, Introduction
Acute kidney injury (AKI) is a common and complex clinical syndrome, frequently manifesting as a complication in hospital settings, and its etiology involves diverse underlying factors [1]. The transitional phase between AKI and the onset of chronic kidney disease (CKD) is medically defined as acute kidney disease (AKD) [2]. A comprehensive systematic review has revealed that approximately 33.6% of all patients with AKI subsequently develop AKD [3]. AKI survivors have elevated risks of recurrent AKI incidents and adverse drug reactions [4,5]. Meticulous reconciliation of medications following discharge is paramount given the likely alterations in patients’ current medication regimens due to AKI [4]. Medications that undergo renal processing, possess renoprotective attributes, or have nephrotoxic potential are modifiable elements that can substantially affect post-AKI outcomes [6–8]. Consequently, the management of medications for AKI survivors must be optimized.
In 2018, the Acute Disease Quality Initiative recommended the inclusion of a comprehensive care bundle for AKI survivors. This bundle, denoted as “KAMPS” (an acronym for kidney function check, advocacy, medication, pressure, and sick-day protocols) (Table 1), pertains to the careful evaluation and subsequent intervention in the context of medications [9]. Recently, the evolving roles and prospective contributions of pharmacists in post-AKI care have garnered increasing attention [10–13]. Pharmacists play crucial roles, such as educating patients on medication management throughout the course of AKD; calibrating drug dosages; ensuring no unnecessary nephrotoxic drug exposure in the post-AKI phase; exercising caution in reintroducing indispensable drugs with potential nephrotoxic effects during acute illness settings, such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs); managing comorbidities; and monitoring patients and collaborating with their care teams [10,13]. Pharmacist interventions have been effective in enhancing medication adherence among both patients with CKD and those with AKD [14,15]. A pioneering pilot study in the United States that included pharmacists in post-AKI care teams in primary care settings highlighted pharmacists’ engagement in discerning medication-related problems (MRPs) and offering effective recommendations [13].
In 2006, Taiwan initiated a multidisciplinary team care program for pre-end-stage renal disease (pre-ESRD) patients. By 2021, the program expanded its ambit to include patients with AKD and integrated pharmaceutical care services. However, the precise scope of pharmacists’ contributions within this evolving landscape remains unclear. To date, very few studies have investigated the efficacy of multidisciplinary post-AKI care; moreover, limited data are available on pharmacist-led outpatient pharmaceutical care for AKI survivors, particularly in Asian populations. Therefore, the present study aimed to evaluate the efficacy of pharmacist-delivered outpatient pharmaceutical care for AKI survivors by assessing pharmacist-provided MRP recommendations, changes in patient medication adherence, and the usage of renoprotective and nephrotoxic medications during their AKD period.
Methods
Patients
This retrospective study was conducted at a single medical center and involved survivors of AKI who were enrolled in a multidisciplinary outpatient AKI care program and subsequently referred to a pharmacist-managed clinic (PMC) at National Taiwan University Hospital between March 2022 and January 2023. The participants were followed up for 6 months after enrollment. Eligible participants included adults (≥18 years) who had developed AKI during hospitalization and exhibited an estimated glomerular filtration rate of <45 mL/min/1.73 m2 within 1 month after discharge. AKI was defined and graded by a nephrologist following the KDIGO (Kidney Disease: Improving Global Outcomes) framework, with criteria including an increase in serum creatinine (SCr) by ≥0.3 mg/dL within 48 hours or an increase in SCr to ≥1.5 times baseline [2]. Baseline SCr was defined as the lowest value within the preceding 180 days before hospital admission, or if this information was lacking, as the lowest SCr level during hospitalization. In addition, individuals requiring dialysis for less than 3 months due to AKI and deemed by physicians to have the potential to discontinue dialysis were eligible for inclusion. To alleviate the risk of information bias, individuals who had previously participated in our institution’s pre-ESRD program or similar multidisciplinary care programs for multidisciplinary CKD care before AKI onset were excluded from the study.
This study was approved by the Research Ethics Committee of National Taiwan University Hospital (No. 202207142RINB; 2022). Written informed consent was waived due to the retrospective nature of the study.
Multidisciplinary team
The AKD multidisciplinary team comprised various specialized professionals, such as nephrologists, nurses, dietitians, and a pharmacist. Each specialist conducted an initial consultation with patients within 30 days after discharge, with all specialists meeting on the same day; this was followed by a revisit after 3 months. The nephrologists assumed a central role in the team, offering advanced kidney disease treatment. The nurses coordinated patient care within the team, and the dietitians offered personalized dietary guidance for the patients. The pharmacist, in accordance with the KAMPS framework (Table 1), engaged in medication therapy management (MTM), which included tasks such as ensuring medication reconciliation, performing comprehensive assessments, evaluating medication adherence, and delivering medication-related education [9]. Pharmaceutical care was provided before or after physician consultations. Following each consultation, a succinct personal medication record was generated, outlining current medications, MRPs, and action plans for each patient. Notably, each care session was meticulously documented within the patients’ electronic medical records.
Outcomes of pharmaceutical care
Pharmaceutical care outcomes were assessed across four key dimensions: MRP recommendations, changes in patient medication adherence, usage of renoprotective medications, and exposure to nephrotoxic agents. MRP recommendations provided by pharmacists were quantified and organized, while medication adherence was evaluated using the Adherence to Refills and Medications Scale (ARMS) [16], with scores ranging from 12 (optimal adherence) to 48 (extremely poor adherence). Instances of nonadherence, particularly regarding renoprotective medications and nephrotoxic drugs, were documented. Renoprotective medication evaluation encompassed ACEIs, ARBs, and sodium-glucose cotransporter 2 (SGLT2) inhibitors. The assessment of nephrotoxic drug usage was guided by previous literature [17], with a comprehensive list provided in Table 2. Nephrotoxic agents were categorized into modifiable and non-modifiable types based on patient usage circumstances. Modifiable agents encompassed medications for which non-nephrotoxic alternatives were available, those lacking clear indications, and drugs that patients self-administered. On the other hand, non-modifiable nephrotoxic agents referred to medications deemed essential for treatment, for which substitutions or alterations were not feasible. The assessment of both nephroprotective and nephrotoxic agents was conducted across four stages (pre-AKI, before discharge, first visit, and second visit), tracking patients’ medication profiles before and after AKI onset and during subsequent follow-up visits.
Statistical analysis
Data on the patients’ characteristics and clinical outcomes were manually extracted from their electronic medical records. Categorical data are presented as the number and percentage values, whereas continuous data are presented as the mean ± standard deviation or median (interquartile range) values. The change in ARMS score was assessed using a paired t test, while categorical variables, such as ARMS categorization (=12 or >12), as well as the utilization of nephrotoxic and renoprotective medications, were analyzed using the McNemar test. Statistical significance was set at p < 0.05. All statistical analyses were performed using STATA (version 14.0; StataCorp).
Results
Patient attendance and characteristics
During the study period, 40 patients were referred to the PMC. Of them, 33 adults (82.5%) attended the PMC. Nineteen patients (57.6%) completed the follow-up visits (Fig. 1). The patients’ absence at follow-up visits was attributed to various factors, including loss to follow-up at a nephrology clinic (21.4%), admission or referral to an emergency department (14.3%), death within 3 months (7.1%), administrative oversight (14.3%), and patient-related factors (42.9%).
The demographic characteristics of the cohort are summarized in Table 3. The mean age was 63 years, with 60.6% being men. Notably, 20 patients (60.6%) had CKD before the onset of AKI. Common comorbidities associated with AKI included diabetes mellitus (54.5%), heart failure (39.4%), and malignancy (24.2%). Among the cohort, 25 patients (75.8%) had stage 3 AKI, with 14 patients requiring dialysis during hospitalization and three patients remaining on dialysis upon discharge. The primary etiological factors contributing to AKI were categorized as cardiorenal syndrome (33.3%), infection (27.3%), and medication-related causes (21.2%). Duplicates of etiology were allowed, indicating that patients might have more than one contributing factor to their AKI. After 6 months of follow-up, 17 individuals achieved a SCr level lower than 1.3 times the baseline, two patients discontinued dialysis, three patients were on long-term dialysis, and three patients passed away. Additionally, 14 patients were still receiving multidisciplinary pharmaceutical care for CKD under the purview of the nephrology department.
Pharmacist intervention
The pharmacist involved in this study provided 14 medication-related recommendations to relevant physicians, of which 10 recommendations (71.4%) were accepted and implemented (Table 4; Supplementary Table 1, available online). These recommendations primarily centered on medication reconciliation, comprising 57% of all suggestions. Specifically, these medication reconciliation-related suggestions predominantly pertained to the cessation and resumption of chronic disease medications prescribed long-term for patients during their hospitalization for AKI. Other MRPs included inappropriate dosage based on current renal function, indication (requiring additional therapy), nephrotoxic medication usage, and inadequate medication efficacy (due to low dosage). Four recommendations were not accepted, likely due to concerns regarding the resumption of ezetimibe and valsartan, management of a potential overdose of erythropoiesis-stimulating agents such as methoxy polyethylene glycol-epoetin beta, and an increase in the dosage of valsartan. For the 19 individuals who completed follow-up visits, the average ARMS score before and after the pharmacist’s consultation showed a nonsignificant change (from 13.4 ± 1.5 to 13.2 ± 1.3, p = 0.72) (Fig. 2). Specifically, among those with an ARMS score of 12 (indicating full adherence to the medication regimen and prescription refills in the past month), the number of patients decreased from 9 (47.4%) to 8 (42.1%). Four individuals showed an improvement in adherence (ARMS score decreased to 12), while five individuals exhibited worsened adherence (ARMS score changed from 12 to >12). The findings suggest no significant difference in adherence change (p = 0.99) (Fig. 2). Further exploration of characteristics associated with poor adherence (ARMS >12) based on AKI stage, PMC visit frequency, and polypharmacy (number of medications ≥5) revealed that individuals with AKI stage 1, those who visited the PMC only once, and those using five or more medications had poorer medication adherence (Supplementary Fig. 1, available online). Additionally, the pharmacist identified 16 instances of medication nonadherence among all the 33 patients, including one patient who self-administered a nephrotoxic drug (nonsteroidal anti-inflammatory drug, NSAID) and three patients who voluntarily reduced their intake of renoprotective medications, specifically ARBs. After the pharmacist-led MTM, nonsignificant increases were observed in the numbers of patients using ACEIs or ARBs (p = 0.13) and those using SGLT2 inhibitors (p = 0.99) (Fig. 3). Two patients refrained from resuming ACEIs or ARBs due to low blood pressure or unstable kidney function after AKI, while one patient refrained from resuming SGLT2 inhibitors because of poor kidney function. Overall, there was no reduction observed in the number of patients who had been exposed to at least one nephrotoxic drug before and after AKI, with a usage rate of 63.6% before AKI and 60.6% to 63.6% during the follow-up period after discharge (Fig. 4). The highest proportion of nephrotoxic drug usage was seen in the antibiotic category (particularly beta-lactam drugs) and proton-pump inhibitors. When analyzing modifiable nephrotoxic agents alone, a significant reduction was observed between pre-AKI and after pharmacist intervention (p = 0.03), with the decrease in NSAID usage being the primary contributing factor (reduced from 27.3% to 3.0%).
Discussion
Our findings highlighted that pharmacists involved in caring for AKI survivors can assist in postdischarge medication reconciliation, provide recommendations for minimizing medication discrepancies, and reduce nephrotoxic drug exposure. Our care team is consistent with multidisciplinary teams formed in other post-AKI studies [11,12]. Our pharmacist delivered post-AKI pharmaceutical care in line with the international consensus, offering services similar to those described in other studies [11–13].
Pharmacists bring a wealth of expertise to the realm of health care. They recognize potential drug interactions, determine necessary drug dosage adjustments, formulate monitoring plans, and limit nephrotoxic drug exposure, thereby optimizing the selection and dosage of medications [18]. Key components of pharmaceutical care encompass vital tasks such as ensuring medication reconciliation, performing comprehensive medication assessments with a focus on drugs eliminated through the renal route and those known to be nephrotoxic, and providing drug-related education. Notably, our unique approach integrates the routine evaluation of medication adherence.
Previous studies assessing the efficacy of multidisciplinary post-AKI care have predominantly focused on team-based interventions with results of optimizing blood pressure management, reducing the urine albumin-to-creatinine ratio, and enhancing patient knowledge [11,12]. However, limited data are available on the efficacy of interventions targeting medication-related behaviors and MRPs. A Mayo Clinic study on post-AKI pharmaceutical care reported that pharmacists, when working closely with primary care providers, can identify and address MRPs [13]. However, in our study, a relatively low number of medication-related recommendations were provided by the pharmacist. This discrepancy may be attributable to the timing of pharmacist consultation in our study, which predominantly occurred after physician consultation; by contrast, in the aforementioned Mayo Clinic study, pharmacist consultation preceded physician consultation. In this study, a substantial proportion of MRPs was associated with medication discrepancies before and after AKI. However, a considerable percentage of omitted medications were not medications that undergo renal processing or have nephrotoxic potential, such as lipid-lowering agents, levothyroxine, and febuxostat. This underscores the importance of comprehensive assessment.
Research on medication adherence in AKI survivors or patients with AKD is either limited or of low quality [15]. CKD studies have indicated that poor adherence increases the risks of kidney function deterioration and mortality [19,20]. Medication adherence is crucial, regardless of the advancement of kidney disease. In our study, we focused on short-term postdischarge adherence since we included patients within the first month after discharge. Most patients demonstrated good adherence, making it challenging to discern the effects of pharmacist intervention. Upon further investigation, we observed that individuals with lower clinic attendance and those with polypharmacy exhibited poorer adherence, consistent with previous findings [21]. However, the subset of individuals who did not attend follow-up visits after 3 months could not be evaluated for differences before and after pharmacist intervention, potentially introducing selection bias into the interpretation of results. Additionally, there was a slight increase in the proportion of individuals with suboptimal adherence (ARMS >12) at the second visit, suggesting a decline in adherence over time since discharge, highlighting the potential necessity for more frequent interventions and longer follow-up periods. Future research should focus on assessing sustained intervention impact and employ larger sample sizes for comprehensive understanding.
An observational post-AKI study revealed that 87% of all AKI survivors were exposed to at least one nephrotoxin; these individuals had higher risks of de novo or progressive CKD, readmission for AKI, and mortality than nonexposed individuals [22]. Few post-AKI outpatient studies have evaluated the rate of success for nephrotoxin avoidance. In our study, approximately 60% of patients had used at least one nephrotoxic medication, and pharmacist-delivered MTM led to a significant reduction in the use of modifiable nephrotoxic drugs, such as NSAIDs. However, the overall rate of nephrotoxic exposure did not decrease significantly due to the use of essential nephrotoxic drugs such as antibiotics, proton-pump inhibitors, immunosuppressants, and cancer therapies. Extended observation is necessary to assess the sustainability of the effects of pharmacist intervention.
Patients with AKI typically discontinue long-term prescription medications, such as ACEIs, ARBs, and SGLT2 inhibitors, during their hospital stay [5,23]. Observational studies have reported a reduction in the mortality rate among AKI survivors using renin-angiotensin-aldosterone system (RAAS) inhibitors, without any increase in the rate of AKI recurrence [6,24]. Nonetheless, the risks of hyperkalemia and hemodynamically mediated AKI necessitate the personalized assessment of medication re-administration [6,10,17,24]. The effects of SGLT2 inhibitors on post-AKI or AKD outcomes remain unclear; however, long-term studies conducted in high-risk patients, such as those with type 2 diabetes, heart failure, or CKD, have demonstrated that SGLT2 inhibitors can delay kidney function decline and reduce AKI risk [25,26]. Hence, pharmacist-mediated postdischarge medication reconciliation is indispensable for AKI survivors. In the pharmaceutical care for AKI survivors, the pharmacist routinely assessed the usage of these medications. At the second visit, there were increases in the number of users of RAAS inhibitors and SGLT2 inhibitors. However, the resumption of medication use could not be solely attributed to pharmacist intervention. Pharmacists’ assistance in educating patients on monitoring blood pressure, blood sugar, and fluid status might have had an indirect impact. Furthermore, since the number of individuals using these two types of medications before AKI was low, it was challenging to observe significant differences in this regard.
Individuals with a history of AKI are at high risk of unfavorable kidney-related outcomes and adverse drug reactions; therefore, effective MTM is crucial [7,9,27,28]. In Taiwan, post-AKI care is an emerging domain of health care. This study presents a practical model for AKD pharmaceutical care and has yielded preliminary results. However, the small sample size, retrospective study design, and lack of a control group may limit the generalizability of our findings. Therefore, extensive studies are required to elucidate the advantages and multifaceted implications of outpatient pharmacist interventions.
In conclusion, the role of pharmacists in AKD bundled care strategy is paramount given the high risks of kidney-related complications and adverse drug reactions in AKI survivors. Our study clarifies the potential benefits of outpatient pharmacist intervention. Further studies are warranted to comprehensively assess the long-term advantages and implications of pharmacist involvement in AKD care.
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