Billy S. Arant

Pediatric Vesicoureteral Reflux Guidelines Panel Summary Report on the Management of Primary Vesicoureteral Reflux in Children

PURPOSE The American Urological Association convened the Pediatric Vesicoureteral Reflux Guidelines Panel to analyze the literature regarding available methods for treating vesicoureteral reflux diagnosed following a urinary tract infection in children and to make practice policy recommendations based on the treatment outcomes data insofar as the data permit. MATERIALS AND METHODS The panel searched the MEDLINE data base for all articles from 1965 to 1994 on vesicoureteral reflux and systematically analyzed outcomes data for 7 treatment alternatives: 1) intermittent antibiotic therapy, 2) bladder training, 3) continuous antibiotic prophylaxis, 4) antibiotic prophylaxis and bladder training, 5) antibiotic prophylaxis, anticholinergics and bladder training, 6) open surgical repair and 7) endoscopic repair. Key outcomes identified were probability of reflux resolution, likelihood of developing pyelonephritis and scarring, and possibility of complications of medical and surgical treatment. RESULTS Available outcomes data on the various treatment alternatives were summarized in tabular form and graphically, and the relative probabilities of possible outcomes were compared for each alternative. Treatment recommendations were based on scientific evidence and expert opinion. The panel concluded that only a few recommendations can be derived purely from scientific evidence of a beneficial effect on health outcomes. CONCLUSIONS For most children the panel recommended continuous antibiotic prophylaxis as initial treatment. Surgery was recommended for children with persistent reflux and other indications, as specified in the document.

Summary of the AUA Guideline on Management of Primary Vesicoureteral Reflux in Children

PURPOSE The American Urological Association established the Vesicoureteral Reflux Guideline Update Committee in July 2005 to update the management of primary vesicoureteral reflux in children guideline. The Panel defined the task into 5 topics pertaining to specific vesicoureteral reflux management issues, which correspond to the management of 3 distinct index patients and the screening of 2 distinct index patients. This report summarizes the existing evidence pertaining to children with diagnosed reflux including those young or older than 1 year without evidence of bladder and bowel dysfunction and those older than 1 year with evidence of bladder and bowel dysfunction. From this evidence clinical practice guidelines were developed to manage the clinical scenarios insofar as the data permit. MATERIALS AND METHODS The Panel searched the MEDLINE(R) database from 1994 to 2008 for all relevant articles dealing with the 5 chosen guideline topics. The database was reviewed and each abstract segregated into a specific topic area. Exclusions were case reports, basic science, secondary reflux, review articles and not relevant. The extracted article to be accepted should have assessed a cohort of children with vesicoureteral reflux and a defined care program that permitted identification of cohort specific clinical outcomes. The reporting of meta-analysis of observational studies elaborated by the MOOSE (Meta-analysis Of Observational Studies in Epidemiology) group was followed. The extracted data were analyzed and formulated into evidence-based recommendations. RESULTS A total of 2,028 articles were reviewed and data were extracted from 131 articles. Data from 17,972 patients were included in this analysis. This systematic meta-analysis identified increasing frequency of urinary tract infection, increasing grade of vesicoureteral reflux and presence of bladder and bowel dysfunction as unique risk factors for renal cortical scarring. The efficacy of continuous antibiotic prophylaxis could not be established with current data. However, its purported lack of efficacy, as reported in selected prospective clinical trials, also is unproven owing to significant limitations in these studies. Reflux resolution and endoscopic surgical success rates are dependent upon bladder and bowel dysfunction. The Panel then structured guidelines for clinical vesicoureteral reflux management based on the goals of minimizing the risk of acute infection and renal injury, while minimizing the morbidity of testing and management. These guidelines are specific to children based on age as well as the presence of bladder and bowel dysfunction. Recommendations for long-term followup based on risk level are also included. CONCLUSIONS Using a structured, formal meta-analytic technique with rigorous data selection, conditioning and quality assessment, we attempted to structure clinically relevant guidelines for managing vesicoureteral reflux in children. The lack of robust prospective randomized controlled trials limits the strength of these guidelines but they can serve to provide a framework for practice and set boundaries for safe and effective practice. As new data emerge, these guidelines will necessarily evolve.

Medical management of mild and moderate vesicoureteral reflux : followup studies of infants and young children. A preliminary report of the southwest pediatric nephrology study group

Mild and moderate vesicoureteral reflux is expected to resolve spontaneously in most children treated medically; however, maximum benefit or minimum risk of such therapy has not been defined. A prospective 5-year followup study of infants and children younger than 5 years at entry with primary vesicoureteral reflux (grades I to III/V) and radiographically normal kidneys after the first recognized urinary tract infection was initiated in 1984. A total of 113 patients was entered from 5 centers and 61% of the patients were less than 2 years old. Vesicoureteral reflux was unilateral in 65 cases (58%) and bilateral in 48 (42%). Of the 226 renal units reflux was grade IV in 4 (2%), III in 51 (22%), II in 81 (36%) and I in 25 (11%), and 65 (29%) had no vesicoureteral reflux. Data on 59 patients who have completed the protocol were analyzed for this report. Breakthrough urinary tract infection occurred in 20 patients. Of the 84 ureters with vesicoureteral reflux at diagnosis reflux resolved in 67%, and it was of lower grade in 22%, same grade in 8% and higher grade in 2%. Grade I vesicoureteral reflux resolved in 82%, grade II in 80% and grade III in 46% of the ureters. Resolution was better when vesicoureteral reflux was unilateral left (74%) than unilateral right (46%) or bilateral (60%). Renal scarring occurred, on average, in 10% of the kidneys without known vesicoureteral reflux or exposed only to nondilating (grades I and II) reflux and in 28% of those with dilating (grade III) reflux. Thirteen cases had breakthrough urinary tract infection but only after the scar was noted in 5. We conclude that under good medical management during 5 years of followup, even mild and moderate vesicoureteral reflux can be associated with renal injury.

Pediatric Vesicoureteral Reflux Guidelines Panel Summary Report: Clinical Practice Guidelines for Screening Siblings of Children With Vesicoureteral Reflux and Neonates/Infants With Prenatal Hydronephrosis

PURPOSE The American Urological Association established the Vesicoureteral Reflux Guideline Update Committee in July 2005 to update the management of primary vesicoureteral reflux in children guideline. The Panel defined the task into 5 topics pertaining to specific vesicoureteral reflux management issues, which correspond to the management of 3 distinct index patients and the screening of 2 distinct index patients. This report summarizes the existing evidence pertaining to screening of siblings and offspring of index patients with vesicoureteral reflux and infants with prenatal hydronephrosis. From this evidence clinical practice guidelines are developed to manage the clinical scenarios insofar as the data permit. MATERIALS AND METHODS The Panel searched the MEDLINE(R) database from 1994 to 2008 for all relevant articles dealing with the 5 chosen guideline topics. The database was reviewed and each abstract segregated into a specific topic area. Exclusions were case reports, basic science, secondary reflux, review articles and not relevant. The extracted article to be accepted should have assessed a cohort of children, clearly stating the number of children undergoing screening for vesicoureteral reflux. Vesicoureteral reflux should have been diagnosed with a cystogram and renal outcomes assessed by nuclear scintigraphy. The screening articles were extracted into data tables developed to evaluate epidemiological factors, patient and renal outcomes, and results of treatment. The reporting of meta-analysis of observational studies elaborated by the MOOSE group was followed. The extracted data were analyzed and formulated into evidence-based recommendations regarding the screening of siblings and offspring in index cases with vesicoureteral reflux and infants with prenatal hydronephrosis. RESULTS In screened populations the prevalence of vesicoureteral reflux is 27.4% in siblings and 35.7% in offspring. Prevalence decreases at a rate of 1 screened person every 3 months of age. The prevalence is the same in males and females. Bilateral reflux prevalence is similar to unilateral reflux. Grade I-II reflux is estimated to be present in 16.7% and grade III-V reflux in 9.8% of screened patients. The estimate for renal cortical abnormalities overall is 19.3%, with 27.8% having renal damage in cohorts of symptomatic and asymptomatic children combined. In asymptomatic siblings only the rate of renal damage is 14.4%. There are presently no randomized, controlled trials of treated vs untreated screened siblings with vesicoureteral reflux to evaluate health outcomes as spontaneous resolution, decreased rates of urinary infection, pyelonephritis or renal scarring. In screened populations with prenatal hydronephrosis the prevalence of vesicoureteral reflux is 16.2%. Reflux in the contralateral nondilated kidney accounted for a mean of 25.2% of detected cases for a mean prevalence of 4.1%. In patients with a normal postnatal renal ultrasound the prevalence of reflux is 17%. The prenatal anteroposterior renal pelvic diameter was not predictive of reflux prevalence. A diameter of 4 mm is associated with a 10% to 20% prevalence of vesicoureteral reflux. The prevalence of reflux is statistically significantly greater in females (23%) than males (16%) (p=0.022). Reflux grade distribution is approximately a third each for grades I-II, III and IV-V. The estimate of renal damage in screened infants without infection is 21.8%. When stratified by reflux grade renal damage was estimated to be present in 6.2% grade I-III and 47.9% grade IV-V (p <0.0001). The risk of urinary tract infection in patients with and without prenatal hydronephrosis and vesicoureteral reflux could not be determined. The incidence of reported urinary tract infection in patients with reflux was 4.2%. CONCLUSIONS The meta-analysis provided meaningful information regarding screening for vesicoureteral reflux. However, the lack of randomized clinical trials for screened patients to assess clinical health outcomes has made evidence-based guideline recommendations difficult. Consequently, screening guidelines are based on present practice, risk assessment, meta-analysis results and Panel consensus.

Etiology of sustained hypertension in children in the Southwestern United States

We reviewed the records of 132 children with persistent hypertension who were evaluated by our pediatric nephrology services between 1987 and 1991. Eightynine (67%) of these children were found to have renal or renovascular disease, 30 (23%) had primary hypertension and 13 (10%) had a non-renal cause for their hypertension. Glomerulonephritis (n=37) and reflux nephropathy (n=26) were the most frequent renal disorders identified. Renal artery thrombosis was the most common cause of hypertension in the neonatal period (in 6 of 12 neonates, 50%) whereas cystic kidney disease was the most common cause of hypertension in the 1st year of life (in 9 of 30 infants, 30%). The prevalence of primary hypertension increased with age; this diagnosis was made in 16 of 46 (35%) hypertensive patients between 12 and 18 years of age and, more surprisingly, in 8 of 27 (30%) children between 7 and 11 years of age. These data confirm that secondary hypertension is the most common cause of hypertension in children but suggest that primary hypertension is more prevalent than previously recognized in patients between 7 and 18 years of age.

Pathophysiologic Evidence of Gentamicin Nephrotoxicity in Neonatal Puppies

Summary: Newborn puppies were paired (n = 21 pairs) at birth, given gentamicin (5 mg/kg/day for 7 days and then 7.5 mg/kg/day) or saline intramuscularly (IM) and studied at 10, 20, or 30 days of age. Peak gentamicin concentrations correlated neither with total body water nor extracellular fluid volume. The ratio of outer/inner cortical gentamicin concentrations increased with therapy (n = 0.579; P < 0.01). Pathologic changes in proximal tubular cells of superficial and juxtamedullary cortices corresponded to tissue accumulation of gentamicin. Inulin clearance was lower but not statistically different in gentamicin puppies at 20 and 30 days, but tubular reabsorption of phosphate was lower at 30 days (P < 0.02). Plasma creatinine decreased during the first month of life in both control and gentamicin puppies (n = −0.370; P < 0.02) and was not different between puppies even at 20 and 30 days when tubular damage was marked. No differences in urine sediment, osmolarity, glucose, and protein concentrations were noted between paired animals. Mean values of gentamicin half-life in gentamicin (control) puppies decreased from 80.3 (84.0) min at 10 days to 45.3 (50.3) min at 20 days, but increased to 61.0 (40.0; P < 0.05) min at 30 days. Similar studies in older puppies and adult animals given gentamicin resulted in an increase in plasma creatinine and gentamicin half-life within 10 days. Results of these studies confirmed that gentamicin nephrotoxicity occurred within 10 days in puppies treated from birth. The relative tolerance of the neonatal puppy to the toxic effects of gentamicin was attributed to the distribution of renal blood flow predominantly to juxtamedullar nephrons at birth which spared superficial nephrons from gentamicin accumulation and toxicity until renal blood flow was redistributed to the outer cortex and filtration in superficial nephrons began after the first wk of life.Speculation: The relative tolerance of the neonate to the nephrotoxic effects of gentamicin and perhaps other aminoglycosides can be explained by the distribution of renal blood flow during development. Nephrons in the juxtamedullary cortex of the neonate receive a major fraction of renal blood flow initially and manifest gentamicin toxicity earlier than do nephrons in the outer cortex. Any impairment to nephron function in the inner cortex of the neonatal kidney during 7 to 10 days of gentamicin therapy would be offset by the successive contribution of more superficial nephrons to overall renal function. Once filtration has begun in all nephrons, gentamicin nephrotoxicity in the infant is comparable to the adult.

Postnatal development of renal function during the first year of life

Several aspects of renal function varyconsiderably during the 1st year of life and differ markedly from the equivalent values in the adult. Glomerular filtration rate (GFR) increases little, prior to the time an infant reaches a conceptional age of 34 weeks, the point in renal development from which the absolute GFR (ml/min) increases gradually to mature values when linear growth is completed during adolescence. GFR corrected for body size is not comparable with adult normal values until after 12 months of age; therefore, whether GFR is estimated from Scr or measured by timed urine collection, there is no easily recalled range of normal values for infants. One must know the changes in the renal function of normal infants that take place following birth during the 1st year of life. Despite several attempts to do so, renal function during the 1st year of life cannot be assessed from urine flow rate. A urine flow rate of less than 1 ml/kg per hour may be normal and appropriate and may not be harmful either to preterm or full-term infants with normal GFR. Impaired concentrating ability of the neonatal kidney is probably of no clinical significance in all but the most extreme circumstances and is not a major factor in an infant becoming dehydrated, developing hypernatremia or being at greater risk of acute renal injury. Acid-base status in infants must be interpreted appropriately to know when alkali therapy should be introduced to avoid growth failure secondary to true metabolic acidosis. When plasma renin activity is measured in the infant with renal failure of hypertension, one must compare the result with the normal range of values related to postnatal age of normal infants.Several aspects of renal function varyconsiderably during the 1st year of life and differ markedly from the equivalent values in the adult. Glomerular filtration rate (GFR) increases little, prior to the time an infant reaches a conceptional age of 34 weeks, the point in renal development from which the absolute GFR (ml/min) increases gradually to mature values when linear growth is completed during adolescence. GFR corrected for body size is not comparable with adult normal values until after 12 months of age; therefore, whether GFR is estimated from Scr or measured by timed urine collection, there is no easily recalled range of normal values for infants. One must know the changes in the renal function of normal infants that take place following birth during the 1st year of life. Despite several attempts to do so, renal function during the 1st year of life cannot be assessed from urine flow rate. A urine flow rate of less than 1 ml/kg per hour may be normal and appropriate and may not be harmful either to preterm or full-term infants with normal GFR. Impaired concentrating ability of the neonatal kidney is probably of no clinical significance in all but the most extreme circumstances and is not a major factor in an infant becoming dehydrated, developing hypernatremia or being at greater risk of acute renal injury. Acid-base status in infants must be interpreted appropriately to know when alkali therapy should be introduced to avoid growth failure secondary to true metabolic acidosis. When plasma renin activity is measured in the infant with renal failure of hypertension, one must compare the result with the normal range of values related to postnatal age of normal infants.

Diuresis and respiratory distress syndrome:Physiologic mechanisms and therapeutic implications

Previous studies have suggested that spontaneous diuresis may be important to the recovery from respiratory distress syndrome in preterm infants. Daily quantification of fluid intake (1) and urine output (O) were recorded, and O/I and alveolar-arterial oxygen gradients (AaDO2) were determined for sequential eight-hour periods in 10 inborn premature infants with RDS. Sequential timed-urine-plasma collections were obtained during the first four days of life to evaluate the role of hormonal and vasoactive factors in the acute phase of RDS. Diuresis (O/I greater than 0.80) occurred at 25 to 32 hours, preceded any significant improvement in AaDO2 (which occurred at 57 to 64 hours), and was associated with a 6.2 +/- 1.4% decrease in body weight. Although there was no significant change in glomerular filtration rate, plasma AVP concentrations, or urinary excretion of AVP in the infants, there were significant decreases in both plasma concentrations and urinary excretion of 6-keto-PGF1 alpha (stable metabolite of prostacyclin) in sequential studies. These results suggest that changes in renal function or AVP may not be of primary importance in the diuresis associated with RDS, and that decreasing levels of prostacyclin, a prostaglandin that increases vascular permeability and lowers blood pressure, may have an important physiologic role.

Urinary arginine vasopressin: pattern of excretion in the neonatal period

ABSTRACT. The pattern of arginine vasopressin (AVP) secretion in the immediate neonatal period is unclear. Plasma concentrations of AVP are reflected by its urinary excretion, thus providing a noninvasive method for studying the pattern of AVP release in the neonate. In these studies, we determined the pattern of urinary AVP excretion (μU/ mg creatinine) during the first 2-4 days after birth in 78 neonates, 53 of whom had various prenatal and/or neonatal complications. In well term (n = 12) and preterm (n =13) infants mean urinary AVP excretion decreased gradually during the first 24-36 h after birth. Although term and preterm infants with perinatal asphyxia had highest initial levels of urinary AVP (>200 μU/mg creatinine) and a significant negative correlation with the 1-min Apgar score was obtained, their pattern of excretion was similar to respective controls. After delivery, elevated values for urinary AVP excretion were found among infants with neonatal courses complicated by intracranial hemorrhage, hypoxic encephalopathy, and pneumothorax. Urine osmolality did not correlate linearly with urinary AVP levels, but rather attained a maximum value of ˜400 mosmol/kg at urinary AVP levels <200 μU/mg creatinine and then plateaued. It is concluded that the decrease in urinary AVP excretion observed soon after birth generally reflects diminution of the hypersecretion of AVP during parturition; neonates with evidence of intrapartum asphyxia initially have increased urinary AVP excretion; however, the pattern of excretion is similar to normal infants. During the neonatal period insults such as pneumothorax and intracranial hemorrhage may cause hypersecretion of this hormone.

Hemodynamic effects of indomethacin in chronically instrumented pregnant sheep

Indomethacin administration has produced decreases in uteroplacental blood flow in several animal studies; therefore, it has been suggested that the maintenance of uterine blood flow is critically dependent on the continued synthesis of vasodilating prostaglandins. However, vasoconstriction following indomethacin administration may be due to mechanisms other than reduced prostaglandin synthesis. We administered indomethacin (2, 5, or 10 mg/kg) intravenously to seven unanesthetized sheep in late pregnancy and determined the time courses of the uteroplacental and systemic hemodynamic responses, comparing these to the concurrent changes in circulating prostaglandins. Indomethacin administration resulted in rapid increases in systemic and uteroplacental vascular resistance (80% to 100%) and mean arterial pressure (approximately 30%) and in decreases in systemic (approximately 30%) and uteroplacental (0% to 30%) blood flows within 5 minutes. Vasoconstriction was transient, however, and after 60 minutes there was no evidence of uterine or systemic vasoconstriction, although systemic and uterine plasma prostaglandin levels remained reduced for 180 minutes. Thus substantial inhibition of prostaglandin synthesis existed without evidence of concurrent systemic or uteroplacental vasoconstriction, suggesting that uterine blood flow is not directly dependent on maintained prostaglandin synthesis in unstressed pregnant sheep. Furthermore, the transient indomethacin-induced vasoconstriction may not be due to inhibition of prostaglandin synthesis.