The small scarred kidney in childhood

Reflux nephropathy is now a generally accepted term to describe small scarred kidneys discovered during childhood; it recognises the close association between this renal lesion and vesicoureteric reflux (VUR). This paper briefly reviews the pathogenic factors involved in reflux nephropathy and suggests that at least two main mechanisms operate: acquired segmental scarring due to intrarenal reflux and congenital maldevelopment (renal dysplasia). The spectrum of renal changes associated with VUR can be usefully divided on this basis and the opportunity to recognise by fetal ultrasound those renal lesions acquired in utero may further enhance our understanding of the congenital maldevelopment group.Presented at the Festschrift for Professor R. H. R. White on March 6, 1992, Birmingham, UK     

Vesicoureteric Reflux and Reflux Nephropathy as Seen at a Tertiary Care Adult Nephrology Service in India—An Analysis of 86 Patients

Clinical features and risk factors for renal failure in patients with reflux nephropathy (RN) as seen in an adult nephrology service are likely to be different than those seen in a pediatric service. There are only a few studies on adults with vesicoureteric reflux (VUR) and RN and data on RN as seen in developing countries is still evolving. Retrospective analysis of records of patients diagnosed to have VUR by conventional micturating cystourethrogram over a 13 year period, as seen in the adult nephrology services of this tertiary care hospital in north India was carried out. Results are presented as mean ± 2 SD. Unpaired t-test was used to compare means, chi-square test to define associations, and logistic regression analysis was done to define risk factors. Out of 86 patients diagnosed to have VUR, 69 (80.2%) were males and 22 (25.6%) were children. The mean age at presentation was 24.3 ± 14.5 years and at onset of symptoms was 19.6 ± 14.8 years. Sixty-nine (80.2%) patients had chronic renal failure (CRF) at presentation, including 33 (38.4%) patients who already had end stage renal failure (ESRF) at presentation in whom reflux was diagnosed during routine pretransplant evaluation and these constituted 5.5% of all ESRF patients. The clinical features at presentation were hypertension in 51 (59.3%), recurrent urinary tract infection (UTI) in 31 (36.1%), history of stones in 7 (8.1%), and gross hematuria in 4 (4.7%). Patients with history of recurrent UTI were more likely to be females (p<0.01) and to present without renal failure (p<0.05). Proteinuria >1 g/day was significantly associated (p<0.02) with hypertension at presentation. Patients who presented with renal failure were more likely to be males (p<0.05), not to have history of recurrent UTI (p<0.05), have proteinuria >1 g/day (p < 0.02) and higher grades (grades IV and V) of reflux (p<0.05). On logistic regression analysis, higher age of onset (odds ratio 4.6, p<0.03), proteinuria >1 g/day (odds ratio 3.8, p<0.05), and male gender (odds ratio 3.5, p<0.05) were significant risk factors for presentation for the first time with renal failure. The clinical features and course of VUR and RN as seen in India are different from those reported from elsewhere. The vast majority of patients in India are males and almost two thirds do not have a past history of UTI. Renal failure is present in more than three fourths of patients when a diagnosis of reflux is made and one third of all patients present with ESRD. Patients with a prior history of UTI are more commonly females and are less likely to have renal failure at presentation. Higher age of onset of symptoms, proteinuria >1 g/day and male gender were risk factors for the development of renal failure. It is likely that these asymptomatic patients remain undetected during childhood, presenting late only after having incurred severe renal damage.     

Vesicoureteric reflux in Kuwaiti children with first febrile urinary tract infection

The prevalence of vesicoureteric reflux (VUR) in children with urinary tract infection (UTI) varies among different racial groups. The purpose of this study was to determine the frequency of VUR and associated renal changes in a group of Arab Kuwaiti children with their first documented febrile UTI and to compare our findings with those reported from other racial groups. One hundred and seventy-four children (38 males and 136 females) fulfilled the study criteria and were divided into three age groups (<1 year, 1–5 years, and >5 years). Patients in each group had both micturating cystourethrography (MCUG) and 99m-Tc-dimercaptosuccinic acid (DMSA) renal scan after diagnosis. VUR was detected in 39 children (22%). Two-thirds of cases had mild reflux (grade I and II). Females (n=32) had more reflux than males (n=7) (24% vs. 18%). Sixty-three patients (36%) had abnormal (DMSA) renal scans (acute pyelonephritis [AP] or renal scars). Of these, 79% were children below 5 years. Abnormal DMSA scans were found in 4 of 38 males (11%) versus 59 of 136 females (43%). Abnormal scans in children with VUR were seen in 1 of 7 males (14%) versus 19 of 32 females (59%). In total, the combination of abnormal scan with VUR occurred in 1 of 38 males (3%) and in 19 of 136 females (14%), whereas abnormal scan without demonstrable VUR was seen in 3 of 38 males (8%) versus 40 of 136 females (29%). Our data showed that the frequency of VUR in Arab Kuwaiti children with febrile UTI is midway between Caucasian and other racial groups. In this study, males had a lower-risk profile than females, the latter having a higher rate of reflux as well as a higher rate of abnormal DMSA scans, irrespective of demonstrable VUR.     

Congenital urethral cysts in boys with vesicoureteric reflux

Four cases of congenital urethral cysts are reported. Diagnosis wasmade by endoscopy. The coincidence of urethral cysts and vesicouretericrefluxes seemed incidental in three cases. Fetal infravesicalobstruction was provable in the fourth infant. Conclusion:Urethral cysts should be considered in boys with vesicoureteric reflux.For the vast majority of cases it seems improbable that urethral cystsplay a role in the pathogenesis of congenital vesicoureteric reflux.     

Quantitation of vesico-ureteral reflux by radionuclide cystography and urodynamics

A method is described for the quantitation of vesico-ureteral reflux by synchronous combined direct radionuclide cystography and urodynamics. Intravesical pressures and volumes are co-ordinated with volumes of reflux. Peak reflux volumes in 11 children diagnosed as having severe (grades 3–4) reflux on conventional contrast cystography ranged from 1 to 50 ml/kidney. A number of different patterns of reflux were observed. Reflux may occur progressively throughout low pressure filling or incrementally with unstable bladder contractions. Reflux during voiding may be maximal as detrusor pressure falls. The method requires wider application to explore the potential for a functional classification of the reflux problem.     

Vesico-uretero-renal reflux and the kidney

The most frequent complications of non-obstructive vesico-uretero-renal reflux (VUR) are segmental renal scars. These scars are confined to segments with intrarenal reflux which are, in addition, exposed to bacterial infection. Primarily, only gaping collecting duct orifices, confined to compound papillae and mainly situated at the kidney poles, allow intrarenal reflux. Scar contraction and obstruction seem to be able to transform closed collecting duct orifices into gaping ones, thereby enlarging the parenchymal area prone to intrarenal reflux and to renal scarring. Contrary to earlier reports, a recent survey has documented that new scars in children develop with significant frequency beyond 5 years of age. There is a greater tendency for scarring to develop with more severe VUR, but new renal scars can develop with all grades of VUR [27]. Early and adequate antibiotic treatment decreases the extent of scarring. The results of experimental studies in which renal scarring developed in piglets with bladder decompensation resulting from intravesical obstruction but without bacterial infection may be relevant to the few children with proximal urethral valves and hypertonic neurogenic bladders but not to the large number with non-neurogenic detrusor instability or detrusor sphincter dyssynergia. Prospective studies have not shown different recurrence rates of urinary tract infections in medically managed compared with surgically managed children. The frequency of acute pyelonephritic attacks decreased significantly after operation.     

Pseudohypospadias with bilateral vesicoureteric reflux: consequences of inappropriate management of stricture urethra

A 17-year-old male boy presented with clinical features of pseudohypospadias (small penile stump with absent distal penile urethra) associated with very small capacity bladder and bilateral grade IV vesicoureteric reflux following suprapubic urinary diversion for multiple urethro-cutaneous fistula and periurethral abscess which developed as a consequence of inappropriate initial management of urethral trauma. This case highlights the importance of the initial management of urethral trauma and the management of its rare complication.     

Height and weight in children with vesicoureteric reflux and renal scarring

Height standard deviation scores (HSDS) and weight-for-height index (WHI) at diagnosis were evaluated in 156 children aged 2 months to 10.8 years (mean 3.7 years) with vesicoureteric reflux (VUR) and normal creatinine clearance, and in 156 age- and sex-matched healthy controls. Forty-three patients had bilateral VUR with scintigraphic signs of renal scarring (B SCAR+), 25 had bilateral VUR without renal scarring (B SCAR–); 40 had unilateral VUR with (U SCAR+) and 48 unilateral VUR without (U SCAR–) renal scarring. B SCAR+ patients had an average HSDS of –0.5±1.4 (SD) which was significantly (P = 0.02) below that of controls (0.05±1 HSDS) and an average WHI of 100.6%±16% which was significantly (P = 0.007) below that of controls (108%±12%); 14% of B SCAR+ patients had a height below –2 HSDS. B SCAR–, U SCAR+, and U SCAR– patients had heights near to O HSDS which was not different from that of controls, as well as WHI between 104% and 107.9%, which was not different from that of controls. HSDS and WHI were significantly (P = 0.00001) correlated in patients but not in controls. B SCAR–, U SCAR+, and U SCAR– patients are similar to healthy controls in weight and in height growth and have, on average, some excess weight as do the latter. In contrast, B SCAR+ subjects have a significant decrease of the relative height and normal WHI. Received May 23, 1995; received in revised form and accepted January 5, 1996     

Intrarenal dimensions

Summary Designs for flexible ureteropyeloscopes should be based on the configuration of the intrarenal collecting system. This study measured retrospectively the ureteroinfundibular angle and infundibular lengths of 30 patients treated for calculus disease. Recommendations are given for the design of flexible ureteropyeloscopes that could visualize the entire normal intrarenal collecting system.     

Clinicopathological study of vesicoureteral reflux (VUR)-associated pyelonephritis in renal transplantation

Abstract:  We retrospectively studied the occurrence of vesicoureteral reflux (VUR)-associated pyelonephritis using renal biopsies obtained from the transplanted kidneys, and correlated the histological changes with clinical parameters. Out of a total of 131 renal biopsies performed between 1990 and 2001 on renal transplant patients at the department of Urology of Nagasaki University Graduate School of Biomedical Sciences, 12 patients showed pyuria more than twice in a single year. Seven of these 12 patients were available for determining VUR by voiding cystourethrography (VCUG). Cystoureterography demonstrated VUR in three of seven studied patients with pyuria. A histopathological examination revealed dilatation of both proximal and distal tubules in renal biopsies of transplant patients with VUR, compared to renal biopsies of transplant patients without VUR, or non-transplanted patients with thin membrane disease. One of the patients with VUR showed advanced features of chronic pyelonephritis in four consecutive biopsies at different time points, suggesting a late stage of reflux nephropathy in the transplanted kidney. We conclude from our study that the occurrence of VUR-related pyelonephritis may be one of the important long-term complications in the survival of renal allografts.     

Endoscopic management of vesicoureteral reflux in adult women

Study Type – Therapy (case series) Level of Evidence 4

OBJECTIVE

• ? To describe our endoscopic management of adult women with vesicoureteral reflux (VUR) and associated outcomes.

PATIENTS AND METHODS

• ? We retrospectively identified 19 adult women who presented for the endoscopic treatment of VUR from November 2001 to January 2008.
• ? Each patient was diagnosed with VUR by voiding cystourethrogram or nuclear cystourethrogram after an episode of pyelonephritis or recurrent urinary tract infections with renal scarring on ultrasound.
• ? A dimercaptosuccinic acid renal scan was performed prior to treatment. All patients underwent endoscopic treatment with dextranomer/hyaluronic acid copolymer (Deflux®). Patients with bilateral VUR received bilateral injections during the same procedure.
• ? Follow‐up imaging was obtained and success was strictly defined as no degree of VUR. Patients with residual VUR received repeat endoscopic treatment.

RESULTS

• ? Nineteen patients with a mean age of 22 years old (range 18–33 years old) underwent endoscopic treatment for VUR. A total of 79% (15/19) had pre‐existing risk factors for VUR, including prior open anti‐reflux surgery (26%), family history of VUR (26%) and childhood diagnosis of VUR (26%).
• ? Imaging revealed that 47% (9/19) had renal scarring and 26% (5/19) had bilateral VUR. The success rate was 79% (19/24) after one treatment, 92% (22/24) after 5 patients received a second treatment, and 96% (23/24) after 2 patients received a third treatment. There were no perioperative complications.

CONCLUSION

• ? Endoscopic management of VUR is both safe and effective in adult women.

     

Enhanced detection of vesicoureteric reflux with isotopic cystography

We compared the accuracy of isotope cystography (IC) and fluoroscopic cystourethrography (FC) in detecting vesicoureteric reflux (VUR) in children. FC and IC were performed in 124 children, 56 boys and 68 girls, aged 1 month to 9.2 years (mean 2.1 years), admitted consecutively for suspected VUR over a 10-month period. VUR was diagnosed by one or both studies in 51 of 124 (41%) patients. The two methods were concordant for the detection of VUR in 84% of kidney-ureter units and in 93% for the detection or exclusion of severe VUR. IC detected VUR more accurately than FC, both when all grades of VUR were considered together (P=0.00001) and when only severe reflux was considered (P=0.004). VUR was missed by FC in 23 of 51 (45%) subjects. Of those 23, 12 had severe VUR detected on one side at least by IC. VUR was missed by IC in 3 subjects. IC is significantly more accurate than FC in the initial diagnosis of VUR, even of severe grade. IC is the method of choice for the first diagnosis of VUR. Boys with VUR diagnosed by IC also need FC to investigate for posterior urethral valves. Received: 4 August 1999 / Revised: 22 November 1999 / Accepted: 23 November 1999     

A model of sterile vesicoureteric reflux in the sheep

Eighteen Coopworth ewe lambs were divided into three groups based on the initial cystourethrogram and cystometry findings at 5 – 7 weeks of age: group 1, 6 lambs with spontaneous low-pressure bilateral vesicoureteric reflux (VUR) on bladder filling were used to study the natural history of reflux; group 2, 5 lambs with no VUR detected were used to establish an experimental model of bilateral VUR using an unroofing surgical procedure; group 3, 7 lambs with spontaneous VUR detected during micturition had the same surgical procedure to increase the degree of VUR. All three animal groups were followed for 4 – 10 months. Spontaneous VUR was demonstrated in 13 of 18 lambs (25/36 ureters). The presence and severity of spontaneously occurring reflux in group 1 lambs diminished with increasing age. VUR was created successfully in group 2 and increased in degree in group 3 animals. The only significant histological finding in all three animal groups with grades II and III VUR was distal renal tubular dilatation. The sheep is a useful and readily available animal for studying VUR. During 4 – 10 months of follow-up, sterile reflux without bladder outflow obstruction resulted in distal renal tubular dilatation, but no renal parenchymal damage. Received April 17, 1997; received in revised form August 5, 1997; accepted August 21, 1997     

Laminin and transforming growth factor beta-1 in children with vesicoureteric reflux

High-grade vesicoureteric reflux (VUR) promotes the development of renal nephropathy (RN) due to scar formation. This process involves transforming growth factor beta-1 (TGF beta₁), which stimulates production of the extracellular matrix proteins, including laminin (LN). The aim of the study was to assess LN and TGF beta₁ concentration according to VUR grade. The study group (1) consisted of 54 patients aged 6.23 ± 4.15 years with VUR, including: A, 19 with grade II; B, 19 with grade III; and C, 16 with grades IV or V reflux. The control group (2) contained 27 healthy patients aged 6.76 ± 4.02 years. LN and total TGF beta₁ concentrations in serum and urine were determined by the immunoenzymatic (EIA) method. To assess total serum TGF beta₁ levels, we used a solid-phase enzyme-linked immunosorbent assay (ELISA). Both serum and urinary levels of LN and TGF beta₁ in VUR patients were higher compared with controls (p < 0.05). The highest urinary concentration of LN and TGF beta₁ was found in subgroup C. A positive correlation was noted between urinary TGF beta₁ and LN. Increased TGF-beta₁ and LN levels in urine of high-grade VUR children suggests a potential role in fibrogenesis. Further trials are needed to investigate the role of serum and urinary LN level in VUR children.     

Cyclic voiding cystourethrography in the diagnosis of occult vesicoureteric reflux

Cyclic voiding cystourethrography (CVC) enhances the detection of vesicoureteric reflux (VUR). We investigated whether more-severe VUR may be overlooked, and whether older children are at risk of having their VUR missed with the conventional single-cycle study. Three hundred and seventy patients, 168 boys and 202 girls aged 1 month to 16 years, consecutively admitted over 1 year for suspicion of VUR, underwent two complete cycles of filling and voiding CVC. One hundred and four subjects, 33 boys and 71 girls, were older than 3 years (mean age 5.7 years, range 3.2–16 years).Sixty-six refluxing ureters from 51 patients were identified in the first cycle and 61 refluxing ureters from 45 patients were identified only with the second cycle. Four instances of grade IV VUR in 4 patients and three of grade V VUR in 3 patients were overlooked completely in the first cycle. Seven episodes of VUR ≤ grade III from 5 patients diagnosed in the first cycle were upgraded to ≥ grade IV at the second cycle. The presence of VUR was identified only in the second cycle in 35 of 74 subjects aged ≤ 3 years and in 10 of 22 aged >3 years (not significant). Of the 10 children aged >3 years, 2, who had diagnosis only at the second cycle, had ≥ grade IV VUR. More-severe VUR may be overlooked or down-graded in a single-cycle study. Two-cycle CVC is also useful in children older than 3 years. Received: 4 June 1998 / Revised: 11 January 1999 / Accepted: 22 January 1999     

Vesicoureteric reflux is not a benign condition

Renal parenchymal defects may be congenital, usually associated with dilated vesicoureteric reflux (VUR), or they may appear in previously normal kidneys and be caused by reflux nephropathy due to VUR combined with urinary tract infection (UTI). A piglet model defined that the 70% of children with VUR and vulnerable pyramids would scar rapidly with their first UTI. Because most defects are present at first imaging after a UTI, and from the lack of benefit from apparently reasonable clinical interventions, many now believe that most defects are congenital, their association with VUR being a shared dysplasia rather than causal. Consequently, guidelines now argue for less assiduous management. These conclusions ignore adult human transplant evidence, adult pig studies, and clinical anecdotes, which indicate that scars may develop in infant kidneys quicker than urine culture can confirm the diagnosis, and that reflux nephropathy has no age limit. Its rarity over 4 years suggests that most vulnerable children develop scars before then, despite all medical efforts. I argue that preventing such scarring will require better diagnosis of infant UTI, quicker treatment, reliable imaging of scars and VUR, and subsequent protection until VUR resolves. To make a difference, we need more assiduous management, not less, and cannot afford to consider VUR to be a benign condition.     

Outcome of pregnancy in women with a history of vesico-ureteric reflux

OBJECTIVES

To review the evidence relating to the outcome of pregnancy in women with vesico‐ureteric reflux (VUR) or a previous history of VUR and to identify the factors contributing to morbidity in pregnancy, with particular emphasis on the role of renal scarring.

METHODS

Searches were carried out in Medline, Pubmed and MD Consult using various combinations of the keywords including: vesicoureteral reflux and pregnancy, maternal vesicoureteral reflux, vesicoureteral reflux in adulthood, reflux nephropathy and pregnancy. All data quoted in this review are from original articles.

RESULTS

The published studies showed that women with VUR that was not associated with renal scarring had no increase in the incidence of gestational hypertension, pre‐eclampsia or fetal morbidity, regardless of whether their VUR was diagnosed in childhood or adulthood. However, women with VUR and normal kidneys did have higher incidence of urinary tract infection during pregnancy, which was not modified by ureteric re‐implantation. Renal scarring was the primary risk factor for morbidity during pregnancy and this risk was independent of the presence or absence of VUR at the time of pregnancy.

CONCLUSION

The evidence does not support the practice of correcting low‐grade VUR in girls with unscarred kidneys because this will reduce their risk of complications in pregnancy. The presence of renal scarring rather than the presence or absence of reflux is the principal determinant of morbidity during pregnancy.