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C19 20-214 – HSR&D Study

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C19 20-214
Incidence, Risk Factors, and Prognosis of COVID-19 Associated Acute Kidney Injury
Edward D Siew MD MSc
Nashville, TN
Funding Period: August 2020 - March 2021

BACKGROUND/RATIONALE:
Emerging data from the coronavirus disease 2019 (SARS-Cov-2) pandemic indicate that up to 20% of severely infected patients develop acute kidney injury (AKI). The prognosis of patients who progress to severe AKI is dismal, with a near 100% mortality-rate among those requiring acute dialysis. In addition, 27-44% of patients exhibit proteinuria or hematuria, which are an uncommon feature in non-SARS-Cov-2 hospitalized AKI, suggesting a more complex and lasting injury. These complications have not been well characterized nor rigorously studied in the single-center case series to date. Given that the prevalence of chronic kidney disease (CKD) among Veterans is higher than the general population, the potential threat of this pandemic to the kidney health of US Veterans is substantial, and accurate information on the overall incidence, nature, risk factors, and prognosis of AKI in this population is desperately needed.

Given the high mortality reported with SARS-Cov-2 associated AKI, it is critical to identify modifiable risk factors to reduce the risk for AKI. The SARS-Cov-2 virus utilizes the functional angiotensin converting enzyme 2 (ACE2) receptor for entry into the cell, which in addition to the lung, are also expressed in kidney proximal tubule cells. Preclinical data suggests that ACE2 expression can be variably affected by the use of renin-angiotensin-aldosterone inhibitors (RAASi), leaving uncertainty over whether these agents may increase or decrease organ dysfunction, including AKI. In the absence of clinical data, multiple medical societies have generally favored continuing therapy in patients with COVID-19 infection. However, RAASi inhibition is associated with an increased risk for AKI in non-COVID acute illness, likely due to known effects on renal vascular autoregulation, especially when combined with diuretics, NSAIDs, and radiocontrast agents as anticipated to be used during COVID-19 hospitalization. As RAASi use is extremely common among VA patients, it is critical to determine the level of concern regarding AKI risk and prognosis.

OBJECTIVE(S):
The goals of this proposal are to: 1) Describe the incidence and nature of AKI in US Veterans hospitalized with COVID-19 infection, 2) Characterize the short-term natural history and prognosis of patients with COVID-19 associated AKI and 3) Measure the association between RAASi inhibition and the development of AKI among SARS-Cov-2 exposed patients and its prognosis.

METHODS:
Aim 1 Approach: The primary outcomes for Aim 1a will include the hospital-based incidence and overall distribution of Kidney Disease: Improving Global Outcomes (KDIGO) AKI stages (severity), the proportion who require acute renal replacement therapy (RRT, dialysis), incident or worsening proteinuria/hematuria (pre-admission versus worst post-admission), and renal recovery or death. Outcomes will be within 90 days of admission. Analyses will be stratified by those who present with AKI on admission (community-acquired AKI) and those who develop AKI >24 hours after admission (hospital-acquired). Descriptive analyses such as frequency, mean/median, standard error, and cross-tabulations will be used to describe and compare baseline patient characteristics between AKI and non-AKI groups. We will compare demographic, comorbid, and inpatient diagnoses and severity of illness features and report on the frequency of known nephrotoxin exposures (NSAIDS, contrast, aminoglycosides). Separate multivariable logistic regression models will be used to identify risk factors for developing AKI, worsening hematuria, and worsening proteinuria separately. This analysis is designed to yield predictive risk factors, as opposed to causal associations. For example, age may have a nonlinear association with AKI risk where risk increases with age until the risk of death becomes great enough that the risk of AKI decreases.

Aim 2 Approach: For Aim 2a, we will construct a propensity matching weighted cohort using an active comparator design (hypertension monotherapy of (RAASi versus calcium channel blocker (CCB) or thiazide diuretics). Prevalent use will be ascertained by pharmacy fill records, requiring fills in 1 to 90 days and 91 to 365 days pre-admission. Adjusted measures of interaction for survival will be estimated with Inverse Probability of Treatment Weighting (IPTW). Poisson regression with robust standard errors will be used to estimate incidence rates (IR) and incidence rate ratios (IRR) for AKI in monotherapy RAASi users versus CCB or Thiazolidinediones (TZD) users. We will compute the number needed to harm, attributable fraction in the exposed (patients exposed to RAASi versus CCBs or TZDs with and without AKI) and population attributable fraction (PAF). For Aim 2b, we will compare mortality rates among RAASi versus CCB users between groups stratified by AKI status. We will also examine ACE inhibitors and angiotensin-receptor blockers (ARB) separately as a prespecified subgroup analysis given potential different actions on ACE2 previously reported.

FINDINGS/RESULTS:
None to date

IMPACT:
Pending results.

PUBLICATIONS:
None at this time.

DRA: None at this time.
DRE: None at this time.
Keywords: None at this time.
MeSH Terms: None at this time.

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