Medication burden in patients with dialysis-dependent CKD: a systematic review

Figures & data

Table 1. Search terms used in the PUBMED, EMBASE, and COCHRANE databases.

Databases	Search terms	n
PUBMED	((‘CKD’[Title/Abstract] OR ‘ESKD’[Title/Abstract] OR ‘ESRD’[Title/Abstract] OR ‘CRF’[Title/Abstract] OR ‘ESRF’[Title/Abstract] OR (‘uremia’[Title/Abstract] OR ‘end stage renal failure’[Title/Abstract] OR ‘chronic renal failure’[Title/Abstract] OR ‘end stage kidney disease’[Title/Abstract] OR ‘end stage renal disease’[Title/Abstract] OR ‘chronic kidney disease’[Title/Abstract])) AND (‘medication regimen complexity’[Title/Abstract] OR ‘treatment complexity’[Title/Abstract] OR ‘drug complexity’[Title/Abstract] OR ‘medicine complexity’[Title/Abstract] OR ((‘difficult’[All Fields] OR ‘difficults’[All Fields]) AND ‘medications’[Title/Abstract]) OR ‘complicated medications’[Title/Abstract] OR ‘medication burden’[Title/Abstract] OR ‘pill burden’[Title/Abstract] OR ‘drug burden’[Title/Abstract]) AND (‘Dialysis’[Title/Abstract] OR ‘Hemodialysis’[Title/Abstract] OR ‘peritoneal dialysis’[Title/Abstract] OR ‘renal replacement therapy’[Title/Abstract] OR ‘kidney replacement therapy’[Title/Abstract])) AND ((humans[Filter]) AND (2013/1/1:2024/03/31[pdat]) AND (english[Filter]))	64
EMBASE	(ckd:ab,ti OR eskd:ab,ti OR esrd:ab,ti OR crf:ab,ti OR esrf:ab,ti OR uremia:ab,ti OR ‘end stage renal failure’:ab,ti OR ‘chronic renal failure’:ab,ti OR ‘end stage kidney disease’:ab,ti OR ‘end stage renal disease’:ab,ti OR ‘chronic kidney disease’:ab,ti) AND ('medication regimen complexity’:ab,ti OR ‘treatment complexity’:ab,ti OR ‘drug complexity’:ab,ti OR ‘medicine complexity’:ab,ti OR ‘difficult medications’:ab,ti OR ‘complicated medications’:ab,ti OR ‘medication burden’:ab,ti OR ‘pill burden’:ab,ti OR ‘drug burden’:ab,ti) AND (dialysis:ab,ti OR hemodialysis:ab,ti OR ‘peritoneal dialysis’:ab,ti OR ‘renal replacement therapy’:ab,ti OR ‘kidney replacement therapy’:ab,ti) AND [humans]/lim AND [01-01-2013]/sd NOT [31-03-2024]/sd	135
COCHRANE	(CKD) OR (ESKD) OR (ESRD) OR (CRF) OR (ESRF)OR (uremia) OR (end stage renal failure) OR (chronic renal failure) OR (end stage kidney disease) OR (end stage renal disease)OR (chronic kidney disease) in Title Abstract Keyword AND (medication regimen complexity) OR (treatment complexity) OR (drug complexity) OR (medicine complexity) OR (difficult medications)OR (complicated medications) OR (medication burden) OR (pill burden) OR (drug burden) in Title Abstract Keyword AND (Dialysis) OR (Hemodialysis) OR (peritoneal dialysis) OR (Renal replacement therapy) OR (kidney replacement therapy) in Title Abstract Keyword - with Cochrane Library publication date Between Jan 2013 and Mar 2024, in Trials	615

Figure 1. PRISMA flow chart for paper selection.

Table 2. Characteristics of included studies.

Study	Country	Research type	Patients	Index	Description	Relevant factor	Outcomes
Al-Mansouri et al. [16]	Qatar	Cross-sectional study	CKD patients at stage 4 and stage 5 (n = 280), hemodialysis patients (n = 223), pre-dialysis patients (n = 57)	Pill burden	Hemodialysis patients 122 (61) pills/week, pre-dialysis patients 109 (33) pills/week	–	Treatment burden
				Number of medications	Hemodialysis patients: 12 (5) oral medications and 3 (2) of parenteral medications. Pre-dialysis patients: 12 (5) oral medications and 1 (2) of parenteral medications.
				Medication types	The most commonly prescribed oral medications were vitamin D (90.4%), sevelamer carbonate (65%), calcium (Ca) as a phosphate binder or supplement (63.2%), cinacalcet (67.5%), and statins (67.1%). Medication utilization pattern in HD patients for erythropoiesis-stimulating agents (ESAs), iron, vitamin D, phosphate binders, Ca-supplement and parathyroid hormone (PTH) medication, was significantly higher compared to non-dialysis. The utilization of diuretics and calcium channel blockers (CCBs) was higher in non-dialysis patients compared to HD patients.
George et al. [18]	India	Intervention cohort study	Patients who were on hemodialysis for 3 months or more (n = 150)	Number of medications	Before deprescription: 10.8 ± 3.2, after deprescription: 7.6 ± 2.3	Proactive deprescription program	Medication adherence
				pill burden	Before deprescription: 17.3 ± 6.6, after deprescription: 11.70 ± 5.1 (pills/d)
Murali et al. [19]	Australia	Cross-sectional study	CKD patients (n = 113), ESKD dialysis patients (n = 107)	Pill burden	ESKD dialysis patients vs. CKD patients: median 21 vs. 9 pills daily	–	Medication adherence
Paik et al. [20]	USA	Retrospective cohort study	Patients with ESRD on hemodialysis (a total of 163,228 to 176,133 patients)	Drug classes	7.4 ± 3.8 (2013), 7.0 ± 3.7 (2014), 7.0 ± 3.7 (2015), 7.0 ± 3.6 (2016), and 6.8 ± 3.6 (2017)	Age, sex, race, and LIS status (low-income subsidy status)	–
				Polypharmacy (≥5 medications)	77.5% in 2013 to 73.8% in 2017.	–	–
								Van Oosten et al. [23]	Netherlands	Retrospective cohort study	N = 27,573, patients with CKD stage G4/G5 not on KRT (kidney replacement therapy) (n = 14,905), patients on dialysis (n = 3872), kidney transplant patients (n = 8796)	The median number of dispensed medications	For all medication use, 10 for CKD stage G4/G5 patients, 12 for dialysis patients and 11 for transplant patients. For chronic medication use, 6 in all patient groups.	–	–
Polypharmacy	All medication use in dialysis patients: ≥5 medications (PP), ≥10 medications (EPP) and ≥15 medications (HPP) prevalences were 93.4, 69.3, and 31.5%, respectively; chronic medication use in dialysis patients: PP, EPP, and HPP prevalences were 70.0, 15.1, and 1.2%.	The most pronounced risk factors for EPP in dialysis patients were diabetes [OR 3.69 (95% CI 3.08–4.43)] and vascular disease [OR 2.08 (95% CI 1.72–2.51)]. An inverse association between PP and aged 75 years in dialysis patients.
Parker et al. [17]	Norway	Prospective cohort study	Patients aged ≥65 years in predialytic CKD stage 5 (eGFR < 15 ml/min/1.73 m^2) and who were receiving HD or PD (n = 157), HD (n = 73), PD (n = 19), predialytic (n = 65)	MRCI	HD 24.7 ± 7.9, PD 23.3 ± 6.4, predialytic 20.5 ± 7.3	Female sex (p = .044), Charlson Comorbidity Index (CCI) of 4 or 5 (p = .029) and using several categories of phosphate binders (p < .001 to .04)	No clear association between medication complexity and self-reported medication adherence
Iwashita et al. [14]	Japan	Cross-sectional study	Patients aged between 50 and 79 years who had been on maintenance hemodialysis for more than 3 years (n = 524)	Drug burden	Oral tablets per day : dialysis 16.4 ± 8.34, nondialysis 16.3 ± 8.55	–	–
				Frequency of oral medications taken	3 times/d (31% and 33%), 4 times/d (24% and 22%), and 5 times/d (31% and 30%)
				Types of oral medications	Phosphate binders (7.0 tablets), antihypertensive (2.8 tablets), antidiabetic (2.0 tablets)
Cirevalli et al. [15]	India	Cross-sectional study	CKD patients (n = 244); under stage 1–5 (pre-dialysis) (n = 107), HD (n = 58), PD (n = 52), renal transplant recipient (RTR) (n = 27)	Pill burden (PB)	Mean total pills/d HD 10 ± 3, PD 13 ± 5	Age, form of dialysis	–
				Drug classes	Mean drug classes/d HD 7 ± 2, PD 8 ± 3	Age, form of dialysis
				Medication types and their proportion	HD: anti-hypertensive drugs (29%), mineral bone derivatives (11%), peptic ulcer drugs (10%); PD: anti-hypertensive drugs (25%), peptic ulcer drugs (11%), oral-hypoglycemics (10%)	–	–
Gupta et al. [22]	India	Cross-sectional study	Hemodialysis patients (n = 188)	Pill burden	The total numbers of pills (pills/day) HD 10.5 ± 3.2	–	Medication adherence
Parker et al. [21]	UK	Single renal network, cross-sectional study	Dialysis patients (n = 236), HHD (home hemodialysis) (n = 57); MHD (maintenance hemodialysis) (n = 117), PD (peritoneal dialysis) (n = 62)	Mean pill burden Blood pressure pill burden Phosphate binders pill burden Epoetins pill burden	Mean pill burden (pills/day) MHD 16 ± 7, HHD 11 ± 7, PD 16 ± 7 Daily BP pill burden MHD 2.7 ± 2.6, HHD 1.1 ± 1.5, PD 3.0 ± 2.5 The mean PB for phosphate binders, MHD 3.1 ± 3.7, HHD 3.1 ± 3.1, PD 3.5 ± 2.5 The mean monthly doses of epoetins, MHD 124 ± 127 mg, HHD 123 ± 126 mg, PD 109 ± 98 mg	Modality setting (form of dialysis)	–

Table 3. Literature quality assessment.

Inclusion of literature	Type of research	Literature quality assessment tool	Evaluation of the results
Al-Mansouri et al. [16]	Cross-sectional study	AHRQ	Good
George et al. [18]	Interventional cohort study	NOS	8 scores
Murali et al. [19]	Cross-sectional study	AHRQ	Weak
Paik et al. [20]	Retrospective cohort study	NOS	9 scores
Van Oosten et al. [23]	Retrospective cohort study	NOS	7 scores
Parker et al. [17]	Prospective cohort study	NOS	8 scores
Iwashita et al. [14]	Cross-sectional study	AHRQ	Good
Cirevalli et al. [15]	Cross-sectional study	AHRQ	Good
Gupta et al. [22]	Cross-sectional study	AHRQ	Weak
Parker et al. [21]	Single renal network, cross-sectional study	AHRQ	Good

Al-Mansouri A, Hamad AI, Al-Ali FS, et al. Pill-burden and its association with treatment burden among patients with advanced stages of chronic kidney disease. Saudi Pharm J. 2023;31(5):678–686. doi:10.1016/j.jsps.2023.03.008.

 PubMed Web of Science ®Google Scholar

George JS, Joseph R, Thomas ETA, et al. Active deprescribing program in chronic kidney disease patients undergoing haemodialysis. Nephrology. 2021;26(11):890–897. doi:10.1111/nep.13936.

 PubMed Web of Science ®Google Scholar

Murali K, Mullan J, Roodenrys S, et al. Medication non-adherence in patients with kidney disease: importance of depression, health literacy and pill burden. Nephrology. 2021;26(Suppl. 2):24. doi:10.1111/nep.13930.

 Google Scholar

Paik JM, Zhuo M, York C, et al. Medication burden and prescribing patterns in patients on hemodialysis in the USA, 2013–2017. Am J Nephrol. 2021;52(12):919–928. doi:10.1159/000520028.

 PubMed Web of Science ®Google Scholar

Van Oosten MJM, Logtenberg SJJ, Hemmelder MH, et al. Polypharmacy and medication use in patients with chronic kidney disease with and without kidney replacement therapy compared to matched controls. Clin Kidney J. 2021;14(12):2497–2523. doi:10.1093/ckj/sfab120.

 PubMed Web of Science ®Google Scholar

Parker K, Bull-Engelstad I, Aasebø W, et al. Medication regimen complexity and medication adherence in elderly patients with chronic kidney disease. Hemodial Int. 2019;23(3):333–342. doi:10.1111/hdi.12739.

 PubMed Web of Science ®Google Scholar

Iwashita Y, Ohya M, Kunimoto S, et al. A survey of drug burden in patients undergoing maintenance hemodialysis in Japan. Intern Med. 2018;57(20):2937–2944. doi:10.2169/internalmedicine.0108-17.

 PubMed Web of Science ®Google Scholar

Cirevalli P, Nimmanapalli HD, Parlapalli LK, et al. Pill burden, drug class distribution and financial burden for buying medicines in different modalities of chronic kidney disease patients: cross-sectional study. Int J Pharm Pharm Sci. 2018;10(6):165–170. doi:10.22159/ijpps.2018v10i6.26186.

 Google Scholar

Gupta V, Jasani R, Kumar R, et al. Pill burden and PILL adherence in dialysis patients. Indian J Nephrol. 2017;27:S93.

 PubMedGoogle Scholar

Parker K, Nikam M, Jayanti A, et al. Medication burden in CKD-5D: impact of dialysis modality and setting. Clin Kidney J. 2014;7(6):557–561. doi:10.1093/ckj/sfu091.

 PubMedGoogle Scholar

Data availability statement

All data generated or analyzed during this study are included in this published article [and its supplementary information files].