 cm, which significantly decreased to 4.48 ± 0.34 cm at the last visit (P = .002). Similarly, the mean preoperative end-systolic diameter (2.98 ± 0.28 cm) significantly decreased to 2.86 ± 0.23 cm (P = .025). The mean preoperative left ventricular diastolic posterior wall thickness and septum thickness were 0.92 ± 0.08 cm and 0.92 ± 0.10 cm, respectively, whereas the last visit values were 0.96 ± 0.11 cm and 0.97 ± 0.12 cm, respectively (P = .026 and P = .019, respectively). Aortic valve thickness was identified via echo­cardiography in 13.7% (8/58) of preoperative LKDs and in 32.0% (24/75) of LKDs at last visit (P = .015). The mean preoperative and last visit ascending aorta diameters were 3.15 ± 0.36 cm and 3.25 ± 0.34 cm, respectively (P = .119). Table 2 shows the observed preoperative and last visit echocardiographic changes in participating LKDs.

In our analysis that compared the 35 healthy controls with similar demographic characteristics and cardiovascular risk factors versus the LKDs, FMD changes were found to be 15.4 ± 6.3% in healthy controls and 12.3 ± 5.7% in LKDs (P = .016). Table 3 presents the characteristics of the LKDs and control group members.

Discussion

This study showed that significant changes occurred concerning several hemodynamic parameters in the remaining kidney and in the heart after nephrectomy in LKDs. Some recent studies have shown that the risks of ESRD, cardiovascular disease, and mortality increase by 10- to 11.3-fold, 1.4-fold, and 1.3-fold, respectively, after a median period of 25 years.3,9 The mid- and long-term effects of hyperfiltration and compensatory hypertrophy on the whole body system and their clinical significance remain unclear. Increases in the glomerular filtration surface area, ultrafiltration coefficient, and renal blood flow after donor nephrectomy may give rise to global hyperfiltration.10 Studies have shown that there may be a 22% to 40% increase in renal blood flow, a 7- to 14-mm Hg increase in mean arterial pressure, and a 28% to 42% increase in GFR after nephrectomy.^10,11 It has been shown that renal blood flow increases 25% to 32% after the 1st week and 29% to 30% after the 1st year after donor nephrectomy, suggesting that blood flow does not change substantially after the early adaptation period.^11-15 In our study, the participants’ mean eGFR level decreased to 40% within the first 2 days after donor nephrectomy relative to their preoperative total eGFR and increased to 4%, 5%, 8%, and 15% at postoperative month 1, postoperative month 6, postoperative year 1, and at last visit, respectively. Overall, total eGFR was lost by 20% at 39 months after nephrectomy. In our study, we observed that eGFR continued to increase over the course of a long follow-up period after its sudden decrease in the early postoperative period after donor nephrectomy. This GFR increase may be attributed to the hyperfiltration and compensatory hypertrophy of the remaining kidney.

Compensatory hypertrophy, which occurs due to glomerular hyperfiltration, begins immediately, and increases of 21% and 24% have been observed on day 3 and day 7, respectively.16 Preoperative kidney volume has been found to be an independent predictor of postoperative early-term renal function.16 In our study, the preoperative kidney volume-to-BMI and kidney volume-to- body surface area ratios were found to be the determinants of kidney volume change. Increases in kidney volume were higher in patients identified as having small kidneys according to their BMI and body surface area.

Another consequence of increased glomerular permeability due to hyperfiltration after living donor nephrectomy is proteinuria. Increases in renal blood flow, filtration coefficients, and glomerular surface areas secondary to glomerular hypertrophy may increase the probability of proteinuria.10 A meta-analysis of 48 studies showed that, in LKDs, the amount of proteinuria was 77% higher than that shown in healthy controls over a mean follow-up of 11 years.17 In our study, the estimated preoperative and last visit proteinuria measurements were 70 ± 50 mg/g and 160 ± 160 mg/g, respectively (P = .001). Preoperative kidney volume-to-BMI ratio was the main determinant of postoperative pro­teinuria. The higher proteinuria shown in larger kidneys versus that shown in average-sized kidneys after nephrectomy may be the result of a greater level of hyperfiltration in large kidneys.

An acquired or congenital low number of nephrons may increase the likelihood of hyper­tension and renal disease in advanced age.¹⁸ The risk of developing hypertension may be increased due to the local and systemic effects of the local vasodilator and vasoconstrictor mediators resulting from hyperfiltration that occurs due to decreased nephron numbers in LKDs.¹⁹ At the same time, increased atherosclerosis after nephrectomy may also enhance this effect.²⁰ Some studies have shown that there is no increased risk of hypertension after nephrectomy; however, other controversial studies have reported a 3.64-fold increase in hypertension risk, which was identified as an independent risk for proteinuria at 1 year after nephrectomy.^20,21 In our study, hyper­tension was detected in 8.6% of LKDs preoperatively and 15.3% of LKDs at last visit. Because the presence of hypertension had been determined based on the results of subjective questionnaires, it might be suggested that these rates are higher than the actual rates. However, living kidney donors with pre­operative hypertension have been shown to have renal function after transplant similar to that shown in normotensive donors.²²

Atherosclerosis and left ventricular hypertrophy may result in increased mortality in both healthy individuals and patients with chronic kidney disease (CKD).²³ Moody and associates designed a com­parative study to examine the association between increased single-nephron GFR after nephrectomy and left ventricular remodeling and atherosclerosis in LKDs and healthy individuals. The authors reported a significant increase in atherosclerosis and hypertrophy of the left ventricle without an increase in blood pressure.²⁰ In our study, no statistically significant change in ejection fraction was identified between the preoperative and the last visit transthoracic echocardiography result. The trans­thoracic echocardiography results revealed a decrease in left ventricular end-systolic and end-diastolic diameters and hypertrophy of the septum and left ventricular posterior wall, which are indirect indications of cardiac stiffness and increased preload.

Changes in FMD may be used to estimate endothelial dysfunction, which has been considered to be the precursor of atherosclerosis. Although FMD is considered to be a person-dependent test, it is also a noninvasive and repetitive test that perhaps can be used for hyperemia-induced vasodilatation. In our study, because we lacked baseline FMD values, changes in FMD in LKDs were compared with FMD measurements in healthy controls; our comparison showed that the percentage of FMD change was significantly lower in LKDs than in healthy controls. Other studies have shown that the rate of FMD change, which was evaluated using a method from Celermajer and associates, was also significantly lower after donor nephrectomy.^24,25 Although 1 study reported similar results in LKDs and healthy controls in terms of cardiovascular events and mortality after 6.8 years of follow-up, another study reported a 1.4-fold increase in risk after 15.1 years of long-term follow-up.3,26 As previously reported, due to the natural course of aging, a decrease in left ventricular mass and an increase for each standard deviation in atherosclerosis-related arterial velocities may increase the risk of cardiovascular events by up to 20%.²⁷

Despite the low mortality rates identified for LKDs in the short and mid-term, increases in long-term mortality rates suggest that cardiovascular risks are increased after nephrectomy. Although sig­nificant differences in ejection fractions and the development of hypertension were not identified in our study, reduced left ventricular end-systolic and end-diastolic diameters may indicate decreased left ventricular elasticity, whereas increased septum and left ventricular wall thickness may be associated with reduced endothelial vasodilatation response due to increased atherosclerosis. Both older LKDs and accelerated atherosclerosis after nephrectomy may cause an increase in the cumulative risk of long-term cardiovascular effects.

Hyperfiltration, which maintains renal function via short- and mid-term compensatory changes to glomerular dynamics, may lead to glomerulo­sclerosis, interstitial fibrosis, permanent kidney damage, and, eventually, ESRD, which is the most important long-term effect of hyperfiltration after living-donor nephrectomy. In our study, 11.3% of LKDs developed stage 3 CKD according to the Chronic Kidney Disease Epidemiology Collaboration formula. None of the LKDs required renal replacement therapy during the follow-up period. Factors affecting low GFR during the follow-up period were examined, and low baseline GFR, advanced age, and male sex were found to be statistically significant factors in the univariate analyses. The factor found to have the greatest effect on the CKD process in the multivariate analysis was baseline eGFR value before donor nephrectomy (P = .001; hazard ratio = 1.083; confidence interval, 1.03-1.13). Studies evaluating long-term outcomes have revealed that older donor age, duration of time after nephrectomy, and, similar to our results, baseline renal function were risk factors for CKD development.^28,29

The major limitations of our study were its retrospective nature, absence of baseline FMD values in LKDs, low number of cases, the use of comparing renal volumes calculated with ultrasonography versus preoperative renal volume calculated with computerized tomography, and the short follow-up. Another limitation was that the echocardiogram, which is an individual-dependant examination, was done by a single cardiologist.

In conclusion, endothelial dysfunction, left ventricular hypertrophy, and loss of elasticity in the left ventricle, all of which are effects of compensatory hyperfiltration after nephrectomy, may be early indicators of long-term cardiovascular risks. The effects of hyperfiltration and renal compensatory hypertrophy after donor nephrectomy on the cardiovascular system should be further evaluated in studies that include a larger number of patients and with a prospective and long-term design.

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