The objective of this post-marketing surveillance (PMS) study is to assess the safety and effectiveness of CRYSVITA injection 10, 20, and 30mg, equivalent to in routine clinical settings

开始日期2023-08-11

申办/合作机构

Kyowa Kirin Korea Co., Ltd.

NCT05509595

/ Completed临床2期IIT

A Phase 2 Study of Burosumab for Fibroblast Growth Factor-23 Mediated Hypophosphatemia in Fibrous Dysplasia

Background:
Fibrous dysplasia (FD) is a disorder that affects bone growth. Affected bone tissue is weakened, and people with FD are prone to deformities, fractures, and other problems. People with FD may also have low blood phosphate levels. This can make bones even weaker. Better treatments are needed.
Objective:
To test a study drug (burosumab) in people with FD who have low blood phosphate levels.
Eligibility:
People aged 1 year or older who have FD and low blood phosphate levels.
Design:
Participants will visit the NIH 3 times in 48 weeks. Each visit will last 5 to 7 days.
Participants will self-inject burosumab under the skin in their belly, upper arm, or thigh. They (or a caregiver) will do this at home 1 or 2 times a month. They will be trained in person on how to inject the drug. Home injections will be guided via telehealth.
During NIH visits, participants will have a physical exam with blood and urine tests. They will have x-rays of different parts of their body. They will have a radioactive tracer injected into their vein; then they will have a bone scan. They will have tests to assess their strength, walking, and movement. They will complete questionnaires about their pain, mobility, and fatigue levels.
Adult participants may have bone biopsies. These will be done under anesthesia with sedation. Small samples of FD-affected bone will be removed for study.
Between NIH visits, participants will go to a local laboratory for blood and urine tests.
Child participants will have an additional follow-up visit 2 weeks after the final NIH visit.

开始日期2022-12-07

申办/合作机构

National Institute of Dental & Craniofacial Research

100 项与布罗索尤单抗相关的临床结果

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100 项与布罗索尤单抗相关的转化医学

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100 项与布罗索尤单抗相关的专利（医药）

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323

项与布罗索尤单抗相关的文献（医药）

2026-09-01·Kidney International Reports

Mineral and Bone Disease in CKD and Kidney Transplantation: Controversies, Gaps, and a Path Forward

Review

作者: Aktas, Ozgur ; Kanbay, Mehmet ; Copur, Sidar ; Drueke, Tilman B ; Massy, Ziad A

The pathophysiology of chronic kidney disease (CKD)-related mineral and bone disorder (CKD-MBD) extends far beyond simple mineral imbalances. Evolving from the traditional understanding of secondary hyperparathyroidism, the conceptual framework has recently been updated to recognize 2 distinct but overlapping clinical syndromes: CKD-associated osteoporosis, which encompasses the significantly increased fracture risk and microarchitectural deterioration in this population; and CKD-associated cardiovascular disease, which accounts for vascular and structural cardiac abnormalities, including medial vascular calcification. Unlike traditional osteoporosis, the 2 clinical syndromes emerge from intricate interactions between declining kidney function and dysregulated mineral metabolism. The early rise in fibroblast growth factor-23 (FGF-23) levels; progressive phosphate retention; diminished vitamin D activation; secondary hyperparathyroidism; and uremic toxin accumulation, particularly uric acid and indoxyl sulfate, orchestrate profound disruptions in osteocyte, osteoblast, and osteoclast function. The complex interaction amplifies in the dialysis population, where protein-energy wasting affects most patients; and intensifies following kidney transplantation because of glucocorticoid, immunosuppressive, and anticoagulant treatments. Consequently, fracture rates in patients with CKD exceed those of age-matched controls by >4-fold, with patients on dialysis therapy facing a ≤ 8-fold increased risk. Available diagnostic and predictive tools need to be improved to adequately identify at-risk patients. The usefulness of additional, more recent biomarkers such as FGF-23, a-Klotho, and various bone turnover parameters remains a matter of debate. Bone biopsy, considered as the diagnostic gold-standard, remains impractical in routine practice. Dual-energy X-ray absorptiometry (DXA) cannot provide information on the type of renal osteodystrophy. Moreover, it demonstrates limitations in the presence of severe vascular calcifications. Trabecular bone scores (TBS) emerge as potential progress in noninvasive bone imaging, showing modest superiority over traditional densitometry in predicting fracture risks among secondary osteoporosis populations, yet large clinical trials with long-term follow-up are required. Therapeutic management spans from parathyroidectomy to pharmacological interventions with bisphosphonates, denosumab, teriparatide, romosozumab, whereas agents such as burosumab remain investigational, with no published clinical trials in this population. However, therapeutic nihilism persists, with most high-risk patients not receiving bone-targeted therapy despite accumulating safety data. Transforming care demands abandoning therapeutic nihilism, embracing personalized risk stratification, and conducting trials in populations historically excluded from bone health research.

2026-07-01·EUROPEAN JOURNAL OF ENDOCRINOLOGY

Hyperparathyroidism after 3 years of burosumab in children affected with X-linked hypophosphatemia

Article

作者: Linglart, Agnès ; Chaussain, Catherine ; Bardet, Claire ; Berkenou, Jugurtha ; Zhukouskaya, Volha V ; Ertl, Diana-Alexandra ; Kamenicky, Peter ; Audrain, Christelle ; Rothenbuhler, Anya

Abstract:

Background/aim:

Hyperparathyroidism (HPTH) is a common feature in patients with X-linked hypophosphatemia (XLH), especially when treated with vitamin D analogs and phosphate supplements. Although the exact mechanism is not clear, it is assumed that prolonged intake of phosphate supplements stimulates parathyroid hormone (PTH) secretion. We prospectively assessed the effect of burosumab on PTH levels in children with XLH.

Patients and methods:

Thirty-seven children (8.8 ± 3.2 years) were switched from phosphate supplements and vitamin D analogs to burosumab and completed at least 3 years of therapy. Biochemical parameters of calcium-phosphate homeostasis were measured at baseline and prospectively every 6 months. Target serum phosphate under burosumab was >1.2 mmol/L (>3.7 mg/dL).

Results:

After 3 years of treatment, there was a global increase of PTH levels from 39.1 ± 18.2 to 54.8 ± 27.6 ng/L (P = .001) (normal range 18.5-88 ng/L). Four of 37 subjects (10.8%) developed secondary HPTH after 3 years. None developed tertiary HPTH. Subjects who developed HPTH had higher serum phosphate at M36 (1.33 vs 1.19 mmol/L, P = .11, respectively), in comparison with those without HPTH. A significant increase in PTH was correlated with the increase in serum phosphate >1.3 mmol/L (P = .012); serum phosphate positively and independently correlated with PTH in logistic regression analysis (odds ratio = 2.1, 95% CI = 1.1-3.8, P = .021).

Conclusion:

We suggest that higher serum phosphate levels in the context of prolonged treatment with burosumab may stimulate PTH secretion in some patients with XLH, leading to HPTH. Careful follow-up and preventive measures to limit the development of secondary HPTH should be applied in treated children.

2026-07-01·BONE

Efficacy and safety of Burosumab in tumor-induced osteomalacia: A systematic review and meta-analysis

Review

作者: de Lima, Isaac Feliciano ; de Oliveira, Caio Teotonio ; Rodrigues, Cainã Gonçalves ; Ribeiro, Paulo Victor Zattar ; Giovacchini, Giovanna ; Antonello, Breno Bopp

INTRODUCTION:

Tumor-induced osteomalacia is a rare paraneoplastic syndrome characterized by defective bone mineralization due to excessive fibroblast growth factor 23 production, leading to hypophosphatemia, phosphaturia, and osteomalacia. Burosumab, a monoclonal antibody that targets fibroblast growth factor 23, has emerged as a promising therapeutic option for patients with tumor-induced osteomalacia. This systematic review and meta-analysis assesses the efficacy and safety profile of Burosumab in managing tumor-induced osteomalacia, particularly in cases refractory to conventional treatments or when surgical resection of the tumor is not feasible.

METHODS:

This systematic review and meta-analysis adhered to the PRISMA guidelines and the Cochrane Handbook. Eligible studies included clinical trials evaluating Burosumab against placebo or standard care in patients with tumor-induced osteomalacia. Key outcomes encompassed serum phosphate levels, histomorphometric osteoid parameters, worst pain scale scores, and safety endpoints. Data extraction and quality appraisal were undertaken independently by two reviewers. Pooled means and events per 100 observations were derived using an inverse-variance random-effects model.

RESULTS:

Four studies met the eligibility criteria, encompassing 44 patients treated with Burosumab. Burosumab effectively stabilized serum phosphate levels (MD = 0.99; IC 95% 0.77-1.21; I² = 0%). Histomorphometric parameters of osteoid tissue demonstrated marked improvements following Burosumab treatment, including reductions in thickness (MD = -4.56; IC 95% -6.72 to -2.40; I² = 29.6%), volume (MD = -5.45; IC 95% -6.91 to -3.99; I² = 0%), however, no significant change was observed in surface area (MD = -0.56; IC95% -3.63 - 2.50; I² = 0%). Burosumab also significantly reduced pain score (MD = -1.11; IC95% -2.27 - 0.04; I² = 0%). Safety analyses revealed that 79.33% (IC 95% 15, 84-98,74; I² = 80.7%) of patients experienced adverse events, which were predominantly mild and seldom necessitated treatment discontinuation.

CONCLUSION:

Burosumab was associated with improvements in serum phosphate and bone histomorphometric parameters. A trend toward pain reduction was observed. The safety profile appeared acceptable, although adverse events were frequent. Findings should be interpreted considering the limited evidence base.

139

项与布罗索尤单抗相关的新闻（医药）

2026-09-01

·Biotech前瞻

百济只是其中之一：特朗普MFN再扩围，9家药企谁受影响最大？

特朗普政府的药价谈判，开始从大型跨国药企向中型制药企业延伸。当地时间8月31日，白宫宣布与爱尔康、安斯泰来、百济神州、BridgeBio、CSL、协和麒麟、太阳制药、梯瓦和优时比等9家药企达成最惠国药价协议。至此，与美国政府达成MFN安排的药企增至26家，覆盖美国约89%的品牌药市场。九家公司还承诺，近期在美国投入至少196亿美元用于制造业建设。国内市场的注意力主要集中在百济神州及替雷利珠单抗，但从产品规模看，百济并不是这批企业中潜在影响最大的一家。九家公司背后涉及前列腺癌、血友病、罕见病、自身免疫病、神经系统疾病和眼科疾病等多个高价值市场，其中不乏年销售额数十亿美元的重磅产品。不只是替雷利珠单抗根据目前披露的信息，百济神州将通过Medicaid项目，以约定价格向符合条件的患者提供替雷利珠单抗。替雷利珠单抗已经在全球50多个市场获批。2026年第二季度，其全球销售额约为2.29亿美元，按单季简单年化接近9亿美元。协议预计覆盖的患者约占替雷利珠单抗美国已获批适应证患者群体的8%，因此短期财务影响可能相对有限。百济神州在美国规模更大的产品是BTK抑制剂泽布替尼。2026年第二季度，泽布替尼全球销售额约12.5亿美元，其中美国市场约8.93亿美元。但截至目前，没有公开信息显示泽布替尼被明确纳入本次具体定价安排。相比之下，其余八家药企中，多家公司拥有规模更大的成熟产品。需要注意的是，白宫只公布了血友病、帕金森病、黄斑变性、青光眼、肝病、皮肤病和癌症等疾病类别，没有披露九家公司逐一对应的药品清单及折扣幅度。因此，上表列出的是相关企业在美国最主要、与白宫所述疾病较为匹配的产品，不代表这些药品已经全部确认降价。安斯泰来和UCB的产品规模更大安斯泰来从现有产品规模看，安斯泰来是这批企业中值得重点关注的一家。其核心产品XTANDI用于前列腺癌，2025财年销售额达到9608亿日元，是全球规模最大的肿瘤药物之一。ADC产品PADCEV同期销售约2212亿日元，地图样萎缩药物IZERVAY销售约776亿日元，CLDN18.2抗体VYLOY销售约631亿日元。白宫公告同时提到癌症和黄斑变性，与安斯泰来的肿瘤及眼科产品组合高度重合。但公司没有公布哪些药物将进入MFN框架，也没有披露价格调整幅度。优时比 UCB的潜在影响同样不容忽视。2026年上半年，IL-17A/F抗体BIMZELX实现销售15.28亿欧元，同比增长91%。优时比已将其峰值销售预期上调至至少70亿欧元。该药在美国覆盖银屑病、银屑病关节炎、强直性脊柱炎和化脓性汗腺炎等多个适应证，是目前增长最快的自身免疫药物之一。同期，CIMZIA销售9.54亿欧元，罕见癫痫药FINTEPLA销售2.39亿欧元，重症肌无力药物RYSTIGGO和ZILBRYSQ分别销售1.92亿和1.39亿欧元。对于优时比而言，短期影响取决于Medicaid患者占比；长期影响则在于，BIMZELX后续适应证和新产品的美国价格可能需要与其他发达国家进一步联动。罕见病企业也被纳入谈判 BridgeBio是目前披露最为明确的一家公司。其确认将ATTR-CM药物Attruby纳入GENEROUS模式，以扩大Medicaid患者的用药可及性。2026年第二季度，Attruby美国净销售额达到2.224亿美元，按单季度简单年化已经接近9亿美元。BridgeBio同时强调，Attruby在Medicare Part D渠道的销售不会受到本次协议直接影响，公司原有患者援助计划也将继续执行。CSL的产品规模更大。其CSL Behring板块2026财年收入达到113.87亿美元，拥有免疫球蛋白、凝血因子、遗传性血管性水肿药物以及血友病B基因疗法HEMGENIX。白宫公告明确提到血友病，但CSL没有公布具体涉及IDELVION、AFSTYLA还是HEMGENIX。公司预计协议不会对2027财年产生重大影响，显示现阶段的价格让步可能主要集中在患者规模较小的Medicaid渠道。协和麒麟则拥有CRYSVITA、POTELIGEO和NOURIANZ三款主要产品。其中，CRYSVITA用于X连锁低磷血症等罕见疾病，2026年收入指引达到2354亿日元；POTELIGEO用于皮肤T细胞淋巴瘤，全年收入指引546亿日元；NOURIANZ是帕金森病辅助治疗药物，全年收入指引74亿日元。白宫特别提到帕金森病，NOURIANZ因而成为最容易被联想到的产品，但协和麒麟只表示“部分药品”参与，并未确认具体品牌。太阳制药、梯瓦和爱尔康分别对应哪些市场？太阳制药在美国的创新药业务主要集中于皮肤科和皮肤肿瘤。其产品包括银屑病药物ILUMYA、斑秃药物LEQSELVI、晚期皮肤鳞癌药物UNLOXCYT、基底细胞癌药物ODOMZO以及痤疮药物WINLEVI。2027财年第一季度，太阳制药全球创新药销售额约3.51亿美元，占公司收入的21.9%，按单季年化约14亿美元。白宫所提到的皮肤病和癌症，与该公司产品结构基本对应。梯瓦的核心创新药包括运动障碍药物AUSTEDO、偏头痛药物AJOVY和精神分裂症长效针剂UZEDY。2026年第二季度，三款产品分别实现销售6.96亿、2.44亿和7700万美元，公司预计全年合计收入约37亿美元。不过，梯瓦与另外八家公司存在一个差异：白宫将其列入已签约名单，但梯瓦自身公告使用的是“拟达成协议”，并称双方仍在谈判。因此，梯瓦协议现阶段更接近原则性共识，最终条款尚待确认。爱尔康则主要对应青光眼市场。其处方药包括ROCKLATAN、RHOPRESSA和SIMBRINZA。2025年，公司Ocular Health业务收入约17.98亿美元，但这一数据还包含干眼及消费者眼健康产品。爱尔康规模更大的人工晶体、眼科手术设备和隐形眼镜业务不属于Medicaid处方药定价范围，本次协议的实际影响应主要集中在眼科处方药板块。不是全面下调美国药价 MFN协议并不意味着九家公司会在美国全面降低药品目录价。按照CMS公布的GENEROUS模式，参与企业主要通过向州Medicaid项目提供补充返利，使药品净支付价格接近选定发达国家的价格水平。各州可以自主决定是否参与，以及选择哪些药品执行MFN价格。2024年，美国Medicaid处方药净支出约600亿美元，较2022年增加100亿美元。企业接受更低净价后，可以换取相对统一的覆盖标准，并减少与各州分别谈判补充返利的成本。这意味着，短期影响主要取决于三项因素：具体纳入哪些药品、Medicaid患者占比，以及降价后能否换来更宽松的准入和更高的用药量。对替雷利珠单抗、Attruby等Medicaid患者比例有限的产品而言，降价未必明显影响整体收入；如果覆盖改善带来患者增量，部分价格损失还可能被销量抵消。更大的影响在未来产品定价相比现有药品的Medicaid返利，协议中有关未来创新药的约束更值得关注。九家公司承诺，未来在美国上市的创新药将提供与其他发达国家相衔接的价格。美国市场长期承担着全球创新药的大部分利润，一旦美国价格与欧洲、加拿大或日本的低价形成联动，药企可能重新安排全球上市顺序。价格较低的国家可能被推迟上市，海外净价谈判也可能趋于强硬。部分企业还可能减少公开折扣，更多使用保密返利，避免某一市场的低价成为美国定价参照。与此同时，这项协议也并非单向降价。九家公司合计承诺至少196亿美元的美国制造业投资，部分企业还将向美国战略原料药储备捐赠抗生素、抗癫痫药和免疫抑制剂原料。部分公司则获得关税豁免、延期或更明确的政策预期。从交易结构看，这是一项由药价、市场准入、关税和本土制造共同组成的政策交换。百济神州因替雷利珠单抗受到国内关注，但从产品规模看，安斯泰来、CSL、UCB和梯瓦的潜在暴露更大；从长期影响看，受到冲击的也不只是九家公司当前的销售收入，而是创新药在美国定高价、再向全球扩散的传统商业模式。

2026-08-29

·青叶待月 & 内分泌小贴士

Klotho在盐敏感性高血压与原发性醛固酮增多症中的作用——从分子机制到肾脏-肾上腺轴的再认识

原发性醛固酮增多症的精准诊疗的路还很长很远…… Klotho在盐敏感性高血压与原发性醛固酮增多症中的作用 ——从分子机制到肾脏-肾上腺轴的再认识摘要 Klotho（α-Klotho，基因符号KL）是一种主要表达于肾脏的I型单次跨膜糖蛋白，兼具FGF23共受体和可溶性内分泌因子双重功能。近年来，随着2026年JCEM发表的rs9563124调控变异研究以及肾脏分区特异性Klotho功能的新发现，Klotho与肾素-血管紧张素-醛固酮系统（RAAS）、盐敏感性高血压及原发性醛固酮增多症（PA）之间的关系受到重新审视。本文系统梳理Klotho的分子结构、合成分泌、生理功能与病理生理意义，重点阐述其对RAAS的负向调控作用、与PA的关联性证据、肾脏-肾上腺轴的生态位定位，以及KL遗传变异的临床意义，并基于现有证据探讨Klotho在疾病诊断、预测和药物研发中的转化前景。当前证据表明，Klotho更宜被定义为"肾单位分区特异的矿物代谢调节蛋白+RAAS/肾上腺CYP11B2的潜在制动因子"，而非简单的"抗衰老激素"；rs9563124等变异是醛固酮反应性与盐敏感性的候选遗传修饰因子，距离PA临床生物标志物仍需独立队列重复与功能验证。关键词：Klotho；盐敏感性高血压；原发性醛固酮增多症；RAAS；肾脏-肾上腺轴；CYP11B2；遗传变异一、Klotho的分子结构、合成与分泌、生理作用及病理生理意义（一）分子结构与"分子式"辨析本文所论Klotho特指α-Klotho（基因符号KL），而非β-Klotho（KLB）。人KL基因定位于染色体13q13.1，编码区含5个外显子[1,2]。UniProt收录的人α-Klotho经典蛋白由1012个氨基酸组成，理论分子量116,181 Da，属于I型单次跨膜蛋白：大的N端结构域位于细胞外，约第982–1002位氨基酸为跨膜区，C端为仅含约11个氨基酸的胞质短尾[2]。关于"分子式"需要特别说明：Klotho是高度N-糖基化的糖蛋白，不像醛固酮（C₂₁H₂₈O₅）那样存在唯一固定的小分子化学分子式。若仅按1012个氨基酸的经典序列计算、忽略所有糖基化及翻译后修饰，全长未修饰多肽的元素组成约为C₅₃₄₁H₈₀₂₄N₁₄₁₀O₁₄₅₂S₃₀，对应约116.18 kDa；但人体成熟Klotho因明显糖基化，在电泳中常见迁移分子量约为125–130 kDa[2,3]。因此严格而言，成熟Klotho糖蛋白不存在唯一固定的"分子式"。结构上，胞外部分主要包含KL1和KL2两个同源结构域。早期文献曾将Klotho描述为糖苷酶样蛋白；但2018年Chen等解析的FGF23–FGFR–Klotho复合物原子结构显示，其结构并不支持经典糖苷酶催化机制，更可靠的表述是：膜Klotho是FGF23信号的非酶性分子支架/共受体[3]。（二）合成与分泌 Klotho在细胞内合成后，经N端信号肽进入内质网—高尔基体，发生糖基化，随后以I型膜蛋白形式插入细胞膜。肾脏是最重要的表达器官，传统观点认为其主要表达于远端肾小管；但2026年最新的肾单位分区研究对这一模型作出了重要修正（详见第四部分）[4,5]。 Klotho存在两种主要分子形式： ① 膜结合型Klotho（membrane-bound Klotho）：留在肾小管上皮细胞膜表面，作为FGF23的必需共受体，与FGFR结合后介导磷-维生素D代谢信号[3,6]。 ② 可溶性Klotho（soluble Klotho, sKlotho）：膜Klotho的胞外结构域被ADAM10/ADAM17等金属蛋白酶在近膜区剪切脱落（ectodomain shedding），释放入血液、尿液和脑脊液，发挥内分泌、旁分泌和自分泌作用[7]。目前最可靠的sKlotho来源模型是：膜Klotho → ADAM10/ADAM17剪切 → 胞外结构域脱落 → 循环sKlotho。过去曾认为KL的另一种选择性剪接转录本可直接编码"分泌型Klotho"，但Mencke等发现该转录本含提前终止密码子，是无义介导降解（nonsense-mediated decay, NMD）的靶标，几乎没有可靠证据证明其大量翻译成真正的分泌蛋白[8]。因此目前更合理的模型是：人体循环sKlotho主要来自膜Klotho的蛋白水解脱落，而非独立的"secreted Klotho"转录本。 Yamada等在接受肾上腺静脉采血的PA患者中测量下腔静脉sKlotho，发现肾上方IVC浓度（476±68.2 pg/mL）显著高于肾下方（434±74.8 pg/mL，P=0.018），存在约8%的"肾静脉流出增加"，直接证实了肾脏是循环sKlotho的重要来源[9]。图1 Klotho蛋白的分子结构与分泌过程示意图（三）生理作用 Klotho的生理功能可分为三个层级，其证据强度依次递减： 1. FGF23–磷–维生素D轴（最坚实的功能）膜Klotho与FGFR构成FGF23信号复合物，参与肾脏排磷、1,25-(OH)₂D调控以及钙磷稳态。这是Klotho最具因果证据的功能，原子结构研究进一步证明Klotho实际上将FGF23与FGFR"架"在一起[3,6]。 2. 肾小管离子运输（分区特异） 2026年最新研究对传统观点作了重要修正：Klotho在近端肾小管（PT）的单细胞表达量虽然低于远端，但PT细胞数量巨大，PT-Klotho对FGF23、排磷和维生素D至关重要，很可能是循环sKlotho的主要来源；而DCT2/CNT中的高表达Klotho更偏向调控Ca²⁺重吸收、TRPV5等钙转运程序以及尿液Klotho[4,5]。远端特异性Klotho敲除会造成明显高钙尿及骨量下降，却不会复制典型高磷血症[5]。 3. 更广泛的sKlotho作用（证据需谨慎）大量动物和细胞研究提示sKlotho可抑制氧化应激、炎症、纤维化、Wnt/TGF-β等通路，改善内皮功能和血管稳态[10,11]。但这部分需要比"FGF23共受体"更谨慎，因为循环sKlotho的真正受体、有效生理浓度和部分FGF23非依赖效应仍有争议；最新综述甚至指出，生理循环sKlotho浓度远低于许多体外实验所使用的浓度[4]。（四）病理生理意义 Klotho缺乏最典型的后果是FGF23抵抗、磷潴留、活性维生素D升高、异位钙化及类似加速衰老的多器官表型。当前的一个重要认识是，"Klotho抗衰老"并不一定意味着存在一个神秘的独立抗衰激素通路；很多小鼠早衰表型实际上可以追溯至Klotho–FGF23–磷/维生素D失衡[4,12]。在临床疾病中，Klotho降低尤其见于急性肾损伤（AKI）和慢性肾脏病（CKD），并与CKD-MBD、血管钙化、内皮功能障碍、动脉硬化和高血压相关[10,13]。最有力的人类因果证据之一来自罕见KL失活突变：纯合p.His193Arg（H193R）可造成严重高磷血症性家族性肿瘤样钙化，患者FGF23很高但无法正常发挥作用，直接证明了人体Klotho–FGF23轴的生理必要性[14]。二、Klotho对RAAS系统的作用与意义 Klotho可以被视为传统RAAS之外的一个"负反馈制动器/环境调节器"。其与RAAS之间存在双向调控关系，且在病理状态下可形成恶性正反馈环。（一）RAAS对Klotho的负向调控 ① AngII下调肾Klotho：AngII持续刺激通过AT1受体（AT1R）下调肾脏KL表达，且这种效应并不只是升高血压后的继发现象；AT1阻断可以抑制这一过程[15]。因此RAAS过度活化本身就可能制造一个"Klotho缺陷肾"。 ② 盐摄入调节Klotho：人群盐干预研究显示，从正常盐转为低盐后血清Klotho上升，而高盐阶段重新下降[16]。高钠摄入可通过抑制1,25(OH)₂D₃合成而下调PTH1R和Klotho表达[17]。（盐摄入与血清Klotho水平呈明确的负相关关系：人群干预、动物及细胞实验均表明，低盐饮食可提升Klotho水平，而高盐摄入则降低其表达与循环浓度，该效应在老年人群和盐敏感性高血压人群中更为显著，且外源性补充Klotho可直接逆转高盐诱导的血压升高和靶器官损伤。其核心分子机制在于，高钠通过抑制肾脏局部1,25(OH)₂D₃的合成，进而下调PTH1R和Klotho的表达，这一通路已在人近端肾小管上皮HK-2细胞实验中得到直接验证。该通路可分为三个环节：首先，高钠经钠磷转运体、钠氢转运体及钠钾ATP酶进入肾小管上皮细胞后，下调1α-羟化酶（Cyp27b1）和24-羟化酶（Cyp24a1）的表达，导致细胞内活性维生素D合成减少——使用钠转运抑制剂或胞外钙螯合剂可逆转该效应，而钠钾ATP酶抑制剂哇巴因则会加重之，证实钠的细胞内转运是上游触发因素。其次，1,25(OH)₂D₃作为VDR的天然配体，激活后者发生核转位并结合到PTH1R与Klotho基因启动子区的维生素D反应元件（VDRE）上，促进二者转录；当高钠导致1,25(OH)₂D₃减少时，VDR招募减弱，PTH1R与Klotho表达同步下调。最后，高钠同时引起胞内钙离子浓度升高，钙过载进一步抑制Klotho表达，形成恶性循环。除上述维生素D通路外，高盐还可通过多条独立通路下调Klotho：一是激活RAAS系统，经醛固酮-盐皮质激素受体通路诱导氧化应激和炎症反应；二是上调Wnt5a/RhoA非经典通路；三是诱导Klotho基因启动子区发生DNA高甲基化，从表观遗传层面长期抑制其转录。这些并行机制共同构成了盐摄入负向调控Klotho的完整网络。） ③ 脱水与激素调节：Tang等发现，脱水尽管升高循环醛固酮和血管加压素，但肾脏Klotho表达反而下降；在HEK293细胞中，ADH（50 nM）和醛固酮（1 μM）均显著降低Klotho的转录和蛋白表达[18]。（从表面看，脱水时机体需要保护肾脏、维持功能，而 Klotho 是关键的肾脏保护和抗衰老因子，理应升高，但实际反而下降，这本质是短期生存优先于长期稳态的生理权衡： - -短期适应价值：抑制 Klotho 可解除其对肾脏 1α- 羟化酶的抑制，使 1,25 (OH)₂D₃合成增加，进而促进肠道和肾小管对钙、钠的重吸收，帮助快速恢复血容量和电解质平衡，优先保证循环稳定。 -- 长期病理代价：若脱水持续或反复发生，会进入恶性循环：脱水 → ADH / 醛固酮升高 → Klotho 下降 → 1,25 (OH)₂D₃过度生成 → 高磷血症、组织钙化 Klotho 下降 → RAAS 系统进一步激活 → 醛固酮分泌更多 → Klotho 表达更低。这也是老年人慢性脱水、容量不足会加速衰老和肾损伤的核心机制之一。脱水下调 Klotho 的其他参与因素：除 ADH 和醛固酮外，脱水时激活的**血管紧张素 II（Ang II）也是 Klotho 的强抑制剂，它通过 AT1 受体通路同样可诱导氧化应激、抑制 Klotho 转录，三者共同作用导致脱水状态下 Klotho 的显著下调。）（二）Klotho对RAAS的抑制作用 ① 肾上腺层面（核心）：Zhou等的关键实验发现，KL半缺失小鼠出现血浆醛固酮升高、肾上腺CYP11B2（醛固酮合酶）表达增加；依普利酮能逆转高血压并减轻肾损害。在人肾上腺皮质NCI-H295R细胞中，降低KL会增加CYP11B2，过表达KL则降低CYP11B2，机制可能涉及SF-1和ATF2等转录因子[19]。 ② 肾脏层面：Klotho改善肾小管钠排泄，减轻容量负荷，间接缓解RAAS过度激活；抑制肾脏局部RAAS组分表达，减轻肾纤维化[10,20]。 ③ 血管层面：Klotho拮抗AngII介导的氧化应激、内皮损伤和血管重构；Klotho缺陷时，盐可通过血管Wnt5a通路促进衰老相关高血压[21]。（三）RAAS–Klotho恶性正反馈环综合上述证据，可以勾勒出一个病理状态下的恶性循环： AngII/AT1R ↑ → 肾Klotho ↓ → Klotho对肾上腺CYP11B2的抑制减弱 → 醛固酮 ↑ → Na⁺潴留、氧化应激、肾/血管损伤 ↑ → Klotho进一步下降这一正反馈环解释了为什么RAAS过度激活一旦启动便难以自限，也为ACEI/ARB/MRA类药物的靶器官保护效应提供了部分机制解释——这些药物可能通过提升Klotho水平而打破恶性循环。（四）对原文一处引文方向的辨析值得特别指出的是，Heydarpour等2026年JCEM接收稿在引言中写道"aldosterone and vasopressin stimulate Klotho expression in cultured renal cells"[1]，但其引用的Tang et al. 2011原始研究实际报告的是相反结果：ADH和醛固酮均显著降低HEK293细胞的Klotho转录和蛋白表达[18]。这很可能是接收稿中的表述/引文方向错误，阅读时应以原始Tang论文为准。若以原始结果为准，则整个反馈环更具逻辑一致性：AngII↑/醛固酮↑ → Klotho↓；Klotho↓ → CYP11B2/醛固酮↑，即形成上述RAAS–Klotho恶性正反馈环。图2 RAAS–Klotho恶性正反馈环与肾脏-肾上腺轴示意图三、Klotho与原发性醛固酮增多症的关联性这里必须严格区分"有生物学联系"和"已经证明与PA有临床因果关系"两个层面。当前证据支持前者，但后者尚未建立。（一）动物与细胞层面：关联很强 Zhou等（2016）的研究提供了目前最直接的实验证据：KL半缺失（KL⁺/⁻）小鼠在16周龄时出现血浆醛固酮升高、自发性持续性高血压，肾上腺皮质中CYP11B2蛋白表达上调；使用醛固酮受体拮抗剂依普利酮可逆转高血压并减轻肾脏损伤[19]。在人肾上腺皮质NCI-H295R细胞中，CRISPR-Cas9敲除Klotho后，AngII刺激下的CYP11B2表达升高；Klotho直接下调CYP11B2及其调控转录因子Nr4a1和Nr4a2，且这种调控具有通路选择性（ERK1/2信号通路似乎不受影响）[19]。因此从机制上讲，Klotho缺乏完全有可能造成一种"高醛固酮倾向状态"（hyperaldosteronism-prone state）。（二）rs9563124研究并非PA研究——关键区分 Heydarpour等2026年的研究是在HyperPATH队列中进行的，该队列明确排除了继发性高血压[1]，因此这并不是一个确诊PA队列。研究发现rs9563124 G等位基因与以下表型显著相关：表型 β值（每G等位） P值盐敏感性血压（SSBP） +2.85 mmHg 0.00185 基础醛固酮 +0.73 ng/dL 0.00156 AngII刺激后醛固酮 +1.95 ng/dL 0.00062 醛固酮反应性（Δ-醛固酮） +1.23 ng/dL 0.00611 血浆肾素活性（PRA） −0.023 0.430（无统计学意义）醛固酮/肾素比值（ARR） +1.694 0.469（无统计学意义）最强效应出现在AngII刺激后的醛固酮（P=0.00062），且效应呈近似等位基因剂量关系：AA → AG → GG，醛固酮逐渐升高[1]。但非常关键的是：PRA和ARR均没有显著关联。而临床PA的核心恰恰是肾素被抑制情况下的不适当/自主性醛固酮分泌，2025年Endocrine Society指南仍以醛固酮+肾素+ARR为筛查核心，并不包含Klotho[22]。因此，rs9563124是"醛固酮反应性和盐敏感性"的候选调节位点，而不是已经证实的"原发性醛固酮增多症风险等位基因"。新论文观察到的是AngII依赖性肾上腺高反应性，而经典PA的本质则更偏向AngII/肾素非依赖性自主分泌。两者可能属于醛固酮失调的连续谱，但中间那一步目前尚未得到证明。（三）人体PA中Klotho的直接证据 Yamada等（2024）在接受AVS的PA患者中测量下腔静脉sKlotho，发现肾上方IVC浓度约476±68.2，肾下方约434±74.8，P=0.018，即存在约8%的"肾静脉流出增加"[9]。但这项研究证明的是肾脏是循环sKlotho的重要来源，它并没有证明PA患者比正常人Klotho更低，也没有证明Klotho与PA严重度、单侧/双侧分型或手术预后相关。（四）Klotho与APCC的假说随着年龄增长，正常肾上腺中会积累醛固酮生成细胞簇（aldosterone-producing cell clusters, APCC；现也常按新病理命名体系讨论micronodules），其中不少携带CACNA1D等醛固酮驱动体细胞突变，并表达CYP11B2[23,24]。Heydarpour等也提出将KL基因型、sKlotho、CYP11B2、APCC病理、肾上腺影像学联合研究[1]。这是一个很有价值的方向，但目前没有证据证明"低Klotho → APCC形成 → PA"。本文更倾向于把Klotho理解成一个可能改变APCC/CYP11B2细胞"生存和分泌环境阈值"的修饰因子（modifier），而不是PA的主要驱动基因（driver）。目前PA的主要已知肾上腺驱动基因仍是KCNJ5、CACNA1D、ATP1A1、ATP2B3、CACNA1H、CLCN2等离子通道/泵基因，KL尚不属于这一级别的PA致病基因[25]。（五）当前认识总结综上所述，Klotho与PA的关联性可以概括为：动物和细胞实验证据充分支持Klotho缺乏→CYP11B2↑→醛固酮↑的机制链；人类遗传学研究（rs9563124）证明KL变异影响AngII刺激后的醛固酮反应性和盐敏感性，但该研究并非PA队列，且PRA/ARR无关联；PA患者中仅有肾脏sKlotho来源的间接证据，缺乏Klotho水平与PA分型、预后的直接关联数据。因此，Klotho目前是PA病理生理的"候选参与因子"，而非已确立的致病基因或临床生物标志物。四、Klotho对肾脏-肾上腺轴的作用与意义及生态位这是2026年rs9563124研究最值得进一步发展的概念。传统RAAS的调控路径是：肾素 → AngII → 肾上腺球状带 → 醛固酮 → 肾脏。而Klotho加进来后，可以形成第二套调控层：肾Klotho状态 ↔ 肾上腺CYP11B2/醛固酮状态。但这个"轴"至少要拆成几个生态位来理解。（一）第一生态位：近端肾小管——系统性Klotho/矿物代谢生态位 2026年最新的肾单位分区研究提示：PT中Klotho单细胞表达量不最高，但PT细胞数量巨大；PT-Klotho对FGF23、排磷和维生素D至关重要；PT很可能是循环sKlotho的主要来源。而整个远端曲管删除Klotho后，尿Klotho几乎消失，但血清sKlotho并未明显下降[4,5]。这修正了过去简单的"远端肾小管=全身Klotho来源"模型。（二）第二生态位：DCT2/CNT——尿Klotho和钙转运生态位 Klotho在DCT2/CNT表达最高，与TRPV5、Calbindin、NCX1等Ca²⁺转运基因共定位。远端特异性Klotho敲除会造成明显高钙尿及骨量下降，却不会复制典型高磷血症[5]。因此，血清sKlotho和尿液sKlotho很可能不是同一个生物学指标，未来把它们笼统当作一个"Klotho水平"可能是不正确的。（三）第三生态位：肾上腺球状带——醛固酮合成生态位 Zhou等发现Klotho与CYP11B2在肾上腺球状带中共定位，而且直接改变肾上腺细胞KL表达就能改变CYP11B2[19]。2024年另有研究报道球状带来源的Klotho可调节年轻雌性小鼠的醛固酮合酶表达[26]。这带来一个非常重要的修正："肾脏-肾上腺Klotho轴"不一定全部由循环肾源性sKlotho介导，可能同时存在： ① 肾来源sKlotho → 肾上腺的内分泌效应； ② 肾上腺本身的局部KL → CYP11B2的自分泌/旁分泌制动作用。目前第二条的直接实验依据反而更明确。Heydarpour等也承认，肾脏是循环sKlotho的主要来源，而肾脏→肾上腺的人体内分泌模型目前仍是假说[1]。（四）第四生态位：衰老/高盐/CKD/APCC——转化研究层这是最值得做转化研究的一层：衰老 / CKD / 高盐 / AngII ↑ → 肾/肾上腺Klotho ↓ → CYP11B2制动减弱 + APCC/体细胞驱动突变随年龄增加 → 自主性或过度醛固酮 ↑ → 钠潴留、纤维化、血管损伤 → 肾Klotho进一步 ↓ 因此，Klotho很可能不是单纯"又一个激素"，而更像一个控制肾脏-肾上腺系统稳态阈值的生态位因子（niche factor）。它不直接驱动醛固酮合成，但设定了肾上腺对AngII刺激的反应阈值；当这个阈值因衰老、CKD、高盐或遗传变异而下调时，同样的AngII刺激会产生更大的醛固酮应答，从而促进盐敏感性高血压和潜在的PA发生发展。五、Klotho相关遗传变异的重要临床意义 KL基因区域的遗传变异可分为两大类：常见非编码调控变异（如rs9563124）和编码区错义变异（如KL-VS单倍型中的rs9536314和rs9527025），此外还有罕见的纯合失活突变（如p.His193Arg）。（一）主要遗传变异汇总变异类型已知主要表型目前临床意义 rs9563124 A>G 调控变异（非编码区） G等位：↑SSBP、↑基础醛固酮、↑AngII刺激醛固酮、↑Δ醛固酮；PRA/ARR无关联研究型风险修饰因子；尚不能临床检测指导PA rs9536314 F352V 错义变异；KL-VS组成部分盐敏感性、pressure-natriuresis右移、衰老/认知等 HTN/盐敏感性证据较有意义，但多效性结果不完全一致 rs9527025 C370S 错义变异；与F352V组成KL-VS 与KL-VS功能及部分衰老表型相关目前主要研究用途 rs1207568 G-395A 启动子变异心血管病、尿石症等群体关联效应小且人群异质性较大 p.His193Arg (H193R) 罕见纯合失活突变 FGF23抵抗、高磷血症、家族性肿瘤样钙化真正具孟德尔致病意义的KL变异图3 Klotho基因遗传变异全景与临床表型关联示意图（二）rs9563124深度解析 rs9563124位于染色体13:33063402，A/G变异，效应等位基因为G，在HyperPATH队列中的次要等位基因频率（MAF）为0.34[1]。其效应表现出以下特征： ① 加性遗传模式：AA → AG → GG，醛固酮水平依次升高，最强信号是AngII刺激后醛固酮（P=0.00062）[1]。 ② 年龄和性别分层（探索性）：SSBP关联在女性和≥50岁参与者中更强；醛固酮表型关联在女性和<50岁参与者中更明显。但作者明确指出这些都是探索性亚组分析，没有足够统计功效证明真正的基因型×性别或基因型×年龄交互作用[1]。 ③ 功能注释支持调控机制：GTEx数据显示rs9563124与KL表达在垂体、尾状核等组织中存在eQTL关联；VannoPortal预测G等位基因可破坏HDAC1、GATA3、GATA2、IRF1等转录因子结合基序，同时创造MEF2A、SOX2、POU2F2、NANOG、TBP等新的结合基序[1,27,28]。但这些都是计算预测，需要实验验证。需要特别指出的是，rs9563124的GTEx eQTL信号目前主要出现在垂体、尾状核等组织，而不是直接在肾脏或肾上腺中得到明确eQTL证据。因此现在还不能说"rs9563124 G → 肾/肾上腺KL下降 → CYP11B2升高"这一整条链已经被实验证明。这是下一步CRISPR/等位基因特异性报告基因/肾上腺类器官实验最值得验证的内容，论文作者自己也提出了reporter assay、染色质可及性分析和CRISPR验证的方向[1]。（三）KL-VS功能单倍型 KL-VS主要由rs9536314（F352V）+ rs9527025（C370S）两个错义变异构成，位于Heydarpour等研究中的Block 7（含5个变异）[1]。单倍型分析显示： ① TGGTA单倍型（频率0.544，保护型）：与更低SSBP（β=−1.90，P=0.018）、更低基础醛固酮（β=−0.52，P=0.020）、更低AngII刺激醛固酮（β=−1.12，P=0.041）相关； ② TGGTG单倍型（频率0.301，风险型）：与更高基础醛固酮（β=+0.48，P=0.048）、更高AngII刺激醛固酮（β=+1.61，P=0.006）、更大醛固酮反应性（β=+1.15，P=0.013）相关[1]。 Citterio等（2020）对盐敏感高血压的研究也相当有意义：rs9536314 G等位基因携带者pressure-natriuresis曲线更右移，需要更高血压才能排出同样的钠；结果在独立队列中得到复制，总样本达866人，且循环Klotho与盐负荷后的血压变化呈负相关[29]。另一方面，KL-VS与寿命和认知的结果并不完全一致：Dubal等曾观察到杂合KL-VS与较高Klotho和更好认知相关[30]，但一个1812人的后续人群研究没有复制出认知优势[31]。因此，常见KL多态性更适合作为风险修饰因子，而不是"好/坏基因"的简单分类。（四）罕见致病突变p.His193Arg 与常见变异不同，p.His193Arg（H193R）是真正具有孟德尔致病意义的KL变异。Ichikawa等（2007）报道纯合H193R突变导致严重高磷血症性家族性肿瘤样钙化，患者FGF23水平很高但无法正常发挥作用（FGF23抵抗），直接证明了人体Klotho–FGF23轴的生理必要性[14]。这一突变也为理解Klotho的功能域提供了天然的人类"基因敲除"模型。（五）临床意义总结综合来看，KL遗传变异的临床意义可以分层理解：①罕见纯合失活突变（如H193R）具有明确的孟德尔致病意义，可导致严重的矿物代谢紊乱；②常见编码变异（KL-VS）和调控变异（rs9563124）主要作为风险修饰因子，影响盐敏感性、醛固酮反应性等数量性状，效应量中等且需独立重复；③所有常见变异目前均属于假说生成的候选基因研究结果，尚未达到临床常规基因检测的证据等级，不能直接用于PA的临床诊断或治疗决策。六、基于Klotho的临床诊断、预测与药物研发启示（一）诊断：Klotho最可能成为"第二层分型指标"，而非替代ARR 至少目前，不能用Klotho取代PA的醛固酮、肾素、ARR、抑制试验或AVS。2025年Endocrine Society指南仍明确以醛固酮+肾素+ARR为核心，手术候选者主要依靠CT+AVS判断侧别[22]。Klotho更有希望进入一种"精准内分泌表型分型"（precision endocrine phenotyping）模型： KL基因型 + 血清/尿液sKlotho + 肾素 + 醛固酮 + 激发后Δ醛固酮 + eGFR + 钠状态而不是单测一个Klotho数值。尤其Heydarpour等的研究提示，动态表型可能比静态值更重要：rs9563124对AngII刺激后醛固酮的关联明显强于基础醛固酮[1]。因此未来比"早晨空腹Klotho"更值得尝试的可能是：Klotho/基因型 × 钠/AngII激发 × 醛固酮反应的组合评估。（二）预测：可能预测盐敏感性、低肾素表型和治疗反应未来值得验证的预测终点包括：①谁更容易产生盐敏感性高血压；②谁在AngII刺激下出现异常强的醛固酮反应；③谁以后进入低肾素醛固酮增多症/显性PA；④谁对盐限制特别敏感；⑤谁对MRA（螺内酯/依普利酮）反应更好；⑥谁对ACEI/ARB更容易恢复Klotho；⑦PA手术后Klotho是否恢复、是否预测心肾重构逆转。但目前这些都属于待验证的预测生物标志物假说，Heydarpour等也明确提出未来需检验rs9563124是否预测盐皮质激素靶向治疗的反应[1]。（三）检测标准化的现实瓶颈这是很多Klotho临床论文容易忽略的问题。不同sKlotho检测方法的表现差异很大。Neyra等发现，免疫沉淀-免疫印迹法（IP-IB）对外源Klotho的回收率为81%–115%，而商业ELISA仅为60%–81%；IP-IB测出的Klotho与eGFR的相关系数为0.80，而商业ELISA仅为0.18；一次冻融就可能明显改变结果[32]。因此在开展PA/Klotho临床研究前，必须先解决：采血条件、冻存、冻融次数、抗体、检测的是全长sKlotho还是片段、血清还是血浆、是否按eGFR校正。否则很容易把"肾功能差导致Klotho低"误判为"醛固酮导致Klotho低"。（四）药物研发的五个方向方向A：直接Klotho替代治疗给予重组可溶性Klotho/KL1/KL1-KL2工程化蛋白。优势是机制直接；问题是蛋白半衰期、组织分布、制剂以及是否真能模拟膜Klotho。特别应避免简单假设"血清Klotho越高越好"——膜Klotho和可溶性Klotho功能不完全相同。方向B：提高内源KL表达寻找能够增加肾/肾上腺KL转录的小分子或表观遗传药物。Klotho表达已知受DNA甲基化和组蛋白修饰调控，组蛋白去乙酰化酶抑制剂在动物模型中可提升Klotho并减轻CKD相关骨损伤[33,34]。这可能比单纯刺激ADAM10/17脱落更合理，因为单纯增强脱落有可能出现"sKlotho↑但膜Klotho↓"，反而损害FGF23共受体功能。方向C：Klotho mRNA/基因治疗这已经不只是理论。ClinicalTrials.gov已登记AKL003（α-Klotho mRNA/LNP）的Phase 1b试验（NCT07544420），主要考察安全性、耐受性和血清α-Klotho蛋白表达；目前尚无疾病疗效结论[35]。另有质粒Klotho基因治疗的早期Phase 1 pilot（NCT07216781），但给药地点位于美国FDA管辖之外，评价其证据质量时需格外谨慎[36]。目前没有任何这些项目证明可以治疗PA。方向D：开发"肾上腺特异性Klotho–CYP11B2"药物这可能反而是与PA最直接的方向。如果最终证明"Klotho信号 → ↓CYP11B2"，则可以寻找：Klotho的CYP11B2抑制性功能结构域；模拟该结构域的肽/小分子；肾上腺靶向Klotho激动剂；或增强肾上腺KL表达的递送系统。这样理论上可以从CYP11B2上游调节醛固酮，而不必全身提高Klotho。但第一步必须搞清楚：Zhou实验中的作用究竟来自膜Klotho、脱落Klotho，还是Klotho下游某个独立信号通路。方向E：把Klotho当作"药效生物标志物"而非直接药靶这可能是最容易先实现的。例如在MRA、ARB、盐限制或醛固酮合酶抑制剂试验中同步检测sKlotho/尿Klotho/KL基因型/CYP11B2表型，看看Klotho恢复是否对应：肾素去抑制、醛固酮信号降低、血压下降、白蛋白尿改善、心肌/血管重构逆转。（五）最值得开展的临床研究设计如果目标是回答"Klotho是否真正参与PA"，本文建议设计四组队列：原发性高血压 → 低肾素高血压 → 双侧PA → 单侧PA。所有人尽量统一钠平衡，然后同时检测： ① KL基因型（尤其rs9563124、KL-VS）； ② 血清sKlotho和尿液sKlotho（分别检测，不合并）； ③ 醛固酮/肾素/ARR； ④ AngII或标准化盐负荷动态表型； ⑤ AVS时上下腔静脉Klotho梯度； ⑥ 肾上腺切除组织的KL/CYP11B2空间表达； ⑦ APCC/micronodule数量； ⑧ KCNJ5/CACNA1D/ATP1A1等体细胞突变测序。然后追踪MRA或肾上腺切除前后Klotho是否恢复。如果最终看到"低肾/肾上腺KL → 高CYP11B2 → 强自主醛固酮 → 治疗后KL恢复"，并且有纵向时间关系和组织证据，那么才真正有资格把"Klotho–肾脏–肾上腺轴"从漂亮的生物学假说升级为PA的新病理生理轴。七、总结与展望 Klotho研究正在经历一个重要的概念转型：从最初的"抗衰老神秘蛋白"转向更为精确的"肾单位分区特异的矿物代谢调节蛋白+RAAS/肾上腺CYP11B2的潜在制动因子"。2026年JCEM发表的rs9563124研究首次在人群深度表型中将KL遗传变异、AngII刺激后的醛固酮反应和盐敏感性血压串联起来，为"肾脏-肾上腺内分泌轴"提供了人类遗传学证据[1]。同年发表的肾脏分区特异性Klotho研究则修正了"远端肾小管=全身Klotho来源"的传统模型，提示近端肾小管可能是循环sKlotho的主要来源，而远端小管更偏向尿Klotho和钙转运[4,5]。然而，距离将Klotho用于PA的临床诊断、分型或治疗决策，还需要至少一轮独立人群重复、PA专门队列以及肾/肾上腺组织层面的因果验证。当前最值得关注的科学问题包括：①rs9563124是否真正改变肾/肾上腺组织中的KL表达；②肾上腺局部Klotho与循环sKlotho在CYP11B2调控中的各自贡献；③血清sKlotho与尿液sKlotho是否代表不同的生物学指标；④Klotho检测的标准化问题；⑤Klotho恢复是否可作为RAAS靶向治疗的药效学终点。从更宏观的视角看，Klotho的故事提醒我们：内分泌系统的调控往往不是单一激素的线性通路，而是多个器官、多种分子形式、多个生态位共同构成的稳态网络。Klotho作为这个网络中的一个"阈值设定因子"，其真正的临床价值可能不在于成为下一个"神奇药物"，而在于帮助我们更精细地理解和分层那些传统激素检测无法识别的"动态内分泌异常"人群，从而推动高血压和PA从"一刀切"治疗走向真正的精准医学。参考文献 [1] Heydarpour M, Gholami S, Karimian M, et al. 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[22] Adler GK, Stowasser M, Correa RR, et al. Primary Aldosteronism: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2025;110(8):2453-2495. doi:10.1210/clinem/dgaf284. [23] Nanba K, Vaidya A, Williams JS, et al. Age-related autonomous aldosteronism. Circulation. 2017;136(4):347-355. doi:10.1161/CIRCULATIONAHA.117.027225. [24] Omata K, Anand SK, Hovelson DH, et al. Aldosterone-Producing Cell Clusters Frequently Harbor Somatic Mutations and Accumulate With Age in Normal Adrenals. J Endocr Soc. 2017;1(7):787-799. doi:10.1210/js.2017-00134. [25] Ragnarsson O, Johannsson G, Bringman G, et al. Emerging methods for subtype differentiation in primary aldosteronism. J Intern Med. 2026. doi:10.1111/joim.70055. [26] Zona Glomerulosa-Derived Klotho Modulates Aldosterone Synthase Expression in Young Female Mice. Endocrinology. 2024;165(5):bqae040. doi:10.1210/endocr/bqae040. [27] GTEx Consortium. The GTEx Consortium atlas of genetic regulatory effects across human tissues. Science. 2020;369(6509):1318-1330. doi:10.1126/science.aaz1776. [28] Huang D, Zhou Y, Yi X. VannoPortal: multiscale functional annotation of human genetic variants for interrogating molecular mechanism of traits and diseases. Nucleic Acids Res. 2022;50(D1):D1408-D1416. doi:10.1093/nar/gkab1035. [29] Citterio L, Delli Carpini S, Lupoli S, et al. Klotho Gene in Human Salt-Sensitive Hypertension. Clin J Am Soc Nephrol. 2020;15(3):375-383. doi:10.2215/CJN.08620719. [30] Dubal DB, Yokoyama JS, Zhu L, et al. Life extension factor Klotho enhances cognition. Cell Rep. 2014;7(4):1065-1076. doi:10.1016/j.celrep.2014.03.076. [31] Müller BW, Drichel D, Hillmer AM, et al. Klotho KL-VS haplotype does not improve cognition in a population-based sample of adults age 55-87 years. Sci Rep. 2021;11(1):13852. doi:10.1038/s41598-021-93211-x. [32] Neyra JA, Moe OW, Pastor J, et al. Performance of soluble Klotho assays in clinical samples of kidney disease. Clin Kidney J. 2020;13(2):235-244. doi:10.1093/ckj/sfz085. [33] Kale A, Raghavan A, Bhandary B, et al. Epigenetic and non-epigenetic regulation of Klotho in kidney disease. Life Sci. 2021;264:118644. doi:10.1016/j.lfs.2020.118644. [34] Lin W, Chen L, Sun L, et al. Klotho preservation via histone deacetylase inhibition attenuates chronic kidney disease-associated bone injury in mice. Sci Rep. 2017;7:46195. doi:10.1038/srep46195. [35] ClinicalTrials.gov. NCT07544420. aKLmRNA-mediated Protein Replacement Therapy (AKL003), Phase 1b. https://clinicaltrials.gov/study/NCT07544420. [36] ClinicalTrials.gov. NCT07216781. Safety and Efficacy of Injectable Klotho Plasmid Gene Therapy in Humans, Phase 1 pilot. https://clinicaltrials.gov/study/NCT07216781. 往期回顾从"减多少公斤"到"怎样改变疾病进程" GLP-1受体激动剂相关高钙血症：证据、机制 GLP-1受体激动剂减重治疗相关脱发的思考从慢性肾脏病到糖尿病肾脏病：规范化诊疗的浅思从隐匿性醛固酮失调到显性原醛：亚临床原发性醛固酮增多症的疾病谱、诊疗挑战与预防前景

2026-08-22

·麦科奥特

算算透析SHPT治疗的经济账：为什么“单药综合达标”是更优解？

MICOT 点击蓝字关注我们 Slide to view different languages 滑动查看不同语言一个维持性血液透析的肾友每周有三天，都要在医院的透析室里度过。每次四个小时，血液在机器里循环，把身体里多出来的水和毒素“洗”出去——这些本该由肾脏处理掉的“垃圾”，现在只能靠这台机器来代替罢工的肾脏。这已经成为他们生命的“必修课”。让他们喘不过气的不仅是日渐削弱的身体，更难熬的是失去养家糊口的能力，却还要面对一次次并发症治疗时，那些越攒越多的缴费单。继发性甲状旁腺功能亢进症（SHPT），是超过70%的终末期肾病血透患者绕不过去的坎。它带来的骨痛、骨折、心血管并发症，让患者的身体和经济雪上加霜。血透患者面临的经济压力，从来不是简单的药价问题。更准确地说，它是一笔贯穿疾病长期管理全过程的“总账”：药费只是其中一部分，治疗效果的好坏、用药种类的多少、不良反应的轻重、检查频率的高低、住院次数的多少、并发症的多少以及由疾病造成的工作能力下降，都可能成为这笔账里沉甸甸的条目。所以，当我们讨论创新药的价值时，不能只问“这款药多少钱？” 还应该进一步追问：“它能否帮患者获得更好的治疗效果吗？它能减少那些搭配着吃的一大把辅助用药吗？它能降低不良反应和并发症的风险吗？长远来看，它能减少反复检查、反复住院带来的长期医疗资源消耗吗？” 说到底，算药学的账，不能只算买药那一刻的"小账"，要算整个治疗过程的"大账"——算健康能不能稳住，算日子能不能过得下去。血透患者的“经济账”：不能只关注药价终末期肾病患者需要长期接受透析治疗维持生命，而继发性甲状旁腺功能亢进症（SHPT）是血透患者长期管理中常见且棘手的并发症之一。据2016年中国CK-NET年度报告，18,083例透析患者医疗总支出接近9.11亿元；另有研究显示，当iPTH超过600 pg/mL时，患者月均总医疗费用较iPTH处于150–300 pg/mL目标范围的患者高出41%。但这笔帐，从来不是某一种药的价格问题。当疾病控制不理想时，患者面对的是环环相扣的连锁反应——更多种类的药物、更频繁的抽血检查、更多的不良反应处理、反复住院，以及层出不穷的并发症。每一项单独看或许不算惊人，但加在一起，就成了压垮一个家庭的沉重负担。因此，无论对患者还是医保支付方，真正该算的帐，不是“这个药贵不贵”，而是“这些钱花得值不值”，也就是说，能够用合理的花费，换来患者更长、更好的生存，同时减少那些不必要的医疗消耗。这也是药物经济学评价的重要出发点。真正沉重的“经济账”，往往来自疾病失控之后 SHPT并不是一个单纯的化验指标异常。长期钙磷代谢紊乱和甲状旁腺激素（PTH）失控，带来的是一连串实实在在的身体折磨——骨痛、容易骨折、血管钙化、甚至心血管出问题，这些都是迟早会面对的现实。首先是骨痛。这不是普通的腰酸背痛，而是高PTH水平下骨头被不断“掏空”后的持续性钝痛。约35% 的做甲状旁腺切除术的患者在术前就已被这种骨痛折磨得日夜难安，严重时“连翻身都像在被拆骨”，睡觉、吃饭、静坐，没有一刻是舒服的。更让人揪心的是骨折。由于骨代谢严重失衡，透析患者的骨头比正常人脆弱得多，透析患者的骨折风险是普通人群的4至17倍。而一次严重骨折意味着住院、手术、卧床康复、家属长期照护——每一次都是身体和钱包的双重消耗；最危险的是心血管并发症，这是一笔“看不见的账单”。高PTH水平加速血管钙化，让血管变硬，心脏负担加重，心梗、心衰、甚至猝死的概率都随之上升。有研究数据表明，PTH水平每升高100 pg/mL，心血管死亡风险增加12%。更令人警醒的是，这三类问题很少单独出现——一项针对中国119例SHPT患者的研究显示，38%的患者在就医时，已发生过心脏事件或骨折等严重并发症——也就是说，等到疼了、倒了、心慌了才去治，往往已经晚了。对于长期透析的患者来说，还有一笔容易被忽略的“隐形账”——疾病对生活能力和劳动能力的吞噬。很多患者正值壮年，却不得不离开工作岗位，从家里的“顶梁柱”变成需要被照顾的人。所以，真正有价值的治疗，目标从来不只是“把化验单上的箭头降下来”。创新药治疗真正应该努力的方向是它应该让疾病得到更稳定、更安全的控制，让患者少经历一次并发症、少住一次院——帮他们把被疾病夺走的生活，一点一点找回来。一个“治标不治本”的治疗困局现有SHPT治疗方案，面临一个临床中始终绕不开的“两难”：维生素D受体激动剂能有效降低PTH，却可能推高血钙、血磷；拟钙剂能抑制PTH分泌，却常伴随血钙过低的风险。两种主流药物各有短板，临床上无论单独使用还是联合用药，都很难同时兼顾PTH、血钙、血磷三项指标的平衡。即便采用联合治疗方案，中国SHPT患者 Ca、P、iPTH三项指标的综合达标率仅为18.4%（源于CNRDS 2025数据）。换句话说，每10个接受规范治疗的患者中，有8到9个人的三项关键指标不能同时达标。PTH可能勉强压下来了，但钙和磷又乱了——指标上按下葫芦浮起瓢，身体里骨痛、骨折、血管钙化、心血管并发症的风险依然在，患者并没有真正拜托并发症的威胁。不能忽视的还有药物本身的安全性风险。传统拟钙剂常引发严重的胃肠道反应，部分患者因恶心呕吐等难以耐受而中断治疗；活性维生素D则可能诱发高钙血症，增加血管钙化风险，由此又衍生出一系列新的治疗需求。为追求单项指标的控制，临床实践中不得不采取联合用药策略。其结果是，患者的月均药费负担显著增加、检查频率也相应提高，医保基金的支出压力也随之持续攀升。然而，即便如此，依然难以实现“全面达标”——这一现实，既暴露出当下SHPT治疗方案的局限性，也成为医患双方共同面对的突出痛点。正因如此，医生和患者都迫切需要一个更全面、更安全、能兼顾骨骼与心血管获益的新选择。药物经济学的核心逻辑：综合达标率提升，才是真正的“减负” 麦科奥特自主研发的MT1013是全球首创的双靶点受体激动剂多肽药物，目前处于III期临床试验阶段，计划于2027年申报上市。与现有药物相比，MT1013的差异化价值在于“单分子、双靶点”的协同机制。它代表了一种全新策略：在通过激活钙敏感受体（CaSR）有效抑制PTH过度分泌的同时，直接发挥成骨活性，驱动骨形成与修复，实现从“被动控制”到“主动修复”的跨越。。 II期临床数据显示 MT1013在iPTH、血钙、血磷综合达标率上约为依特卡肽的2.5倍：MT1013组34.48%–39.29% vs 依特卡肽组18.4%；低钙血症发生率为7.7%，低于依特卡肽的15.2%；显著降低与心血管风险相关的FGF23（成纤维细胞生长因子23）水平。 “综合达标率”提高，意味着什么？对于患者而言，意味着疾病得到更有效控制，减少因指标波动带来的身体痛苦和长期经济负担。对于临床医生而言，意味着减少为了分别控制不同指标而不断叠加、调整治疗方案的压力，使管理更加简化。从药物经济学角度看，更值得关注的是：如果一种治疗方案能用更少的药物组合，实现更高比例患者的综合达标，那么需要评价的就不只是“药品价格”，而是整个治疗方案的成本与价值。而更具临床意义的是，综合达标率的提升直接关联着心血管预后的改善。中国DOPPS研究显示，血钙、血磷、PTH三项同时达标的透析患者，心血管死亡风险降低39.6%（HR=0.604）；且PTH水平与心血管钙化显著正相关（r=0.47, P<0.001）。这些数据印证了一个关键事实——综合达标不是终点，降低心血管事件、改善长期生存才是治疗的终极目标。而MT1013的“单分子、双靶点”设计，让一种药物同时实现PTH有效下降与钙磷平衡维持，不再需要复杂的联合用药方案。用更高的综合达标率，直接降低了药物联用的必要性，减少了用药种类和数量；用更好的安全性，减少不良反应及其后续管理成本；用更稳定的疾病控制，减少严重并发症和住院带来的支出——这是创新药真正创造的经济价值，更是实现临床硬终点获益的可行路径。 2025年，MT1013与现有主流药物依特卡肽的头对头II期研究被美国肾脏病学会（ASN）年会收录为 “Late-Breaking Science”（最新突破性科学成果），标志着国际顶级学术界对其“同类首创”潜力的高度认可。 2026年，麦科医药就MT1013已与云顶新耀达成独家商业化合作，覆盖中国及亚太区，首付款及里程碑金额最高达12.4亿元。可以看出资本市场和产业界对其临床价值与市场潜力的认同。从“治疗一种疾病”到“提高整个治疗体系的效率” 创新药的意义，从来不只是创造一个新的分子。对于麦科奥特而言，真正值得长期探索的，是能否从疾病机制和临床需求出发，找到更有效、更精准的治疗方式。MT1013对SHPT的探索，正是这一研发理念的深入实践——希望通过机制创新，在多个关键治疗目标之间建立更有效的协同。 MT1013的III期临床数据，将不只是验证一个新药的疗效与安全性，更是验证一种治疗理念的机会——让SHPT管理回归“以患者为中心”的效率逻辑。对患者，意味着更简单的用药方案与更稳定的疾病控制；对医生，意味着更精简的决策路径与更确定的治疗结果；对医保，则意味着将有限支付资源更高效地转化为真实临床获益。从临床未满足需求出发，用机制创新提升治疗效率，进一步探索临床价值与经济价值的统一——这正是麦科奥特在创新药研发道路上长期坚持的方向。 MICOT For patients on maintenance hemodialysis, three days a week are spent in the hospital dialysis unit, with each session lasting four hours. During treatment, blood circulates through a dialysis machine to remove excess fluid and metabolic waste that would normally be cleared by functioning kidneys. For these patients, dialysis has become an unavoidable part of life. What weighs on them is not only their declining physical health, but also the loss of their ability to support their families, compounded by mounting medical bills from repeated treatment of complications. Secondary hyperparathyroidism (SHPT) is a common and challenging complication affecting more than 70% of patients with end-stage renal disease (ESRD) receiving hemodialysis. The bone pain, fractures, and cardiovascular complications associated with SHPT can further compound both the physical and financial burden on patients. The economic burden faced by patients on hemodialysis extends far beyond the cost of medications. More precisely, it is an overall burden accumulated throughout long-term disease management. Medication costs are only one component; treatment effectiveness, the number of medications required, the severity of adverse events, the frequency of laboratory testing, the number of hospitalizations, the burden of complications, and disease-related loss of work capacity can all contribute substantially to the overall cost burden. Therefore, when considering the value of an innovative therapy, the question cannot simply be, “How much does the drug cost?” We should also ask: “Can it help patients achieve better treatment outcomes? Can it reduce the number of additional medications required alongside the primary therapy? Can it lower the risk of adverse events and complications? Over the long term, can it reduce healthcare resource utilization associated with repeated testing and hospitalizations?” Ultimately, the value of a medicine should not be assessed solely by its acquisition cost. It should be evaluated across the entire treatment journey—including whether it can achieve sustained disease control, reduce complications and healthcare utilization, and ultimately help patients maintain their health and quality of life. The Economic Burden of Hemodialysis: Looking Beyond Medication Costs Patients with end-stage renal disease require long-term dialysis to sustain life, while secondary hyperparathyroidism (SHPT) is one of the common and challenging complications encountered in the long-term management of patients receiving hemodialysis. According to the 2016 China Kidney Disease Network (CK-NET) Annual Report, total medical expenditure for 18,083 dialysis patients approached RMB 911 million. Separately, research has shown that when intact parathyroid hormone (iPTH) levels exceed 600 pg/mL, patients’ average monthly total medical costs are 41% higher than those of patients whose iPTH levels fall within the target range of 150–300 pg/mL. However, this economic burden is not simply a matter of the price of any single medication. When disease control is suboptimal, patients may face a cascade of interconnected consequences: more medications, more frequent blood tests, additional management of adverse events, repeated hospitalizations, and an increasing burden of complications. Each individual cost may not appear substantial, but together they can become a significant burden for patients and their families. Therefore, for both patients and healthcare payers, the more important question is not simply whether a drug is expensive, but whether the expenditure delivers sufficient value—whether reasonable spending can contribute to longer and better lives while reducing unnecessary healthcare resource utilization. This is also a fundamental starting point for pharmacoeconomic evaluation. The Greatest Economic Burden Often Emerges When Disease Is Poorly Controlled SHPT is far more than an abnormal laboratory value. Long-term disturbances in calcium-phosphate metabolism and uncontrolled parathyroid hormone (PTH) levels can lead to a range of serious clinical consequences, including bone pain, increased fracture risk, vascular calcification, and cardiovascular complications. Bone pain is one of the most immediate consequences. This is not ordinary back pain, but a persistent, dull ache associated with skeletal changes under conditions of elevated PTH levels. Approximately 35% of patients undergoing parathyroidectomy were already experiencing significant bone pain before surgery; in severe cases, even turning over in bed can be intensely painful, making sleeping, eating, or sitting still difficult. Fractures are an even more serious concern. Severe disturbances in bone metabolism can make patients on dialysis substantially more vulnerable to fractures, with fracture risk reported to be 4 to 17 times higher than in the general population. A serious fracture may lead to hospitalization, surgery, prolonged bed rest and rehabilitation, as well as long-term caregiving by family members—imposing both a physical and financial burden. Cardiovascular complications may be the most serious consequences, creating a hidden but substantial burden. Elevated PTH levels may contribute to vascular calcification, vascular stiffness, and increased cardiac workload, thereby increasing the risk of myocardial infarction, heart failure, and even sudden death. Study data indicate that for every 100 pg/mL increase in PTH levels, the risk of cardiovascular mortality increases by 12%. More concerningly, these complications rarely occur in isolation. A study of 119 Chinese patients with SHPT found that 38% had already experienced serious complications, such as cardiac events or fractures, when they sought medical care. In other words, waiting until symptoms such as pain, falls, or palpitations occur before seeking treatment may mean that the disease has already progressed significantly. For patients receiving long-term dialysis, there is another easily overlooked “hidden cost”: the impact of disease on functional capacity and the ability to work. Many patients are still in their working years, yet are forced to leave the workforce and shift from being a primary provider for their families to becoming someone who requires care. The goal of truly valuable treatment, therefore, should go beyond simply lowering abnormal laboratory values. Innovative therapies should strive to provide more stable and safer disease control, reduce complications and hospitalizations, and ultimately help patients regain the quality of life that the disease has taken from them. A Treatment Dilemma: Addressing Individual Parameters Without Achieving Overall Disease Control Current treatment options for SHPT presenta persistent clinical challenge. Vitamin D receptor activators (VDRAs) can effectively lower PTH levels but may increase serum calcium and phosphate, while calcimimetics can suppress PTH secretion but are often associated with a risk of hypocalcemia. Each of these two major treatment classes has its limitations, and in clinical practice, whether used alone or in combination, it remains difficult to achieve simultaneous control of PTH, serum calcium, and serum phosphate. Even with combination therapy, the composite target-attainment rate for serum calcium (Ca), phosphate (P), and iPTH among Chinese patients with SHPT was only 18.4%, according to 2025 data from the China National Renal Data System (CNRDS). In other words, approximately 8 to 9 out of every 10 patients receiving standard treatment fail to achieve simultaneous target attainment across all three key parameters. PTH may be brought under control, only for calcium and phosphate to become imbalanced. As a result, the risks of bone pain, fractures, vascular calcification, and cardiovascular complications may persist, leaving patients still exposed to the threat of complications. The safety risks associated with these therapies also cannot be overlooked. Conventional calcimimetics may cause gastrointestinal adverse events, and some patients may discontinue treatment because of intolerance to symptoms such as nausea and vomiting. Active vitamin D may induce hypercalcemia and potentially increase the risk of vascular calcification, creating additional treatment needs. In an effort to control individual parameters, combination therapy is often required in clinical practice. This can increase patients’ average monthly medication costs and the frequency of laboratory monitoring, while also placing greater pressure on healthcare payer resources. Yet even with such treatment strategies, achieving comprehensive target attainment remains challenging. This highlights the limitations of current SHPT treatment regimens and represents an important unmet need for both physicians and patients. For this reason, both physicians and patients need new treatment options that offer more comprehensive and safer disease control while addressing both skeletal and cardiovascular outcomes. The Core Logic of Pharmacoeconomics: Higher Composite Target Attainment May Reduce the Overall Treatment Burden MT1013, independently developed by Micot, is a first-in-class dual-target receptor agonist peptide. It is currently in Phase III development, with a regulatory submission planned for 2027. Compared with existing therapies, MT1013’s differentiated value lies in its single-molecule, dual-target mechanism. It represents a novel therapeutic approach: by activating the calcium-sensing receptor (CaSR), MT1013 effectively suppresses excessive PTH secretion while simultaneously exerting direct osteogenic activity to promote bone formation and repair—representing a shift from passive disease control toward active skeletal restoration. Phase II clinical data showed: MT1013 achieved a composite target-attainment rate for iPTH, serum calcium, and serum phosphate approximately 2.5 timesthat observed with etelcalcetide, with rates of 34.48%–39.29% in the MT1013 arm versus 18.4% in the etelcalcetide arm. The incidence of hypocalcemia was 7.7%, compared with 15.2% in the etelcalcetide arm. MT1013 also significantly reduced levels of fibroblast growth factor 23 (FGF23), which has been associated with cardiovascular risk. What Does Higher Composite Target Attainment Mean? For patients, higher composite target attainment may mean more effective disease control, potentially reducing the physical burden and long-term economic burden associated with fluctuations in key laboratory parameters. For clinicians, it may reduce the need to continually add or adjust therapies to control individual parameters separately, thereby simplifying overall disease management. From a pharmacoeconomic perspective, the more important consideration is that if a treatment regimen can enable a higher proportion of patients to achieve composite target attainment with a simpler medication regimen, the relevant assessment should extend beyond drug price to the overall cost and value of the treatment strategy. Of greater clinical significance, higher composite target attainment is associated with better cardiovascular outcomes. The China Dialysis Outcomes and Practice Patterns Study (DOPPS) found that dialysis patients achieving simultaneous target attainment for serum calcium, serum phosphate, and PTH had a 39.6% lower risk of cardiovascular death (HR = 0.604). The study also found a significant positive correlation between PTH levels and cardiovascular calcification (r = 0.47, P < 0.001). These findings underscore an important point: composite target attainment is not an endpoint in itself; reducing cardiovascular events and improving long-term survival are the ultimate goals of treatment. MT1013’s single-molecule, dual-target design is intended to enable effective PTH reduction while maintaining calcium-phosphate balance with a single agent, potentially reducing the need for complex combination regimens. By enabling a higher proportion of patients to achieve composite target attainment, MT1013 may reduce medication burden and the need for combination therapy; a favorable safety profile may reduce adverse events and their downstream management costs; and more stable disease control may reduce healthcare expenditures associated with serious complications and hospitalization.Together, these factors represent potential economic value generated by an innovative therapy and may provide a pathway toward improved clinical outcomes, including hard clinical endpoints. In 2025, the head-to-head Phase II study of MT1013 versus the established therapy etelcalcetide was accepted for presentation as Late-Breaking Science at the American Society of Nephrology (ASN) Kidney Week, highlighting the international nephrology community’s recognition of its potential as a first-in-class therapy. In 2026, Micot entered into an exclusive commercialization agreement with Everest Medicines for MT1013 covering China and the Asia-Pacific region, with upfront and milestone payments totaling up to RMB 1.24 billion. The agreement reflects recognition from both the capital markets and the biopharmaceutical industry of the program’s clinical value and market potential. From Treating a Disease to Improving the Efficiency of the Overall Treatment System The significance of an innovative medicine extends beyond simply creating a new molecule. For Micot, the long-term goal is to identify more effective and precise treatment approaches grounded in disease mechanisms and unmet clinical needs. The development of MT1013 for SHPT represents a practical application of this R&D philosophy, seeking to use mechanistic innovation to achieve greater synergy across multiple key therapeutic goals. The Phase III clinical data for MT1013 will do more than evaluate the efficacy and safety of a new medicine; they will also provide an opportunity to assess a broader treatment philosophy—one that seeks to make SHPT management more patient-centered and efficient. For patients, this could mean simpler treatment regimens and more stable disease control; for physicians, a more streamlined decision-making pathway and more predictable treatment outcomes; and for healthcare payers, more efficient allocation of limited resources toward meaningful clinical benefit. Starting from unmet clinical needs, using mechanistic innovation to improve treatment efficiency, and exploring how clinical value can be aligned with economic value—this is the direction that Micot has long pursued in innovative drug development. MICOT

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适应症	国家/地区	公司	日期
FGF23阳性低磷血症	韩国	Kyowa Kirin Korea Co., Ltd.	2020-09-17
肿瘤源性骨软化症	美国	Kyowa Kirin, Inc. /Sancuso/	2020-06-18
低磷血症佝偻病	日本	Kyowa Kirin Co., Ltd.	2019-09-20
骨软化	加拿大	Kyowa Kirin Co., Ltd.	2019-01-28
家族性低磷酸盐血症性佝偻病	欧盟	Kyowa Kirin Holdings BV	2018-02-19
家族性低磷酸盐血症性佝偻病	冰岛	Kyowa Kirin Holdings BV	2018-02-19
家族性低磷酸盐血症性佝偻病	列支敦士登	Kyowa Kirin Holdings BV	2018-02-19
家族性低磷酸盐血症性佝偻病	挪威	Kyowa Kirin Holdings BV	2018-02-19

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适应症	最高研发状态	国家/地区	公司	日期
慢性疼痛	临床3期	美国	Ultragenyx Pharmaceutical, Inc.	2018-01-31
Jadassohn皮脂腺痣	临床3期	美国	Ultragenyx Pharmaceutical, Inc.	2018-01-31
低磷血症	临床1期	美国	Ultragenyx Pharmaceutical, Inc.	2019-07-01

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT04188964 (Pubmed \| Lancet Diabetes Endocrinol)	临床1/2期	家族性低磷酸盐血症性佝偻病	16	Burosumab	積構醖窪製獵顧築願窪(鏇積艱壓壓遞糧艱遞鹹) = All participants had TEAEs with no differences in incidence across cohorts 顧構餘繭觸網襯膚夢簾 (遞憲襯選衊蓋壓築艱憲 )	积极	2026-06-01
WCO_IOF_ESCEO2026	N/A	家族性低磷酸盐血症性佝偻病	6	Burosumab	願糧壓糧構衊蓋餘廠遞(襯糧範壓蓋淵網襯窪糧) = 衊醖鑰鑰鏇鬱齋觸遞顧襯淵鏇鑰觸製鏇觸鑰鹽 (繭襯膚鑰獵衊遞觸夢觸 ) 更多	积极	2026-04-16
WCO_IOF_ESCEO2026	N/A	家族性低磷酸盐血症性佝偻病	6	Burosumab 1 mg/kg	餘觸糧遞觸夢觸鏇觸選(衊衊夢鑰壓醖獵鑰顧艱) = 鏇積壓製膚蓋鏇顧繭築範廠願願醖窪鏇繭淵襯 (糧艱範糧網鬱艱醖夢簾 ) 更多	积极	2026-04-16
NCT05509595 (CTgov)	临床2期	骨纤维发育不良 \| 低磷血症	12	Burosumab	衊選鹹壓網蓋襯衊觸膚 = 鏇簾襯淵網憲餘構鏇製製夢鏇選構憲遞鹽積鏇 (醖蓋醖鏇醖製壓襯淵獵, 構積鑰齋願願艱遞鏇夢 ~ 製觸鬱衊顧襯網觸製簾) 更多	-	2026-02-02
WCO_IOF_ESCEO2025	N/A	家族性低磷酸盐血症性佝偻病	22	phosphate salts and calcitriol	襯壓鬱築蓋顧觸廠鹽膚(壓淵窪衊積觸壓窪鬱構) = 壓選鬱顧獵艱願齋醖繭簾鑰製選製網膚醖壓簾 (廠簾築觸簾顧築築衊築, 2 ~ 5) 更多	积极	2025-04-10
ESPE2024	N/A	家族性低磷酸盐血症性佝偻病	19	Burosumab (X-linked hypophosphatemic rickets)	膚鑰繭廠蓋網壓鏇廠壓(齋壓壓鏇鹹願糧蓋醖鏇) = 顧鹹鑰窪廠憲窪遞艱襯齋鑰願蓋構艱顧餘構顧 (鏇鏇顧獵憲糧餘鏇夢簾 ) 更多	积极	2024-11-16
ESPE2024	N/A	家族性低磷酸盐血症性佝偻病	24	Burosumab	積淵夢鹽簾鏇積網遞遞(顧艱壓廠鹹構襯餘觸鏇) = 膚窪獵網範範鬱憲廠製糧餘願窪糧壓膚窪製鑰 (積膚膚鬱鹽顧製鬱鹹醖, 0.2) 更多	积极	2024-11-16
ENDO2024	临床3期	家族性低磷酸盐血症性佝偻病 PHEX mutation	-	Burosumab	願壓鹹鹽遞顧廠獵窪蓋(鏇齋願廠膚網壓遞衊糧) = 衊蓋選艱選艱餘餘築夢鏇窪願壓夢齋憲積鑰選 (蓋繭衊蓋壓膚積鏇鑰廠 ) 更多	-	2024-06-01
NCT04146935 (CTgov)	临床4期	家族性低磷酸盐血症性佝偻病	10	Burosumab Injection [Crysvita]	鏇鬱鏇壓繭膚選窪顧獵(遞築遞積鑰簾簾選願願) = 鬱艱獵製蓋窪積衊鬱齋壓憲範鏇簾鹽襯齋餘範 (選範築淵壓構願窪觸廠, 鏇窪壓簾糧膚襯衊齋憲 ~ 醖衊簾獵蓋築糧糧鏇衊) 更多	-	2023-08-24
IMPROVEMENT IN PATIENT OUTCOMESFOLLOWING INITIATION OF BUROSUMAB INADULTS WITH XLH: A SINGLE CENTRE EXPERIENCE (WCO_IOF_ESCEO2023)	N/A	家族性低磷酸盐血症性佝偻病 FGF23	28	Burosumab	艱膚願繭積簾選鏇鹽鹽(廠製鏇鑰齋憲網淵憲窪) = 願鹽鹹艱顧襯築願簾鬱鏇衊網糧窪願襯襯艱憲 (艱醖網觸鬱簾壓鑰醖觸 ) 更多	积极	2023-05-04