Bacterial and Host Genetic Risk Factors in Acute Pyelonephritis

Bacterial and Host Genetic Risk Factors That Predispose Children to Acute Pyelonephritis and Renal Scarring

No single host or pathogen trait identified by previous research can be correlated with all cases of childhood acute pyelonephritis or APN (i.e., kidney/upper urinary tract infections) and APN-associated renal scarring (the outcome with the highest morbidity), making it difficult for physicians to determine which patients will be affected. Our proposal is to comprehensively study the relationships between the clinical manifestations of urinary tract infections (UTIs), the host risk factors and immune response, and the microbial species that cause these conditions. The result of the study will be a clinical severity score to personalize diagnostic and treatment strategies for infants with UTI, with the goal of decreasing the morbidity of APN/renal scarring and improving patient outcomes.

Urinary tract infections (UTIs) are the most common serious bacterial infections in young children, with acute pyelonephritis or APN (i.e., kidney/upper urinary tract infections) and APN-associated renal scarring causing the most potential long-term damage to a child's health. Approximately two-thirds of young children with febrile UTI (UTIF or UTI presenting with fever) will have APN, making UTIF a major indicator of APN. Other than the presence of fever, it is currently difficult for physicians to determine which infant patients have or will develop APN and renal scarring. Individual risk factors for the host (e.g., uncircumcised males, cytokine production) and the pathogen (e.g., presence of fimbriae for adhesion) have individually been linked to APN and renal scarring, but no single trait identified can be correlated with all cases. Multiple factors on both sides of the host-pathogen relationship likely interact to determine the severity of the illness and the outcome. Although the NIDDK/NIH is currently funding two clinical trials to investigate the rate of recurrent UTI and the rate of renal scarring in children (Randomized Intervention of Children with Vesicoureteral REflux, RIVUR; and Careful urinary Tract Infection Evaluation, CUTIE) neither of these studies will be able to identify the child's initial risk for having APN since patient recruitment will occur too long after treatment of the UTI. Also, neither study proposes as a specific goal to obtain bacteriological samples with which to study the microbe's role in the pathogenesis of APN. Thus, to the best of our knowledge, no comprehensive study exists that aims to analyze the relationships between the clinical manifestations of UTIs, the host risk factors and immune response, and the microbial species that cause these conditions. Our proposed collaborative study between Children's National Medical Center (CNMC) and the J. Craig Venter Institute (JCVI) will collect clinical data as well as urine and blood samples from six distinct infant patient populations presenting with UTIF and correlate the clinical, host, and pathogen data for each patient with the severity of the disease and development of APN and renal scarring. Metagenomic and genomic sequencing on the urine and isolated bacteria, respectively, will allow us to comprehensively study both the culturable and unculturable pathogens responsible for the UTI. Using a genome-wide association study (GWAS) we will evaluate the polymorphisms of all known UTI-associated host genes, paying particular attention to the immune system host genes previously identified as potentially linked to APN. To correlate all collected data a publicly available database and website will be created to allow physicians and scientists to traverse the data. Using the data collected in the database, the final result of the study will be a clinical severity score to personalize diagnostic and treatment strategies for infants with UTIF, with the goal of decreasing the morbidity of APN and improving patient outcomes. An improved understanding of the microbial risk factors associated with APN and renal scarring will allow for better diagnostic approaches and improved methods for treating patients, inclusive of novel medications in at risk individuals.

Inclusion Criteria:

• Infants admitted to the inpatient ward at Children's National Medical Center for the treatment of a febrile urinary tract infection (see definitions) will be screened for inclusion into the research protocol.

• UTIF: A UTIF will require the presence of

  • (1) fever and/or symptoms consistent with UTI,
  • (2) pyuria based on urinalysis, and
  • (3) culture-proven infection with a single organism. Specifically, the study definition of UTIF will require:

• Fever: A documented temperature of at least 100.4 °F or 38°C, measured anywhere on the body either at home or at doctor's office.

Positive dipstick analysis: Pyuria on urinalysis (>10 WBC/mm3 (uncentrifuged specimen) OR >5 WBC/hpf (centrifuged specimen), OR >1+ leukocyte esterase on dipstick).

• Culture documentation of UTI: Evidence of bacteria (>5 x 104 CFU/mL (catheterized or suprapubic aspiration urine specimen). Bag collected specimens will not be acceptable

Exclusion Criteria:

• Infants who do not conform to the above inclusion criteria and who have co-morbidities such as duplication abnormalities, diabetes mellitus, over weight status, anatomical defects of the urinary tract and neuropathic bladder dysfunction.