Pediatric Nephrology

, Volume 25, Issue 12, pp 2523–2529

Long-term cardiovascular effects of pre-transplant native kidney nephrectomy in children

Authors

  • Marco Cavallini
    • Division of Pediatric NephrologyBambino Gesú Hospital
  • Giacomo Di Zazzo
    • Division of Pediatric NephrologyBambino Gesú Hospital
  • Ugo Giordano
    • Division of Pediatric CardiologyBambino Gesú Hospital
  • Giacomo Pongiglione
    • Division of Pediatric CardiologyBambino Gesú Hospital
  • Luca Dello Strologo
    • Division of Pediatric NephrologyBambino Gesú Hospital
  • Nicola Capozza
    • Renal Transplantation UnitBambino Gesú Hospital
  • Francesco Emma
    • Division of Pediatric NephrologyBambino Gesú Hospital
    • Division of Pediatric NephrologyBambino Gesú Hospital
    • Division of Nephrology and Dialysis, Department of Nephrology and UrologyOspedale Bambino Gesù - IRCCS
Original Article

DOI: 10.1007/s00467-010-1638-3

Cite this article as:
Cavallini, M., Di Zazzo, G., Giordano, U. et al. Pediatr Nephrol (2010) 25: 2523. doi:10.1007/s00467-010-1638-3
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Abstract

Left ventricular (LV) hypertrophy (H) and hypertension are prevalent in children with end-stage renal disease (ESRD) and after renal transplantation. Severe hypertension prior to renal transplantation has traditionally been an indication for native kidney nephrectomy. The impact of nephrectomy on cardiovascular disease has not been well documented. We retrospectively evaluated echocardiographic and ambulatory blood pressure monitoring (ABPM) data in 67 young adults who had undergone transplantation in the pediatric age with a mean follow-up of 10.4 years. Unilateral or bilateral nephrectomies had been performed in 32 patients. The number of antihypertensive drugs used prior to transplantation was significantly higher in the nephrectomized groups. At follow-up the amount of antihypertensive medications was similar between groups and no significant differences were observed in mean arterial blood pressure (MAP) or LV mass index (LVMi). LVH was observed in 50% of non-nephrectomized patients, 45.4% of patients with unilateral nephrectomy, and 44.4% of patients without native kidneys (p = n.s.). In conclusion, unilateral or bilateral nephrectomies prior to transplantation do not appear to influence blood pressure control or the prevalence of LVH after renal transplantation. Longitudinal studies with repeated assessment of LVMi, before and after renal transplantation, are needed to assess the impact of residual activity of native kidneys on arterial blood pressure and cardiac structural changes, even in normotensive patients, to evaluate cardiovascular morbidity.

Keywords

Renal transplantationVentricular massCardiac hypertrophyBlood pressure

Introduction

End-stage renal disease (ESRD) in pediatric patients is associated with increased risk of premature cardiovascular disease, accounting for up to 45% of deaths in the ANZDATA Registry [1]. Successful renal transplantation allows improvement of known cardiovascular risk factors that are related to chronic renal failure (CRF) including uremia per se, anemia, hypoalbuminemia, hyperparathyroidism, and volume overload. Advancements in renal transplantation (tx) have dramatically improved the long-term outcome of pediatric patients with ESRD [2]. Nevertheless, life expectancy remains shortened in comparison with the normal population, and cardiovascular disease remains the main cause of death, accounting for nearly 40% of premature deaths [3, 4].

Left ventricular hypertrophy (LVH) represents one of the prominent features of cardiovascular disease in patients with CRF and has been observed in approximately 75% of children at the beginning of dialysis and more than 80% of children after renal transplantation [5, 6].

Likewise, hypertension has also been reported in 80% of pediatric patients at the beginning of dialysis [7]. Despite appropriate treatments, the prevalence of hypertension after 1 year of dialysis remains 50% and 30% in children treated with hemodialysis and peritoneal dialysis respectively [7, 8]. After renal transplantation, the incidence of hypertension remains significant. In a recent study, Becker-Cohen et al., for example, have observed a 53% prevalence of hypertension in transplanted children after a mean follow-up of 5.1 years (range 0.25–13.5) [9].

Although the pathogenesis of hypertension is complex, overt or hidden, fluid overload is one of the most important factors in patients with ESRD, which is often enhanced by misevaluation of body dry mass or inadequate dialysis prescription. Conversely, soon after transplantation, the new kidney allows the clearing of excess water, but hypertension frequently develops as a side-effect of long-term calcineurin inhibitor and steroid therapy. In addition, hypertension after renal transplantation could also be upheld by sympathetic nerve activation and/or renin release from the remaining native kidneys.

In the past, many centers, including our own, have performed pre-transplant nephrectomies in hypertensive patients with ESRD. However, the efficacy of bilateral native kidney nephrectomy in preventing post-transplant hypertension has not been extensively studied. Data from the NAPRTCS registry indicate that the incidence of hypertension was in fact similar between nephrectomized and non-nephrectomized patients 5 years after transplantation [10]. Similarly, adult studies that were mostly performed in the 1970s and 1980s failed to generate convincing evidence to support systematically removing the native kidneys in hypertensive transplant candidates [1115]. To date, there have been no longitudinal studies assessing the impact of pre-transplant nephrectomy on blood pressure and cardiovascular disease in children.

The aim of this study was to analyze retrospectively in a cohort of pediatric recipients the effects of pre-transplant nephrectomy on the long-term risks of developing chronic hypertension and cardiac disease, as assessed by left ventricular mass measurements.

Materials and methods

Subjects

The study population included patients with childhood onset CRF. Patients who had a congenital heart defect or other primary myocardial disease were excluded from the study. Only patients who had undergone a nephrectomy for hypertension were included in the nephrectomized groups. Patients who had undergone nephrectomy for intractable nephrosis or severe polyuria were excluded. The medical records were reviewed for age, sex, race, cause of chronic kidney disease (CKD), number of antihypertensive drugs, duration of renal failure and pre-transplant nephrectomy. Clinical and laboratory data were collected on the day of the evaluation, including height, weight, and serum creatinine levels.

Ambulatory blood pressure monitoring

Ambulatory blood pressure monitoring (ABPM) was performed with a Spacelabs 90207 automatic cuff-oscillometric device (Spacelabs Medical, Issaquah, WA, USA). The cuff size was adjusted to the upper arm circumference. ABPM measurements were performed according to a standardized protocol [16]. ABPM measurements were performed every 15 min during the daytime and every 20 to 30 min at night. ABPM profiles were divided into day-time (8:00 a.m. to 8:00 p.m.) and night-time periods (12:00 a.m. to 6:00 a.m.). The 24-h mean arterial blood pressure (MAP) values were calculated and compared with published reference data from healthy children and adults [17]. To control for differences in age and sex, MAP values were expressed as standard deviation scores (SDS).

Echocardiography

Measurements of the interventricular septum, posterior wall, and internal dimension in systole and diastole were performed on two to five cardiac cycles, according to the American Society of Echocardiography recommendations [18] using digital calipers on M-mode stop-frames, from a perfectly oriented short-axis or long-axis parasternal view, whenever this was possible. LV mass (LVM), therefore, was obtained according to a necropsy-validated formula [19], the reliability of which has been determined in test–retest analyses [20]. For accounting for differences in body size, LV end-diastolic diameter (LVEDD) was normalized for height. LVM was normalized for height in meters raised to the allometric power 2.7, which linearizes the relation between LVM and height [21], and is expressed in g/m2.7 (LVMi). A gender-specific partition value of 46.7 g/m2.7 for women and 49.2 g/m2.7 for men (representing the 97.5th percentile of normal distribution) was used to detect LVH [22].

Statistics

Data were analyzed with SPSS 11.0 software (SPSS, Chicago, IL, USA). Contiguous variables are expressed in the text and tables as mean ± SD if data passed normality tests (Shapiro–Wilk and Kolmogorov–Smirnov tests) and as median (range) if they did not fit a normal distribution. Data between groups were compared using the Mann–Whitney U test. Categorical data were compared with Fisher’s exact test. Binary logistic regression was used to compare patients with or without LVH, using a cut-off value of 38 g/m2.7. All tests were two-sided, with p values considered significant if <0.05.

Results

The study population was composed of 67 young adults, 31 male (46%) and 36 female (54%). Children who had pre-emptive renal transplantation were not included. All patients were on chronic dialysis before renal transplantation. No comorbidities were present. All patients received a cadaver donor kidney. The mean age at transplantation was 13 years (range 3.6–21.9). The vast majority of patients were treated with cyclosporine. In the first part of their follow-up they received Sandimmun®, which was shifted to Neoral® when available. Trough levels were monitored until 1996, when we started monitoring the C2 levels. Trough levels were maintained between 150 and 250 ng/ml. When C2 monitoring was started, levels were kept at around 800–900 ng/ml during the first year post-transplant and tapered thereafter. Mean dose was 2.86 ± 0.56 mg/kg/day (mean C2 levels 166.4 ± 35 mg/dl) in patients with native kidneys left in place; 3 ± 1.08 mg/kg/day (mean C2 levels 170 ± 54 mg/dl) in patients with unilateral nephrectomy; and 3.54 ± 1.62 mg/kg/day (mean C2 levels 177 ± 81 mg/dl) in patients with bilateral nephrectomy. Steroid dosage remained unchanged in the follow-up period, according to our protocol: initially 60 mg/m2, tapered to 30 mg/m2 for 30 days, then to 15 mg/m2 for 30 days, and then quickly shifted to every other day. Patients who were treated initially with azathioprine were shifted to mycophenolate-mofetil when it became available. Approximately two-thirds of patients (65.7%) were taking a calcium channel blocker, 64.1% were taking an alpha- or beta-blocker, and 52.2% an angiotensin-converting enzyme inhibitor or angiotensin receptor blockers. The mean age when the cardiac evaluation was performed was 23.7 years (range 11.7–37). Fourteen patients had undergone a bilateral pre-transplant nephrectomy, 18 had undergone a unilateral nephrectomy, mostly at the time of transplantation and the native kidneys were left in place in the remaining 35 patients. In all patients, the indication for nephrectomy was severe hypertension. The clinical characteristics of the three groups of patients are reported in Table 1. The age and gender distribution was similar in the three groups. Likewise, there were no differences in the duration of renal replacement therapy prior to transplantation or in the type of underlying renal disease (glomerular or tubulointerstitial). The number of antihypertensive drugs used prior to transplantation was significantly higher in the nephrectomized groups, in comparison to the non-nephrectomized subjects. Conversely, the amount of antihypertensive medications was similar between groups at the time of cardiac evaluation, which was performed after a mean follow-up of 10.4 years (range 6.9–17.5). At that moment, no significant differences were observed in MAP or LVMi between groups (Fig. 1; Table 1). Despite an average MAP close to normal (mean SDS of the entire population = 0.2), the mean LVMi was close to 2 SDS in all three groups. The proportions of LVH were 50% in the non-nephrectomized patients, 45.4% in patients with unilateral nephrectomy, and 44.4% in patients without native kidneys (p = n.s.). No significant correlation was found among post-transplant glomerular filtration rate (GFR), MAP, and LVMi values. When analyzing patients according to their creatinine clearance at the time of follow-up (40 patients with GFR >60 ml/min/1.73 m2 vs 27 patients with GFR <60 ml/min/1.73 m2), no differences in MAP or LVMi were observed (GFR >60: LVMi 40.36 ± 11.75; MAP 86.8 ± 9.44; GFR <60: LVMi 39.6 ± 11.5; MAP 87.8 ± 12.7).
Table 1

Clinical and cardiovascular characteristics of the patients

Independent variable

Units

No nephrectomy

Unilateral nephrectomy

Bilateral nephrectomy

p

Number of patients

n

35

18

14

Gender

Male:female

17:18

7:11

7:7

n.s.

Age at transplantation

Years

14.1 ± 4.3

13.3 ± 4.3

11.5 ± 5.7

n.s.

Age at follow-up

Years

24.9 ± 5.0

23.5 ± 4.7

21.2 ± 5.8

n.s.

Length of follow-up

Years

10.8 ± 2.8

10.1 ± 2.6

9.7 ± 2.2

n.s.

Creatinine clearance

ml/min/1.73 m2

70.4 ± 26.8

55.4 ± 26.8

75.8 ± 26.6

a

Duration of dialysis prior to tx

Months

26.2 ± 21.6

24.3 ± 13.8

31.4 ± 20.7

n.s.

Type of renal disease

Glom/tub-int

11:24

6:12

8:6

n.s.

LVMi

g/h2.7

39.9 ± 10.5

40 ± 14

40.3 ± 11.6

n.s.

LVMi

SDS

2.0 ± 1.7

2.0 ± 2.3

2.0 ± 1.8

n.s.

MAP

mmHg

88.5 ± 10.4

87.4 ± 10.8

83.6 ± 11.5

n.s.

MAP

SDS

0.4 ± 1.3

0.25 ± 1.3

−0.2 ± 1.6

n.s.

Number of BP medications pre-tx

n

0.4 (0-3)

1.3 (0-3)

2 (0-4)

b, c

Number of BP medications post-tx

n

1.9 (0-4)

1.5 (0-3)

1.9 (0-4)

n.s.

tx renal transplantation; LVMi left ventricular mass index; MAP mean arterial pressure; Glom glomerular disease; tub-int tubulointerstitial disease

aUnilateral vs bilateral nephrectomy (p = 0.044)

bNo vs unilateral nephrectomy (p = 0.003)

cNo vs bilateral nephrectomy (p≤0.001)

https://static-content.springer.com/image/art%3A10.1007%2Fs00467-010-1638-3/MediaObjects/467_2010_1638_Fig1_HTML.gif
Fig. 1

a Left ventricular mass index (LVMi) and b mean arterial pressure (MAP) according to the number of pre-transplant nephrectomies

Finally, the risk of developing LVH was assessed by logistic regression after dividing the cohort into non-hypertrophic (n = 36) and hypertrophic patients (n = 31). As shown in Table 2, no significant association with the independent variables that were studied was observed at the univariate level, with the exception of a borderline association with the number of antihypertensive medications taken after transplantation (p = 0.06). Given these results, a multivariate analysis was not conducted.
Table 2

Risk of left ventricular hypertrophy (LVH; univariate binary logistic regression)

Independent variables

Reference/units

OR

5–95% CI

p

Gender

Male

0.89

0.37

2.62

0.98

Age at transplantation

Years

0.94

0.85

1.04

0.24

Follow-up

Years

0.97

0.81

1.71

0,76

Age at last follow-up

Years

0.94

0.85

1.04

0.22

Creatinine clearance

ml/min/1.73 m2

0.99

0.98

1.01

0.57

Duration of dialysis prior to tx

Months

1.02

0.99

1.05

0.24

Number of BP medications pre-tx

n

0.88

0.58

1.32

0.53

Number of BP medications post-tx

n

1.60

0.97

2.65

0.06

Monolateral nephrectomy

n

1.24

0.67

2.31

0.49

Bilateral nephrectomy

n

1.38

0.41

4.68

0.61

MAP

mmHg

1.02

0.98

1.07

0.30

MAP

SDS

1.25

0.87

1.80

0.24

Discussion

Cardiovascular morbidity is a primary concern in patients with ESRD, even after successful renal transplantation. To date, the natural history of LVH after transplantation remains unclear, with some authors who have reported improvement in LVMi after restoration of a normal renal function [23], while others have not confirmed these findings [24]. Moreover, data from the ESCAPE trial, which included a large cohort of children with CRF, demonstrated dissociation between the development of LVH and hypertension [25]. Specifically, these studies showed that a large proportion of normotensive children with CRF develop cardiac hypertrophy as renal failure progresses.

Hypertension in CRF is multifactorial. Fluid overload probably plays an important role in a significant proportion of patients. In addition, factors originating from the damaged kidneys can influence blood pressure control. These include hormones, such as renin and the activation of the sympathetic system. Abnormal sympathetic reactivity has been documented, for example, in patients with ESRD [26]. Regulation of sympathetic tone is at least in part under the control of renal nerves, as documented by successful treatment of drug-resistant hypertension with endoluminal ablation of renal artery innervation [27].

In the past, it has been proposed that removing kidneys in patients with ESRD may improve blood pressure control [15]. Although native kidneys undergo a progressive atrophy during the dialysis and post-transplant periods, their contribution to hypertension after transplantation is not clearly understood. On these bases, we have retrospectively studied 67 patients to evaluate the long-term effects of pre-transplant nephrectomy on blood pressure control and development of LVH.

Despite the limitations of the present study, we were able to include a significant number of patients who were being studied after a long follow-up (mean 10.3 years), allowing long-term cardiac and blood pressure changes to be assessed that influence the overall morbidity of children who have undergone a renal transplantation.

Our ABPM data failed to show differences in MAP between nephrectomized and non-nephrectomized patients. The degree of hypertension was also assessed by the number of antihypertensive drugs that were used prior to and after transplantation as a surrogate for the severity of hypertension [28, 29]. Due to selection biases, groups were not comparable, indicating that patients with more severe hypertension were more likely to have undergone nephrectomy. The number of antihypertensive drugs increased significantly after transplantation only in the non-nephrectomized group (p < 0.001), to reach a value similar to that of nephrectomized patients. The number of antihypertensive drugs before and after transplantation was unchanged in patients who were nephrectomized. In our opinion, these results probably indicate that post-transplant hypertension is primarily influenced by other factors that are not related to the presence of native kidneys, including side-effects of immunosuppressive drugs. However, our data do not allow the fact that long-term prevalence of hypertension would have been higher in nephrectomized patients had they not undergone this procedure to be ruled out. In addition, we did not observe any differences in LVMi. Data on the effects of transplantation in improving CRF-related LVH are conflicting in children [6, 3033]. Regardless of the impact of restoring normal renal function on cardiac mass and morphology, most cross-sectional studies indicate a significant prevalence of LVH over time, ranging from 50 to 80%. Prospective studies [34, 35] confirm that LVH remains common in children and adolescents after renal transplantation, despite improved renal function.

In comparison to these studies, our patients were analyzed after a significantly longer follow-up and further confirm the high prevalence of LVH that persists in the long term. In addition, our data show that, similar to patients with CRF and ESRD, blood pressure and LVMi are poorly correlated, even in patients with well-functioning grafts.

These observations suggest that similar to hypertension, LVH has a multifactorial genesis in transplanted patients. Among factors that influence cardiac mass, it has been suggested that cyclosporine A promotes LVH even in normotensive patients [36].

The main limitation of the present study is related to the cross-sectional analysis and lack of pre-transplant ultrasound and ABPM data. Based on the ESCAPE trial data, it is likely that a significant proportion of patients had LVH prior to transplantation. Despite these limitations, our results indicate that there is little support in favor of pre-transplant nephrectomy limiting long-term cardiovascular morbidity. Most unilateral nephrectomies in our study were performed immediately prior to transplantation and required the surgical time to be increased and in several cases a larger incision to be performed. Bilateral nephrectomies imply additional surgery prior to transplantation. Even if these procedures are relatively safe, increased hospital stay, higher number of complications and increased risk of blood transfusions have been reported [37, 38].

In conclusion, unilateral or bilateral nephrectomies prior to transplantation do not appear to influence blood pressure control or the prevalence of LVH after renal transplantation. Longitudinal studies with repeated assessment of LVMi, before and after renal transplantation, are needed to assess the impact of the residual activity of native kidneys on arterial blood pressure and cardiac structural changes, even in normotensive patients, to evaluate cardiovascular morbidity.

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