Long-term cardiovascular effects of pre-transplant native kidney nephrectomy in children
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- 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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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.
KeywordsRenal transplantationVentricular massCardiac hypertrophyBlood pressure
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 . 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 . 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 . 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) .
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 . 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 [11–15]. 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
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 . 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 . To control for differences in age and sex, MAP values were expressed as standard deviation scores (SDS).
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  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 , the reliability of which has been determined in test–retest analyses . 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 , 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 .
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.
Clinical and cardiovascular characteristics of the patients
Number of patients
Age at transplantation
14.1 ± 4.3
13.3 ± 4.3
11.5 ± 5.7
Age at follow-up
24.9 ± 5.0
23.5 ± 4.7
21.2 ± 5.8
Length of follow-up
10.8 ± 2.8
10.1 ± 2.6
9.7 ± 2.2
70.4 ± 26.8
55.4 ± 26.8
75.8 ± 26.6
Duration of dialysis prior to tx
26.2 ± 21.6
24.3 ± 13.8
31.4 ± 20.7
Type of renal disease
39.9 ± 10.5
40 ± 14
40.3 ± 11.6
2.0 ± 1.7
2.0 ± 2.3
2.0 ± 1.8
88.5 ± 10.4
87.4 ± 10.8
83.6 ± 11.5
0.4 ± 1.3
0.25 ± 1.3
−0.2 ± 1.6
Number of BP medications pre-tx
Number of BP medications post-tx
Risk of left ventricular hypertrophy (LVH; univariate binary logistic regression)
Age at transplantation
Age at last follow-up
Duration of dialysis prior to tx
Number of BP medications pre-tx
Number of BP medications post-tx
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 , while others have not confirmed these findings . Moreover, data from the ESCAPE trial, which included a large cohort of children with CRF, demonstrated dissociation between the development of LVH and hypertension . 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 . 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 .
In the past, it has been proposed that removing kidneys in patients with ESRD may improve blood pressure control . 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, 30–33]. 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 .
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.