Pyelonephritis, renal scarring, and reflux nephropathy: a pediatric urologist s perspective

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1 DOI /s x MR UROGRAPHY Pyelonephritis, renal scarring, and reflux nephropathy: a pediatric urologist s perspective Edwin A. Smith Received: 8 June 2007 / Accepted: 10 July 2007 / Published online: 11 December 2007 # Springer-Verlag 2007 Abstract Imaging of children with a clinical diagnosis of pyelonephritis is performed to characterize the extent of the infection, to identify associated renal injury and to uncover risk factors for future infections and renal damage. Although there is general agreement regarding the need for parenchymal imaging and the need to exclude processes that are either functionally or anatomically obstructive, there is controversy regarding the need for routine cystography, especially when parenchymal involvement has not been documented. A protocol that limits the use of cystography for evaluation of urinary tract infections must assume that the diagnosis of reflux is at least of variable clinical significance. It is now clear that vesicoureteral reflux and reflux nephropathy represent a diverse population that includes both congenital and acquired processes. MR imaging will improve our understanding of vesicoureteral reflux, pyelonephritis and renal scarring and might help us to identify and manage those patients most at risk for recurrent infections and renal injury. To recognize the potential contributions of this newer imaging technique it is helpful to look at our understanding of the pathophysiology of pyelonephritis, reflux and reflux nephropathy. Keywords Pyelonephritis. Vesicoureteral reflux. Reflux nephropathy. MR urography. Children The author has no financial interests, investigational or off-label uses to disclose. E. A. Smith (*) Department of Urology, Emory University School of Medicine, 5445 Meridian Mark Road, Atlanta, GA 30342, USA smithea@aol.com Introduction Imaging of children who have developed a clinical picture of pyelonephritis is directed toward characterization of the extent of the current infection and associated renal injury and toward identification of risk factors for future infections and damage. Which studies are selected from the menu of possible modalities is dependent on the importance ascribed to potential radiographic findings. Risk factors for pyelonephritis that might be uncovered during imaging include vesicoureteral reflux (VUR), obstructive processes and other mechanisms promoting urinary stasis. In the United States the standard evaluation of an infant or young child after the first documented febrile urinary tract infection (UTI) includes renal bladder sonography and voiding cystourethrography. This approach finds support in the American Academy of Pediatrics Practice Parameter, which was specifically directed at children age 2 months to 2 years [1]. In practice, these recommendations are often extended to both younger and older children. Although little dispute will be found regarding the need for some form of parenchymal imaging and the need to exclude processes that are either functionally or anatomically obstructive, there is greater controversy regarding the need for cystography, particularly when parenchymal involvement has not been documented. The strong association between VUR, pyelonephritis and renal scarring has also produced a strong argument in favor of diagnosing reflux [2]. A protocol that limits the use of cystography for evaluation of UTIs must assume that the diagnosis of reflux is at least of variable clinical significance. Skeptics suggest that diagnosis and treatment of VUR does not offer a substantive advantage over conservative therapies because DO00587; No of Pages

2 most renal injury has already occurred at the time of VUR diagnosis [3]; surgical therapy of VUR has failed to show superiority to conservative treatment in terms of preservation of renal function [4 6]; and most patients with the most significant sequelae of VUR including hypertension and renal failure have congenital rather than acquired reflux nephropathy (RN) [7]. Children with VUR unquestionably represent a diverse population. Radiographic studies have contributed greatly to our knowledge of the pathophysiology of pyelonephritis and the evolution of scarring. Our current principles of UTI and VUR management have evolved based on experimental VUR studies, numerous clinical studies and experience in daily practice of managing children with VUR. Although an association between pyelonephritis, reflux and renal injury is certain, the optimal protocol for specifically identifying and managing patients most at risk for recurrent infections and renal injury remains unclear. MR imaging promises to add to our understanding and could become a routine part of patient evaluations when a febrile UTI has been diagnosed. To recognize the potential contributions of this newer imaging technique it is helpful to look at our past and current understanding of the pathophysiology of pyelonephritis, reflux and RN. Pathophysiology of pyelonephritis and renal scarring The initiation of a bacterial UTI nearly always occurs by retrograde passage of feces-derived organisms from the perineum to the urethra and finally to inside the bladder. An individual child s vulnerability to this process is multifactorial and related to both bacterial virulence and host susceptibility. VUR represents one of many host factors that promotes ascending infection. Irrespective of risk factors, once inoculation of the renal parenchyma occurs a cascade of pathophysiologic events ensues. The events of this welldescribed pathway might be reflected by tissue characteristics on imaging, especially renal parenchymal scintigraphy. Bacterial invasion of the renal parenchyma results in an intense response that leads to tissue damage caused by focal ischemia and the direct effect of released toxins. The inflammatory response elicits migration of granulocytes to the affected region with subsequent compromise of the microvasculature as these cells fill and obstruct the arterioles and peritubular capillaries. Interstitial edema accompanies inflammation and causes compression of peritubular capillaries, glomeruli and arterioles of the medulla, contributing to focal ischemia and tubular injury. A second mechanism of tubular injury is caused by production of superoxides during tissue reperfusion and by release of lysozymes as granulocytes phagocytize the invading bacteria. The oxygen free radicals generated by superoxides and S77 toxic enzymes released by granulocytes are destructive substances, indiscriminant in both killing of bacteria and injuring tubular epithelium [8]. Tubular cell death releases the inflammatory process into the interstitium, which perpetuates the ongoing damage. The end result can be permanent parenchymal injury or scarring represented by a pattern of tubular atrophy or loss and interstitial fibrosis. It is notable that this pathophysiologic process has the potential to occur whether or not reflux is present [9]. Furthermore, renal scarring represents a pathologic endpoint with some gross and histologic features shared by postinfection injury and congenital reflux injury, the most prominent distinguishing feature being the presence of dysplasia in congenital cases [10]. Because imaging ultimately is a reflection of tissue histology, separation of acquired and congenital lesions has often been difficult radiographically. Delineating the underlying cause of reflux-related injury in an individual patient is usually dependent on knowledge of the patient s clinical and radiographic history, including in utero imaging and parenchymal changes that could accumulate after infections. At present, renal parenchymal scintigraphy using Tc 99m dimercaptosuccinic acid (DMSA) is considered the imaging modality with the greatest sensitivity and specificity for capturing acute inflammatory changes and the evolution to scarring [11]. The delivery of DMSA to renal tubules is dependent on intrarenal blood flow and cellular uptake, which can be affected as described. Animal studies of experimental acute pyelonephritis have compared the results of DMSA imaging with histopathology and found a sensitivity of 89% and specificity of 100% for detection and localization of inflammation. Significant contributions regarding the pathophysiology of childhood UTI have been realized through DMSA imaging. Among children presenting with febrile UTI, DMSA documentation of parenchymal inflammation is found in 50 80% [12]. These figures contrast with a low rate of parenchymal involvement in children who present with symptoms consistent with a lower UTI [13]. Surprising results were recorded when a comparison was made between results of cystography and DMSA scan in children presenting with febrile UTIs. The majority of children with positive DMSA scans (60 68%) did not have VUR at the time of investigation. However, if VUR was present, most patients (80 90%) were found to have positive DMSA scans. Furthermore, moderate- to high-grade reflux is two times as likely to be associated with an abnormal DMSA scan versus low grades of reflux [14]. Scarring following pyelonephritis with documented parenchymal involvement appears to be equally likely whether or not VUR is present. However, the higher likelihood of acute pyelonephritic damage and subsequent scarring with higher grades of reflux should not be ignored [15]. Children with higher grades of reflux also appear

3 S78 more likely to have larger areas of parenchymal involvement when pyelonephritis occurs [16]. Reflux nephropathy The term reflux nephropathy was introduced bybailey[17] to describe the gross pathologic changes of kidneys that had sustained injury as a consequence of VUR and UTI. This nomenclature replaced the older term of chronic atrophic pyelonephritis, which erroneously suggested the presence of an ongoing low-grade infection [17]. Yet, from the beginning it was evident that there were two different populations of children with reflux-related renal injury. Children with acquired RN are understood to have scarring as a sequel to pyelonephritis and are more likely to be female with a tendency toward less-severe grades of reflux. Scarring is radiographically demonstrated to be patchy or segmental, although with progressive injury a more global pattern might be seen [18]. The female-to-male ratio in this group is in the range of 4 5:1 and reflects the female predominance of UTIs beyond the first year of life [19]. Most patients with congenital injury are discovered at an earlier age, usually following a prenatal diagnosis of hydronephrosis; most are male, and most have high-grade VUR [20]. Morphologically these kidneys are often hypoplastic, have a smooth contour and have diminished renal function. Their histology suggests aberrant embryological development with dysplasia often present, identified by the hallmark feature of primitive tubules [10]. Cartilage and cysts might also be found. The experimental studies of acquired RN find their roots in the efforts of Hodson and Edwards [21], who recognized reflux as a mechanism for delivery of bladder dynamics to the upper tracts and as a mechanism for delivery of bacteria to the renal parenchyma. Their studies employed a piglet model because the intrarenal anatomy is similar to that of the human kidney. Renal scars could be produced by a water-hammer effect of refluxing urine, with areas of scarring coinciding precisely with areas of intrarenal reflux. Their model required placing a ring around the urethra, resulting in outflow resistance and elevated bladder pressures. Clinical correlates of this design are represented by the patterns of secondary reflux in neuropathic bladders or posterior urethral valves. The studies of Hodson and Edwards [21] showed the urodynamic effects of reflux to be a key factor in renal scarring. However, when infection was present in addition to abnormal bladder pressures, scarring was accelerated [21]. The relationships between reflux, infection and bladder pressures were further dissected by Ransley and Risdon [3]. Also using a piglet model, it was demonstrated that at physiologic bladder pressures scarring occurs only when VUR is combined with UTI. As a Pediatr Radiol (2008) 38 (Suppl 1):S76 S82 corollary, sterile reflux does not cause scarring unless associated with elevated bladder pressures. The significance of the morphology of papillary and compound papillae and the regional distribution of these types of papillae were also defined. The papillary configuration contains collecting ducts with nonrefluxing slit-like orifices that enter on the side of the papillae. The compound papillae, which are usually located in the polar regions, possess collecting ducts that enter the concave surface of the papillae. Compound papillae were found to be more susceptible to the wave of reflux that might extend into the collecting ducts. Hence, transfer of bacteria into the parenchyma occurs more readily at the polar regions, which are more susceptible to scarring [3]. The role of elevated bladder pressures in producing more rapid and profound injury was reproduced and is important to clinicians evaluating children with reflux and voiding dysfunction. Two theories have been advanced to explain the occurrence of congenital RN. First, the theory of Mackie and Stephens [22] describes the correlation between the position of the origin of the ureteral bud on the mesonephric duct as a determinant of the ultimate position of the ureteral orifice on the trigone and as a determinant of the integrity of the renal tissue. An abnormally caudal origin leads to a laterally displaced refluxing ureter and a dysplastic kidney [22]. The alternative theory evokes a transient urethral obstruction as the cause of a decompensated vesicoureteral junction and as the cause of renal injury by the transfer of elevated bladder pressures to the parenchyma during a critical period in development. Because by definition no anatomic obstruction is found in patients with primary VUR, proponents have suggested that the obstruction might be functional. Some support is found through the observations of Sillen et al. [23, 24], who have documented detrusor sphincter dysynergia and elevated voiding pressures in male infants with high-grade VUR. The advent of maternal-fetal medicine has provided an opportunity to evaluate congenital RN before UTI develops. In approximately 20% of infants with prenatal hydronephrosis primary VUR will be detected [25]. A significant number of patients, ranging from 30% to 86%, with antenatal reflux will be found to have cortical defects by DMSA renal scan, the majority of defects being found in infants with high-grade reflux [18, 25, 26]. Recently, the pattern of scarring has been shown to be more diverse than initially reported. In addition to the small kidney with diminished function and dysplasia that has been explained by the theory of Mackie and Stephens, focal segmental defects have been detected that are seemingly better explained as being a result of sterile reflux [27]. It is important to recognize that pyelonephritis can occur in congenitally abnormal kidneys so that injury in an individual patient might be both congenital and acquired.

4 Evidence has been presented that in the presence of grades 3 5 reflux, kidneys that harbor scars might be more likely to develop breakthrough UTIs and less likely to have VUR resolution [28]. There is difficulty in disentangling congenital and acquired scars and the relative contributions of each process by current imaging modalities. Yet, this is of prime importance, especially when discussion begins concerning patients with the most severe sequelae of RN, hypertension and renal failure. Sequelae of reflux nephropathy RN is said to be the most common cause of severe hypertension in the pediatric population. Its occurrence is influenced by the degree of parenchymal damage, the involvement of one or both kidneys, the degree of renal insufficiency and the age of the patient [9]. In a long-term study with follow-up spanning 18 to 35 years, Smellie et al. [29] found that 7.5% of children diagnosed with UTI and VUR developed hypertension. Another long-term study of patients with RN diagnosed in childhood and followed for an average of 14 years found an incidence of hypertension of 38% [30]. In contrast, Wolfish et al. [31] examined 129 patients with primary reflux with follow-up of 10 years. None of their patients developed hypertension, leading the authors to the conclusion that hypertension does not occur unless dysplasia or other renal abnormalities are present [31]. Establishment of the true incidence and characteristics of patients at risk for hypertension has been challenging because many studies lack detailed information regarding UTI history, degree and management of VUR, the degree of scarring and even the method of measuring blood pressure [32]. The incidence of RN in registries and institutional records of patients has been explored in several studies that suggest that RN accounts for 7 17% of worldwide endstage renal disease (ESRD) [7]. Interpretation of these reviews has been confounded by inclusion of patients with both primary and secondary reflux and by inclusion of patients who have congenital versus acquired injury. In a retrospective single-institution study of 122 children with ESRD, hypertension or renal insufficiency, Vallee et al. [33] found that 6 (5%) had RN as the etiology of their renal injury. Four of the six were boys, three with ESRD and one with hypertension. Both females had hypertension. Among the six there was only one patient with a history of UTI [33]. Although detractors argue that the results point to a failure of current reflux management to have an impact on the most severe consequences of VUR, it could also be argued that children with reflux and postinfection injury have been eliminated from the ESRD group by proactive management. A study by Craig et al. [7] attempted to address whether diagnosis and treatment of VUR has had an impact on the ESRD population. Their study extended from 1971 to 1998, an interval in which the rewards of treatment change from observation to active treatment might be recognized. The authors found no significant improvement in the incidence of RN in the ESRD population and expressed skepticism about the need for reexamination of the benefit of conventional medical and surgical reflux treatment [7]. Considerations for imaging children with UTI S79 The rationale for comprehensive imaging including upper and lower urinary tract studies following the first febrile UTI has been based on a number of observations that are readily recited by pediatric urologists: (1) there is always some uncertainty as to whether the first documented UTI is truly the first UTI; (2) young children who have a UTI are highly likely to develop a second infection [34]; (3) VUR is found in 20 40% of children with UTI and obstructive lesions are found in 0 4% [35, 36]; (4) young children have the greatest risk of renal scarring [37]; (5) repeated infections can lead to additional renal scarring [38]. Taken independently, each of these statements is well supported in the literature and in daily practice. There is little debate regarding the need to diagnose obstructive processes. Controversy exists regarding the need to perform voiding cystourethrography in all age groups, in children without confirmation of parenchymal involvement and after the first infection. These questions have not been answered by controlled trials. This controversy is fueled by the contention that there is insufficient evidence demonstrating a benefit for either medical or surgical therapy for reflux versus observation and treatment of infections as they occur (intermittent treatment) [5]. The argument proceeds that if intervention for reflux is unproductive then there is no merit in investigations to diagnose reflux. Antibiotic prophylaxis was first introduced by Normand and Smellie [39] in 1965 with a report of a nonrandomized patient group in which an eightfold greater risk for UTI recurrence was documented for the no-prophylaxis group. Since then several nonrandomized studies have reached conflicting conclusions regarding UTI recurrence and renal scarring with and without prophylaxis. Garin et al. [40] recently reported results of a multicenter randomized controlled study of antibiotic prophylaxis versus intermittent treatment for children age 3 months to 18 years with and without VUR. The group s conclusions were that mild to moderate VUR does not increase the likelihood for UTI, pyelonephritis or renal scarring. Important limitations are a study interval of 1 year and inclusion of only children with grades 1 3 VUR [40]. The Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR) study is

5 S80 sponsored by The National Institutes of Health and will begin to recruit children age 2 months to 6 years with VUR grades 1 4 in This important prospective double-blind study will randomize children to either antibiotic prophylaxis or placebo. Over a 2-year interval primary endpoints of number, timing, and recurrence of UTI and secondary endpoints of scarring based on DMSA renal scan and antimicrobial resistance in uropathogens will be assessed. The majority of studies addressing intervention for reflux have compared antibiotic prophylaxis to antireflux surgery. In the International Reflux Study no difference in outcomes with regard to the incidence of UTI or new renal scarring was found between the medical and surgical groups. However, pyelonephritis was more likely to be diagnosed in the medical group. Some evidence of a preventative benefit from surgery was also observed because scars appeared in the surgical group early in follow-up, suggesting that the offending infectious event occurred before surgery was undertaken [41, 42]. Although the optimum treatment for VUR requires continued investigation, the association with UTI and scarring is unquestioned. An estimated 1% of children with no UTI have VUR. Yet, among children with UTI, 20 40% are found to have VUR [36]. The rate of positive VCUG studies increases with decreasing age as a general trend [43, 44]. As stated, higher grades of reflux also correlate with greater severity of renal scarring [43, 45]. It is true that in many patients, particularly those with low grades of reflux, the disease might follow a relatively benign course. However, until prognostic factors can be accurately defined that indicate when a child is not at risk for recurrence of infection or significant renal injury, urologists will continue to evaluate clinical pyelonephritis. The combination of sonography and voiding cystourethrography has proved effective for the identification of anatomic features that carry an association with UTI recurrence and renal scarring including VUR, ureterovesical junction obstruction, posterior urethral valve, and bladder wall thickening. Other factors that deserve equal consideration as promoters of infection or scarring include dysfunctional voiding, constipation [46], and previous scarring [47]. There is also evidence that the damage associated with pyelonephritis might be eliminated or minimized with prompt institution of antimicrobials [48, 49]. These elements should also be considered in the design of future studies so that homogeneous study groups are developed. Cortical imaging The role of cortical imaging, specifically DMSA, for evaluation of children with pyelonephritis is still evolving. General agreement exists concerning its usefulness for: (1) further evaluation of illness in a patient with a complicated presentation in whom pyelonephritis is suspected but not fully supported on other clinical grounds; (2) further definition of the functional significance of parenchymal abnormalities detected by US; (3) evaluation of congenital high-grade reflux; and (4) surgical decision-making when breakthrough infections have occurred in medically managed patients. More controversial is the use of cortical imaging to determine parenchymal involvement before ordering a VCUG. Placing the emphasis on renal scarring or the potential for renal scarring, some authors have suggested that DMSA results should determine the need for VCUG [50]. This recommendation follows the observation that children without scarring following UTI are unlikely to develop scarring even if future attacks occur. Under this protocol, children older than 1 2 years would undergo renal bladder US to exclude anatomic problems that should be surgically addressed and DMSA to exclude scarring and the need for cystography [9]. Proponents indicate that this strategy would reduce by half the number of cystography procedures, a study that is attended by risk of infection, trauma and anxiety for both parent and child. This protocol must be substantiated by prospective trials but carries appeal as a method for detecting children with renal lesions and VUR that carry a risk for renal injury while avoiding invasive imaging and treatment of children who are not at risk [51]. Is there a role for MR imaging? Pediatr Radiol (2008) 38 (Suppl 1):S76 S82 MR urography (MRU) offers an exquisite degree of anatomic detail of the urinary tract along with functional information about the concentration and excretion of individual kidneys, a combination that previously was approachable only with performance of multiple complementary studies [52]. Renal anatomic features important to the diagnosis of RN such as renal contour and caliceal configuration are readily imaged. The presence of dysplasia might be suggested by loss of corticomedullary differentiation with parenchymal loss, an abnormally small kidney (hypodysplasia), and cystic changes [53]. The physiologic processes that are captured with DMSA imaging can also be favorably exploited to reveal the acute and chronic changes of pyelonephritis. Imaging has proved effective in distinguishing areas with compromised perfusion and interstitial edema. Initial comparative studies have shown that the functional information provided by MRU is at least equal to that from DMSA, and in many circumstances MRU overcomes the limitations of renal scintigraphy. Lonergan et al. [54] found that gadolinium-enhanced inversion-recovery MR imaging detects greater numbers of pyelonephritic lesions and has superior interobserver agreement. The recognized advantages include absence of

6 radiation, lack of background artefact, greater information about tubular function, and the ability to produce excellent imaging and quantitative information despite poor function or bilateral disease. The cost of MR imaging and the need for sedation are negative factors at present. The information derived from MRU might provide insight into some controversies of reflux management. The greater anatomic detail and tubular functional assessment might allow differentiation between congenital and acquired renal scarring, especially if features of dysplasia are present. The evolution of scarring and the effects of treatment protocols might be followed with greater accuracy, and distinguishing features in children at greater risk for hypertension or renal insufficiency might be discerned. The expected sensitivity of MRU promises to make this imaging modality the new gold standard for parenchymal imaging. Will MRU become a standard part of the evaluation of febrile UTIs? If anatomy and parenchymal involvement, not VUR, are determined to be the most important initial imaging considerations, we might find that MRU provides the most comprehensive information for patient management. Conclusion The incomplete understanding of the natural history of VUR and its relationship to renal scarring and RN has resulted in a variety of opinions regarding both the evaluation of pyelonephritis and the importance of diagnosis and treatment of VUR. Four decades after Hodson and Edwards [21] suggested an association between VUR and renal injury, the most fundamental questions of VUR management remain obscure because of the lack of appropriately designed studies to answer clearly which children are at risk and which children will benefit from medical or surgical management of this condition. An orderly approach to this relatively common clinical problem will occur only when there is convincing delineation of prognostic factors. 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