CHAPTER 25 Reflux Nephropathy J. MICHAEL ZERIN In 1973, Bailey and Heale and colleagues introduced the term “reflux nephropathy” to provide a more precise and scriptive namie for the condition that had previously been now as nonobstructive chronie atrophic pyelonephritis « and to emphasize the critical role of vesitoureteral relax (VOR) in its pathogenesis. Since that time, reflux nephrop- athy has become # commonly vsedterm* and tf mets descriptive than its predecessor. However, despite its em. hasis on the role of VUR—or possibly because of it it Is to stress the equally critical role of bacterial infection of the upper urinary tract in the pathogenesis of this dis. case, Henes, in its general urage th trm “res neg. athy” has unfortunately evolved to encompass a variety of forms of renal injury that occur in patients who have-or have had-—VUR, including both those who have had docu mentédepisodes of urinary tract infection (UTI) and those who ave not 2 Although it is true that UTI is not a factor in the thoggnes fall ronal abnormal that are sen in patieptS-avhovliave VUR, renal injury is significantly lese Connon the presence of sterile refs and the rie sf any—ofssterile reflux in the pathogenesis of such renal abnonnelivies is more poorly understood. High-grade VUR can have a deleterious effect on renal growth, particularly when it coexists with elevated pressure in the bladder ™ In children in whom renal carting and atrophy do develop in the absence of documented symptomatic UT, the refi is usually associated with other conditions—suich as ob- structive uropathy, neurogenic dysfunction, or “non-neuro- gente viding function that are emscver soared with an inereased risk of bacteriuria." which leaves open the possibility that such children might have been subject to recurrent, albeit undocumented UTI. Similany, “asyinp- tomatic” children who are screened because they havera sibling with VUR and are then discovered to have both VUR and reflux nephropathy might also have had subetini- cal infections that for whatever reason were never diag. nosed "© This presumption cannot, of course, be proved. The situation is more uncertain in the fetus and neonate with VUR and coexistent renal dysplasia, unilateral renal agenesis, multicystic dysplastic kidney, or ureteropel- Vic junetion abstraction, in ibm UTI canoes bee aes 2-28 However, in such patients, a causal relationship be- tween VUR and abnormalities in the upper urinary tact ‘may not in fact exist. PATHOGENESIS OF REFLUX NEPHROPATHY Reflux nephropathy is an aoquired disorder that results froma Sequense of evens that is usualy inated easy te infancy oF childhood. toss 2. Bacteria-laden urine that has reached the calf 1 The fist and essential event in the pabiogeistof rellux nephropathy isthe introduction of featlegas bacteria (usually Escherichia cot) from the patent own fecal reservoir into the lower urinary bess Infection that is limited to the lower uth at Coys") poses litle if any visk of renal parenghytnl fai Tn chlren who alo hve VUR, bce om ¢ transported to the upper-urinary tact dashes wave of reflux of infected urine from the blader Thus VOR isthe primary mechanism by which cts Hal infection Sn the lower urinary tract van to the renal parenchyma, VUR may not, howe the only mechanism for transport of bacteria to the "upper urinary tract in ascending pyelonephritis-Acute cortical defects consistent with acute ‘pyelonephritis can be demonstrated during renal cereal Rite ‘graphic scans using technetium-99m-labeled:Aimer- caren sid (SDMA) of agnet nance imaging (MBI) in some. children wl clinical findings suggesting act renal nfo Bot Jn whom VOR cannot be documented at Wiig cstourethrography (VCU). #2 Hematiiengas issemination of infection to the ldney san te able explanation for this observation given the ab sence of bacteremia in most infants and childradiylith aonreflux pyelonephritis. Whether this abide" WOR nes ht ree ey mechanisms other than reflax-by which bacters ean ascend to the upper urinary tract or simply thateyCU does not detect all cases of reffx has not beentddler- mined. However, this latter ditineton cur little practical significance because the risk oft scarring after acute pyelonephritis appears i tame roars of wher flab Preset thermore, a mechanism by which the bacteria are nonmobile oa their own—might be fiom the lower urinary tract to the Kidne absence of VUR has not yet been identified. gain acces to the medullary parenchyma of ‘dual renal lobes through incompetent pa orifices. This phenomenon is commonly ref as “intrarenal reflux.” Hodson and cole that papillary incompetence ours most compound pyramids * Compound medley are more frequent in the fenal poles. As acate ascending infection of the renal pls (acute baceral pyelonephritis) typieay tora lobar dation ahi the aie Because ofits characteristic lobar distributionfield and coworkers referred to ascending infection in the kidney as “lobar nephronia,” analogous to “lobar pneumonia.” The papillary duct orifces are incom: petent more frequently in infents than in older chil- Gren and adults.* 4, When acute teal infstion is untreted o when the initiation of antibiotic therapy is significantly delayed, Se eae eyed crete etciee and even populations of nephrons ean oceur:+* When the change are fea, a they frequently are esl in the progress of reflux nephropathy, the scar appears es a focal area of cortical thinning producing an inwardly sof | conver groove or valley in the renal contour overh sme | SRE ie (hig a541) With opened episodes nts of infection, the volume of remaining Functional renal ae tissue ean be depleted, Ifthe extent of parenchymal vact destruction is sufficiently severe, renal insufficiency wal can result. Over time, physiologic stresses on the cn remaining intact nephrons, such as hyperfitration, fan in tim lead to focal glomerular sclerosis and secondary systemic hypertension. ‘The occasional presence of scars in children who were ead | hing investigated for the first time because of recent UTI hy [pts led some to erroneously conclude that the scars in she I patients with reflux nephropathy are congenital rather than fcqited, Although it is true that the existence of these sas. cannot be.explained by a single, recent infection, it EELS Give fat in avy clon oth their UT, this infection was often preceded by one or more sibclinigal episodes of bacteriuria ™ When it was first de- tebed in, 1099, the so-called Ask-Upmark kidney, for ex- ample, was thought to be a specific type of congenital FIGURE 25-1 + Drawing of a left Kidney with postinfectious coral ‘St. the mide porn of the lidney, everson (dubbing) of the [pound ealyees and thinning ofthe overlying renal parenchyma result 8 4 groove. or valley when the adjacent renal lobes are unaffected, When the process affects the uppermost (or lowermost) renal lobes, the Feely ovet the distorted calyx is thinned, but no groove or valley present because only one side has sa adjacent renal lobe. 26 Refix Neghropathy «++ 1089 FIGURE 25-2 + Draviog of left Kidney. The abnormal teas ofthe Kidney bear a striking setemblance to tho focal renal scars of refx sephptyStedy cenle of inee ie Compa ith Fig 2) (Modifed fom AskUpmark E: Uber jovenlle maligne feghvolevoee und ih verti er toruagon Inder nerenentwekhang, ‘Kea Pathol Microbiol Soand 6:85, 1920.) : segmental: renal hypoplasia that was-seem in-youing women ‘with. renal: insufficiency. and hypertension’ (Pig. 25-2). However, itis now clear-that this conditionémerely: repre~ sents an advanced stage’of reflux nephropathy.» Simi- larly, the presence’ of reflux in a’neonate-or young infant ith imaging Endings of renal dysplasia or~ renal Tnfsreoof¢ eample, from renal ven thombeosts—bas Ted to confusion with reflux nephropathy. The coexistence of VUR with renal dysplasia—with or without coexistent obstruction—has been much more commonly recognized since the introduction of antenatal sonography.!*#-#® How- fever, renal dysplasia and renal infarction are both. histo- pathologically distinguishable from refx nephropathy, onlsr carpi hve been seen of normal Klaeys becoming scarred, often in children as old as 7 years of age" (Figs. 25-3 and 25-4). Without infection, focal scar- ring does not occur (Fig. 25-5). Once the scarring process begins, however, several years may pass before fibrous ‘tation becomes complete. Maturlon of a scar should not be mistaken for continuing infection. Histological ex- Mnation of the mature sear of course, wil show no Sgn of an acute inflammatory reaction. RISK FACTORS FOR URINARY TRACT INFECTION ‘The risk of UTI developing in an individual child is related to an imbalance between “host resistance”—that is, the resistance ofthe host to becoming infected —and “bacterial virulence" —that is, the virulence of the bacterial species that colonize the lower urinary tract™ (Fig. 25-6). Tn this context, the term “virulence” {s not used to imply that the bacteria are extremely poisonous or that they cause a dis- ease that has an unusually rapid, severe, or malignantFIGURE 25-3 + So logend on oppavte pagecourse, Instead, “virulence” is used simply to indicate that rtain bacteria possess properties that allow them to more ssossflly overcome host defenses Host Resistance Many specific and nonspecific host resistance factors ot defense’ mechanisms protect the childs Iidney from bacte- tal infection, Gender and age are both vefy Important ary in life, UTI occurs as often in boys as in gis. After A'months of age, infection becomes dramatically more common in gils—up to four to six times more common, "the bacteriological makeup of the fecal flora is very injortant in regard to the likelihood of UTI developing Gilden who are susceptible to colonization of thelr fees and tht ower unary tact ty vine btn are more likely to acquire symptomatic UTI than are those tho do not harbor such bacteria in thelr eolonie floras” © On the other hand, colonization ofthe lower urinary tract ty nonvirulent bacterial strains that compete with, more trulent strains for nutritional resources and urothelial binding sites may actualy be protective in some children © Tis phenomenon is reerred to as “asymptomatic Bacter- tin" Because the colonizing bacterial speties inthis cond ton are."protective"—that i, they ae incapable of tnvad- ing the -urothelium and therefore ‘cannot produce true incon treatment with antibiotis: ean be fllowed by the emergence of more virulent strains that are capable of producing symptomatic infection. The reasons for individual differences in susceptibility to colonization by different bacterial species have not been completely elucidated. The levels of specie vaginal anti- fody levels, urine pH, and urine protein and nutrient content all influence bacterial vabiiy, Specie antibodies tthe bacterium or its adhesin (see later serve to protect the host agnnst bacterial colonization or invasion, ‘These nay be a spectrum of the hosts ability to mount an anti= body response. Girls who have lower levels of vaginal IgA sppear to beat greater risk for repeated UTIL" ta young Ents, the immune defense system is immature, whic ‘ay in part explain the susceptbiltyof infants and young Ahilren to bacterial infection and searring ofthe hidoey The human urothelium bears receptors that enable bnc- toi to attach tothe cells ning the lower urinary tract and prevent them from being washed away during cnctartin, These receptors are composed of glycolipids ofthe globo: series © The density of these receptors on the uroepi- thelial surface influences the susceptility to colonization Patients with more receptors (higher receptor density) are 4 groater risk of colonization of the urinary tract by Dacte- ta than are those with fewer receptors. Experimental in- feetions have been prevented by pretreating bacteria with receptor analogues. These receptor analogues in- Refine Nephropathy +++ 1091 terfere with bacterial adhesion to the uroepithelial recep- tors by binding irreversibly with bacterial fimbriae:® This technique has not yet found clinical application Periodic, complete emptying of urine from the urinary tract isa very eflective physiological mechanism for reduc ing the frequency and severity of UTI in susceptible indi- viduals: * Abnormalities that impede the normal ante grade flow of urine can be associated with more severe or refractory infection that is more likely to result in perma- nent injury to the renal parenchyma. Abnormalities that impede antegrade flow of urine can be grouped into three categories 1. Disorders that result in retrograde flow of urine 2. Disorders that obstruct antegrade flow of urine 3. Disorders that are associated with incomplete or infre- quent emptying VUR is the principal example of a disorder that results fn retrograde ow of urine within the urinary tract Ale though the ureterovesical junction lacks.a true muscular sphincter, compression of the submucosal segment of the ureter within the bladder wall—the “submucosal tun- nel’—usually prevents reflux. Over 90% of cases of VUR in children are caused by a primary developmental abnor- malty of the submucosal ureter whereby the ‘ureteral ori- fice is located too far laterally, with consequent shortening of the submucosal tunnel Primary reflux tends to: dimin- {sh in severity in most children as they grow-older. Although the mechanism for spontaneous resolution of primary VUR isnot established, gradual elongation ofthe submucosal ureter as the child grows and the bladder base enlarges seems plausible # VUR can also occur secondary to-defor- rity of the ureterovesical junction, such as by a bladder diverticulum o:ureteroel, and in chidren'with Bader ‘outlet or urethral obstruction or with neurogenic dysfunc- ton or dysfunctional ving * Improvement in secondary rellux depends oa success treatment of the disorder that are causing the reflux. Secondary reflux is generally unlikely to improve spontaneously ‘VUR not only provides a ready-made pathway for bacte: ria in the bladder to reach the kidney but can also be associated with aberrant micturition.® Each time that a patient with reflux voids, only part of the urine passes out through the urethra. The remainder refluxes into the ureter(s) and pyelocalyceal system(s) As the wave of reflux recedes, the refluxed urine rapidly refils the bladder and results in a volume of stagnant urine that remains until the nest voiding, when aberrant micturition will occur again. Bactetial Virulence Bacterial virulence factors are similarly myriad. Bacteria that reproduce more rapidly—some uropathogenic species FIGURE 25-3 + Development of scars. A, Volding eystouredvopram demonstrsting ght grade 4 refx with intrarenal reflux ito the upper renal lobes (eros), B,Intavenoue rogram. The Kdney appears normal wth normal rent {REE elles. CA tena ogre 2 pear ter demonsaes ning of renchyml thickness and normal cays! coafguration in the "end parenchyma and cubbing ofthe eaices in the renal sito which intrarenal efut had previously heen demonstrated (arrow)... Aa intravenous urogram # yenrs ner shows further progression and Aeturation ofthe serrng prover (arrow) The urine wus store thoughout the period of alow C21092 ++ Specie Disorders of the Urinory Tact Ft int of at FIGURE 25-4 + Maturation of sa. A, An intovenrs go ‘ows anormal upper poe ofthe lef dey By An tens hve ee she tthe el prey the upper seal lobe. The sa oie deters cas (rte The precncymel thang exer ily an ately wel. CA nem enous args es show further matsason ofthe ser fre)FIGURE 25-5 + Int anbigvous genitals. al eux without infecton A, Voidng estourethogrim done to évilate the ‘ade 5 relax i prosnt with invarenalreur Into the upper renal lobes (arrows) (compare with Fig Ratu Nephropathy +++ 1093 nce of the ute ian saat with 5-2) B, An [Eraccnous¥arogran 4 sears ter shows tht the right Idney har sontiuad to appear somal In spta of the intrarenal relat because the Chit had ‘eer ad a wy tac nection, of E. coli duplicate as frequently as every 33 min- ties and are hatter in the environment of the host urinary tract are also more likely to be of pathological Significance. Some more virulent species exhibit nutritional natarie croororm \ FIGURE 25-6 + Baliace between hott resistance factors and bacterial Valence factors (Prom Lebowits RL, Mandal Unasy tae fection ‘ebideen: Putting racy ins ple. Radclogy 1651, 1987) advantages over other species, such as an ability to Seques- ter iron ‘Over 90% of cxses of acute pyelonephritis in children ave caused by E. colt strains that possess bacterial wall antigens that bind specifically to the uroepithelial recep- tors. These. antigens markedly enhance virulence by in- creasing adherence to the host's uroepithelium—hence they are called “adhesins"—thereby preventing the bacteria, from being washed sway during micturition. ‘These adhe- sins are often firmbrae (pil), 4** which are fllamentous proteinaceous appendages of the bacterial cell wall. The Inore specific the match between the bacterial adhesins and the host uroepithelial cell receptors, the greater the likelthood that colonization will occur Bacterial endotoxins (lipopolysaccharides) can paralyze the breteral smooth musculature,* thereby impeding uni- dicectional flow of urine and permitting more bacteria to remain in the area, even when the area has fewer adhesin- receptor linkages. Endotoxins may also play a role in tissue Taraye or ten toy once fnvaion has taken place Host-Bacterial Interaction The phenomena just deseribed suggest that reflux nephrop- athy'is a biological system in which the host and the bacterial environment are in constant competition and in which the degree of balance between the two prevents1094 +++ Specie Disorders of the Urinay Tract disease or enables it to become manifested.*" Deficient hhost defenses compensate for fewer bacterial virulence factors, and the most virulent bacteria cause disease in the least compromised host. For example, a resistant host, such as an older child with no VUR, high levels of IgA, and low receptor density who has primenly nonvirulent colonic bacteria, is not at risk. On the other hand, a severely compromised host—for example, an infant with VUR, ine trarenal reflux, low levels of gh and high sce density—is at great risk for infection of the kidney and reflux’ nephropathy, even from bacteria with fewer viru- lence factors. A partially compromised host—for example, fan infant with high receptor density but no VUR—inay acquire renal infection, but only when colonized by a vin. lent strain of bacteria Practical and theoretical methods exist for interfering with this natural model at many levels. The most important method is treatment of the acute UTI with an apprepriate antibiotic in therapeutic doses and for an appropriate length of time; Treatment beginning soon after the onset of symptoms appears to abort the scarring process in the kidney. Conversely, treatment that is delayed for more than several days, although effective in sterilizing the urine, will not prevent soars.® ‘A variety of mothods exist for interfering with bacterial adherence, (Fig. 25-7): jgiven in sub-bactericidal doses, some antibiot- ‘prevent colonization of the lower urinary tract—and thereby also UTI—by interfering with the tie of baealsdhenas = Sorin ne ‘bictiestherapy is very effective in reducing the fre- ‘Gllehcy Ol bacteriuria end is currently the standard “ethod for preventing bacteriuria in children who have VOR 2. Host’ antibody (IgA) molecules seem to be able to FIGURE 25-7 + Diagrammatic representation of known methods for meri wth cel teres ht eh ci, eee a pathogenic bacterium (shaded) to «hort urotell ell roeptr ean be blocked by antibody, competing nonpathogenic bacteria (rot shaded), thet receptor analogies, o interference with the syathesi of fin briae Cantbi elac) (From Labowite RL, Mandel} Uri tact feta acre: Puting rly in pe. Ral 165, 187 block the adhesin-oceptor linkage in vivo, ay thetic receptor analogues have been shown to bey the process in vitro (See earlier discussion) Hos fit practi therapeutic application of this prea as ot yt been develope 8. Competing nonvirulent bacteria can attach to epithe Tal el receptor ses and thus prevent indo dia from. attaching. However, this method also qtr, rently has no clinical application in practice. THE DIAGNOSIS OF ACUTE URINARY TRACT INFECTION IN CHILDHOOD. ‘The diagnosis of UTI is made when a significant nub of 4 single strain of pathogenic bactera—usually E colts cultured from the urine of a child who has signs or symp. toms of infection. ® Unfortunately, both underdiapaoee and overdiagnosis of UTI are comon, Overreliaee on cultures of contaminated urine specimens or on urinal and clinical symptoms alone (without culture) i the most ‘common reason. Catheterization and suprapubic epiation of the bladder are the most reliable methods for eblaiing an uncontaminated specimen of urine in a childe © Suprepbie apron sly done baie ina However, pediatricians and_parents alike are ao often hese to atheteize acl to obtamn a vel spe of urine for culture. Specimens that are obtained from Jnfants by collecting urine in « plastic bag that Bas been Se lige spate bg ta routinely contaminated and the procedire should be sot be used in screening for UTI The reliability of clean- catch” specimens increases with age, probably related to improved attention to technique. However, in uncreum- ised boys and in girls who have vaginal reflux, uncoatami- rated “clean-catch” specimens can be impossible to ab- tain‘ Tt should be emphasized, however, thatthe fat that an episode of bacteriuria was poorly documented does not necessarily imply that it did: not occur * Moreover children who have had poorly documented UTI—or even ‘no UTI—can still occasionally have reflux and other urolog- ical abnormalities. For this reasont is generally pradeat for the radiologist to evaluate the child once a diagnosis of UTI has been made, even if documentation ofthe infection is inadequate. Uroradiology ‘The scats of refhac nephropathy typically develop'in 4 *@ 6 months and, when unsomplctc, have anaes imaging features. In the past, excretory urography Ws &2 pamary ‘modality used for both diagnosing reflux nephip>®™ thy and monitoring such children. The typical exe") rpgaphic image i acd with refs nephropah a deformed (“clubbed”) calyx with thinning of the aegvr renal parenchyma? (Fig, 25-8). This abnormality pruae ‘noch or valley oth surface of they tel opposite tlie affected calyx, except in the extreme Fal regions. In these latter areas—the most medial upPE! lower renal lobes—a notch may not develop becat one adjacent normal renal lobe ie proses, tilFIGURE 25-8 + Renal sur shown. by intravenous wrograply. A, Focal notch or {Roove (arrow) adjacent ton deformed calyx onthe wppen outer pect ofthe ley nly thi rnd lobe i alfected. B, Thining ofthe venal parencnma adjacent to 8 Atoried enipe in the uppermos renal Ibe (arrow). C, Tunaing of the renal parenchyma adjacent tot deformed cab inthe oper medial portion ofthe Te ey Cameo). ena parenchymal thickness on the upper redial spac of the Ie ney Is much les then inthe sue region onthe right. The upper tafundbulom td caer on the lel have changed thee orientation (as compared th the same Felon on the righ because ofthe los of surounding renal parenchyns and e Reflux Nephropathy + ++ 1095 {IRL Mons relation ofthe sexy proces ghing the smpeesson af "medal dng” ofthe eajers. D, Focal, lobar sears resulting in grooves or retchesaljcent to defored chi) eajees shown on the weplvogeim phason the ena aresogrum (aro1096 ++ + Specie Dorders ofthe Urinary Tro nal pole may appear truncated, The scars are typically Larger cortical sears are usually readily demonstrated song lobar in distibution because of the ascending nature of graphically, ulthough smaller seas are less well visu tle the infection and are focal—th d is, normal renal lobes are sonographically than with either excretory urographyé**" usually found immediately adjacent to the affected lobes =DMSA2 isee Figs, 25-1 and 25-8 to 25-10), Careful comparison of measurements of the lengths of Although excretory urography was primavily used in the the kidneys both with published normative standards aa past, it has been almost entirely replaced by renal ultriso- with measurements froin earlier examinations in the same nography both in screening children with UTI and in moni-_ patient cannot be overemphasized because they can be toring renal-growth and morphology in children who have key indicators in suggesting the presence of generilzel VUR®# (see Figs. 25-9 and 25-11). Scintigraphic renal parenchymal thinning, even in the absence of visible focal imaging with ®*Te-mercaptoscetyltrighcine (or “*Te-la- scarring" (Figs. 25-11 and 25-12). During episndes of beled dethylenetsamine pentacetic ai) is used fo eval, acute renal parenchymal infection, before sas develop the uating renal function and urinary tract obstruction,# and Kidneys frequently appear normal at gray-scale sonography scinugaphic renal cortical imaging with “Te-DMSA 's Lobar or goeralied renal enlargement can ocour eee or evaluating sonal cordon searing" "==" (Fig. at t inflammatory edema id is often subte ™™ By taf 0), thls Bding is nongpectse although it canbe suggete of Although both computed tomography (CT) and MRI pyelonephtis in. the proper clinical setting. pare ‘ean also provide excellent anatomical and functional infor- when cortical echogenicity is abnormal or suggestive. of tation in children who have reflux nephropathy, they play segmental or lobar involvement. = e little if any part in the diagnosis oF follow-up of such Segmental or lobar reduetion in pesfusion and excretory childzen, fonction within the infected area(s) of the kidneys is inore Ultrasonography is not without its Imittions, however. specific for pyelonephritis but cannot be detected ith FIGURE 25-0 + Sears shown by ultnspnograply. A, Sacked decreme in patency thickness fn the Inver medi aspect of the del age has heen tured wth the kidney rented verily for comparison sth Figure 25-8) B, Another patient ith at ala Prelcayceal ster at marked thinsing of the en pareel pe oer dilated eas nthe fower pole ofthe kidney frrte). ihFIGURE 25-10 Sate shown by renal conical singe (using Te Melat cimeresptosuoinie sci} Severd focal photopene eis are ‘wel fare) paysite ultrasonography: *Te-DMSA is currently the Bont widely used-vand probably the most sensitive Dols for doeumenting these changes in segmental and ‘bar enal perfusion "=" (se Fig. 25-10), Analogous fadings can also be seen in some patents wth MM pore Doppler ultrasound snagins™ (Colo Fig 4, flow fg)p. 1061), and enhanced CT (Fig, 25-13). These Sages are mst offen seen in the renal ples, consistent wh our understanding of the pathogeneis of scending prelonephnits, as discussed eater, However, despite the Eee tht these areas of decreased perfosion correspond listopathologically to areas of acute segmental or lobar fection of the renal parenchyma, they Frequently do not Progress to frank sear formation when teatneit of the ‘fection is prompt and effective Vesicoureteral Reflux VUR is most effectively and eff seni (Guo ontred) YoU onvelde eystograpiy®® VU i supertr inte ability Characterize refer and for showing the datalled anatomy Of the child’s lower urinary tract. However, the direct rela. iently shown by either Yionship between the curation of Buoroscopy and the radia tion dose to the patient's gonads necessitates interml Refux Nephropathy «++ 1097 ‘monitoring during this examination. For this reason, radio nuclide eystography is often favored for screening and follow-up in departments with radiologists who are experi- enced in pediatric nuclear medicine’ because it exposes the child’s gonads to a lower dose of radiation. During, radionuclide eystography, the gonadal radiation dose is re lated to the quantity and kinetics of the radiopharmaceuti- cal that is used and the length of time that it remains in the patients urinary tract and is unrelated to the imaging process itself, thus permitting continuous monitoring. ‘When radionuclide cystography is unavailable, heightened awareness of the importance of gonadal dose reduction in combination with careful tailoring of the approach to VCU_ by using intermittent digital fuorescopy ean permit perfor- mance of the VCU with s comparably ow gonadal dase It is important to point out that ultrasonography alone cannot be used to exclude clinically significant VUR, even when the study is normal. Blane and associates showed that only 26% of children who have reflux during VCU will have any abnormality detected on ultrasound performed on the same day* (Fig, 25-14). The reason for this result should be apparent, Keflux is an intermittent, event, and the dilatation that the reflux produces is not present at any other time. As a result, if the child is not refluxing when the Kidneys are being scarned-—which is likelythe collecting system and ureter will not be distended. Nondlilgting rellux would not be expected to result in hydronephrosis in any event. Conversely, in children who have. both reflux: and sonographic evidence of hydronepbrésis, the dilitation is generally not caused by the refx per se-lastead usually “signifies the presence of other abnormalities in addition to VUR, such as coexisting obstruction,:neurogenic dysfunc- tion, or dysfunctional voiding, Hence voiding cystography (cither VCU or radionuclide cystography) is the only reli- able examination for diagnosing VUR and should be per- formed whenever the pretence of relux would alter man- agement of the child. Intrarenal Reflux ‘The reported low incidence of intrarenal reflux as docu- ‘mented at VCU is undoubtedly a gross underestimate of the actual incidence. Visualization of intrarenal reflux is unpredictable and usually fleeting’ 7 (see Fig, 25-5) and depends on meticulous filming of the entire kidney at the peak of the reflux. Although recognition of intrarenal reflux has been crucial to understanding the pathophysiol ogy of reflux nephropathy, its demonstration in an individ- tml chilis rarely of practical importance for planning ‘management. The Sequelae of Renal Scarring Reflux nephropathy is thought to be responsible for 10% 10 B01 aE cats of sod age ronal hncwee™o The pthogenesssooms to be tht the nephrons not damaged yy the inflammation/soarring process (the so-called) rem- nant nephron population) must filter more than the usual amount of blood per nephron, % This increase in the single-nephron glomerular filtration rate results in nonspe-1098 + + + Specific Diotdes of he Uinery Tact FIGURE 25-11 + Refuse nephropathy manifested songra any cng pent gh ol ey Sathut Jie foal sas ing wth,mjelomeningcele ek fia and rectrent riary fat infec, A, Voting etbrograp at 7 years of age showed left grade 2 re ‘ea nonna-appearing collecting stem. B and C, Renal ule ound wt 7 sears of ge shows nonmal-ppearng kidneys Wi Symmetrea renal legls (ght Wines 89 cr left Kd, 85 BaF and E Reval aso at 10 ves of age sons hyper Copy of the iit ley sth oo evidence of tater gronth Te Sesh selted ip sie anromete end Tenge ght les, 11.8 cm let Kidney, 8.4m), No seer E the patient Ind let ureteral reimplantation tha complicated by complete obstruction a the let ureters Tr ence Ste Mout ter she bad et nephrectomy. The Stpltectony specimen shoved hitopuhologel change of sore relax nephropathy = Ce aeRefux Nephropathy +++ 1099 95th percentile Renal length (em) Rigi kidoey 2 Leh kitey ae 5 T z TTT ip oe 4 Age (years) To - Febale Ur [2830 » Onpopiyis [ S290 om popiyide s IVP. Nommal Us. Ri Sem, ti7éem US: RU63em, Le 83 em Vou: Regsadetv vuR | || VCUG: Rignde IVER | a amo ~ On prophylaxis US: Ri60em, L163¢m YCUG: Ru gre I VUR AOUNE/25-12 + Annotated ronal growth chart a a boy with rfc nephopstyyconseque tg. Renal lengths a ve consecutive examinations are ploted agunetnarmative standards for renal length bused on ef Lat. bosh IVP and US ‘er vormal However, despite antbiote prophyacs, edmplanation, and the abrence of futher ialzaton, the night kane grew lite wheres the let ‘sey hypertrophied, thereby resulting in ieresing asymtoery offal length over tne, IVP = intravenous pyelography Lt = lef mo = montis stages He = sights US = wlraonography: UTI = urinary tract infetion; VCUG = voiding eystauethrgrapy, VUR = vesioouetra refx yo ert of age. (From Zerin JM, Blane Ck: Sonographic asscerment of renal lng in cildeen’ A reappraisal, Podate Radiol 24101, 1098) 1 a [P47 Reweinsin | [39;0 apenas] [Gaye saempmmaic Divs Benen || ig escmtiztén | [ts Reson tosy WoUS: Novi — to right roux and acute pylonephiis at 8 months of ROURE 25-19 « An eahanoed computed tonagihle san of «Gear ‘wath sete yelanepit ofthe le hey (ee Calor Pi 8) wt loweitenuston ain he ter ape of het dey Spe fsa pylonphe (Prom Dacher FN Plier C. Monroe ne Doppler sonographic pater of cite ppelonepitis eden mpason with CT ApH 1661451, 1986),M00 +++ Specie Dio 4s ofthe Utinory Tract cific damage to these remnant nephrons in the form of focal-or segmental glomerular sclerosis. This acquired glomefilopatliy. frequently coincides with the onset of pro- feiniiiavand*subsequent decrease in clearance of cresti- ‘The“combisiation of (1) damage to one population of nephrons by inflammation/scarring and, in theory, (2) dam- age to the remaining population by hyperfitration-induoed glomerular sclerosis can result in end-stage renal disease. The greater the inital magnitide of infection-induced scarving, the smaller the population of remaining normal nephrons. This reduced population of normal nephrons leads to a greater magnitude of hyperfitration by each of these remnant nephrons and, it seems, a greater likelihood of glomerular sclerosis. CHALLENGES AND IMAGING RECOMMENDATIONS. Diagnostic and therapeutic challenges in reflux nephropa- thy are as follows: 1. Prompt, accurate diagnosis of UTI in infants and young children, who are at special risk for renal sear: ring because of their age 2. Appropriate antibiotic treatment, without delay, to bart the scarring process 3. Diagnostic uroradiological evaluation, beginning with ultrasonography and voiding cystography—or *Te- DMSA scintigraphy in some departments—to detect children who have reflux, as well as to document any changes related to reflux nephropathy that are already apparent FIGURE 25-14 + Song. and voiding atuteivoant hea’. ‘nontvl pl wh sor diag ‘ef a orig tureroply Tec that wat ak doteed Sake Stosonogrpy doe the ne de 4, Uirasbund shove anal ‘Bases tarmes) with no Ione pros Yoel sows. Lier Sy Ultraround shows» normal i Idney (arcs). C, VOU minus tte showed de 9 gh and fade tet sec From Blne Binion oa ed senogrphy ot see cee ing ertmioaon fr vesouetrd ha} Urol 15072 19) 4, Protecting a child who is found to have reflux fom further infection developing by administering “peo- phylactc” antibiotics unt the reflux disappears spon- taneously or is corrected surgically or until theshild grows older When a young child has a well-documented UTIs isis Important t ascertain whether the chids defenses 7a Tk” by obstruction, rfl, or both, The fst imaging) should usually be evaluation of the lower urinary tri¢t, bj VGU (or nuclear eystography)**™ and renal ultrasound * ‘61 these studies ae normal orf only mild to modirate reflux is present with no evidence of renal scarring, abet fant miclustion, obstructive uroplly, or newogenleB* Fonction, no other uroradiologieal imaging tests are 8622 sary. If the study results are norma’ and the chi hs Subsequent episodes of upper tract infection, repeat Sonography and VCU occasionally reveal abnormal Ser ot preset one nial tn, With a oD tract infection, repeated imaging i usually uaneces tho screening VCU or ulreound is markedly ab ®™Te-DMSA. scintigraphy can be performed to det presence and extent of renal seas when tis inl Aaill alter management, Diuretic renal scineigraphi ning or excretory urography can also be used to. 94 funetional implications of the reflux nephropathy: In an older child or teenager, especially if onl ucinay tract signs and symptoms ave reported ultrasound findings alone provide reassurance that Mg oes not have reflux nephropathy or significant obi ‘Although itis true that normal sonographic finding exclude VUR.” by this age these children should bil risk of refs nephropathy developing de novo, 224 ‘were still present. 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