鈣離子阻斷劑Lercanidipine可以增加大鼠腹膜透析脫水量

Abstract

背景與目的 腹膜透析作為末期腎臟病病人的替代療法，其成功與否取決於是否能達成足夠的廢物及水分移除。有許多因素可影響腹膜透析的功效，例如腹膜本身的運輸速率，腹膜面積，透析藥水濃度等等。 過去有研究顯示鈣離子阻斷劑如verapamil，diltiazem可增加腹膜透析廓清率及脫水量，推測其機轉可能與改變腹膜小血管血行動力學，血管擴張增加物質交換面積，或與降低腹膜炎性反應有關。某些較新的鈣離子阻斷劑如manidipine，lercanidipine還有另一特性會造成乳糜腹水，增加腹膜透析液中三酸甘油脂的排除，因此推測第三代鈣離子阻斷劑lercanidipine對腹膜的血行動力學、炎性反應或淋巴吸收有影響，造成廓清率，脫水量及血脂肪的變化。 方法 由大鼠的單次急性腹膜透析模式探討：1. lercanidipine相對於其他鈣離子阻斷劑〈以amlodipine為代表〉會增加腹膜透析的脫水率2. 此現象之機轉是否涉及腹膜構造之變化 3. 此現象之機轉是否可能為腹膜腔內炎性反應變化造成。此外文獻指出腹膜腔內細胞激素濃度會影響腹膜功能，其機轉可能為經血管內皮細胞生長素(vascular endothelial growth factors, VEGF)增加腹膜腔之血管表面積(vascular surface area)所致，並有研究指出腹膜間皮細胞型態及血管分部亦與細胞激素及VEGF-A或VEGF-C有關，故本計畫亦擬由正常人腹膜間皮細胞培養，加入不同鈣離子阻斷劑後觀察懸浮液中細胞激素和血管內皮細胞生長素的濃度差異來探討鈣離子阻斷劑影響腹膜透析的可能原因。 結果 Lercanidipine可以增加腹膜透析脫水率，平均脫水量為47.3 ± 13.1 ml/kg body weight，比amlodipine組35.4 ± 6.7 ml/kg body weight (p = 0.04)和對照組35.8 ± 8.3 ml/kg body weight皆有有意義的增加 (p = 0.03)。實驗動物的腹膜平衡試驗、鹽篩濾(sodium sieving)、組織學變化和有效淋巴吸收速率(effective lymphatic absorption rate, ELAR)皆無差別，因此導致脫水率增加的機轉仍待進一步探討。此外，lercanidipine可降低腹膜腔內的interferon-γ (INF-γ) 濃度，但對interleukin - 1β (IL-1β) 和VEGF-C則沒有差別。 討論與結論 本研究發現lercanidipine會增加腹膜透析的脫水率，而且此現象並非為所有鈣離子阻斷劑共有，但是其可能機轉以及對臨床的影響仍待進一步研究。

Background The success of peritoneal dialysis (PD) is determined by the adequacy of fluid and metabolic waste removal. There are several factors that may influence PD adequacy, including the peritoneal transport rate, peritoneal perfusion and surface area and the osmolarity gradient between dialysate and systemic blood flow. It was known that calcium channel blockers (CCBs) like verapamil or diltiazem can increase either the clearance or ultrafiltration (UF) of PD, probably due to dilatation of peritoneal capillaries and therefore increase the exchange surface area, or some suggested that CCBs may decrease peritoneal cytokine and inflammation and therefore increase UF. More recently, some other CCBs like manidipine or lercanidipine can even cause chyloperitoneum as well as the increase of UF. How dose lercarnidipine influence PD, and whether this agent affect peritoneal hemodynamics, inflammation or lymphatic absorption, is the center of focus of this current study. Method In attempt to clarify this issue, we plan to: 1. prove that lercarnidipine does increase UF in comparison with control or other CCBs in acute peritoneal dialysis model in animal study, 2. examine the peritoneum of the experiment animal to determine whether this difference is caused by structural change, and 3. measure inflammatory cytokine level in the dialysate to see if any difference exists. Besides, due to the recent finding that pro-inflammatory cytokines may provoke angiogenesis and increase the level of VEGF family, which may be responsible for functional and structural change of the peritoneum, we also plan to explore the influence of CCBs on VEGF-C in PD. Results The mean ultrafiltration (UF) of a single session of peritoneal dialysis in Wistar rat is 47.3 ± 13.1 ml/kg body weight, which is significantly higher than the UF of animals on amlodipine (35.4 ± 6.7 ml/kg body weight, p = 0.04) and control (35.8 ± 8.3 ml/kg body weight, p = 0.03)。The peritoneal equilibration test, sodium sieving, peritoneal histology and effective lymphatic absorption rate (ELAR) of the three groups showed no difference, therefore the underlying mechanism of the increase in UF remain unclear. Besides, lercanidipine lowered the intraperitoneal interferon-γ (INF-γ), but had no influence on interleukin - 1β (IL-1β) and VEGF-C level。 Conclusion We found that lercanidipine can increase the ultrafiltration of peritoneal dialysis, but the implication, impact and the underlying mechanism still need further investigation.