Chronic kidney disease (CKD) is a common disease affecting up to 16% of the global population1. Given that patients with CKD are at an increased risk of multiple comorbidities, they commonly need a multitude of medications to prevent further progression of CKD and its complications. Nonetheless, polypharmacy not only impairs health-related quality of life (HRQoL) but is also associated with various medication-related problems, such as drug-drug interactions (DDIs) and reduced medication adherence2. In particular, older CKD patients are more susceptible to the adverse effects of polypharmacy due to age-related changes in drug metabolism and clearance3. In a recent sharing, Dr. Lui Siu Fai, the Chairman of the Hong Kong Kidney Foundation (HKKF), and Dr. Wong Sze Ho Sunny, the Chairman of the Hong Kong Society of Nephrology, highlighted the burden of polypharmacy among CKD patients and discussed the strategies for optimising medication practice for these patients.  

 

The Prevalence of Polypharmacy among CKD Patients 

Dr. Wong highlighted 1,428 new cases of end-stage kidney disease (ESKD) requiring dialysis or kidney transplantation in Hong Kong in 2023. Cumulatively, more than 11,200 patients with kidney diseases received dialysis at centres under the Hospital Authority. Essentially, he noted that diabetes mellitus (DM) and hypertension are the 2 major causes of kidney disease, accounting for 53% and 13% of the new cases last year, respectively. Thus, proper management of DM, hypertension, and other comorbidities is crucial for controlling the onset and potential impacts of kidney diseases.

 

However, Dr. Wong commented that patient compliance with medication treatment is suboptimal. “Some patients may skip some prescribed medications or not follow the required time intervals,” he noted. Remarkably, Dr. Wong addressed the inadequate communication between healthcare professionals and patients. Many patients do not understand the medications prescribed by their physicians. In contrast, physicians may only be able to provide the optimal medications with the information on existing treatments received by the patients.

 

In medication treatment for CKD patients, there has yet to be a consensus on the definition of polypharmacy. However, the condition is commonly described as the concurrent use of more than 5 different medications per day by a patient to treat a particular disease or group of diseases⁴. Polypharmacy is increasingly becoming a potential problem for CKD patients, as they are often treated for other chronic comorbidities or multimorbidities.

 

Dr. Lui presented a recent study by the HKKF, which indicated that local CKD patients take an average of 13-15 medications per day while the maximum case takes 35 drugs. These findings reflected the severity of polypharmacy among local CKD patients, which complies with the published scenario. Notably, Schmidt et al. (2019) conducted a prospective observational study on 5,217 patients with moderately severe CKD under routine care by nephrologists in Germany. The results suggested that the prevalence of polypharmacy at baseline and after 4 years of follow-up was almost 80%, ranging from 62% in patients with CKD Stage G1 to 86% in those with CKD Stage G3b. Remarkably, the median number of medications the patients took per day was 8, whereas some patients took more than 20 daily (Figure 1). Beta-blockers, angiotensin-converting enzyme inhibitors (ACEi) and statins were the most frequently used medications⁵.

 

Figure 1. Total number of medication intakes per patient at baseline⁵

 

The report of Schmidt et al. further highlighted that increasing CKD G stage, age and body mass index (BMI), DM, cardiovascular disease (CVD) and a history of smoking were significantly associated with both the prevalence of polypharmacy and its maintenance during follow-up⁵.

 

 

The Vicious Cycle of Polypharmacy and CKD

As Dr. Wong noted, DM and hypertension substantially increase the risk of CKD, whereas managing these conditions normally requires multiple medications. This contributes to the occurrence and persistence of polypharmacy in CKD patients⁶. In contrast, polypharmacy has been reported to be associated with adverse renal outcomes. For instance, a retrospective study by Kimura et al. (2021) on a cohort of 1,117 Japanese patients with non-dialysis-dependent CKD indicated that the use of a high number of medications was associated with a high risk of kidney failure, CV events, and all-cause mortality⁷.

 

The Threat for Older CKD Patients

The issue of polypharmacy in older patients is particularly noteworthy. Ageing alters many physiologic processes, causing older people to have different pharmacokinetic and pharmacodynamic responses to drugs⁸. Besides, the majority of older people suffer from multimorbidity, which in turn contributes to multiple medications. The reported prevalence of polypharmacy among older populations in different healthcare settings ranged from 27.0 to 96.5%⁹. Given that ageing and multimorbidity are key drivers of polypharmacy, the awareness of appropriate prescriptions for older patients with renal insufficiency is particularly critical.

 

The Multifaceted Burden of Polypharmacy in CKD

Polypharmacy among CKD patients is strongly associated with various drug‑related problems. For instance, it is a main reason for potentially inappropriate medication (PIM) use, with the risk of PIMs increasing with the number of prescribed medications¹⁰. A recent analysis of 27 studies by Hamzaei et al. (2024) reported that the prevalence of inappropriate prescribing in CKD ranged from 12.6% to 96% in hospital settings. Also, inappropriate prescribing was associated with a higher risk of hospitalisation, higher bleeding rate, and higher risk of all-cause mortality¹¹. Besides, it is essential to be aware that a high drug burden would result in non-adherence to treatment among patients. Practically, the medication non-adherence rates in dialysis populations varied between 3-80% (depending on the definition), with a median of 50%¹².

 

Apart from PIMs and non-adherence, polypharmacy also increases the risk of DDIs, which in turn results in an augmented risk of morbidity and mortality among CKD patients, diminished quality of life, as well as prolonged hospitalisation. While multimorbidity is common among CKD patients, the risk for DDIs increases when numerous prescribers are involved in treating the same patients while additional drugs are prescribed¹³. The prevalence of potential DDIs in CKD patients undergoing haemodialysis and/or pharmacological treatment has been reported to range between 27.5% and 89.1%¹⁴. This highlights the importance of interdisciplinary communication in managing CKD patients.

 

In addition to the pathophysiological outcomes, the adverse impact of polypharmacy on the HRQoL cannot be ignored. A recent analysis of the data from the Medical Expenditure Panel Survey (MEPS) between 2010 and 2019 by Adjeroh et al. (2023) found that both major polypharmacy (5-9 medications) and hyperpolypharmacy (≥10 medications) were significantly associated with a lower HRQoL, as measured by Physical Component Summary (PCS) and Mental Component Summary (MCS) scores, compared with patients taking ≤4 medications. Furthermore, among the 649 non-dialysis CKD patients involved, the prevalences of major polypharmacy and hyperpolypharmacy were 48.24% and 29.48%, respectively¹⁵. These results reflected the high prevalence of polypharmacy among CKD patients and also its negative impact on HRQoL.

 

The burden of polypharmacy is undoubtedly significant and adversely affects CKD patients and their families in various aspects. Remarkably, the direct and indirect costs of polypharmacy imposed on the healthcare system and economy are considerable. Thus, effective strategies for optimising medication treatment are highly desirable.

 

The Clinical Challenges in Prescribing Medications

To reduce polypharmacy, it is crucial to understand the barriers hindering optimal medication management. In this regard, the cross-sectional survey by Aspden et al. (2015) provided insight into medication non-adherence among patients with kidney diseases. The study evaluated self-reported data of 100 patients with ESKD undergoing dialysis. It classified the possible reasons for medication non-adherence as unintentional or intentional/related to health beliefs¹².

 

Difficulty with access to medications is one of the unintentional reasons for non-adherence to treatment. While the difficulty may be due to socioeconomic or financial restrictions, social and government support would help reduce this issue. Besides, poor comprehension by the patients also prevents them from properly complying with the prescribed medication. Improving health literacy and reducing language barriers are essential to overcome this barrier. Moreover, some cases of non-adherence are simply because the patients forgot to take the medication, particularly in polypharmacy and patients with cognitive impairment. Support by caregivers or family members would help promote adherence among these patients. Nonetheless, poor tolerability of the medications also accounts for a significant proportion of non-adherence¹².

 

There are 2 primary intentional reasons for medication non-adherence. The first one is patients’ low perception of medication’s importance. Low health literacy and cultural beliefs are possible risk factors in this case. On the other hand, the high perception of potential harm from medications significantly prevents patients from complying with them. Proper health education and enhancing health literacy are vital for improving the intentional factors¹².

 

The "5 Rights" in the Optimal Medication for CKD Patients

Dr. Lui emphasised that one of the goals in managing CKD patients is to slow the decline of renal function. Accordingly, proper prescription of medications controlling the risk factors, in particular DM and hypertension, is of paramount importance. Hence, identifying high-risk populations is essential.

 

“Even though the right medications are prescribed, optimal outcomes cannot be achieved if the dosage is inappropriate,” Dr. Lui commented. He further opined that formulating the optimal medication protocol involves both healthcare professionals and patients. While health education for the public is crucial, Dr. Lui emphasised that improving health literacy for both clinicians and the public is urgently needed. Therefore, the HKKF has launched various activities, including symposia and the Kidneys Talk Online Series, to highlight clinical issues in managing CKD for clinicians, raise awareness of kidney health, and promote treatment adherence among the public.

 

Richard Knight, the Immediate Past President of the American Association of Kidney Patients (AAKP), addressed that the best treatment includes the right treatment for the right patient at the right time. Whereas the treatment is in alignment with the patients’ hopes and dreams, as well as empowers them to pursue their life goals. In echo to this quote, Dr. Lui summarised the ultimate goal in optimising medication for CKD patients in the “5 Rights” advocacy, which refers to treating the Right patients at the Right time with the Right drugs at the Right dosage to reach the Right treatment target. With the collaboration between healthcare professionals, patients, government, and non-government stakeholders in improving access to medications, knowledge of drug treatment, and patient support, the 5 Rights advocacy in CKD patients will definitely be achievable.

 

References

1. Naseralallah et al. Front Pharmacol 2023; 14: 1122898.  2. Van Oosten et al. Clin Kidney J 2021; 14: 2497–523.  3. Secora et al. Drugs Aging 2018; 35: 735–50.  4. Fasipe et al. Archives of Medicine and Health Sciences 2018; 6: 40.  5. Schmidt et al. Clin Kidney J 2019; 12: 663–72.  6. Al-Khulaifi et al. Clin Ther 2023; 45: e217–21.  7. Kimura et al. Clin J Am Soc Nephrol 2021; 16: 1797–804.  8. Scott et al. JAMA Intern Med 2015; 175: 827–34.  9. Wang et al. Front Public Health 2023; 11. DOI:10.3389/FPUBH.2023.1116583.  10. Okpechi et al. Syst Rev 2021; 10: 1–7.  11. Hamzaei et al. Basic Clin Pharmacol Toxicol 2024; published online Feb 13. DOI:10.1111/BCPT.13986.  12. Aspden T, Wolley et al. BMC Nephrol 2015; 16. DOI:10.1186/S12882-015-0097-2.  13. Zafar et al. PLoS One 2023; 18. DOI:10.1371/JOURNAL.PONE.0291417.  14. Papotti et al. Current Research in Pharmacology and Drug Discovery 2021; 2: 100020.  15. Adjeroh et al. PLoS One 2023; 18. DOI:10.1371/JOURNAL.PONE.0293912.