DISEASE OF THE MONTH J Am Soc Nephrol 9: 2377-2383, 1998

Reflux Nephropathy

MICHAEL J. DILLON and CHULANANDA D. A. GOONASEKERA Renal Unit, Great Ormond Street Hospitalfor Children and Department of Nephrourology, Institute of Child Health, London, United Kingdom.

Reflux nephropathy is a term that was proposed in 1973 by renal scarring is often present with an increasing incidence Bailey to describe the coarse renal scarring of one on both with age; 10% in preterm infants (15), 26% in children under kidneys associated with primary vesicoureteric reflux (VUR) 8 yr (16), 47% in children older than 8 yr (16), and 94% in and urinary tract infection (UTI) ( 1) (Figure 1 ). It was intended adults (14). There are also data pointing to a relationship that this would replace the older terminology of “chronic between the degree of VUR and the extent of the scarring atrophic pyebonephritis” that had been used for many years and (17, 1 8), although there is some disagreement on this issue wrongly implied that there was a continuing bow-grade infec- (19,20) and between the degree of scarring and the delay in the tion present in affected kidneys. The presence of primary VUR diagnosis of UT! and the total “pyebonephritic” episodes and UTI without urinary obstruction would appear to be pre- (21,22). It would seem that scarring is predominantly some- requisites for this definition, but the situation is not simple. thing that is identified or develops in younger subjects (<5 yr) Acute pyebonephritis followed by renal scarring has been re- (16,23). Hodson (24) estimated that the prevalence in the ported in the absence of demonstrable reflux (2,3), emphasiz- population was of the order of 1 in 250. New scars can develop ing the robes of bacterial virulence and possible host defense with time (2,25,26), and there is a link with recurrent UTI, factors in its development (4). In addition, there is evidence especially involving the upper tract (25,26) and also with supporting the view that renal scarring with reflux can occur in certain bacterial pathogens (27). Although females predomi- the absence of infection, particularly in infants in whom pre- nate in the available data concerning reflux nephropathy, there natal hydronephnosis and VUR had been demonstrated and is evidence pointing to proportionally greater numbers of males postnatabby scars identified (5-9). Furthermore, renal scarring having severe scarring associated with complications such as with VUR is well recognized in subjects exposed to functional renal failure (28,29). on anatomical bladder outflow obstruction adding another com- ponent to the terminobogicab confusion that surrounds this Genetics subject and which has hampered attempts at understanding the There is increasing recognition that VUR has a familial pathogenic mechanisms involved and interpreting long-term component. Linkage with HLA antigens or haplotypes has follow-up data. What would seem to be clear is that there is an been demonstrated in some studies (30). Segregation analysis association between neflux nephropathy and primary vesi- has pointed to VUR being inherited via a single dominant gene coureteric reflux in the majority of cases but that there is a need perhaps acting together with random environmental effects to distinguish between acquired postnatal and congenital pre- (30,3 1 ). Gene frequency has been estimated at 1 in 600, prob- natal scarring and to separately consider scarring in association ably the most common dominantly inherited disease in hu- with obstruction. mans, and new mutations seem unlikely as predicted by the

above segregation analysis computer model (3 1 ). Other studies Epidemiology have also suggested a dominant pattern of inheritance, with The incidence of reflux nephropathy in the population is by 50% of siblings of index cases having VUR (32,33) and a risk definition closely linked to that of VUR. The data are limited of 1 in 2 for VUR in offspring of an affected parent (34). but evidence points to the incidence of primary VUR in the In view of the well recognized association of VUR with general population of 0. 1 to 1 % ( 10, 1 1), although the incidence other conditions including prune belly syndrome, ectrodactyly- is much greater (12 to 50%) in children, predominantly white ectodermal dysplasia-clefting syndrome, coboboma-ureteral- girls, presenting with UTI ( 10, 12). There is some evidence that renal syndrome, Robinow dwarfism, chromosome abnormali- black girls with UTI have a bower incidence of VUR than their ties of short arms of chromosomes 8 on 10, Hirschsprung’s white counterparts, although this is disputed. In the majority disease, and Apert’s disease, attempts have been made to (80%), VUR resolves with time and hence is most frequently clarify whether genes associated with some of these conditions manifest in childhood (13,14). At the time VUR is confirmed, might be candidates for the VUR gene (35,36). It is known that PAX genes are expressed in the developing kidney, optic cup, optic vesicle, and central nervous system, Correspondence to Michael J. Dillon, Nephro-urology, Institute of Child Health, 30 Guilford Street, London. United Kingdom WC 1 N 1 EH. and in the kidney are expressed in the metanephros in cell l046-6673/09012-2377$03.00/0 lineages that are destined to differentiate into the ureter, renal Journal of the American Society of Nephrology pelvis, and the branching collecting duct system (37,38). It is Copyright 0 1998 by the American Society of Nephrology also known that in PAX-2 “knockout” mice, impaired meta- 2378 Journal of the American Society of Nephrology J Am Soc Nephrol 9: 2377-2383, 1998

terms of scarring some description is relevant. Hitherto, renal scars have been detected by intravenous urognaphy (IVU) with the characteristic appearance being focal parenchymal thinning of the renal parenchyma and corresponding calyceal deformity or clubbing (43) (Figure 2). Varying degrees of scarring may be detected from single polar lesions to more extensive in- volvement and in some cases small shrunken kidneys with little or no function. IVU evidence of scarring, however, may not be evident for some period of time after an initial causative pyebonephritic episode in those cases of acquired disease (44). More recently, the widespread use of 99MTcDMSA (dimer- captosuccinic acid) scintigraphy has replaced the IVU for the detection and assessment of renal scans (45,46) (Figure 3). Advantages over the IVU include the provision of a quantita- tive assessment of differential function, reduced radiation to gonads, absence of contrast-induced reactions, and avoidance of the problem of poor visualization of the kidneys due to overlying bowel shadowing. There is evidence of increased sensitivity and specificity compared with the IVU in detecting scars (46) but it must be borne in mind that the two techniques have different physiologic bases. DMSA is bound to the renal tubular cells and gives an image of functional tubular mass, whereas the IVU uses the excretion of contrast that in imaging terms provides structural information.

Pathogenesis In considering the pathogenesis of renal scarring, it is es- sentiab to distinguish between the common acquired segmental scarring associated with VUR and infection and the primary “scarring” seen congenitally in which the etiology is very different and linked to abnormal metanephric development (7,8). It is considered that acquired scarring is a sequel to an Figure 1. Macroscopic appearance of kidney with refiux nephropathy. episode or episodes of acute pyebonephritis caused by infected urine, in the presence of VUR entering the collecting ducts of the kidney via so called “refluxing” papillae (47). The immune nephric growth, decreased nephron number, and megaureter and inflammatory responses that this induces is followed, on consistent with gross VUR and blindness occurs (37,38). Mu- resolution, by interstitial damage and ultimately the develop- tations of the PAX2 gene have been identified in a family with optic nerve cobobomas, renal anomalies, and VUR (39,40), but not in patients with primary VUR (35,41). Furthermore, other key nephnogenesis genes such as KGF receptor (FGFR2) and the GDNF receptor (RET) that, like PAX-2, are expressed in the developing ureter and are located on the bong arm of chromosome 10 (l0q) have been excluded as candidates for familial VUR (4 1 ). These data suggest that VUR in humans is genetically heterogeneous. However, in relation to scar formation in RN as opposed to VUR itself, there is some evidence for a role of angiotensin-converting enzyme gene polymorphism (42). D allele homozygosity in this study introduced a ninefold risk of scar development in children with VUR.

Diagnosis It is not the purpose of this review to elaborate in detail on the investigative procedures for detecting the presence of UT! or VUR, although these are clearly important in the develop- Figure 2. Intravenous urogram showing focal thinning of renal pa- ment of renal scarring in the majority of cases. However, in renchyma and calyceal clubbing in refiux nephropathy. J Am Soc Nephrol 9: 2377-2383. 1998 Reflux Nephropathy 2379

Figure 3. 99MTc DMSA scan showing multiple areas of deficient isotope uptake coinciding with renal scars (courtesy of Dr. I. Gordon). Figure 4. 99MTc DMSA scan showing small smooth right kidney in a child with prenatal vesicoureteric reflux and “congenital” scarring ment of scar tissue in the affected segment of the kidney (4). (courtesy of Dr. I. Gordon). From animal work evidence has emerged pointing to the need for infection in addition to reflux for this process to occur, although in an obstructed system scarring can develop with series (52-54). It is the most common cause of severe hyper- sterile neflux (48). The histologic findings of this form of reflux tension in childhood (55,56). In adults, the prevalence of nephropathy are: interstitial infiltration with chronic inflamma- hypertension in reflux nephropathy is much higher (38 to 50%) tory cells, tubular basement membrane thickening, epitheliab (14,57-59). Malignant hypertension due to neflux nephropathy cell atrophy, collapse of tubular lumen, dilation of other tu- is uncommon but has been reported in younger children and bubes with atrophic epithelium, eosinophilic casts, medial and adolescents (60) and also in women with reflux nephropathy intimab thickening of arteries and arterioles, perigbomerular taking oral contraceptives (61). There is a higher incidence of fibrosis, collapse and hyalinization of glomerular tufts, and hypertension in pregnancy in the presence of maternal reflux compensatory hypertrophy in adjacent unscarred renal tissue nephropathy and at this time sometimes clinically latent reflux (49). It is important to emphasize here that the histopathobogic nephropathy is manifested (58,62,63). Hypertension secondary profile of this type of scarring contains no dysplastic features to reflux nephropathy at time of conception increases the risk that are characteristic of the “congenital” reflux nephropathy of fetal death four- to fivefold (63). that would appear to have a different etiopathogenesis (7,8). On the other hand, “congenital” neflux nephropathy is found Risk Factors for the Development of Hypertension predominantly in boys in whom there has been evidence of The risk of developing hypertension in reflux nephropathy prenatal VUR and the affected kidney appears small and appears to be highest during adolescence and adulthood smooth (7,8) (Figure 4). It seems likely that these small kid- (29,53,59), although one group reported an absence of hyper- neys are similar or identical to the hypoplastic kidneys with tension (64). This study, however, only followed patients for a dysplastic features reported by Hinchliffe et al. (50) and the mean of 9.6 yr. which may have been an insufficient period of congenitally small kidneys associated with VUR described by time for hypertension to become manifest. The much higher

Hinaoka et al. (5 1 ). There is no clear association with urinary prevalence of hypertension in adult subjects is, on the other infection in affected children, and histopathobogically the char- hand, difficult to assess due to confounding factors such as the acteristic feature is of anomalous metanephnic development increasing risk of essential hypertension, oral contraception, (7,8). The renal dysplasia identified histologically in the kid- and the development of renal insufficiency. neys reflects intrauterine mabdevebopment as an important eb- Gender has some role in the development of hypertension. In ement in these boys (8). However, in addition, there was in a spite of the higher incidence of reflux nephropathy in females, number of patients evidence of segmental scarring as seen in males, proportionally, have a higher risk of hypertension as acquired renal damage, indicating that these kidneys may also well as other complications such as proteinunia and renal be subject to infection-associated pathology in postnatal life failure (29). (8). The degree of reflux and the degree of scarring would appear to be related to the development of hypertension (57,58,65), Hypertension but hypertension can occur in the presence of unilateral scar- Hypertension affects approximately 10% of children with ring (60,65) and may be present regardless of the degree of renal scans, although figures vary (5 to 27%) from series to scarring (66). What is clean is that hypertension, when present, 2380 Journal of the American Society of Nephrology J Am Soc Nephrol 9: 2377-2383, 1998

accelerates the progress of renal failure in reflux nephropathy ficiency. Jacobson et al. (59) followed 30 patients from child- (10,53). Histologically, the finding of focal segmental gbomer- hood for 27 yr by which time three (10%) were in end-stage ubosclerosis is significantly associated with hypertension (67). renal failure and 27 (90%) had GFR and renal plasma flow Whether this is due to the degree of renal scarring causing levels that were less than those of healthy control subjects (59). hyperfiltration of remaining nephrons or some other mecha- Another bong-term study undertaken by Zhang and Bailey (57) nism is not clear, but the association exists. of 294 patients (mean age at presentation 17.3 yr; SD 14.4 yr) reported six (2%) patients with renal insufficiency at presen- Renin-Angiotensin System tation but 71 (24%) at follow-up (mean age at follow up 34.2 The nenin-angiotensin system has for many years been im- yr; SD 13.7 yr). In this study, proteinuria and renal insuffi- plicated in the genesis of hypertension in reflux nephropathy. ciency were significantly more frequent in those with severe A number of studies measuring peripheral plasma nenin activ- bilateral reflux (57). ity (PRA) point to a contribution from the renin-angiotensin system to hypertension (60,68-73), but others claim that there is no evidence to support this (74,66). Long-term studies have Etiology shown that with time, PRA standard deviation scores as well as The etiology of chronic renal failure in reflux nephropathy is blood pressure standard deviation scores, in children with incompletely understood. Progression is usually associated reflux nephropathy, increase during childhood and adolescence with proteinuria (78-80), and hypertension has usually been a with some reduction in early adult life (60,71-73). No direct feature at some time during the clinical course (79). Pregnancy, correlation between PRA and blood pressure could be demon- particularly with hypertension and some reduction of renal strated, but the findings suggest a dissociation between blood function early on in gestation, is associated with the risk of pressure and renin in reflux nephropathy with age (75). further deterioration (8 1). Most patients with reflux nephrop- Additional studies have identified localized regions of renin athy and renal impairment have proteinuria associated with release that coincide with scarred areas in affected kidneys on gbomerulosclerosis on renal biopsy or on nephrectomy histo- renal vein renin sampling (70), but others have disputed this logic examination (79). Focal segmental gbomerubosclerosis observation (74). has also been identified in contralateral unscarred kidneys in Histopathobogically, the scarred areas of kidney are associated unilateral disease, suggesting a robe for a humoral factor or a with arterial damage and it would not be unlikely that this might hyperfiltration phenomenon (82). Focal segmental gbomerubo- lead to segmental ischemia with resulting renin-driven hyperten- sclerosis has also been demonstrated fairly consistently in sion (76). However, it has been noted that not all patients with a pediatric nephrectomy specimens from children with reflux high plasma renin are hypertensive (71), and in some patients nephropathy in which there would appear to be an association plasma renin reverts to normal spontaneously (72). Whether this is with hypertension and also between hypertension and the de- due to the complete loss of blood supply to scarred previously gree of proteinuria (67). ischemic areas of kidney with cessation of renin release or some Several mechanisms have been proposed to explain these other explanation remains unclear. Peripheral renin measurements findings, including immunologic inj ury, macnomolecubar trap- are, after all, very crude guides for nenin activity at the tissue bevel ping and mesangiab dysfunction, vascular alterations with boss and need to be interpreted cautiously (77). of blood vessels plus hypertension, and adaptive hemodynamic alterations leading to gbomenular hyperfiltration (28,83). Al- Other Factors Contributing to Hypertension though the hyperfiltration theory (83) has been favored for Other factors that might play some part in the development some time, there is now a feeling that altered intrarenal and of hypertension in subjects with reflux nephropathy include gbomerubar hemodynamics possibly mediated through the reduced production of renomedublary vasodilators; hypervol- renin-angiotensin system may play an important role (84). emia with renal impairment, especially with bilateral but not unilateral scarring; circulating ouabain-like inhibitors; and a genetically determined predisposition to develop essential hy- Management pertension. Data from studying intermediate phenotypes, how- Infection and VUR ever, and gathering family histories of essential hypertension It is not intended to enter into the complex and heated have failed to identify, thus far, any associations. arguments that are associated with the management of UT! and the issue of whether reflux prevention surgery should or should Renal Insufficiency not be undertaken in children with VUR. Suffice it to say that It is well recognized that reflux nephropathy is a cause of evidence available thus fan from several national and interna- renal impairment and indeed end-stage renal disease. Data tionab studies and trials has not shown significant differences in from North America, Australia, New Zealand, and Europe terms of new renal scars, new areas of parenchymal thinning, have shown that between 5 and 12% of patients entering progression of existing scars, or renal growth between patients end-stage renal disease programs have neflux nephropathy. treated medically (with prophylactic urinary antiseptics) or Long-term follow-up studies of patients with reflux nephrop- treated surgically (ureteric reimplantation) (85- 87). There are, athy have also shown significant numbers entering end-stage however, data showing that new scar formation is associated programs, as well as manifesting lesser degrees of renal insuf- with breakthrough infection (88). J Am Soc Nephrol 9: 2377-2383. 1998 Reflux Nephropathy 2381

Hypertension mediate affect on the boys with prenatal hydronephrosis, VUR, Adequate control of hypertension is considered one of the and scarring before birth. most useful measures in reflux nephropathy with not only the immediate benefit of controlling the blood pressure but also with the potential to curtail the progression to end-stage renal Acknowledgments failure (89). In this context, use of angiotensin-converting Dr. Goonasekera was supported by John Herring and Friends Fund enzyme inhibitors, especially if there is evidence of extensive (Child Health Research Appeal Trust). scarring and proteinuria, may have an especially beneficial role (90). In circumstances in which hypertension is severe and difficult to control, nephrectomy may have a place if disease is References lateralized (e.g. , a small scarred kidney on one side but a 1. Bailey RR: The relationship of vesico-uretenic reflux to urinary normal unaffected contralateral kidney) (9 1 ). However, be- tract infection and chronic pyebonephnitis-reflux nephnopathy. cause disease is so often bilateral, this approach needs caution C/in Nephrol 1: 132-141, 1973 since the cure of hypertension may not be achieved (66). 2. Smellie IM, Ransley PG. Nonmand ICS, Prescod N, Edwards D: Uncontrolled increases in blood pressure can certainly cause Development of new renal scars: A collaborative study. Br Med J marked deterioration of renal function; hence, there is a neces- 290: 1957-1960, 1985 3. Bisset GS, Strife IL, Dunbar IS: Unognaphy and voiding cys- sity to regularly monitor bevels of blood pressure throughout tourethrognaphy: Findings in girls with urinary tract infection. life whether hypertension has been detected or not. Am J Roentgenol 148: 479-482, 1987 4. Roberts IA: Mechanisms of renal damage in chronic pyebone- Renal Impairment phnitis (reflux nephnopathy). Curr Top Patho/ 88: 265-287, 1995 Management of renal failure in reflux nephnopathy needs 5. 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