Potential Greater Mortality Risk From CKD Linked to Polypharmacy


Major polypharmacy use was found to increase risk of mortality between 22% and 135% for American adults with chronic kidney disease (CKD) in this subanalysis of data from the REGARDS study.

Among 3 categories of polypharmacy use evaluated in the REasons for Geographic And Racial Differences in Stroke (REGARDS) study, major polypharmacy use (≥ 8 generic ingredients) was associated with greater risk of mortality in the presence of chronic kidney disease (CKD).

The other 2 categories also considered were minor polypharmacy use (6-7 generic ingredients) and no polypharmacy (0-5 generic ingredients). CKD was defined by self-report or a glomerular filtration rate below 60 mL/min/1.73 m2. Patient data were collected via a telephone interview (demographics, socioeconomic status [SES], medical and lifestyle variables) and a home visit (medication use over the past 2 weeks).

These findings appeared recently in Pharmacology Research & Perspectives.

“Based on possible drug-drug interactions and adverse drug reactions, polypharmacy poses plausible risks,” the authors wrote. “Individuals with CKD may be especially vulnerable to any adverse effects of polypharmacy because kidney function is critical for drug excretion; however, data are very limited on CKD’s role in the polypharmacy-mortality association.”

Overall, mortality increased between 22% (HR, 1.22; 95% CI, 1.07-1.40) and 135% (HR, 2.35; 95% CI, 2.15-2.56) among the more than 30,000 adults included in the authors’ analysis (45%, male; 41%, Black; 56%, “Stroke Belt” residents; 24%, normal body mass index [BMI]; 11%, CKD), who were all at least 45 years old (mean patient age, 64.9 years) and from across the United States. There was also an oversampling of Black Americans and Stroke Belt and Buckle Belt residents from North and South Carolina, Georgia, Tennessee, Alabama, Mississippi, Arkansas, and Louisiana.

Noting such polypharmacy risks as comorbidities (eg, diabetes, atrial fibrillation, hypertension); the demographics of female sex, older age, and White race; and the SES indicators of lower education, lower social status, and unemployment, the investigators used up to 8 models to evaluate the relationship between polypharmacy and mortality.

Study retention was high, with less than 3% of respondents lost to follow-up over 7 years (median follow-up, 4.9 years) that included telephone calls every 6 months “to ascertain vital status,” the authors wrote.

Their analysis also produced the following results:

  • 2538 deaths
  • Total major, minor, and no polypharmacy use, respectively: 21.1%, 15.8%, and 63.2% (log rank P < .0001)
  • Patients classified as having major vs minor polypharmacy use were more likely to be female and live in the Stroke Belt, have less education and lower income, have a higher BMI and more comorbidities (eg, CKD, hypertension, dyslipidemia, diabetes, coronary artery disease), and self-report worse health.
  • Patients who were male, Black, and of older age; had less education or lower income; were considered smokers; had worse self-reported health; and had comorbidities had increased mortality rates.
  • CKD had a significant association with mortality, which increased with each CKD level.

The authors noted that there are benefits to polypharmacy, including that it “may decrease mortality in individuals with more severe kidney disease for whom a regimen of multiple drugs may be beneficial.” However, when it is introduced unnecessarily or used inappropriately, there is greater chance of patient exposure to serious risks, such as “increasing mortality in individuals with mild renal impairment who may suffer greater toxicity.”

No medication is universally innocuous, they highlighted.

Data were not collected on medication indication, dose, or dosage, nor did the authors distinguish between eye drops/skin creams and pills/injectables “when aggregating total generic ingredients,” they explained as limits on their findings. Medication misclassification was another potential limit on generalizability.

“Further research is warranted to understand the impact of drug dosages and the relative contributions of different drug classes,” they concluded, “as well as the specificity of the biological pathway(s) and exploration or potential CKD-based polypharmacy vulnerability.”


Cashion W, McClellan W, Judd S, et al. Polypharmacy and mortality association by chronic kidney disease status: the REasons for Geographic And Racial Differences in Stroke study. Pharmacol Res Perspect. Published online August 2, 2021. doi:10.1002/prp2.823

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