Introduction
The kidneys play a key role in whole body fluid and electrolyte homeostasis and hence in long-term regulation of the arterial pressure. Abnormal renal autoregulation of glomerular perfusion and filtration as well as intrinsic renal disease can either cause hypertension or be a consequence of this condition [
1]. Obstruction at the level of the pelvo-ureteric junction and subsequent development of hydronephrosis is a fairly common condition in newborns, with an incidence of approximately 1% [
2]. Currently there is limited clinical knowledge regarding the influence of hydronephrosis on arterial pressure regulation. Although hypertensive effects of hydronephrosis have been suggested in experimental studies and clinical case reports [
3‐
5], this has not been substantiated by prospective studies in humans. It has been shown that the function of the hydronephrotic kidney in many cases remains surprisingly well preserved for several years [
6,
7]. This observation has lead to a worldwide trend towards non-operative treatment, but the long-term effects on cardiovascular and renal function of this treatment policy are not known [
2].
Recently, we showed for the first time in a prospective case study that surgical relief of hydronephrosis, secondary to ureteral obstruction in children, is associated with a lowering of arterial pressure [
8]. Moreover, other studies have shown that both rats and mice with chronic partial unilateral ureteral obstruction (PUUO) or congenital hydronephrosis develop hypertension [
9‐
11]. In previous experimental studies we demonstrated that hypertension and salt-sensitivity significantly correlated with the degree of hydronephrosis and that the disease was associated with oxidative stress and nitric oxide (NO) deficiency in the diseased kidney [
12‐
15]. Finally, surgical relief of the obstruction in rats with hydronephrosis significantly attenuated arterial pressure [
16].
In this prospective study, our aim was to further study ambulatory arterial pressure (24 h) and different markers of NO homeostasis and oxidative stress in blood or urine in pediatric patients with congenital hydronephrosis before and after surgical correction of the ureteral obstruction. Specifically, we investigated the hypothesis that preoperative arterial pressure is higher in children with hydronephrosis, which can be reduced by surgical management, and that this reduction in arterial pressure would be associated with attenuated oxidative stress and normalized NO homeostasis.
Discussion
The results of the current prospective study are in agreement with those of our previous experimental [
9,
10,
16] and clinical studies [
8], demonstrating that hydronephrosis in pediatric patients is associated with increased arterial pressure, which can be reduced by surgical relief of the obstruction. As previously shown in experimental rodent models of hydronephrosis [
12‐
15], using partial ureteral obstruction, we show for the first time that also patients with hydronephrosis display elevated levels of markers associated with oxidative stress, which can be reduced following management of the obstruction.
There are currently only two clinical studies in children with hydronephrosis that have discussed the effects of surgical treatment on arterial pressure. The first study by de Waard et al. was a retrospective study that suggested a reduction of arterial pressure after surgical management of dilated or obstructed upper urinary tracts [
4]. The second study, conducted by our research group, was a small prospective study demonstrating that systolic and diastolic pressures were reduced following surgical correction of hydronephrosis in children with pelvic ureteric obstruction [
8]. However, the latter study did not include a matched control group and the mechanisms were not further investigated. In the current study, we included two age- and sex-matched control groups in order to strengthen our hypothesis of increased arterial pressure in hydronephrosis and its reduction after surgical treatment. The first group consisted of healthy children, but we also included another control group of healthy children who had undergone 24-h ambulatory arterial pressure monitoring before undergoing small surgery for other reasons. We found no difference in arterial pressure between the healthy and operated control groups. Based on our results we conclude that higher arterial pressure in pediatric children with hydronephrosis cannot be explained by preoperative stress. Importantly, the reduction of arterial pressure in young children with hydronephrosis occurred even though 6 months had passed since the surgery, and one would expect the arterial pressure to increase slightly with increased age [
27].
Oxidative stress is characterized by the increased production of reactive oxygen species (ROS) and reduced antioxidant capacity. This oxidative stress is prevalent in patients with kidney disease and has been suggested as an important pathogenic mechanism associated with an increased risk of cardiovascular disease [
28‐
30]. Several experimental studies have shown that also ureteral obstruction-induced injuries in mice are associated with oxidative stress [
31‐
34]. In our previous studies, we demonstrated that hydronephrosis, induced by partial unilateral obstruction, leads to the development of hypertension in both rats and mice [
9,
10]. Underlying pathological mechanisms in this model include altered prostaglandin and thromboxane signaling [
35,
36] in the diseased kidney together with oxidative stress and reduced NO bioavailability [
12‐
15]. To the best of our knowledge, the above-mentioned pathological mechanisms have never been investigated in patients with hydronephrosis.
The measurement of oxidative stress in body fluids is complicated because of the very short half-life of ROS. Isoprostanes, which are mainly formed through free-radical catalyzation of arachidonic acid, are now considered to be reliable biomarkers of oxidative stress [
37]. Here we show that pathways associated with oxidative stress due to impaired prostaglandin and thromboxane signaling [
38,
39], as well as biomarkers of oxidative stress and lipid peroxidation (F
2-isoprostanes) [
37,
40], were significantly increased in patients with hydronephrosis and, importantly, they were all reduced following surgery.
Oxidative stress due to the increased generation of ROS from vascular NADPH oxidase and mitochondria is often associated with reduced NO levels due to scavenging (i.e., reaction with superoxide leading to peroxynitrite formation) [
41]. However, in contrast to the results obtained in our previous experimental studies using adult rodents, we did not observe any signs of reduced NO bioavailability or signaling in young patients with hydronephrosis. Actually, NOS activity appeared to be increased before surgery and normalized following management of the obstruction. This finding warrants future investigations, but we speculate that in patients characterized with oxidative stress an upregulation of enzymatic systems that generate NO (including NOS) may partially maintain vascular NO homeostasis despite the increased generation of ROS. This study only included children, but it is possible that this compensation (upregulation) of the NO generating system due to oxidative stress may become exhausted over time and hence lead to progressively increased arterial pressure with a higher risk of developing renal injuries. If this hypothesis of imbalance between oxidant and antioxidant systems hold true, as described in patients with chronic kidney disease [
28‐
30], surgical management of hydronephrosis would be suggested in all cases, even if the arterial pressure is normal and the patient has no other symptoms/diagnosis.
In conclusion, this novel prospective study demonstrates significantly higher arterial pressure and oxidative stress in children with hydronephrosis compared with healthy controls. The elevated arterial pressure can be normalized by surgical correction of the obstruction, which supports our previous experimental and clinical case report studies. Currently, normalized reference values of 24-h ambulatory blood pressure in very young children are limited [
27,
42,
43]. Once reference data in this young age group become available, together with additional data on arterial pressure in pediatric patients with hydronephrosis, we hope that cutoff values can be defined and that these will assist decision-making regarding surgical management of hydronephrosis to avoid the adverse effects of high arterial pressure in the future.
Acknowledgements
We thank Annika Olsson and Carina Nihlen (Dept. of Physiology and Pharmacology, Karolinska Institutet) for their excellent technical contributions. We thank Cristina Gomez for her advice and assistance in performing the urinary eicosanoid quantification. This work was supported by grants from the Swedish Research Council (2016-01381 MC, 65X-03522-43-3 AEGP), the Swedish Heart and Lung Foundation (20140448), by Research Funds from the Karolinska Institutet, and Her Highness The Crown Princess Lovisa’s Fund for Scientific Research.
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