1 Introduction

Technological advances occurred in twentieth century in Western society led to significant changes in food intake and composition. Progress after progress, along with over availability of food, the Western diet boosted the intakes of red meat, refined grains, foods with high contents of fat and sugar, such as desserts and drinks, and high-fat dairy products. This new dietary pattern is high in saturated fat, trans-fatty acids, sucrose and fructose, proteins from red meat and sodium, but low in mono-unsaturated and polyunsaturated fatty acids, plant-derived proteins, potassium and fiber content. This is called meat-sweet diet or standard American diet [1]. The meat-sweet diet has been associated with many modern-day chronic diseases, such as cardiovascular disease and kidney failure [1], causing some of the most ranked causes of death in Italy in 2019 according to the World Health Organizzation (WHO) [https://www.who.int/data/gho/data/themes/mortality-and-global-health-estimates/ghe-leading-causes-of-death]. Indeed, a combination of dietary factors contributes to the impairment of renal vascularization and of excretion of waste metabolites, causing arterial hypertension and renal calculi, as a first step to a major event [1].

1.1 Essential Hypertension (Htn)

Htn ranks among the most common chronic medical condition, and it is defined as persistent elevation of systematic arterial blood pressure (systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg). It’s estimated that nowadays 1.39 billion people are affected by Htn, and its prevalence is expected to increase over the next 20 years, also because of continuous ageing of the population [2]. Furthermore, embracing unhealthy lifestyles, as physical inactivity and a sweet-meat diet, cause increase of body weight, so that the prevalence of hypertension worldwide will continue to rise [3]. It is estimated that the number of subjects affected by hypertension will build up by 15–20% by 2025, reaching close to 1.5 billion [3]. Htn is associated with a large global burden of cardiovascular diseases and premature death, especially caused by ischemic heart disease, ischemic and/or hemorrhagic stroke, other cardiovascular disease (i.e., chronic heart failure) and chronic kidney disease (CKD) [2]. Indeed, several large prospective cohort studies have reported that Htn is also a strong independent risk factor for CKD, end stage renal disease and nephrolithiasis (NL) [4, 5].

1.2 Nephrolithiasis

NL, also named kidney stone diseases, is a term used for the formation of crystal concretions, that typically take shape in the kidney, and that moves out via urethra. More than 50 different stone’s chemical compositions have been described. The vast majority of them are composed by calcium oxalate (CaOx) and calcium phosphate, covering almost eighty percent of cases, leaving the rest to struvite, uric acid, cystine and ammonium acid urate stones [6]. Approximately half of the patients affected by NL will undergo a second episode within 10 years, with a twenty percent as 5-years recurrence rate, increasing to each symptomatic NL episode if appropriate prevention plan is not initiated [7]. Moreover, a slight percentage of kidney stones may remain silent, eluding diagnostic and therapeutic efforts on the first event and on future prevention of the others. Despite the lack of symptoms, they demonstrated themselves to be harmful as well [8]. Indeed, in all cases the stone can cause acute renal failure due to obstruction and/or hydronephrosis, it can become a nidus for infection, or it is also considered as one of the most common and independent risk factors for a CKD, demonstrating to be a significant burden on the health care system [9]. Between 1997 and 2012, the mean annual incidence of NL increased 1% annually, particularly in women and in young age, also causing a rising in the cost for health care systems, that are estimated to rise up to one billion in the next 10 years [10]. NL has been highly associated for long time to other chronic conditions, such as metabolic syndrome (MetS), clinically defined by the combination of abdominal obesity, dyslipidemia, Htn, and elevated fasting plasma glucose or diabetes [5, 11]. In particular, MetS and Htn have been identified as a proper risk factor to the occurrence and recurrence of NL and CKD [5, 12]. From what has been said, prevention programs appear to be the most valuable tool to downgrade the upcoming wave of Htn, NL and, finally, end-stage renal impairment or dialysis dependance. Despite that, dietary factors remain the most important and potentially modifiable risk factor one can work on [13].

1.3 Dietary Habits for Primary and Secondary Prevention of Htn and NL

Available scientific evidence states the harmful effects of high meat protein and low calcium intake from diet, as in the sweet-meat diet, whereas the high content of fruits and vegetables, alongside with adequate fluid intake, are associated with the lowest risk for incident kidney stones [13]. Some studies also found that the vegetarian diet associated with consumption of dairy products is the most protective diet from kidney stones occurrences. Moreover, high potassium, magnesium and citrate intake from vegetables and fruit are associated with the lowest risk of kidney stones and recurrence [14, 15]. The same dietary patterns also play a key role in the management of Htn, demonstrating it to be a success story for Htn control, lower risk of incidental Htn diagnosis and in prevention of cardiovascular events. In this scenario, the benefits of fruit and vegetables intake appear even to be dose related [16].

1.4 Potassium Homeostasis

Potassium is an essential mineral for human nutrition and it is the major intracellular positive ion. The entire body content of potassium is estimated at 135 g for an adult man weighing 70 kg. The potassium bioavailability and intestinal absorption are very high, but it is mainly regulated at the renal level through the modulation of its urinary excretion. [17]. Urinary potassium excretion is a gold standard indicator of potassium intake from vegetables, fruits, and dairy products. If the consumption of these food is slow, low values for potassium intake are expected [18].

Despite all the available data, few is known about the influence that the potassium intake may have in patients affected by both CaOx renal calculi and Htn. Besides, considering the actual relationship between Htn and NL, this real-life cross-sectional study seeks to demonstrate if the potassium intake estimated by 24 h collection (a recognized gold standard for monitoring potassium intake [19]) is different in patients affected by Htn and with or without NL, living in southern Italy, a region which stands out for an unique high incidence of NL [20].

2 Materials and Methods

2.1 Patients

This retrospective case-control study was performed by analyzing medical records of patients of European ancestry, coming from Campania, in Italy. From January 1st, 2022 to December 31st, 2022 subjects were consecutively recruited to elude selection bias, among patients referring for clinical management of NL to Bone and Mineral Metabolism laboratory of Federico II University (Bone-Lab), and for clinical management of Htn to Hypertension and Organ Damage Hypertension related laboratory of the Federico II University of Naples (Hypertension-Lab). The Bone-Lab is recognized by the Italian Society of Osteoporosis, Mineral Metabolism and Skeletal Diseases [Società Italiana dell’Osteoporosi e delle Malattie dello Scheletro (SIOMMMS) and by the European Calcified Tissue Society (ECTS). The Hypertension-Lab is recognized by the European Society of Hypertension (ESH), and by the Italian Society of Hypertension [Società Italiana di Ipertensione Arteriosa (SIIA)]. All data were obtained as part of clinical management and hospital care and the informed consent was signed by each patient involved in this study at the time of enrollment. Patients were all on free diet when the determinations were obtained. They were under different anti-hypertensive treatment with one or more drugs [angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blockers (ARBs), and/or calcium channel blockers (CCBs), and/or thiazides diuretics, and/or be-ta-blockers (BBs)] from at least two months at moment of enrollment, and they did not change therapy recently. Patients that were selected were under optimal blood pressure control, both during ambulatory blood pressure monitoring and home blood pressure monitoring, to reduce the impact that lack of compliance for Htn treatment may have on the results and according to ESH guidelines [21].

Only patients with CaOx stones have been selected for this study, to reduce the bias of NL secondary to other causes. For the same reason, patients that at the time of the enrolment were affected by CKD (estimated glomerular filtration rate < 60 ml/min/1.73 m2), malabsorption, hyperparathyroidism, urinary tract infections, hypercystinuria, Gitelman’s syndrome, Liddle’s syndrome, Bartter’s syndrome, hypomagnesemic hypercalciuric nephrocalcinosis, insipidus diabetes, and any other tubules and/or Henle’s loop diseases, were excluded from this study. Also, patients that were under potassium sparing diuretics (amiloride, triamterene and spironolactone), or Henle’s loop diuretics (furosemide, torasemide) or under any laxative medication for any reason were excluded from the study. In case of 24 h urine volume lower than 500 ml or higher than 5000 ml, or in case of duration of urine collection lower than 20 h or higher than 28 h, the sample was ruled out to exclude the risk of measurement error.

2.2 NL Diagnosis

According to Schepens et al, NL was diagnosed when a calcification was found in the kidney collecting system and presented with a diameter superior to 2 millimeters at ultra-sound evaluation [22]. All the ultra-sound evaluations were performed by the same operator who was unaware of the patient’s clinical and metabolic status, using Philips HP Agilent Sonos 4500 as instrument. At any episode of symptomatic NL, the stone has been collected and analyzed according to Gambaro et al. [23].

2.3 Urinary Potassium Evaluation

We asked to all subject to perform a 24 h urinary collection. Patients were instructed to begin at usual time of awakening. At that time, patients passed the collection and after the first flush, the collection began. The collection finished at exactly the same time the next morning. The sample container was storage in a cool place, closed and protected from light. In case of 24 h urine volume lower than 500 ml or higher than 5000 ml, or in case of duration of urine collection lower than 20 h or higher than 28 h, the sample was ruled out to exclude the risk of measurement error.

2.4 Data Form

A standardized, pre-piloted schedule was used to extract relevant clinical and laboratory data for this study. The extracted information is listed as follow: age; gender; body mass index (BMI); a diagnosis of MetS [defined if patient has any three of the following: Waist circumference more than 40 inches in men and 35 inches in women; elevated triglycerides 150 milligrams per deciliter of blood (mg/dL) or greater, or current drug treatment for hypertriglyceridaemia; reduced high-density lipoprotein cholesterol less than 40 mg/dL in men or less than 50 mg/dL in women, or current drug treatment for dyslipidemia; elevated fasting glucose of l00 mg/dL or greater; blood pressure values of systolic 130 mmHg or higher and/or diastolic 85 mmHg or higher, or current anti-hypertensive drug treatment in a patient with a history of hypertension]; anti-hypertensive treatment; age at the time of the first NL episode; number of NL episode occurred from the first one to the time of enrollment [24]. Laboratory parameter evaluated were sodium and potassium from serum and from 24 h urine collection for this analysis.

2.5 Statistical Analysis

All statistical analyses were performed using the IBM SPSS Statistics, version 23 (International Business Machines Corporation, Inc., Armonk, New York, United States of America). Continuous variables are reported as mean (standard deviation-SD) or median [25th–75th] if not normally distributed, were compared with the Analysis of variance (ANOVA) for normally distributed data or Mann–Whitney test if skewed. The Chi-squared test was used to evaluate differences between categorical variables. A multivariable linear regression analysis was carried out to determine the independent association between (log-transformed) urinary potassium excretion and NL status, adjusting for the main potential confounders. A p value < 0.05 was considered statistically significant. A post-hoc evaluation detected a power of 97% (alpha error: 5%) for this study.

3 Results

During the reported lapse of time, we collected data from 119 SF-Hs affected by NL and Htn at the Bone-Lab and data from 119 nSF-Hs affected by Htn at the Hypertension-Lab. All the patients were on free diet at the time of enrollment, under different Htn treatment and they didn’t change anti-hypertensive treatment in the last 2 months. After the last evaluation at the Hypertensive-Lab, Htn was well controlled in all subjects and they didn’t need further changing of anti-hypertensive treatment.

Among SF-Hs, there were 56 male subjects (47.1%), they were 49.0 [40.0–58.0] years old and they had 27.1 [24.9–31.2] kg/m2 as BMI. SF-Hs reported a first episode of NL when they were 32 [25–45] years old. From the time of the first episode to the last date of data collection, subjects were diagnosed with 4 [2,3,4,5,6,7,8] episodes of symptomatic kidney stones, all diagnosed by ultra-sound evaluation. In according to Gambaro et al, the stone analysis composition was performed, resulting all in CaOx [6, 23]. Among the SF-Hs group, patients were treated for Htn as following: 39 (32.8%) patients received BBs, 41 (34.5%) received CCBs, 55 (46.2%) received ACE inhibitors, 25 (21.0%) received ARBs, 24 (20.2%) received thiazide diuretics. Among the group, 57 (47.9%) patients were under more than one medication for Htn management.

In the nSF-Hs group, there were 66 males (55.5%), they were 57.0 [48.0–62.0] years old and they had 27.6 [24.4–30.8] kg/m2 as BMI. In the nSF-Hs group, patients were treated for Htn as following: 32 (26.9%) patients received BBs, 41 (34.5%) received CCBs, 39 (32.8%) received ACE inhibitors, 35 (29.4%) received ARBs, 22 (18.5%) received thiazides diuretics. Of them, 53 (44.5%) patients were under more than one medication for Htn management. No statistically significant difference between males and females were reported in the single group of SF-Hs and nSF-Hs for the examined parameters.

The two groups were significantly different for age (p < 0.001) and for MetS (p < 0.001). There was no other statistically difference between the groups for the collected variables (gender and BMI), as depicted in Table 1.

Table 1 Clinical characteristics of all patients at the time of enrollment at the Hypertensive-Lab or at Bone-Lab
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The urinary potassium levels in the 24 h collection in the SF-Hs group was 57 [46–69] mmol/24-h, while nSF-Hs had 69 [51–84] mmol/24-h (Fig. 1). This result was statistically significant (p < 0.001). No other laboratory parameters (serum sodium and potassium levels, twenty-four urinary sodium levels) were found to be significantly different.

Fig. 1
figure 1

Urinary Potassium Excretion in patients affected by Hypertension and Nephrolithiasis (SF-Hs) and in patients affected by Hypertension but not by Nephrolithiasis (nSF-Hs). Black line in the boxes represents the median value for each group. Grey squares indicate the standard deviation. *p < 0.001

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This difference was confirmed by the multivariable linear regression analysis in the unadjusted model and adjusted model for age, gender and MetS (Model 1) and adjusted model for age, gender, MetS and BMI (model 2), as reported in Table 2.

Table 2 Difference in urinary potassium excretion according to nephrolithiasis status: the multivariable regression analysis
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There was no significant association between the number of NL episodes and the potassium urinary levels in the 24 h collection in the SF-Htn group.

4 Discussion

Our study results demonstrated that the lower urinary potassium excretion in the 24 h collection is associated with a higher risk of recurrent NL in patients already affected by a pharmacologically well monitored Htn.

To the date during the NL follow-ups, the urinary potassium 24 h excretion has been only taken into account as hint to diagnose bowel disease, use of diuretics and/or laxatives, that can influence the occurrence of CaOx kidney stones. Nevertheless, the daily urinary potassium excretion is a good indicator of a diet rich in potassium, directly related to the potassium intake and absorption [19]. The major contributors to potassium intake from food are dairy (specifically milk and yogurt), fruit (specifically tropical fruit), and vegetables (specifically potatoes), providing 21%, 6%, and 5%, of potassium intakes, respectively [25]. It is mostly absorbed by small intestines, and then it meets distribution to the cellular membranes, where it plays its role in the process of membrane re-/depolarization. The least remaining is extracellularly located and the serum concentration are determined by internal redistribution from liver and muscles, and excretion by kidney, gut and sweat. The kidney represents the major route of potassium excretion, demonstrating to be a good marker of the dietary intake of potassium from diet (www.efsa.europa.eu/en/efsajournal/pub/4592).

In our study, the prevalence of nSf-Hs and Sf-Hs participants with an adequate potassium intake (i.e. urinary excretion ≥ 90 mmol/day) was 6% and 18%, respectively. These data are in agreement with those of most countries worldwide, in which the potassium intake is low [26,27,28,29,30,31]. In this context, according to the results of our study, we can state that an increase of around 10 mmol in potassium excretion (estimated potassium intake of around 500 mg, assuming 1 mmol = 39 mg, and that around 70% of potassium ingested is excreted in the urine) may be sufficient to reduce the NL risk. This amount may be represented just by a serving of fruit more per day.

Malavolti et al demonstrated that a complete adherence to the Mediterranean (Med) diet guarantee the suggested amount of potassium [32]. The Med diet consists of fish, monounsaturated fats from olive oil, fruits, vegetables, whole grains, legumes and/or nuts, and moderate alcohol consumption [33]. In particular, vegetables and fruits increase pH, potassium, magnesium, citrate, phytate and other stone inhibitors, resulting in the end in a decrease in the supersaturation of calcium oxalate. Also, they present with a low content in proteins and sodium chloride, further reducing calcium excretion alongside with sodium and protein kidney removal [34]. Moreover, higher dietary potassium intake has been associated with higher urine volume that persists for 3 h, and higher potassium leak from kidney to avoid rising in potassium serum levels, that could be dangerous [35]. All of these processes result in the decrease of stone formation [34, 35]. The best Med diet adherence is indeed associated with the lower risk of developing kidney stones [36].

Adherence to dietary and lifestyle modification has been already proved to strongly impact on stone incidence and recurrence. Given that, different dietary patterns other than Med diet have been studied in regard to NL prevention. Available scientific evidence highlights that a diet low in animal proteins, balanced in low-fat dairy products, and with a reduced salt content is the best way to decrease the risk of kidney stone disease [37]. This is achieved with Dietary Approaches to Stop Hypertension (DASH) diet with a measured recurrence risk of 50% [38], or with a balanced vegetarian diet, allowing consumption of dairy products, with a predicted recurrence rate of 60% [14]. DASH diet has been specifically designed for managing hypertension and cardiovascular risk. It is characterized by high fruit, vegetables, nut, legumes, low-fat dairy products, grains and low or completely absent intake of sodium by sweetened beverages and red and processed meat [38]. Vegetarian diet is instead defined by prohibition of meat and fish intake, but allowance to eggs and milk derivatives. Fruit and vegetables are the main components of such a diet, guaranteeing NL prevention for the same above mechanisms. Also, it has been proved to not significantly affect calcium metabolism and bone turnover, neither rising nor lowering calcium excretion from kidney regardless of sodium discharge [39]. Alas, it needs to be balanced with the assumption of nutritional supplements to avoid clinical deficiencies in some vitamins, such as vitamin D and B12, zinc, iron and n-3 fatty acids [14].

In summary, Med, DASH and vegetarian diet are all featured by high consumption of fruits and vegetables, that provides a wide array of nutrients, including high potassium concentrations, that impact on the stone risk [38]. However, adherence to such a dietary modification must be taken into account, and for this very reason the dramatic change in lifestyle that the vegetarian diet would represent, it is not suggested for patients with both NL and/or Htn. All things considered, we can conclude that consumption of an extra serving of fruits and nutritional plants are enough to influence risk of CaOx stones in patients affected by Htn.

It should also be taken into account that recently a close attention has been focused on diet-based prevention of cardio-vascular events too [40]. Indeed, several observational and intervention studies showed an inverse relationship between dietary potassium intake, blood pressure [41] and cardiovascular risk [42,43,44,45]. Recently, one research by Ma et al. demonstrated a relationship between sodium and potassium dietary excretion and cardiovascular risk in a dose-response manner [40]. For this reason, a strong selling point of our study is that all the patients were under optimal blood pressure control, demonstrating that nor blood pressure compensation nor the treatment chosen for Htn affected the potassium urinary excretion.

In conclusion, our data results proved that patients affected by Htn had a higher potassium urinary excretion in 24 h collection, compared to those affected by Htn and NL, proving it to be a protective factor against recurrent NL. Given so, dietary interventions can be taken into account as promising methods for kidney protection, to reduce the future burden of the CKD that will weight on each national Health Sanitary system, in particular in western countries that present with the less adherence to a diet rich in potassium and with higher prevalence to sweet-meat dietary pattern habit.

Our study presents both points of limit and points of strength. The retrospective nature of the research fails (1) to prove a concrete causal-effect relationship between low urinary levels of potassium and the recurrence of NL and (2) to detect the consecutio temporum between the vicious food habit and the recurrence of NL. In addition, the number of our sample is limited, and it probably underestimates the additional differences among the two groups. Lastly, the free diet doesn’t provide accurate information regarding the food intake. Furthermore, data regarding pH, urinary calcium was not available, because they didn’t form part of the usual clinical evaluation of patients affected by Htn. On the other side, given the real-life design of the study, our sample is far more representative of a community dwelling population, also conducted on free diet. Another advantage is represented by the multivariate analysis, which is helpful to reduce the weight of the confounding variables. This can be considered as a pioneer study, to lead the way for next prospective studies that can prove the subsequent association between a diet poor in potassium and the recurrence of NL, and to disentangle the effects of possible bias from those of other compounds of potassium rich foods [46, 47].