Adverse Drug Reactions in Patients with CKD

Abstract

Background and objectives: Little is known about the burden of adverse drug reactions in CKD. We estimated the incidence of overall and serious adverse drug reactions and assessed the probability of causation, preventability, and factors associated with adverse drug reactions in patients seen by nephrologists.

Design, setting, participants, & measurements: The Chronic Kidney Disease-Renal Epidemiology and Information Network cohort included 3033 outpatients (65% men) with CKD and eGFR<60 ml/min per 1.73 m², with follow-up for 2 years. Adverse drug reactions were identified from hospitalization reports, medical records, and participant interviews and finally assessed for causality, preventability, and immediate therapeutic management by experts in pharmacology.

Results: Median (interquartile range) age was 69 (60-76) years old; 55% had eGFR≥30 ml/min per 1.73 m², and 45% had eGFR<30 ml/min per 1.73 m². Participants were prescribed a median (range) of eight (five to ten) drugs. Over 2 years, 536 patients had 751 adverse drug reactions, 150 (in 125 participants) classified as serious, for rates of 14.4 (95% confidence interval, 12.6 to 16.5) and 2.7 (95% confidence interval, 1.7 to 4.3) per 100 person-years, respectively. Among the serious adverse drug reactions, 32% were considered preventable or potentially preventable; 16 caused death, directly or indirectly. Renin-angiotensin system inhibitors (15%), antithrombotic agents (14%), and diuretics (10%) were the drugs to which the most adverse drug reactions were imputed, but antithrombotic agents caused 34% of serious adverse drug reactions. The drug was discontinued in 71% of cases, at least temporarily. Adjusted hazard ratios for serious adverse drug reaction were significantly higher in patients with eGFR<30 versus ≥30 ml/min per 1.73 m² (1.8; 95% confidence interval, 1.3 to 2.6), in those prescribed more than ten versus less than five medications (2.4; 95% confidence interval, 1.1 to 5.2), or in those with poor versus good adherence (1.6; 95% confidence interval, 1.4 to 2.4).

Conclusions: Adverse drug reactions are common and sometimes serious in patients with CKD. Many serious adverse drug reactions may be preventable. Some specific pharmacologic classes, particularly antithrombotic agents, are at risk of serious adverse drug reactions.

Clinical trial registry name and registration number: Chronic Kidney Disease-Renal Epidemiology and Information Network (CKD-REIN), NCT03381950.

Keywords: Chronic; Cohort Studies; Drug-Related Side Effects and Adverse Reactions; Medical Records; Renal Insufficiency; Renin-Angiotensin System; adverse drug reactions; antithrombotic agents; chronic kidney disease; diuretics; glomerular filtration rate; hospitalization; pharmacoepidemiology; risk factors.

Graphical abstract

Figure 1.

Description of the process for identifying and validating adverse drug reactions in the Chronic Kidney Disease-Renal Epidemiology and Information Network (CKD-REIN) cohort.

Figure 2.

Higher incidence rates of adverse drug reactions (ADRs) and serious ADRs in patients with eGFR<30 ml/min per 1.73 m². Incidence rates are represented with their 95% confidence interval whiskers. P values test the difference between incidence rates according to baseline eGFR.

Figure 3.

Distribution of serious ADRs causing or resulting from hospitalization according to baseline eGFR (n=145). Renal disorders and bleeding are the most frequent serious ADRs. Results are expressed as percentages. The denominators used are the total number of ADRs in patients with eGFR<30 or ≥30 ml/min per 1.73 m².

Figure 4.

The most common pharmacological classes responsible for ADRs and serious ADRs are renin-angiotensin system inhibitors, antithrombotic agents, and diuretics. Adverse drug reactions caused by agents acting on the renin-angiotensin system (RAS), antithrombotic agents, or diuretics accounted for 39% of ADRs. Serious ADRs caused by these three classes accounted for 58% of serious ADRs. Results are expressed as percentages. The denominators used are the total number of ADRs in patients with eGFR<30 or ≥30 ml/min per 1.73 m².