World Trade Center Kidney-Link
Condition: Chronic Kidney Diseases; Obstructive Sleep Apnea
MeSH terms: Sleep Apnea Syndromes; Sleep Apnea, Obstructive; Kidney Diseases; Renal Insufficiency, Chronic
Study type: Observational

Summary: 
      This study focuses on the prevalence and identification of kidney disease among participants
      of the WTC Health Program and the study team are planning to assess kidney disease in a
      multi-factorial manner. The first aim of this study is to correlate kidney dysfunction with
      9/11 exposure, and the study team predicts that exposure to 9/11 is an independent risk
      factor in kidney disease among the WTC Health Program participants. Secondly, the study team
      proposes that a well-established WTC-related condition, obstructive sleep apnea (OSA), is
      independently associated with kidney disease. In addition, the study team believe there is a
      temporal causative relationship between evidence of kidney disease and the severity of OSA.
      Finally, the last aim is to further identify and explore potential mechanisms and phenotypes
      of kidney disease in participants of the WTC Health Programs.

      Regardless of whether the analyses support or reject these hypotheses, the findings will be
      of equally great public health importance. Successful completion of the proposed research
      would address a critical knowledge gap regarding the risk of kidney damage among this group
      of patients, and would inform future mechanistic studies with the potential to impact
      prevention.
    

Detailed description: 
      Exposure to environmental toxins results in significant long-term health effects in workers.
      More than 91,000 rescue and recovery workers and volunteers at the World Trade Center (WTC)
      sustained exposure to thousands of tons of coarse and fine particulate matter. Thousands of
      responders are currently treated for WTC-related health conditions or may be at risk for
      worsening health. Toxic effects of particulate matter are known to affect the pulmonary,
      renal and cardiovascular systems. The specific effects of the exposure to 9/11 are partly
      known, and require further investigation, as outlined in the Zadroga Act (Public Law111-347).

      This study builds on the preliminary data to address a critical knowledge gap about the risk
      of kidney damage among WTC responders, the progression of kidney decline since exposure, and
      the association of kidney disease with a defined WTC-related diagnosis, obstructive sleep
      apnea (OSA). Successful completion of the proposed research would address a critical
      knowledge gap regarding the risk of kidney damage and the relationship to important chronic
      diseases (OSA and immune-mediated disease) among WTC participants, and would inform future
      mechanistic studies with the potential to impact disease prevention.

      Specific Aim 1: To quantify the risk of kidney damage and the relationship to 9/11 exposure
      among WTC Health Program participants. Currently, the cohort of 406 first responders
      represents the sole dedicated evaluation of kidney disease in WTC Health Program
      participants. The study team will test the hypothesis that exposure to 9/11 is independently
      associated with kidney disease and enrich the enrollment of the current study population with
      a diversified population including categories of workers who have not been enrolled, as well
      as a control group of urban workers (NYC) not exposed to the dust from the WTC.

      Aim 1a. The study team hypothesize that albuminuria and decreased estimated glomerular
      filtration rate (eGFR) will occur more frequently in WTC responders than in the general
      population and will correlate with the degree of exposure as defined by the previously
      defined WTC exposure score (adjusting for demographics, family history of chronic kidney
      disease (CKD), and diagnosed, treated or laboratory confirmed diabetes and hypertension). The
      study team will also assess established urine biomarkers of proximal tubular injury,
      including β2-M, Kidney Injury Molecule-1 (KIM-1), and Interleukin 18 (IL-18), as well as
      markers of distal tubular function, Loop of Henle function, and tubulointerstitial
      inflammation.

      Aim 1b. The study team hypothesize that initial exposure to 9/11 contributed to reduction in
      renal function over time. The study team will quantify change in renal function over time by
      analyzing eGFR at WTC Health Program Visit 1 (V1) and subsequent visits, adjusting for known
      co-morbid conditions.

      Aim 1c. The study team will create a repository of WTC responders with established kidney
      disease (including relatively rare disease) to qualitatively evaluate and describe the
      spectrum of kidney disease in the entire WTC population and compare to patterns of kidney
      disease in the general population. The study team will actively enlist those with a verified
      physician diagnosis of kidney disease, and collect biopsy reports and slides for review.

      Specific Aim 2: Evaluate the association of kidney disease and the established WTC-related
      condition, OSA.

      Aim 2a. OSA is particularly prevalent among WTC cohorts. The study team hypothesize that
      there is an independent association between prevalent OSA and prevalent kidney disease.

      Aim2b. The study team hypothesize that OSA independently contributes to the progression of
      kidney disease. The study team will assess the temporal relationship of eGFR decline to the
      presence and severity of OSA, using longitudinal data from the WTC data center.

      Specific Aim 3: To evaluate potential mechanisms of kidney injury in WTC Health Program
      participants.

      Aim3a. In order to understand the role of chronic inflammation, the study team will evaluate
      established inflammatory markers which have been implicated as potential mediators of both
      OSA and CKD, including IL-10, IL-13, IL-1β, IL-2, IL-4, IL-6, IL-8, TNF-α, IFN-γ, IL-12p70.,
      high sensitivity C-reactive protein (hs-CRP), and white blood cell count (WBC).

      Aim3b. Based on the preliminary data noting increases in heavy metal levels in urine and
      blood, the study team will narrow the focus to evaluate the role of cadmium and lead in the
      development of kidney disease with evaluations of lead content in bone (marker of long-term
      exposure) as well as in blood. Since study participants include law enforcement personnel
      (with known exposure to lead), the characterization of bone lead levels will have an
      important health impact, whether or not a relationship to 9/11 is detected.

      Aim3c. In a registry cohort of WTC responders with established kidney disease the study team
      will explore potential mechanisms as determined by the observed patterns of disease by
      developing a comprehensive repository of data on WTC Health Program participants with common
      and rare kidney diseases, the study team will define specific clinical profiles and identify
      potential mechanisms that warrant future study. Importantly, the study team will develop a
      process across all WTC Health Programs (inclusive of approximately 50,000 individuals), to
      monitor those with early kidney disease as well as those with biopsy-proven kidney disease,
      at any stage.
    

Observational model: Case-Control
Time perspective: Cross-Sectional
Sampling method: Non-Probability Sample
Study population: 
        World Trade Center rescue and recovery workers and volunteers who are enrolled or being
        seen in any WTC Clinical Centers of Excellence
      
Biospecimen description: 
      Serum, plasma, urine
    
Keywords: albuminuria; sleep apnea; particulate matter; renal injury