血清鈣濃度與腎臟疾病患者長期死亡率有關

作者：Laurie Barclay, MD  
出處：WebMD醫學新聞

　　January 15, 2010 — 根據一項於1月7日發表在美國腎臟醫學會臨床期刊的重要前瞻性世代研究結果，血清鈣濃度與非依賴透析（NDD）慢性腎臟疾病（CKD）患者長期死亡率有關。
　　
　　維吉尼亞Salem研究機構與Salem退伍軍人事務醫學中心的Csaba P. Kovesdy醫師與其同事們寫到，透析病患的血清鈣濃度過高與死亡率上升有關，但是這個關係在NDD CKD病患是否一樣仍然未知。與低血清鈣有關的預後也尚未確立。
　　
　　透過Cox統計模式，研究者們分析試驗前、時間變異及時間平均血鈣濃度與1243位中度和後期NDD CKD男性所有原因死亡率之間的關係。
　　
　　血清鈣濃度和死亡率之間的關係與使用那種統計模式有關。在決定長期平均暴露於鈣的模式中（試驗前固定共變項以及時間平均模式），較高的鈣濃度與死亡率增加有關。試驗前鈣濃度高出1 mg/dl，多變項校正危險比值為1.31（95%信賴區間[CI]為1.13-1.53；P<0.001）。
　　
　　相對的，在時間變異模式中，以死亡率預後與最後一次依賴變項（血鈣）觀察值連結決定鈣平均暴露量，較低的鈣濃度與較高的死亡率有關。
　　
　　研究作者們寫到，鈣穩定可興奮細胞膜，因此，較低的血鈣濃度會增加神經肌肉興奮性，這可能解釋為什麼較低的血鈣濃度在時間變異模式中與較高的短期死亡率有關，可能與心律不整發生率較高有關。較高的血鈣濃度被推測在造成尿毒症病患心血管鈣化上扮演不可或缺的角色。這樣的作用機轉可能是這項研究中高時間平均鈣濃度與死亡率增加有關的一個可能解釋，顯然地，長時間暴露在高血鈣濃度之下更可能使血管鈣化。
　　
　　這項研究限制包括回溯性與觀察性研究設計，使得這項研究無法確認因果關係，受試者限制在同一機構的男性，以及可能的殘餘影響因子。除此之外，延長收納病患時間引發了醫學執業長期趨勢可能影響收納時間為主結果的考量。
　　
　　研究作者們的結論是，慢性高血鈣和急性低血鈣都與中重度NDD CKD男性病患死亡率增加有關。因此，維持正常血鈣濃度對這個病患族群可能是有益的，但是將需要以前瞻性研究來獲得最佳的治療潛力。應該在設計適當的臨床研究中評估包括高血鈣或低血鈣治療療程是否有任何潛在的不良效應。
　　
　　這項研究由Genzyme提供給Kovesdy醫師（無薪資助）以及國家糖尿病、消化系統與腎臟疾病經費提供給Kovesdy醫師與共同作者Kalantar-Zadeh醫師的研究者發起經費贊助。Kovesdy醫師與Kalantar-Zadeh醫師接受Genzyme、Shire與Fresenius公司的經費贊助以及/或是演講費。


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.