Syed M A, Horwitz M J, Tedesco M B, Garcia-Ocaña A, Wisniewski S R, Stewart A F
Division of Endocrinology and Metabolism, University of Pittsburgh School of Medicine, Pennsylvania 15213, USA.
J Clin Endocrinol Metab. 2001 Apr;86(4):1525-31. doi: 10.1210/jcem.86.4.7406.
All would agree that hypercalcemia occurs among patients with humoral hypercalcemia of malignancy (HHM) as a result of osteoclastic bone resorption. Some studies suggest that enhanced renal calcium reabsorption, which plays an important pathophysiological role in the hypercalcemia occurring in primary hyperparathyroidism, is also important pathophysiologically in HHM. Other studies have not agreed. In large part, these differences result from the inability to accurately assess creatinine and calcium clearance in critically ill subjects with HHM. To circumvent these issues, we have developed steady state 48-h PTH-related protein (PTHrP) infusion and 8-h hypercalcemic calcium clamp protocols. These techniques allow assessment of the effects of steady state PTHrP and calcium infusions in normal healthy volunteers in a setting in which renal function is stable and measurable and in which the filtered load of calcium can be matched in PTHrP- and calcium-infused subjects. Normal subjects were infused with saline (placebo), PTHrP, or calcium. Subjects receiving PTHrP, as expected, displayed mild hypercalcemia (10.2 mg/dL), suppression of endogenous PTH-(1--84), and phosphaturia. Subjects receiving the hypercalcemic calcium clamp displayed indistinguishable degrees of hypercalcemia and PTH suppression. Despite their matched degrees of hypercalcemia and PTH suppression, the two groups differed importantly with regard to fractional calcium excretion (FECa). The hypercalcemic calcium clamp group was markedly hypercalciuric (FECa averaged 6.5%), whereas FECa in the PTHrP-infused subjects was approximately 50% lower (between 2.5--3.7%), and no different from that in the normal controls, which ranged from 1.5--3.0%. These studies demonstrate that PTHrP is able to stimulate renal calcium reabsorption in healthy volunteers. These studies suggest that PTHrP-induced renal calcium reabsorption, in concert with the well established acceleration of osteoclastic bone resorption, contributes in a significant way to the hypercalcemia observed in patients with HHM.
所有人都认为，恶性肿瘤体液性高钙血症（HHM）患者出现高钙血症是破骨细胞性骨吸收的结果。一些研究表明，在原发性甲状旁腺功能亢进症发生的高钙血症中起重要病理生理作用的增强的肾钙重吸收，在HHM中在病理生理上也很重要。其他研究则不认同这一观点。很大程度上，这些差异是由于无法准确评估患有HHM的危重症患者的肌酐和钙清除率。为了规避这些问题，我们开发了稳态48小时甲状旁腺激素相关蛋白（PTHrP）输注和8小时高钙血症钙钳夹方案。这些技术能够在肾功能稳定且可测量、并且在接受PTHrP和钙输注的受试者中钙滤过负荷可以匹配的情况下，评估稳态PTHrP和钙输注对正常健康志愿者的影响。正常受试者接受生理盐水（安慰剂）、PTHrP或钙输注。正如预期的那样，接受PTHrP的受试者出现轻度高钙血症（10.2mg/dL）、内源性PTH-（1-84）抑制和磷尿。接受高钙血症钙钳夹的受试者表现出程度相同的高钙血症和PTH抑制。尽管两组的高钙血症程度和PTH抑制程度相当，但在钙排泄分数（FECa）方面两组存在重要差异。高钙血症钙钳夹组明显高钙尿（FECa平均为6.5%），而接受PTHrP输注的受试者的FECa约低50%（在2.5-3.7%之间），与正常对照组（范围为1.5-3.0%）无差异。这些研究表明，PTHrP能够刺激健康志愿者的肾钙重吸收。这些研究表明，PTHrP诱导的肾钙重吸收，与已明确的破骨细胞性骨吸收加速协同作用，在很大程度上导致了HHM患者中观察到的高钙血症。
