Skip Navigation



NDT Advance Access published online on August 20, 2008
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn468
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
24/1/137    most recent
gfn468v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Losito, A.
Right arrow Articles by Ferrara, G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Losito, A.
Right arrow Articles by Ferrara, G.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© 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


Increased acid excretion in kidney stone formers with essential hypertension

Attilio Losito1, Emidio Giovanni Nunzi1, Carla Covarelli2, Elisabetta Nunzi3 and Gaetano Ferrara1

1 Struttura Complessa Nefrologia e Dialisi 2 Struttura Complessa Anatomia Patologica, Ospedale Santa Maria della Misericordia 3 Clinica Urologia ed Andrologica, Università degli studi di Perugia, Perugia, Italy

Correspondence and offprint requests to: Attilio Losito, via Dei Mille 5, San Mariano, 06070 Perugia, Italy. Tel: +39-075-5782609; Fax: +39-075-5782566; E-mail: alosito3{at}gmail.com



   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background. Although several studies have reported that kidney stone disease and hypertension are associated, the link between the two conditions has not been identified. This study investigated urinary excretion of different solutes, particularly citrate and acids, in kidney stone formers and examined their association with high blood pressure.

Methods. The retrospective study included 234 consecutive subjects, aged 47.0 ± 15.6, attending our metabolic clinic after episodes of kidney stones. Essential hypertension was present in 82 patients (35.0%). A difference in the urinary excretion of some of the investigated components was found between subjects with normal blood pressure and those with hypertension.

Results. The results showed that hypertensive subjects were older and had a higher body mass index (BMI) and serum uric acid. They had a significantly lower urinary pH (5.6 ± 0.4 versus 6.0 ± 0.5) and citrate (2.55 ± 1.36 versus 2.83 ± 1.65 mmol/24 h), higher titratable acid (38.8 ± 19.0 versus 26.8 ± 15.0 mEq/24 h) and ammonium (41.6 ± 17.6 versus 34.2 ±12.4 mmol/24 h). Logistic regression analysis with the presence of hypertension as the dependent variable produced a model with the following predictors: age (P < 0.0001), BMI (P = 0.026), titratable acid (P = 0.025) and low urinary citrate level (P = 0.033). Urinary acid excretion increased with the stage of hypertension. No difference was found in the urinary excretion of other solutes.

Conclusions. These findings suggest that essential hypertension and acid excretion are linked in stone formers.

Keywords: citraturia; hypertension; kidney stones; urinary acid



   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 References
 
Several studies have suggested that nephrolithiasis and hypertension are positively associated in humans and animals [1–3]. In humans, prior occurrence of nephrolithiasis significantly increases the risk of high blood pressure [4]; metabolic studies show that patients with primary hypertension have a greater risk of renal stone formation [5,6].

Attention has concentrated on the association, and several hypotheses have been advanced. Predisposing factors such as female sex and excess body weight seem to be common features. Dietary factors like excessive salt and animal protein intake appear to play a role [7]. A common genetic basis linking high blood pressure to kidney stone formation has also been repeatedly proposed [8,9] but not clearly demonstrated.

It has also been proposed that the link between hypertension and renal stone formation may lie in abnormal urinary concentrations of some lithogenic solutes: calcium, uric acid and oxalate [10,11]. A recent report has suggested that hypertension and low urinary citrate levels may be associated in subjects without kidney stones [12]. The link between decreased citrate urinary excretion and altered renal handling of acids is well recognized, but the association with hypertension in stone formers has not been studied [13].

The present study investigated whether hypocitraturia and increased acid excretion are associated in kidney stone-forming subjects with high blood pressure. The study was performed in an appropriately sized sample population of stone formers, who underwent a full metabolic assessment.



   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 References
 
This retrospective cohort study included data from 234 patients (136 males), who were consecutively enrolled in a metabolic study while attending our renal stone clinic.

All patients met the inclusion criteria of either three renal stone episodes in the previous 5 years or one episode per year in the last 3 years. Clinical examination and standard tests ruled out systemic diseases and secondary hypertension. Accurate anamnesis ruled out the use of medications responsible for ‘drug-induced’ kidney stones. All patients underwent a sonographic examination of the kidneys before the metabolic assessment, and the presence of any sign of obstructive nephropathy was considered an exclusion criteria.

Office blood pressure was repeatedly measured by a physician with a mercury sphygmomanometer following the recommendations of the European Society of Hypertension and classified according to the JNC 7 [14,15]. The reported values are those obtained and recorded for each patient at the time of the detection of arterial hypertension. The class and the number of antihypertensive drugs were recorded. All drug treatments were suspended 3 days before the beginning of the metabolic study. Diuretics were stopped 1 week before to allow a full washout of their effects on body volumes, blood and urine components [16]. Patients were instructed to maintain their normal lifestyle and diet. Each patient received a container for a 24-h urine collection. On Day 2 of the study, blood samples were drawn from a forearm vein, a 2-h urine collection was performed for creatinine, calcium and citrate for separate analysis of relative ratios and a sample of the 24-h urine collection was sent for chemical analysis. The 2-h urine collection was used for the metabolic assessment under ‘laboratory’ conditions and to avoid mistakes in home urine collection. The 24-h collection was used for the study of the patients under everyday conditions. Subjects were asked not to change their eating and drinking habits. No dietetic analysis was performed. The BMI was determined as an index of fatness and obesity. Dietary protein intake was assessed by normalized urinary nitrogen appearance (nUNA) [17].

The metabolic assessment was based on a full blood chemistry profile and urinary solute measurements. Blood and urine chemistry included nitrogen, creatinine, uric acid, sodium, potassium chloride, calcium, magnesium and phosphate, as measured by an automatic analyser (Shimadzu CL 300). Body weight was used for normalization of urinary solutes. Body surface area (BSA) was used for indexing creatinine clearance to 1.73 m2 and was calculated by the formula of Du Bois and Du Bois. Parathyroid hormone was measured by chemiluminescence (Immunolite 2000-Medical System).

Urinary stone risk was evaluated in urine on the basis of the following parameters: volume, pH (pH meter), titratable acids (NaOH titration), ammonium (colorimetric assay) sulphate (turbidimetric assay), oxalate (enzymatic-colorimetric assay), citrate (UV assay). Urine supersaturation (SS) with respect to calcium oxalate (CaOx), uric acid (UA) and brushite (Br) was calculated using the ‘LithoRisk’ program [18]. Normal values for SS were CaOx <5, UA <1 and Br <2 [19].

Statistics
Data are expressed as mean ± standard deviation (SD). ANOVA and the Student's t-test were used to compare the means of values between groups of subjects. The general linear method (GLM) and univariate and multivariate procedures were used for the analysis of the association between hypertension and the different variables. Differences among means of chosen variables in hypertensive and normotensive subjects were also evaluated with post hoc tests (Bonferroni). The model also estimated the marginal means of the different variables (averaged across all levels of the covariates such as age, BMI and body weight). A logistic regression (forward stepwise) was performed to select the variables predicting the presence of hypertension. Sex, age, body weight, BMI and urinary pH, titratable acid, calcium, citrate, oxalate, phosphate, sulphate and sodium were first analysed separately, and then entered in a stepwise way into the model as covariates. Age, body weight and BMI were also examined in the model for their interaction with urinary variables.

The commercial software SPSS 13.0 was used to perform the statistical analysis.



   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 References
 
Demographics and clinical characteristics of the 234 renal stone formers are shown in Table 1. In 88 patients (37.6%), chemical analysis of the stone was not available. Stone compositions were CaOx monohydrate (51), CaOx dehydrate (22), CaOx–UA (25), CaOx–calcium apatite (11), calcium apatite (7), UA (22), struvite (4), Br (3) and ammonium urate (1). One female patient with struvite stones had a positive clinical history for chronic urinary infection.


View this table:
[in this window]
[in a new window]

  		Table 1 Demographics and clinical characteristics of 234 stone formers

 
Urine SS for CaOx was found in 99 subjects, for Br in 88 and for UA in 66. Calciuria >0.1 mmol/kg/24 h was present in 45 subjects.

Systemic hypertension (JNC7 stages 2 and 3) was detected in 82 patients (35.0%), 48 of whom were males (35.2%) and 34 females (34.6%). Antihypertensive treatment was being administered to 79 patients (23 subjects took diuretics) with an average number of drugs of 1.5 ± 0.6. A pre-hypertension stage was present in 54 subjects (23%). In 98 patients blood pressure was normal.

Hypertensive and normotensive subjects were investigated for differences in clinical characteristics, demographics and urinary solute excretion. No difference was found in the length of stone history between the two groups.

Age, body weight and BMI were higher in hypertensive subjects (Table 2). Serum concentration of UA was higher in hypertensive patients (t = 4.17, P < 0.001) (Table 2).


View this table:
[in this window]
[in a new window]

  		Table 2 Comparison of hypertensive and normotensive stone formers

 
Patients with hypertension showed a lower excretion of citrate, a lower pH and higher excretion of titratable acids, ammonium and sulphate (Table 2). The difference in the urinary excretion with normotensive subjects remained statistically significant also in multivariate analysis (GLM). In the analysis, age, nUNA and BMI were first tested separately and then entered in the multivariate analysis (Table 3).


View this table:
[in this window]
[in a new window]

  		Table 3 Urinary acid excretion in normotensive and hypertensive subjects after the adjustment of the mean concentrations for age, BMI and nUNA

 
We made a comparison of the mean values of urinary pH, titratable acids, ammonium and sulphate between subjects with normal blood pressure, pre-hypertension, stage 1 and stage 2 hypertension, and we found significant differences (Figure 1). The statistical significance of the difference was assessed by the Bonferroni test for multiple comparisons. With this analysis, the difference was significant for pH (F = 2.807, P < 0.05) and titratable acids (F = 2.625, P < 0.05).


Figure 1
View larger version (21K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 1  Urinary pH and acid excretion in different stages of hypertension. Adjusted means and 95% confidence intervals of pH (upper left panel), titrable acid (upper right panel), sulphate (lower left panel) and ammonia (lower right panel) in stone formers' urine. Bars in each panel represent, from left to right, subjects without hypertension, with prehypertension, stage 1 and stage 2 hypertension.

 
The logistic regression with the presence of hypertension as a dependent variable produced a significant model (chi-square 74.709, P < 0.0001) indicating the following variables as predictors of hypertension: age (P < 0.0001, RR 1.074, 95% CI 1.047–1.101), BMI (P = 0.026, RR 1.096, 95% CI 1.043–1.218), titratable acid (P = 0.025, RR 1.028, 95% CI 1.003–1.052) and low urinary citrate concentration (P = 0.045, RR 0.730, 95% CI 0.547– 0.989).

The analysis of components in the 2-h urine collection showed that the excretion of citrate was lower in hypertensive than in normotensive patients: 0.16 ± 0.10 mmol versus 0.21 ± 0.16 mmol. No other differences in solute excretion were observed.

In the group of patients with available chemical analysis of stones (146), UA alone or in combination with other components was present in stones of 48 subjects.

The presence of UA in stones was 42% in stone formers with hypertension versus 22% in normotensive subjects (chi-square 4.317, P = 0.0377). Other components of stones did not present significant differences between groups.

Serum potassium and chloride were comparable between normotensive and hypertensive subjects.

The dietary protein intake, estimated by nUNA, is shown in Table 1. In 58 subjects (24%), the estimated daily protein intake was >1.093 (third quartile). No significant differences were found in nUNA between hypertensive and normotensive subjects. No difference was found between the different groups of antihypertensive drug and diuretics with respect to urinary concentrations of acids and solutes.



   Discussion
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
References
 
Our study confirms a high prevalence of hypertension in renal stone formers. The new finding is that in a population of stone formers, essential hypertension is associated with a lower urinary citrate and higher acid excretion. In a sample of the general population, body size and urinary pH were reported to be inversely related [20]. In our patients with high blood pressure BMI, urinary concentrations of hydrogen ions and titratable acids were higher than in normotensive subjects. The urinary excretion of these solutes also increased with the stage of hypertension.

In females with high BMI, an association between nephrolithiasis and increased blood pressure has recently been reported [21]. While we confirm the increase in BMI is associated with high blood pressure, female gender played no role in our model.

In our cohort of stone formers, urinary excretion of calcium was not different in normotensive and hypertensive findings that are at variance with the report of a link between high urinary calcium and familial hypertension in stone formers [11]. The high serum UA and the increased prevalence of UA stones in the group with hypertension, we found in this study, are in keeping with the lower urinary pH of hypertensive subjects, and the low urinary citrate in this group of patients may be the consequence of an increased metabolic production of acid [12]. The finding of hyperuricaemia in hypertension is not new [22]. Its cause has not been fully elucidated although an association with an abnormality of the metabolism of lactic acid has been suggested [20]. With regard to diet, although we have not found a difference in nUNA, indicating a different protein intake, the higher sulphate excretion might indicate a higher intake in animal proteins, that are high in sulphate, with an overall normal protein content. The lack of a proper dietetic analysis does not allow us to draw conclusions in this connection. Whereas a hypothetical increase in animal protein intake might account for an increase in urinary acid excretion, it does not explain how this corresponds to the degree of hypertension or to the low citrate excretion. Urine was collected on a normal working day, with the aim of examining the average daily intake of nutrients. Nonetheless, under test conditions, a different diet might have been adopted. This difference and even eventual mistakes in urinary collection at home cannot explain increased acid excretion in hypertensive subjects and the difference between different degrees of hypertension. Furthermore, in the 2-h urine collection, citrate, during the metabolic study, was confirmed to be lower in hypertensive patients.

The association between low citrate, high titratable acid and high BMI with hypertension may indicate two underlying mechanisms. The first links hypertension to body mass with increased acid excretion as a collateral finding. The other suggests that increased acid excretion and related low urinary citrate level are markers of subclinical acidosis or an altered acid excretion mechanism. A possible association between hypertension and altered acid–base state is supported by experimental evidence. In animal models of hypertension, metabolic acidosis and increased acid excretion were found before the development of hypertension [23]. In two strains of spontaneously hypertensive rats, plasma pH and bicarbonate concentration were lower than those in normotensive controls [24]. Furthermore, salt sensitivity seems to be associated with increased metabolic acid production in animals and humans [25,26]. Therefore, stone forming may, like salt sensitivity, predispose to hypertension.

In conclusion, despite its limitations, this cross-sectional study shows high urinary acid excretion in renal stone formers with hypertension increasing with the stage of hypertension and suggests that a metabolic imbalance may be responsible. Renal and metabolic mechanisms underlying this association deserve specially designed investigations.



   Acknowledgments
 
The authors would like to thank Dr Geraldine Anne Boyd for editing this paper for English.

Conflict of interest statement. None declared.



   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

  1. Tibblin G. High blood pressure in men aged 50. Acta Med Scand (1967) 470(Suppl):5–84.
  2. Madore F, Stampfer MJ, Rimm EB, et al. Nephrolithiasis and risk of hypertension. Am J Hypertens (1998) 1:46–53.
  3. Wexler BC, McMurtry JP. Kidney and bladder calculi in spontaneously hypertensive rats. Br J Exp Pathol (1981) 62:369–374.[Web of Science][Medline]
  4. Robertson WG, Peacock M, Baker M, et al. Studies on the prevalence and epidemiology of urinary stone disease in men in Leeds. Br J Urol (1983) 55:595–598.[Web of Science][Medline]
  5. Cirillo M, Laurenzi M. Elevated blood pressure and positive history of kidney stones: results from a population-based study. J Hypertens (1988) 6(Suppl_4):S485–486.[Web of Science]
  6. Borghi L, Meschi T, Guerra A, et al. Essential arterial hypertension and stone disease. Kidney Int (1999) 55:2397–2406.[CrossRef][Web of Science][Medline]
  7. Hess B, Ackermann D, Essig M, et al. Renal mass and serum calcitriol in male idiopathic calcium renal stone formers: role of protein intake. J Clin Endocrinol Metab (1995) 80:1916–1921.[Abstract]
  8. Mente A, Honey RJ, McLaughlin JM, et al. High urinary calcium excretion and genetic susceptibility to hypertension and kidney stone disease. J Am Soc Nephrol (2006) 17:2567–2575.[Abstract/Free Full Text]
  9. Tisler A, Pierratos A, Honey JD, et al. High urinary excretion of uric acid combined with high excretion of calcium links kidney stone disease to familial hypertension. Nephrol Dial Transplant (2002) 17:253–259.[Abstract/Free Full Text]
  10. Cappuccio FP, Strazzullo P, Mancini M. Kidney stones and hypertension: population based study of an independent clinical association. BMJ (1990) 300:1234–1236.[Abstract/Free Full Text]
  11. McCarron DA, Pingree PA, Rubin RJ, et al. Enhanced parathyroid function in essential hypertension: a homeostatic response to a urinary calcium leak. Hypertension (1980) 2:162–168.[Abstract/Free Full Text]
  12. Taylor EN, Mount DB, Forman JP, et al. Association of prevalent hypertension with 24-hour urinary excretion of calcium, citrate, and other factors. Am J Kidney Dis (2006) 47:780–789.[CrossRef][Web of Science][Medline]
  13. Sakhaee K, Williams RH, Oh MS. Alkali absorption and citrate excretion in calcium nephrolithiasis. J Bone Miner Res (1993) 8:789–794.[Web of Science][Medline]
  14. O’Brien E, Asmar R, Beilin L, et al, on behalf of the European Society of Hypertension Working Group on Blood Pressure Monitoring. European Society of Hypertension recommendations for conventional, ambulatory and home blood pressure measurement. J Hypertens (2003) 21:821–848.[CrossRef][Web of Science][Medline]
  15. Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure. JAMA (2003) 289:2560–2572.[Abstract/Free Full Text]
  16. Reyes AJ. Effects of diuretics on outputs and flows of urines and urinary solutes in healthy subjects. Drugs (1991) 41(Suppl 3):35–59.[Medline]
  17. Maroni BJ, Steinman TI, Mitch WE. A method for estimating nitrogen intake of patients with chronic renal failure. Kidney Int (1985) 27:58–65.[Web of Science][Medline]
  18. Marangella M, Petrarulo M, Daniele PG, et al. LithoRisk: a software for the calculation and visualization of risk profiles of nephrolithiasis. G Ital Nephrol (2002) 19:693–698.
  19. Monk RD, Bushinsky DA. Nephrolithiasis and nephrocalcinosis. In: Comprehensive Clinical Nephrology—Feehally J, Floege J, Johnson RJ, eds. (2007) Philadelphia: Mosby/Elsevier. 641–659.
  20. Taylor EN, Curhan GC. Body size and 24-hour urine composition. Am J Kidney Dis (2006) 48:905–915.[CrossRef][Web of Science][Medline]
  21. Gillen DL, Coe FL, Worcester EM. Nephrolithiasis and increased blood pressure among females with high body mass index. Am J Kidney Dis (2005) 46:263–269.[CrossRef][Web of Science][Medline]
  22. Cannon PJ, Stason WB, Demartini FE, et al. Hyperuricemia in primary and renal hypertension. N Engl J Med (1966) 275:457–64.[Web of Science][Medline]
  23. Lucas PA, Lacour B, McCarron DA, et al. Disturbance of acid-base balance in the young spontaneously hypertensive rat. Clin Sci (Lond) (1987) 73:211–215.[Medline]
  24. Lucas PA, Lacour B, Comte L, et al. Abnormal parameters of acid-base balance in genetic hypertension. Kidney Int (1988) 25(Suppl):S19–S22.
  25. Batlle DC, Sharma AM, Alsheikha MW, et al. Renal acid excretion and intracellular pH in salt-sensitive genetic hypertension. J Clin Invest (1993) 91:2178–2184.[Web of Science][Medline]
  26. Sharma AM, Kribben A, Schattenfroh S, et al. Salt sensitivity in humans is associated with abnormal acid-base regulation. Hypertension (1990) 16:407–413.[Abstract/Free Full Text]
Received for publication: 12. 5.08
Accepted in revised form: 24. 7.08


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Nephrol Dial TransplantHome page
B. Afsar, M. Yilmaz, and T. Eyileten
Do patients with uric acid stones exhibit abnormal circadian blood pressure--a hypothesis
Nephrol. Dial. Transplant., June 1, 2009; 24(6): 2004 - 2004.
[Full Text] [PDF]

Home page
 Nephrol Dial TransplantHome page
A. Losito
Reply
Nephrol. Dial. Transplant., June 1, 2009; 24(6): 2004 - 2005.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
24/1/137    most recent
gfn468v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Losito, A.
Right arrow Articles by Ferrara, G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Losito, A.
Right arrow Articles by Ferrara, G.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?