Denosumab in Chronic Kidney Disease
Denosumab is novel agent used to treat osteoporosis and prevent fractures associated with malignancies. Not much literature exists on use of this agent in advanced chronic kidney disease (CKD) and end-stage renal disease (ESRD) patients. A最近的文章在the美国肾脏疾病杂志presents a case report of severe hypocalcemia after using this agent in a dialysis patient. Dr. Brendan McCormick (BM) discusses this report with eAJKD Blog Editor Kenar Jhaveri (eAJKD).
BM：Denosumab anti-resorptive药物增加s bone mineral density by decoupling osteoclastic from osteoblastic activity, analogous to the action of bisphosphonates. The mechanism of action is entirely different from bisphosphonates. Denosumab is a monoclonal antibody directed against receptor activator of NF-κB (RANK) ligand. Binding of RANK ligand to the RANK receptor normally results in activation of osteoclasts, and thus inactivating the RANK ligand with denosumab prevents osteoclast activation, and decouples osteoclastic and osteoblastic activity favoring net bone formation.
There are two approved indications for denosumab. The first is in the treatment of post menopausal osteoporosis.A large randomized controlled trialdemonstrated an increase in BMD and decrease in fracture risk in this population. It has also been shown to reduce skeletal-related events such as pain and fractures in patients with胸部和前列腺癌metastatic to bone. Denosumab is not excreted via the kidneys, and it has been shown conclusively that denosumab does not seem to accumulate in kidney failure. It has been promoted as safe to use in CKD based on this fact and the experience in a relatively small number of patients with CKD stages 3 and 4 enrolled in these RCTs.
eAJKD:Briefly discuss your case, and what makes it unique?
BM：Other than anabstract presented by Block and colleaguesat the 2010 National Kidney Foundation’s Spring Clinical Meetings, there are no reports of the use of denosumab in patients with CKD stage 5. Even though pharmacokinetics suggest that denosumab may be safe, our experience with three hemodialysis patients suggest that there is a risk of severe hypocalcemia with this compound. We hypothesize that this is a pharmacodynamic phenomenon, that is to say that patients with renal osteodystrophy are much more prone to hypocalcemia when osteoclastic function is down-regulated by denosumab.
eAJKD:TheFREEDOM trialexcluded patients with advanced CKD and ESRD. What do you think the effect would be of such an agent on CKD stage 5 and ESRD patients when used for osteoporosis?
BM：Denosumab对CKD 5期患者骨矿物质密度的影响很可能是增加骨矿物质密度，但这并不一定意味着骨折风险或血管疾病风险降低。透析人群中BMD评分与断裂风险之间存在非常弱的联系，众所周知，CKD 5期患者的很大一部分患者的营业率较低。在该人群中，使用抗吸收剂（例如Denosumab（或双膦酸盐））进一步降低骨转换，可能会加剧这种情况，并实际上可能增加裂缝的风险并增加血管钙化。另一方面，尽管相关的低钙血症可能会进一步提高其PTH水平，但患有高离职骨疾病（骨炎纤维瘤）的人可能会有所改善。患有高离职骨疾病的人也可能最容易患有严重的低钙血症，因为这些患者更依赖于骨碎屑活性，以维持其血清钙，因为低维生素D水平不能上调钙的肠道吸收。
eAJKD:这个代理,根据品牌Xgeva,使用to treat cancer associated hypercalcemia (specifically in prostate and breast cancer patients). Studies showed no adverse effects on patients with CKD and acute kidney injury. Any comments on that?
BM：XGEVA被批准用于防止骨骼有关的事件，例如疼痛和已转移到骨骼的癌症患者的骨折。在患有骨转移和CKD阶段5的人中，它尚未对其进行研究。据我所知，XGEVA未获得FDA的批准用于治疗恶性高钙血症，尽管最近有案例报告内科年鉴that shows a marked drop in serum calcium and improvement of acute kidney injury in a patient with myeloma-related hypercalcemia. Malignant hypercalcemia is in large part related to increased secretion of RAND ligand induced by production of cytokines by tumor cells. Denosumab use is quite logical from a pathophysiologic perspective. Those with acute kidney injury should not experience the same severe hypocalcemia as those with CKD stage 5 as they do not have renal osteodystrophy and are not dependent on upregulation of osteoclasts by RAND activation to maintain serum calcium.
eAJKD:What bone biopsy changes would you anticipate in a patient with advanced CKD or ESRD who receives this agent?
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