血清钙浓度与肾脏疾病患者长期死亡率有关


  【24drs.com】January 15, 2010 — 根据一项于1月7日发表在美国肾脏医学会临床期刊的重要前瞻性世代研究结果,血清钙浓度与非依赖透析(NDD)慢性肾脏疾病(CKD)患者长期死亡率有关。
  
  维吉尼亚Salem研究机构与Salem退伍军人事务医学中心的Csaba P. Kovesdy医师与其同事们写到,透析病患的血清钙浓度过高与死亡率上升有关,但是这个关系在NDD CKD病患是否一样仍然未知。与低血清钙有关的预后也尚未确立。
  
  透过Cox统计模式,研究者们分析试验前、时间变异及时间平均血钙浓度与1243位中度和后期NDD CKD男性所有原因死亡率之间的关系。
  
  血清钙浓度和死亡率之间的关系与使用那种统计模式有关。在决定长期平均暴露于钙的模式中(试验前固定共变项以及时间平均模式),较高的钙浓度与死亡率增加有关。试验前钙浓度高出1 mg/dl,多变项校正危险比值为1.31(95%信赖区间[CI]为1.13-1.53;P<0.001)。
  
  相对的,在时间变异模式中,以死亡率预后与最后一次依赖变项(血钙)观察值连结决定钙平均暴露量,较低的钙浓度与较高的死亡率有关。
  
  研究作者们写到,钙稳定可兴奋细胞膜,因此,较低的血钙浓度会增加神经肌肉兴奋性,这可能解释为什么较低的血钙浓度在时间变异模式中与较高的短期死亡率有关,可能与心律不整发生率较高有关。较高的血钙浓度被推测在造成尿毒症病患心血管钙化上扮演不可或缺的角色。这样的作用机转可能是这项研究中高时间平均钙浓度与死亡率增加有关的一个可能解释,显然地,长时间暴露在高血钙浓度之下更可能使血管钙化。
  
  这项研究限制包括回溯性与观察性研究设计,使得这项研究无法确认因果关系,受试者限制在同一机构的男性,以及可能的残余影响因子。除此之外,延长收纳病患时间引发了医学执业长期趋势可能影响收纳时间为主结果的考量。
  
  研究作者们的结论是,慢性高血钙和急性低血钙都与中重度NDD CKD男性病患死亡率增加有关。因此,维持正常血钙浓度对这个病患族群可能是有益的,但是将需要以前瞻性研究来获得最佳的治疗潜力。应该在设计适当的临床研究中评估包括高血钙或低血钙治疗疗程是否有任何潜在的不良效应。
  
  这项研究由Genzyme提供给Kovesdy医师(无薪资助)以及国家糖尿病、消化系统与肾脏疾病经费提供给Kovesdy医师与共同作者Kalantar-Zadeh医师的研究者发起经费赞助。Kovesdy医师与Kalantar-Zadeh医师接受Genzyme、Shire与Fresenius公司的经费赞助以及/或是演讲费。

Serum Calcium Linked to Long-Term Mortality in Renal Disease

By Laurie Barclay, MD
Medscape Medical News

January 15, 2010 — Serum calcium is linked to long-term mortality in non-dialysis-dependent (NDD) chronic kidney disease (CKD), according to the results of a historic prospective cohort study reported online January 7 in the Clinical Journal of the American Society of Nephrology.

"Elevated serum calcium has been associated with increased mortality in dialysis patients, but it is unclear whether the same is true in [NDD CKD]," write Csaba P. Kovesdy, MD, from Salem Veterans Affairs Medical Center and Salem Research Institute in Virginia, and colleagues. "Outcomes associated with low serum calcium are also not well-characterized."

Using Cox models, the investigators analyzed associations of baseline, time-varying, and time-averaged serum calcium with all-cause mortality in 1243 men with moderate and advanced NDD CKD.

The association of serum calcium with mortality varied on the basis of which statistical models were applied. In models determining long-term average exposure to calcium (baseline fixed-covariate and time-averaged models), higher calcium was associated with increased mortality. For baseline calcium level 1 mg/dL higher, multivariable adjusted hazard ratio was 1.31 (95% confidence interval [CI],1.13 - 1.53; P < .001).

In contrast, in time-varying models determining shorter-term average exposure to calcium by associating the outcome of mortality with the last observed values of the dependent variable (calcium), lower calcium levels were linked to higher death rates.

"Calcium stabilizes the membranes of excitable cells; thus, lower serum calcium can increase neuromuscular excitability, which may explain why lower calcium levels in our time-varying models could have been associated with higher short-term death rates, possibly through a higher incidence of cardiac arrhythmias," the study authors write. "It has been postulated that elevated calcium may play an integral role in engendering cardiovascular calcification in uremic patients. Such a mechanism of action could be a possible explanation for the increased mortality associated with higher time-averaged calcium levels in our study, because it appears more likely that prolonged exposure to higher serum calcium levels would be more likely to promote vascular calcification."

Limitations of this study include retrospective and observational design precluding determination of causality, participants limited to male patients from a single institution, and possible residual confounding. Furthermore, enrolling patients during an extended time period raises the concern that secular trends in medical practices could have affected outcomes based on the time of enrollment.

"Chronic hypercalcemia and acute hypocalcemia are both associated with increased mortality in male patients with moderate and advanced NDD CKD," the study authors conclude. "Thus, maintaining normal serum calcium levels may be beneficial in this patient population, but prospective studies will be needed to determine what the target range for serum calcium should be and how such a target should be achieved to derive the best therapeutic potential. Therapeutic regimens inducing either hypercalcemia or hypocalcemia should be assessed for any potentially deleterious effects in properly designed clinical trials."

This study was supported by an investigator-initiated grant from Genzyme to Dr. Kovesdy (without salary support) and by an National Institute of Diabetes and Digestive and Kidney Diseases grant to Dr. Kovesdy and coauthor Dr. Kalantar-Zadeh. Dr. Kovesdy and Dr. Kalantar-Zadeh have received grant support and/or honoraria from Genzyme, Shire, and Fresenius.

Clin J Am Soc Nephrol. Published online January 7, 2010.

    
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