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NDT Advance Access published online on October 3, 2008
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn548
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© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


Association between metabolic syndrome and nephrolithiasis in an inpatient population in southern Italy: role of gender, hypertension and abdominal obesity

Domenico Rendina1,2, Giuseppe Mossetti1, Gianpaolo De Filippo3, Domenico Benvenuto2, Carmen Liliana Vivona2, Alessia Imbroinise2, Giorgia Zampa1, Salvatore Ricchio2 and Pasquale Strazzullo1

1 Department of Clinical and Experimental Medicine, Federico II University Medical School, Naples 2 Spinelli Hospital, Belvedere Marittimo (CS) 3 Pediatric Endocrinology Unit, Gaetano Rummo Hospital, Benevento, Italy

Correspondence and offprint requests to: Giuseppe Mossetti, Department of Clinical and Experimental Medicine, Federico II University Medical School, via Sergio Pansini, 5-80131 Naples, Italy. Tel: +39-817462017; Fax: +39-815466152; E-mail: giumosse{at}unina.it



   Abstract
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 Abstract
Introduction
 Methods
 Results
 Discussion
 Strengths and limitations of...
 General relevance and...
 References
 
Background. Metabolic syndrome (MetS) and nephrolithiasis (NL) are quite common disorders. While some of the components of MetS have been proposed as precursors of NL in population studies, no data are available about the possible association between NL and MetS as such. The primary objective of the study was to evaluate the relationship between MetS and NL. The secondary outcome was to examine the relationship between MetS single constitutive elements and NL considering the strict correlation occurring among these factors.

Methods. We studied 2132 Caucasian inpatients of the ‘Spinelli’ Hospital in southern Italy (males/females = 0.95; mean age 63.8 ± 15.8 years; body mass index 26.1 ± 3.9 kg/m2). The MetS diagnosis was performed according to the Heart Association/National Heart, Lung, and Blood Institute criteria. The presence of NL was assessed by ultrasound examination of the kidneys and upper urinary tract.

Results. Seven hundred twenty-five subjects (34.0%) had a positive diagnosis of MetS. Two hundred twenty subjects (10.3%) had echographic evidence of NL, while 199 subjects reported a past history of NL (9.3%). The presence of MetS, as well as the male sex, and the occurrence of a previous episode of NL (in male subjects only) were each independently related to echographic evidence of NL. Among the individual components of MetS, high blood pressure and abdominal obesity (in female individuals only) were also independently related to echographic evidence of NL.

Conclusions. MetS is significantly associated with echographic evidence of NL. A gender-related difference in the clinical expression of NL was also observed.

Keywords: longitudinal study cohort; medical questionnaire; metabolic syndrome; nephrolithiasis; renal echography



   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 Strengths and limitations of...
 General relevance and...
 References
 
The metabolic syndrome (MetS) is a constellation of interrelated risk factors carrying an increased risk of atherosclerotic cardiovascular disease, type 2 diabetes mellitus and all-cause mortality [1–4]. Despite different definitions of MetS have been proposed, there is general consensus regarding its main components: obesity, hypertension and disorders of carbohydrate and lipid metabolism (i.e. elevated serum triglyceride and apolipoprotein B, increased small LDL particles and a reduced level of HDL-cholesterol). Individuals with these characteristics commonly harbour a pro-inflammatory state, resulting in a pro-thrombotic condition [5].

For many years, there were few data concerning the relationship between MetS and the risk of developing renal diseases; however, recent epidemiologic analyses have found that patients with MetS are at high risk for chronic kidney diseases [6–9]. In this scenario, some of the components of MetS have been associated with the occurrence of nephrolithiasis (NL) or with biochemical abnormalities that in turn are related to NL [10–22]. In particular, despite the clinical expression of each MetS constitutive element appears strictly interrelated to others, some studies evaluated the relationship between one Mets risk factor (i.e. hypertension or obesity) and the occurrence of NL using ad hoc prepared medical questionnaires. Conversely, other studies dealt with the association between individual components of MetS and/or insulin resistance and urinary metabolic risk factors for NL, e.g. excretion of uric acid, calcium, oxalate or citrate [10–22]. It is not known, however, whether MetS itself is associated with NL beyond the effect of its individual components. To evaluate this question, we carried out a cross-sectional study of a hospital-based population (n = 2132) living in southern Italy, a region featuring a relatively high prevalence of NL [23]. The prevalence of NL in our study cohort was evaluated by an ultrasound (US) scan of renal pelvis and parenchyma. A validated medical fixed-sequence questionnaire was also drawn by all enrolled patients to evaluate the previous personal history of kidney stone disease [13]. A secondary outcome of the study was the evaluation of the relationship between single metabolic components of MetS and the occurrence of NL.

To our best knowledge, no large epidemiological survey has been previously performed using contextually an instrumental objective evaluation of renal system as well as a medical questionnaire to explore the association between NL and MetS and/or its single constitutive elements as in the present study.



   Methods
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 Introduction
 Methods
Results
 Discussion
 Strengths and limitations of...
 General relevance and...
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Study protocol
All Caucasian patients consecutively referred for any reason to the ‘Spinelli’ Hospital in the town of Belvedere Marittimo (Cosenza, Italy) from 1 January 2004 to 31 December 2005 were considered for possible participation in the study. During this time, 2816 subjects were hospitalized at least once. For patients admitted to the hospital more than once (1547, 54.9%), only the data collected during the first hospitalization were considered for the present study.

Exclusion criteria
Exclusion criteria were acute or chronic renal failure (estimated glomerular filtration rate (GFR) <60 mL/min/ 1.73 m2 [24]), hyperthyroidism, primary or secondary hyperparathyroidism, congenital abnormalities and dysgenesis of the kidneys and of the renal pelvis, pharmacological treatment for osteoporosis and/or other metabolic bone disorders, major debilitating physical illnesses, including neoplastic disease, which significantly affected the subject's nutritional state, and/or incomplete clinical or anamnestic data collection. There were no pregnant women in the study population. None of the patients reported symptoms attributable to NL or have an invasive or not invasive urologic treatment during the 12 months preceding the enrolment. All the subjects enrolled gave their written informed consent to use their clinical data for the purposes of the present study that was in accordance with the Declaration of Helsinki and was approved by the local Ethics Committee.

The patients were examined in the morning within the hospital premises. Their weight and height were measured, and their body mass index (BMI, the weight in kilograms divided by the square of the height in meters) was calculated. Blood pressure was measured three times while the subjects were seated, and the last two measurements were averaged for analysis. A fasting venous blood sample was drawn to determine serum levels of glucose, total and HDL-cholesterol, triglycerides, total calcium, alkaline phosphatase, sodium, potassium, chloride, magnesium, phosphate, creatinine, intact parathormone and thyroid-stimulating hormone. Only in selected women (see later), FSH and 17β-oestradiol serum levels were also measured.

Diagnosis of NL
A fixed-sequence questionnaire aimed at detecting a history of upper urinary tract stones was administered to all participants [13]. US inspection of the renal pelvis and parenchyma in multiple anatomic planes was performed in each subject using a Philips HP Agilent Sonos 4500® system with a 3.5 MHZ convex US transducer. According to Schepens et al. [25], renal calcifications were classified as NL, if the calcification was located in the collecting system, and nephrocalcinosis, if the calcification occurred within the renal parenchyma. For the purposes of our study, shadowing calcified foci in the renal collecting system with a diameter ≥2 mm at US were termed as calculi. All the US evaluations were performed by the same operator who was unaware of the patient's metabolic status.

Diagnosis of MetS
The diagnosis of MetS was made, according to the American Heart Association (AHA)/National Heart, Lung and Blood Institute (NHLBI) criteria [2], in subjects who fulfilled any three of the following criteria: (1) waist circumference ≥102 cm in men and ≥88 cm in women; (2) serum triglycerides >1.7 mmol/L or current drug treatment for hypertriglyceridaemia; (3) serum HDL-cholesterol <1.03 mmol/L in men and <1.3 mmol/L in women or drug treatment for low HDL-cholesterol; (4) systolic blood pressure (BP) ≥130 mmHg and/or diastolic BP≥ 85 mmHg or current antihypertensive drug treatment in a patient with a history of hypertension and (5) fasting serum glucose ≥5.6 mmol/L or drug treatment for elevated blood glucose.

Diagnosis of hyperparathyroidism
According to Bilezikian and Silverberg [26], the diagnosis of primary hyperparathyroidism was made on the basis of the combination of an elevated total serum calcium concentration and an elevated or inappropriately normal parathyroid hormone level. The occurrence of secondary hyperparathyroidism was excluded on the basis of a normal renal function (estimated GFR >60 mL/min/1.73 m2) and normal serum concentration of total calcium, phosphate, magnesium, alkaline phosphatase and intact parathormone. According to Boonen et al. [27], 25(OH)D3 serum levels were determined only in patients with confirmed hyperparathyroidism, to evaluate the presence of a hypovitaminosis D.

Menopause diagnosis
Menopause was diagnosed in the case of suspension of menstrual periods for 12 or more months after spontaneous cessation of menses, bilateral ovariectomy or serum FSH > 40 IU/L and/or 17β-oestradiol levels <20 pmol/L in women aged 40 years or more without regular menses.

Statistical analysis
Statistical analysis was performed using the SPSS(c) (SPSS Inc., Chicago, IL, USA) statistical package (version 11.5). The results were expressed as mean ± standard deviation for continuous variables and as absolute and percent values for discrete variables. The unpaired Student's t-test was used for continuous variables to evaluate between-group differences in a given variable. For the comparison of discrete variables, the {chi}2 or Fisher's exact test was used. Logistic regression analysis was used to evaluate the association of a given variable with the echographic evidence of NL accounting for confounders.



   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 Strengths and limitations of...
 General relevance and...
 References
 
Out of 2816 potentially eligible individuals (M:F 0.93; mean age 64.7 ± 19.4 years; BMI 26.3 ± 4.2 kg/m2), 2132 subjects were included in the present analysis (see flow chart in Figure 1). All of them were born and lived in southern Italy and were of Caucasian origin. The reasons for in-hospital admission, featured by 2002 clinical classification software [28], are reported in Table 1.


Figure 1
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  		Fig. 1 Flow chart of the study. ASL (Azienda Sanitaria Locale) Cosenza 1 = local health authority Cosenza 1. In the geographical area examined the density population is almost 140 inhabitants/km2 and the hospitalization rates (number of in-hospital admissions/1000 inhabitants/year) are 155, 299 and 390 for adults <64 years, from 65 to 75 years and >75 years old, respectively (http://www.ministerosalute.it/servizio/sezSis.jsp?label = usl). During the study, about half of the studied were admitted to the ‘Spinelli’ Hospital more than once, but only parameters collected during the first in-hospital admission were considered for the present cross-sectional study.

 

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  		Table 1 Causes of in-hospital admission

 
Table 2 shows the clinical characteristics of the study population. Seven hundred twenty-five subjects (mean age 66.8 ± 11.9 years, BMI 28.4 ± 4.4 kg/m2) had a positive diagnosis of MetS. Two hundred twenty subjects (mean age 65.3 ± 11.1 years, BMI 26.2 ± 4.0 kg/m2) had echographic evidence of NL, while 199 subjects reported a past history of kidney stone disease (mean age 60.9 ± 12.4 years, BMI 25.9 ± 4.0 kg/m2). Echographic evidence of NL and a past history of kidney stone disease were significantly more common in males, while MetS and some of its components (i.e. high waist circumference and hypertension) were more frequently observed in females (P < 0.01 for all the differences).


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  		Table 2 Clinical characteristics of the study population

 
Kidney stones were located in the left kidney in 111 patients (50.5%), in the right kidney in 65 (29.5%) and in both kidneys in 44 patients (20.0%). The stone diameter was between 2 and 5 mm in 79 patients (35.9%), between 5 and 7 mm in 55 patients (25.0%) and >7 mm in the residual 86 patients (39.1%) [29]. Ultrasonically detectable hydronephrosis was observed in 45 patients (20.5%), all having a stone diameter ≥5 mm. The large majority of the patients with echographic evidence of NL (179/220; 81.4%) had an asymptomatic form of the disorder upon admission to the hospital: their general characteristics were similar to those of the whole group. No significant difference was apparent in the kidney stone diameter or localization between subjects with symptomatic or asymptomatic NL.

Table 3 features a comparison of the relevant clinical data in the participants with echographic evidence of NL and the remaining study population. Over half of the subjects with echographic evidence of NL (50.9%) met the criteria for MetS. At univariate analysis ({chi}2 test), echographic evidence of NL was associated with higher male-to-female ratio [odds ratio (OR) 1.5, 95% confidence interval (CI) 1.2–2.0; P < 0.01], positive past history of NL (OR 2.1, 95% CI 1.8–2.4; P < 0.01) and occurrence of MetS (OR 2.2, 95% CI 1.7–2.9; P < 0.01). Among the individual components of MetS, high waist circumference (OR 1.9, 95% CI 1.5–2.5; P < 0.01) and high blood pressure (OR 2.7, 95% CI 2.0–3.6; P < 0.01) were both significantly associated with echographic evidence of NL.


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  		Table 3 Clinical characteristics of the subjects with or without echographic evidence of nephrolithiasis

 
As reported in Figure 2, a model of multivariate logistic regression analysis including the entire study population confirmed that male sex (OR 1.8; 95% CI 1.2–2.6; P < 0.01), occurrence of MetS (OR 2.0, 95% CI 1.3–3.0; P < 0.01) and past history of NL (OR 2.6; 95% CI 1.5– 4.7; P < 0.01) were each significantly and independently related to echographic evidence of NL, upon adjustment for age. As a significant number of study participants reported a history of NL even in the absence of current evidence of stones, we performed an additional analysis considering as stone formers both the patients with current (objective) evidence of NL and those with a report of previous episodes of kidney stone disease (n = 298): the results of this analysis confirmed the clinical association between MetS and NL (OR 1.2, 95% C.I. 1.1–1.3; P = 0.002). A significant association was also detected between past or current kidney stone disease and in-hospital admission related to cardiovascular disorders (i.e. diagnostic categories 7.2 and 7.3 in Table 1), the most frequent clinical consequences of MetS (OR 1.7, 95% CI 1.2–2.6; P = 0.02).


Figure 2
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  		Fig. 2 Logistic regression analysis of parameters related to echographic evidence of nephrolithiasis in the entire study population. MetS = meta- bolic syndrome. NL = nephrolithiasis. MetS diagnosis was made according to the AHA/NHLBI criteria (2). For each variable, data are expressed as odds ratio (95% confidence interval).

 
Since sexual dimorphism was apparent in the expression of NL, we further analysed the above relationships separately in male and female participants. Among men, logistic regression confirmed MetS (OR 1.9, 95% CI 1.2–3.1; P = 0.03) and past history of NL (OR 3.7, 95% CI 1.7–7.7; P < 0.01) as variables significantly related to echographic evidence of NL, independently of age. Among women, a similar multivariate analysis indicated that only MetS (OR 2.2, 95% CI 1.3–3.7; P < 0.01) was significantly related to echographic evidence of NL accounting for age and past history of NL (Figure 3). The association between MetS and echographic evidence of NL in women was also observed when the variable ‘occurrence of menopause’ took the place of ‘age’.


Figure 3
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  		Fig. 3 Logistic regression analysis of parameters related to echographic evidence of nephrolithiasis in males and females enrolled subjects. MetS = metabolic syndrome. NL = nephrolithiasis. MetS diagnosis was made according to the AHA/NHLBI criteria (2). For each variable, data are expressed as odds ratio (95% confidence interval).

 
In a separate logistic regression model including the individual components of MetS (Table 4), hypertension was the only MetS component significantly related to echographic evidence of NL among men, accounting for age, high waist circumference, high serum triglycerides, low HDL-cholesterol and elevated fasting serum glucose levels. Among women, both hypertension and high waist circumference were independently and directly related to echographic evidence of NL, accounting for age and all other MetS components. These results in women were also confirmed when the variable ‘occurrence of menopause’ took the place of ‘age’.


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  		Table 4 Logistic regression analysis, echographic evidence of kidney stone disease and selected variables

 
Since hypertension was the only MetS component significantly related to echographic evidence of NL in both men and women, additional analyses were performed to evaluate the prevalence of NL among participants with high BP. As reported in Table 2, 887 patients (41.6% of the entire study population) met the AHA/NHLBI criteria for high BP. Two hundred twenty of them (24.8%) had an isolated form of high BP whereas in the remaining 667 subjects (75.2%) high BP was associated with at least one other MetS component. The prevalence of NL was 9.1% (20/220) among subjects with isolated high BP versus 20.8% (119/667) among those with high BP plus one or more other components of MetS. The latter subgroup had a risk of NL significantly higher compared to the former (OR 2.2, 95% C.I. 1.3–3.6; P = 0.002).



   Discussion
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 Abstract
 Introduction
 Methods
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 General relevance and...
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MetS is associated with doubling the risk of cardiovascular disease, with a fivefold increase in risk for type 2 diabetes and with a non-negligible greater risk for chronic renal disease [1–9]. Our study results from a large population of older adults demonstrate for the first time that MetS is also associated with a twofold greater occurrence of objectively demonstrated NL. This finding is strengthened by the observation of a greater prevalence of past and/or current NL in patients hospitalized for cardiovascular diseases. Although among the individual components of MetS, high BP per se carried a significant relationship to NL in both men and women, the combination of high BP and one or more other components of MetS was associated with a further increase in the risk of NL. In other words, the combination of high BP with other components of MetS significantly increases the probability of concomitant NL. Other findings were that past history of kidney stone disease was significantly related to current echographic evidence of NL in men but not in women, while abdominal obesity was significantly associated with NL in women only.

A common pathogenetic background between MetS and NL has been recognized in the occurrence of insulin resistance (IR). IR plays a crucial role in the initiation and maintenance of the various clinical features of MetS [6] and also significantly influences the urinary salts supersaturation [15,20–22]. Kidney stone formation results from a phase change in which urinary dissolved salts condense into solids, and all phase changes are driven by salts supersaturation, which is usually approximated by the ratio of the urinary salt concentration to its solubility and is calculated by computer algorithms [29]. In addition to urine volume, calcium and oxalate concentrations are the main determinants of calcium oxalate (CaOx) urine supersaturation. Urine calcium concentration and pH are the main determinants of calcium phosphate (CaP) supersaturation, and urinary pH is the main determinant of uric acid supersaturation [29]. IR directly influences urinary salts supersaturation by affecting urinary pH as well as calcium, phosphate, urate and citrate excretion [15,20–22]. Experimental studies also indicate that some genetic variants of the vitamin D receptor (VDR) significantly influence the occurrence of IR as well as of idiopathic hypercalciuria and hypocitraturia [30–34]. Thus, a common genetic background between MetS and the two most frequent metabolic risk factors for NL could be hypothesised.

On the other hand, a statistical association between hypertension and NL in both cross-sectional and prospective epidemiological investigations has been reported by our group and by others [10,12,13,17,19,35–37]. As renal tubular calcium handling may be altered in hypertensive patients, leading to increased urinary calcium excretion [38], hypercalciuria seems to be a plausible pathogenetic link between the two conditions in subjects who carry genetic susceptibility and possibly other risk factors for NL [39].

The sexual dimorphism observed with respect to the incidence of NL has no obvious explanation. The occurrence of menopause could at least partly explain this observation. The fall of oestrogen production significantly influences the emergence of MetS in postmenopausal women by increasing BMI and visceral fat accumulation [40]. Previous studies indicate that obesity was associated with the greater risk of kidney stones and that the magnitude of this association varied by gender, with a stronger influence in women [11,17,41,42]. Moreover, ovarian failure significantly increases bone turnover and urinary calcium excretion and, at the same time, reduces the excretion of inhibitors of urinary crystal nucleation and growth (i.e. citrate) [43–45]. Our finding that a past history of NL was a significant predictor of echographic evidence of NL in men but not in women suggests that NL makes its first appearance in women at a later age than in men and is compatible with these considerations.



   Strengths and limitations of the study
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Strengths and limitations of...
General relevance and...
 References
 
Major strengths of our study are the large sample size, the use of objective instrumental evaluation of the occurrence of NL, the restricted geographical habitat and the homogenous origins and lifestyles of the study population. An important issue is the generalizability of the study results. The Italian National Health Service is organized in geographical areas, defined as Local Health Authorities (ASL). The ‘Spinelli’ Hospital operates in the ASL Cosenza 1 (Figure 1) together with a few other similar institutions and was awarded the UNI EN ISO 9001: 2000 quality certificate for provision of diagnostic and therapeutic health care services for hospitalized patients in general medicine and cardiology. Thus, it is not a stone referral centre, for which reason the possibility of a preferential selection of NL patients for hospitalization is unlikely. Strictly speaking, our eligible study population was representative of the adult population hospitalized for any reason in the ASL Cosenza 1 during the study time. Nevertheless, considering the causes of in-hospital admissions (Table 1), it can be assumed that our study population is representative to a reasonable extent of the entire middle-aged and elderly population living in the ASL Cosenza 1 during the study time.

A further limitation of the study is the lack of measurement of biochemical parameters relevant to the metabolic evaluation of NL, namely, urinary calcium, phosphate, urate, oxalate and citrate excretion. The cross-sectional nature of the present study also prevents a prospective evaluation of the statistical associations detected.



   General relevance and perspectives
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Strengths and limitations of...
 General relevance and...
References
 
The overall prevalence of asymptomatic kidney stone disease in this middle-aged and elderly population was remarkably high. There is consistent evidence that incidental ultrasonographic evidence of NL is often followed by progressive renal function impairment [29,46–48] and that as many as 77% of these patients may experience kidney stone disease progression, with 26% eventually requiring surgical intervention [48]. On the other hand, MetS is also increasingly common in the general population and, given its association with age, represents a serious problem in progressively older populations such as those of economically developed and developing countries [49]. Therefore, the results of the present study highlight a major health problem with important implications on diagnostic and preventive grounds and provide an indication for systematic screening of NL in subjects with MetS, particularly in the presence of other recognized risk factors for this disorder.



   Acknowledgments
 
The authors are grateful to Dr Pasquale Ferraro, medical director, and to all medical and paramedical staff of the Spinelli Hospital, Belvedere Marittimo, Cosenza, Italy. We are also indebted to Pasquale and Italiacornelia Rendina for their statistical advice.

Conflict of interest statement. None declared.



   References
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Received for publication: 19. 3.08
Accepted in revised form: 8. 9.08


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