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

Key Points: The prevalence of polypharmacy in patients with CKD was over 80%. Polypharmacy was highest in patients with a kidney transplant and those receiving dialysis. Polypharmacy is associated with worse clinical outcomes, lower quality of life, and medication-related problems in patients with CKD. Background: Despite the high prevalence of polypharmacy in patients with CKD, the extent of polypharmacy across patients with (different stages of) CKD, as well as the association with clinical outcomes remains unknown. This systematic review aimed to evaluate the prevalence of polypharmacy in (different subgroups of) patients with CKD and assess the association between polypharmacy and patient-important outcomes. Methods: MEDLINE, Embase, and the Cochrane Library were searched from inception until July 2022. Studies that reported the prevalence of polypharmacy, medication use, or pill burden in patients with CKD (including patients receiving dialysis and kidney transplant recipients) and their association with patient-important outcomes (i.e., mortality, kidney failure, quality of life [QoL], and medication nonadherence) were included. Two reviewers independently screened title and abstract and full texts, extracted data, and assessed risk of bias. Data were pooled in a random-effects single-arm meta-analysis. Results: In total, 127 studies were included (CKD 3–5 n=39, dialysis: n=38, kidney transplant n=13, different CKD stages n=37). The pooled prevalence of polypharmacy, based on 63 studies with 484,915 patients, across all patients with CKD was 82% (95% confidence interval, 76% to 86%), and the pooled mean number of prescribed medications was 9.7 (95% confidence interval, 8.4 to 11.0). The prevalence of polypharmacy was higher in patients who received dialysis or a kidney transplant compared with patients with CKD 3–5 but did not differ between studies with regards to region or patients' mean age or sex. In patients with CKD, polypharmacy was associated with a higher risk of all-cause mortality, kidney failure, faster eGFR decline, lower QoL, and higher medication nonadherence, adverse drug reactions, and potentially inappropriate medications. Conclusions: The prevalence of polypharmacy in patients with CKD was over 80%, and highest in patients with a kidney transplant and those receiving dialysis. No causes of heterogeneity were identified, indicating that polypharmacy is an issue for all patients with CKD. Polypharmacy is associated with worse clinical outcomes, lower QoL, and medication-related problems in patients with CKD. Clinical Trial registry name and registration number: PROSPERO (CRD42022331941).

Elevated serum urea levels are common in moderate-to-advanced chronic kidney disease (CKD). Several studies have shown that urea is a direct and indirect uraemic toxin, especially with regard to cardiovascular disease. We sought to determine whether serum urea levels are associated with adverse cardiovascular events and death before renal replacement therapy (RRT) in patients with CKD. CKD-REIN is a prospective cohort of CKD nephrology outpatients not receiving maintenance dialysis. The 2507 patients included in the analysis were divided into three groups according to the baseline serum urea level (T1 <10.5, T2 10.5–15.1 and T3 ≥15.1 mmol/L). Cox proportional hazard models were used to estimate hazard ratios (HRs) for first atheromatous or non-atheromatous cardiovascular (CV) events and all-cause mortality before RRT. The models were adjusted for baseline comorbidities, laboratory data and medications. Of the 2507 included patients {median [interquartile range (IQR)] age: 69 [61–77]; mean (standard deviation) estimated glomerular filtration rate (eGFR) 33.5 (11.6) mL/min/1.73 m²}, 54% had a history of cardiovascular disease. After multiple adjustments for CV risk factors (including eGFR), patients in T3 had a higher risk of atheromatous and non-atheromatous CV events than patient in T1 (n events = 451, HR [95% CI]: 1.93 [1.39; 2.69]). The adjusted HRs for death before RRT (n events = 407) were 1.31 [0.97; 1.76] and 1.73 [1.22; 2.45] for patients T2 and those in T3, respectively. Our data suggested that urea is a predictor of CV outcomes beyond CV risk factors including eGFR.

Adverse drug reactions (ADRs) are common in patients with chronic kidney disease (CKD). The impact of kidney function decline on serious ADR risk has been poorly investigated. We sought to comprehensively describe ADRs and assess the relationship between eGFR and serious ADR risk. Prospective cohort study. 3,033 participants in French Chronic Kidney Disease-Renal Epidemiology and Information Network (CKD-REIN) cohort study, a nationwide sample of nephrology outpatients with moderate-to-advanced CKD. Demographic and biological data (including eGFR), medication prescriptions. ADRs (preventable or not) were prospectively identified from hospital discharge reports, medical records, and patient interviews. Expert pharmacologists used validated tools to adjudicate ADRs. Restricted cubic splines in fully adjusted cause-specific Cox proportional hazard models were used to evaluate the relationship between eGFR and the risk of serious ADRs (overall and by subtype). During a median follow-up period of 4.7 years, 360 patients experienced 488 serious ADRs. Kidney and urinary disorders (n=170) and hemorrhages (n=170) accounted for 70% of serious ADRs. The most common medications classes were antithrombotics and renin-angiotensin system inhibitors. The majority of those serious ADRs were associated with hospitalization (n=467), with 32 directly or indirectly associated with death, and 22 associated with life-threatening event. More than 27% of the 488 serious ADRs were preventable or potentially preventable. The eGFR is a major risk factor for serious ADRs. Risk of AKI was 2.2% higher and risk of bleeding ADRs were 8% higher for each 1 mL/min/1.73m² lower baseline eGFR. The results cannot be extrapolated to patients who are not being followed up by a nephrologist. ADRs constitute a major cause of hospitalization in CKD patients for whom lower eGFR level is a major risk factor.