http://informahealthcare.com/rnf ISSN: 0886-022X (print), 1525-6049 (electronic) Ren Fail, 2014; 36(3): 345–350 ! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/0886022X.2013.866008
CLINICAL STUDY
Salt sensitivity of blood pressure in non-dialysis patients with chronic kidney disease Lin Meng, Bin Fu,Tongyan Zhang, Zunmin Han, and Meijuan Yang Department of Nephrology, Second Affiliated Hospital to Tianjin University of Traditional Chinese Medicine, Tianjin, China Abstract
Keywords
Background: Chronic kidney disease (CKD) is a world-wide public health problem. Hypertension is both a cause and a complication of CKD, and a risk factor for progression of kidney disease. The effect of salt intake on blood pressure (BP) and the salt sensitivity in non-dialysis patients with CKD were studied. Methods: One hundred and thirty non-dialysis patients with CKD were enrolled in the present study. Daily urinary excretion of sodium (representative of daily sodium intake) and BP was monitored in conditions of original eating habits. Estimated glomerular filtration rate (eGFR) was measured by the creatinine clearance (Ccr). Results: There was a linear positive relationship between the salt intake and systolic blood pressure (SBP) (b ¼ 0.250, p ¼ 0.004). It had been found that the log of BP/24-h urinary sodium (salt sensitivity index) had linear relationship with the log of eGFR (bsyst ¼ 0.364, p ¼ 0.000, bdiast ¼ 0.345, p ¼ 0.000, respectively). Multi-stepwise regression analysis showed SBP was mainly influenced by salt intake and eGFR. There was a negative correlation between diastolic blood pressure (DBP) and age. Conclusion: These results demonstrated a linear relationship between the salt intake and SBP in non-dialysis patients with CKD. The salt sensitivity of BP rose with the decline of renal function.
Blood pressure, chronic kidney disease, salt intake, salt sensitivity
It is well known that chronic kidney disease (CKD) is a worldwide public health problem, with increasing incidence and prevalence, high cost, and poor outcomes. Hypertension is both a cause and a complication of CKD. In addition, hypertension is a risk factor for progression of kidney disease.1 Recent studies provided evidence that over salted diet is an important factor in the genesis and development of hypertension. Based on the results of the DASH and DASHSodium Trials,2 the NKF-K/DOQI Work Group recommended that most individuals with CKD and hypertension should reduce sodium intake to less than 100 mmol/d (2.4 g/ d).1 However, this conclusion has a snag because the study population of the DASH and DASH-Sodium Trials were nonrenal insufficiency. We attempt to provide experimental evidence to support our view that the worse renal function is, the more restriction of sodium dietary is needed. The aim of the present study, therefore, is to test the hypothesis that there lies a linear relationship between the salt intake and systolic blood pressure (SBP) in patients with CKD and that the salt sensitivity of BP rises with the decline of renal function. In patients with CKD, the number of intact nephron falls off as GFR turns down, decreases the ability of kidneys to excrete sodium and the salt sensitivity of BP will
Address correspondence to Bin Fu, Second Affiliated Hospital to Tianjin University of Traditional Chinese Medicine, Tianjin 300150, China. Tel: þ86 22 60335393; E-mail: [email protected]
Received 13 August 2013 Revised 24 October 2013 Accepted 10 November 2013 Published online 17 December 2013
rise with the decline of renal function. It is hoped that the hypothesis will be tested with our proposed method. We examined the average daily BP and recorded sodium intake in 130 non-dialysis-dependent CKD patients with different estimated GFR (eGFR) and observed the trait of salt sensitivity of BP. Our study population included different stages of non-dialysis-dependent CKD patients; in addition, we verified the conclusion by multi-angle analysis.
Methods Patients
20 14
Introduction
History
One hundred and thirty Chinese adult patients hospitalized in the Second Affiliated Hospital to Tianjin University of Traditional Chinese Medicine (from August 2011 to April 2012) were enrolled in this study. Every patient has been confirmed as non-dialysis-dependent CKD of any stage 1 to 5 according to the K/DOQI guidelines.1 The exclusion criteria were (1) instability in vital indications, or (2) presence of volume depletion of body fluid, such as massive upper gastrointestinal bleeding or septic shock, etc. or (3) secondary hypertension except for renal parenchymal hypertension or (4) failure to provide relative information and refusal of medical examination the study needed. The patients were informed of the purposes and methods of the study before consent was obtained and the study was approved by the Human Ethics Committees of the Second Hospital Affiliated to Tianjin University of Traditional Chinese Medicine (Tianjin, China).
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Observation indexes All eligible subjects kept the original eating habits and were given written instructions on how to collect the 24-h urine. Some subjects were excluded for the above-cited exclusion criteria. A urine aliquot (100 ml) from the 24-h urine collection was assayed. Urine sodium, potassium, albumin, and creatinine were determined by standard analytical methods. The 24-h excretion of sodium was representative of dietary sodium intake. A blood sample was drawn; plasma concentrations of creatinine were determined by enzymatic methods. Then the creatinine clearance (Ccr) as a reliable measure of eGFR was calculated according to urinary creatinine (Ucr) and serum creatinine (Scr): Ccr ¼ [Ucr V]/[Scr 24 60] (mL/min). Meanwhile, BP was measured at 6:00, 10:00 and 14:00 respectively, mean BP was calculated to represent as BP of the day. The height and weight were recorded in the same day, thus body surface area (BSA) could be obtained by the equation of BSA [cm2] ¼ 71.84 height [cm]0.725 weight [kg]0.425 (Du Bois formula),3 eGFR was corrected by BSA: Corrected eGFR [mL/min] ¼ Ccr 1.73 /BSA. Body mass index (BMI) was calculated using the following formula: BMI [kg/m2] ¼ (body weight [kg])/(height[m])2. BP/dietary sodium intake was regarded as salt sensitivity index. Defined Daily Dose (DDD) recommended by World Health Organization (WHO) was used as a parameter to record the dose of antihypertensive drugs.4 Besides WHO, DDD stemmed from the Clinical Guide to Chinese Pharmacopoeia 2005 edition,5 16th Edition of New pharmacology6 and instructions of medicines (Appendix 1). Statistics Adopted Microsoft Excel software to establish database, and analyzed the data with SPSS 17.0 software (SPSS Inc., Chicago, IL). After the Kolmogorov–Smiromov (K–S) normality test, the data according with normal distribution are given as mean SD. Non-normal distributions are presented as the median and P25,P75. Linear regression analysis (R2coefficient of determination) was used to evaluate the relationship between dietary sodium intake and BP. Using the same method, we try to discover the relationship of BP and dietary sodium intake with the change of eGFR. The correlations between BP and body mass index, age, dietary sodium intake, the 24-h excretion of potassium, eGFR, semiquantitative of antihypertensive drugs (DDD)were analyzed through multiple linear regression. p50.05 was considered statistically significant.
Results Study population One hundred and thirty Chinese adult subjects (80 male, 50 female) were enrolled in the study. The general characteristics of subjects during basal conditions are given in Table 1. As can be observed, chronic glomerulonephritis (CGN) and diabetic nephropathy (DN) were the principle causes of CKD, the above two accounted for 80% of the study subjects. CKD patients are generally accompanied by hypertension, in this study hypertensive patients were accounting for 77.69%. The subjects were divided into five groups according to CKD stages defined by the National Kidney Foundation Kidney
Ren Fail, 2014; 36(3): 345–350
Table 1. General characteristics of the study population during basal conditions. Subjects characteristic Gender Men, n (%) Women, n (%) Age, years Protopathy Glomerulonephritis Diabetic nephropathy ANCA-related vasculitis Multicystic kidney disease Others eGFR, mL/min/1.73 m2 SBP, mm Hg DBP, mm Hg
80 (61.5%) 50 (38.5%) 61.96 13.27 42% 38% 4% 2% 14% 21.08 (median) 138.55 19.22 80.67 10.87
Disease Outcomes Quality Initiative,7 those belonging to stage 1 were 10 subjects, 16 subjects in stage 2, 22 subjects in stage 3, 32 subjects in stage 4, and 50 subjects in stage 5, accounting for 8%, 12%, 17%, 25% and 38%, respectively. There were 94 subjects who use antihypertensive drugs, accounting for 72.3%, the media of DDD was 2, P25 was 1, P75 was 3. Mean urinary sodium excretion was 174.69 93.69 mmol/24 h. Those who met dietary allowance recommended by K/DOQI guidelines for salt dose56 g accounted for only 23.08% of all subjects. The effect of salt intake on BP in patients with CKD In this study, linear regression analysis was used to evaluate the relationship between salt intake (24-h urinary sodium) and BP in the subjects. There was a linear positive relationship between the salt intake and the SBP: Y ¼ 0.051X þ 129.591, p50.05, with statistical significance (Figure 1). As you can see from this picture, SBP was found to increase after increased salt intake. The non-standardized coefficient about 24-h urinary sodium (24hUNa) and diastolic blood pressure (DBP) is B ¼ 0.014, p ¼ 0.184, without statistical significance. The relationship between 24 hUNa and BP was compared among the groups (Table 2). It can be concluded that there was no correlation between the salt intake and the SBP in stage 1–2, but there was a linear regression relationship in stage 3, 4 and 5. This kind of relationship was stronger in stage 5 than in stage 3 and 4. The influence of renal function on the relationship between salt intake and BP It was found that the log of BP/24 hUNa (salt sensitivity index) as the function(y) had linear relationship with the log of eGFR as the parameter(x). The regression equitation is Y ¼ 0.199X þ 0.526, p50.05 (SBP; Figure 2), Y ¼ 0.195X, p50.05 (DBP; Figure 3). Multivariate stepwise regression analysis of BP Multivariate stepwise regression analysis was performed including the following as variables: age, Body Mass Index, 24hUNa, 24-h urinary proteinuria (U-Pro), the 24-h excretion of potassium, the log of DDD and the log of eGFR. It demonstrated that the salt intake and the log of eGFR were
Salt sensitivity in CKD patients
DOI: 10.3109/0886022X.2013.866008
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Figure 1. The relationship between salt intake and SBP. Table 2. The relationship of salt intake and blood pressure in different groups. SBP and the salt intake Installments Stage Stage Stage Stage Stage
1 2 3 4 5
DBP and the salt intake
Unstandardized coefficients (B)
Adjusted R square
p
Unstandardized coefficients (B)
Adjusted R square
p
0.033 0.029 0.113 0.094 0.88
0.067 0.024 0.165 0.22 0.101
0.235 0.434 0.034 0.04 0.014
0.004 0.004 0.068 0.018 0.013
0.121 0.07 0.193 0.008 0.011
0.873 0.884 0.024 0.391 0.498
B: Unstandardized coefficients, p: Represents probability.
associated with the SBP. The regression equation is Y ¼ 0.061X1 3.436X2 þ 140.832, p50.05. There was a negative correlation between DBP and age. The regression equation is Y ¼ 0.195X1 þ 94.174, p50.05 (Tables 3 and 4). Relationship of the dosage of the antihypertensive drugs and salt intake in the patients whose BP was controlled under 140/90 mmHg Seventy-six subjects whose BP was controlled to the target level of under 140/90 mmHg accounted for 58.46%. Linear Regression Analyses was carried out between the dosage of the antihypertensive drugs (DDD) and salt intake (24-h urinary sodium) in every stage of CKD. The dosage of the antihypertensive drugs increased with more salt intake in CKD 4 and 5, though no relation was found in stage 1–3 (Table 5). Compared the dosage of the antihypertensive drugs that subjects whose BP was below 140/90 mmHg took in every stage of CKD (Figure 4). We found that the worse renal function was, the more antihypertensive drugs were needed to achieve successful BP control.
Discussion In both general population and animal studies, there was positive correlation between the salt intake and BP. According to this study, salt intake had linear relationship with SBP, more salt caused the increase of SBP, but this kind of relationship was not shown in DBP. Compared with the general population, there lay an obvious contradiction. How did we explain this apparent discrepancy? On the one hand, simply review the pathogenesis of renal hypertension. Activation of renin–angiotensin system, increase of sympathetic nervous system activity, the increased synthesis of endothelin, substance decrease for lowering BP secreted by kidney, and the abnormity of renalase, etc., may involved in the pathogenesis of renal hypertension, while the primary mechanism appear to be expansion in extracellular fluid (ECF) volume.8 Furthermore, plasma renin activity (PRA) is suppressed in the increase of volume load.9 The mechanism of Excessive salt intake induced hypertension might mainly be associated with expansion in ECF volume.10 Salt intake and ECF are more related to hypertension in CKD. Even if
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Figure 2. The regularity of SBP and dietary sodium intake with the change of eGFR.
Figure 3. The regularity of DBP and dietary sodium intake with the change of eGFR.
GFR decreased in certain degree, kidney can still perform the duty of sodium excretion. Continuous decrease of GFR may cause the kidneys’ ability to excrete sodium impaired. If sodium intake is not quickly adjusted, sodium retention and ECF will be caused. SBP is significantly affected by volume loading in CKD, so SBP increases. On the other hand, epidemiological investigation showed DBP appear the same
upward tendency as SBP with years up to age 50 years. The age of 50 to 60 is transition period. After age 50 or 60 years old, SBP continues to rise but DBP tends to remain constant, even begin to decline.11 The reason is mainly arteriosclerosis, the decrease of arterial elasticity and the reduce of vascular compliance. The carotid-femoral pulse wave velocity (CFPWV) is faster in arteriosclerosis. The time will advance from
Salt sensitivity in CKD patients
DOI: 10.3109/0886022X.2013.866008
Table 3. Multivariate regression analysis of SBP and DBP. (Prior to stepwise analysis). SBP b
B
DBP p
b
p
0.023 0.274 0.028 0.085 0.245 0.122 0.042 —
0.828 0.008 0.813 0.433 0.036 0.272 0.686 0.000
B
BMI 0.146 0.025 0.814 0.074 Age 0.004 0.003 0.979 0.215 Salt intake 0.034 0.168 0.159 0.003 U-Pro 1.036 0.138 0.194 0.340 24 h urine potassium 0.185 0.173 0.131 0.141 lgeGFR 4.222 0.232 0.036 1.192 lgDDD 1.834 0.067 0.511 0.614 Constant 132.588 — 0.000 93.471
Table 4. Results of stepwise regression analysis with SBP and DBP as dependent variables. DV
IV
B
b
p
SBP
Salt intake lgeGFR Constant Age Constant
0.061 3.436 140.832 0.195 94.174
0.299 0.190 — 0.249 —
0.004 0.063 0.000 0.011 0.000
DBP
Notes: DV, dependent variable; IV, independent variable. The relationship between the variable lgeGFR and salt intake SBP did not reach statistical significance (p 5 0.05). But we still thought salt intake and lgeGFR were the main factors for SBP. Table 5. The relationship between the dosage of the antihypertensive drugs (DDD) and salt intake. Stage 1 Stage 2 Stage 3 Stage 4 Stage 5
(DDD)antihypertensive drugs
Adjusted R square 0.113 0.048 0.004 0.385 Unstandardized coefficients (B) 0.000 0.007 0.006 0.016 Unstandardized coefficients (std. error) 0.003 0.006 0.006 0.004 Standardized coefficients (b) 0.103 0.357 0.322 0.644 p 0.778 0.231 0.334 0.001
0.227 0.013 0.005 0.519 0.023
2.0 1.5 1.0 0.5 0.0 stage 1
stage 2
stage 3
stage 4
stage 5
Stages of Chronic Kidney Disease
Figure 4. Compare of the dosage of the antihypertensive drugs in every stage of CKD.
diastole to systole when reflected wave arrived in the Central artery, then appear systole delayed pressure peaks, result in SBP increased and DBP decreased.12 The average age of the subjects in this study was 61.96 13.273, accounting for 61.5% above 60 years old, larger proportion of males (61.5%), high salt intake and CKD promoted arteriosclerosis,12–16 lead
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to DBP decreased. So, there was no linear regression relationship between salt intake and DBP. We revealed sodium sensitivity became greater as renal function declined, which was demonstrated from multi-angle. (1) By means of comparison of the relationship between 24-h urinary sodium and BP in different stages, the extent of SBP changed with salt intake in stage 5 was greater than stage 3 and 4. (2) There was linear relationship between the log of BP/24hUNa (salt sensitivity index) and the log of eGFR,that is to say, the influence of salt intake on BP (systolic, diastolic) increased with eGFR decreasing. (3) Multiple regression analysis showed SBP was affected by urinary sodium excretion and eGFR. (4) The doses of antihypertensive drugs increased with the increase of salt intake in stage 4 and 5, it can be inferred that salt intake had more remarkable effects on BP, as kidney function declined severely in CKD. Liu believed that the decrease of the renal parenchyma made BP more sensitive to excess salt intake, which supported this study. Cianciaruso B, etc., found especially for patients with renal failure, salt restriction brought more changes in BP, confirmed the findings of the present study.17 The kidneys were the vital organs of sodium balancing, the salt loading responses of patients with CKD, affected not only by the environmental (relatively high salt) or genetic factors (salt sensitivity), but also by acquired kidney defects (CKD) which caused the inability of renal natriuresis. All of the above resulted in high sensitivity of BP to salt intake in patients with CKD. There were some methodological flaws in the present study, i.e., definition of 24 h average BP, we attempted to use ambulatory blood Pressure measurement (ABPM) recommended by current guidelines18–20 or measure once every 2 h to get mean BP, but restricted by funds and conditions, it was unable to complete. ABPM can provide data related to circadian BP rhythm and nocturnal hypertension, thus detailed information about the salt sensitivity and circadian rhythm of BP in patients with CKD can be discovered. Currently, it is believed that there is a close relationship between salt sensitivity of BP and the non-dipper pattern of circadian BP rhythm.21–23 Unfortunately, this study is not able to provide relevant data in our subjects. Besides, dietary sodium intake was measured by the 24-h excretion of sodium, in the long run, sodium intake and sodium excretion were balanced although there lay sodium retention in CKD patients. We will try to improve these imperfections in the further study.
Conclusion In conclusion, there lay a linear relationship between the salt intake and SBP in non-dialysis patients with CKD. Furthermore, the salt sensitivity of BP rose with the decline of the renal function. Further studies are in proceeding to find out appropriate amount of dietary salt intake for patients with CKD.
Declaration of interest The authors report no conflicts of interests. The authors alone are responsible for the content and writing of this article.
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References 1. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Kidney Disease Outcome Quality Initiative. Am J Kidney Dis. 2002;39:S1–S266. 2. Sacks FM, Svetkey LP, Vollmer WM, et al. DASH-sodium collaborative research group: effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet. DASH-Sodium Collaborative Research Group. N Engl J Med. 2001;344:3–10. 3. Du Bois EF. The measurement of the body surface area in man. Arch Intern Med. 1916;15:868–881. 4. Merlo J, Wessling A, Melander A. Comparison of dose standard units for drug utilization studies. Eur J Clin Pharmacol. 1996;50: 27–30. 5. Xu H. The Clinical Guide to the Chinese Pharmacopoeia. In: China T, Xu H, eds. Tianjin: Tianjin Electronic Press; 2005:464–537, 590–599, 673–710, 953–960. 6. Chen X, Jin Y, Tang G. New Pharmacology. Beijing, China: People’s Medical Publishing House; 2007:392–406. 7. Levey AS, Coresh J, Balk E, et al. National Kidney Foundation: National Kidney Foundation. National Kidney Foundation practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Ann Intern Med. 2003;139:137–147. (Erratum in 2003;139:605). 8. Johnson RJ, Herrera-Acosta J, Schreiner GF, Rodriguez-Iturbe B. Subtle acquired renal injury as a mechanism of salt-sensitive hypertension. N Engl J Med. 2002;346:913–923. 9. Mailloux LU. Hypertension in chronic renal failure and ESRD: prevalence pathophysiology, and outcomes. Semin Nephrol. 2001; 21:146–156. 10. Johnson RJ, Herrera-Acosta J, Schreiner GF, Rodriguez-Iturbe B. Subtle acquired renal injury as a mechanism of salt-sensitive hypertension. N Engl J Med. 2002;346:913–923. 11. Franklin SS, Gustin W IV, Wong ND, et al. Hemodynamic patterns of age-related changes in blood pressure. The Framingham Heart Study. Circulation. 1997;96:308–315. 12. Minawaer Y, Liu J, Reyihan X. Clinical analysis of influential factors on arterial stiffness in early metaphase chronic kidney disease patients. J Xinjiang Med Univ. 2011; 34:733–736.
13. He FJ, Marciniak M, Visagie E, et al. Effect of modest salt reduction on blood pressure, urinary albumin, and pulse wave velocity in white, black, and Asian mild hypertensives. Hypertension. 2009;54:482–388. 14. Mercier N, Labat C, Louis H, et al. Sodium, arterial stiffness, and cardiovascular mortality in hypertensive rats. Am J Hypertens. 2007;20:319–325. 15. Yang W, Zhang S, Sun Z, Zhu Y, Zhang S, Sun J. Relationship between the estimated glomerular filtration Rate and bachial-Ankle pulse wave velocity in healthy population. Chin Circul J. 2011;26: 287–290. 16. Miyatake N, Shikata K, Makino H, Numata T. Relationship between the estimated glomerular filtration rate and pulse wave velocity in Japanese. Intern Med. 2010;49:1315–1320. 17. Cianciaruso B, Bellizzi V, Minutolo R, et al. Salt intake and renal outcome in patients with progressive renal disease. Miner Electrolyte Metab. 1998;24:296–301. 18. Writing group of 2010 Chinese guidelines for the management of hypertension: 2010 Chinese guidelines for the management of hypertension. Chin J Hypertens. 2011;8:701–743. 19. Mancia G, De Backer G, Dominiczak A, et al. Management of Arterial Hypertension of the European Society of Hypertension; European Society of Cardiology: 2007 guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens. 2007;25:1105–1187. 20. Chobanian AV, Bakris GL, Black HR, et al. Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. National Heart, Lung, and Blood Institute; National High Blood Pressure Education Program Coordinating Committee: Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003;42:1206–1252. 21. Kimura G. Kidney and circadian blood pressure rhythm. Hypertension. 2008;51:827–828. 22. Kimura G. Sodium, kidney, and circadian rhythm of blood pressure. Clin Exp Nephrol. 2001;5:13–18. 23. Fukuda M, Goto N, Kimura G. Hypothesis on renal mechanism of non-dipper pattern of circadian blood pressure rhythm. Med Hyp. 2006;67:802–806.
Appendix 1. DDD of antihypertensive drugs summary
Types of drugs Calcium channel blockers (CCB)
Names of drugs Nifedipine controlled released tablets nifedipine delayde-release tablets Amlodipine tablets Felodipine tablets
DDD (mg) 30 20 5
Angiotensin II receptor blocking drugs (ARB)
Valsartan capsules Losartan potassium tablets
80 100
Angiotensin-converting enzyme inhibitors (ACEI)
Benazepril tablets Enalapril tablets
10 10
b-blockers (b-RB)
Metoprolol tablets
50
Diuretics (DU)
Spironolactone Furosemide tablets Hydrochlorothiazide tablets Furosemide injection Torasemide injection
75 40 25 40 20
a-blockers (a-RB)
Alfuzosin tablets
10
Compound antihypertensive drugs
Carvedilol rbesartan and Hydrochlorothiazide tablets
25 162.5
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CLINICAL STUDY
Salt sensitivity of blood pressure in non-dialysis patients with chronic kidney disease Lin Meng, Bin Fu,Tongyan Zhang, Zunmin Han, and Meijuan Yang Department of Nephrology, Second Affiliated Hospital to Tianjin University of Traditional Chinese Medicine, Tianjin, China Abstract
Keywords
Background: Chronic kidney disease (CKD) is a world-wide public health problem. Hypertension is both a cause and a complication of CKD, and a risk factor for progression of kidney disease. The effect of salt intake on blood pressure (BP) and the salt sensitivity in non-dialysis patients with CKD were studied. Methods: One hundred and thirty non-dialysis patients with CKD were enrolled in the present study. Daily urinary excretion of sodium (representative of daily sodium intake) and BP was monitored in conditions of original eating habits. Estimated glomerular filtration rate (eGFR) was measured by the creatinine clearance (Ccr). Results: There was a linear positive relationship between the salt intake and systolic blood pressure (SBP) (b ¼ 0.250, p ¼ 0.004). It had been found that the log of BP/24-h urinary sodium (salt sensitivity index) had linear relationship with the log of eGFR (bsyst ¼ 0.364, p ¼ 0.000, bdiast ¼ 0.345, p ¼ 0.000, respectively). Multi-stepwise regression analysis showed SBP was mainly influenced by salt intake and eGFR. There was a negative correlation between diastolic blood pressure (DBP) and age. Conclusion: These results demonstrated a linear relationship between the salt intake and SBP in non-dialysis patients with CKD. The salt sensitivity of BP rose with the decline of renal function.
Blood pressure, chronic kidney disease, salt intake, salt sensitivity
It is well known that chronic kidney disease (CKD) is a worldwide public health problem, with increasing incidence and prevalence, high cost, and poor outcomes. Hypertension is both a cause and a complication of CKD. In addition, hypertension is a risk factor for progression of kidney disease.1 Recent studies provided evidence that over salted diet is an important factor in the genesis and development of hypertension. Based on the results of the DASH and DASHSodium Trials,2 the NKF-K/DOQI Work Group recommended that most individuals with CKD and hypertension should reduce sodium intake to less than 100 mmol/d (2.4 g/ d).1 However, this conclusion has a snag because the study population of the DASH and DASH-Sodium Trials were nonrenal insufficiency. We attempt to provide experimental evidence to support our view that the worse renal function is, the more restriction of sodium dietary is needed. The aim of the present study, therefore, is to test the hypothesis that there lies a linear relationship between the salt intake and systolic blood pressure (SBP) in patients with CKD and that the salt sensitivity of BP rises with the decline of renal function. In patients with CKD, the number of intact nephron falls off as GFR turns down, decreases the ability of kidneys to excrete sodium and the salt sensitivity of BP will
Address correspondence to Bin Fu, Second Affiliated Hospital to Tianjin University of Traditional Chinese Medicine, Tianjin 300150, China. Tel: þ86 22 60335393; E-mail: [email protected]
Received 13 August 2013 Revised 24 October 2013 Accepted 10 November 2013 Published online 17 December 2013
rise with the decline of renal function. It is hoped that the hypothesis will be tested with our proposed method. We examined the average daily BP and recorded sodium intake in 130 non-dialysis-dependent CKD patients with different estimated GFR (eGFR) and observed the trait of salt sensitivity of BP. Our study population included different stages of non-dialysis-dependent CKD patients; in addition, we verified the conclusion by multi-angle analysis.
Methods Patients
20 14
Introduction
History
One hundred and thirty Chinese adult patients hospitalized in the Second Affiliated Hospital to Tianjin University of Traditional Chinese Medicine (from August 2011 to April 2012) were enrolled in this study. Every patient has been confirmed as non-dialysis-dependent CKD of any stage 1 to 5 according to the K/DOQI guidelines.1 The exclusion criteria were (1) instability in vital indications, or (2) presence of volume depletion of body fluid, such as massive upper gastrointestinal bleeding or septic shock, etc. or (3) secondary hypertension except for renal parenchymal hypertension or (4) failure to provide relative information and refusal of medical examination the study needed. The patients were informed of the purposes and methods of the study before consent was obtained and the study was approved by the Human Ethics Committees of the Second Hospital Affiliated to Tianjin University of Traditional Chinese Medicine (Tianjin, China).
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L. Meng et al.
Observation indexes All eligible subjects kept the original eating habits and were given written instructions on how to collect the 24-h urine. Some subjects were excluded for the above-cited exclusion criteria. A urine aliquot (100 ml) from the 24-h urine collection was assayed. Urine sodium, potassium, albumin, and creatinine were determined by standard analytical methods. The 24-h excretion of sodium was representative of dietary sodium intake. A blood sample was drawn; plasma concentrations of creatinine were determined by enzymatic methods. Then the creatinine clearance (Ccr) as a reliable measure of eGFR was calculated according to urinary creatinine (Ucr) and serum creatinine (Scr): Ccr ¼ [Ucr V]/[Scr 24 60] (mL/min). Meanwhile, BP was measured at 6:00, 10:00 and 14:00 respectively, mean BP was calculated to represent as BP of the day. The height and weight were recorded in the same day, thus body surface area (BSA) could be obtained by the equation of BSA [cm2] ¼ 71.84 height [cm]0.725 weight [kg]0.425 (Du Bois formula),3 eGFR was corrected by BSA: Corrected eGFR [mL/min] ¼ Ccr 1.73 /BSA. Body mass index (BMI) was calculated using the following formula: BMI [kg/m2] ¼ (body weight [kg])/(height[m])2. BP/dietary sodium intake was regarded as salt sensitivity index. Defined Daily Dose (DDD) recommended by World Health Organization (WHO) was used as a parameter to record the dose of antihypertensive drugs.4 Besides WHO, DDD stemmed from the Clinical Guide to Chinese Pharmacopoeia 2005 edition,5 16th Edition of New pharmacology6 and instructions of medicines (Appendix 1). Statistics Adopted Microsoft Excel software to establish database, and analyzed the data with SPSS 17.0 software (SPSS Inc., Chicago, IL). After the Kolmogorov–Smiromov (K–S) normality test, the data according with normal distribution are given as mean SD. Non-normal distributions are presented as the median and P25,P75. Linear regression analysis (R2coefficient of determination) was used to evaluate the relationship between dietary sodium intake and BP. Using the same method, we try to discover the relationship of BP and dietary sodium intake with the change of eGFR. The correlations between BP and body mass index, age, dietary sodium intake, the 24-h excretion of potassium, eGFR, semiquantitative of antihypertensive drugs (DDD)were analyzed through multiple linear regression. p50.05 was considered statistically significant.
Results Study population One hundred and thirty Chinese adult subjects (80 male, 50 female) were enrolled in the study. The general characteristics of subjects during basal conditions are given in Table 1. As can be observed, chronic glomerulonephritis (CGN) and diabetic nephropathy (DN) were the principle causes of CKD, the above two accounted for 80% of the study subjects. CKD patients are generally accompanied by hypertension, in this study hypertensive patients were accounting for 77.69%. The subjects were divided into five groups according to CKD stages defined by the National Kidney Foundation Kidney
Ren Fail, 2014; 36(3): 345–350
Table 1. General characteristics of the study population during basal conditions. Subjects characteristic Gender Men, n (%) Women, n (%) Age, years Protopathy Glomerulonephritis Diabetic nephropathy ANCA-related vasculitis Multicystic kidney disease Others eGFR, mL/min/1.73 m2 SBP, mm Hg DBP, mm Hg
80 (61.5%) 50 (38.5%) 61.96 13.27 42% 38% 4% 2% 14% 21.08 (median) 138.55 19.22 80.67 10.87
Disease Outcomes Quality Initiative,7 those belonging to stage 1 were 10 subjects, 16 subjects in stage 2, 22 subjects in stage 3, 32 subjects in stage 4, and 50 subjects in stage 5, accounting for 8%, 12%, 17%, 25% and 38%, respectively. There were 94 subjects who use antihypertensive drugs, accounting for 72.3%, the media of DDD was 2, P25 was 1, P75 was 3. Mean urinary sodium excretion was 174.69 93.69 mmol/24 h. Those who met dietary allowance recommended by K/DOQI guidelines for salt dose56 g accounted for only 23.08% of all subjects. The effect of salt intake on BP in patients with CKD In this study, linear regression analysis was used to evaluate the relationship between salt intake (24-h urinary sodium) and BP in the subjects. There was a linear positive relationship between the salt intake and the SBP: Y ¼ 0.051X þ 129.591, p50.05, with statistical significance (Figure 1). As you can see from this picture, SBP was found to increase after increased salt intake. The non-standardized coefficient about 24-h urinary sodium (24hUNa) and diastolic blood pressure (DBP) is B ¼ 0.014, p ¼ 0.184, without statistical significance. The relationship between 24 hUNa and BP was compared among the groups (Table 2). It can be concluded that there was no correlation between the salt intake and the SBP in stage 1–2, but there was a linear regression relationship in stage 3, 4 and 5. This kind of relationship was stronger in stage 5 than in stage 3 and 4. The influence of renal function on the relationship between salt intake and BP It was found that the log of BP/24 hUNa (salt sensitivity index) as the function(y) had linear relationship with the log of eGFR as the parameter(x). The regression equitation is Y ¼ 0.199X þ 0.526, p50.05 (SBP; Figure 2), Y ¼ 0.195X, p50.05 (DBP; Figure 3). Multivariate stepwise regression analysis of BP Multivariate stepwise regression analysis was performed including the following as variables: age, Body Mass Index, 24hUNa, 24-h urinary proteinuria (U-Pro), the 24-h excretion of potassium, the log of DDD and the log of eGFR. It demonstrated that the salt intake and the log of eGFR were
Salt sensitivity in CKD patients
DOI: 10.3109/0886022X.2013.866008
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Figure 1. The relationship between salt intake and SBP. Table 2. The relationship of salt intake and blood pressure in different groups. SBP and the salt intake Installments Stage Stage Stage Stage Stage
1 2 3 4 5
DBP and the salt intake
Unstandardized coefficients (B)
Adjusted R square
p
Unstandardized coefficients (B)
Adjusted R square
p
0.033 0.029 0.113 0.094 0.88
0.067 0.024 0.165 0.22 0.101
0.235 0.434 0.034 0.04 0.014
0.004 0.004 0.068 0.018 0.013
0.121 0.07 0.193 0.008 0.011
0.873 0.884 0.024 0.391 0.498
B: Unstandardized coefficients, p: Represents probability.
associated with the SBP. The regression equation is Y ¼ 0.061X1 3.436X2 þ 140.832, p50.05. There was a negative correlation between DBP and age. The regression equation is Y ¼ 0.195X1 þ 94.174, p50.05 (Tables 3 and 4). Relationship of the dosage of the antihypertensive drugs and salt intake in the patients whose BP was controlled under 140/90 mmHg Seventy-six subjects whose BP was controlled to the target level of under 140/90 mmHg accounted for 58.46%. Linear Regression Analyses was carried out between the dosage of the antihypertensive drugs (DDD) and salt intake (24-h urinary sodium) in every stage of CKD. The dosage of the antihypertensive drugs increased with more salt intake in CKD 4 and 5, though no relation was found in stage 1–3 (Table 5). Compared the dosage of the antihypertensive drugs that subjects whose BP was below 140/90 mmHg took in every stage of CKD (Figure 4). We found that the worse renal function was, the more antihypertensive drugs were needed to achieve successful BP control.
Discussion In both general population and animal studies, there was positive correlation between the salt intake and BP. According to this study, salt intake had linear relationship with SBP, more salt caused the increase of SBP, but this kind of relationship was not shown in DBP. Compared with the general population, there lay an obvious contradiction. How did we explain this apparent discrepancy? On the one hand, simply review the pathogenesis of renal hypertension. Activation of renin–angiotensin system, increase of sympathetic nervous system activity, the increased synthesis of endothelin, substance decrease for lowering BP secreted by kidney, and the abnormity of renalase, etc., may involved in the pathogenesis of renal hypertension, while the primary mechanism appear to be expansion in extracellular fluid (ECF) volume.8 Furthermore, plasma renin activity (PRA) is suppressed in the increase of volume load.9 The mechanism of Excessive salt intake induced hypertension might mainly be associated with expansion in ECF volume.10 Salt intake and ECF are more related to hypertension in CKD. Even if
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Figure 2. The regularity of SBP and dietary sodium intake with the change of eGFR.
Figure 3. The regularity of DBP and dietary sodium intake with the change of eGFR.
GFR decreased in certain degree, kidney can still perform the duty of sodium excretion. Continuous decrease of GFR may cause the kidneys’ ability to excrete sodium impaired. If sodium intake is not quickly adjusted, sodium retention and ECF will be caused. SBP is significantly affected by volume loading in CKD, so SBP increases. On the other hand, epidemiological investigation showed DBP appear the same
upward tendency as SBP with years up to age 50 years. The age of 50 to 60 is transition period. After age 50 or 60 years old, SBP continues to rise but DBP tends to remain constant, even begin to decline.11 The reason is mainly arteriosclerosis, the decrease of arterial elasticity and the reduce of vascular compliance. The carotid-femoral pulse wave velocity (CFPWV) is faster in arteriosclerosis. The time will advance from
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DOI: 10.3109/0886022X.2013.866008
Table 3. Multivariate regression analysis of SBP and DBP. (Prior to stepwise analysis). SBP b
B
DBP p
b
p
0.023 0.274 0.028 0.085 0.245 0.122 0.042 —
0.828 0.008 0.813 0.433 0.036 0.272 0.686 0.000
B
BMI 0.146 0.025 0.814 0.074 Age 0.004 0.003 0.979 0.215 Salt intake 0.034 0.168 0.159 0.003 U-Pro 1.036 0.138 0.194 0.340 24 h urine potassium 0.185 0.173 0.131 0.141 lgeGFR 4.222 0.232 0.036 1.192 lgDDD 1.834 0.067 0.511 0.614 Constant 132.588 — 0.000 93.471
Table 4. Results of stepwise regression analysis with SBP and DBP as dependent variables. DV
IV
B
b
p
SBP
Salt intake lgeGFR Constant Age Constant
0.061 3.436 140.832 0.195 94.174
0.299 0.190 — 0.249 —
0.004 0.063 0.000 0.011 0.000
DBP
Notes: DV, dependent variable; IV, independent variable. The relationship between the variable lgeGFR and salt intake SBP did not reach statistical significance (p 5 0.05). But we still thought salt intake and lgeGFR were the main factors for SBP. Table 5. The relationship between the dosage of the antihypertensive drugs (DDD) and salt intake. Stage 1 Stage 2 Stage 3 Stage 4 Stage 5
(DDD)antihypertensive drugs
Adjusted R square 0.113 0.048 0.004 0.385 Unstandardized coefficients (B) 0.000 0.007 0.006 0.016 Unstandardized coefficients (std. error) 0.003 0.006 0.006 0.004 Standardized coefficients (b) 0.103 0.357 0.322 0.644 p 0.778 0.231 0.334 0.001
0.227 0.013 0.005 0.519 0.023
2.0 1.5 1.0 0.5 0.0 stage 1
stage 2
stage 3
stage 4
stage 5
Stages of Chronic Kidney Disease
Figure 4. Compare of the dosage of the antihypertensive drugs in every stage of CKD.
diastole to systole when reflected wave arrived in the Central artery, then appear systole delayed pressure peaks, result in SBP increased and DBP decreased.12 The average age of the subjects in this study was 61.96 13.273, accounting for 61.5% above 60 years old, larger proportion of males (61.5%), high salt intake and CKD promoted arteriosclerosis,12–16 lead
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to DBP decreased. So, there was no linear regression relationship between salt intake and DBP. We revealed sodium sensitivity became greater as renal function declined, which was demonstrated from multi-angle. (1) By means of comparison of the relationship between 24-h urinary sodium and BP in different stages, the extent of SBP changed with salt intake in stage 5 was greater than stage 3 and 4. (2) There was linear relationship between the log of BP/24hUNa (salt sensitivity index) and the log of eGFR,that is to say, the influence of salt intake on BP (systolic, diastolic) increased with eGFR decreasing. (3) Multiple regression analysis showed SBP was affected by urinary sodium excretion and eGFR. (4) The doses of antihypertensive drugs increased with the increase of salt intake in stage 4 and 5, it can be inferred that salt intake had more remarkable effects on BP, as kidney function declined severely in CKD. Liu believed that the decrease of the renal parenchyma made BP more sensitive to excess salt intake, which supported this study. Cianciaruso B, etc., found especially for patients with renal failure, salt restriction brought more changes in BP, confirmed the findings of the present study.17 The kidneys were the vital organs of sodium balancing, the salt loading responses of patients with CKD, affected not only by the environmental (relatively high salt) or genetic factors (salt sensitivity), but also by acquired kidney defects (CKD) which caused the inability of renal natriuresis. All of the above resulted in high sensitivity of BP to salt intake in patients with CKD. There were some methodological flaws in the present study, i.e., definition of 24 h average BP, we attempted to use ambulatory blood Pressure measurement (ABPM) recommended by current guidelines18–20 or measure once every 2 h to get mean BP, but restricted by funds and conditions, it was unable to complete. ABPM can provide data related to circadian BP rhythm and nocturnal hypertension, thus detailed information about the salt sensitivity and circadian rhythm of BP in patients with CKD can be discovered. Currently, it is believed that there is a close relationship between salt sensitivity of BP and the non-dipper pattern of circadian BP rhythm.21–23 Unfortunately, this study is not able to provide relevant data in our subjects. Besides, dietary sodium intake was measured by the 24-h excretion of sodium, in the long run, sodium intake and sodium excretion were balanced although there lay sodium retention in CKD patients. We will try to improve these imperfections in the further study.
Conclusion In conclusion, there lay a linear relationship between the salt intake and SBP in non-dialysis patients with CKD. Furthermore, the salt sensitivity of BP rose with the decline of the renal function. Further studies are in proceeding to find out appropriate amount of dietary salt intake for patients with CKD.
Declaration of interest The authors report no conflicts of interests. The authors alone are responsible for the content and writing of this article.
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References 1. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Kidney Disease Outcome Quality Initiative. Am J Kidney Dis. 2002;39:S1–S266. 2. Sacks FM, Svetkey LP, Vollmer WM, et al. DASH-sodium collaborative research group: effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) diet. DASH-Sodium Collaborative Research Group. N Engl J Med. 2001;344:3–10. 3. Du Bois EF. The measurement of the body surface area in man. Arch Intern Med. 1916;15:868–881. 4. Merlo J, Wessling A, Melander A. Comparison of dose standard units for drug utilization studies. Eur J Clin Pharmacol. 1996;50: 27–30. 5. Xu H. The Clinical Guide to the Chinese Pharmacopoeia. In: China T, Xu H, eds. Tianjin: Tianjin Electronic Press; 2005:464–537, 590–599, 673–710, 953–960. 6. Chen X, Jin Y, Tang G. New Pharmacology. Beijing, China: People’s Medical Publishing House; 2007:392–406. 7. Levey AS, Coresh J, Balk E, et al. National Kidney Foundation: National Kidney Foundation. National Kidney Foundation practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Ann Intern Med. 2003;139:137–147. (Erratum in 2003;139:605). 8. Johnson RJ, Herrera-Acosta J, Schreiner GF, Rodriguez-Iturbe B. Subtle acquired renal injury as a mechanism of salt-sensitive hypertension. N Engl J Med. 2002;346:913–923. 9. Mailloux LU. Hypertension in chronic renal failure and ESRD: prevalence pathophysiology, and outcomes. Semin Nephrol. 2001; 21:146–156. 10. Johnson RJ, Herrera-Acosta J, Schreiner GF, Rodriguez-Iturbe B. Subtle acquired renal injury as a mechanism of salt-sensitive hypertension. N Engl J Med. 2002;346:913–923. 11. Franklin SS, Gustin W IV, Wong ND, et al. Hemodynamic patterns of age-related changes in blood pressure. The Framingham Heart Study. Circulation. 1997;96:308–315. 12. Minawaer Y, Liu J, Reyihan X. Clinical analysis of influential factors on arterial stiffness in early metaphase chronic kidney disease patients. J Xinjiang Med Univ. 2011; 34:733–736.
13. He FJ, Marciniak M, Visagie E, et al. Effect of modest salt reduction on blood pressure, urinary albumin, and pulse wave velocity in white, black, and Asian mild hypertensives. Hypertension. 2009;54:482–388. 14. Mercier N, Labat C, Louis H, et al. Sodium, arterial stiffness, and cardiovascular mortality in hypertensive rats. Am J Hypertens. 2007;20:319–325. 15. Yang W, Zhang S, Sun Z, Zhu Y, Zhang S, Sun J. Relationship between the estimated glomerular filtration Rate and bachial-Ankle pulse wave velocity in healthy population. Chin Circul J. 2011;26: 287–290. 16. Miyatake N, Shikata K, Makino H, Numata T. Relationship between the estimated glomerular filtration rate and pulse wave velocity in Japanese. Intern Med. 2010;49:1315–1320. 17. Cianciaruso B, Bellizzi V, Minutolo R, et al. Salt intake and renal outcome in patients with progressive renal disease. Miner Electrolyte Metab. 1998;24:296–301. 18. Writing group of 2010 Chinese guidelines for the management of hypertension: 2010 Chinese guidelines for the management of hypertension. Chin J Hypertens. 2011;8:701–743. 19. Mancia G, De Backer G, Dominiczak A, et al. Management of Arterial Hypertension of the European Society of Hypertension; European Society of Cardiology: 2007 guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens. 2007;25:1105–1187. 20. Chobanian AV, Bakris GL, Black HR, et al. Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. National Heart, Lung, and Blood Institute; National High Blood Pressure Education Program Coordinating Committee: Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003;42:1206–1252. 21. Kimura G. Kidney and circadian blood pressure rhythm. Hypertension. 2008;51:827–828. 22. Kimura G. Sodium, kidney, and circadian rhythm of blood pressure. Clin Exp Nephrol. 2001;5:13–18. 23. Fukuda M, Goto N, Kimura G. Hypothesis on renal mechanism of non-dipper pattern of circadian blood pressure rhythm. Med Hyp. 2006;67:802–806.
Appendix 1. DDD of antihypertensive drugs summary
Types of drugs Calcium channel blockers (CCB)
Names of drugs Nifedipine controlled released tablets nifedipine delayde-release tablets Amlodipine tablets Felodipine tablets
DDD (mg) 30 20 5
Angiotensin II receptor blocking drugs (ARB)
Valsartan capsules Losartan potassium tablets
80 100
Angiotensin-converting enzyme inhibitors (ACEI)
Benazepril tablets Enalapril tablets
10 10
b-blockers (b-RB)
Metoprolol tablets
50
Diuretics (DU)
Spironolactone Furosemide tablets Hydrochlorothiazide tablets Furosemide injection Torasemide injection
75 40 25 40 20
a-blockers (a-RB)
Alfuzosin tablets
10
Compound antihypertensive drugs
Carvedilol rbesartan and Hydrochlorothiazide tablets
25 162.5
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