PROF.

MATTIAS CARLSTROM (Orcid ID : 0000-0001-9923-8729)

Accepted Article
Article type : Mini Review

HYDRONEPHROSIS AND RISK OF LATER DEVELOPMENT OF

HYPERTENSION

Mattias Carlström1

1. Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden

Short title: Hydronephrosis and Hypertension

Correspondence: Mattias Carlström (PharmD, PhD)

Associate Professor of Physiology

Department of Physiology and Pharmacology, Biomedicum Q5B, Karolinska Institutet
Solnavägen 9, 17165 Stockholm, Sweden
Email: mattias.carlstrom@ki.se

ABBREVIATIONS

ABPM ambulatory blood pressure monitoring

ADMA asymmetrical dimethylarginine

GFR glomerular filtration rate

NADPH nicotinamide adenine dinucleotide phosphate

NO nitric oxide

This article has been accepted for publication and undergone full peer review but has not
been through the copyediting, typesetting, pagination and proofreading process, which may
lead to differences between this version and the Version of Record. Please cite this article as
doi: 10.1111/apa.14482
This article is protected by copyright. All rights reserved.
 NOS nitric oxide synthase

RAAS renin-angiotensin-aldosterone system

Accepted Article
RBF renal blood flow

ROS reactive oxygen species

RSNA renal sympathetic nerve activity

SDMA symmetrical dimethylarginine

SOD superoxide dismutase

UPJO ureteropelvic junction obstruction

NCC epithelial Na-Cl cotransporter

γ-ENaC epithelial sodium channel gamma subunit

ABSTRACT

Aim: Congenital ureteral obstruction is a fairly common condition in infants, and its clinical

management has been long debated during the last decade. The long-term physiological

consequences of today’s conservative non-surgical management in many asymptomatic

hydronephrotic children is unclear.

Methods: Experimental studies in rats and mice, retrospective studies in children and

adults, as well as prospective studies in children are included in this mini-review.

Results: Experimental models of hydronephrosis in rats and mice have demonstrated that

partial ureteropelvic junction obstruction (UPJO) is casually linked with development of

hypertension and renal injuries in later life. The mechanisms are multifactorial and involve

increased activity of the renin-angiotensin-aldosterone system and renal sympathetic nerve

activity. Furthermore, oxidative stress and nitric oxide deficiency in the affected kidney

appear to play important roles in the development and maintenance of hypertension. Clinical

case reports in adults and recent prospective studies in children have associated

hydronephrosis with elevated blood pressure, which could be reduced by surgical

management of the obstruction.

This article is protected by copyright. All rights reserved.

 Conclusion: Based on current experimental and clinical knowledge regarding the link

between partial UPJO and changes in blood pressure, it is proposed that today’s non-
Accepted Article
operative management of hydronephrosis should be reconsidered to reduce the risk of

developing elevated blood pressure or hypertension in later life.

Key words: blood pressure, hypertension, hydronephrosis, ureteral obstruction

KEY NOTES

 Elevated blood pressure in children with hydronephrosis is currently not an indication

for surgical management.

 Experimental studies and clinical case reports as well as recent prospective pilot

studies have demonstrated a causal link between hydronephrosis and elevated blood

pressure

 Today’s conservative (non-operative) management of hydronephrosis in children

without symptoms should be reconsidered in order to reduce the risk of developing

hypertension later in life.

INTRODUCTION

Hydronephrosis is a fairly common condition with dilatation of the renal pelvis. The most

frequent cause of antenatal and neonatal hydronephrosis is uretero-pelvic junction

obstruction (UPJO). The condition is associated with a reduction in the urine flow from the

renal pelvis into the ureter, and if left untreated this can lead to chronic infection, urolithiasis

and often progressive deterioration of renal function (1). Most cases of UPJO are congenital

and with increasing use of ultrasound, the incidence of hydronephrosis among newborn

This article is protected by copyright. All rights reserved.

 infants is about 1-2% (2). Despite being a fairly common condition, the pathophysiology of

congenital urinary tract obstruction is still poorly understood and best clinical management
Accepted Article
has been debated among urologists for many years.

Treatment options for UPJO include active surveillance or minimally invasive endourologic

techniques to open, laparoscopic or robotic pyeloplasty (1). Clinical studies demonstrating

that the renal blood flow (RBF) and glomerular filtration rate (GFR) were well preserved in

children (3-5), led to a worldwide trend towards non-operative management of unilateral

neonatal hydronephrosis. However, the long-term physiological consequences of this

conservative treatment strategy with respect to renal and cardiovascular functions are

unknown.

The kidneys play an important role in blood pressure regulation, and many forms of renal

disease including UPJO may lead to hypertension. Experimental models of hydronephrosis

in rats and mice have demonstrated that ureteropelvic junction obstruction is casually linked

with development of hypertension and renal injuries in later life (Figure 1). However,

elevated blood pressure in children with hydronephrosis has not been reported in the

literature as an indication for surgery. Most children with hydronephrosis are not reported to

be hypertensive, but there are several case reports of patients who became normotensive

after relief of the obstruction by either nephrectomy or pyeloplasty, e.g. (6-13). Currently,

there are few small clinical studies that have investigated the changes in blood pressure

following surgical management of hydronephrosis in children, and hence large prospective

clinical trials are warranted to determine the best treatment policy. In this mini review, recent

experimental and clinical studies regarding the link between UPJO and elevated blood

pressure are discussed. A scheme of proposed underlying mechanisms linking

hydronephrosis with later development of hypertension is illustrated in Figure 2.

This article is protected by copyright. All rights reserved.

 EXPERIMENTAL STUDIES OF URETERAL OBSTRUCTION

Several different experimental models have been established to investigate obstructive

Accepted Article
nephropathy. Complete unilateral ureteral obstruction, for a short period of time, is the most

commonly used model. However, this type of obstruction is very rare, although often referred

to in clinical discussions. The effects of long-term partial UPJO have been less intensively

explored but would provide more useful information for the clinicians. Below follows a brief

summary of knowledge regarding obstructive nephropathy and effects on blood pressure in

models of ureteral obstruction.

Obstructive nephropathy

Obstructive nephropathy, which is the most important cause of renal insufficiency in children,

is not a simple result of mechanical hindrance to urine flow, but a complex syndrome leading

to alterations of both glomerular haemodynamics and tubular function (14). The syndrome is

the result of interaction of vasoactive factors and immunological components that are

activated in response to ureteral obstruction (14). Both complete and partial UPJO have

been used as models for obstructive nephropathy leading to tubular atrophy, interstitial

inflammation and subsequently loss of nephrons. The pathophysiological mechanisms

following ureteral obstruction are not yet clearly delineated, but increased activity of the

renin-angiotensin-aldosterone system (RAAS) (15, 16), activation of the immune system and

infiltration of macrophages play important roles (17, 18). Hydronephrosis is also associated

with oxidative stress due to increased production of reactive oxygen species (ROS) in the

obstructed kidney (19-24), which may stimulate the secretion of inflammatory molecules that

in turn further increase ROS and give rise to a vicious cycle perpetuating renal pathological

changes (25).

This article is protected by copyright. All rights reserved.

 Blood Pressure

Anaesthetized animals with partial UPJO have been reported as both normotensive (26, 27)
Accepted Article
and hypertensive (28-30). This discrepancy is likely due to the effects of anaesthesia on

blood pressure but could also due to differences in the duration and the severity of the

UPJO. More recent studies have investigated the long-term effects of partial UPJO on blood

pressure in conscious animals using either radio-telemetry or tail-cuff techniques.

Both rats and mice with experimentally-induced hydronephrosis, due to partial unilateral

UPJO, developed hypertension that was salt-sensitive and correlated directly with the

degree of hydronephrosis (15, 31) (Figure 1). Moreover, mice with congenital

hydronephrosis that had developed spontaneously or was genetically-induced also displayed

hypertension and renal injuries (32). Relief of the obstruction by unilateral nephrectomy or

ureterovesicostomy attenuated both hypertension and salt-sensitivity in hydronephrotic

animals, whereas these variables were augmented following removal of the contralateral

non-obstructed kidney (33) thus suggesting that the hypertensive mechanisms are primarily

located within the diseased kidney. These findings, demonstrating that hydronephrosis in

two different species (rats and mice) and of different origin was associated with hypertension

strengthens the hypothesis that similar pathological changes probably also occur in humans.

MECHANISMS UNDERLYING HYPERTENSION IN HYDRONEPHROSIS

Renin-angiotensin-aldosterone system

Secondary hypertension including renal hypertension are associated with increased activity

of the RAAS, thus leading to increased vascular resistance, abnormal renal autoregulation,

sodium and water retention. In clinical case reports, hydronephrotic patients with

hypertension have displayed increased renin levels in plasma (6, 7, 10, 12, 34, 35). The

degree of RAAS activation appears to be influenced by the duration of the obstruction, the

presence or absence of a contralateral normal kidney and other intrarenal factors.

Experimental studies have demonstrated that complete UPJO is associated with enhanced

intrarenal RAAS activity throughout the period of obstruction (36). In studies with partial

This article is protected by copyright. All rights reserved.

 UPJO, elevated plasma levels or renal expression of renin and angiotensin II type 1 receptor

were found in rats (15, 16) (Figure 1), but were not significantly altered in mice (31).
Accepted Article
Elevated renin concentrations were normalised following pyeloplastic surgery or removal of

the hydronephrotic kidney (33), suggesting that the diseased kidney is critically involved.

However, elevated RAAS activity cannot entirely explain why hypertension develops, as

conditions with severe hydronephrosis were not associated with increased renin levels. This

could possibly be explained by damaged juxtaglomerular cells in the severely obstructed

kidney or that renin secretion via negative feedback mechanisms is inhibited by increased

extracellular volume and substantially increased blood pressure. This concept is supported

by studies made by Tauchi et al. who found a negative correlation between plasma

angiotensin II and blood pressure levels in adult hydronephrotic animals (29) Angiotensin II

plays an important role in the development of obstructive nephropathy, and it has been

suggested that chronic AT1-receptor blockade may protect neonatally obstructed kidneys

against renal dysfunction (37). A recent study showed that plasma renin activity and

angiotensin II were reduced in mice with left hydronephrosis compared with sham-operated

controls. Interestingly, expression of angiotensin-converting enzyme (ACE) was increased

whereas ACE2 was reduced in cardiac tissue of hydronephrotic mice (38). These abnormal

regulations of the RAAS were normalized by treatment with an ACE inhibitor (enalapril) and

an angiotensin receptor blocker (losartan). A recent study investigated further investigated

the role of increased RAAS activity and abnormal tubular sodium transportation in pediatric

patients and rats with UPJO (39). It was concluded that hydronephrosis is associated with

elevated urinary plasmin levels in both pediatric patients and rats, which may lead to

proteolytic activation of tubular sodium transporters. Indeed, hydronephrosis was associated

with increased expression of the aldosterone-stimulated Na-Cl cotransporter (NCC) and

epithelial sodium channel gamma subunit (γ-ENaC) in the rat kidney (39). Moreover, the

authors showed that treatment with an ACE inhibitor for one week significantly attenuated

hypertension in UPJO rats. The blood pressure lowering effect was more profound in

This article is protected by copyright. All rights reserved.

 hydronephrotic rats compared with sham-operated control animals, thus strengthening the

role of increased RAAS activity in hydronephrosis and hypertension (39).

Accepted Article
Autonomic nervous system

Accumulating evidence show reciprocal interactions between the brain and kidneys for

cardiovascular regulation, which at least in part is mediated by the autonomic nervous

system (40). The renal medulla plays an important role in cardiovascular regulation, through

interactions with the autonomic nervous system. Deterioration of the renal medulla is

observed in hydronephrosis, and a recent study investigated if this condition is associated

with alterations in autonomic control of the heart. Arnold et al., showed that rats with

spontaneous hydronephrosis exhibited impairments in autonomic regulation, including higher

resting heart rate, impaired indexes of parasympathetic function, a shift in sympathovagal

balance toward sympathetic dominance, but no significant differences in indirect indexes of

sympathetic activity (41). The circulating levels of angiotensin II was not increased, but

microinjections of candesartan (i.e. angiotensin II AT1 receptor antagonist) within the solitary

tract nucleus (NTS) restored baroreflex sensitivity in rats with mild and moderate

hydronephrosis, suggesting that increased angiotensin II signaling within the brain may

contribute to the baroreflex dysfunction in these animals. In contrast, no significant effect

was observed following microinjection of candesartan in rats with severe hydronephrosis,

suggesting that other mechanisms are involved.

Sympathetic efferent and afferent nerve fibers are located in the proximity of the renal

arteries and in the pelvic region, respectively, and are considered to be involved in

cardiorenal syndrome and in hypertension (40, 42). Increased renal sympathetic nerve

activity (RSNA) is linked with increased renin secretion, abnormal renal autoregulation,

sodium and water retention, and development of salt-sensitive hypertension (42, 43). As

discussed recently, renal denervation has been associated with therapeutic effects in both

experimental and clinical studies of hypertension and renal disease (44). A recent study,

This article is protected by copyright. All rights reserved.

 using the model of UPJO-induced hydronephrosis, demonstrated that renal denervation of

the partially obstructed kidney attenuated the development of hypertension and salt-
Accepted Article
sensitivity in the hydronephrotic rats (Figure 1), but had no effect in healthy control animals

(16). The mechanisms contributing to increased RSNA warrants further investigation but

may be secondary to increased RAAS activity.

Oxidative stress and nitric oxide deficiency

Oxidative stress is the result of increased production of ROS and/or decreased activity of

antioxidant defense systems. Accumulating evidence show that oxidative stress and

subsequent nitric oxide (NO) deficiency in the kidney plays an important role in the

development of hypertension and renal disease (43, 45, 46).

Oxidative stress: Patients with mild to moderate renal insufficiency as well as those with end-

stage renal disease receiving dialytic therapy have been found to display oxidative stress

(25, 47, 48). The high abundance of polyunsaturated fatty acids renders the kidney

particularly vulnerable to ROS attack. Increased oxidative stress has been shown to

contribute to the renal pathological changes that take place in a kidney following complete

UPJO obstruction (19, 21, 49) Studies in rodents with chronic partial UPJO demonstrated

increased excretion of oxidative stress markers (e.g. 8-iso-prostaglandin F2α) (50). Moreover,

mice with partial UPJO-induced hydronephrosis overexpressing the antioxidant enzyme

superoxide dismutase 1 (SOD1) were protected from the development of hypertension,

whereas mice lacking SOD1 displayed aggravated hypertension (50) Intervention studies

using the SOD-mimetic tempol normalised renal autoregulatory responses (i.e.

tubuloglomerular feedback) and attenuated hypertension in rats with hydronephrosis, but

had no effects in healthy control animals (50). In rabbits with different degree of

hydronephrosis, Cao et al. demonstrated that severely obstructed kidneys were more

susceptible to oxidative damage and mitochondrial injury than mildly obstructed kidneys

when subjected to higher degrees of kidney perfusion pressure. Finally, a recent study by

This article is protected by copyright. All rights reserved.

 Peleli et al. demonstrated that hypertension in rats with hydronephrosis due to partial UPJO

was causally linked with increased nicotinamide adenine dinucleotide phosphate (NADPH)
Accepted Article
oxidase-derived ROS generation compared with healthy sham-operated animals (16)

(Figure 1). Taken together, these findings demonstrate that hydronephrosis due to UPJO is

coupled with oxidative stress and support the idea that ROS may contribute to hypertension

by reducing the NO levels in hydronephrosis.

Nitric oxide deficiency: Numerous studies have showed that impairment of the classical L-

arginine NO synthase (NOS) pathway importantly contributes to the development of

hypertension and progressive renal disease, and strategies that restore NO

production/signaling have beneficial effects in both experimental and clinical studies. Recent

experimental studies have demonstrated that hypertension in rats with hydronephrosis, due

to chronic partial or bilateral UPJO, was linked with increased circulating levels of the

endogenous NOS inhibitors asymmetrical (ADMA) and symmetrical (SDMA)

dimethylarginine (51). This may result in reduced NO production in hydronephrosis and

thereby contribute to development, progression or maintenance of hypertension. The

concept of reduced NO bioavailability in hydronephrosis and associated hypertension, was

further supported by findings demonstrating reduced expression of NOS protein in the cortex

and medulla of the obstructed kidney and attenuated blood pressure elevation following

pharmacological inhibition of NOS (i.e. L-NAME treatment) in hydronephrotic animals.

Moreover, supplementation with L-arginine to boost NOS-derived NO formation normalized

renal autoregulation and lowered blood pressure in hydronephrotic rats but had no

significant effects in healthy control animals (51).

Studies in isolated and perfused renal afferent arterioles showed that contractile responses

during NOS inhibition was abolished in the hydronephrotic kidney. In kidneys overexpressing

SOD1, strong but similar responses were observed in ipsilateral hydronephrotic kidneys,

contralateral non-obstructed kidneys and in healthy control kidneys. This strong response to

This article is protected by copyright. All rights reserved.

 a NOS inhibitor was abolished in renal arterioles from mice lacking SOD1 (52). Taken

together, these findings imply that oxidative stress, coupled with NO deficiency in the
Accepted Article
obstructed kidney, plays an important role in the development and maintenance of

hypertension. The abnormal regulation of RAAS, ROS and NO may impair renal

autoregulation and contribute to renal dysfunction and development of hypertension (43).

CLINICAL STUDIES OF URETERAL OBSTRUCTION AND BLOOD PRESSURE

Currently there are no large prospective randomized clinical studies that have investigated

the long-term effects on blood pressure following conservative or surgical management.

Twenty-four-hour ambulatory blood pressure monitoring (24h-ABPM) is the gold standard

method in the diagnosis and therapeutic monitoring of arterial hypertension in the adult

population. In the pediatric population the statistical use of ABPM reference values has been

compromised by the non-Gaussian distribution of blood pressure. However, normative

standards for 24h blood pressure data are available for children aged 5-16 years (53). Office

blood pressure data is available for neonates, children and adolescents (54).

Retrospective studies in children

A retrospective study conducted by de Waard et al. evaluated the proportion of children with

UPJO (n=227 patients, mean age 6.5 years) who were diagnosed with hypertension

preoperatively, and how the blood pressure behaved after relief of the obstruction. The

authors concluded that approximately 5% of the children with UPJO were hypertensive, and

that relief of the obstruction normalized blood pressure in more than 90% of all cases (8).

Interestingly, there was a clear correlation between the age of the children and their blood

pressure level, suggesting that a large proportion of children with hydronephrosis may

develop hypertension in later life. The low frequency of hypertension in this study might be

explained by the young age of the children included and also the fact that it is difficult to

measure blood pressure in neonates and infants due to excessive movements. These

results are therefore not generalizable.

This article is protected by copyright. All rights reserved.

 Retrospective studies in adults

In an ongoing retrospective cohort study, medical records of more than 200 hundred adult
Accepted Article
patients undergoing surgical management of hydronephrosis due to UPJO were assessed.

After exclusion criteria (i.e. chronic diseases, antihypertensive treatment, lack of matched

blood pressure recordings) blood pressure recordings were analyzed in 48 patients before

and after surgical management of the UPJO. Systolic, diastolic and mean arterial pressure

were significantly reduced following relief of the obstruction. Sub-analysis revealed that

higher age was associated with higher blood pressure and a greater reduction in blood

pressure following surgical management of the obstruction.

Prospective studies in children

In two recent small clinical studies the effect of congenital hydronephrosis, due to UPJO, on

blood pressure regulation has been investigated (55, 56). Both studies showed that

ambulatory blood pressure in hydronephrotic patients aged from infancy to 13 years of age

was significantly higher before surgery compared with that measured 6 months following

surgical management (i.e. pyeloplasty) of the UPJO (Figure 1). The latter study also

demonstrated that patients with hydronephrosis had higher blood pressure compared with

age-matched and healthy children. Assessment of bilateral renal function by MAG3

scintigraphy suggested a positive correlation between the degree of reduced functional

share in the affected kidney and the reduction of blood pressure following surgery. In

agreement with that observed in experimental studies analyses of oxidative stress markers

(i.e. 8-isoprostanes) in matched urine and plasma samples showed higher levels before

surgery compared with healthy controls, and these abnormal levels were reduced 6 months

post correction of the UPJO (55).

This article is protected by copyright. All rights reserved.

 SUMMARY AND CONCLUSIONS

Hydronephrosis, caused by UPJO, is a fairly common condition in newborns. The

Accepted Article
observation of rather well preserved renal function, at a young age, has led to a worldwide

trend towards non-operative management of unilateral neonatal hydronephrosis. However,

the long-term physiological consequences of this new strategy are not known. Experimental

studies, clinical case reports and recent retrospective as well as prospective studies have

demonstrated a causal relationship between hydronephrosis and elevated blood pressure.

The underlying mechanisms contributing to the development of hypertension are complex

and involve increased activity of the renin-angiotensin-aldosterone system, increased renal

sympathetic nerve activity, oxidative stress and NO deficiency in the obstructed kidney

(Figure 2). Opinions are divided regarding indications for surgical interventions in children

with hydronephrosis. The use of different urinary biomarkers in newborns for predicting the

clinical outcome has been suggested, but further refinements of these models are needed

(57, 58). On the basis of the new knowledge regarding the long-term physiological

consequences of partial UPJO, it is proposed that today’s non-operative management in

hydronephrotic children should be reconsidered with the aim of reducing the risk of

hypertension in later life. Large prospective clinical trials are warranted to determine the best

treatment policy, but in the meanwhile, it is suggested that elevated blood pressure in

children with hydronephrosis should be an indication for surgical management.

ACKNOWLEDGEMENTS

This work was supported by grants from the Swedish Research Council (2016-01381), the

Swedish Heart and Lung Foundation (20170124).

CONFLICT OF INTERESTS

None

This article is protected by copyright. All rights reserved.

 REFERENCES

1. Krajewski W, Wojciechowska J, Dembowski J, Zdrojowy R, Szydelko T.

Accepted Article
Hydronephrosis in the course of ureteropelvic junction obstruction: An
underestimated problem? Current opinions on the pathogenesis, diagnosis and
treatment. Adv Clin Exp Med 2017; 26 5:857-64.
2. Podevin G, Mandelbrot L, Vuillard E, Oury JF, Aigrain Y. Outcome of urological
abnormalities prenatally diagnosed by ultrasound. Fetal Diagn Ther 1996; 11 3:181-
90.
3. Dhillon HK. Prenatally diagnosed hydronephrosis: the Great Ormond Street
experience. Br J Urol 1998; 81 Suppl 2:39-44.
4. Koff SA, Campbell KD. The nonoperative management of unilateral neonatal
hydronephrosis: natural history of poorly functioning kidneys. J Urol 1994; 152 2 Pt
2:593-5.
5. Ulman I, Jayanthi VR, Koff SA. The long-term followup of newborns with severe
unilateral hydronephrosis initially treated nonoperatively. J Urol 2000; 164 3 Pt
2:1101-5.
6. Abramson M, Jackson B. Hypertension and unilateral hydronephrosis. J Urol 1984;
132 4:746-8.
7. Wanner C, Luscher TF, Schollmeyer P, Vetter W. Unilateral hydronephrosis and
hypertension: cause or coincidence? Nephron 1987; 45 3:236-41.
8. de Waard D, Dik P, Lilien MR, Kok ET, de Jong TP. Hypertension is an indication for
surgery in children with ureteropelvic junction obstruction. J Urol 2008; 179 5:1976-8;
discussion 8-9.
9. Ameur A, Zarzur J, Jira H, Touiti D, el Alami M, Abbar M. [Hydronephrosis arterial
hypertension. Report of 4 cases]. Ann Urol (Paris) 2002; 36 3:157-61.
10. Kawano S, Yano S, Takahashi S, Nomura Y, Ogata J. A case of hypertension due to
unilateral hydronephrosis in a child. Eur Urol 1986; 12 5:357-9.
11. Palmer JM, Zweiman FG, Assaykeen TA. Renal hypertension due to hydronephrosis
with normal plasma renin activity. N Engl J Med 1970; 283 19:1032-3.
12. Riehle RA, Jr., Vaughan ED, Jr. Renin participation in hypertension associated with
unilateral hydronephrosis. J Urol 1981; 126 2:243-6.
13. Chalisey A, Karim M. Hypertension and hydronephrosis: rapid resolution of high
blood pressure following relief of bilateral ureteric obstruction. J Gen Intern Med
2013; 28 3:478-81.
14. Wen JG, Frokiaer J, Jorgensen TM, Djurhuus JC. Obstructive nephropathy: an
update of the experimental research. Urol Res 1999; 27 1:29-39.
15. Carlstrom M, Wahlin N, Sallstrom J, Skott O, Brown R, Persson AE. Hydronephrosis
causes salt-sensitive hypertension in rats. J Hypertens 2006; 24 7:1437-43.
16. Peleli M, Al-Mashhadi A, Yang T, Larsson E, Wahlin N, Jensen BL, et al. Renal
denervation attenuates NADPH oxidase-mediated oxidative stress and hypertension
in rats with hydronephrosis. Am J Physiol Renal Physiol 2016; 310 1:F43-56.
17. Chevalier RL. Chronic partial ureteral obstruction and the developing kidney. Pediatr
Radiol 2008; 38 Suppl 1:S35-40.
18. Klahr S, Morrissey J. Obstructive nephropathy and renal fibrosis. Am J Physiol Renal
Physiol 2002; 283 5:F861-75.

This article is protected by copyright. All rights reserved.

 19. Kawada N, Moriyama T, Ando A, Fukunaga M, Miyata T, Kurokawa K, et al.
Increased oxidative stress in mouse kidneys with unilateral ureteral obstruction.
Kidney Int 1999; 56 3:1004-13.
Accepted Article
20. Sugiyama H, Kobayashi M, Wang DH, Sunami R, Maeshima Y, Yamasaki Y, et al.
Telmisartan inhibits both oxidative stress and renal fibrosis after unilateral ureteral
obstruction in acatalasemic mice. Nephrol Dial Transplant 2005; 20 12:2670-80.
21. Moriyama T, Kawada N, Nagatoya K, Takeji M, Horio M, Ando A, et al. Fluvastatin
suppresses oxidative stress and fibrosis in the interstitium of mouse kidneys with
unilateral ureteral obstruction. Kidney Int 2001; 59 6:2095-103.
22. Lin KC, Krieg RJ, Jr., Saborio P, Chan JC. Increased heat shock protein-70 in
unilateral ureteral obstruction in rats. Mol Genet Metab 1998; 65 4:303-10.
23. Pat B, Yang T, Kong C, Watters D, Johnson DW, Gobe G. Activation of ERK in renal
fibrosis after unilateral ureteral obstruction: modulation by antioxidants. Kidney Int
2005; 67 3:931-43.
24. Manucha W, Carrizo L, Ruete C, Molina H, Valles P. Angiotensin II type I antagonist
on oxidative stress and heat shock protein 70 (HSP 70) expression in obstructive
nephropathy. Cell Mol Biol (Noisy-le-grand) 2005; 51 6:547-55.
25. Singh D, Kaur R, Chander V, Chopra K. Antioxidants in the prevention of renal
disease. J Med Food 2006; 9 4:443-50.
26. Morsing P, Stenberg A, Muller-Suur C, Persson AE. Tubuloglomerular feedback in
animals with unilateral, partial ureteral occlusion. Kidney Int 1987; 32 2:212-8.
27. Stenberg A, Olsen L, Engstrand U, Persson AE. Pressure and flow measurements in
the partially obstructed ureter of the rat. Scand J Urol Nephrol 1988; 22 4:279-88.
28. Josephson S, Lannergren K, Eklof AC. Partial ureteric obstruction in weanling rats. II.
Long-term effects on renal function and arterial blood pressure. Urol Int 1992; 48
4:384-90.
29. Tauchi K, Kanehara H. Hypertension and the renin-angiotensin system in the
congenital hydronephrosis rat with non-obstructive pelviureteric junction
abnormalities. Exp Nephrol 1996; 4 1:60-4.
30. Pettersson BA, Aperia A, Elinder G. Pathophysiological changes in rat kidneys with
partial ureteral obstruction since infancy. Kidney Int 1984; 26 2:122-7.
31. Carlstrom M, Sallstrom J, Skott O, Larsson E, Wahlin N, Persson AE.
Hydronephrosis causes salt-sensitive hypertension and impaired renal concentrating
ability in mice. Acta Physiol (Oxf) 2007; 189 3:293-301.
32. Sallstrom J, Peuckert C, Gao X, Larsson E, Nilsson A, Jensen BL, et al. Impaired
EphA4 signaling leads to congenital hydronephrosis, renal injury, and hypertension.
Am J Physiol Renal Physiol 2013; 305 1:F71-9.
33. Carlstrom M, Wahlin N, Skott O, Persson AE. Relief of chronic partial ureteral
obstruction attenuates salt-sensitive hypertension in rats. Acta Physiol (Oxf) 2007;
189 1:67-75.
34. Pak K, Kawamura J, Yoshida O. Hypertension with elevated renal vein renin
secondary to unilateral hydronephrosis. Urology 1980; 16 5:499-501.
35. Weidmann P, Beretta-Piccoli C, Hirsch D, Reubi FC, Massry SG. Curable
hypertension with unilateral hydronephrosis. Studies on the role of circulating renin.
Ann Intern Med 1977; 87 4:437-40.
36. Chevalier RL. Molecular and cellular pathophysiology of obstructive nephropathy.
Pediatr Nephrol 1999; 13 7:612-9.

This article is protected by copyright. All rights reserved.

 37. Topcu SO, Pedersen M, Norregaard R, Wang G, Knepper M, Djurhuus JC, et al.
Candesartan prevents long-term impairment of renal function in response to neonatal
partial unilateral ureteral obstruction. Am J Physiol Renal Physiol 2007; 292 2:F736-
48.
Accepted Article
38. Zhang Y, Ma L, Wu J, Chen T. Hydronephrosis alters cardiac ACE2 and Mas
receptor expression in mice. J Renin Angiotensin Aldosterone Syst 2015; 16 2:267-
74.
39. Zachar R, Al-Mashhadi A, Dimke H, Svenningsen P, Jensen BL, Carlstrom M.
Hydronephrosis is associated with elevated plasmin in urine in pediatric patients and
rats and changes in NCC and gamma-ENaC abundance in rat kidney. Am J Physiol
Renal Physiol 2018.
40. DiBona GF. Nervous kidney. Interaction between renal sympathetic nerves and the
renin-angiotensin system in the control of renal function. Hypertension 2000; 36
6:1083-8.
41. Arnold AC, Shaltout HA, Gilliam-Davis S, Kock ND, Diz DI. Autonomic control of the
heart is altered in Sprague-Dawley rats with spontaneous hydronephrosis. Am J
Physiol Heart Circ Physiol 2011; 300 6:H2206-13.
42. DiBona GF, Kopp UC. Neural control of renal function. Physiol Rev 1997; 77 1:75-
197.
43. Carlstrom M, Wilcox CS, Arendshorst WJ. Renal autoregulation in health and
disease. Physiol Rev 2015; 95 2:405-511.
44. Carlstrom M. Therapeutic value of renal denervation in cardiovascular disease? Acta
Physiol (Oxf) 2017; 220 1:11-3.
45. Wilcox CS. Oxidative stress and nitric oxide deficiency in the kidney: a critical link to
hypertension? Am J Physiol Regul Integr Comp Physiol 2005; 289 4:R913-35.
46. Drummond GR, Selemidis S, Griendling KK, Sobey CG. Combating oxidative stress
in vascular disease: NADPH oxidases as therapeutic targets. Nat Rev Drug Discov
2011; 10 6:453-71.
47. Wiswedel I, Hirsch D, Carluccio F, Hampl H, Siems W. F2-isoprostanes as
biomarkers of lipid peroxidation in patients with chronic renal failure. Biofactors 2005;
24 1-4:201-8.
48. Siems W, Quast S, Carluccio F, Wiswedel I, Hirsch D, Augustin W, et al. Oxidative
stress in chronic renal failure as a cardiovascular risk factor. Clin Nephrol 2002; 58
Suppl 1:S12-9.
49. Kinter M, Wolstenholme JT, Thornhill BA, Newton EA, McCormick ML, Chevalier RL.
Unilateral ureteral obstruction impairs renal antioxidant enzyme activation during
sodium depletion. Kidney Int 1999; 55 4:1327-34.
50. Carlstrom M, Brown RD, Sallstrom J, Larsson E, Zilmer M, Zabihi S, et al. SOD1-
Deficiency Causes Salt-Sensitivity and Aggravates Hypertension in Hydronephrosis.
Am J Physiol Regul Integr Comp Physiol 2009.
51. Carlstrom M, Brown RD, Edlund J, Sallstrom J, Larsson E, Teerlink T, et al. Role of
nitric oxide deficiency in the development of hypertension in hydronephrotic animals.
Am J Physiol Renal Physiol 2008; 294 2:F362-70.
52. Carlstrom M, Lai EY, Steege A, Sendeski M, Ma Z, Zabihi S, et al. Nitric oxide
deficiency and increased adenosine response of afferent arterioles in hydronephrotic
mice with hypertension. Hypertension 2008; 51 5:1386-92.

This article is protected by copyright. All rights reserved.

 53. Wuhl E, Witte K, Soergel M, Mehls O, Schaefer F, German Working Group on
Pediatric H. Distribution of 24-h ambulatory blood pressure in children: normalized
reference values and role of body dimensions. J Hypertens 2002; 20 10:1995-2007.
Accepted Article
54. Flynn JT, Kaelber DC, Baker-Smith CM, Blowey D, Carroll AE, Daniels SR, et al.
Clinical Practice Guideline for Screening and Management of High Blood Pressure in
Children and Adolescents. Pediatrics 2017; 140 3.
55. Al-Mashhadi A, Checa A, Wahlin N, Neveus T, Fossum M, Wheelock CE, et al.
Changes in arterial pressure and markers of nitric oxide homeostasis and oxidative
stress following surgical correction of hydronephrosis in children. Pediatr Nephrol
2017.
56. Al-Mashhadi A, Neveus T, Stenberg A, Karanikas B, Persson AE, Carlstrom M, et al.
Surgical treatment reduces blood pressure in children with unilateral congenital
hydronephrosis. Journal of pediatric urology 2015; 11 2:91 e1-6.
57. Chevalier RL. Obstructive nephropathy: towards biomarker discovery and gene
therapy. Nat Clin Pract Nephrol 2006; 2 3:157-68.
58. Decramer S, P ZUR, Wittke S, Mischak H, Bascands JL, Schanstra JP. Identification
of urinary biomarkers by proteomics in newborns: use in obstructive nephropathy.
Contrib Nephrol 2008; 160:127-41.

This article is protected by copyright. All rights reserved.

Accepted Article

This article is protected by copyright. All rights reserved.

 Figure 1. Experimental and clinical studies suggesting a link between hydronephrosis
and hypertension
Accepted Article
Panel A: Studies by Carlstrom et al., demonstrated for the first time that chronic partial
UPJO of the left kidney was associated with hypertension in rats. Blood pressure was
measured by telemetry in conscious animals. The elevated blood pressure was salt
sensitive, e.g. increase further in response in response to a high salt intake (4% NaCl) and
decrease when fed a low salt diet (0.2% NaCl). Moreover, the severity of hypertension and
the salt-sensitivity correlated directly with the degree of hydronephrosis (i.e. mild, moderate
and severe obstruction). If UPJO was managed surgically either by pyeloplasty or
nephrectomy the blood pressure was significantly reduced in the hydronephrotic rats (data
not shown). Panel B-E: Renal denervation attenuated the development of hypertension in
rats with UPJO-induced hydronephrosis (B), and this favorable effect on blood pressure was
associated with reduced NADPH oxidase-derived oxidative stress (C) and normalized renin
and angiotensin II type 1 receptor expression in the UPJO kidney (D-E, respectively). Panel
F: A prospective pilot study in pediatric children with hydronephrosis due to UPJU
demonstrated elevated blood pressure compared with age-matched and healthy children
(Controls). Panel G-H: Six months following surgical management of the hydronephrosis by
pyeloplasty both systolic and diastolic pressures was significantly reduced compared with
blood pressure that measure before the operation. * Denotes statistically significant (P0.05)
differences between indicated groups. † in Panel A denotes significant difference (P0.05)
between controls and all hydronephrotic groups on the same salt diet. Figure is modified with
permission from previous original publications, i.e. Panel A by Carlstrom et al. (15, 33),
Panel B-E by Peleli et al. (16), Panel G-I by Al-Mashhadi et al., (55, 56).

Figure 2. Proposed mechanisms contributing to the development of hypertension in

hydronephrosis induced by partial UPJO.

Hydronephrosis due to chronic ureteropelvic junction obstruction (UPJO) has been

associated with several pathophysiological mechanisms that may alter organ function in
adult life. Impairment of autonomic control (e.g. impaired baroreflex sensitivity and a shift in
sympathovagal balance toward sympathetic dominance) and increased renal sympathetic
nerve activity (RSNA) have been coupled with increased activity and signaling of the renin-
angiotensin-system (RAAS) in the kidney and the brain (particularly within the solitary tract
nucleus). These interrelated mechanisms can increase NADPH oxidase-derived formation of
reactive oxygen species and abnormal mitochondrial function (oxidative damage and

This article is protected by copyright. All rights reserved.

 mitochondrial injury). Subsequent oxidative stress and nitric oxide deficiency can impair
renal autoregulatory functions. For example, hydronephrotyic kidneys display abnormal
afferent arteriolar vasoreactivity and have enhance tubuloglomerular feedback responses,
Accepted Article
which can both be linked to abnormal angiotensin II and nitric oxide signaling. These
complex mechanisms may in the chronic setting contribute to abnormal cardiovascular
function (i.e. elevated blood pressure) and reduced renal function. These abnormalities are
often associated or interrelated with organ injuries that can accelerate the declined organ
function.

This article is protected by copyright. All rights reserved.

Accepted Article

This article is protected by copyright. All rights reserved.