Urinary proteins, vitamin D and genetic polymorphisms as risk factors for febrile urinary tract infection and relation with bacteremia: a case control study

PLoS One. 2015 Mar 25;10(3):e0121302. doi: 10.1371/journal.pone.0121302. eCollection 2015.


Objective/purpose: Febrile urinary tract infection (UTI) is a common bacterial disease that may lead to substantial morbidity and mortality especially among the elderly. Little is known about biomarkers that predict a complicated course. Our aim was to determine the role of certain urinary cytokines or antimicrobial proteins, plasma vitamin D level, and genetic variation in host defense of febrile UTI and its relation with bacteremia.

Methods: A case-control study. Out of a cohort of consecutive adults with febrile UTI (n = 787) included in a multi-center observational cohort study, 46 cases with bacteremic E.coli UTI and 45 cases with non-bacteremic E.coli UTI were randomly selected and compared to 46 controls. Urinary IL-6, IL-8, LL37, β-defensin 2 and uromodulin as well as plasma 25-hydroxyvitamin D were measured. In 440 controls and 707 UTI patients polymorphisms were genotyped in the genes CXCR1, DEFA4, DEFB1, IL6, IL8, MYD88, UMOD, TIRAP, TLR1, TLR2, TLR5 and TNF.

Results: IL-6, IL-8, and LL37 are different between controls and UTI patients, although these proteins do not distinguish between patients with and without bacteremia. While uromodulin did not differ between groups, inability to produce uromodulin is more common in patients with bacteremia. Most participants in the study, including the controls, had insufficient vitamin D and, at least in winter, UTI patients have lower vitamin D than controls. Associations were found between the CC genotype of IL6 SNP rs1800795 and occurrence of bacteremia and between TLR5 SNP rs5744168 and protection from UTI. The rare GG genotype of IL6 SNP rs1800795 was associated with higher β-defensin 2 production.

Conclusion: Although no biomarker was able to distinguish between UTI with or without bacteremia, two risk factors for bacteremia were identified. These were inability to produce uromodulin and an IL6 rs1800795 genotype.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antimicrobial Cationic Peptides
  • Bacteremia / blood
  • Bacteremia / genetics
  • Bacteremia / microbiology*
  • Bacteremia / urine
  • Case-Control Studies
  • Cathelicidins / urine
  • Female
  • Fever / blood
  • Fever / genetics
  • Fever / microbiology*
  • Fever / urine
  • Humans
  • Interleukin-6 / urine
  • Interleukin-8 / urine
  • Male
  • Middle Aged
  • Polymorphism, Genetic
  • Risk Factors
  • Urinary Tract Infections / blood
  • Urinary Tract Infections / genetics
  • Urinary Tract Infections / microbiology*
  • Urinary Tract Infections / urine
  • Uromodulin / urine
  • Vitamin D / analogs & derivatives*
  • Vitamin D / blood
  • beta-Defensins / urine


  • Antimicrobial Cationic Peptides
  • Cathelicidins
  • DEFB1 protein, human
  • Interleukin-6
  • Interleukin-8
  • Uromodulin
  • beta-Defensins
  • Vitamin D
  • 25-hydroxyvitamin D

Grant support

Support was provided by Bronovo research fund (no grant number), [www.bronovo.nl/vrienden-van-bronovo/projecten/onderzoek] to JD and Stichting Franje 1 fonds (no grant number) to JD. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.