Journal of Human Hypertension (1998) 12, 497–504  1998 Stockton Press. All rights reserved 0950-9240/98 $12.00 http://www.stockton-press.co.uk/jhh REVIEW ARTICLE Reflux nephropathy and hypertension

CDA Goonasekera and MJ Dillon Institute of Child Health and Great Ormond Street Children’s Hospital NHS Trust, London WC1N 1EH, UK

Renal scarring associated with vesico-ureteric reflux fore regular follow-up remains the only current means (VUR), most commonly detected in young children, is of recognising these subjects. Although prevention of associated with a significant risk of developing hyper- renal scar development in children with VUR may offer tension in later life. Hypertension in reflux nephropathy some benefit in reducing the incidence of hypertension, contributes significantly to morbidity including deterio- there is no uniform action that can definitely achieve ration of renal function. The mechanism of onset of this, particularly in the very young, before any urinary hypertension is not clear although abnormalities of the infection occurs. Primary VUR seems to be a disorder renin-angiotensin system and sodium/potassium with mendelian dominant inheritance and location of the ATPase activity have been described in some cases. It gene may offer some hope of early identification within is becoming clear that radiologically detectable renal certain families. Timely introduction of preventative scars or small kidneys may histologically indicate a var- measures may then be possible even though reser- iety of diagnoses. Prediction of the risk of developing vations exist about their effectiveness. hypertension in individual cases is difficult and there-

Keywords: reflux nephropathy; hypertension

What is reflux nephropathy? The problem Reflux nephropathy is defined as focal renal scarring From a number of studies there is evidence that of one or both kidneys resulting from primary renal scars increase the risk of developing hyperten- vesicoureteric reflux (VUR) and urinary tract infec- sion and progressive renal failure during later tion (UTI). Primary VUR is common in young chil- life.1,18–20 Hypertension affects at least 10% of chil- dren (estimated incidence in the general population dren with renal scars,21–23 and is the commonest 0.1–1%,1,2 in children presenting with UTI 12– cause of severe hypertension in childhood.24–27 In 50%1,3), but disappears with time in the majority 4,5 adults with reflux nephropathy the prevalence of (80%). A substantial number of subjects with VUR 5,28,29 have established renal scars at diagnosis6–8 with an hypertension is much higher (38–50%) increasing incidence with age (10% in preterm reflecting the continued risk of developing hyperten- infants with VUR,9 26% in children less than 8 sion at any age. Jacobson et al (1989) found that 6 6 hypertension in some adults with renal scarring did years, 47% in children older than 8 years and 94% 30 in adults5) or develop new scars at follow-up (5– not occur until 27 years of follow-up. 58%).7,8,10,11 There is a correlation between the Malignant hypertension due to reflux nephro- 12,13 pathy is uncommon but has been reported in extent of scarring and grade of VUR although 20,31 14 younger children and adolescents and in women there is some disagreement on this issue. It is also 32 clear that renal scars may be seen in the absence of taking oral contraceptives. The incidence of hyper- demonstrable VUR.15 It is considered that renal scar- tension is higher in pregnancy in subjects with Ͻ reflux nephropathy33 when first manifestations of ring mainly occurs in younger subjects ( 5 29,34 years).6,16 and that it is more likely to occur in the clinically latent reflux nephropathy may be seen. 7 If hypertension is present at conception, the risk of presence of urological abnormalities, with recur- 35 rent UTI10 particularly with upper tract involvement fetal death increases by four to five-fold. (eg, pyelonephritis),7 and certain bacterial patho- Although reflux nephropathy was first defined as gens.17 pyelonephritic scarring associated with UTI and VUR the current terminology includes several forms of renal damage associated with VUR and resulting in cortical scarring, clubbed calyces and generalised parenchymal loss (as in obstructive uropathy). Additionally, renal dysplasia, renal hypoplasia, the Ask-Upmark kidney,36,37 and even small kidneys Correspondence: MJ Dillon, Nephrourology Unit, Institute of due to renal growth retardation38,39 are known either Child Health and Great Ormond Street Children’s Hospital NHS Trust, 30 Guilford Street, London WC1N 1EH, UK to co-exist with or be misdiagnosed as reflux Received 28 November 1997; revised 9 April 1998; accepted 16 nephropathy in many cases due to non-availability April 1998 of an investigation that will reliably distinguish Reflux nephropathy and hypertension CDA Goonasekera and MJ Dillon 498 between the above pathologies. Risdon and col- mental tubular atrophy with glomerular metamor- leagues found histopathological evidence for renal phosis but no significant inflammation52 suggesting dysplasia in a subgroup of children (only in males) mechanisms other than infection are involved in the who had had unilateral nephrectomies for reflux pathogenesis. Whatever their aetiology, these kid- nephropathy.40 With the recent introduction of pre- neys also have the potential to cause hypertension. natal ultrasound a group of patients has been disco- Conversely, histological appearances highly sugges- vered who have dilatation of the urinary tract ante- tive of reflux nephropathy can occur in radiologi- natally and on postnatal cystography primary VUR cally normal kidneys.19 is identified.41 These neonates are mainly boys with two-thirds having bilateral reflux and between a third and a half demonstrating reduced renal func- Risk factors for the development of tion on isotope renography, even in the absence of hypertension 42 a preceding UTI. Crabbe showed that four of 24 Age kidneys (in 15 children with primary VUR who were non-infected) were globally abnormal (ie, small kid- The risk of developing hypertension in reflux neys without focal scarring) suggesting that some of nephropathy appears to be highest during ado- 22,30,53,54 these children may have had abnormal renal paren- lescence and adulthood. Some studies chyma from birth.43 Therefore renal hypoplasia and undertaken in younger children report an absence 55 dysplasia may mimic scarring, co-exist with VUR of hypertension. Severe hypertension due to reflux with or without UTI and are known to be associated nephropathy, however, may occur at any age, with hypertension.18,44 especially in pre-adolescent children. The Ask-Upmark kidney, as originally described36 The hypertension risk in adults is difficult to was an abnormal kidney with an external circumfer- assess due to confounding factors such as intake of ential groove marking the site of an elongated calyx oral contraceptives, increasing risk of essential with a very thin band of parenchyma (a segment hypertension and cumulative nature of reported lacking a medullary pyramid in relation to the data. The estimated prevalence of hypertension, dilated calyx, ie, renal segmental hypoplasia) asso- however, in adults with renal scarring is 10– 5,14,56,57 ciated with VUR and often also categorised as reflux 50%, much higher than it is in children and nephropathy. It appears to be in over 50% of cases is commonly associated with proteinuria and renal complicated by hypertension45,46 and seems to be insufficiency. associated in terms of hypertension with complete cure more frequently by nephrectomy than is seen in Sex other patients with reflux nephropathy.46 Although Ask-Upmark himself considered these kidney Reflux nephropathy is commoner in females (M:F lesions were congenital in origin some investigators ratio of 1:5),56,57 but males more often appear to have disagree,45,47 Neither the prevalence of this con- bilateral scarring, persistent reflux54 and compli- dition among subjects with reflux nephropathy nor cations such as proteinuria, hypertension or renal the true incidence of hypertension among this sub- failure.54 group is known. This mixture of pathology that often co-exists or Genetics overlaps with pyelonephritic scarring suggests that a number of studies that were undertaken in the past, There is now convincing evidence obtained by seg- many of which were dependent on the diagnosis of regation analysis suggesting familial occurrence of reflux nephropathy made postnatally by intravenous primary VUR is possibly inherited via a single domi- urography, may have included a proportion of cases nant gene acting together with random environmen- with abnormal parenchyma from birth. This may tal effects.58,59 The gene frequency is estimated to be have contributed to the vast differences in the 1:600, and new mutations seem unlikely as pre- reported incidences of reflux nephropathy and its dicted by the above segregation analysis computer associated complications. The data may have been model.59 Forty-five percent of gene carriers are pre- further contaminated by reno-vascular hypertension dicted to have VUR or reflux nephropathy as adults in children and adolescents that can also be associa- and 15% are predicted to go on to develop renal fail- ted with reflux nephropathy24,48 and by the finding ure compared to 0.05% and 0.001%, respectively, of reflux nephropathy in some adults previously for those not carrying the gene.59 However, there are thought to have primary hypertension.49 In addition, no genetic clues yet for the recognition of subjects at methodological flaws in various studies as high- risk of hypertension due to renal scarring60 although lighted by Shanon and Feldman50 may have contrib- ACE gene D allele homozygosity appear to increase uted to differences in the reported incidence of the risk of scar formation in children with VUR.61 hypertension in reflux nephropathy. Non-scarred kidneys in association with VUR but Degree of reflux and the degree of scarring with a reduced contribution to renal function (Ͻ43%) on DMSA isotope scanning have been Hypertension is more likely in patients with severe described, which may have a pathogenesis similar bilateral reflux28 and in the presence of bilateral to that of the previously referred to small abnormal scarring,28,29,62 but can occur in the presence of uni- kidneys; a vascular, renal dysplastic or obstructive lateral scarring20,62 and irrespective of the degree of aetiology.51 Histologically these kidneys show seg- scarring.63 Hypertension, when present, accelerates Reflux nephropathy and hypertension CDA Goonasekera and MJ Dillon 499 the progression of renal failure in reflux nephro- Current theory holds that renal scarring is central pathy,1,19,22,64–66 making early diagnosis and treat- to the pathogenesis of hypertension in patients with ment important.67–69 UTI and VUR.22,44,79,80,87 Arterial damage in scarred The mechanisms involved in the development of areas could lead to segmental ischaemia and thus renal scars, that may also be relevant in the develop- renin driven hypertension.88–90 It has been noted, ment of hypertension, however, are not well under- however, that not all patients with high renin levels stood. Microvascular injury with loss of vessels,70 are hypertensive79 and in some patients plasma bacterial infection,71 immune responses to irritant renin levels revert to normal spontaneously.80 It urinary substances (Tamm–Horsfall protein) forced might be speculated that such a reversion to normal into the interstitium during intrarenal reflux have could follow the complete loss of the blood supply been blamed.72 Focal glomerular sclerosis, a lesion to previously scarred ischaemic areas of kidney found in patients with proteinuria and reflux causing necrosis and cessation of renin release. nephropathy, has been identified not only in scarred kidneys, but also may be seen in contralateral, Sodium transport unscarred kidneys without VUR, suggesting a role for a humoral factor or perhaps a hyperfiltration Abnormal sodium transport is a feature of human phenomenon.49 A histological review of 86 paedi- hypertension, in particular the sodium-potassium atric nephrectomy specimens from patients with ATPase (Na/K ATPase) dependent pump and VUR showed focal segmental glomerulosclerosis sodium-lithium countertransport (LCT).91–93 Digi- (FSGS) in 18 patients but no association with age, talis-like sodium transport inhibitors may be gender, renal hypoplasia or postnatal cortical loss.73 involved in the aetiology of the former,94–96 Within the index population FSGS was significantly especially in the presence of renal impairment.97 It associated with hypertension.73 The cortical scar- has recently been demonstrated that there is a ring with destruction of nephrons may be a factor reduction in Na/K ATPase pump sites (Bmax) in a subjecting the remaining nephrons to compensatory group of children and adolescents with reflux hypertrophy and hyperfiltration causing FSGS as in nephropathy and a proposal has been made that a renal agenesis74 or unilateral nephrectomy.75 Other circulating ouabain-like inhibitor may be to blame mechanisms such as altered prostaglandin syn- contributing to the onset of hypertension.98 Lithium thesis76 and glomerular hypertension77 may have a countertransport, the best characterised intermedi- role in precipitating the onset of FSGS in these ate phenotype in human hypertension,99 however, cases.73 The association between FSGS and hyper- appears to be uninfluenced in reflux nephropathy tension in these cases, however, is unexplained. suggesting that essential hypertension and family history of hypertension are unlikely contributors to hypertension in these cases.98 Mechanisms of hypertension Plasma renin activity (PRA) Renal artery stenosis The renin-angiotensin system has been implicated The finding of contralateral renal artery stenosis due in the genesis of hypertension in reflux nephro- to fibro-muscular dysplasia in some patients in pathy, with a raised peripheral plasma renin activity whom unilateral reflux nephropathy was thought to (PRA) being a frequent finding.78,79 PRA either be responsible for the hypertension has caused increases to abnormal levels80,81 or fails to decrease further confusion.100 The interpretation of such normally with chronological age82 in children with observations is that the observed renal scarring is renal scarring but offers no predictive value in due to intra-renal renovascular pathology resulting identification of subjects who may develop hyper- in parenchymal damage. The problem may be more tension in later life.20 Furthermore there is no direct common than has been reported since very few chil- correlation between PRA and blood pressure in dren with what is considered to be reflux nephro- reflux nephropathy, although clearly in some cases pathy undergo angiographic investigation to exclude high blood pressure and high renin levels normalise renovascular disease as a cause of the ‘scarred’ kid- with removal of the affected kidney. ney or kidneys. Scarring without the characteristic A rise and subsequently a levelling out of systolic calyceal abnormalities of reflux nephropathy in chil- blood pressure standard deviation scores together dren in whom there is no history of UTI or VUR with a rise in PRA standard deviation scores with are those in whom such underlying pathology might age during childhood and teenage years but with a exist. It has also been considered that the so called reduction in adulthood is seen in reflux nephro- ‘Ask-Upmark’ kidney36 which mimics reflux pathy.20 These findings suggest a dissociation nephropathy has a possibly intrauterine renovascu- between blood pressure and renin in reflux nephro- lar aetiology.101 pathy with age.83 Other factors such as hormonal contraceptives that reduce PRA,84 but can cause Other vasoactive substances hypertension85 may confound these observations. Some argue that PRA may not be reflective of the It has been noted that some patients with reflux renin activity at the tissue level86 and therefore nephropathy with raised plasma renin may remain observations of PRA in reflux nephropathy can only normotensive.20 This kind of phenomena has not be a very crude guide to the actions of renin-angio- been clearly explained and natural anti-hyperten- tensin system in this condition. sive vasoactive peptides may be involved, for Reflux nephropathy and hypertension CDA Goonasekera and MJ Dillon 500 example natriuretic hormones,102,103 prosta- pressed (as in a true normal kidney) by increased glandins,104 renomedullary lipids,105 adrenomedul- blood pressure and increased renin release from the lin106 and nitric oxide.107 The role of such com- contralateral diseased kidney. pensatory hypotensive systems or lack of them in There is, however, controversy regarding the val- the onset of hypertension in reflux nephropathy is idity of renal vein renin ratios in unilateral reflux yet to be clearly defined. The role of endothelin in nephropathy. In a study of 17 normotensive and 12 reflux nephropathy, the most powerful vasoconstric- hypertensive patients with strictly unilateral tor yet known, is also unclear at present.108 nephropathy, there were only three normotensive and two hypertensive patients with a renal vein Management renin ratio exceeding 1.5, indicating that the renin- angiotensin system may not consistently have a role Most subjects with reflux nephropathy associated in the hypertension of unilateral reflux nephro- hypertension are managed conservatively and may pathy.117 On the other hand it could be argued that continue to be so even after surgical intervention. in the normotensive unilateral scarred kidney Angiotensin-converting enzyme (ACE) inhibitors are patients with a renal vein renin ratio of more than useful therapeutic agents in this condition not only 1.5 the non-scarred kidney must be normal as because they are effective anti-hypertensives but opposed to ‘apparently’ normal and responds to the also because of their positive effects on cardiac func- effects of increased blood pressure by natriuresis tion, peripheral vasculature, proteinuria and renal ultimately producing normotension. sparing properties.28,109,110 Adequate control of Most clinicians agree that there is little benefit hypertension is considered one of the most obtained by surgical correction of VUR if the subject important measures that would help curtail pro- has developed hypertension, proteinuria or renal gression of these cases to end-stage renal fail- insufficiency. However, there is still much disagree- ure.111–113 ment concerning the indications for anti-reflux sur- Hypertension in this population, however, is cur- gery earlier on in the disease process. There is evi- rently recognised by comparison of blood pressure dence that anti-reflux surgery has helped measurements against the general standards significantly to reduce the number of urinary tract intended for normal population.114 It is very likely, infections but not the incidence of hypertension or therefore, that a proportion of cases who have had other complications.14,22 There is no difference if a a ‘relative’ rise in blood pressure, not reaching a comparison is made between medical and surgical defined level of abnormality yet having a detrimen- management in terms of new scar development or tal effect on the progression of their renal disease the progression of renal scars.118 The Birmingham could be missed. These subjects would, hence, not Reflux Study Group compared operative versus non- qualify for anti-hypertensive therapy (for example operative management of children with gross reflux ACE inhibitors) until a later stage in their condition, over 5 years and concluded that neither treatment when much renal damage might have occurred. This can claim superiority in terms of reducing the inci- aspect has not been previously studied, and may not dence of breakthrough UTI, renal excretory function, be feasible until the blood pressures of these chil- concentrating ability, renal growth, progression of dren are recorded on centile charts as are currently existing scars, or new scar formation.119,120 Some utilised for body weight or height. At least for the suggest that if surgery is to be beneficial it must be time being, therefore, it may be appropriate to con- undertaken very early in life, as renal damage asso- sider anti-hypertensive therapy at least in children ciated with reflux invariably develops in early child- in whom there is evidence of target organ damage hood. Adequate antibiotic prophylaxis, however, such as proteinuria and a ‘relative’ rise in blood could also be equally effective. The complications pressure in comparison to their previous measure- of early surgery, however, especially the later devel- ments. opment of mega-ureters obviously counter balance It is known that the hypertension of reflux nephro- any benefits. Furthermore, the group of patients, pathy can be benefited by nephrectomy.115 Removal particularly males, who have VUR without UTI but of a scarred kidney when the contralateral kidney is associated with renal dysplasia, may not benefit at thought to be normal does not, however, always cure all from anti-reflux surgery. hypertension.63 Moreover, differential renal vein There is no evidence, however, to suggest that renin activity measurements in hypertensive prophylactic nephrectomy is of value in reducing patients with unilateral scarring may not localise the the risk of developing hypertension121 in reflux increased renin release to the scarred kidney and nephropathy, whatever the cause. attention must therefore be paid to the PRA in the renal vein of the radiologically normal kidney. Prevention of reflux nephropathy While the ratio of renal vein renin in the scarred versus the normal kidney may be greater than 1.5 (a Prevention of renal scarring appears to be the only figure that implies localised release from the affec- available method of preventing reflux nephropathy ted kidney), renal injury to the apparently normal associated hypertension, as there are no concrete kidney should be suspected when the ratio of renal predisposing factors or reliable predictive factors vein renin from the normal kidney to that in the that will identify cases at risk. Factors that are of inferior vena cava below the renal veins is increased importance in the development of pyelonephritic as well.116 This is because a pathological renin drive scarring include youth,7,122 reflux,123 the character of from the apparently normal kidney is not sup- UTI and the number of pyelonephritic episodes.124 Reflux nephropathy and hypertension CDA Goonasekera and MJ Dillon 501 Prevention of the development of renal scars in VUR Recommendations will, therefore, depend on early identification of patients at risk, ie, infants and children after the first It is clear that reflux nephropathy needs lifelong UTI, siblings and offspring of affected individuals, follow-up as associated complications including as well as the aggressive treatment of UTI,87,125 mini- hypertension can ensue at any age. What is not clear misation of intra-vesical pressure as well as edu- is whether children with VUR but no demonstrable cation of parents, physicians and patients. scars radiologically are free of the risk of hyperten- There are no major studies at present that are sion since radiological normality does not necessar- directed at improving the ability to prevent this dis- ily mean normal kidneys. ease. There is a wide diversity of opinion concern- Hypertension when present, should be thoroughly ing the approach to be taken. For instance, there is investigated to exclude other pathologies such as no clear protocol for the identification and manage- renovascular disease especially in the presence of ment of siblings or offspring of affected subjects, that unilateral scarring. Renal vein renin studies may be might play a role in preventing reflux nephropathy helpful in some cases when deciding upon surgical especially in infancy. Such a programme might be treatment, but do not necessarily guarantee that the of paramount importance and lead to a reduction of therapy will be curative. There are no definite fea- late complications such as hypertension and renal tures in reflux nephropathy that will identify sub- failure that would far outweigh the costs of jects at increased risk of developing hypertension implementation. On the other hand there is strong and therefore, unfortunately, regular follow-up criticism of this timed invasive approach, including remains the only means of recognising subjects who resistance toward the extensive investigation of girls may require treatment. at their first UTI (excluding infants), in view of it The levels of blood pressure that enhances pro- not being considered to be cost-effective.126 Ante- gression of renal damage in reflux nephropathy are natal scanning may identify some subjects who may currently obscure. The existing definitions are go on to develop renal scars and although not that empirical and further studies are necessary to obtain sensitive offers some hope for early detection. new definitions, perhaps based on relative rises in Prevention of VUR, on the other hand is more blood pressure, so that early interventions can be complicated. The familial aggregation of some cases initiated. has led to the belief, already referred to, that primary VUR is probably associated with a single dominant gene. Although initial investigations by linkage References analysis have been made, there are no clues to the 1 Smellie JM, Normand C. Reflux nephropathy in child- 127 location of the gene yet. However, identification hood. In: Hodson J, Kincaid-Smith P (eds). Reflux of the VUR gene, although helping to prevent some Nephropathy. Masson Publishing Co Inc: New York, morbidity of this condition (by intensified focus on 1979, pp. 14–20. prophylactic measures) and unnecessary investi- 2 Burger HR. 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