A Novel Role for D-Alanylation of Lipoteichoic Acid of Enterococcus faecalis in Urinary Tract Infection

Background

Enterococci are the third most common cause of healthcare-associated infections, which include urinary tract infections, bacteremia and endocarditis. Cell-surface structures such as lipoteichoic acid (LTA) have been poorly examined in E. faecalis, especially with respect to urinary tract infections (UTIs). The dlt operon is responsible for the D-alanylation of LTA and includes the gene dltA, which encodes the D-alanyl carrier protein ligase (Dcl). The involvement of LTA in UTI infection by E. faecalis has not been studied so far. Here, we examined the role of teichoic acid alanylation in the adhesion of enterococci to uroepithelial cells.

Results

In a mouse model of urinary tract infection, we showed that E. faecalis 12030ΔdltA mutant colonizes uroepithelial surfaces more efficiently than wild type bacteria. We also demonstrated that this mutant adhered four fold better to human bladder carcinoma cell line T24 compared to the wild type strain. Bacterial adherence could be significantly inhibited by purified lipoteichoic acid (LTA) and inhibition was specific.

Conclusion

In contrast to bacteraemia model and adherence to colon surfaces, E. faecalis 12030ΔdltA mutant colonized uroepithelial surfaces more efficiently than wild-type bacteria. In the case of the uroepithelial surface the adherence to specific host cells could be prevented by purified LTA. Our results therefore suggest a novel function of alanylation of LTA in E. faecalis.     

Glycolipids are involved in biofilm accumulation and prolonged bacteraemia in Enterococcus faecalis

Biofilm production is thought to be an important step in many enterococcal infections. In several Gram-positive bacteria, membrane glycolipids have been implicated in biofilm formation. We constructed a non-polar deletion mutant of a putative glucosyltransferase designated biofilm-associated glycolipid synthesis A ( bgsA ) in Enterococcus faecalis 12030. Analysis of major extracted glycolipids by nuclear magnetic resonance spectroscopy revealed that the cell membrane of 12030Δ bgsA was devoid of diglucosyl–diacylglycerol (DGlcDAG), while monoglucosyl–diacylglycerol was overrepresented. The cell walls of 12030Δ bgsA contained longer lipoteichoic acid molecules and were less hydrophobic than wild-type bacteria. Inactivation of bgsA in E. faecalis 12030 and E. faecalis V583 led to an almost complete arrest of biofilm formation on plastic surfaces. Overexpression of bgsA , on the other hand, resulted in increased biofilm production. While initial adherence was not affected, bgsA -deficient bacteria did not accumulate in the growing biofilm. Also, adherence of E. faecalis Δ bgsA to Caco-2 cells was impaired. In a mouse bacteraemia model, E. faecalis 12030Δ bgsA was cleared more rapidly from the bloodstream than the wild-type strain. In summary, BgsA is a glycosyltransferase synthetizing DGlcDAG, a glycolipid and lipoteichoic acid precursor involved in biofilm accumulation, adherence to host cells, and virulence in vivo .     

Deletion of the glycosyltransferase <Emphasis Type="Italic">bgsB of Enterococcus faecalis</Emphasis>leads to a complete loss of glycolipids from the cell membrane and to impaired biofilm formation

Background  

Deletion of the glycosyltransferase bgsA in Enterococcus faecalis leads to loss of diglucosyldiacylglycerol from the cell membrane and accumulation of its precursor monoglucosyldiacylglycerol, associated with impaired biofilm formation and reduced virulence in vivo. Here we analyzed the function of a putative glucosyltransferase EF2890 designated biofilm-associated glycolipid synthesis B (bgsB) immediately downstream of bgsA.     

The nonbilayer/bilayer lipid balance in membranes. Regulatory enzyme in Acholeplasma laidlawii is stimulated by metabolic phosphates, activator phospholipids, and double-stranded DNA

In membranes of Acholeplasma laidlawii a single glucosyltransferase step between the major, nonbilayer-prone monoglucosyl-diacylglycerol (MGlcDAG) and the bilayer-forming diglucosyl-diacylglycerol (DGlcDAG) is important for maintenance of lipid phase equilibria and curvature packing stress. This DGlcDAG synthase is activated in a cooperative fashion by phosphatidylglycerol (PG), but in vivo PG amounts are not enough for efficient DGlcDAG synthesis. In vitro, phospholipids with an sn-glycero-3-phosphate backbone, and no positive head group charge, functioned as activators. Different metabolic, soluble phosphates could supplement PG for activation, depending on type, amount, and valency. Especially efficient were the glycolytic intermediates fructose 1,6-bisphosphate and ATP, active at cellular concentrations on the DGlcDAG but not on the preceding MGlcDAG synthase. Potencies of different phosphatidylinositol (foreign lipid) derivatives differed with numbers and positions of their phosphate moieties. A selective stimulation of the DGlcDAG, but not the MGlcDAG synthase, by minor amounts of double-stranded DNA was additive to the best phospholipid activators. These results support two types of activator sites on the enzyme: (i) lipid-phosphate ones close to the membrane interphase, and (ii) soluble (or particulate)-phosphate ones further out from the surface. Thereby, the nonbilayer (MGlcDAG) to bilayer (DGlcDAG) lipid balance may be integrated with the metabolic status of the cell and potentially also to membrane and cell division.     

Intervening with urinary tract infections using anti-adhesives based on the crystal structure of the FimH-oligomannose-3 complex

Background

Escherichia coli strains adhere to the normally sterile human uroepithelium using type 1 pili, that are long, hairy surface organelles exposing a mannose-binding FimH adhesin at the tip. A small percentage of adhered bacteria can successfully invade bladder cells, presumably via pathways mediated by the high-mannosylated uroplakin-Ia and α3β1 integrins found throughout the uroepithelium. Invaded bacteria replicate and mature into dense, biofilm-like inclusions in preparation of fluxing and of infection of neighbouring cells, being the major cause of the troublesome recurrent urinary tract infections.

Methodology/Principal Findings

We demonstrate that α-d-mannose based inhibitors of FimH not only block bacterial adhesion on uroepithelial cells but also antagonize invasion and biofilm formation. Heptyl α-d-mannose prevents binding of type 1-piliated E. coli to the human bladder cell line 5637 and reduces both adhesion and invasion of the UTI89 cystitis isolate instilled in mouse bladder via catheterization. Heptyl α-d-mannose also specifically inhibited biofilm formation at micromolar concentrations. The structural basis of the great inhibitory potential of alkyl and aryl α-d-mannosides was elucidated in the crystal structure of the FimH receptor-binding domain in complex with oligomannose-3. FimH interacts with Manα1,3Manβ1,4GlcNAcβ1,4GlcNAc in an extended binding site. The interactions along the α1,3 glycosidic bond and the first β1,4 linkage to the chitobiose unit are conserved with those of FimH with butyl α-d-mannose. The strong stacking of the central mannose with the aromatic ring of Tyr48 is congruent with the high affinity found for synthetic inhibitors in which this mannose is substituted for by an aromatic group.

Conclusions/Significance

The potential of ligand-based design of antagonists of urinary tract infections is ruled by the structural mimicry of natural epitopes and extends into blocking of bacterial invasion, intracellular growth and capacity to fluxing and of recurrence of the infection.     

Enterococcus faecalis Endocarditis Severity in Rabbits Is Reduced by IgG Fabs Interfering with Aggregation Substance

Background

Enterococcus faecalis is a significant cause of infective endocarditis, an infection of the heart endothelium leading to vegetation formation (microbes, fibrin, platelets, and host cells attached to underlying endothelial tissue). Our previous research determined that enterococcal aggregation substance (AS) is an important virulence factor in causation of endocarditis, although endocarditis may occur in the absence of AS production. Production of AS by E. faecalis causes the organism to form aggregates through AS binding to enterococcal binding substance. In this study, we assessed the ability of IgGs and IgG Fabs against AS to provide protection against AS⁺ E. faecalis endocarditis.

Methodology/Principal Findings

When challenged with AS⁺ E. faecalis, 10 rabbits actively immunized against AS⁺ E. faecalis developed more significant vegetations than 9 animals immunized against AS⁻ E. faecalis, and 9/10 succumbed compared to 2/9 (p<0.005), suggesting enhanced aggregation by IgG contributes significantly to disease. IgG antibodies against AS also enhanced enterococcal aggregation as tested in vitro. In contrast, Fab fragments of IgG from rabbits immunized against purified AS, when passively administered to rabbits (6/group) immediately before challenge with AS⁺ E. faecalis, reduced total vegetation (endocarditis lesion) microbial counts (7.9×10⁶ versus 2.0×10⁵, p = 0.02) and size (40 mg versus 10, p = 0.05). In vitro, the Fabs prevented enterococcal aggregation.

Conclusions/Significance

The data confirm the role of AS in infective endocarditis formation and suggest that use of Fabs against AS will provide partial protection from AS⁺ E. faecalis illness.     

Daptomycin resistance in enterococci is associated with distinct alterations of cell membrane phospholipid content

Background

The lipopeptide antibiotic, daptomycin (DAP) interacts with the bacterial cell membrane (CM). Development of DAP resistance during therapy in a clinical strain of Enterococcus faecalis was associated with mutations in genes encoding enzymes involved in cell envelope homeostasis and phospholipid metabolism. Here we characterized changes in CM phospholipid profiles associated with development of DAP resistance in clinical enterococcal strains.

Methodology

Using two clinical strain-pairs of DAP-susceptible and DAP-resistant E. faecalis (S613 vs. R712) and E. faecium (S447 vs. R446) recovered before and after DAP therapy, we compared four distinct CM profiles: phospholipid content, fatty acid composition, membrane fluidity and capacity to be permeabilized and/or depolarized by DAP. Additionally, we characterized the cell envelope of the E. faecium strain-pair by transmission electron microscopy and determined the relative cell surface charge of both strain-pairs.

Principal Findings

Both E. faecalis and E. faecium mainly contained four major CM PLs: phosphatidylglycerol (PG), cardiolipin, lysyl-phosphatidylglycerol (L-PG) and glycerolphospho-diglycodiacylglycerol (GP-DGDAG). In addition, E. faecalis CMs (but not E. faecium) also contained: i) phosphatidic acid; and ii) two other unknown species of amino-containing PLs. Development of DAP resistance in both enterococcal species was associated with a significant decrease in CM fluidity and PG content, with a concomitant increase in GP-DGDAG. The strain-pairs did not differ in their outer CM translocation (flipping) of amino-containing PLs. Fatty acid content did not change in the E. faecalis strain-pair, whereas a significant decrease in unsaturated fatty acids was observed in the DAP-resistant E. faecium isolate R446 (vs S447). Resistance to DAP in E. faecium was associated with distinct structural alterations of the cell envelope and cell wall thickening, as well as a decreased ability of DAP to depolarize and permeabilize the CM.

Conclusion

Distinct alterations in PL content and fatty acid composition are associated with development of enterococcal DAP resistance.     

Key role of the diglucosyldiacylglycerol synthase for the nonbilayer-bilayer lipid balance of Acholeplasma laidlawii membranes

In the single membrane of Acholeplasma laidlawii, a specific glucosyltransferase (DGlcDAG synthase) synthesizes the major, bilayer-forming lipid diglucosyldiacylglycerol (DGlcDAG) from the preceding major, nonbilayer-prone monoglucosyldiacylglycerol (MGlcDAG). This is crucial for the maintenance of phase equilibria close to a potential bilayer-nonbilayer transition and a nearly constant spontaneous curvature for the membrane bilayer lipid mixture. The glucolipid pathway is also balanced against the phosphatidylglycerol (PG) pathway to maintain a certain lipid surface charge density. The DGlcDAG synthase was purified approximately 5000-fold by three chromatographic techniques and identified as a minor 40 kDa membrane protein. In CHAPS mixed micelles, a cooperative dependence on anionic lipid activators was confirmed, with PG as the best. The dependence of the enzyme on the soluble UDP-glucose substrate followed Michaelis-Menten kinetics, while the kinetics for the other (lipid) substrate MGlcDAG exhibited cooperativity, with Hill coefficients in the range of 3-5. Vmax and the Hill coefficient, but not Km, for the MGlcDAG substrate were increased by increased PG concentrations, but above 3 mol % MGlcDAG, the rate of synthesis was constant. Hence, the DGlcDAG synthase is more affected by the lipid activator than by the lipid substrate at physiological lipid concentrations. The enzyme was shown to be sensitive to curvature "stress" changes, i.e., was stimulated by various nonbilayer lipids but inhibited by certain others. Certain phosphates were also stimulatory. With the two purified MGlcDAG and DGlcDAG synthases reconstituted together in the presence of a potent nonbilayer lipid, the strong responses in the amounts of MGlcDAG and DGlcDAG synthesized mimicked the responses in vivo. This supports the important regulatory functions of these enzymes.     

Mutational Analysis of Highly Conserved Residues in the Phage PhiC31 Integrase Reveals Key Amino Acids Necessary for the DNA Recombination

Background

Amino acid sequence alignment of phage phiC31 integrase with the serine recombinases family revealed highly conserved regions outside the catalytic domain. Until now, no system mutational or biochemical studies have been carried out to assess the roles of these conserved residues in the recombinaton of phiC31 integrase.

Methodology/Principal Findings

To determine the functional roles of these conserved residues, a series of conserved residues were targeted by site-directed mutagenesis. Out of the 17 mutants, 11 mutants showed impaired or no recombination ability, as analyzed by recombination assay both in vivo and in vitro. Results of DNA binding activity assays showed that mutants (R18A, I141A, L143A,E153A, I432A and V571A) exhibited a great decrease in DNA binding affinity, and mutants (G182A/F183A, C374A, C376A/G377A, Y393A and V566A) had completely lost their ability to bind to the specific target DNA attB as compared with wild-type protein. Further analysis of mutants (R18A, I141A, L143A and E153A) synapse and cleavage showed that these mutants were blocked in recombination at the stage of strand cleavage.

Conclusions/Significance

This data reveals that some of the highly conserved residues both in the N-terminus and C-terminus region of phiC31 integrase, play vital roles in the substrate binding and cleavage. The cysteine-rich motif and the C-tail val-rich region of phiC31 integrase may represent the major DNA binding domains of phiC31 integrase.     

Novel Interactions of Glycosaminoglycans and Bacterial Glycolipids Mediate Binding of Enterococci to Human Cells

Enterococcus faecalis is among the most important nosocomial pathogens. The intestinal mucosa is considered to be the main site used by these bacteria for entrance and dissemination. A better understanding of the mechanisms involved in colonization and invasion of enterococci may help to devise methods to prevent infections in hospitalized patients. Glycosaminoglycans, which are present on the surface of all eukaryotic cells, were investigated with regard to their role as host receptors for adhesion of E. faecalis. Competitive binding assays, enzymatic digestion, and reduction of the sulfation of the glycosaminoglycan chains indicated that heparin and heparan sulfate, but not chondroitin sulfate B, played important roles in adhesion of E. faecalis 12030 to Caco2 cells. By using proteinases and carbohydrate oxidation by sodium meta-periodate to modify the bacterial surface, it could be demonstrated that a sugar-containing molecule rather than a protein is the bacterial ligand mediating adhesion to eukaryotic cells. Preincubation of Caco2 cells with the enterococcal glycolipid diglucosyldiacylglycerol but not other carbohydrate cell wall components inhibited bacterial binding. These results may indicate that heparin and/or heparan sulfate on host epithelial cells and diglucosyldiacylglycerol, either itself or as a partial structure of lipoteichoic acid, are involved in enterococcal adhesion to colonic epithelia, the first step in translocation from the intestinal tract.Enterococci are currently the third most common pathogen isolated from bloodstream infections and the second most common nosocomial pathogen in the United States (1, 2). Enterococci are responsible for three to four cases of nosocomial bloodstream infection per 10,000 hospital discharges (3). These bacteria contribute significantly to additional hospitalization and patient mortality (4). Enterococci are endogenously resistant to a variety of antibiotics and have increasingly acquired more resistance mechanisms to antimicrobials, allowing them to survive in hospital and nursing home settings (5). The difficulty in treating serious enterococcal infections emphasizes the importance of understanding virulence factors that may be targeted by alternative therapeutics. The rapid increase in vancomycin-resistant enterococcal strains (6) and their general ability to pass this trait on to other pathogens, i.e. Staphylococcus aureus (7), indicates we are confronting an urgent and expanding problem on multiple fronts.Enterococci seem to have a propensity to colonize and infect certain tissues (such as the gastrointestinal tract, the urogenital tract, and the cardiac endothelia), although they are never found to cause disease in other tissues (e.g. lower respiratory tract). A main route of invasive infection by enterococci is likely initiated by adherence of the microbe to host cells followed by translocation to the gastrointestinal submucosa (8). Glycosaminoglycans (GAGs)² expressed on the surface of mammalian epithelial cells often represent prominent receptors for pathogens (9, 10). It has been shown previously that heparan sulfate proteoglycans on professional and nonprofessional phagocytes mediate invasion of Enterococcus faecalis into cells, where they can resist specific killing mechanisms (11). Because of their complex nature, heparan sulfate proteoglycans are made up of a variety of different structures that have a well defined distribution in different tissues, which is likely an important factor in binding of bacteria to cells (12). In this study we evaluated the role of host glycosaminoglycans and bacterial surface structures in mediating binding of E. faecalis to mammalian cells.     

The hedgehog signal induced modulation of bone morphogenetic protein signaling: an essential signaling relay for urinary tract morphogenesis

Background

Congenital diseases of the urinary tract are frequently observed in infants. Such diseases present a number of developmental anomalies such as hydroureter and hydronephrosis. Although some genetically-modified mouse models of growth factor signaling genes reproduce urinary phenotypes, the pathogenic mechanisms remain obscure. Previous studies suggest that a portion of the cells in the external genitalia and bladder are derived from peri-cloacal mesenchymal cells that receive Hedgehog (Hh) signaling in the early developmental stages. We hypothesized that defects in such progenitor cells, which give rise to urinary tract tissues, may be a cause of such diseases.

Methodology/Principal Findings

To elucidate the pathogenic mechanisms of upper urinary tract malformations, we analyzed a series of Sonic hedgehog (Shh) deficient mice. Shh^−/− displayed hydroureter and hydronephrosis phenotypes and reduced expression of several developmental markers. In addition, we suggested that Shh modulation at an early embryonic stage is responsible for such phenotypes by analyzing the Shh conditional mutants. Tissue contribution assays of Hh-responsive cells revealed that peri-cloacal mesenchymal cells, which received Hh signal secreted from cloacal epithelium, could contribute to the ureteral mesenchyme. Gain- and loss-of-functional mutants for Hh signaling revealed a correlation between Hh signaling and Bone morphogenetic protein (Bmp) signaling. Finally, a conditional ablation of Bmp receptor type IA (BmprIA) gene was examined in Hh-responsive cell lineages. This system thus made it possible to analyze the primary functions of the growth factor signaling relay. The defective Hh-to-Bmp signaling relay resulted in severe urinary tract phenotypes with a decrease in the number of Hh-responsive cells.

Conclusions/Significance

This study identified the essential embryonic stages for the pathogenesis of urinary tract phenotypes. These results suggested that Hh-responsive mesenchymal Bmp signaling maintains the population of peri-cloacal mesenchyme cells, which is essential for the development of the ureter and the upper urinary tract.     

The enzymatic synthesis of membrane glucolipids in Acholeplasma laidlawii.

In membranes of the prokaryote Acholeplasma laidlawii, the physiological regulation of the two major membrane lipids, monoglucosyldiacylglycerol (MGlcDAG) and diglucosyldiacylglycerol (DGlcDAG), is governed by factors affecting the equilibria between lamellar and non-lamellar phases of the membrane lipids. The synthesis of the glucolipids is considered to be a two-step glucosylation: (i) DAG+UDP-Glc----MGlcDAG+UDP; and (ii) MGlcDAG+UDP-Glc----DGlcDAG+UPD. This was corroborated by in vivo pulse labelling experiments showing turnover of MGlcDAG but not DGlcDAG. The enzymatic synthesis of MGlcDAG was localized to fresh or freeze-dried membranes in vitro. Synthesis of DGlcDAG was minor in such membranes but of substantial magnitude in intact cells. Synthesis of MGlcDAG was stimulated by small amounts of SDS but completely inhibited upon solubilization of the membranes by a variety of detergents. The inhibitory effect of several UDP-Glc analogs on glucolipid synthesis demonstrated the importance of UDP-Glc as the sugar donor. Synthesis of both glucolipids was lost in freeze-dried plus lipid-extracted cells but restored when lipids were transferred back to the extracted cell membrane. By selectively adding specific lipids, a strong dependence on the acceptor lipid DAG, as well as the need for general matrix lipids for enzyme activity, was established. In addition, the anionic phosphatidylglycerol (PG), but not the other phospholipids, had a strong stimulatory effect. The presence of different phosphorylating agents stimulated the synthesis of DGlcDAG and partially inhibited that of MGlcDAG. This, together with the lipid dependency, may constitute mechanisms for the regulation of the enzyme activities in vivo.     

E. coli Nissle 1917 Affects Salmonella adhesion to porcine intestinal epithelial cells

Background

The probiotic Escherichia coli strain Nissle 1917 (EcN) has been shown to interfere in a human in vitro model with the invasion of several bacterial pathogens into epithelial cells, but the underlying molecular mechanisms are not known.

Methodology/Principal Findings

In this study, we investigated the inhibitory effects of EcN on Salmonella Typhimurium invasion of porcine intestinal epithelial cells, focusing on EcN effects on the various stages of Salmonella infection including intracellular and extracellular Salmonella growth rates, virulence gene regulation, and adhesion. We show that EcN affects the initial Salmonella invasion steps by modulating Salmonella virulence gene regulation and Salmonella SiiE-mediated adhesion, but not extra- and intracellular Salmonella growth. However, the inhibitory activity of EcN against Salmonella invasion always correlated with EcN adhesion capacities. EcN mutants defective in the expression of F1C fimbriae and flagellae were less adherent and less inhibitory toward Salmonella invasion. Another E. coli strain expressing F1C fimbriae was also adherent to IPEC-J2 cells, and was similarly inhibitory against Salmonella invasion like EcN.

Conclusions

We propose that EcN affects Salmonella adhesion through secretory components. This mechanism appears to be common to many E. coli strains, with strong adherence being a prerequisite for an effective reduction of SiiE-mediated Salmonella adhesion.     

S100A8/A9 is not involved in host defense against murine urinary tract infection

Background

Inflammation is commonly followed by the release of endogenous proteins called danger associated molecular patterns (DAMPs) that are able to warn the host for eminent danger. S100A8/A9 subunits are DAMPs that belong to the S100 family of calcium binding proteins. S100A8/A9 complexes induce an inflammatory response and their expression correlates with disease severity in several inflammatory disorders. S100A8/A9 promote endotoxin- and Escherichia (E.) coli-induced sepsis showing its contribution in systemic infection. The role of S100A8/A9 during a local infection of the urinary tract system caused by E. coli remains unknown.

Methodology/Principal Findings

We investigated the contribution of S100A8/A9 in acute urinary tract infection (UTI) by instilling 2 different doses of uropathogenic E. coli transurethrally in wild type (WT) and S100A9 knockout (KO) mice. Subsequently, we determined bacterial outgrowth, neutrophilic infiltrate and inflammatory mediators in bladder and kidney 24 and 48 hours later. UTI resulted in a substantial increase of S100A8/A9 protein in bladder and kidney tissue of WT mice. S100A9 KO mice displayed similar bacterial load in bladder or kidney homogenate compared to WT mice using 2 different doses at 2 different time points. S100A9 deficiency had little effect on the inflammatory responses to E. Coli-induced UTI infection, as assessed by myeloperoxidase activity in bladder and kidneys, histopathologic analysis, and renal and bladder cytokine concentrations.

Conclusions

We show that despite high S100A8/A9 expression in bladder and kidney tissue upon UTI, S100A8/A9 does not contribute to an effective host response against E. Coli in the urinary tract system.     

Upper and Lower Urinary Tract Outcomes in Adult Myelomeningocele Patients: A Systematic Review

Background

The introduction of sophisticated treatment of bladder dysfunction and hydrocephalus allows the majority of SB patients to survive into adulthood. However, no systematic review on urological outcome in adult SB patients is available and no follow-up schemes exist.

Objectives

To systematically summarize the evidence on outcome of urinary tract functioning in adult SB patients.

Methods

A literature search in PubMed and Embase databases was done. Only papers published in the last 25 years describing patients with open SB with a mean age >18 years were included. We focused on finding differences in the treatment strategies, e.g., clean intermittent catheterization and antimuscarinic drugs versus early urinary diversion, with regard to long-term renal and bladder outcomes.

Results

A total of 13 articles and 5 meeting abstracts on urinary tract status of adult SB patients were found describing a total of 1564 patients with a mean age of 26.1 years (range 3–74 years, with a few patients <18 years). All were retrospective cohort studies with relatively small and heterogeneous samples with inconsistent reporting of outcome; this precluded the pooling of data and meta-analysis. Total continence was achieved in 449/1192 (37.7%; range 8–85%) patients. Neurological level of the lesion and hydrocephalus were associated with incontinence. Renal function was studied in 1128 adult patients. In 290/1128 (25.7%; range 3–81.8%) patients some degree of renal damage was found and end-stage renal disease was seen in 12/958 (1.3%) patients. Detrusor-sphincter dyssynergy and detrusor-overactivity acted as adverse prognostic factors for the development of renal damage.

Conclusions

These findings should outline follow-up schedules for SB patients, which do not yet exist. Since renal and bladder deterioration continues beyond adolescence, follow-up of these individuals is needed. We recommend standardization in reporting the outcome of urinary tract function in adult SB patients.