Asian Journal of Urology (2021) 8, 275e279 Available online at www.sciencedirect.com ScienceDirect journal homepage: www.elsevier.com/locate/ajur Original Article Impact of the adherence to medical treatment on the main urinary metabolic disorders in patients with kidney stones Braulio Omar Manzo a,*, Jose David Cabrera a, Esteban Emiliani b, Hector Manuel Sánchez a, Brian Howard Eisner c, Jose Ernesto Torres a a Urology Department, Hospital Regional de Alta Especialidad del Bajı´o, Blvd. Milenio #130, Col. San Carlos la Roncha, León, Guanajuato, Mexico b Urology Department, Fundación Puigvert, Universidad Autónoma de Barcelona, Barcelona, Spain c Urology Department, Massachusetts General Hospital, Harvard Medical School, Boston, USA Received 9 November 2019; received in revised form 6 January 2020; accepted 1 June 2020 Available online 6 August 2020 KEYWORDS Abstract Objective: To assess the effect of the adherence to medical treatment on urinary Kidney stones; parameters in the 24-h metabolic study of patients with kidney stones. Renal stones; Methods: A retrospective, longitudinal, descriptive, and observational study was carried out Metabolic disorders; by reviewing the hospital electronic medical record from 2014 to 2018. The adherence to drug Medical treatment; treatment was measured 6 months after its initiation, and the numerical values of the meta- Citrate; bolic studies were compared. Wilcoxon tests were performed to compare the difference Oxalate; before and after treatment. Lithiasis Results: Ninety patients were evaluated, with 73.3% of adherence. The 180-day overall adher- ence rate was 61.2% in patients treated with a single drug and 85.4% in patients treated with multiple drugs. There is a statistically significant increase in citrate levels in patients with good adherence in comparison with non-adherent patients (pZ0.031 vs. pZ0.528). Conclusions: Medical treatment and dietary measures in patients with kidney stones have an initial impact at 6 months on the values of the main urinary metabolic alterations that predis- pose to calculi formation; the most significant is seen in those patients with adherence to med- ical treatment for hypocitraturia. ª 2021 Editorial Office of Asian Journal of Urology. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/). * Corresponding author. E-mail address: bmanzo@urocem.com (B.O. Manzo). Peer review under responsibility of Second Military Medical University. https://doi.org/10.1016/j.ajur.2020.07.002 2214-3882/ª 2021 Editorial Office of Asian Journal of Urology. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 276 B.O. Manzo et al. 1. Introduction metabolic alteration. Standardized treatment regimens were as follows: For hypocitraturia were given potassium The recurrence rate of renal stones is about 50% at 5-year citrate (KCit) 2 g PO BID bid; for hypercalciuria were given follow-up if pharmacologic treatment is not given [1e3]. hydrochlorothiazide (HCT) 25 mg PO QD; for hyper- The most critical factors that contribute to calcium stones uricosuria were given allopurinol (Allo) 300 mg PO QD, and formation are hypercalciuria, hypocitraturia, hyper- finally, hyperoxaluria was managed with low oxalate/ uricosuria, and hyperoxaluria [4,5]. Nowadays, the 24-hour calcium-rich diet [15]. For patients with two or more al- urine collection is the gold standard method to identify terations of 24-hour urine composition, they received such abnormalities to guide the pharmacological treatment multiple treatments with two or more prescriptions, as well and dietary modifications [6]. as combined dietary modifications (Supplementary mate- Adherence to an established treatment is defined as the rial). Compliance or adherence to dietary modifications was extent to which patients take medications prescribed by evaluated by self-reported dietary compliance as described their health care providers. Also, adherence is a corner- by previous authors [16,17]. stone for an adequate response and resolution of any human disease like all metabolic disorders responsible for 2.1. Determination of adherence kidney stones [7e10]. Additionally, adherence is a crucial gauge of health care quality, and nonadherence is associ- Adherence to drug treatment was determined by reviewing ated with poor health outcomes and substantial economic the electronic medical record. To estimate adherence, we costs [11]. Despite the above, nonadherence to drug ther- use the formula for the proportion of days covered (PDC) apy is one of the main limitations in the treatment of described by Dauw et al. [18]. The PDC is calculated as the chronic diseases, reducing the benefits that could be ob- number of days covered by a specific drug divided by the tained [12]. Efforts to accurately measure and improve total number of days in the follow-up period. For patients adherence have received increasing attention from pa- taking more than one medication, we estimated the tients, physicians, payers, and all the rest of healthcare adherence by calculating the average class-specific PDC stakeholders. values. We used a follow-up period of 180 days after the Unfortunately, today there is no consensual standard for first drug prescription in our study, and then we multiplied what adequate adherence constitutes and how to measure the PDC by 100 to express it as a percentage. According to it adequately. A 50% adherence rate has been described for previous studies, we defined a good adherence if this per- chronic illness such as hypertension and type 2 diabetes in a centage was equal or greater than 80%. Patients with less 6-month follow-up [13]. Prior studies on this topic have than 80% and those who lost the prescription or had irreg- reported a 70% compliance rate for stone patients followed ular follow-up were considered as having poor adherence. explicitly in a comprehensive kidney stone center. It is likely that compliance for the typical patient, in a non- 2.2. Statistical analysis specialized center, is significantly lower [14]. Therefore, the purpose of the current study was to describe the pa- The program used for statistical purposes was IBM SPSS tients’ compliance rates to the stone prevention regimens version 25 (IBM Corp., Armonk, NY). A univariate analysis and to evaluate its influence in the 24-hour urine parame- was carried out using frequencies and percentages for ters at 6 months of follow-up. categorical data and measures of central tendency and corresponding dispersion according to the distribution of 2. Methods the data in the quantitative variables, following the Kolmogorov-Smirnov normality test. Wilcoxon tests were performed to compare the difference before and after A retrospective cohort study was conducted, with a longi- medical treatment. A p<0.05 and a 95% bilateral confi- tudinal, descriptive, and observational design approved by dence interval were considered statistically significant. the ethics committee with the registration number (CI/ HRAEB/2019/040). From 2014 to 2018, we analyzed all adult patients with kidney stones diagnosis and stone-free 3. Results state after their surgical procedure. All patients had two metabolic studies, including 24-hour urine panel and uri- Ninety patients met inclusion criteria (i.e., stone-free sta- nary pH determination in single sample separately with tus after surgery and at least 180 days of follow-up for dipstick (Chemstrip by Roche Diagnostics, Indianapolis, metabolic stone evaluation and treatment). The de- USA), and a reflectance photometer (Urisys 1100, Di- mographic data of the 90 patients are presented in Table 1. agnostics, Laval QC): The first one performed at the time of The relative prevalence of the 24-hour urine abnormalities, determining stone-free status and the second in the follow- taking into account that many patients had more than one up after medical intervention at 6 months. Medical treat- disorder, was as follows: Hypocitraturia (41.26%), hyper- ment was directed depending on the patient’s metabolic uricosuria (14.28%), hypercalciuria (16.40%) and hyper- abnormality in the first metabolic evaluation. We defined oxaluria (28.04%) (see Table 1). hypocitraturia as urine citrate of <320 mg/day, hyper- Of the 90 patients included in this study, 36 (40%) were oxaluria as a urine oxalate of >0.4 mmol/day, hyper- treated with monotherapy (single drug); the most frequent calciuria >200 mg/day and hyperuricosuria as a urine uric treatment was KCit (nZ29), followed by HCT (nZ7) and no acid of >0.7 g/day. All patients received a printed sheet single patient had monotherapy treatment with allopurinol. with the dietary recommendations corresponding to each Forty-one (45.5%) patients were treated with multi-drug The impact of adherence to medical treatment 277 adherent versus those who were not, a statistical difference Table 1 Baseline and demographic characteristics. was seen in potassium citrate-adherent patients showing a Characteristics Patients Percentage (%) significant increase (Table 3) in the urine citrate (from Gender, n 60 mg/day to 141.5 mg/day) (pZ0.031). Non-adherent pa- Male 50 55.6 tients (Table 4) failed to demonstrate such an increase in the Female 40 44.4 urine citrate (130 mg/day to 248.5 mg/day) (pZ0.5). Age (year) 45.4 (13.2)a For patients with hyperuricosuria, there was a decrease DM2, n 8 8.9 of 25% in uric acid levels. In those patients with hyper- HTN, n 25 27.8 calciuria, there was a decrease of 12% in calcium levels. BMI (kg/m2) 28.8 (4.3)a Finally, in those patients with hyperoxaluria, there were no Normal, n 17 18.9 changes in the urine oxalate levels. However, neither Overweight, n 42 46.7 adherent nor non-adherent patients demonstrated a sta- Grade I Obesity, n 30 33.3 tistically significant difference in urinary parameters at six- Grade II Obesity, n 1 1.1 month follow-up (pZnon significant for all). These results Stone volume (mm2) 252 (124e447.3)b are shown in Tables 3 and 4. Number of Stones, n 2 (1e3)b Urinary Metabolic 189 Disorders, n 4. Discussion Hypocitraturia 78 41.26 Hyperoxaluria 53 28.04 Adherence to medical treatment is a complicated issue to Hypercalciuria 31 16.40 evaluate. Some strategies to evaluate this include Hyperuricosuria 27 14.28 surveying the patients, directly observing medication tak- ing, measuring drug or metabolites in plasma/urine, or DM2, Type II Diabetes; HTN, hypertension; BMI, body mass index. a using electronic medication monitors. Previous studies Mean (Standard Deviation). b evaluating compliance used the self-reporting patients Median (Quartile). (directly surveying the patients) being the simplest to achieve and considered to be reliable in the published literature [11,12]. Similar to Dauw et al. [18], we evaluated therapy. The most frequent combination was KCitþHCT patient’s adherence to the proportion of days formula in (nZ12), KCitþAllo (nZ9), KCitþHCTþAllo (nZ8), order to evaluate the impact of the adherence to medical HCTþAllo (nZ6), KCitþMg (nZ3), CitþCalcitriol (nZ3). treatment and dietary modifications on the primary meta- Thirteen (14.4%) patients with hyperoxaluria were managed bolic disorders that predispose to stone formation in pa- just with dietary therapy. The 180-day overall adherence tients diagnosed with kidney stones. rate was 73.3% (61.2% in patients treated with a single drug Reducing recurrence is the main objective of preventive and 85.4% in patients treated with multiple drugs). The treatment, and it should be individualized concerning the overall differences in the urine parameters of patients after specific metabolic alteration of each patient. Thiazides are pharmacologic treatment are seen in Table 2. the standard management for idiopathic hypercalciuria; Patients were sub-stratified by medication therapy and compared to placebo, a significant decrease in stone divided into good and poor adherence to medical treatment recurrence (more than 60% of reduction) has been docu- (Tables 3 and 4). When comparing patients who were mented [15]. Hypocitraturia is treated by alkali Table 2 Differences between the first metabolic study and its control 6 months after the start of medical treatment. Metabolic disorder Before, mean (range) After, mean (range) p-Value Hypocitraturia (nZ78) Urinary pH 6 (5e7) 6 (5.5e6.75) 0.473 24 h urine Cit (mg/d) 62 (20.5e208) 189 (40e274) 0.015* 24 h volume (mL) 1900 (1485e2585) 2210 (1600e2740) 0.561 Hyperuricosuria (nZ27) Urinary pH 6 (5.5e6.7) 6 (5.5e6.8) 0.606 24 h urine UA (g/d) 0.8 (0.5e10) 0.7 (0.5e0.9) 0.021* 24 h volume (mL) 2100 (1780e2800) 2145 (1500e2970) 0.764 Hypercalciuria (nZ31) Urinary pH 6 (5.3e6.5) 6 (5.8e6.5) 0.425 24 h urine Ca (mg/d) 302.4 (172.2e367.4) 261.8 (208e342) 0.854 24 h volume (mL) 2200 (1720e2970) 2360 (1700e2920) 0.984 Hyperoxaluria (nZ53) 24 h urine Ox (mmol/d) 0.6 (0.5e0.8) 0.6 (0.5e0.8) 0.906 24 h volume (mL) 2390 (1845e2950) 2440 (1800e2965) 0.468 *Statistically significant. Wilcoxon tests were performed to compare the difference before and after medical treatment. A p<0.05 and a 95% bilateral confidence interval were considered statistically significant. 278 B.O. Manzo et al. Table 3 Changes showed in the 24-hour urine parameters in patients with adherence to medical and dietary treatment. Metabolic alteration Variable Before, mean (range) After, mean (range) p-Value Hypocitraturia (nZ78) 24 h Cit (mg/d) 60 (18e191.5) 141.5 (29.2e274) 0.031* Hyperuricosuria (nZ27) 24 h UA (g/d) 0.8 (0.4e22.6) 0.6 (0.4e0.9) 0.088 Hypercalciuria (nZ31) 24 h Ca (mg/d) 297.5 (167.7e366.9) 261.8 (191.7e342.0) 0.889 Hyperoxaluria (nZ53) 24 h Ox (mmol/d) 0.6 (0.5e0.8) 0.6 (0.4e0.7) 0.286 *Statistically significant. Wilcoxon tests were performed to compare the difference before and after medical treatment. A p<0.05 and a 95% bilateral confidence interval were considered statistically significant. preparations based on citrate and has been shown to stone disease) have experienced recurrent or persistent maintain stone-free rates of 92% in surveillance vs. 58% in complicated urinary stones. Therefore, our patients may be placebo patients [19]. Allopurinol has been indicated for highly motivated to comply with preventive measures and the treatment of calcium oxalate stones associated with treatments that were given. Additionally, opposite to pre- hyperuricosuria; its use has shown up to a 50% decrease in vious studies, our patients summitted to multiple therapies the recurrence of lithiasis vs. placebo [20]. In hyper- for more than one metabolic alteration, showed higher oxaluria, the reduction of dietary oxalate is essential; only compliance. A big concern, suffering, and even the loss of 52% of patients have adequate compliance with dietary one renal unit could be one reason for this high adherence measures and fluid consumption, achieving a significant in patients with multiple metabolic diagnoses, but this decrease in urinary oxalate levels [16,21,22]. needs to be further studied. Nonetheless, we observed, as In the current study, we found that adherence to pre- described above, that adherence to therapy only resulted scribed measures described above resulted in significant in significant changes in patients with hypocitraturia. differences in 24-hour urine composition only in patients These findings may be unique to our patient population. taking potassium citrate. At first glance, this is somewhat As described above, there exists level 1 evidence that each surprising, considering that hypercalciuric patients received of the three medication therapies: Potassium citrate, thia- a thiazide diuretic and hyperuricosuric patients received zide diuretics, and allopurinol results in a significant reduc- allopurinol. We feel that the best possible explanation for tion in recurrent stone events. However, these studies were these findings is likely the diet that is typical of the region in all performed in a distinct population (United States) where Mexico where our patients come. This diet is a diet rich in dietary habits may be different from those of our patients sodium and animal protein. Sodium is known to reduce or [20,24,25]. We feel that our findings have significant impli- block the hypocalciuric effects of thiazide diuretics, and a cations for the treatment of patients in Mexico with recur- diet rich in animal protein may result in increased urinary rent calcium oxalate stone disease. One could assume if uric acid excretion and reduce the uric acid lowering effects future studies confirm these findings, that the optimal of allopurinol. On the other hand, these dietary tendencies medication for stone prevention for patients in this region of would not be expected to reduce the effects of potassium Mexico would be potassium citrate-based therapies. citrate, which works by causing systemic alkalization, Our study has several limitations, which are inherent in a inducing citrate excretion into the urine. Another finding to retrospective study, such as the definition of adherence. As assess was that urinary pH did not change significantly after reported in previous studies, it is not possible to assess potassium citrate treatment, as is commonly expected. We accurately if the patient took or not the medication, use the urine dipstick (Urisys by Roche) as the pH deter- despite the records in the file and pharmacy. Previous mination evaluation method, and it has been described that studies have been based on self-patient reporting to mea- this kind of study (photometry readers) has considerable sure compliance or adherence to medical treatment and inaccuracy that could cause bias in our results [23]. dietary measures. Also, non-adherent patients could have In our study, 73.3% (61.2% in single drug and 85.4% with taken another dietary or herbal treatments not reported to multiple drugs) of patients showed adherence to medical doctors that could affect their metabolic profile. The study treatment and dietary recommendations. This adherence was conducted in a third level hospital, with a specialized rate is a high percentage compared to the reported in lithiasis clinic, in which complex and recurrent cases of previous studies. One possible explanation for the high kidney stones are treated so that it could be not repre- adherence of our population is that the majority of patients sentative of the general population. Although the follow-up treated in our center (a tertiary referral center for complex time of our population could be considered a short time Table 4 Changes showed in the 24-hour urine parameters in patients with no adherence to medical and dietary treatment. Metabolic alteration Variable Before, mean (range) After, mean (range) p-Value Hypocitraturia (nZ78) 24 h Cit (mg/d) 130 (32e322) 248.5 (80.7e281.5) 0.528 Hyperuricosuria (nZ27) 24 h UA (g/d) 0.8 (0.6e5.9) 0.7 (0.6e4.9) 0.327 Hypercalciuria (nZ31) 24 h Ca (mg/d) 305.1 (226.1e305.1) 228.7 (213.2e228.7) 0.655 Hyperoxaluria (nZ53) 24 h Ox (mmol/d) 0.4 (0.3e0.7) 0.6 (0.5e0.8) 0.374 The impact of adherence to medical treatment 279 follow-up for chronic diseases, all the previous studies [6] Corder CJ, Leslie SW. 24-Hour urine collection [Updated 2020 evaluating adherence to medical treatment have reported May 27]. [Internet]. In: StatPearls. Treasure Island (FL): just 6 months of follow-up [16e18]. Long-term follow-up is StatPearls Publishing; 2020. Available from: https://www. necessary to document the constancy to adherence in ncbi.nlm.nih.gov/books/NBK482482/. [7] Pak CY. Etiology and treatment of urolithiasis. 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