Drug-Related Problems and Associated Factors among Patients Admitted with Chronic Kidney Disease at Jimma University Medical Center, Jimma Zone, Jimma, Southwest Ethiopia: A Hospital-Based Prospective Observational Study

Background There is an alarming rise of chronic kidney disease prevalence globally associated with significant morbidity and mortality necessitating special attention as one of the major growing public health problems. Medication-related problems are common in hospitalized patients including chronic kidney disease and may lead to increase hospital stay and health care cost and augment the risk of morbidity and mortality. Objective To determine prevalence of medication-related problems and associated factors among chronic kidney disease patients admitted to Jimma University Medical Center from April to September 2018. Methods A hospital-based prospective observational study was conducted among 103 chronic kidney disease patients admitted to Jimma University Medical Center from April to September 2018. Data regarding patient characteristics, medications, diagnosis, length of hospitalization, and laboratory results were collected through review of patients' medical charts. Data were analyzed by using Statistical Package for the Social Sciences (SPSS) version 21.0. Univariate and multivariate logistic regression was utilized to assess the associations between dependent and independent variables. Statistical significance was considered at p value <0.05. Results Out of 103 chronic kidney disease patients, 81 (78.6%) of patients had MDRs, on average 1.94 ± 0.873 per patient. The rate of overall MRPs was 30.95 per 100 medication orders. The most common MRPs among CKD patients were need additional drug therapy (62 (31%)), nonadherence (40 (20%)), and dose too low (36 (18%)). The most common cause of need additional drug therapy (52 (26%)) was untreated medical conditions; nonadherence (19 (9.5%)) was mostly due to that the patient/caregiver forgets to take/give the medication, and dose too low (29 (14.5%)) was mostly due to that the dose is too low to produce the desired response. Polypharmacy (AOR = 4.695, 95% CI: 1.370–16.091), number of comorbidities (AOR = 3.616, 95% CI: 1.015–1.8741), and stage of CKD (AOR = 3.941, 95% CI: 1.221–12.715) were independent predictors for MRPs. Conclusions We have demonstrated that medication-related problems are high among chronic kidney disease patients. Marital statuses, stage of CKD, polypharmacy, and comorbidity were independent predictors for MRPs. Interdisciplinary health professionals should work to decrease the high prevalence of MRPs among chronic kidney disease patients.


Back Ground
Chronic kidney disease is one of the global health problems requiring early detection and treatment to prevent its progression [1] and associated with increased morbidity, mortality, and health care costs for both individual patients and health care system [2]. e global prevalence of CKD is estimated to be 11%-13% [3]. In sub-Saharan Africa (SSA), CKD is estimated to be 3-4 folds more than in developed countries [4] and comorbidity, implying concomitant use of many drugs, makes the management of these patients particularly challenging [5]. Medication-related problems (MRPs) are the major challenge to health care providers and they may affect morbidity, mortality, and patients' quality of life. CKD patients are on high risk for MRPs because of the polypharmacy and the impaired renal excretion [6,7]. MRPs may lead to reduced quality of life, increased hospital stay, increased overall health care cost, and even increases the risk of morbidity and mortality. All patients' problems involving medications can be grouped into one of the seven types of MRPs. ese include unnecessary drug therapy; need additional drug therapy, ineffective drug, dosage too low, adverse drug reactions (ADRs), dosage too high, and noncompliance [8,9].
Since MRPs are very common in patients with CKD, identification, prevention, and management of these problems require a comprehensive, interdisciplinary approach [10][11][12][13][14]. It is estimated that the annual cost of drug-related morbidity and mortality is nearly 177 billion dollars in the United States [15]. Many drugs are eliminated by the kidneys and therefore may require dose adjustment in patients with renal impairment and dosing of all drugs, including antibiotics should be optimized and monitored so as to prevent ADR, avoid further renal injury, and to facilitate treatment outcomes [16][17][18]. e treatment of CKD stage V needs a large number and variety of drugs, which are linked to a number of MRPs, high cost, and short-term mortality [19][20][21][22][23]. A high number of prescribed medications due to a high number of comorbidities and complications associated with the disease, poor medication adherence, and frequent dosage changes may contribute to drug-related morbidity and MRPs [4,[24][25][26][27][28][29].
Identifying MRPs is a major task which could be taken care of by a clinical pharmacist in coordination with other health care providers through medication reconciliation [30][31][32][33]. On the other hand, educational intervention at discharge and follow-up of patients by the clinical pharmacists may also prevent adverse events and can improve patients' awareness of their drug therapy which in turn would improve their adherence to drug therapy [34][35][36]. e prevalence of CKD cases found to be significant in Ethiopia. In a developing country like Ethiopia, the role of a clinical pharmacist is much needed as there is a need to seal the existing gap in health care settings of the country [37]. e aim of this study was to determine prevalence of MRPs and associated factors among CKD patients admitted to Jimma University Medical Center from April to September 2018.

Study Setting and Population.
e study was conducted at Jimma University Medical Center (JUMC), which is the only referral hospital for the south region, serving 20 million catchment areas.
e study was conducted from April 1 to September 30, 2018, among CKD patients admitted to JUMC. Patients were eligible for inclusion if they were greater than 18 years of age and willing to give their informed consent. e dependent variable was MRPs and independent variables included patients' related factors: age, sex, BMI, educational status, residence, monthly income, marital status, and occupation; disease-related factors: stage of CKD, length of hospital stay, comorbid condition, past medical history, and reason of admission; drug-related factors: number of drugs per prescription, past medication history, and drug class.

Study Design.
A hospital-based prospective observational study was used to determine the magnitude of medication-related problems and associated factors among CKD patients. e sample size was calculated by using simple proportion formula with estimated prevalence of MRPs among CKD patients, p � 81.5% [21], 95 confidence interval, and sample error of 5%, n � 231. 180 CKD patients admitted to JUMC in 2017. e final sample size, 103, was calculated using the correction formula.

Data Collection Procedures.
Well-designed questionnaires were prepared after reviewing different literatures. e questionnaire was translated from English to local language Afan Oromo and Amharic and back to English by a licensed linguist. Semi-structured interview was conducted to record patients' sociodemographic data, past medical and medication history, date of admission/discharge, and allergy/ADR history and the patient chart to collect comorbidities, current and discharge medications, and laboratory investigations. All drugs which were prescribed for CKD patients were recorded and evaluated for presence, types, and patterns of MRPs. Identified MRPs were recorded and classified using MRP registration format which was taken from Pharmaceutical Care Practice: e Clinicians Guide [8]. MRPs were categorized by type and medication class. Pretest was done to ensure the validity of the tools.

Data Processing and Statistical
Analysis. Data were checked for completeness, grouped, then entered to EpiData version 4.2.0.0 software, and exported to the Statistical Package of the Social Sciences (SPSS) version 21.0 for analysis. Descriptive statistics like mean and percentage were used to present sociodemography and clinical characteristics of participants. Binary logistic regression was used to see the association between independent and dependent variables, and variables with a p value <0.25 were a candidate for multivariate analysis and those variables with a p value <0.05 were considered as significant in multivariate analysis. e ADR was assessed by using the Naranjo ADR Probability Scale [38]. Subsequently, the appropriateness of drug therapy was evaluated using the 2014 Ethiopian Standard Treatment Guideline, UpToDate, Clinical Practice Recommendations for Primary Care Physicians and Health care Providers, the KDIGO 2012 Clinical Practice Guideline, and the WHO guideline. Identified MRPs were recorded and classified using MRP registration format which was taken from Pharmaceutical Care Practice [39]. en, the possible intervention measures were proposed and communicated with either the internist/resident/senior physician or the patient in order to resolve or prevent MRPs.

Ethical Consideration.
Institutional review board approval was obtained from Jimma University and written informed consent was obtained from each study participant.

Operational Definitions
2.6.1. Chronic Kidney Disease. CKD is defined as abnormalities of the kidney structure or function, present for 3 months, with implications for health [30].

Social Drug Use.
Use of alcohol, cigarette smoking, and chewing khat for one or more than one year. 2.6.5. Polypharmacy. Use of five or more medication concomitantly.
2.6.6. MRPs. Events involving drug treatment that are actually or potentially harmful to a patient's health or prevent patients to optimally benefit from treatment.

Need Additional Drug
erapy. Additional drug therapy is required to treat or prevent a medical condition or illness from developing.

Sociodemographic Characteristics of the Study Participants.
During the six month study period, 103 CKD patients were included. Most of the study participants were in age group of 18-40 years with a mean age of 45.83 ± 17.7. Majority of the study participants 72 (69.9%) were males, 65 (63.5%) had no regular income, 66 (64.1%) were living in rural area, and 73 (70.9%) were married. Most of the study participants were 53 (51.5%) farmers and 34 (33.0%) had secondary education (Table 1).

Prevalence of Medication-Related
A total number of 646 medications were prescribed, and the mean number of prescribed medications per patient was 6.26 ± 1.85. From these, 219 drugs were involved in 200 different types of MRPs. e most common drug classes associated with the occurrence of MRPs among study participants include cardiovascular medications (31.9%), gastrointestinal (19.1%), and analgesic (19.1%) ( Table 4).

Predictors of Medication-Related Problems.
e association of independent variables with dependent variables was investigated using both univariate and multivariate logistic

Discussion
In our study, most of the study participants 90 (87.4%) were newly diagnosed CKD patients (within 3 months of study enrollment) and 67 (65%) were in CKD stage V. e reasons for this were most study participants live in rural areas, had a history of many medical conditions, did not take their medications properly, and came to JUMC after developing ESRD. We found a high frequency of MRPs in 81 (78.6%) patients among CKD patients with an average of 1.94 ± 0.873 MRPs per patient. e rate of overall MRPs was 30.95 per 100 medication orders. is result is lower than the result obtained from studies conducted in Indonesian (42.7 MRP per 100 medication orders) [2] and higher than the result found in USA (6.58 MRPs per 100 medication orders) [14]. Each study participant had at least one type of MRPs and the number of MRPs per participant ranges between 2 and 4. Conversely, a study conducted in France [40] reported that MRPs experienced by 93% to 99% of studied patients and ranged between 2 and 6 MRPs per patient. ese discrepancies might be due to differences in the study population, study period, and study setting. Our analysis on MRPs showed need additional drug therapy (31% of all MRPs), which is almost similar to the studies conducted in France (30%) [13,27]. In contrast to this finding, need additional drug therapy accounted for a larger proportion of the MRPs in studies conducted in USA (61.5%) [14], India, (40.6%) [41], Canada (51.3%) [42], and Pakistan (40.19) [6]. is is because of more comorbidities and complex CKD management algorithm identified in most study settings. However, the finding of this study was greater than the results obtained from midwestern America (17.5%) [14], USA (16.9%) [4], France (24.1%) [43], and Switzerland (18%) [44]. Dose too low accounted for 18% of all MRPs identified, which was consistent with studies conducted in France (19%) [27] and Nigeria (20.9%) [7]. is may be due to the similar study design used. Conversely, dose too low accounted for higher proportion of the MRPs in studies conducted in USA (33.5%) [19], France (25.5%) [13], Pakistan (31.1%) [6], and Beirut (10%) [45]. e difference can be explained by the difference in study design used and health care setting in which the studies were conducted.
is difference might be an underestimate due to the lack of comprehensive documentation at the point of admission in     (20) e patient/caregiver prefers not to take/give the medication 12 (6) e patient/caregiver forgets to take/give the medication 19 (9.5) e drug product is too expensive for the patient 4 (2) International Journal of Nephrology this study. However, this study's finding was higher than what was found in Netherlands (5%) [20] and Singapore (3.1%) [47]. Inappropriate drug monitoring and failure of adjusting renal-dosed drugs as per the renal function could be the reason. Another common aspect of MRPs is unnecessary drug therapy 4.8%, which was consistent with studies conducted in Canada (5.5%) [42]. In comparison, this finding is lower than the studies conducted in America (30.9%), [14], Netherlands (25.5%), [20], Switzerland (10%) [48], Nigeria (36.75%) [7], Malaysia (20.9%) [49,50], and Pakistan (21.2%) [6]. Despite the difference of figures in many countries, polypharmacy is common among CKD population due to the nature of its management. Ineffective drug therapy contributed for 10% of all MRPs identified. In comparison, studies conducted in India, (40.6%) [41], Canada (51.3%) [42], Beirut (28%) [45], and USA (14.9%) [4] showed larger proportion of ineffective drug therapy. is might be due to in developed countries CKD patients treated for many years which can result in drug resistance, while most of the study participants in this study were newly diagnosed patients. ADR (2%) is another important subset of MRPs identified. Conversely, studies conducted in USA (20.7%) [19], India (40%) [41] Canada (6.8%) [42], and Singapore (25%) [47] had higher ADR of all MRPs. e difference in this prevalence could be explained by the fact that the other studies were carried out over a long period thus identify more ADRs. Nonadherence was accounting for 20% of all MRPs identified, which was higher than the studies conducted in USA (16.9%) [51], Netherlands (5.6%), [20], and India (11.1%) [39]; however, lower than what was found in Canada (28%) [42] and Singapore (28.1%) [47]. ese findings can be attributed to failure of the patients to understand their disease process and the benefits of adhering to medications as prescribed. Indeed, a study in France established an obvious lack of knowledge concerning CKD and its treatment objectives which led to a potential for nonadherence [21]. e high number of drugs per participant as well as comorbidities could also contribute to the high prevalence of nonadherence [52].
Marital status was significantly associated with the number of MRPs which is different from most findings [4,27,42] where marital status was not an independent predictor of MRPs. is difference might be due to marital status difference of study participants and large sample of the current study. Polypharmacy was significantly associated with a number of MRPs which is similar with studies conducted in France and India [27,42,53]. e number of comorbidities was significantly associated with the number of MRPs which is in agreement with studies conducted in USA and India [14,41]. Possible reasons for prescribers not picking up some of the comorbidities and inadequate information transfer between the patient and the prescriber.  International Journal of Nephrology Stage V CKD patients were significantly associated with the number of MRPs which is consistent with the study conducted in Norway [43]. is was due to CKD stage V patients are known to suffer from numerous comorbidities and complications. As a result, the treatment needs a large number and variety of drugs [21]. A total of 218 clinical interventions were undertaken at three levels of the intervention. Out of these interventions, 178 (81.6%) were accepted, 174 (79.8%) were totally solved, and 40 (18.3%) MRPs were partially solved due to lack of cooperation of prescriber and patient. Amongst the MRPs indentified, 78.1% were successfully resolved. Conversely, a study conducted in Nigeria [7] showed the acceptance of clinical interventions was 67.54%, and 7.86% was successfully resolved.

Conclusion
We have demonstrated that MRPs are high in CKD patients. Marital statuses, stage of CKD, polypharmacy, and comorbidity were independent predictors for MRPs.

5.1.
Recommendations. JUMC should implement strategies to decrease the high prevalence of MRPs among CKD patients and should assign an interdisciplinary health care provider in inpatient settings to decrease the prevalence of MRPs among CKD patients. Since CKD patients are at high risk to present with comorbidities, physicians should consider all while treating them. e health care provider should adhere to dose adjustment recommendationsand should prescribe essential medicines only to reduce polypharmacy, and if possible, polypharmacy should be avoided. CKD patients should adhere to their medications.

ADR:
Adverse drug reaction AKI: Acute kidney injury CCB: Calcium-channel blocker CKD: Chronic kidney disease CVD: Cardiovascular disease DRPs: Drug-related problems ESRD: End-stage renal disease

Data Availability
e data used to support the findings of this study are available from the corresponding author upon request.

Conflicts of Interest
All authors have no conflicts of interest with the material presented in this article.