Elevated fluid intake and the risk for pyelonephritis in urinary tract infection

In the current issue of Acta Physiologica, Hamilton et al. investigate in a mouse model of urinary tract infection (UTI) the therapeutic value of elevated fluid intake for the risk of ascension to pyelonephritis, after cystitis has been established.¹ Urinary tract infection is considered the most common bacterial infection causing immense burden to affected patients and healthcare systems.² Women are more frequently affected than men. It is estimated that 50% of women will be affected at least once during their lifetime, and 30%–40% suffer from recurrent UTI. Costs are estimated to reach $2 billion per year in the USA.² Confinement to the lower urinary tract (cystitis) is considered a benign disease; however, the infection may ascend to the kidney (pyelonephritis) or in the worst case cause bacteremia and sepsis (urosepsis).^{2, 3} The most effective therapy is antibiotic.⁴ However, with regard to prevalence and further provocation of resistances, non-antibiotic treatment options are of growing importance.⁴ Major non-antibiotic recommendations are cranberry products and elevated fluid intake.⁴ While there is evidence and recommendation for increased fluid intake for prevention of recurrent UTI, it is unclear, whether this also helps to reduce the risk of ascension to pyelonephritis once cystitis is established. The latter question has been investigated by Hamilton et al.¹ The authors found that increasing fluid intake and thereby urine production, not only failed to reduce the risk for ascension but substantially augmented the occurrence and severity of pyelonephritis.

The urinary tract is not only open to the body surface, but the orifice anatomically close to the microbiotic reservoir of the gastrointestinal tract. Accordingly, UTI is a constant battlefield between bacteria and host, featuring a wide array of mechanisms on both the side of bacterial virulence and host defense.^{3, 5} By far (80%) the most common pathogens causing UTI are uropathogenic Escherichia coli (UPEC).^{3, 5} Most virulence factors of UPEC are genetically clustered in pathogenicity-associated islands³ and include mechanisms for attachment to the urinary epithelium (adhesins), for survival and immune escape, as well as pathogenic toxins. The most important adhesins are fimbriae or pili,^{3, 5} multimeric proteins assembled to form hair-like structures protruding from the outer membrane of the bacterium. Several types have been described (Type-1-, P-, FIC-, S-, curli-fimbria, and Dr-adhesin). Type-1-fimbria attach to mannose-rich polysaccharides on the surface of the urothelium, allowing attachment to and possibly invasion of the bladder wall and accordingly are important for cystitis. P-fimbria attach to galactose moieties on the renal epithelium and prevail in pyelonephritic UPECs.^{3, 5} Survival in the harsh environment of urine is supported by the polysaccharide capsule, which also helps to resist immunologic attack and phagocytosis. The scarce iron is scavenged through siderophores such as aerobactin, which is secreted by the bacterium, chelates iron, and is subsequently reclaimed.^{3, 5} Toxins include hemolysin, which can lyse erythrocytes and other cells,^{3, 5} and cytotoxic necrotizing factor (CNF1), inducing stress fiber formation by disturbing intracellular rho-signalling. Host defense mechanisms include mechanical factors of outward-directed urine flow, valvular functions within the urinary tract, and the specialized multilayered urothelium with superficial uroplakin.^{3, 5} Type A intercalated cells of the tubular epithelium are capable of phagocytosis, immune modulation, and secretion of small antimicrobial peptides (AMPs).⁶ Antimicrobial peptides are small (5–20 kDa) cationic amphipathic peptides, which are bactericidal by disrupting bacterial cell membranes. Important members are RNAse7, alpha- and beta-defensins, catelicidins, and adrenomedullin.⁶ Another line of defense is the secretion of uromodulin or Tamm–Horsfall protein.⁷ This 100 kDa glycoprotein is secreted by tubular cells of the thick ascending limb and early proximal tubule.⁷ Uromodulin serves several functions such as inhibition of kidney stone formation, stimulation of tubular reabsorption of sodium, calcium, and magnesium, immunomodulation, and systemic effects on oxidative stress and vascular calcification; however, the most intriguing function probably is in antibacterial defense of UTI.⁷ Although uromodulin is not bactericidal, it can polymerize to a three-dimensional “fishing-net,” which may entangle urinary bacteria to facilitate their elimination by micturition. In addition, mannose moieties on uromodulin's glycoprotein structure may serve as “false” receptors for type-1-fimbriae of UPEC, thereby inhibiting their attachment to the urothelium.⁷

The study of Hamilton et al. builds on a mouse model of UTI developed and optimized by the group over several years.⁸ UTI is induced by inoculation of a defined number of UPEC into the bladder of female mice. Animals then receive either ordinary chow or gel food for 24 h and pyelonephritis incidence and severity is determined in the kidneys. Separate animals showed that gel-feeding augmented urine production and diminished urine osmolarity substantially. Nonetheless, both incidence and severity of pyelonephritis were markedly enhanced in the gel-fed mice. Most severe infection was associated with urinary osmolalities of the same animals at 400–800 mosmol/kg. Compared to an average of ~1500 mosmol/kg of the chow-fed mice this urinary osmolality indicates substantial urinary dilution and hence major urine flow. Chow-fed animals with more concentrated urine had less severe or no pyelonephritis. Urinary uromodulin concentration was lower in gel-fed animals particularly in those with more severe pyelonephritis. Additional experiments on human urine samples revealed faster growth of EPEC in male than female urine, but lower levels of urinary uromodulin, at least when normalized to urine osmolality. This indicates that the higher incidence of cystitis in women is not caused by weak host defense, but thus presumably by closer vicinity to the gastrointestinal tract and shorter ascension pathway and occurs despite higher uromodulin levels and more adverse growth conditions in female urine. An interesting side finding is that average uromodulin concentrations were ~10-fold higher in mice than humans, which might be an adaptation to shorter ascension pathways and a putatively larger threat for UTI in mice.

Certainly, it is not clear at this stage, to what extent the findings in this mouse model are transferrable to humans, warranting further investigations. Nonetheless, the result of exaggerated instead of mitigated risk for ascending pyelonephritis resulting from elevated fluid intake in this preclinical setting is so astonishing, that it urges renewed evaluation of fluid therapy in UTI patients, particularly in the setting when cystitis is already established. Given the complexity of the interactions between virulence factors and defense mechanisms, the magnitude of fluid intake, gender, genetic factors, and the individual microbiome of UPECs may likely impact on the benefit or harm of fluid therapy in UTI.

The author declares no conflict of interest.