帕米膦酸对慢性重症患者无肾毒性

美国休斯敦——在内分泌学会2012年会上，纽约西奈山医学院的Rifka C. Schulman博士报告称，一项单中心回顾性研究表明，呼吸机依赖患者静脉使用帕米膦酸以预防骨吸收过度并不会对肾功能造成不良影响，即便是用于患有慢性肾病(CKD)的患者。

这项回顾性观察性研究总共纳入了315例西奈山医院呼吸监护病房收治的急性重症脱险后依赖呼吸机的慢性重症患者。其中115例接受帕米膦酸(阿可达)30~90 mg静脉滴注4 h，具体剂量需根据患者的体重来计算。另外200例患者则不接受帕米膦酸治疗。所有受试者都使用了钙三醇、碳酸钙和麦角钙化醇以保护其骨骼。

在受试人群中，204例患者没有或仅有1~2期CKD，41例患有3期CKD，33例患有4期CKD，其余37例为需要接受血液透析的5期CKD患者。

这项研究的主要终点是帕米膦酸给药后肾小球滤过率(GFR)和肌酐水平的变化。结果显示，帕米膦酸组的所有患者，无论其CKD状态或用药剂量如何，在静脉输注开始后即刻、输注后7天或者14天均未出现过GFR下降≥25%的情况。

在帕米膦酸组中，没有或仅有轻度CKD的患者亚组输注后7天的中位GFR较基线无变化；3期和4期CKD患者亚组的GFR中位降幅均为4%；5期CKD患者亚组在输注7天后GFR的中位降幅为9%。在对照组中，0~3期CKD患者亚组的中位GFR无变化；4期或5期CKD患者亚组的GFR在这7天内平均上升了6%。Schulman博士指出，这样的肾功能小幅波动是没有临床意义的。

肌酐水平方面，患者的CKD状态越差，7天后肌酐水平较之基线的增幅就越大，但帕米膦酸组和对照组患者的上升幅度基本一致。例如，帕米膦酸组的4期和5期CKD患者肌酐分别上升了6.7%和18.2%，而对照组的4期和5期CKD患者也分别上升了8.8%和20.8%。

Schulman博士观察发现，超过90%的慢性重症患者都存在与骨吸收过度相关的代谢性骨病，表现为骨转化生物标志物N末端肽水平升高。究其原因可能包括制动、炎症、神经内分泌系统异常、维生素D水平低、继发性甲状旁腺功能亢进，以及使用大剂量皮质类固醇和其他药物对骨骼造成了不良影响。

危重症患者的骨丢失很难逆转。对于从慢性重症中康复的患者，骨丢失会增加骨质疏松症和骨折的易感性，也会降低患者的生活质量。因此Schulman博士及其同事在患者的24 h尿N末端肽水平高于70 nmol BCE/mmol肌酐或者血清水平高于40 nmol BCE/L时，会考虑采用帕米膦酸来预防骨丢失。

Schulman博士说：“由于许多慢性重症患者都患有慢性肾病，因此人们普遍对于采用双膦酸盐预防这类患者的骨吸收过度存在疑虑。希望上述结果有助于打消疑虑，让慢性重症患者的代谢性骨病得到更加积极的控制，这可能会对患者的患病率和死亡率产生有利的下游效应。”

该研究由Select Medical公司资助。Schulman博士声明无相关经济利益冲突。 

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By: BRUCE JANCIN, Clinical Endocrinology News Digital Network

HOUSTON – Intravenous pamidronate for management of bone hyperresorption in ventilator-dependent patients doesn’t adversely affect renal function, even in those with chronic kidney disease, according to a single-center retrospective study.

"This stands in contrast to prevailing concerns about bisphosphonate therapy to manage bone hyperresorption in chronically critically ill patients, many of whom have chronic kidney disease," Dr. Rifka C. Schulman reported at the annual meeting of the Endocrine Society.

"It is hoped that these results will remove barriers to more aggressive management of metabolic bone disease in chronic critical illness, which may have salutary downstream effects on morbidity and mortality," declared Dr. Schulman of the Mount Sinai School of Medicine in New York.

She presented a retrospective observational study of 315 patients admitted to the Mount Sinai Hospital respiratory care unit with ventilator-dependent chronic critical illness after surviving a bout of acute critical illness. In all, 115 received 30-90 mg of intravenous pamidronate (Aredia) infused over 4 hours, with dosing based on body weight. The other 200 patients did not receive pamidronate. All participants got calcitriol, calcium carbonate, and ergocalciferol to help protect their bones.

The study population consisted of 204 patients with either no or stage 1-2 chronic kidney disease, 41 with stage 3 CKD, 33 with stage 4 disease, and 37 with stage 5 CKD who were on hemodialysis.

The primary study end points were change in glomerular filtration rate and creatinine level following pamidronate administration. Importantly, none of the pamidronate-treated patients showed a 25% or greater reduction in GFR immediately after or at 7 or 14 days post infusion, regardless of their CKD status or dose received.

The group with no or only mild CKD showed no change in median GFR between baseline and day 7 post infusion. Those with stage 3 CKD had a median 4% drop in GFR. So did those with stage 4 disease. Patients with stage 5 CKD had a median 9% reduction in GFR on day 7. Among controls, those with stage 0-3 CKD had no change in median GFR, while those with stage 4 or stage 5 disease averaged a 6% increase in GFR during 7 days. These small fluctuations in renal function aren’t clinically meaningful, according to Dr. Schulman.

Creatinine levels rose between baseline and day 7 in lockstep with CKD status, but to the same extent in pamidronate-treated patients and controls. For example, creatinine climbed by 6.7% and 18.2%, respectively, in pamidronate-treated patients with stage 4 and stage 5 CKD, and by 8.8% and 20.8% in stage 4 and 5 controls.

She observed that metabolic bone disease involving bone hyperresorption with elevated levels of the bone turnover biomarker N-telopeptide is present in more than 90% of patients with chronic critical illness. Contributing factors include immobilization, inflammation, neuroendocrine abnormalities, low vitamin D levels and secondary hyperparathyroidism, and the use of high-dose corticosteroids and other medications with an adverse impact on bone.

Bone loss during critical illness is challenging to reverse. It predisposes to osteoporosis, fractures, and poor quality of life in patients who recover from chronic critical illness. That’s why Dr. Schulman and her coinvestigators favor turning to pamidronate when patients have a 24-hour urine N-telopeptide of 70 nmol BCE/mmol creatinine or a serum level in excess of 40 nmol BCE/L.

The study was supported by a grant from Select Medical. Dr. Schulman reported having no financial conflicts.

学科代码：呼吸病学 骨科学 肾脏病学 重症监护　　　关键词：内分泌学会年会 帕米膦酸以预防骨吸收过度 肾脏毒性
来源： EGMN