High urinary excretion of uric acid combined with high excretion of calcium links kidney stone disease to familial hypertension

Andras Tisler1, Andreas Pierratos2, John D'Arcy Honey2, Shelley B. Bull4, Laszlo Rosivall3 and Alexander G. Logan4

1 First Department of Medicine, Semmelweis University, Budapest, Hungary, 2 Lithotripsy Unit, St Michael's Hospital, Wellesley Central Division, University of Toronto, Toronto, Canada, 3 Department of Pathophysiology, Semmelweis University, Budapest, Hungary and 4 Samuel Lunenfeld Research Institute, Division of Clinical Epidemiology, Mount Sinai Hospital, University of Toronto, Toronto, Canada



   Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Past studies identified an association between kidney stone disease (KSD) and hypertension. We recently reported a high occurrence of hypertension in families of patients with hyperuricosuric KSD. As hypercalciura frequently coexists with hyperuricosuria and high urinary excretion of calcium is found in patients with hypertension, we hypothesized that hyperuricosuria that is accompanied by hypercalciuria better describes the familial association between KSD and hypertension.

Methods. Four hundred and eighty-six KSD patients, aged 18–50 years, attending a lithotripsy unit collected a 24-h urine sample for metabolic analysis and provided information on family history of hypertension. The familial occurrence of hypertension was compared among four groups of patients: those who had combined elevation of both urinary calcium and uric acid excretions (‘combined’ abnormality, n=56), those who had hyperuricosuria without concomitant hypercalciuria (‘pure’ hyperuricosuria, n=67), those who had hypercalciuria without concomitant hyperuricosuira (‘pure’ hypercalciuria, n=52), and a control KSD patient group (‘other’ abnormality, n=311). The prevalence of treated hypertension in patients from the four groups was 16%, 12%, 2%, 10%, respectively.

Results. Thirty-four per cent of the patients with the ‘combined’ abnormality had a positive family history of hypertension, defined as two or more first-degree relatives with treated hypertension, that was significantly higher than in patients with either ‘pure’ hyperuricosuira (15%, P<0.02), ‘pure’ hypercalciuria (8%, P<0.001), or patients with ‘other’ abnormality (10%, P<0.001). The adjusted OR for positive family history of hypertension in the ‘combined’ abnormality group compared to the control KSD patient group was 5.6 (2.39–13.30). The prevalence of hypertension in siblings of patients with the ‘combined’ abnormality (13%) was significantly higher than in siblings of patients with either ‘pure’ hyperuricosuria (3%, P<0.001), ‘pure’ hypercalciuria (1%, P<0.001), or siblings of control patients with ‘other’ abnormality (4%, P<0.001). The adjusted OR for hypertension in siblings of a patient with ‘combined’ abnormality compared to a control KSD patient was 3.4 (1.97–5.91). Patients in the ‘combined’ abnormality group were also characterized by significantly elevated urinary sodium, phosphorus, citrate and potassium excretions.

Conclusions. Our data suggest that there is a strong, independent association between familial occurrence of hypertension and the phenotype characterized by combined elevation of both urinary uric acid and calcium excretions. The association is not present in those with ‘pure’ hyperuricosuria or ‘pure’ hypercalciuria. Ascertainment of patients based on this phenotype may identify more homogeneous populations for genetic analysis of hypertension.

Keywords: familial aggregation; hypercalciuria; hypertension genetics; hyperuricosuria; kidney calculi; phenotype



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Human essential hypertension (HT) is a complex trait that clusters in families due to the inheritance of susceptibility loci or shared environmental factors or both [1]. Genetic analysis of patients characterized by clinical phenotypes that aggregate in families has successfully identified genes responsible for some Mendelian forms of HT. A logical extension of this approach is to define highly specific, familially determined, intermediate phenotypes that identify more homogeneous subsets of the essential hypertensive population in order to uncover genes involved in the development of essential HT [2]. The association between HT and kidney stone disease (KSD) raises the possibility of a common genetic or familial background that links these two conditions [35]. Because the strength of the association between KSD and HT is modest with relative risks around two, we undertook a family study to determine whether these two conditions share a common familial component that is determined by a specific urinary biochemical abnormality in the hope of further refining the phenotype. We recently reported strong familial predisposition to HT in young KSD patients who had elevated urinary excretion of uric acid (UA) [6]. The association was not present in KSD patients with other urinary metabolic abnormalities.

Several lines of evidence suggest that high urinary excretion of UA is not a unique urinary metabolic link between KSD and HT, and that other biochemical abnormalities may accompany hyperuricosuria. First, hypercalciuria is consistently found in patients with HT [7], particularly among those with salt sensitive forms of the disease [8]. Furthermore, hypercalciuria, the most prevalent metabolic risk factor for KSD, frequently coexists with hyperuricosuira in patients with KSD [9]. Second, hypertensive males exhibit a high lithogenic risk profile characterized not only by hyperuricosuria but elevated urinary excretion of calcium (Ca) and oxalate as well [10]. This latter observation implies a more complex metabolic derangement, possibly involving nutritional factors and individual susceptibility.

We hypothesize, therefore, that elevated urinary UA levels accompanied by increased urinary Ca excretion might better describe the common metabolic link between the familial, possibly genetic, association between KSD and HT. To test this we compared the familial occurrence of HT among four groups of young KSD patients: those with the combined elevation of both UA and Ca excretions, those with elevated UA excretion without concomitant hypercalciuria, those with elevated Ca excretion without concomitant high urinary UA excretion, and a control KSD patient group. We tested the hypothesis first on our group of patients enrolled in 1997 [6], and then evaluated the reproductibility of results in a second group of KSD patients enrolled in 2001.



   Subjects and methods
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Patients and data collection
All KSD patients between the ages of 18–50 years who attended the Lithotripsy Unit at St Michael's Hospital, Wellesley Central Division during the enrollment periods were eligible for inclusion. The first group of patients were enrolled during a 4-month period in 1997 and the second group over a 5-month period in 2001. The Lithotripsy Unit serves a population base of about 6 million people and provides care to more than 2000 KSD patients of all ages annually. Each patient attending the unit was asked to collect a 24-h urine specimen while on a self-selected diet and provide a blood sample for metabolic analyses. The urine samples were analysed for urinary excretion of UA, Ca, oxalate, citrate, magnesium, phosphorus, sodium, potassium and creatinine (Cr). The excretion values were normalized to Cr excretion to avoid bias produced by under or overcollection of the urine specimens.

Patients who had UA/Cr or Ca/Cr excretion values above the 75th percentile of the age and gender specific distribution of the Lithotripsy Unit database as their most extreme urinary metabolic abnormality and had accompanying Ca/Cr or UA/Cr excretions above the 75th percentile, respectively, were considered to have the ‘combined’ hyperuricosuric hypercalciuric metabolic abnormality. Those patients who were hyperuricosuric but had urinary Ca/Cr excretions below the 75th percentile were considered to have ‘pure’ hyperuricosuria. Those patients who were hypercalciuric but had urinary UA/Cr excretions below the 75th percentile were considered to have ‘pure’ hypercalciuria. Patients whose urinary UA/Cr as well as Ca/Cr excretions were below the 75th percentile of the corresponding distributions were considered to have ‘other’ abnormality. This group of KSD patients served as controls. The database that was used to define the age specific percentile values was collected over the years at the Lithotripsy Unit and included, in the 18–50 years age group, more than 2000 male and female KSD patients, respectively.

Before their appointment to the unit the patients were interviewed over the telephone about the occurrence of HT among first-degree relatives. Only individuals receiving antihypertensive medications were considered to have HT. Patients who were uncertain about the HT status of their relatives were excluded from the analysis. Several groups have assessed the validity of self-knowledge and family history information about the diagnosis of hypertension, although none restricted their evaluation to treated hypertensive subjects [11,12]. The sensitivity and specificity of personal knowledge of hypertension were found to be 0.97 and 0.86, respectively. For family history information specificity was over 90%, while sensitivity ranged from 25% for siblings to 81% for parents. Estimated odds ratio (OR) in studies of familial aggregation falls with decreasing specificity and sensitivity, but the magnitude of the effect is substantially greater when specificity is low.

Statistical analysis
First we performed the main analysis on the groups of patients enrolled in 1997 and 2001 separately. As the results were similar in these two groups we combined all patients together to increase the statistical power of the study. The familial occurrence of HT in the four patient groups was analysed by two methods.

First, the prevalence of positive family history of HT, defined as two or more first-degree relatives with treated HT, was compared among the patients with ‘combined’ abnormality, ‘pure’ hyperuricosuria, ‘pure’ hypercalciuria, and ‘other’ abnormality by Fisher's exact test. OR were estimated by logistic regression using the ‘other’ abnormality group as reference. Adjustments were made for the age, body mass index (BMI), personal hypertensive status and the number of first-degree relatives of the proband. The latter was included as a covariate because probands with larger families are more likely to have relatives with treated HT. Since none of the children had HT, they were excluded from these analyses.

Second, separate analyses were performed to compare the prevalence of treated HT among the fathers, mothers and siblings of the patients from the four groups. Odds ratios for HT in a relative (i.e. in a father, mother or sibling) of a patient with a particular urinary excretion pattern was obtained by logistic regression using the ‘other’ metabolic abnormality for reference. Age, BMI and personal history of HT of the index case were included as covariates.

Continuous variables were compared with analysis of variance, using contrast statements for the six pairwise comparisons between the groups. The analyses were performed by the SAS statistical software release 6.11. To correct for multiple comparisons, only tests that resulted in two-sided P values below 0.02 were considered statistically significant. OR are presented with 95% confidence interval in brackets.



   Results
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
There were 318 age eligible patients in 1997 and 392 in 2001 who attended the Lithotripsy Unit during the enrollment periods. Of these, six patients were excluded because they could not be reached by phone despite three attempts, five patients had wrong telephone numbers recorded at registration, 19 patients did not speak English, 14 patients were adopted, eight patients declined participation, 43 patients were uncertain about the HT status of their first-degree relatives, and 129 failed to collect a 24-h urine specimen. Thus 486 patients, 212 in 1997 and 274 in 2001, were enrolled in this study. Excluded subjects did not differ significantly in mean age, sex distribution, BMI, number of family members, prevalence of family history of HT and the prevalence of personal history of HT from those included. Based on the urine chemistry results 56 KSD patients were considered to have the ‘combined’ urinary abnormality characterized by high UA and Ca excretions, 67 to have ‘pure’ hyperuricosuria, 52 to have ‘pure’ hypercalciuria, and 311 to have ‘other’ abnormality.

Demographic data and the prevalence of positive personal history of HT of the patients in the four groups are given in Table 1Go, separately for patients from 1997 and 2001. The patients in the ‘combined’ urinary abnormality group had significantly more first-degree relatives than those in the ‘other’ abnormality group, and significantly more patients in the ‘combined’ urinary abnormality group had treated HT compared to those in the ‘pure’ hypercalciuria group.


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Table 1. Demographic data and the prevalence of hypertension in the four kidney stone disease patient groups

 
Table 2Go shows the prevalence of strong family history of HT in the four patient groups, with the data given separately for patients from 1997 and 2001. As the prevalences were not significantly different between these two groups, we combined the results obtained from the patients from 1997 and 2001 together. Among patients in the ‘combined’ abnormality group 34% had at least two first-degree relatives with treated HT. This was significantly higher than in KSD patients with either ‘pure’ hyperuricosuria (15%, P<0.02),‘pure’ hypercalciuria (8%, P<0.001), or in patients with ‘other’ abnormality (10%, P<0.001). The prevalence of positive family history of HT in patients with ‘pure’ hyperuricosuria or ‘pure’ hypercalciuria was not significantly different from that in the ‘other’ abnormality group. The univariate OR for positive family history of HT in a KSD patient with combined elevation of both UA and Ca excretions was 4.8 (2.46–9.39) compared to a KSD patient with ‘other’ abnormality. After adjustment for the covariates in multivariate model the association between the ‘combined’ urinary abnormality and positive family history of HT retained significance with an adjusted OR of 5.6 (2.39–13.30). Age was not significantly related to family history of HT. As expected, personal history of HT, BMI and family size were significantly related to family history of HT resulting in an OR of 8.5 (3.84–18.6) for positive personal history, 1.1 (1.01–1.12) for a unit increase in BMI, and 1.1 (1.02–1.26) for increase in the size of the family by one person.


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Table 2. The prevalence of strong positive family history of hypertension in the four kidney stone disease patient groups

 
The prevalence of treated HT in the fathers, mothers and siblings of the KSD patients from the four groups is given in Table 3Go. The prevalence of HT in the fathers or mothers of the patients was not significantly different among the four groups. The overall prevalence of treated HT among the 1441 siblings of all patients was 5%. The prevalence of HT in siblings of patients with the ‘combined’ abnormality (13%) was significantly higher than in siblings of patients with ‘pure’ hyperuricosuria (3%, P<0.001), in siblings of patients with ‘pure’ hypercalciuria (1%, P<0.001), or in siblings of KSD patients with ‘other’ abnormality (4%, P<0.001). The difference between the ‘pure’ hyperuricosuria, ‘pure’ hypercalciuria, and ‘other’ abnormality groups was not significant. The univariate OR for HT in a sibling of a KSD patient with combined elevation of both UA and Ca excretions compared to a KSD patient with ‘other’ urinary metabolic abnormality was 3.3 (1.98–5.61). Adjustment for age, BMI and personal history of HT of the index case did not change this result (OR=3.4 (1.97–5.91)).


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Table 3. The prevalence of treated hypertension among the first-degree family members of patients from the four kidney stone disease groups

 
Serum and urine biochemical values of the four groups are presented in Table 4Go. As expected, urinary UA/Cr excretion was higher in the ‘combined’ urinary abnormality and ‘pure’ hyperuricosuria groups, and urinary Ca/Cr was higher in the ‘combined’ urinary abnormalities and ‘pure’ hypercalciuria groups. Urinary Mg/Cr excretion paralleled that of Ca/Cr excretion. Besides these differences, however, patients in the ‘combined’ urinary abnormality group had significantly higher normalized urinary sodium, phosphorus, potassium and citrate excretions compared to the patients in the ‘other’ abnormality group. When these variables were included in the main multivariate logistic model as covariates, the association between the ‘combined’ urinary metabolic abnormality and family history of HT did not change, and none of these variables were significantly associated with positive family history of HT.


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Table 4. Serum and urine biochemical data in the four kidney stone disease patient groups

 



   Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
In this study we extended our previous observation that high urinary excretion of UA links KSD to familial occurrence of HT [6]. We found that only those KSD patients who have combined elevations of both UA and Ca excretions show aggregation of HT in their first-degree relatives. We found this association in our original sample of patients from 1997 [6] and confirmed the results in another sample in 2001. Our data suggest that high urinary excretion of UA with the presence of high urinary Ca output may represent a common metabolic abnormality behind the association of KSD and HT, and that this association has familial determinants. High urinary UA excretion without the presence of concomitant hypercalciuria or high urinary Ca excretion without the presence of concomitant high urinary UA levels does not seem to increase the risk of familial HT. The association between this ‘combined’ urinary abnormality and familial occurrence of HT is independent of personal hypertensive status, BMI and age of the index case.

The association between KSD and HT has been confirmed in several cross-sectional and follow-up studies [35]. Analysis of the temporal relationship between these two diseases provided conflicting results. Madore et al. [3,4] found that the development of KSD disease precedes that of HT, while Cappuccio et al. [5] provided evidence that it is HT that increases the risk of KSD. To resolve the controversy one may assume that a common metabolic abnormality links these two diseases [13] and that the sequence of manifestation depends on other, yet unknown factors. The intermediate phenotype based on this common metabolic abnormality could be used for selecting more homogeneous patient populations for genetic analysis of human essential HT. This seems to be relevant as our analysis indicated independent familial determinants in the association.

In unselected hypertensive [5] or KSD [3,4] patients the relative risk for the other disease is relatively low. This could decrease the power of a linkage study that bases patient enrollment only on the phenotype of HT and KSD. This obstacle may be overcome by further phenotypic characterization of the association. In our current study the estimate of the OR for strong family history of HT in a patient with the ‘combined’ hyperuricosuric hypercalciuric abnormality was about six, which in genetic epidemiologic terms represents a strong relationship, more suitable for linkage studies.

In our study we focused on relatively young probands [2]. Furthermore, we used definitions for HT and positive family history of HT to specifically identify those with more severe manifestations of HT. Phenotypic features that appear at an earlier age, and that are more severe manifestation of a disease are more likely to be familially determined [2]. These two methods, therefore, likely increased the chance of finding an association that is familially determined. The fact that the higher occurrence of HT in families of patients with the ‘combined’ abnormality was mainly due to the higher occurrence of HT in their siblings seems to support familial, possibly genetic factors behind the association. Genetically determined traits are more likely to manifest at a younger age (i.e. in siblings), whereas environmental and other factors may play an increasingly important role in older individuals (i.e. in parents) [2].

While our data clearly indicate an association between the metabolic abnormality characterized by high urinary excretion of UA with Ca in the proband and familial occurrence of HT, the study was not designed to explore the mechanism of the disease. There is indirect evidence to support our findings. In patients with KSD, Capisti et al. [14] found a high prevalence of HT in those with UA stones; and Bello et al. [15] in those who had hypercalciuria or hyperuricosuria or the two conditions together. In patients with essential HT, high urinary excretion of Ca has consistently been documented [7] and it could also be detected in normotensive individuals predisposed to HT [16]. These observations were explained either by abnormalities in renal tubular Ca handling, or by changes in renal sodium absorption with secondary volume expansion and hypercalciuria [13]. These studies, however, did not report on changes in UA excretion. Abnormalities in UA metabolism, particularly elevated serum levels, frequently accompany HT [17] and elevated serum levels are found in those predisposed to HT [18]. Furthermore, the activity of xanthine oxidase, the enzyme in the last step of UA production is correlated with BP in normotensive individuals [19]. More recently, Borghi et al. [10] reported high lithogenic risk in male hypertensives characterized by obesity, with significantly increased urinary excretions of UA, Ca, oxalate, and high excretions of sodium and phosphorus. These data are in strong support of our findings as our patients who had high excretion of UA with Ca also showed elevated urinary excretions of sodium and phosphorus (Table 4Go). Borghi et al. [10] explained their findings by the interaction of obesity or salt sensitivity with high nutritional intake of salt and meat protein. While increased protein intake is a known risk factor for KSD, its effect in the development of HT is less likely [20]. Sodium, however, increases urinary excretion of Ca [8] and may contribute to HT in sensitive individuals. There is also evidence that in experimental settings sodium loading increases UA production in salt sensitive rats [21].

While obesity is known to have familial determinants and to be associated with stone disease risk [22], it did not account for our findings as they were independent of the effect of BMI. Thus another metabolic, possibly familially determined, feature that interacts with nutritional factors, such as salt sensitivity, could have contributed to our findings. Salt sensitivity has clear familial determinants [23] and is also related to obesity [24]. This hypothesis, however, is not supported by the observation that inclusion of sodium excretion in the logistic model did not result in significant association with family history of HT. While our data suggest that the phenotype characterized by high urinary excretion of UA, Ca and familial HT may be useful to select patients and family members for linkage studies, clearly more studies under strict dietary conditions are needed to understand the pathophysiology behind the phenotype. Results of such studies may reveal candidate genes to be used in the genetic studies as well.

The determination of the family history status of the probands using stringent criteria was done in an unbiased fashion before the results of the urine chemistries were known. Biochemical characterization of the patients, however, was based only on the results of a single 24-h urine collection while on a self-selected diet, which represents the major limitation of our study. Urinary excretion of UA and Ca is influenced by dietary factors and may vary from day to day. Repeated urine collections and standardized diets are, therefore, suggested to obtain a more detailed metabolic profile of KSD patients [9]. Unfortunately, it was not feasible to perform such urine collections in the current epidemiological study. A similar method of urine collection has been used in a recent cohort study to obtain KSD metabolic risk profile of the participants [25]. Although we found similar results in two samples of patients (from 1997 and 2001) that confirms the reproducibility of our results, further biochemical characterization of the patients with repeated urine collections and fixed diets is needed in later studies.

Drug treatment of hypertension can significantly alter the urinary excretion of substances. Treatment of HT in the index cases, however, is unlikely to have biased our group assignment. The analyses were repeated after the exclusion of those 48 patients with treated HT and the estimate for the association remained the same although with wider confidence intervals due to the loss of statistical power. The adjusted OR for the association between family history of HT and the ‘combined’ metabolic abnormality was 6.5 (2.47–17.4).

In summary, in young KSD patients we found a strong association between family history of HT and a clinical phenotype characterized by high urinary excretions of both uric acid and Ca, independent of BMI, age, family size, and personal hypertensive status of the proband. In contrast, high urinary excretion of UA or Ca alone does not seem to increase the risk of familial HT. Our data suggest that this phenotype may represent the common underlying metabolic abnormality behind the association of KSD and HT and that this association has independent familial determinants. Ascertainment of patients based on this phenotype may identify more homogeneous populations for genetic analysis of HT.



   Acknowledgments
 
This study was supported by grants-in-aid from the Medical Research Council of Canada (MT12579), Heart and Stroke Foundation of Ontario (NA3664) and the Kidney Foundation of Canada. Dr Tisler was a renal fellow from the Ist Department of Medicine, Semmelweis University, Budapest, Hungary, and received an International Fellowship Training award from the International Society of Nephrology and personal support awards from the Hungarian Kidney Foundation and the University of Toronto, Department of Medicine. The authors thank Sandra Perlikowsky for her contribution in data collection and management.



   Notes
 
Correspondence and offprint requests to: Dr Andras Tisler, Ist Department of Medicine, Semmelweis University, 2/a Koranyi S. u., H-1083, Budapest, Hungary. Email: atisler{at}mail.matav.hu, cc: alogan{at}mtsinai.on.ca Back



   References
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 29.11.00
Accepted in revised form: 13. 9.01





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