Past history of nephrolithiasis and incidence of hypertension in men: a reappraisal based on the results of the Olivetti Prospective Heart Study
Pasquale Strazzullo1,,
Gianvincenzo Barba2,
Pietro Vuotto1,
Eduardo Farinaro3,
Alfonso Siani2,
Vincenzo Nunziata1,
Ferruccio Galletti1,
Mario Mancini1 and
Francesco P. Cappuccio4
1 Department of Clinical and Experimental Medicine, Unit of Clinical Genetics and Pharmacology, Hypertension and Mineral Metabolism and
3 Department of Preventive Medical Sciences, Federico II University Medical School, Naples,
2 Institute of Food Science and Technology, National Research Council, Avellino, Italy and
4 Department of General Practice and Primary Care, St George's Hospital Medical School, London, UK
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Abstract
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Background. We have previously reported that in the Olivetti Prospective Heart Study cohort the incidence of nephrolithiasis was higher in hypertensive participants than in normotensive ones. As the time sequence and the mechanisms underlying the association between nephrolithiasis and hypertension remain controversial, we further tested the hypothesis that in a cohort of normotensive males a history of nephrolithiasis predicts the development of future hypertension.
Methods. The analysis was conducted in 381 male workers at Olivetti who were normotensive at the baseline examination and who were re-examined 8 years later.
Results. A past history of nephrolithiasis is associated with an increased risk of hypertension of 1.96 (95% CI=1.253.07) relative to subjects with a negative history, after adjusting for age.
Conclusion. In this 8-year follow-up study, a history of nephrolithiasis resulted in an increased risk of developing hypertension in the future. As the reverse was also true, as previously reported, a clear-cut time sequence, as well as the mechanisms linking these two conditions, remain to be identified.
Keywords: hypertension; nephrolithiasis; population study
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Introduction
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Arterial hypertension and kidney stone disease are both highly prevalent conditions in modern affluent societies [1]. Since the time when Giovan Battista Morgagni described the case of a patient with anatomical findings suggestive of long-standing hypertension and the presence of kidney stones [2], several cross-sectional surveys have established that these two conditions occur together more often than might be predicted by chance [35]. More recently, Madore et al. [6] reported prospective data from the Health Professionals Follow-up Study, which suggested that male patients with a history of nephrolithiasis had an increased risk of subsequently developing hypertension. On the other hand, our group, in the context of the Olivetti Prospective Heart Study, has shown that arterial hypertension is a significant predictor of kidney stone disease in a cohort of middle-age male workers followed for 8 years [7]; and Borghi et al. [8] in a 5-year follow-up study have reported that patients with essential hypertension were more likely to develop kidney stones than age-matched normotensive controls. For a more complete evaluation of this important yet controversial issue, in the Olivetti study population we further tested the hypothesis of Madore et al. [6] that a positive history of kidney stones may in turn be a predictor of future hypertension.
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Methods
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Study population
Of 688 untreated male individuals aged 2158 years, first examined in 1987, 509 were normotensive and were considered for this re-analysis. Three-hundred-eighty-one of them (74.9%) were re-examined in 19941995 after an average interval of 8 years. The baseline characteristics of this group and of the 128 men lost to follow-up were comparable in all relevant respects, including mean age, body mass, and blood pressure.
Study procedures
The methodology of the study has previously been described in detail [7]. The examinations were carried out in the morning in the Olivetti factory premises in Marcianise and Pozzuoli near Naples, on fasting participants. The study included a physical examination, a blood test and a fasting, timed urine collection.
Measurement of exposure
A detailed fixed-sequence questionnaire aimed at detecting a history of upper urinary tract stones was administered to all participants. The criteria for definition of a positive history of nephrolithiasis were the following: (i) spontaneous passage of one or more stones at any time in the past; (ii) X-ray or ultrasound evidence of one or more stones in the upper urinary tract; (iii) surgical removal of stones from kidney or ureter; and (iv) characteristic clinical findings judged by a physician at the time of symptoms based on available medical records (<15% of all cases reported).
Blood pressure measurement
At the baseline and at follow-up examinations, blood pressure was measured between 08:00 and 11:00 after the subject had been sitting upright for 10 min. Systolic and diastolic (phase V) blood pressures were taken three times, 2 min apart, with a random-zero sphygmomanometer (Gelman Hawksley Ltd) by trained observers who had attended training sessions for standardization of the measurement procedure. The first reading was discarded and the average of the last two readings recorded and used in the analysis. Participants were defined as hypertensive if they had a blood pressure
160
95 mmHg or if they were on a regular drug treatment for high blood pressure.
Anthropometric and biochemical measurements
Age, body weight, and height were recorded with standardized procedures, as described [7]. A fasting venous blood specimen was taken for determination of serum electrolyte and creatinine concentrations by standard methods. For measurement of creatinine and electrolyte excretion, a morning timed urine collection was obtained at follow-up examination from each participant after ingestion of 400 ml of tap water.
Statistical methods
Results are expressed as mean, standard deviation (SD) or 95% confidence intervals (CI), as appropriate. Differences between means were tested by Student's t-test for paired or unpaired data as appropriate.
2 cross-tabulation statistics were used to test differences between frequencies. Risk ratio (95% CI) was taken as an estimate of the relative risk of disease (hypertension) associated with the exposure (history of nephrolithiasis). The MantelHaenszel pooled estimate of the risk ratio (95% CI) was used in a stratified analysis to adjust for the confounding effect of age. Logistic regression analysis was used to estimate the relative risk of disease associated with exposure when more than one variable was considered. Two-tailed P values <0.05 were taken as statistically significant.
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Results
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At baseline examination 58 of 381 subjects (15.2%) reported a history of kidney stone disease and 323 (84.8%) did not. The baseline characteristics of these two groups are reported in Table 1
. Subjects with a positive history of nephrolithiasis were slightly older; body mass index, systolic and diastolic pressure, and serum creatinine concentration did not differ between the groups. By selection, all participants were normotensive at baseline.
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Table 1. Characteristics of normotensive men with or without a history of kidney stone disease at baseline examination
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The blood pressure values and the renal function indexes at the follow-up visit for the two groups are shown in Table 2
. Follow-up systolic and diastolic pressure levels were significantly higher in the group with a positive history of nephrolithiasis.
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Table 2. Blood pressure and renal function indexes at follow-up examination in men with or without a history of kidney stone disease
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The increase of blood pressure over the 8-year follow-up period in each group was evaluated by paired comparison. Systolic BP increased in both exposed and non-exposed individuals (119.9±11.5 vs 127.6±15.3 mmHg, P<0.001, non-exposed, baseline vs follow-up; 122.4±10.2 vs 132.6±15.9 mmHg, P< 0.001, exposed, baseline vs follow-up) whilst diastolic BP increased only in exposed individuals (82.6±7.0 vs 82.7±8.7 mmHg, P=0.80, non-exposed, baseline vs follow-up; 83.8±6.2 vs 86.3±10.3 mmHg, P<0.05, exposed, baseline vs follow-up). The differences between the two groups in BP changes over the 8 years were evaluated by unpaired comparison. Systolic blood pressure change was not different between groups (7.6±14.3 vs 10.2±13.3 mmHg, non-exposed vs exposed, P=0.209) whilst diastolic BP change was slightly, yet not significantly greater in exposed individuals (0.1±8.8 vs 2.5±8.6 mmHg, non exposed vs exposed, P=0.061).
Men with a history of nephrolithiasis had a significantly greater urinary calcium excretion rate than subjects with no such history. By contrast, there were no differences in serum creatinine concentration and creatinine clearance between the two groups (Table 2
). Likewise, no differences were found in urinary sodium and uric acid excretion rates.
At the 8-year follow-up examination, the overall incidence of hypertension was 16.8%. Nineteen men out of 58 (32.8%) in the group with the positive history of kidney stones and 45 of 323 (13.9%) in the control group had developed arterial hypertension. Forty-seven per cent of the hypertensive patients in the first group and 42% of those in the second group had been prescribed antihypertensive drugs. None of the hypertensive subjects with a history of nephrolithiasis had serum creatinine levels
125 µmol/l.
The incidence of arterial hypertension during the follow-up period was significantly greater in men with positive histories of kidney stones than in men without (32.8 vs 13.9%,
2 with Yates correction=11.2, P<0.001), with a relative risk of 2.35. After adjustment for age, this relative risk still remained significantly higher (Table 3
). On logistic regression analysis, including age, body mass, baseline serum creatinine, and blood pressure as covariates, the odds ratio between men with or without a history of nephrolithiasis for risk of future hypertension was 2.23 (95% CI 1.054.75).
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Discussion
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The results of this re-analysis of the Olivetti Prospective Heart Study cohort indicate that a positive history of kidney stones is indeed associated with an enhanced risk of developing arterial hypertension. These findings are in accordance with those of Madore et al. [6] which indicated that prior occurrence of nephrolithiasis increased the risk of subsequent hypertension. Madore et al. hypothesized that this greater risk of hypertension could be related to some kind of renal dysfunction secondary to the formation of stones, nevertheless there were no measures of renal function indicated in their study. In our study, we found no evidence that the higher incidence of hypertension in individuals with a history of nephrolithiasis was associated with deterioration of renal function as assessed by serum creatinine levels and creatinine clearance, although more subtle renal function abnormalities were not ruled out.
Although the participants with positive histories of nephrolithiasis were slightly older, the difference in age explains only a minor portion of the different rates of hypertension in the two groups. There also was a small, not significant difference in baseline blood pressures between the two groups; on logistic regression analysis, however, nephrolithiasis clearly remained an independent predictor of future hypertension when age, body mass and baseline blood pressures, and serum creatinine levels were included as co-variates. At the time of their follow-up visits, men with a history of nephrolithiasis had significantly greater urinary calcium excretion rates than men without. Although the estimate of habitual urinary calcium excretion by a single, timed urine collection may not be accurate, this finding is in line with the reported high prevalence of hypercalciuria in patients with kidney stone disease [911].
Another limitation of the present study is the fact that the Olivetti Study cohort was made up of white males only, and thus may not be regarded as representative of the general population of Italy. For this reason, the results of this study can only be applied to a comparable white male population.
A previous analysis of the population of the Olivetti Study had shown that arterial hypertension in men with negative histories of nephrolithiasis at baseline was associated with a greater risk of developing kidney stones in the future [7]. This finding has been confirmed by the recent report of Borghi et al. [8] showing that nephrolithiasis occurred more frequently among hypertensive than among age-matched normotensive subjects in a 5-year follow-up study.
Taking these observations together, we speculate that a common precursor to both hypertension and nephrolithiasis could explain the statistical association between these two conditions. A large body of evidence indicates that alterations in calcium metabolism play an important role in the pathogenesis of both hypertension and kidney stone disease [12,13]. In particular, hypercalciuria is not only a common precursor of renal calculi, but consistently has been found with greater frequency in patients with essential hypertension [8,1417]. Within the limitations recognized above, the finding of a higher calcium excretion rate in men with a history of kidney stones is at least compatible with the hypothesis that an alteration of calcium metabolism is the common precursor of nephrolithiasis and hypertension. These conditions could develop at an earlier or later time depending on the influence of other factors, for example dietary habits and genetic background. Studies are warranted to further elucidate the links between the two conditions, given their heavy impact as major problems for public health.
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Acknowledgments
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We thank Dr A. Scottoni, Dr U. Candura and Ms R. Bartolomei for their support in organizing and helping coordinate the work in the field, and the workers of the Olivetti factory for their cooperation. We acknowledge the hard work of the following: in 1987 Drs E. Celentano, A. DeLeo, G. Fusco, R. Galasso, N. Giorgione, D. Giumetti, L. Iacoviello, F. Jossa, S. Portolano; in 19941995 Drs F. Jossa, F. Noviello, E. Ragone, F. Stinga. We also thank Dr M. C. Mellone, Ms E. Della Valle, Mr R. Iacone and Ms P. Cipriano for their technical assistance in the laboratory. Dr F. P. Cappuccio is a member of St George's Cardiovascular Research Group. This work was supported in part by grants from the Ministero Pubblica Istruzione (60% funds 1985 and 1986), Ministero della Universita e Ricerca Scientifica of Italy (COFIN 1999) and by Modinform s.p.a. (Olivetti Group).
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Notes
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Correspondence and offprint requests to: Pasquale Strazzullo, MD, Department of Clinical and Experimental Medicine, Federico II University of Naples Medical School, Via S. Pansini 5, I-80131 Napoli, Italy. Email: strazzul{at}unina.it 
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Received for publication: 26. 6.00
Revision received 2. 6.01.