Association between vitamin D, antimicrobial peptides and urinary tract infection in infants and young children.

AIM: Vitamin D stimulates production of the endogenous antimicrobial peptides cathelicidin and ß-defensin-2, which are expressed in the urinary tract. We investigated vitamin D status and levels of cathelicidin and ß-defensin-2 and their association with urinary tract infection (UTI). METHODS: The study included 120 children under three years of age: 76 children with UTIs and 44 otherwise healthy children with congenital hydronephrosis. Serum 25-hydroxycholecalciferol levels were measured by direct competitive electro-chemiluminescence immunoassay, and plasma cathelicidin and ß-defensin-2 concentrations were analysed by enzyme-linked immunosorbent assay. RESULTS: We found that vitamin D insufficiency and deficiency are prevalent in young children (21%). Serum vitamin D levels negatively correlated with age and were significantly lower in girls. Levels of vitamin D positively correlated with levels of cathelicidin but not with ß-defensin-2. Low concentrations of vitamin D were associated with UTIs in girls, but we did not see any correlation with the recurrence of infection at one-year follow-up. CONCLUSION: Vitamin D deficiency is common and may prove to be a risk factor for UTIs especially in girls. We hypothesise that adequate supplementation with vitamin D may become a way to prevent first-time UTIs.

Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome.

BACKGROUND: Atypical hemolytic-uremic syndrome is a genetic, life-threatening, chronic disease of complement-mediated thrombotic microangiopathy. Plasma exchange or infusion may transiently maintain normal levels of hematologic measures but does not treat the underlying systemic disease. METHODS: We conducted two prospective phase 2 trials in which patients with atypical hemolytic-uremic syndrome who were 12 years of age or older received eculizumab for 26 weeks and during long-term extension phases. Patients with low platelet counts and renal damage (in trial 1) and those with renal damage but no decrease in the platelet count of more than 25% for at least 8 weeks during plasma exchange or infusion (in trial 2) were recruited. The primary end points included a change in the platelet count (in trial 1) and thrombotic microangiopathy event-free status (no decrease in the platelet count of >25%, no plasma exchange or infusion, and no initiation of dialysis) (in trial 2). RESULTS: A total of 37 patients (17 in trial 1 and 20 in trial 2) received eculizumab for a median of 64 and 62 weeks, respectively. Eculizumab resulted in increases in the platelet count; in trial 1, the mean increase in the count from baseline to week 26 was 73×10(9) per liter (P<0.001). In trial 2, 80% of the patients had thrombotic microangiopathy event-free status. Eculizumab was associated with significant improvement in all secondary end points, with continuous, time-dependent increases in the estimated glomerular filtration rate (GFR). In trial 1, dialysis was discontinued in 4 of 5 patients. Earlier intervention with eculizumab was associated with significantly greater improvement in the estimated GFR. Eculizumab was also associated with improvement in health-related quality of life. No cumulative toxicity of therapy or serious infection-related adverse events, including meningococcal infections, were observed through the extension period. CONCLUSIONS: Eculizumab inhibited complement-mediated thrombotic microangiopathy and was associated with significant time-dependent improvement in renal function in patients with atypical hemolytic-uremic syndrome. (Funded by Alexion Pharmaceuticals; C08-002 ClinicalTrials.gov numbers, NCT00844545 [adults] and NCT00844844 [adolescents]; C08-003 ClinicalTrials.gov numbers, NCT00838513 [adults] and NCT00844428 [adolescents]).

Renal function during and after childhood acute poststreptococcal glomerulonephritis.

It is still debatable whether acute poststreptococcal glomerulonephritis (APSGN) can lead to permanent renal impairment. The clinical, immunological, and histological findings during the acute disease have been described thoroughly, however, the hemodynamic events are still poorly understood. In this retrospective study, the inulin and p-aminohippurate clearances were measured to evaluate glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) within a month of onset of the disease (acute stage) in 26 children, and 2-12 months after onset (follow-up) in 22 children with APSGN. During the acute stage, the mean GFR was 77+/-23 (SD) ml/min per 1.73 m(2), the mean ERPF 537+/-138 ml/min per 1.73 m(2), and the filtration fraction (FF) 14%+/-3%, compared with values for controls of 115+/-11 ml/min per 1. 73 m(2), 607+/-72 ml/min per 1.73 m(2), and 19%+/-2%, respectively (n=42). At follow-up, GFR was 114+/-15 ml/min per 1.73 m(2), ERPF 600+/-68 ml/min per 1.73 m(2), and FF 19%+/-3%. Thus, during the disease both GFR and ERPF fell below values for controls, but later were restored. The GFR, however, was more reduced than the ERPF, as indicated by the reduced FF. This might reflect a relative hyperperfusion of individual nephrons, which might start processes later deleterious to the nephrons. This finding, however, needs to be further investigated and we have therefore started a long-term follow-up of these patients.

Amoxicillin promotes vaginal colonization with adhering Escherichia coli present in faeces.

This study is aimed at a better understanding of the pathogenesis of urinary tract infection (UTI) by examining factors influencing the bacterial ecology of the genital tract. It comprises two sets of experiments in a monkey model. In the first the persistence and transmission between individuals of a P-fimbriated Escherichia coli (strain DS17) in faeces was examined and in the second we studied the influence of amoxicillin on the occurrence of this strain in the vagina. Orally administered E. coli DS17 was shown to spread to cage mates and to persist in the gut for at least 17-18 months. One of four monkeys so colonized developed three separate UTIs with the DS17 strain. The second set of experiments comprised four other monkeys, who either harboured the E. coli DS17 strain in the faeces and/or in small amounts in the vagina, probably through contamination during defaecation. Amoxicillin induced a persistent vaginal E. coli DS17 colonization in nine of ten experiments. The study thus shows that uropathogenic E. coli may persist for long time in the faeces and that, in this situation, amoxicillin may promote an abnormal, vaginal E. coli colonization similar to that characteristic of females prone to recurrent UTI and often preceding manifest urinary infections.

Elimination of vaginal colonization with Escherichia coli by administration of indigenous flora.

A persistent vaginal colonization with a pyelonephritogenic strain of Escherichia coli, induced by administration of amoxicillin, was established in four adult cynomolgus monkeys. This colonization mimicked the one seen in urinary tract infection-prone human females. Attempts to eliminate the E. coli colonization and restore normal conditions were made. Either suspensions of lactobacilli or vaginal fluid from a healthy unmanipulated monkey was administered as repeated vaginal flushes for 5 to 9 days. A total elimination of vaginal E. coli was observed in two of six experiments with lactobacilli, and a decrease was observed in the other four. A better result was obtained with flushes of vaginal fluid, which eliminated the E. coli colonization in eight of eight experiments. In two of these, a single flush was sufficient to obtain a decolonization. The ability of fresh vaginal fluid to eliminate E. coli from the vagina could be transferred from one monkey to another. This study demonstrates the role of the normal flora in the defense against genital colonization with potentially pathogenic adhering E. coli. The possible clinical relevance of these findings must be further examined.

The prepuce: a mistake of nature?

Retrospective studies suggest that circumcision of newborn boys will reduce the frequency of male early infantile urinary tract infection (UTI) by about 90%. If they are correct, this will be the first known instance of a common potentially lethal disease being preventable by extirpation of a piece of normal tissue. To reconcile the phenomenon with existing views of evolution and biology, it is suggested that the effects of one unphysiological intervention are counterbalancing those of another--ie, colonisation of the baby's gastrointestinal tract and genitals in maternity units by Escherichia coli strains of non-maternal origin, to which the baby has no passive immunity. As an alternative to circumcision to prevent early infantile male UTI, more natural colonisation could be promoted by strict rooming-in of mother and baby or by active colonisation of the baby with his mother's anaerobic gut flora.