Serum Chloride Is an Independent Predictor of Mortality in Hypertensive Patients
Linsay McCallumPanniyammakal JeemonClaire E. HastieRajan K. PatelCatherine WilliamsonAdyani Md RedzuanJesse DawsonWilliam SloanScott MuirDavid MorrisonGordon T. McInnesEllen Marie FreelJames WaltersAnna F. DominiczakNaveed SattarSandosh Padmanabhan
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Chloride (Cl-) is the major extracellular anion in the body, accompanying sodium (Na+), and is primarily derived from dietary sources. Data suggest that increased dietary Cl- intake increases blood pressure, yet paradoxically, higher serum Cl- appears associated with lower mortality and cardiovascular risk. This implies that serum Cl- also reflects risk pathways independent of blood pressure, serum Na+, and bicarbonate (HCO3-). We analyzed 12,968 hypertensive individuals followed up for 35 years, using Cox proportional hazards model to test whether baseline serum Cl- was an independent predictor of mortality. To distinguish the effect of Cl- from Na+ and HCO3-, we adjusted for these electrolytes and also performed the analysis stratified by Na+ /HCO3- and Cl- levels. Generalized estimating equation was used to determine the effect of baseline Cl- on follow-up blood pressure. The total time at risk was 19,7101 person-years. The lowest quintile of serum Cl- (<100 mEq/L) was associated with a 20% higher mortality (all-cause, cardiovascular and noncardiovascular) compared with the remainder of the subjects. A 1 mEq/L increase in serum Cl- was associated with a 1.5% (hazard ratio, 0.985; 95% confidence interval, 0.98-0.99) reduction in all-cause mortality, after adjustment for baseline confounding variables and Na+, K+ , and HCO3- levels. The group with Na+ > 135 and Cl- > 100 had the best survival, and compared with this group, the Na+ >135 and Cl- <100 group had significantly higher mortality (hazard ratio, 1.21; 95% confidence interval, 1.11-1.31). Low, not high Serum Cl- (<100 mEq/L), is associated with greater mortality risk independent of obvious confounders. Further studies are needed to elucidate the relation between Cl- and risk.Keywords:
Serum chloride
Bicarbonate
Bicarbonate
Total inorganic carbon
Assimilation (phonology)
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Confounding may be present in nonrandomized etiological research involving human populations. It can result in erroneous conclusions about the effect of exposure on a disease outcome or about any form of causality between predictors and outcomes. Confounding can wholly or partially account for the apparent effect of the risk factor under consideration or mask the underlying, true association. Not controlling for the effects of confounding can lead to biased results, thus compromising the validity of study conclusions. The three goals of this article are: (1) to define a confounder or a confounding variable, (2) to discuss strategies for controlling the effects of confounding, and (3) to illustrate the perverse effects of confounding with the help of an example.
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The effect of luminal bicarbonate concentration on proximal tubular acidification was studied. Rat proximal convoluted tubules were perfused in vivo with solutions of varying bicarbonate concentration, and bicarbonate absorption was measured using microcalorimetry. Bicarbonate absorption was found to increase linearly with mean luminal bicarbonate concentrations up to 45 mM, but above this level it showed evidence of partial saturation. Bicarbonate permeability was measured and found to be 2.6 +/- 0.3 x 10(-7) cm2/s. Using this permeability, net bicarbonate absorption could be divided into two parallel components, both sensitive to luminal bicarbonate concentration: 1) proton secretion and 2) a passive bicarbonate leak. Proton secretion, when examined as a function of luminal bicarbonate concentration, exhibited saturation kinetics with an apparent Km of 16 mM and a Vmax of 200 pmol . mm-1 . min-1.
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Background Although most people with relapsing onset multiple sclerosis (R-MS) eventually transition to secondary progressive multiple sclerosis (SPMS), little is known about disability progression in SPMS. Methods All R-MS patients in the Cardiff MS registry were included. Cox proportional hazards regression was used to examine a) hazard of converting to SPMS and b) hazard of attaining EDSS 6.0 and 8.0 in SPMS. Results 1611 R-MS patients were included. Older age at MS onset (hazard ratio [HR] 1.02, 95%CI 1.01–1.03), male sex (HR 1.71, 95%CI 1.41–2.08), and residual disability after onset (HR 1.38, 95%CI 1.11–1.71) were asso- ciated with increased hazard of SPMS. Male sex (EDSS 6.0 HR 1.41 [1.04–1.90], EDSS 8.0 HR 1.75 [1.14–2.69]) and higher EDSS at SPMS onset (EDSS 6.0 HR 1.31 [1.17–1.46]; EDSS 8.0 HR 1.38 [1.19–1.61]) were associated with increased hazard of reaching disability milestones, while older age at SPMS was associated with a lower hazard of progression (EDSS 6.0 HR 0.94 [0.92–0.96]; EDSS 8.0: HR 0.92 [0.90–0.95]). Conclusions Different factors are associated with hazard of SPMS compared to hazard of disability progres- sion after SPMS onset. These data may be used to plan services, and provide a baseline for comparison for future interventional studies and has relevance for new treatments for SPMS RobertsonNP@cardiff.ac.uk
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1. In the rat dietary chloride restriction has been shown to cause an elevation of the plasma bicarbonate and urinary net acid excretion, provided dietary sodium is available. Likewise the degree of elevation of plasma bicarbonate during chloride depletion, produced by prior exposure to 8% CO2 for 24 hr, was dependent on whether sodium (as the neutral phosphate) was or was not being ingested. 2. Correction of the hypochloraemia and the elevated plasma bicarbonate following exposure to CO2 and subsequent recovery on a low chloride diet is more complete in the rat than the dog. Evidence is presented that the plasma chloride rises in the rat because of the movement of chloride out of intracellular sites, and that chloride depletion and/or the associated metabolic alkalosis elevates endogenous acid production. 3. Chloride depleted rats were re-exposed to 8% CO2 in air. Renal chloride conservation remained intact. The hypochloraemia and rise in plasma bicarbonate in response to CO2 were not dependent on chloruresis although urinary acid excretion and the rise in serum bicarbonate were inhibited when the plasma chloride did not fall. 4. Consideration of these experiments with the related micropuncture experiments of Warren et al. (1970) suggests that: (a) the intimate relationship between hypochloraemia and the elevation of plasma bicarbonate in respiratory acidosis is related to reciprocal changes in proximal tubular absorption of chloride and bicarbonate; (b) chloride depletion can increase bicarbonate absorption in the proximal tubule and urinary net acid excretion; (c) a rise in TF/P Cl in the proximal tubule does not necessarily correlate with changes in external chloride balance; (d) the distal chloride conserving mechanism is unaffected by rates of sodium or phosphate excretion, exposure to carbon dioxide, or increases in the rate of tubular bicarbonate absorption.
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Acid–base homeostasis
Net acid excretion
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Serum chloride
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Rat proximal convoluted tubules were microperfused in vivo to examine the effect of flow rate on bicarbonate absorption. When tubules were perfused with 25 mM bicarbonate, increases in perfusion rate from 15 to 33 to 49 nl/min caused bicarbonate absorption to increase from 105 +/- 4 to 176 +/- 8 to 209 +/- 7 pmol X mm-1 X min-1, respectively. Only 15% of this stimulation could be attributed to a flow-induced increase in the measured axial luminal bicarbonate concentration profile. In addition, effects of flow on passive bicarbonate diffusion or convection could not account for the observed stimulation. When tubules were perfused with 58 mM bicarbonate (a concentration previously shown to achieve maximal rates of proton secretion), increasing flow rate from 15 to 49 nl/min did not stimulate bicarbonate absorption. Thus, when examined as a function of mean luminal bicarbonate concentration, increases in flow increased the rate of proton secretion without affecting the maximal rate. The data are most consistent with flow-dependent stimulation of bicarbonate absorption, secondary to flow-dependent changes in luminal bicarbonate concentration, occurring by two mechanisms: 1) flow-dependent increases in the measured axial luminal bicarbonate concentration profile and 2) flow-dependent decreases in radial luminal bicarbonate concentration gradients.
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The hazard ratio and median survival time are the routine indicators in survival analysis. We briefly introduced the relationship between hazard ratio and median survival time and the role of proportional hazard assumption. We compared 110 pairs of hazard ratio and median survival time ratio in 58 articles and demonstrated the reasons for the difference by examples. The results showed that the hazard ratio estimated by the Cox regression model is unreasonable and not equivalent to median survival time ratio when the proportional hazard assumption is not met. Therefore, before performing the Cox regression model, the proportional hazard assumption should be tested first. If proportional hazard assumption is met, Cox regression model can be used; if proportional hazard assumption is not met, restricted mean survival times is suggested.风险比（hazard ratio，HR）和中位生存时间是生存分析时的常规分析和报告指标。本文简要介绍了HR和中位生存时间的关系以及比例风险假定在这两者之间的作用，分析了检索出的58篇文献中的110对风险比和中位生存时间比的差异，并通过实例阐明了产生这种差异的原因。结果表明，在不满足比例风险假定时，Cox回归模型计算得到的风险比是不合理的，且与中位生存时间之比不等价。因此，在使用Cox回归模型前，应先进行比例风险假定的检验，只有符合比例风险假定时才能使用该模型；当不符合比例风险假定时，建议使用限制性平均生存时间。.
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Abstract Background Chloride disorders (hypochloremia, hyperchloremia) and bicarbonate disorders (hypobicarbonatemia, hyperbicarbonatemia) are common in clinical medicine and indicate metabolic and/or respiratory acid–base disorders. The normally inverse relationship between chloride and bicarbonate concentrations in the blood is altered, however, by changes in fluid balance, i.e., water excess or deficit, with resulting changes in sodium and other electrolyte concentrations and by anion gap metabolic acidosis, which lowers bicarbonate concentrations but not the chloride concentrations. Methods We used formulas derived over a decade ago that utilize dry slide laboratory technology to adjust plasma chloride and bicarbonate concentrations for changes in water balance, as reflected in changes in plasma sodium concentrations and in the plasma anion gap. We then prospectively validated these formulas in 736 consecutive adults, 499 having abnormal basic metabolic panel results and 237 having normal panel results, using modern wet laboratory technology. Results Plasma chloride and bicarbonate concentrations were inversely correlated (2-tailed P-value <0.0001), but the correlations were only modest (Spearman r: −0.48 for the abnormal group and −0.41 for the normal group). After adjusting the plasma chloride and bicarbonate concentrations using the 2 prior formulas, the inverse correlations were very high, with Spearman r: −0.998 for the abnormal group and −0.999 for the normal group. Conclusions Adjusting plasma chloride and bicarbonate concentrations for any water imbalance and anion gap alterations leads to very high inverse correlations between these 2 anions, allowing accurate assessment of either subtle or overt acid–base disorders.
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Hyperchloremia
Hypochloremia
Anion gap
Acid–base imbalance
Acid–base homeostasis
Serum chloride
Sodium bicarbonate
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Abstract Although most acid‐base disorders cause opposite and equal changes in serum chloride and bicarbonate concentrations, this inverse relationship can be distorted by changes in the anion gap and/or water balance. Therefore, we examined the relationship between chloride and bicarbonate before and after adjusting for anion gap and serum sodium concentration. Patients with abnormal electrolytes were grouped by chloride and bicarbonate concentrations (low, normal, and high). Then, chloride and anion gap‐adjusted bicarbonate were adjusted for water excess (or deficit), manifesting as hyponatremia (or hypernatremia), after which patients were reclassified. Classification by chloride and bicarbonate changed in 82% of the 135 patients after adjustment for anion gap and sodium. Serum chloride and bicarbonate were each low (concordant) in 23 patients, while 18 had discordant chlorides and bicarbonates (9 low/high, 9 high/low). After adjustments, chloride and bicarbonate were discordant in 40 patients (31 low/high, 9 high/low) and concordant in none. The correlation between serum chloride and bicarbonate improved from −0.459 to –0.998 after adjustments for sodium and anion gap. A very close inverse relationship between serum chloride and bicarbonate concentrations is commonly distorted by concomitant water disturbances and anion gap acidoses in internal medicine patients admitted with electrolyte disorders. J. Clin. Lab. Anal. 20:154–159, 2006. © 2006 Wiley‐Liss, Inc.
Bicarbonate
Sodium bicarbonate
Anion gap
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