Antimicrobial prophylaxis for children with vesicoureteral reflux.

BACKGROUND: Children with febrile urinary tract infection commonly have vesicoureteral reflux. Because trial results have been limited and inconsistent, the use of antimicrobial prophylaxis to prevent recurrences in children with reflux remains controversial. METHODS: In this 2-year, multisite, randomized, placebo-controlled trial involving 607 children with vesicoureteral reflux that was diagnosed after a first or second febrile or symptomatic urinary tract infection, we evaluated the efficacy of trimethoprim-sulfamethoxazole prophylaxis in preventing recurrences (primary outcome). Secondary outcomes were renal scarring, treatment failure (a composite of recurrences and scarring), and antimicrobial resistance. RESULTS: Recurrent urinary tract infection developed in 39 of 302 children who received prophylaxis as compared with 72 of 305 children who received placebo (relative risk, 0.55; 95% confidence interval [CI], 0.38 to 0.78). Prophylaxis reduced the risk of recurrences by 50% (hazard ratio, 0.50; 95% CI, 0.34 to 0.74) and was particularly effective in children whose index infection was febrile (hazard ratio, 0.41; 95% CI, 0.26 to 0.64) and in those with baseline bladder and bowel dysfunction (hazard ratio, 0.21; 95% CI, 0.08 to 0.58). The occurrence of renal scarring did not differ significantly between the prophylaxis and placebo groups (11.9% and 10.2%, respectively). Among 87 children with a first recurrence caused by Escherichia coli, the proportion of isolates that were resistant to trimethoprim-sulfamethoxazole was 63% in the prophylaxis group and 19% in the placebo group. CONCLUSIONS: Among children with vesicoureteral reflux after urinary tract infection, antimicrobial prophylaxis was associated with a substantially reduced risk of recurrence but not of renal scarring. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; RIVUR ClinicalTrials.gov number, NCT00405704.).

Predictors of Antimicrobial Resistance among Pathogens Causing Urinary Tract Infection in Children.

OBJECTIVE: To determine which children with urinary tract infection are likely to have pathogens resistant to narrow-spectrum antimicrobials. STUDY DESIGN: Children, 2-71 months of age (n = 769) enrolled in the Randomized Intervention for Children with Vesicoureteral Reflux or Careful Urinary Tract Infection Evaluation studies were included. We used logistic regression models to test the associations between demographic and clinical characteristics and resistance to narrow-spectrum antimicrobials. RESULTS: Of the included patients, 91% were female and 76% had vesicoureteral reflux. The risk of resistance to narrow-spectrum antibiotics in uncircumcised males was approximately 3 times that of females (OR 3.1; 95% CI 1.4-6.7); in children with bladder bowel dysfunction, the risk was 2 times that of children with normal function (OR 2.2; 95% CI 1.2-4.1). Children who had received 1 course of antibiotics during the past 6 months also had higher odds of harboring resistant organisms (OR 1.6; 95% CI 1.1-2.3). Hispanic children had higher odds of harboring pathogens resistant to some narrow-spectrum antimicrobials. CONCLUSIONS: Uncircumcised males, Hispanic children, children with bladder bowel dysfunction, and children who received 1 course of antibiotics in the past 6 months were more likely to have a urinary tract infection caused by pathogens resistant to 1 or more narrow-spectrum antimicrobials.

Interactions of vitamin D and the proximal tubule.

Severe vitamin D deficiency (reduction in serum 25(OH)D concentration) in infants and children can cause features of the Fanconi syndrome, including phosphaturia, glycosuria, aminoaciduria, and renal tubular acidosis. This indicates that vitamin D and its metabolites influence proximal tubule function. Filtered 25(OH)D bound to vitamin D binding protein (DBP) is endocytosed by megalin-cubilin in the apical membrane. Intracellular 25(OH)D is metabolized to 1,25(OH)2D or calcitroic acid by 1-α-hydroxylase or 24-hydroxylase in tubule cell mitochondria. Bone-produced fibroblast growth factor 23 (FGF23) bound to Klotho in tubule cells and intracellular phosphate concentrations are regulators of 1-α-hydroxylase activity and cause proximal tubule phosphaturia. Aminoaciduria occurs when amino acid transporter synthesis is deficient, and 1,25(OH)2D along with retinoic acid up-regulate transporter synthesis by a vitamin D response element in the promoter region of the transporter gene. This review discusses evidence gained from studies in animals or cell lines, as well as from human disorders, that provide insight into vitamin D-proximal tubule interactions.

The RIVUR trial: a factual interpretation of our data.

Vesicoureteral reflux (VUR) increases the risk of urinary tract infection (UTI) and renal scarring. Many prospective studies have evaluated the role of antimicrobial prophylaxis in the prevention of recurrent UTI and renal scarring in children with VUR. Of these, the RIVUR trial was the largest, randomized, placebo-controlled, double blind, multicenter study, involving 607 children aged 2-72 months with grade I-IV VUR and a first or second symptomatic UTI. The median age of children in the RIVUR trial was 12 months, 92% were female, 91% were randomized after a first UTI, 86% had a febrile index UTI, and 71 (56%) of 126 toilet-trained children had bladder bowel dysfunction. Trimethoprim/sulfamethoxazole reduced the risk of UTI recurrences by 50% (hazard ratio 0.50; 95% confidence interval 0.34-0.74) as compared to placebo. No significant difference was seen in renal scarring between the two groups. However, this does not invalidate the role of prophylaxis in preventing renal scars because RIVUR and other recent prospective studies were not designed to address renal scarring as a primary study endpoint. In view of the RIVUR Trial and other studies that showed similar results, albeit in selected groups of patients, the debate on antimicrobial prophylaxis should shift from "no prophylaxis" to "selective prophylaxis" in children with VUR.

Differential regulation of TauT by calcitriol and retinoic acid via VDR/RXR in LLC-PK1 and MCF-7 cells.

The interaction between taurine and the absorption of fat-soluble -vitamins, such as vitamin A and D, has been an interesting topic in the field of -nutrition science, because taurine-conjugated bile acid optimizes fat and fat-soluble vitamin absorption. However, whether the hormone calcitriol (1,25-dihydroxyvitamin D(3)) and retinoic acid regulate the expression of the TauT gene is unknown. In this study, we test the hypothesis that the TauT gene is regulated by vitamin D(3) (VD(3)) and retinoic acid (RA) via activation of the vitamin D receptor (VDR) and retinoic acid receptor (RXR). Taurine uptake, Western blotting, gene reporter assay, and immunohistochemical analysis of TauT, VDR, and RXR were used in VD(3)- and/or RA-treated LLC-PK1 and MCF-7 cells. We demonstrated that VD(3) alone had little effect on TauT expression in both LLC-PK1 and MCF-7 cells. Expression of TauT was significantly increased by RA, which was synergized by the addition of VD(3) after RXR activation in LLC-PK1 cells. In contrast, expression of TauT was significantly decreased by the combination of VD(3) and RA in MCF-7 cells. Regulation of TauT by VD(3)/RA appears to occur at the transcriptional level, as determined by a reporter gene assay of the TauT promoter. Immunohistochemical study showed that VDR and RXR were activated by VD(3) and RA, respectively, in both LLC-PK1 and MCF-7 cells. The activated VDR and RXR also colocated in nuclei of both cells, suggesting that a VDR/RXR complex is involved in the transcriptional regulation of TauT. Our results show that expression of TauT is differentially regulated by VD(3) and RA via formation of VDR and RXR complexes in the nuclei in a cell type-dependent manner.

Knockdown of TauT expression impairs human embryonic kidney 293 cell development.

Studies have demonstrated that TauT deficiency results in small kidneys in TauT knockout mice. Our studies have shown that TauT is a direct target of several genes, including p53 and WT1, which play an important role in renal development. However, whether the TauT gene is directly involved in renal development is largely unknown. In the present study, we created a TauT-deficient cell model by RNAi in human embryonic kidney 293 cells, and the effect of TauT on renal development was investigated. Knockdown of TauT significantly decreased the growth rate, cell migration, and colony formation of 293 cells. Inhibition of TauT caused cell cycle G2 arrest. Microarray analysis showed that several genes involved in cell cycle regulation or cell division, such as CDK6 and CDC7, were significantly downregulated in TauT-deficient 293 cells as compared to control 293 cells. In conclusion, the results from this study suggest that TauT plays a role in the development of renal cells. Knockdown of TauT impairs kidney development, possibly through regulation of cell cycle-related genes.

Rickets: Part I.

Rickets is characterized by impaired mineralization and ossification of the growth plates of growing children caused by a variety of disorders, the most frequent of which is nutritional deficiency of vitamin D. Despite ample knowledge of its etiology and the availability of cost-effective methods of preventing it, vitamin D deficiency rickets remains a significant problem in developing and developed countries. This two-part review covers the history, etiology, pathophysiology and clinical and radiographical findings of vitamin D deficiency rickets. Other less frequent causes of rickets and some of the disorders entering into the differential diagnoses of rickets are also considered. Controversial issues surrounding vitamin D deficiency include determination of what constitutes vitamin D sufficiency and the potential relationship between low levels of vitamin D metabolites in many individuals and unexplained fractures in infants.

Rickets: Part II.

This is the continuation of a two-part review of rickets. This part emphasizes the specific pathophysiology, clinical features, pathoanatomy and radiographic findings of vitamin D deficiency rickets. Other forms of rickets, differential diagnostic considerations and the potential relationship between low levels of vitamin D metabolites and unexplained fractures in infants are also discussed.

The RIVUR voiding cystourethrogram pilot study: experience with radiologic reading concordance.

PURPOSE: Two reference radiologists independently review voiding cystourethrograms for the National Institutes of Health sponsored RIVUR (Randomized Intervention for Children with Vesicoureteral Reflux) trial for children with vesicoureteral reflux. A pilot study was required from all clinical centers before enrolling patients. MATERIALS AND METHODS: Digital images were reviewed. Responses were compared and discrepancies adjudicated by teleconference to a final assessment. RESULTS: A total of 75 studies from 19 sites were reviewed. Discrepancies in vesicoureteral reflux grade level were noted on the left and right side in 11 (15%, kappa 0.85) and 12 (16%, kappa 0.83) ureters, respectively. Other areas of disagreement were the presence of paraureteral diverticulum (left 11%, kappa 0.31; right 9%, kappa 0.34), urethral anatomy (15%, kappa 0.33), whether the child voided (8%, kappa 0.21), the presence of ureteral duplication (left 7%, kappa 0.64; right 3%, kappa 0.78) and the presence of bladder trabeculation (5%, kappa 0.32). Of 83 ureters in which reflux was seen there was grade disagreement about 23 (28%). Of 61 ureters initially assessed as grade II or III reflux by both readers, there was disagreement on 9 (15%). Of these 9 discrepancies 7 (78%) were adjudicated to the higher grade (grade III). CONCLUSIONS: Discrepancies in the assessment of intermediate grade vesicoureteral reflux were noteworthy. Recommendations for patients with grade II or III reflux advanced by studies which rely on a single reading, which categorize only grade III or higher reflux as significant, may not be valid.

The role of taurine in renal disorders.

This article examines the actions of taurine on models of renal dysfunction, the potential mechanisms of taurine action and the possible clinical significance of these findings. Our laboratory has written previously on the role of taurine in renal function and we have focused upon the normal physiology of the kidney and on the mechanisms and regulation of the renal transport of taurine. This review is a distinct change of emphasis in that we describe a number of studies which have evaluated various aspects of renal dysfunction, including hypertension and proteinuria, specific glomerular and tubular disorders, acute and chronic renal conditions, urinary tract conditions including infection and nephrolithiasis, and diabetic nephropathy. The subject of chronic kidney disease and renal transplantation will also be examined relative to ß amino acid. The studies evaluated will be mainly recent ones, recognizing that older reviews of the role of this taurine in the kidney are available.

Early animal models of rickets and proof of a nutritional deficiency hypothesis.

In the period between 1880 and 1930, the role of nutrition and nutritional deficiency as a cause of rickets was established based upon the results from 6 animal models of rickets. This greatly prevalent condition (60%-90% in some locales) in children of the industrialized world was an important clinical research topic. What had to be reconciled was that rickets was associated with infections, crowding, and living in northern latitudes, and cod liver oil was observed to prevent or cure the disease. Several brilliant insights opened up a new pathway to discovery using animal models of rickets. Studies in lion cubs, dogs, and rats showed the importance of cod liver oil and an antirachitic substance later termed vitamin D. They showed that fats in the diet were required, that vitamin D had a secosteroid structure and was different from vitamin A, and that ultraviolet irradiation could prevent or cure rickets. Several of these experiments had elements of serendipity in that certain dietary components and the presence or absence of sunshine or ultraviolet irradiation could critically change the course of rickets. Nonetheless, at the end of these studies, a nutritional deficiency of vitamin D resulting from a poor diet or lack of adequate sunshine was firmly established as a cause of rickets.

New thoughts concerning the epidemic of rickets: was the role of alum overlooked?

Recent emphasis on the re-emergence of nutritional rickets has renewed interest in the etiology and therapy of this devastating disorder. At its peak in the 19th and 20th century, rickets was a major area of study for countless experts in childhood disorders and numerous theories abounded as to its cause. These included, among others, infections, confinement or intestinal disturbances, and were largely discarded after the discovery of the role of vitamin D and the importance of ultraviolet irradiation. Once a good explanation had been found for the cause of the disorder and the curative power of vitamin D proven, whether it was obtained from the diet or through exposure to sunlight, there was no apparent need to look any further into the etiology of rickets. But in fact there may have been other contributory factors, recognition of which might have lessened the severity of the disease or hastened recovery. One of these theories might be of particular interest to pediatric nephrologists because it relates to insoluble aluminum-based phosphate binders. Namely, alum used as an adulterant in bread in certain locations may have contributed to metabolic bone disease during the great epidemic of rickets.

Post-streptococcal acute glomerulonephritis in children: clinical features and pathogenesis.

Post-streptococcal acute glomerulonephritis (PSAGN) is one of the most important and intriguing conditions in the discipline of pediatric nephrology. Although the eventual outcome is excellent in most cases, PSAGN remains an important cause of acute renal failure and hospitalization for children in both developed and underdeveloped areas. The purpose of this review is to describe both the typical and less common clinical features of PSAGN, to outline the changes in the epidemiology of PSAGN over the past 50 years, and to explore studies on the pathogenesis of the condition with an emphasis on the search for the elusive nephritogenic antigen.

Milk composition in free-ranging polar bears (Ursus maritimus) as a model for captive rearing milk formula.

The goals of this study were to have an improved understanding of milk composition and to help create a suitable milk formula for cubs raised in captivity. Milk samples were evaluated for fat, fatty acids, carbohydrate, vitamin D(3), 25(OH)D(3), vitamin A (retinol), vitamin E (α-tocopherol), protein, and amino acids. Total lipids in milk did not differ for cubs (mean ± SEM = 26.60 ± 1.88 g/100 ml vs. yearlings 27.80 ± 2.20 g/100 ml). Milk lipids were of 23.6% saturated fatty acid for cubs and 22.4% for yearlings. Milk consumed by cubs and yearlings contained 43.8 and 42.0% mono-unsaturated fatty acids and 23.4 and 21.9% polyunsaturated fatty acids, respectively. Carbohydrate content was higher in milk for cubs (4.60 ± 0.64 g/100 ml) than for yearlings (2.60 ± 0.40 g/100 ml). Vitamin D(3) concentration of milk was 18.40 ± 5.00 ng/ml in early lactation compared with 7.60 ± 2.00 ng/ml for mid-lactation. 25(OH)D(3) was lower in milk consumed by cubs (162.00 ± 6.70 pg/ml) than in milk consumed by yearlings (205.00 ± 45.70 pg/ml). Vitamin A concentrations were 0.06 ± 0.01 and 0.03 ± 0.01 µg/ml for cubs and yearlings, respectively. Vitamin E was higher in milk consumed by cubs (20.16 ± 4.46 µg/ml) than by yearlings (7.30 ± 1.50 µg/ml). Protein content did not differ in milk available to cubs (11.40 ± 0.80 g/100 ml compared with milk for yearlings 11.80 ± 0.40 g/100 ml). Taurine was the most abundant free amino acid at 3,165.90 ± 192.90 nmol/ml (0.04% as fed basis).

Stress-responsive gene TauT and acute kidney injury.

BACKGROUND: Cisplatin is a commonly used chemotherapeutic agent that has a major limitation because of its nephrotoxicity. We have demonstrated that cisplatin down-regulates the expression of the taurine transporter gene (TauT) in renal cells and that forced overexpression of TauT protects against cisplatin-induced apoptosis in renal cells in vitro and in vivo. In the present study, we have investigated how TauT is regulated by p53 and c-Jun and its role during acute kidney injury (AKI). METHODS: Regulation of TauT by p53 and c-Jun was determined by reporter gene assay, DNA binding, Western blot analysis, and immunohistochemistry. RESULTS: TauT was down-regulated by p53 and up-regulated by c-Jun. Two potential binding sites for c-Jun were identified in the promoter region of TauT. Inhibition of c-Jun N-terminal kinase (JNK) enhanced TauT promoter activity. Overexpression of TauT protects against cisplatin-induced kidney injury in a TauT transgenic mouse model. CONCLUSIONS: Our findings suggest that TauT plays a critical role in renal function. Expression of TauT is negatively regulated by p53 and positively regulated by c-Jun, which is mediated by the JNK signaling pathway. The outcome level of TauT may determine the fate of renal cells during stress-induced AKI.

Metabolic bone disease in lion cubs at the London Zoo in 1889: the original animal model of rickets.

In 1889 Dr. John Bland-Sutton, a prominent London surgeon, was consulted about fatal rickets in over 20 successive litters of lion cubs born at the London Zoo. He evaluated the diet and found the cause of rickets to be nutritional in origin. He recommended that goat meat with crushed bones and cod-liver oil be added to the lean horsemeat diet of the cubs and their mothers. Rickets were reversed, the cubs survived, and subsequent litters thrived. Thirty years later, in classic controlled studies conducted in puppies and young rats, the definitive role of calcium, phosphate and vitamin D in prevention and therapy of rickets was elucidated. Further studies led to identifying the structural features of vitamin D.Although the Bland-Sutton diet provided calcium and phosphate from bones and vitamins A and D from cod-liver oil, some other benefits of this diet were not recognized. Taurine-conjugated bile salts, necessary for intestinal absorption of fat-soluble vitamins, were provided in the oil cold-pressed from cod liver. Unlike canine and rodent species, felines are unable to synthesize taurine, yet conjugate bile acids exclusively with taurine; hence, it must be provided in the diet. The now famous Bland-Sutton "experiment of nature," fatal rickets in lion cubs, was cured by addition of minerals and vitamin D. Taurine-conjugated bile salts undoubtedly permitted absorption of vitamins A and D, thus preventing the occurrence of metabolic bone disease and rickets.

Taurine and the renal system.

Taurine participates in a number of different physiologic and biologic processes in the kidney, often reflected by urinary excretion patterns. The kidney is key to aspects of taurine body pool size and homeostasis. This review will examine the renal-taurine interactions relative to ion reabsorption; renal blood flow and renal vascular endothelial function; antioxidant properties, especially in the glomerulus; and the role of taurine in ischemia and reperfusion injury. In addition, taurine plays a role in the renal cell cycle and apoptosis, and functions as an osmolyte during the stress response. The role of the kidney in adaptation to variations in dietary taurine intake and the regulation of taurine body pool size are described. Finally, the protective function of taurine against several kidney diseases is reviewed.