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).