Biochemical, Pharmacological, and Therapeutic Effects of Triple Antihypertensive Therapy with Amlodipine, Valsartan and Hydrochlorothiazide in Elderly Hypertensive Patients with Calcium Phosphate Nephrolithiasis

Antihypertensives are widely prescribed in the geriatric population and could influence kidney stone risk but many aspects are still unknown. Thiazides are used to control lithogenic factors and recurrences in patients with calcium lithiasis. The aim of our study was to evaluate the relationship between essential arterial hypertension and stone disease, by studying the pharmaco-therapeutic effects of a fixed-dose combination of amlodipine + valsartan + hydrochlorothiazide (Aml + Val + HCTZ) 10/320/25 mg, on the urinary stone risk in a study group of hypertensive geriatric patients. A longitudinal, randomized, three years follow-up clinical and experimental study was conducted during June 1, 2014 July 31, 2017. A number of 60 eligible geriatric patients, treated only with a fixed-dose combination of Aml + Val + HCTZ 10/320/25 mg, as a single-tablet, were enrolled in the study. All the patients were stone formers, with more than three episodes of crystalluria in the last two years. The patient’s age ranged between 55 and 65 years. Exclusion criteria: patients with heart failure, kidney chronic diseases, use of drugs known to affect renal function, patients with multi-morbidities. All patients had similar blood pressure values, and tension was well controlled throughout the whole study period. In the elderly patients, the treatment with 25 mg/day of hydrochlorothiazide (from the combination of Aml + Val + HCTZ 10/320/25 mg) has a beneficial and prolonged efficacy in treatment of recurrences in patients with calcium oxalate and phosphate lithiasis Our study reveals that in the elderly patients with hypertension and nephrolithiasis as a comorbidity, thiazides 25 mg/day of hydrochlorothiazide (from the combination of Aml + Val + HCTZ 10/320/25 mg) has a beneficial effect in order to control lithogenic factors and recurrences in patients with calcium phosphate lithiasis.

Geriatric patients have a lot of co-morbidities that make antihypertensive therapy even more difficult. Nephrolithiasis (kidney stone) has a prevalence and incidence that has increased markedly in elderly population [4]. Studies by Knoll T and coworkers have revealed that about 10%-20% of all patients with nephrolithiasis are older than 65 years [5].
Antihypertensives are widely prescribed in the geriatric population and could influence kidney stone risk but many aspects are still unknown [6].
The pathogenic link between hypertension and renourinary stone disease is not fully understood. A possible association between nephrolithiasis and stone risk profile, including supersaturation of lithogenic salts, hypertension has been suggested by a high number of studies [7,8].
A significant correlation between arterial pressure and calcium excretion has been revealed by many researchers especially in older patients when hypertension is associated with excessive body weight [9][10][11][12].

Objectives
The aim of our study was to evaluate the relationship between essential arterial hypertension and stone disease, * email: danscipu@yahoo.com, deliaberceanu@yahoo.com # Authors with equal contribution by studying the pharmaco-therapeutic effects of a fixeddose combination of Aml + Val + HCTZ 10/320/25 mg, on the lithogenous risk in a study group of hypertensive geriatric patients.

Experimental part
Material and method Study design A longitudinal, randomized, three years follow-up clinical and experimental study was conducted during June 1, 2014 -July 31, 2017. A number of 60 eligible geriatric patients, treated only with a fixed-dose combination of Aml + Val + HCTZ 10/320/25 mg, as a single-tablet, were enrolled in the study. All the patients were stone formers, with more than three episodes of crystalluria in the last two years. The patient's age ranged between 55 and 65 years.
The patients received fixed-dose combination of Aml + Val + HCTZ 10/320/25 mg, as a single-tablet once-daily during the three years study period.
In order to participate in this survey, all 60 patients expressed written consent, according to the criteria set out in the Helsinki Declaration [13].

Inclusion criteria
In the study were enrolled geriatric patients with diagnosis of arterial hypertension according to current European guidelines, with previous calcium phosphate urolithiasis.

Fourier-transform infrared spectroscopic analysis
Infrared absorption spectra were traced with a JASCO FT-IR 4200 device (with automatic reading of the absorption bands, interferometer Michelson 45°). The measuring range was set to 4000-600 cm -1 . Spectra were taken at the normal temperature and pressure existing in the laboratory. The smoothness of the line of 100 % T was 100 ± 1.0 % T (repeating the continuous measurement).
The samples were prepared after KBr pelleting, by mixing the ground bone with KBr (1 mg sample/100 mg KBr) under vacuum, as usually applied for Fourier-transform infrared spectroscopic studies [18].
The crystalline hydroxyapatite was obtained from amorphous calcium phosphate at pH 8.5; preparation was done by the method of Boskey and Posner [19].

Urinary stone risk evaluation
Supersaturation calculations for calcium oxalate, calcium phosphate, and struvite were obtained using the technique introduced in 1977 by Finyalson B [20].
Statistical analyses were performed using the SPSS software package (version 23.0 for Windows, SPSS Inc, Chicago, IL.). Results were expressed as mean and standard deviation. The difference was considered significant when the p-value < 0.05.

Results and discussions
In the study were enrolled 60 elderly patients, respectively 25 women (41.67%) and 35 men (58.33%). Of the 60 cases evaluated, at the beginning of the study, 8 patients (13.33%) had renal urinary microlithiasis and 52 patients (86.67%) presented macroscopic renal urinary calculi.
All patients had similar blood pressure values, and tension was well controlled throughout the whole study period (p>0.05).
The age of the patients enrolled in the study ranged between 55 and 65 years (table 1).
Each patient underwent a complexe examination plan, with anamnestic, clinical and paraclinical steps, as in the example bellow ( fig. 1).
The Fourier-transform infrared spectra revealed seven spectral bands,as pointed out in table 2. There are revealed two spectral bands specific to phospho-calcic compounds -the specific band for carbonatapatite -at 793.56 cm -1 and that of hidroxyapatite at 633.50 cm -1 , in a female patient with nephrolithiasis since four years and hypertension since only two years, receiving a fixed-dose combination of Aml + Val + HCTZ 10/320/25 mg, as a single-tablet once-daily.  In all the geriatric patients enrolled in the study, one revealed that fixed-dose combination of Aml + Val + HCTZ 10/320/25 mg is very useful in reducing blood pressure and monitoring it in case of long-term administration, due to optimal pharmacokinetic profile of the three component drugs, as described for the first time by Coulhan and coworkers in 2009 [21].
Among the patients taken in the study, 36 (60%) were recurrent stone formers therefore they had a high urinary stone risk.
In the whole, the treatment with Aml + Val + HCTZ 10/ 320/25 mg reduced the urinary stone risk by lowering the main parameters which composed it, as following: -urinary phosphorus (mg/day) -from 904±32 at 612±18 (at the end of the study); -calciuria (mg/day) -from 256±14 at 148±28 (at the end of the study); -oxaluria (mg/day) -from 34±18 at 21±16 (at the end of the study).
The participants were followed for the occurrence of a kidney stone event while maintaining continuous usage on their drug, but no calculus was reported.
In accordance with recent valuable researches undertaken in this scientific field, we tried to reveal and understand the comorbidity of patients with arterial hypertension and nephrolithiasis [22]. In this context, our results were in accordance with Fernández-Rodríguez and co-workers, who pointed out that in the elderly patients, the treatment with 25 mg/day of hydrochlorothiazide (from the combination of Aml + Val + HCTZ 10/320/25 mg) has a beneficial and prolonged efficacy in treatment of recurrences in patients with calcium oxalate and phosphate lithiasis [23].

Conclusions
Our study reveals that in the elderly patients with hypertension and nephrolithiasis as a comorbidity, thiazides -25 mg/day of hydrochlorothiazide (from the combination of Aml + Val + HCTZ 10/320/25 mg) have a beneficial effect in order to control lithogenic factors and recurrences in patients with calcium phosphate lithiasis.