當前提出的致病機轉與現有治療，仍無法完全解釋與穩定慢性腎臟病（CKD）的進展及其相關的心血管疾病。至目前為止，吾人或許仍忽略了某些相關的潛在威脅甚或惡性循環。我們假設，因CKD而滯留於人體的某些代謝物質（俗稱尿毒素）可能引起腎臟的損傷，因而進一步在CKD的不可逆進展中引起惡性循環。此外，我們亦推測為了控制CKD的高血磷，吾人所使用的含鈣或非含鈣的磷結合劑，可能經由某些特殊機制，而在治療CKD的心血管疾病與血管鈣化中扮演著不同的角色。 研究的第一部分，我們進行了體外細胞實驗，以一種已知的尿毒素:對甲酚 (p-Cresol, PC)，處理大鼠與人類的腎臟近端小管細胞（RPTC）。我們發現，PC顯著降低了RPTC細胞成長速度並增加了RPTC細胞凋亡。進一步實驗顯示，PC乃是經由JNK與p62蛋白活化，造成RPTC的自噬性細胞死亡 (autophgic cell death)。而此種細胞死亡是經由活化了caspase 8相關的細胞凋亡 (apoptosis) 路徑。此發現意味因CKD進展而滯留於體內的尿毒素PC，可能引起CKD的惡性循環。 在研究的第二部分，我們進行了一個為期48週，隨機與對照臨床試驗的事後分析，評估兩種不同磷結合劑對CKD患者的影響。我們發現，血液透析患者經過長期非含鈣的磷結合劑 (Sevelamer) 治療高磷血症，除了達到降低血磷值的預期效果外，亦具有降低血清FGF23（和心血管疾病有關的壞因子），並伴隨著血清中較高Klotho（和抗血管鈣化與抗老化有關的好因子）的現象，而此種血中Klotho的變化乃是首次被吾人所發現。 我們的研究證明了尿毒素PC會造成RPTC的自噬性細胞凋亡， PC在CKD惡化過程中可能扮演某些角色及可能造成惡性循環。另一方面，非含鈣的磷結合劑Sevelamer的使用，在治療CKD相關的心血管疾病與血管鈣化時，除了達到降血磷的目的，亦具有其他抗血管鈣化的作用，譬如改變了血清FGF23及Klotho的濃度。當然這兩部分的研究，未來仍需要進一步的實驗來加以檢視及探討。 Current proposed mechanisms and available therapies are not uniformly successful in explaining or stabilizing the chronic kidney disease (CKD) progression and CKD-related cardiovascular disease (CVD). There may be some potential threats or vicious cycle in CKD we overlooked. We originally postulated that some retained substance (uremic toxin) in CKD may play a role of renal injury in a vicious cycle of CKD progression. Besides, for long-term control of hyperphosphatemia in CKD, we think calcium-based or non-calcium-based phosphate-binders may play different roles in CKD-related CVD, except for hyperphophatemia . In the first part of our study, we conducted an in-vitro experiment of treating renal proximal tubular cells (RPTC) with p-cresol (PC,) a uremic toxin. We found the cell proliferation was significantly decreased and the apoptosis was significantly increased after PC treatment. We further concluded PC triggered autophagic RPTC death via JNK-mediated p62 accumulation and then activated caspase 8- dependent cell death pathway. It implies the retained uremic toxin, such as p-cresol, may cause a vicious cycle of CKD progression. In the second part, we conducted a post-hoc analysis of a 48-week, open-Label, controlled randomized parallel-group study to evaluate the impact of different phosphate-binders on CKD patients. We discovered maintenance HD patients after 48-week sevelamer treatment, a non-calcium-contained phosphate binder, had lower serum FGF23 (the bad guy for CVD) levels accompanied with higher serum Klotho (the good guy for anti-vascular calcification) levels. Our research successfully proves the potential roles of p-cresol and phosphate-binders in CKD progression and CVD treatment. Further studies are needed to shed more light on this road.
