This article discusses urinary tract infection (UTI) in the context of its most important sequelae, reflux nephropathy, and emphasizes the need for aggressive evaluation, treatment, and follow-up. Urinary tract infection serves as the prime marker from which suspicion is raised that significant underlying anatomical abnormalities, such as vesicoureteral reflux (VUR) and reflux nephropathy, may be present. For the clinician, the inter-relationship between VUR, reflux nephropathy, and UTI must be fully understood.
URINARY TRACT INFECTIONS
In order to more precisely discuss UTI, some terms must be defined. Simply put, a UTl can be defined as the growth of an abnormal amount of bacteria in urine, which should be sterile. The threshold number of colonies/mL of urine varies according to the method of collection: any number of colonies when obtained via a suprapubic tap; >103 colonies when obtained from an intermittent catheterization; >105 colonies when obtained from a midstream clean-catch collection.1
Urinary tract infections can be subdivided based on the presence and localization of symptoms and their relationship to other urinary structural abnormalities. Asymptomatic (covert) bacteriuria usually is discovered by routine screening urinalysis and urine culture. The pathogenicity of the organisms responsible for these infections have been questioned.2 If they prove to be not as pathogenic as those organisms found in symptomatic UTI, then differing conclusions regarding sequelae might be made if they are not evaluated separately. Symptomatic UTI presents with urgency, frequency, dysuria, and even fever. The symptoms can be associated with upper or lower urinary tract disease, although upper urinary tract disease also may reveal such signs and symptoms as higher fever, abdominal or costovertebral angle (CVA) tenderness, changes in bowel habits, and nausea and vomiting.
For the purposes of this discussion, a complicated UTI is an upper or lower UTI associated with some structural or functional genitourinary abnormality. These include VUR, obstructive uropathy (posterior urethral valves, ureterovesicle or ureteropelvic junction obstruction), voiding dysfunction, prior or current instrumentation, and renal stones. These types of abnormalities are just what we wish to evaluate and diagnose by the radiologic work-up done after a UTI is diagnosed.
One percent to 2% of prepubertal children have bacteriuria on screening with urinalysis; 14% to 35% of these will have VUR.3 Minninberg reported that of 59 645 children 4 to 18 years of age who were screened, 2% had bacteriuria and 14% of them had VUR.4 Trie prevalence of asymptomatic bacteriuria is 1% in preschoolers- 1.2% to 1.8% in females and 0.03% in males.5 In regard to symptomatic UTI, the prevalence in neonates is 0. 14%, with a preponderance of males. In older children, symptomatic infections develop in 1.5% to 2% of 1 to 5 year olds.6 Of children who present with symptomatic UTI, 18% to 50% will have VUR.4·7
The most common bacterial cause for UTI remains gram-negative organisms, with up to 80% of UTIs caused by Escherichia coli. In fact, nine serotypes of E coli account for 60% of UTIs. Patients can have E cou ascend the ureters and attach to antigens expressed on the ureteral epithelium, causing renal parenchymal infection without reflux needing to be present.8 Other gram-negative organisms include Pseudomonas, Klebsiella, and Proteus species; most of these organisms are seen with complicated UTIs. Gram-positive bacteria such as Staphylococcus aureus and Staphylococcus epidermidis may be seen in patients with indwelling catheters or shunts. Other organisms, such as enterococcus, Streptococcus species, and Candida albicans also need to be considered, especially the latter in patients who have received antibiotic treatment over long periods of time.
Host factors contribute to the severity of UTIs and their method of spread. In neonates, bacteria reach the kidney via hematogenous spread. Later in life, organisms ascend the urinary tract from below, usually from periurethral colonization. Associated anatomic abnormalities, such as VUR, obstructive uropathy, renal calculi, and abnormal bladder emptying, can lead to urinary stasis. Urine provides an excellent medium for bacterial multiplication. Natural defense mechanisms can be overcome by instrumentation of the urinary tract and placement of indwelling bladder catheters. The bladder's epithelium can be injured by foreign bodies and drugs, limiting the body's ability to ward off infections with its own immunologic factors (secretory IgA) and complete emptying of the bladder by voiding.
The growth of bacteria on culturing urine that is normally sterile strongly suggests a UTI. If urine is obtained properly, transported quickly, and stored at a temperature ^40C, the results should be reliable, raise-positive cultures occur because of warm storage, the presence of vaginitis, and improper cleaning of the periurethral area prior to collection. Some have suggested that bag urine specimens often give falsepositive results on culture, while a negative culture using that method is likely to be valid.1 If the specimen can be removed quickly from the bag, false-positive results will be less likely and a reasonable interpretation can be made. Thus, one may avoid a painful, invasive procedure such as catheterization. False-negative urine culture results occur because of improper removal of cleansing disinfectant, prior antibiotic therapy, and diluted urine specimens.
Multiple organisms cultured from one or more specimens usually indicate contamination, but they can be the cause of infection in patients with abnormal urinary tract anatomy. If organisms such as diphtheroid bacilli and some Staphylococcus species are present, the likelihood of contamination is high and the culture should be repeated.
Dipslide cultures can be performed in the office and offer a relatively easy way to diagnose UTIs and to follow the effectiveness of antibiotic treatment.
Urinalysis is helpful in diagnosing UTIs, although no single actor is absolutely confirmatory. Pyuria can suggest infection, but conditions other than UTI can cause pyuria, and UTI can be present in the absence of pyuria. Current dipsticks detect the presence of urinary leukocyte esterase and nitrite, both of which are highly suggestive but not diagnostic of a UTI. Leukocyte esterase measures esterases from destroyed leukocytes. As noted, conditions other than UTI can cause pyuria and esterase release. Nitrites are produced by urinary bacteria. False-positive and falsenegative tests occur with both markers, and they do not obviate the need for obtaining a urine culture.9
Both upper and lower LTTIs are the most common cause for hematuria, both gross and microscopic (>5 red blood cells per high-power field),10 but there are numerous other causes. Proteinuria most often indicates parenchymal involvement but still is not diagnostic for UTI. Thus, with the exception of a positive urine culture, no single laboratory finding is diagnostic of a UTI.
Clinically, we need to think in terms of lower or upper UTIs. The symptoms of dysuria, urgency, and frequency combined with low-grade fever usually indicate lower tract disease. While it is useful to think of constitutional symptoms such as fever, flank pain and CVA tenderness, and nausea and vomiting as being associated with upper tract/parenchymal disease, these symptoms are not always present.
The specificity of the symptoms changes with the age of the child. Typically, the newborn and younger infant will present with nonspecific symptoms including fever, weight loss, decreased appetite, apnea, jaundice, and signs of sepsis. As the patient ages, the signs and symptoms become more specific to the urinary tract, and frequency, dysuria, urgency, and abdominal pain are seen commonly. Also of note in the older child is the onset of bed-wetting in a previously toilet-trained child. Any abnormal voiding habits including infrequent urinary voiding, poor urinary stream, straining on urination, and chronic constipation should alert one to possible underlying structural or neural conditions that require further investigation. These conditions include spina bifida occulta, neurogenic bladder, and obstructive uropathy. Voiding dysfunction can induce uncontrolled bladder contraction, leading to incontinence. When the child voluntarily contracts the external sphincter during this uncontrolled bladder contraction, an obstruction results with the generation of high vesicle pressures. While this dysfunction cannot occur before the child is toilet trained, it is felt to represent a delay in maturation that should correct itself over time.11
The physical examination in a child with UTI should include a blood pressure check to rule out hypertension caused by reflux nephropathy (see below), abdominal palpation to evaluate the presence of an abdominal or flank mass, and inspection for urethral or vaginal inflammation.
VESICOURETERAL REFLUX AND REFLUX NEPHROPATHY
Urinary tract infection is the most common clinical feature of VUR, serving as the primary indicator for further work-up.12 As we shall see, the goal is not simply to diagnose a UTI or VUR, but to use these markers to implement treatment plans to prevent the serious sequelae that result from these conditions. Thirty percent to 50% of children with a LTTI have VUR.4 Bailey12 has studied the inheritance of VUR and through a computer model has postulated that the best fit is that of a single dominant gene. The gene frequency is 1 in 600 and mutation is felt to be rare. Because of this increased familial occurrence, radiological investigation of siblings of index cases is recommended, using the voiding cystourethrogram (VCUG).
The mechanism for primary, nonobstructive VUR is felt to be related to a low ratio of the intramural vesicular ureteral length-to-orifice diameter, which is normally 5:1. This can be as low as 1.4:1. Vesicoureteral reflux resolves spontaneously in 20% to 30% of patients every 2 years for an overall long-term disappearance rate of up to 80%. 13 Spontaneous resolution of VUR as patients get older is seen in 85% of nondilating grades of reflux (Grades I to III), compared with 41% in more severe, dilating grades of reflux (Grades IV and V).1*13 There appears to be a natural maturational process (elongation of the intramural length) with some patients outgrowing their reflux. The location, size, and shape of the ureteral orifice also have an effect on VUR and its consequences. Increased frequency and severity of VUR and renal scarring are associated with abnormal configuration and lateral placement of the ureteral orifice.14
The likelihood of demonstrating VUR in association with UTI diminishes with increasing age. In infants up to 12 months of age, 70% with UTI had associated VUR; this decreased to 40% in the second year of life, 25% in 2 to 8 year olds, and 4-4% in adults.15 There is a subset of children with recurrent pyelonephritis and findings of reflux nephropathy who have no radiographic evidence of VUR. As mentioned above, Winberg et al8 have postulated that E coli with P-fimbria have special characteristics that enable them to attach to the ureteral mucosa, causing dysperistalsis leading to backflow of infected urine to the kidney in the absence of VUR.
Severe nonobstructive reflux in neonates and young infants carries more significant consequences than lesser reflux in older children. Kidneys that showed progressive damage were associated with gross VUR, irrespective of the presence or absence of UTI. Some have suggested that the generalized damage associated with diffuse atrophy sometimes seen in infant kidneys, as opposed to the more typical focal scarring seen later in childhood, may be related to a "back pressure" type of damage that has its origins in the antenatal period.16
What causes a scar to form and why are they typically located in the polar regions of the kidney? Ransley and Risdon17 described two types of papillae, compound and simple, with markedly different susceptibilities to intrarenal reflux. Compound papillae drain multiple renal parenchymal lobes; their concave orifices are round and open when high pressure is present. Compound papillae more typically are found in the polar regions of the kidney and explains why focal scarring more often occurs there. The simple papillae have orifices that open onto a convex surface obliquely, and more often are found in the mid-regions of the kidney. When there is rising pressure in the calyx, these orifices close, preventing intrarenal reflux. Because two thirds of human kidneys have at least one papilla capable of intrarenal reflux, only one third of kidneys are immune to intrarenal reflux and its effects.
Renal scars are found in only a minority of infants and children. Depending on the series, from 33% to 60% of children with VUR have renal scarring on the first intravenous pyelogram (IVP).18 In the compilation of a number of studies, Minninberg4 found a 34% incidence of renal scarring in patients with VUR. An even smaller subset of patients have bilateral reflux nephropathy, some of whom progress to end-stage renal disease (ESRD). The prevalence of reflux nephropathy as a cause of ESRD in pediatric patients has been reported to be 10% and represents an estimated annual incidence of 0.1 to 0.4 cases per million children younger than 15 years of age.19
The relative role of UTI and VUR, or both, in the pathogenesis of renal scarring continues to be debated. Much evidence in patients with VUR points to an important etologie role for UTI. High-pressure VUR without UTI leading to generalized parenchymal thinning may be a different entity. In the presence of UTI, the pathologic picture is markedly worsened.20 Refluxing patients with recurrent UTI have a higher incidence of renal scarring, as well as a probability twice that of patients with nonrecurrent Un of having renal scars at presentation.7
Most new scars appear before the age of 5 years. After this age, the kidney is less susceptible and, because VUR is congenital, those most susceptible to scarring tend to present early. On occasion, however, new scars do appear after the age of 5 years.21 In feet, Smellie's study showed that new scarring developed as late as 10 years of age. One third of these kidneys were felt to be normal at age 5 years. Aram has proposed that the combination of young age, infected urine, and high bladder pressure during voiding are the most dangerous for developing renal scarring.22
Does the grade of reflux influence the incidence of scarring? Twenty-five percent of patients with Grade I to III reflux develop scars compared with 80% of patients with Grades IV and V. But, since 80% of all patients with reflux have the lower grades of reflux (I to III), overall more patients with scars will be found in this group. Thus, diligence and aggressive work-up and treatment is warranted in these seemingly less severely affected patients.22
Certainly, the most significant sequelae of reflux nephropathy is its progression to chronic renal failure and ESRD. If there is only unilateral involvement, total renal function should remain normal, and one would expect to see compensatory hypertrophy of the contralateral kidney and the unaffected portion of the scarred kidney by renal ultrasound or scan. If this is not observed, bilateral disease is likely, or another underlying renal disease may be present. Patients with normal glomerular filtration rates because of sufficient renal functional reserves and compensatory hypertrophy can have significant bilateral disease with normal serum creatinine levels.
A significant complication of reflux nephropathy is hypertension related to renal scarring, whether unilateral or bilateral. Up to 30% of patients with reflux nephropathy will have elevated blood pressures, and 30% of children seen for persistent hypertension have reflux nephropathy.13,23 Aggressive, early therapy is warranted in order to prevent the long-term effects of hypertension on other organs, as well as its effect on the progression of renal insufficiency.
Peripheral renin activity has been reported to be elevated in children with reflux nephropathy. Intrarenal angiotensin II, a potent vasoconstrictor, may play a role in scar progression. Thus, some have advocated the use of angiotensin-converting enzyme inhibitors in norraotensive patients with bilateral disease and proteinuria.24
Proteinuria is an important prognostic sign, indicative of a focal and glomerulosclerosis-appearing glomerulopathy on biopsy. One gram of proteinuria daily is associated with progressive renal failure in older patients, and this increases with worsening renal function.2
The most significant sequelae of reflux nephropathy is chronic renal failure with ESRD. Ten percent of pediatric patients presenting to dialysis centers in Europe had reflux nephropathy. Arant reported his experience at Texas Southwestern Medical Center where 19% of children with ESRD had reflux nephropathy due to primary VUR as their underlying diagnosis. Based on a compilation ot studies, Arant determined that 2.7% of children will have at least one UTI before reaching the age of 5 years. Of these, 40% will, have VUR. Sixteen percent will exhibit renal scarring on radiologic examination. Between 15% and 50% of those with scars will develop hypertension, and 1 % of those with VUR will progress to ESRD by the age of 30 years. Thus, the risk of hypertension following UTIs is 1:100 and the risk of chronic renal failure with ESRD is 1:500 for those developing hypertension.22 Any effort to decrease the incidence of reflux nephropathy as a cause of ESRD will have long-term beneficial effects for a fair number of patients in terms of decreased morbidity and mortality and reduced costs for renal dialysis and transplantation.
Management of UTIs includes early diagnosis, the use of appropriate imaging studies, effective antibiotic therapy, and surgical intervention where warranted. Early diagnosis requires a high index of suspicion. The ultimate goal is the earliest possible identification of VUR or other conditions that can lead to renal scarring, in order to effect a complete treatment plan quickly.
The subject of imaging of the kidneys and urinary tract as part of the work-up for UTI has been debated in the literature over a number of years. In order to draw one's own conclusion, clear objectives for imaging must be delineated. As has been discussed, visualization should reveal structural and functional anomalies of the bladder, VUR, hydroureter and hydronephrosis, renal size, and renal scarring and contracture. Proper evaluation includes a VCUG to show reflux, an IVP or a nuctear renal cortical scan to show scarring, and an ultrasound to show structural abnormalities. While some centers still use an IVP for the detection of renal scars, the increased sensitivity of renal cortical scans enable detection of scars 6 months to 2 years earlier, leading to their increasing use for this diagnostic purpose.25,26
The VCUG assesses the presence and severity (grade) of ureteral reflux. This is important because the grade of reflux influences both medical and surgical therapeutic devices. During the procedure, contrast material is infused into the bladder, and the rapidity and degree of reflux is observed radiologically. The rapidity with which reflux occurs is less important than the maximum degree of the reflux, because the latter determines the likelihood of renal scarring.27 The VCUG determines whether reflux occurs under low or high pressure, with high or low bladder volumes, during early or late bladder filling, or during voiding. A classification of ureteral reflux (Grades I to V) has been adopted internationally (Figure 1).
The advantages to performing the standard VCUG are the ability to provide a detailed morphology of the collecting system, bladder, and urethra, especially in males (the visualization of the urethra in females is not nearly as important), and the ability to accurately grade the degree of reflux present. A major disadvantage is the high radiation dose that is administered, particularly to the gonads.
Figure I.The grades of reflux (l-V) illustrating the International Classification. Reprinted with permission from Lerner GR1 Fleischmann LE, Perlmutter AD. Reflux nephropathy. Pediatr Clin North Am. 1987;34:747-770. Copyright «1987 WB Saunders.
Direct radionuclide cystography, in addition to its advantage of exposing the gonads to a lower dose of radiation, allows continuous monitoring of the bladder and ureters for the presence of reflux. Its main disadvantages are that it cannot demonstrate Grade I reflux, grading of higher degrees of reflux is less precise, and bladder and urethral structural abnormalities (such as posterior urethral valves) are poorly outlined. For this reason, it should not be used for the primary investigation in males, but once the presence of reflux or bladder pathology has been determined, this method can be used in follow-up for either sex.
Obtaining the VCUG should await the documentation of sterile urine, allowing bladder irritability to subside. An irritable bladder does not permit complete filling of the bladder, and false negatives for VUR result. This may take as long as 2 weeks after treatment has been started. Continuing antibiotic coverage until the VCUG is completed is advisable. The method of obtaining the VCUG should be standardized in regard to the filling volume and pressure used, so that results between institutions are comparable.2,28
Upper urinary tract evaluation can be accomplished with ultrasound and radionuclide scintography (renal cortical scan). Sonography offers an excellent method to delineate and follow renal size and growth, obstructive lesions, and gross architectural defects. It is a noninvasive procedure that requires no ionizing radiation; however, it is much less sensitive than renal cortical scans in detecting acute inflammation and early renal scars.29
Renal cortical scans have been used increasingly over the past 5 years. Dimercaptosuccinic acid (DMSA) binds to renal tubules and has a high affinity for the cortex. Therefore, it is useful for assessing acute and permanent focal scars. Because its uptake is determined by intrarenal blood flow and tubular uptake, it gives excellent renal imaging but cannot assess renal function. The presence of areas of decreased uptake without parenchymal loss indicates acute pyelonephritis, while decreased uptake in conjunction with loss of volume represents old focal scars.29 Progression to scarring can be expected within 6 to 12 months and can be seen on repeat scan at that time. Studies comparing IVP and DMSA scanning show that permanent scars can be up to 1 to 3 years earlier with DMSA scanning.26
Glucoheptonate is another agent useful in renal cortical scanning. It too is taken up by renal cortical tubules but its affinity for these tubules is less than seen with DMSA, which can lead to images of poorer quality. An advantage in using this isotope is that it also is filtered by the glomeruli and excreted. This can give an estimate of renal function, as well as morphologic changes due to scarring.1,29
Advantages of renal cortical scanning include:
* earlier diagnosis of acute inflammation and permanent scars than IVP or renal ultrasound allow,
* overlying bowel gas or bone will not cause inferior images,
* high osmotic load (which can alter renal function) is not presented to the kidney,
* allergic reactions are rare,
* images can be obtained even in patients with poor renal function and in newborns,29 and
* the gonadal radiation dose is less than that from an WY, especially if multiple films or tomograms are required.
The level of experience with the use of these agents the above indications varies at different centers, and their interpretations may vary. As experience with the use of these diagnostic methods increases, their comparable values also should increase.30
Because scars can occur up to the age of 10 years, some investigation of the urinary tract is recommended following a UTI. The younger the patient (particularly those younger than 2 years) and the more severe the symptoms, the more aggressive the work-up should be. The patients who are most vulnerable to renal scarring are not only younger, but also have high-pressure VUR and recurrent UTIs. However, recent studies have shown that acute pyelonephritis occurred in patients without the presence of VUR, and that renal scars were noted on follow-up as frequently as in patients with VUR.31,32
The first febrile UTI in girls younger than 5 years of age, in boys of any age, in older girls with recurrent UTI, and in any child with pyelonephritis should be investigated radiographically. The initial evaluation should include a VCUG, a renal ultrasound, and a renal cortical scan (Figure 2). A VCUG and renal ultrasound can be done initially in those with asymptomatic UTI (Figure 3). It has been proposed by some that patients older than 3 years of age with no prior history of multiple febrile illnesses or UTIs might await the appearance of another infection if the original infection is solely cystitis. Follow-up in patients with VUR may be done by radionuclide cystogram. Serial renal cortical scans allow the documentation and progression of early scars (Figure 2). This method can be helpful in follow-up of patients with prior documented acute inflammation. In fact, the early diagnosis of inflammation and scarring might lead one to prescribe low-dose antibiotic prophylaxis, whether or not VUR is present.29
The treatment of UTI should be specific for the causative agent. Therapy should begin immediately at presentation with a broad-spectrum antibiotic and then be changed, if necessary, when the culture and sensitivity results become available. The decision to use oral or parenteral antibiotics has rested with the constitutional symptoms present, particularly vomiting, and whether pyelonephritis or resistant gramnegative organisms are suspected. Close follow-up including clinical assessment and repeat urine cultures at 48 to 72 hours of therapy is essential to ensure that adequate treatment is achieved.
As already noted, reflux disappears at a rate of 20% to 30% every 2 years, and the majority of nondilated ureters (Grades I and II) will spontaneously cease refluxing over time.13 It is in these patients that initial or subsequent damage can be prevented or minimized by keeping the urine sterile while waiting for the reflux to cease spontaneously. Arant33 has examined nondilating reflux (Grades I to III) in a prospective study. One hundred thirteen children with normal kidneys as determined by IVP were studied, the majority younger than 2 years of age. At the time of the report, 59 had completed 5 years of follow-up. All patients received daily antibiotic prophylaxis until their reflux resolved. Reflux resolved spontaneously in 80% of those with Grades I and II. Renal scarring occurred in 10% of kidneys exposed to either no reflux or to Grade I or II reflux. Scarring increased to 28% in those with Grade III reflux. It should be noted that these children were monitored under a strict medical protocol, and it may be that is what is required to ensure improved results, regardless of the level of reflux. There is agreement that antireflux surgery in nondilating reflux has few if any indications.34 If a child has reflux nephropathy and only Grade I or II reflux, then it may be presumed that the patient had a higher degree of reflux previously and that antireflux surgery will not be effective since the damage has already occurred.35
Once eradication of any acute or newly diagnosed infection is accomplished, long-term prophylaxis should be considered if reflux of any grade in infancy and early childhood and of Grades III to V in children older that 5 years continues, or if recurrent UTIs (more than three per year) or pyelonephritis occur.36 The drugs most commonly used are trimethoprim/ sulfamethoxazole or nitrofurantoin. If side effects occur with the combination drug, then trimethoprim alone is an acceptable alternative. The prophylactic dose is half the therapeutic dose. Should reinfection occur while on a prophylactic antibiotic, that drug should be stopped and specific treatment with another antibiotic should be instituted based on reculture and sensitivity studies. Once the infection is successfully treated, the same prophylactic antibiotic may be used again. If reinfection occurs two to three times in a short period of time, bacterial resistance may have emerged and another prophylactic antibiotic should be used, or noncompliance should be considered.
The question of when to consider reimplantation surgery has been hotly debated. The International Reflux Study in Children was undertaken to help resolve whether surgery or medical therapy in Grades III and IV reflux produced a better outcome. Those with Grade V reflux were excluded because there was general agreement that some form of surgical intervention was warranted. Patients were randomized to either a surgical or medical treatment group and followed for 5 years. Acute pyelonephritis occurred more frequently in the medical group even though they continued on prophylactic antibiotics until reflux resolved compared with the surgical group that remained on antibiotics only until reflux was documented to be resolved. Yet the total number of all forms of UTI was similar in both groups. The incidence of new scars was the same in both groups, except that in the surgical group scars occurred within the first 2 years of treatment, while in the medical group scars were distributed evenly over the 5 -year study period. Scarring occurred even in the absence of acute pyelonephritis, and pyelonephritis is not always associated with reflux.34
As was also noted in Arant's study on nondilating reflux treatment, better results were obtained from those centers enrolling a large number of children who were managed in specialty clinics.37 Based on this prospective study, some would say that the only absolute indication for surgical intervention is failure of medical therapy. Certainly, if patients cannot or will not take long-term prophylactic antibiotics, or if there are numerous breakthrough infections, surgery remains an alternative to long-term medical therapy, especially for children with higher grades of reflux. Another conclusion is that early recognition of reflux, if only for its importance as a marker for renal scars, is important. Also, attention should be paid to genitourinary abnormalities other than structural abnormalities, such as dysfunctional voiding, that could lead to renal damage.11·34
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