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     

ACE gene insertion/deletion polymorphism and renal scarring in children with urinary tract infections

Urinary tract infection is a common bacterial disease that presents during childhood and may lead to renal scarring. Several studies have shown a strong association between the angiotensin converting enzyme (ACE) deletion polymorphism and renal scarring in children with vesicoureteric reflux (VUR). The purpose of this study was to investigate the possible correlation between the ACE deletion polymorphism and renal scarring in 186 children with urinary tract infection (UTI), of whom 90 were renal scar positive and 96 were renal scar negative. The control group consisted of 129 children with no UTI. Renal scars were diagnosed by means of ^99mTc-dimercapto-succinic acid scans, and ACE genotypes were determined as II, ID, and DD by PCR analyses. The ACE genotype distribution was 10% II, 67% ID, and 23% DD in the renal scar-positive group, 18% ΙΙ, 42% ID, and 40% DD in the renal scar-negative group, and 22% II, 47% ID, and 31% DD in the control group. No correlation was found between the DD genotype and renal scar formation in children with UTI. The same results were obtained following strafication of the patients by VUR and age of the first urinary tract infection. In conclusion, the results of this study suggest that the DD genotype is not an independent risk factor for renal scarring in children with UTI.     

The deletion polymorphism of the ACE gene is not an independent risk factor for renal scarring in children with vesico-ureteric reflux.

BACKGROUND: The deletion (D) polymorphism of the gene encoding angiotensin-I converting enzyme has been implicated as a risk factor for progressive renal disease in several conditions. This study was designed to evaluate the association between homozygosity for the D allele and susceptibility to renal scarring in children with vesico-ureteric reflux (VUR). METHODS: Two-hundred-and-six children with VUR (all grades) were recruited into the study. Patients were stratified into two groups according to the presence or absence of renal scarring. One-hundred-and-twelve patients (group 1) had evidence of renal scarring. Ninety-four children had no evidence of renal scarring (group 2). ACE genotypes were determined by polymerase chain reaction (PCR) amplification of genomic DNA samples. RESULTS: There was no association between the DD polymorphism and the presence of renal scarring. Genotype frequencies in group 1 were: II, 29; ID, 56; and DD, 27; and in group 2 were: II, 12; ID, 52; DD, 30 (P=0.21). Neither was there evidence supporting a 'dominant' D allele. There was no association between the DD genotype and the presence of proteinuria or reduced renal function (P>0.05). Hypertension was seen more frequently in those individuals with the DD genotype, compared with the other two genotypes (P=0.012). CONCLUSION: We cannot confirm previous reports that children with vesico-ureteric reflux who are homozygous for the deletion polymorphism of the ACE gene are more susceptible to renal scarring than heterozygotes and II homozygotes.     

Endoscopic correction of primary vesicoureteric reflux

One hundred and three children with primary vesicoureteric reflux treated by endoscopic injection of Polytef paste between March 1984 and February 1986 have been followed up for periods ranging from 3 to 23 months. Seventy-five per cent of refluxing ureters showed absence of reflux after one injection of Polytef paste; 14% of ureters required two to four sub-ureteric injections of Polytef paste for the correction of vesicoureteric reflux; 8% of ureters showed improvement in the grade of reflux after the initial injection of Polytef paste. Duplex systems were more difficult to correct and recurrence of reflux was much higher than in primary reflux. Follow-up intravenous urograms showed no evidence of ureteric obstruction in the treated ureters. The procedure is safe, simple and effective in correcting all grades of vesicoureteric reflux. To obtain best results, attention should be paid to minute details of the technique and the injection made with pinpoint accuracy.     

Renal scarring secondary to vesicoureteric reflux. Critical assessment and new grading

One hundred and fifty children with proven urinary tract infection who were assessed by renal ultrasound (U/S), intravenous urography (IVU) and dimercaptosuccinic acid (99mTc DMSA) scan, were studied to identify the sensitivity of each examination and the pick-up rate of renal scarring secondary to vesicoureteric reflux. Sixty-three of these children who had the examinations carried out within a 6-month period were assessed in detail. A DMSA scan is the most accurate method of detecting early renal scars in the young age group (0-2 and 2-5 years), followed by ultrasound. The examinations are equally sensitive over the age of 5. A new grading system of the severity of renal scarring is presented.     

Renal scarring and primary reflux in adults

Twelve of 20 adults with primary reflux had radiographic features of pyelonephritis. Six of the 12 patients had no history of urinary tract infection during childhood. The severity of renal scarring did not correlate with a positive childhood history. The pathophysiologic aspects of renal scarring and therapeutic implications are discussed.     

Renal scarring caused by vesicoureteric reflux and urinary infection: a study in pigs

The diminishing risk of acute renal scarring with urine infections (reflux nephropathy) after infancy is unexplained, but might reflect kidney maturation. The mechanisms of reflux nephropathy scarring are best explained by a piglet model in which vesicoureteric reflux allows infected urine to enter those segments of renal parenchyme that are drained by compound papillae. We carried out a similar study in adult pigs to determine whether protective maturation occurs. Adult pigs were exposed to urine infection after surgery to produce unilateral vesicoureteric reflux. The intravesical portion of one ureter was deroofed in six female adult Gottingen mini-pigs and the bladder and the ureteric mucosae stitched around the perimeter of the new orifice. One week later Escherichia coli was injected into the urinary bladder to produce cystitis. Three weeks later the animals were killed humanely and the urinary tracts were examined. The animals sustained persistent urine infections; the untreated ureters and kidneys remained normal. However, on the operated side, the ureters were thickened and dilated, vesicoureteric reflux was shown in four cases, and the kidneys had one or more flattened area overlying a renal segment, which showed severe inflammatory changes and early scar formation. The risk of reflux nephropathy scarring is not eliminated by maturation of the kidney in pigs. It is unlikely that the much-reduced risk of initiating scarring that is seen in older children with urine infections is due to a protective maturation of the human kidney. A possible explanation is that most children born with risk factors for developing scarring will have already sustained scars when very young.     

ACE and AT1 receptor gene polymorphisms and renal scarring in urinary bladder dysfunction

The objective of this study was to investigate whether DNA polymorphisms of the renin-angiotensin system (RAS) genes were associated with renal scar formation in pediatric patients with bladder dysfunction (BD). Although these children are born healthy, due to persistence of immature voiding habits and evolution of BD, some develop progressive renal damage. It has been suggested that the DD genotype of the angiotensin I-converting enzyme (ACE) gene might be an adverse renal prognostic factor. The insertion/deletion (I/D) polymorphism of the ACE gene and the A1166C polymorphism of the angiotensin II type 1 receptor (ATR1) gene were identified by polymerase chain reaction amplification in 42 children with BD (aged 5–14 years) and 198 healthy adult controls. Twelve children had urgency syndrome and 30 had dysfunctional voiding. Renal scarring was found in 16 patients, while 26 patients had normal kidneys on dimercaptosuccinic acid scan. In children with renal lesions there was significant over-representation of the DD genotype compared with either controls or patients without renal damage (P<0.05). On multivariate analysis, the DD genotype was the only factor that had a significant impact on renal scar formation, introducing a 2.51-fold risk (odds ratio 2.51, 95% confidence interval 1.04–6.04, P=0.04). The A1166C gene polymorphism was not significantly associated with the development of parenchymal damage in children with BD. Our findings introduce ACE I/D gene polymorphism as an independent risk factor for parenchymal destruction in pediatric patients with BD.M. Kosti and A. Stankovi contributed equally to this work     

Late recurrent urinary tract infections may produce renal allograft scarring even in the absence of symptoms or vesicoureteric reflux

BACKGROUND: The significance of late urinary tract infections (UTIs) after renal transplantation and their association with scarring and graft dysfunction remains controversial. We sought to define the prevalence of renal scarring in allograft recipients with a history of late recurrent UTIs, to determine whether the presence of vesicoureteric reflux (VUR) confers an increased risk of scarring and to establish whether scarring correlates with graft dysfunction. METHODS: Among 307 renal allograft recipients, we identified 56 (18%) with late recurrent UTIs (> or =3/year). A total of 32 patients had undergone further investigation by both 2,3 dimercapto-succinic acid single-photon emission computed tomography (99mTc-DMSA SPECT) scan and micturating cystourethrogram (MCUG). RESULTS: Of the 32 patients, 24 (75%) had scars on 99mTc-DMSA SPECT and 15 (47%) had reflux on MCUG. Thirteen of these 15 patients with reflux (87%) had scars, although there was no significant correlation between number of scars and degree of reflux. Eleven of 17 patients (65%) with UTIs but without VUR had scars, as did 12 of 14 (86%) with previous graft pyelonephritis. The pattern of scarring (typically multiple focal cortical defects) suggested infection as the cause. This pattern was not seen in a contemporary cohort with vascular occlusions and was rarely seen in patients with chronic allograft nephropathy. Scarring was not associated with inferior graft survival (median follow-up, 15 years). CONCLUSIONS: In patients with late UTIs, renal scarring is a frequent finding. Scarring may occur even in asymptomatic patients without VUR. The lack of an effect on graft survival may reflect successful intervention with prophylactic antibiotics and surveillance urine cultures. Late recurrent UTIs may be damaging to renal allografts, even in the absence of reflux.     

Urinary diversion in infants with primary high-grade vesicoureteric reflux, urinary sepsis and renal function impairment

INTRODUCTION: General consensus on the optimal treatment of septic infants with primary high-grade vesicoureteric reflux (VUR) and renal function impairment has not been reached. Our study aims at evaluating the role of temporary urinary diversion. MATERIALS AND METHODS: Twenty male infants, affected by sepsis and primary high-grade VUR, underwent urinary diversion in 1996-2001 because of estimated risk of renal function deterioration, due to non-compliance with the antibiotic treatment. Plasmatic creatinine clearance, ultrasonography, micturition cystography and scintigraphy were evaluated. RESULTS: Creatinine clearance was abnormal in 13 infants on admission, in 10 after urinary diversion and in 6 after second surgery. Renal damage (focal or diffuse) was evident in 16 patients, without modifications after surgery. No patient developed urinary tract infections (UTI). Vesicostomy was done in 12 cases, ureterostomy in 8. Nephrectomy was performed in 3 cases with poor renal function, and ureteroneocystostomy in 17. CONCLUSIONS: Urinary diversion in septic infants with high-grade VUR can represent an alternative approach to the conservative or surgical treatment in selected patients presenting risk of renal function impairment. This procedure allowed an easy management of UTI without worsening of renal function while waiting for a better anatomical status to perform reconstructive surgery.     

Comparison of DMSA scintigraphy with intravenous urography for the detection of renal scarring and its correlation with vesicoureteric reflux.

A series of 208 patients was prospectively assessed for reflux nephropathy by intravenous urography (IVU) and 99mTc-dimercaptosuccinate (DMSA) scintigraphy. All patients were studied at least 3 months after their most recent urinary tract infection and micturating cystourethrography (MCU) was performed prior to the scintigraphic studies. DMSA scintigraphy detected significantly more cortical abnormalities than did IVU. There was also a correlation between cortical abnormalities in the DMSA studies and the degree of reflux on MCU. The validity of DMSA as a cortical imaging agent is evaluated and the histological evidence for its efficacy derived from the animal model is reviewed, lending weight to its establishment as the "gold standard" for renal cortical scarring.     

ACE gene polymorphism and renal scar in children with acute pyelonephritis

The pathogenesis of renal scarring after acute pyelonephritis (APN) in children is multifactorial. In addition to well-known risk factors (young age, high grade of vesicoureteral reflux, P-fimbriated Escherichia coli, and treatment delay), a role for genetic predisposition has been suggested. Since the ACE gene deletion polymorphism is a known risk factor for progressive glomerulosclerosis in chronic renal diseases, we have investigated the relationship between the ACE genotypes and the development of renal scarring after APN. Fifty-nine children (43 males and 16 females) with APN diagnosed by urine culture and technetium-99m-dimercaptosuccinic acid ((99)Tc-DMSA) renal scan were studied. ACE genotypes were determined as II, ID, and DD using the polymerase chain reaction technique. A follow-up (99)Tc-DMSA renal scan was performed to evaluate the development of renal scars 3-6 months after treatment. The distribution of ACE genotypes and the allele frequencies were compared in the renal scar-positive ( n=39) and -negative group ( n=20). ACE genotype frequency after stratification by risk factors was also evaluated. The distribution of ACE genotypes did not differ between the renal scar-positive (II 25.9%, ID 35.9%, DD 28.2%) and -negative group (II 35.0%, ID 45.0%, DD 20.0%), before and after stratification by each risk factor. ACE gene deletion polymorphism did not affect the development of renal scar as an independent variable in children with APN.     

Angiotensin converting enzyme gene polymorphism in primary vesicoureteral reflux

We studied the insertion/deletion (I/D) polymorphism of the angiotensin converting enzyme (ACE) gene in 78 patients with primary vesicoureteral reflux (VUR), and examined renal function by dimercaptosuccinate (DMSA) renoscintigraphy and diethylenetriaminepenta-acetic acid (DTPA) renogram in each genotype. Patients were classified into three genotypes according to the ACE gene I/D polymorphisms: 32 in II genotype, 36 in ID, and 10 in DD. The incidence of presumably congenital unilateral small kidneys was high in DD patients (70%). Glomerular filtration rate obtained from DTPA renogram was 120.7±35.7 ml/min (expressed as mean±SD) in II genotype, 111.7±33.3 in ID, and 88.0±18.0 in DD. The total quantitative DMSA tracer uptake of both kidneys was also low in patients with the D allele. This study shows that the D allele of ACE gene is closely related to small congenital kidneys with refluxing ureters in patients with primary VUR, and in accordance with previous reports, this allele is also related to the progression of reflux nephropathy. Received: 27 November 2000 / Revised: 10 April 2001 / Accepted: 10 April 2001     

Features of primary vesicoureteric reflux detected by prenatal sonography

Primary vesicoureteric reflux (VUR) was detected by prenatal sonography in 34 infants (55 renal units); males accounted for 31 cases. Associated genitourinary anomalies were common, occurring in 29% of the patients. Some element of hydroureteronephrosis was noted at initial cystography in 89% of refluxing renal units, but the degree of renal abnormality at 99Tc DMSA renography was not predicted by the severity of VUR. Overall, 60% of refluxing renal units were renographically abnormal. Although a high rate of urinary infection was encountered during follow-up, most DMSA assessments were carried out prior to infection and hence likely reflect congenital rather than acquired abnormalities. It was concluded that renal impairment associated with high grade primary VUR is frequently present at birth and not secondary to subsequent infection.     

Primary vesicoureteric reflux and renal damage in the first year of life

We retrospectively examined 93 children (47M/46F) with primary vesicoureteric reflux (VUR) followed for a mean period of 3.5 years. They were divided into two groups. Group A included 34 babies (25M/9F) with a prenatal diagnosis of pelvic dilatation. Mean age at presentation was 12 days and no urinary tract infection (UTI) occurred before our first examination. VUR was unilateral in 21 (62%) patients and bilateral in 13 (38%). It was mild (grades I–III) in 12 (25%) refluxing renal units (RRU) and severe (grades IV–V) in 35 (75%). Renal damage (RD) was present, at diagnosis, in 40 (85%) RRU. There was a greater prevalence of abnormal kidneys in male units (88%) than in female units (75%). Group B included 59 infants (22M/37F) less than 1 year old with UTI. The mean age at first examination was 7.6 months. VUR was unilateral in 32 (54%) infants and bilateral in 27 (46%), mild in 60 (70%) RRU and severe in 26 (30%). At diagnosis, 54 (63%) RRU presented RD, which was more common in females (66%) than in males (44%). Our study confirms that primary VUR associated with prenatal hydronephrosis usually affects males and is severe. VUR diagnosed after UTI, instead, is more common in females and is frequently mild. Although in the first type of reflux RD is often present at diagnosis, then probably congenital, it may always progress after UTI; hence the importance of early diagnosis and careful follow-up in each infant with primary VUR. Received: 9 August 1999 / Revised: 3 April 2000 / Accepted: 7 July 2000     

Gene discovery and vesicoureteric reflux

Vesicoureteric reflux (VUR) is a congenital urinary tract defect caused by abnormal insertion of the ureter within the bladder wall. This leads to a defective ureterovesical junction in which urine flows retrogradely from the bladder to the kidneys. Although VUR is associated with recurrent urinary tract infections, renal malformations, hypertension, and reflux nephropathy, its relationship to each of these clinical entities is poorly understood. Mutations in genes expressed by the developing kidney and urinary tract can cause VUR in mice, and some of these same genes have been identified in humans with VUR. By discovering the genes that are associated with VUR, new hypotheses will be generated such that, eventually, the relationship between VUR and its complications will be understood.     

ACE I/D gene polymorphism predicts renal damage in congenital uropathies

We investigated angiotensin converting enzyme gene (ACE I/D) polymorphism as a risk for progressive renal damage in congenital uropathies. The ACE I/D genotype was determined in 196 Caucasian patients with congenital uropathies and 163 individuals with no clinical or sonographic evidence of any urological malformations. The study group included patients with ureteropelvic junction obstruction (n=49), primary obstructive megaureter (n=19), primary vesicoureteral reflux (VUR) (n=67), and posterior urethral valves (n=27). Thirty-four patients were excluded because of additional diseases or insufficient follow-up. There was no difference in the ACE I/D distribution between children with uropathies and normal controls (II 16%, ID 56%, DD 28% vs. II 26%, ID 50%, DD 24%). Renal lesions were found in 99 of 162 children by ultrasonography, intravenous pyelography, and nuclear scans. In these children there was significant over-representation of the DD genotype (II 11%, ID 53%, DD 36%) compared with normals (P<0.005, X²=14.9) or with patients with uropathies but no renal lesions (II 23%, ID 62%, DD 15%, P<0.005, X²=14.9). Because ACE I/D has been linked with progressive deterioration of renal function, we evaluated a subset of patients with initially normal kidneys who developed radiographic renal lesions (n=28). Among these patients there was an even greater over-representation of the DD genotype (II 0%, ID 43%, DD 57%, P<0.001, X²=22.6) compared with patients with uropathies but no radiographic lesions. Multivariate analysis revealed that the DD genotype is a risk factor for parenchymal destruction, which was independent of time of diagnosis, surgical intervention, or urinary tract infection. This finding was particularly relevant in patients with VUR who constituted the majority with initially normal kidneys who developed radiographic damage (22/28). Indeed, the odds ratio of developing parenchymal damage with VUR was significantly increased if the individual had the DD genotype (4.2, 95% confidence interval 1.4–13.0). In conclusion the ACE I/D gene polymorphism is a risk factor for renal parenchymal damage in patients with congenital urological abnormalities and appears particularly relevant in children with VUR, where it is an independent predisposing factor. Received: 3 November 1998 / Revised: 3 March 1999 / Accepted: 3 March 1999     

ACE I/D gene polymorphism in primary FSGS and steroid-sensitive nephrotic syndrome

The role of angiotensin-converting enzyme (ACE) insertion/deletion (I/D) gene polymorphism in various renal disorders has been investigated. We evaluated the association between the clinical characteristics and ACE genotypes of Turkish children with primary focal segmental glomerulosclerosis (FSGS) and steroid-sensitive nephrotic syndrome (SSNS). Patients with FSGS (n=30) were classified into two groups: one with remission together with stable renal function (n=22) and the other without remission and with impaired renal function (n=8). We classified children with SSNS (n=43) that were followed for at least 4 years into two subgroups as having more frequent (n=19) and less frequent relapses (n=11). The DD genotype was more frequent in the SSNS group than that in controls (37% vs. 17%, ²=4.98, P=0.025). However, among SSNS subgroups, the frequency of the DD genotype was not different. The distribution of ACE genotype was similar among patients with FSGS and SSNS. There was no difference in the ACE I/D distribution between children with FSGS and normal controls (II 10%, ID 60%, DD 30% vs. II 13%, ID 70%, DD 17%). The frequency of the DD genotype was higher in FSGS patients with declining renal function (63%) than in those with stable renal function (18%) (P=0.031). Progressive renal impairment was significantly more frequent in patients with FSGS with the homozygous D allele compared with FSGS patients with ID and II genotypes. Our results indicate that the DD genotype may be a risk factor for the development of progressive renal impairment in children with FSGS; however, larger studies are required to confirm this.The abstract of this study was accepted as a poster for the 36th meeting of the European Society of Paediatric Nephrology, Bilbao, September 2002. This study was supported in part by a grant from the Istanbul University Research Fund (no T-849/17072000)     

Cyclic voiding urosonography for detecting vesicoureteric reflux in renal transplant recipients.

BACKGROUND: The clinical significance of vesicoureteric reflux (VUR) in renal transplant recipients remains controversial. Voiding urosonography (VUS), a new modality for detecting VUR, can be used in these patients. The sensitivity of X-ray and radionuclide cystography for detecting VUR may be improved with cyclic procedures. The aim of our study was to evaluate whether cyclic VUS is superior to the single-cycle procedure. METHODS: Cyclic VUS was performed in 27 renal transplant recipients. Eight were children or adolescents and the remaining 19 recipients were adults. VUS was performed according to accepted guidelines. After the first micturition, the catheter was left in place and the entire procedure was repeated under the same conditions. RESULTS: Both initial cycle and cyclic VUS detected 17 out of 27 (63%) VURs in the same patients. The sensitivity was not improved by cyclic VUS. However, there were differences between the initial cycle and cyclic VUS (P=0.028) when comparing the number of negative results and the grades of VURs detected. This difference was even more pronounced when analysing only positive results. In the initial cycle, five out of 17 (29%) VURs were grade III, compared with 10 out of 17 (59%) grade III VURs in the same patients using the cyclic procedure (P=0.008). CONCLUSIONS: Cyclic VUS did not improve the detection sensitivity for VUR in our study. However, given that VUR grade may be important for the management of renal transplant recipients, the use of cyclic VUS may provide a useful diagnostic tool for these patients.