Nephrology

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Aug 16, 2007 - Ramazan Yigitoglu e Adrian Covic f. Departments of aInternal Medicine, Section of Nephrology, bFamily Medicine, cInternal Medicine, Section ...
Original Report: Patient-Oriented, Translational Research American

Journal of

Nephrology

Am J Nephrol 2007;27:516–521 DOI: 10.1159/000107489

Received: June 14, 2007 Accepted: July 16, 2007 Published online: August 16, 2007

Relation between Serum Calcium, Phosphate, Parathyroid Hormone and ‘Nondipper’ Circadian Blood Pressure Variability Profile in Patients with Normal Renal Function Mehmet Kanbay a Bunyamin Isik b Ali Akcay a Adem Ozkara b Feridun Karakurt c Faruk Turgut a Rabia Alkan d Ebru Uz a Nuket Bavbek a Ramazan Yigitoglu e Adrian Covic f Departments of a Internal Medicine, Section of Nephrology, b Family Medicine, c Internal Medicine, Section of Endocrinology, d Internal Medicine, and e Biochemistry, Fatih University Faculty of Medicine, and f Department of Nephrology Clinic and Dialysis and Transplantation Center, C.I. Parhon University Hospital, Ankara, Turkey

Abstract Background and Aims: In patients with renal disease, an association between abnormal circadian blood pressure profile and abnormalities in bone and mineral metabolism, including vascular calcifications, is well known. However, such a link has not yet been reported in hypertensive patients with normal renal function. We aimed to evaluate if higher serum phosphate, calcium, parathyroid hormone (PTH) level and the calcium!phosphate (Ca!P) product would be associated with a nondipper hypertension, in patients with normal renal function and without any PTH disorder. Methods: 190 hypertensive subjects with the following inclusion criteria were enrolled: (1) normal phosphate and PTH levels; (2) glomerular filtration rate (GFR) 160 ml/min, and (3) no history of calcium, phosphate, vitamin D medication and hyperparathyroidism. Results: Of the total population, 76 patients (40%) were classified as dippers and 114 (60%) as nondippers. Nondipper patients had higher levels of phos-

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phate (3.70 8 0.61 vs. 3.35 8 0.44 mg/dl, p = 0.001), Ca!P product (35.4 8 6.5 vs. 31.5 8 5.0, p = 0.001) and PTH (75.7 8 28.8 vs. 46.6 8 17.1 pg/ml, p = 0.000) compared to dipper patients. Independent predictors (multiple regression) for nondipper hypertension were PTH (␤ = 0.43, p = 0.001) and phosphate (␤ = 0.9, p = 0.03). Conclusion: We demonstrate a graded independent relation between higher levels of phosphate, PTH, Ca!P product and the risk of nondipping in hypertensive patients with an estimated GFR of 160 ml/ min and normal mineral metabolism. Copyright © 2007 S. Karger AG, Basel

Introduction

Ambulatory blood pressure (BP) monitoring (ABPM) is an accepted and increasingly used method for evaluating hypertension and the efficacy of prescribed antihypertensive treatment, including valuable information about the short-term and circadian variation of BP. For the same level of office BP, an individual with an abnormal nocturnal decline in BP (‘nondipper’) has a greater general and cardiovascular risk [1, 2]. A nondipping proMehmet Kanbay, MD 35. Sokak, 81/5, Bahcelievler TR–06490 Ankara (Turkey) Tel. +90 312 222 03 98, Fax +90 312 441 54 98 E-Mail [email protected]

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Key Words Calcium ⴢ Phosphate ⴢ Parathyroid hormone ⴢ Calcium ! phosphate product ⴢ Dipping-nondipping blood pressure

Patients and Methods All consecutive outpatients referred to the Department of Hypertension and Nephrology at Fatih University School of Medicine between April 2006 and September 2006 were included: 190 subjects (60% women and 40% men) were screened and those who met the following inclusion criteria were enrolled: (1) normal phosphate and PTH levels; (2) glomerular filtration rate (GFR) 1 60 ml/min (MDRD4 formulae, see below); (3) no history of calcium, phosphate and vitamin D medication, and (4) no history of corticosteroid or hormone replacement therapy. Patients with secondary hypertension, renal, thyroid or liver (cirrhosis, elevated liver enzymes) dysfunction, hyperparathyroidism or using vitamin D and/or calcium supplements were not included in the study. Hypertension was defined as a systolic BP of 6140 mm Hg, diastolic BP 690 mm Hg, or the use of antihypertensive medications.

Relation between Serum Ca, P, PTH and ‘Nondipper’ Circadian Variability

Ambulatory BP Monitoring All subjects underwent 24-hour ABPM on a usual working day. They were instructed to act and work normally. ABPM was performed using a Reynolds Medical Tracker NIBP2 oscillometric monitor. Each patient used an arm cuff of similar size to the one used for routine office BP measurement in the non-dominant arm. The device was programmed to measure BP every 15 min between 06: 00 a.m. and 11: 00 p.m., and every 30 min between 11:00 p.m. and 06:00 a.m. All subjects were instructed to rest or sleep between 10:00 p.m. and 6:00 a.m. Patients were defined as ‘dippers’ if the systolic BP during the nocturnal time fell by 10% of the diurnal BP or more. Likewise, a patient whose nocturnal systolic BP fell by !10% or even rose was defined as ‘nondipper’. Shift workers and patients who do not rest or sleep at night were not included in the study. The study was conducted according to the Helsinki Declaration and approved by the ethics committee of Fatih University School of Medicine. Clinical Information and Laboratory Data Clinical information including height, weight, medical history, current medications, laboratory data, and smoking history was recorded. Body weight was measured with the subjects in light clothing without shoes. The body mass index was calculated as weight (kg) divided by the square of the height (m2). The serum parameters analyzed were creatinine, albumin, hemoglobin, total calcium, phosphate, intact PTH, uric acid, C-reactive protein, urine protein and creatinine (to calculate the spot morning urine protein creatinine ratio). Intact PTH (normal range 10–69 pg/ml) was determined by chemiluminescence (Immulyte 2000; DPC, Los Angeles, Calif., USA). The total serum calcium level was corrected by the serum albumin concentration, and calcium!phosphate (Ca!P) product was calculated. The GFR was calculated using the Modification of Diet in Renal Disease 4-variable equation [11]. We also calculated GFR using the Cockcroft-Gault equation (reference). Statistical Analysis Data are expressed as mean values 8 SD. Since PTH values were not normally distributed we used the natural logarithm as a method to normalize the data. Continuous variables were compared using the t test. The ANOVA test was used for multiple group comparisons of normally distributed variables and MannWhitney U test was used for non-normally distributed values. ␹2 was used to test differences in frequency distributions. All potential (physiologically meaningful) determinants for the night/day BP ratio were investigated in a univariate screening procedure. Correlations between normally distributed variables were tested using the Pearson correlation coefficient and the Spearman correlation coefficient for the non-normally distributed variables. Significant determinants identified from these analyses were studied in a stepwise multiple regression model using the F statistic. All variables associated with the night/day BP ratio with a level of significance of !0.1 were included in the tested model. Variables were forced in the model using a stepwise procedure. A p ! 0.05 for the final model was considered as statistically significant. All data were analyzed using the SPSS software package (version 12.0; SPSS, Chicago, Ill., USA). Two-sided p values of !0.05 were considered to be statistically significant.

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file is associated with a greater risk for target organ damage; several studies have demonstrated that left ventricular hypertrophy, coronary artery disease, cerebrovascular disease, renal disease and progression of renal disease, obstructive sleep apnea and insulin resistance are more prevalent and more important in nondippers than in dippers [1–7]. Currently, the pathogenesis of nondipper hypertension remains largely unclear in patients without any renal or endocrine subjacent pathology. Clearly, multiple mechanisms may be involved. An attractive working hypothesis would be to link abnormalities in the autonomic nervous system with structural and functional changes in the arterial vessel wall caused by atherosclerosis and/or arteriosclerosis. In patients with renal disease (a ‘model’ of extreme vascular changes), an association between an abnormal circadian BP profile and abnormalities in bone and mineral metabolism, including vascular calcifications, has been reported [8]. At the other end of the spectrum, in primary hyperparathyroidism patients with normal renal function, Letizia et al. [9] also showed an increased rate of nondipper hypertension, in comparison with essential hypertension. However, such a link has not yet been reported in hypertensive patients with normal renal function, but might be of particular interest in view of the graded independent relation between higher levels of serum phosphate and the risk of death/cardiovascular events, recently described by Tonelli et al. [10]. The aim of the present investigation is to evaluate if higher serum phosphate, calcium, parathyroid hormone (PTH) levels (both in the normal range) and the calcium!phosphate (Ca!P) product would be associated with a nondipper hypertension profile, in patients with normal renal function and without any PTH disorder.

Table 1. Demographic and laboratory parameters of dipper and nondipper patients

Dippers (n = 76) Males/females Age Body mass index, kg/m2 Diabetes mellitus Hypertension Smoking Statin Angiotensin converting enzyme inhibitor Angiotensin receptor II blocker Calcium channel blocker Diuretic agent C-reactive protein, mg/l GFR, ml/min Proteinuria, mg/day Uric acid, mg/dl Total cholesterol, mg/dl LDL-cholesterol, mg/dl HDL-cholesterol Triglycerides, mg/dl Hemoglobin level

49/27 51.4813.4 27.781.26 7 (9.2%) 47 (61.8%) 26 (34.2%) 31 (40.7%) 12 (15.8%) 16 (21%) 8 (10.5%) 23 (30.2%) 2.7181.4 71.6810.2 192884 5.381.5 194.2838.4 121.3824.2 39.288.5 132.6854.2 13.481.4

Nondippers (n = 114) 68/46 53.4812.8 28.181.31 10 (8.8%) 87 (76.3%) 42 (36.8%) 48 (42.1%) 17 (14.9%) 23 (20.2%) 13 (11.4%) 32 (28.0%) 2.5581.3 69.5810.9 198872 5.681.3 196.7826.7 123.1831.4 41.7812.9 143.5848.6 13.681.4

p value 0.4 0.1 0.3 0.01 0.3 0.5 0.6 0.7 0.2 0.1 0.2 0.6 0.8 0.1 0.4 0.3 0.2 0.09 0.7

Table 2. 24-hour ambulatory blood pressure monitoring of dipper and nondipper patients

Results

One hundred and seven (56.3%) patients were taking one or more antihypertensive medications. Of the total population, 76 patients (40%) were classified as dippers and 114 (60%) were classified as nondippers. The clinical characteristics and laboratory values of dipper and nondipper patients are shown in table 1. Nondipper patients had greater use of antihypertensive medications, including thiazide diuretics. The dose of thiazide diuretics was 12.5 mg/day in 78.2% (18 patients) and 25 mg/day 21.8% in dippers. In nondippers the dose of thiazide diuretics was 12.5 mg/day in 81% (26 patients) and 25 mg/day in 19% (6 patients). In addition, serum calcium levels were 518

Am J Nephrol 2007;27:516–521

Nondippers

p value

120.8811.0 74.187.6 124.8811.8 108.389.9 77.187.9 64.687.5

124.9812.5 73.488.9 125.6812.6 122.9819.6 74.289.0 71.089.1

0.02 0.67 0.67 0.00 0.03 0.01

similar between patients either using or not using thiazide in both dipper and nondipper patients (p = NS). The results of 24-hour ABPM measurements are shown in table 2. The only significant differences between dipper and nondipper patients appear to be related to phosphate, Ca!P and PTH levels (table 3). No other statistical significant difference was found regarding demographic, clinical and biochemical characteristics (p 1 0.05). Nondipper patients had higher levels of phosphate (3.6 8 0.5 vs. 3.3 8 0.4 mg/dl, p = 0.001), Ca!P product (35.5 8 6.2 vs. 31.5 8 4.8, p = 0.001) and PTH (72.2 8 28.1 vs. 49.0 8 19.4 pg/ml, p = 0.0001) compared to dipper patients. We further looked at the most abnormal patients – those with higher BP during night than during day (night/ Kanbay et al.

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24-hour systolic blood pressure, mm Hg 24-hour diastolic blood pressure, mm Hg Daytime systolic blood pressure, mm Hg Nighttime systolic blood pressure, mm Hg Daytime diastolic blood pressure, mm Hg Nighttime diastolic blood pressure, mm Hg

Dippers

Phosphate (mg/dl)

Parathyroid hormone (pg/ml)

a

90 80 70 60 50 40 30 20 10 0 Dippers

Nondippers

b

Risers

3.9 3.8 3.7 3.6 3.5 3.4 3.3 3.2 3.1 3.0 Dippers

Nondippers

Risers

Fig. 1. a Serum parathyroid hormone levels for dippers, nondippers with a night/day systolic blood pressure of 0.9–1, and risers with a night/day systolic blood pressure of 11, (p = 0.0001). b Serum phosphate levels for dippers, nondippers with a night/day systolic blood pressure of 1–0.9, and risers with a night/day systolic blood pressure of 11 (p = 0.002).

Dippers

Nondippers p value

Calcium, mg/dl 9.380.5 9.580.5 Phosphate, mg/dl 3.380.4 3.680.5 31.584.8 35.186.2 Ca!P product, mg2/dl2 Parathyroid hormone, pg/ml 49.0819.4 72.2828.1

0.2 0.001 0.001 0.0001

day BP ratio 11, so-called ‘risers’, recognized to be at a particular risk of cardiovascular events [4]). Patients with high BP during the night had the highest levels of phosphate (3.75 8 0.5 mg/dl) and PTH (76.8 8 33.6 pg/ml); a significant gradient was observed between dippers, nondippers with a night/day BP ratio of 0.9–1 and nondippers with night/day BP ratio of 11 (p ! 0.05 for trend; fig. 1; for PTH, p = 0.0001; for phosphate, p = 0.002). Finally we divided our population into 3 groups according to the PTH level (!60, 60–69, and 170 pg/ml) to evaluate how a subgroup of patients with high PTH values influence the findings. While there was a significant difference in the percentage of patients with dipper and nondipper status between the group of patients with PTH !60 and 170 pg/ml (35 vs. 72%, p ! 0.001), a similar proportion of patients with high-normal PTH levels (60–69 pg/ml) were classified as nondippers (76%; p = 0.27 vs. group with PTH 170 pg/ml). All potential (physiologically meaningful) determinants for the night/day BP ratio were investigated in a Relation between Serum Ca, P, PTH and ‘Nondipper’ Circadian Variability

univariate screening procedure (see ‘Patients and Methods’). Subsequently, all parameters related to the night/ day BP ratios, with a significance level of !0.1, were introduced in a stepwise multiple regression analysis including phosphate, PTH, and the Ca!P product. The final regression model included serum phosphate levels and PTH, and the only independent predictors of nondipper hypertension were PTH (␤ = 0.43, p = 0.001) and phosphate (␤ = 0.9, p = 0.03). A negative correlation between GFR, phosphate (r = –0.273, p = 0.013) and PTH (r = –0.186, p = 0.04) was observed in this population. Low GFR may also be a risk factor for nondipping hypertension. Therefore, to better investigate any impact of abnormalities in the renal function, we also divided patients into 2 groups according to GFR: group 1 with an estimated GFR of 190 ml/min (44 patients), and group 2 with and estimated GFR of 60–90 ml/min (146 patients). The prevalence of nondipping hypertension in groups 1 and 2 was 53 and 63.2%, respectively (p = NS). Similar findings were seen when GFR was estimated according to the Cockroft-Gault equation (p = NS).

Discussion

In this study, we examined the possible associations between calcium, phosphate, Ca!P product, PTH and nondipper hypertension. Our analysis showed that there is an independent association between baseline serum phosphate, PTH level, Ca!P product and nondipper hypertension. To the best of our knowledge, these are the Am J Nephrol 2007;27:516–521

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Table 3. Serum levels of calcium, phosphate, parathyroid hormone and calcium!phosphate (Ca!P) product in dipper and nondipper patients

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independent of renal function and other confounding factors. One possible mechanism for such an epidemiological observation is the direct causative role of high phosphate levels in the etiopathogenesis of secondary hyperparathyroidism; of note high PTH levels are also associated with an increased risk of mortality [16, 18, 22]. In previous studies, it has been suggested that PTH might be a direct ‘cardiovascular toxin’, for example left ventricular hypertrophy is more common in patients with high PTH levels on dialysis [22, 23]. Most importantly, Saleh et al. [24] found that PTH is an independent predictor of left ventricular hypertrophy in patients without renal disease. At the same time, 1,25-dihydroxyvitamin D levels are inversely correlated with the extent of coronary artery calcification in patients without renal disease [25]. In our study, in view of the good kidney function of the patients, it is interesting that nondippers with high PTH values had slightly higher phosphate levels than dippers. We do not know the reason for this. One limitation of a cross-sectional study is that it is difficult to determine the temporality of exposures and outcomes. Thus, it is unclear if high phosphorus and high PTH result in nondipping status, or whether nondipping status reflects early subtle differences in renal function that then result in phosphorus retention and stimulation of PTH release. Additional possible mechanisms for nondipping in patients with higher serum phosphate and PTH might be related to activation of the renin-angiotensin-aldosterone axis, and of the endothelin and adrenomedullin systems [16, 25, 26]. Gennari et al. [25] found a direct effect of PTH on renin secretion which could contribute to the pathogenesis of hypertension and to vessel sensitization to various pressor agents. Xiang et al. [27] suggested that the cardiac hypertrophy seen in VDR knockout mice is a consequence of activation of both the systemic and cardiac renin-angiotensin system, supporting the notion that 1,25-dihydroxyvitamin D regulates cardiac functions, at least in part, through the renin-angiotensin system. Furthermore, the studies of Li et al. [28] reveal a critical role of the vitamin D endocrine system in the regulation of BP and volume homeostasis, and suggest that low calcemic vitamin D analogs may potentially be developed into a new class of antihypertensive agents to control renin production and BP. All these studies showed that PTH, phosphate, calcium and vitamin D play a direct role in the regulation of BP. Our study has several limitations. First it is cross-sectional, and thus does not take into account longitudinal variations in dipping status and in the main biochemical levels. Second, we did not measure serum vitamin D, ionKanbay et al.

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first data in the literature to revealed such a relationship between BP circadian profile and bone and mineral metabolism in patients with normal renal function (estimated GFR 160 ml/min). Previous studies have shown an important adverse prognostic significance of a blunted nocturnal BP decrease in patients with hypertension. Cardiovascular disease (left ventricular hypertrophy, coronary artery disease), cerebrovascular disease, microalbuminuria, and renal damage were found to be more prevalent/more important in nondipper hypertensive subjects compared to normal individuals [2–8]. Moreover, Davidson et al. [12] showed that nondipping is associated with a subsequent decline in renal function independent of the baseline renal functions and other risk factors for renal impairment. In ESRD a nondipping pattern is associated with 1-year progression in LVH/LV dilatation [13]. Besides causing renal disease, nondipping is an independent predictor of a new cardiovascular disease and cerebrovascular disease development [4, 10]. The etiopathogenesis of abnormal BP variation patterns in hypertensive patients is not fully and precisely understood, with some authors reporting no significant differences in the diurnal changes of various hormonal profiles, including renin, aldosterone, and cortisol, between dippers and nondippers [14]. Nevertheless, one important generally accepted mechanism is related to the imbalance between the sympathetic (SNS) and parasympathetic (PNS) tone, in particular, the failure to shift from SNS to PNS during sleep. Kohara et al. [15] reported significantly higher plasma catecholamine levels in nondippers compared to dippers. Moreover, it was shown that while dippers have a low sympathetic nervous activity during the nighttime, nondippers have a relatively low sympathetic nervous tone during the daytime and abnormal parasympathetic nervous activity during the night [16]. Structural and functional abnormalities of the large arteries in hypertensive patients are also well recognized [17] and these might influence diurnal BP variation. Certainly the calcifications and mural thickening seen in the large arteries from patients with atherosclerosis will ‘splint’ arterial baroreceptors and play a role in generating the dysautonomia-related abnormal circadian BP rhythm. Hyperphosphatemia has been independently linked with calcification of the coronary arteries and aorta, as well as with cardiovascular and all-cause mortality in the setting of chronic kidney disease [16, 18–20]. Kestenbaum et al. [21] described an association between elevated phosphate levels and the risk of cardiac mortality and myocardial infarction among chronic kidney disease patients,

ized calcium, urine calcium levels, which might also play a role in dipping status. Third, to complete our hypothesis, detailed autonomic function studies and vascular studies (vascular calcification scores, measures of stiffness and intima-media thickness) would have been necessary, but our aim was not to define the true nature of the relationship we first describe in this population of hypertensive patients with normal renal function.

In conclusion, even if the mechanisms of our findings remain incompletely understood, we demonstrate a graded independent relationship between higher levels of phosphate, PTH, Ca!P product and the risk of nondipping in individuals with an estimated GFR of 160 ml/ min. This relationship needs to be confirmed by further prospective studies and to be defined by studies elucidating the pathogenetic mechanisms.

References

Relation between Serum Ca, P, PTH and ‘Nondipper’ Circadian Variability

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