Cinacalcet Hydrochloride

THOUSAND OAKS, Calif. , Feb. 4, 2025 /PRNewswire/ -- Amgen (NASDAQ:AMGN) today announced financial results for the fourth quarter and full year of 2024 versus comparable periods in 2023. "Robust growth in sales and earnings throughout 2024 reflects the momentum of our business. With strong performance globally, we are investing heavily in our rapidly advancing pipeline to deliver innovative therapies across our four therapeutic areas," said Robert A. Bradway, chairman and chief executive officer. Key results include: References in this release to "non-GAAP" measures, measures presented "on a non-GAAP basis," "free cash flow" (computed by subtracting capital expenditures from operating cash flow), "EBITDA, or earnings before interest, taxes, depreciation and amortization" (computed by adding interest expense, provision for income taxes, and depreciation and amortization expense to GAAP net income) and "debt leverage ratio" (calculated as the ratio of GAAP total debt to EBITDA) refer to non-GAAP financial measures. Adjustments to the most directly comparable GAAP financial measures and other items are presented on the attached reconciliations. Refer to Non-GAAP Financial Measures below for further discussion. Product Sales Performance General Medicine Rare Disease Except for TAVNEOS ® , the products listed below were added through the acquisition of Horizon on Oct. 6, 2023. Inflammation Oncology Established Products Product Sales Detail by Product and $Millions, except percentages Q4 '24 Q4 '23 YOY Δ U.S ROW TOTAL TOTAL TOTAL Repatha ® $         315 $         291 $         606 $         417 45 % EVENITY ® 325 106 431 318 36 % Prolia ® 775 390 1,165 1,107 5 % TEPEZZA ®(1) 456 4 460 448 3 % KRYSTEXXA ®(1) 346 — 346 272 27 % UPLIZNA ®(1) 93 8 101 65 55 % TAVNEOS ® 76 5 81 44 84 % Ultra-Rare products (1) 205 9 214 164 30 % TEZSPIRE ® 296 — 296 177 67 % Otezla ® 514 110 624 629 (1 %) Enbrel ® 1,008 7 1,015 1,015 — % AMJEVITA ® /AMGEVITA ™ 153 141 294 160 84 % BLINCYTO ® 245 136 381 241 58 % Vectibix ® 134 112 246 251 (2 %) KYPROLIS ® 236 136 372 350 6 % LUMAKRAS ® /LUMYKRAS ™ 53 32 85 77 10 % XGEVA ® 369 192 561 527 6 % Nplate ® 221 116 337 386 (13 %) IMDELLTRA ® 67 — 67 — N/A MVASI ® 108 65 173 188 (8 %) EPOGEN ® 19 — 19 55 (65 %) Aranesp ® 90 218 308 319 (3 %) Parsabiv ® 39 36 75 89 (16 %) Neulasta ® 72 26 98 239 (59 %) Other products (2) 294 67 361 295 22 % Total product sales $      6,509 $      2,207 $      8,716 $      7,833 11 % N/A = not applicable (1) Horizon-acquired products, and the Ultra-Rare products consist of RAVICTI ® , PROCYSBI ® , ACTIMMUNE ® , QUINSAIR ® and BUPHENYL ® . (2) Consists of (i) Aimovig ® , KANJINTI ® , AVSOLA ® , RIABNI ® , PAVBLU ™ , NEUPOGEN ® , WEZLANA ™ /WEZENLA ™ , BEKEMV ™ , IMLYGIC ® , Corlanor ® and Sensipar ® /Mimpara ™ , where Biosimilars total $218 million in Q4 '24 and $135 million in Q4 '23; and (ii) Horizon-acquired products including RAYOS ® , PENNSAID ® and DUEXIS ® . $Millions, except percentages FY '24 FY '23 YOY Δ US ROW TOTAL TOTAL TOTAL Repatha ® $      1,139 $      1,083 $      2,222 $      1,635 36 % EVENITY ® 1,131 432 1,563 1,160 35 % Prolia ® 2,885 1,489 4,374 4,048 8 % TEPEZZA ®(1) 1,835 16 1,851 448 * KRYSTEXXA ®(1) 1,185 — 1,185 272 * UPLIZNA ®(1) 314 65 379 65 * TAVNEOS ® 256 27 283 134 * Ultra-Rare products (1) 726 32 758 164 * TEZSPIRE ® 972 — 972 567 71 % Otezla ® 1,699 427 2,126 2,188 (3 %) Enbrel ® 3,288 28 3,316 3,697 (10 %) AMJEVITA ® /AMGEVITA ™ 202 559 761 626 22 % BLINCYTO ® 800 416 1,216 861 41 % Vectibix ® 519 526 1,045 984 6 % KYPROLIS ® 948 555 1,503 1,403 7 % LUMAKRAS ® /LUMYKRAS ™ 214 136 350 280 25 % XGEVA ® 1,507 718 2,225 2,112 5 % Nplate ® 970 486 1,456 1,477 (1 %) IMDELLTRA ® 115 — 115 — N/A MVASI ® 449 278 727 800 (9 %) EPOGEN ® 125 — 125 226 (45 %) Aranesp ® 386 956 1,342 1,362 (1 %) Parsabiv ® 203 153 356 362 (2 %) Neulasta ® 318 113 431 848 (49 %) Other products (2) 1,115 230 1,345 1,191 13 % Total product sales $    23,301 $      8,725 $    32,026 $    26,910 19 % * Change in excess of 100% N/A = not applicable (1) Horizon-acquired products, and the Ultra-Rare products consist of RAVICTI ® , PROCYSBI ® , ACTIMMUNE ® , BUPHENYL ® and QUINSAIR ® . (2) Consists of (i)Aimovig ® ,KANJINTI ® ,RIABNI ® ,AVSOLA ® ,NEUPOGEN ® ,Corlanor ® , IMLYGIC ® ,BEKEMV ™ , PAVBLU ™ , WEZLANA ™ /WEZENLA ™ and Sensipar ® /Mimpara ™ , where Biosimilars total $725 million in FY '24 and $490 million in FY '23; and (ii) Horizon-acquired products including RAYOS ® , PENNSAID ® and DUEXIS ® . Operating Expense, Operating Margin and Tax Rate Analysis On a GAAP basis: On a non-GAAP basis: $Millions, except percentages GAAP Non-GAAP Q4 '24 Q4 '23 YOY Δ Q4 '24 Q4 '23 YOY Δ Cost of Sales $   3,112 $   3,112 — % $   1,536 $   1,278 20 % % of product sales 35.7 % 39.7 % (4.0) pts 17.6 % 16.3 % 1.3 pts Research & Development $   1,724 $   1,534 12 % $   1,698 $   1,494 14 % % of product sales 19.8 % 19.6 % 0.2 pts 19.5 % 19.1 % 0.4 pts Selling, General & Administrative $   1,878 $   2,274 (17 %) $   1,819 $   1,764 3 % % of product sales 21.5 % 29.0 % (7.5) pts 20.9 % 22.5 % (1.6) pts Other $        61 $          5 * $        — $        — N/A Total Operating Expenses $   6,775 $   6,925 (2 %) $   5,053 $   4,536 11 % Operating Margin operating income as % of product sales 26.5 % 16.2 % 10.3 pts 46.3 % 46.7 % (0.4) pts Tax Rate 19.8 % 10.0 % 9.8 pts 14.8 % 15.9 % (1.1) pts pts: percentage points * change in excess of 100% N/A = not applicable $Millions, except percentages GAAP Non-GAAP FY '24 FY '23 YOY Δ FY '24 FY '23 YOY Δ Cost of Sales $ 12,858 $   8,451 52 % $   5,736 $   4,573 25 % % of product sales 40.1 % 31.4 % 8.7 pts 17.9 % 17.0 % 0.9 pts Research & Development $   5,964 $   4,784 25 % $   5,878 $   4,700 25 % % of product sales 18.6 % 17.8 % 0.8 pts 18.4 % 17.5 % 0.9 pts Selling, General & Administrative $   7,096 $   6,179 15 % $   6,782 $   5,518 23 % % of product sales 22.2 % 23.0 % (0.8) pts 21.2 % 20.5 % 0.7 pts Other $      248 $      879 (72 %) $        — $        — N/A Total Operating Expenses $ 26,166 $ 20,293 29 % $ 18,396 $ 14,791 24 % Operating Margin operating income as % of product sales 22.7 % 29.3 % (6.6) pts 46.9 % 49.8 % (2.9) pts Tax Rate 11.3 % 14.5 % (3.2) pts 14.5 % 16.5 % (2.0) pts pts: percentage points N/A = not applicable Cash Flow and Balance Sheet $Billions, except shares Q4 '24 Q4 '23 YOY Δ FY '24 FY '23 YOY Δ Operating Cash Flow $         4.8 $         0.5 $         4.2 $     11.5 $       8.5 $      3.0 Capital Expenditures $         0.4 $         0.2 $         0.1 $       1.1 $       1.1 $      0.0 Free Cash Flow $         4.4 $         0.3 $         4.1 $     10.4 $       7.4 $      3.0 Dividends Paid $         1.2 $         1.1 $         0.1 $       4.8 $       4.6 $      0.3 Share Repurchases $         0.2 $          — $         0.2 $       0.2 $        — $      0.2 Average Diluted Shares (millions) 542 540 2 541 538 3 Note: Numbers may not add due to rounding $Billions 12/31/24 12/31/23 YTD Δ Cash and Investments $       12.0 $       10.9 $         1.0 Debt Outstanding $       60.1 $       64.6 $        (4.5) Note: Numbers may not add due to rounding 2025 Guidance For the full year 2025, the Company expects: Fourth Quarter Product and Pipeline Update The Company provided the following updates on selected product and pipeline programs: General Medicine MariTide (maridebart cafraglutide, AMG 133) AMG 513 Olpasiran (AMG 890) Repatha Rare Disease TAVNEOS TEPEZZA KRYSTEXXA UPLIZNA Dazodalibep Daxdilimab Fipaxalparant Inflammation TEZSPIRE Rocatinlimab (AMG 451/KHK4083) Otezla Blinatumomab Inebilizumab Ordesekimab (AMG 714/PRV-015) AMG 104 (AZD8630) Oncology BLINCYTO IMDELLTRA Xaluritamig (AMG 509) AMG 193 Bemarituzumab LUMAKRAS/LUMYKRAS Nplate Biosimilars TEZSPIRE is being developed in collaboration with AstraZeneca. AMG 104 is being developed in collaboration with AstraZeneca. Rocatinlimab, formerly AMG 451/KHK4083, is being developed in collaboration with Kyowa Kirin. Ordesekimab, formerly AMG 714 and also known as PRV-015, is being developed in collaboration with Provention Bio , a Sanofi Company . For the purposes of the collaboration, Provention Bio conducts a clinical trial and leads certain development and regulatory activities for the program. Xaluritamig, formerly AMG 509, is being developed pursuant to a research collaboration with Xencor, Inc. IDE397 is an investigational MAT2A inhibitor from IDEAYA Biosciences. OPDIVO is a registered trademark of Bristol-Myers Squibb Company. KEYTRUDA is a registered trademark of Merck & Co., Inc. OCREVUS is a registered trademark of Genentech, Inc. Non-GAAP Financial Measures In this news release, management has presented its operating results for the fourth quarters and full years of 2024 and 2023, in accordance with U.S. Generally Accepted Accounting Principles (GAAP) and on a non-GAAP basis. In addition, management has presented its full year 2025 EPS and tax guidance in accordance with GAAP and on a non-GAAP basis. These non-GAAP financial measures are computed by excluding certain items related to acquisitions, divestitures, restructuring and certain other items from the related GAAP financial measures. Management has presented Free Cash Flow (FCF), which is a non-GAAP financial measure, for the fourth quarters and full years of 2024 and 2023. FCF is computed by subtracting capital expenditures from operating cash flow, each as determined in accordance with GAAP. Management has also presented Earnings Before Interest, Taxes, Depreciation and Amortization (EBITDA) and debt leverage ratio for 2024, both of which are non-GAAP financial measures. EBITDA is computed by adding interest expense, provision for income taxes, and depreciation and amortization expense to GAAP net income. Debt leverage ratio is calculated as the ratio of GAAP total debt to EBITDA. The Company believes that its presentation of non-GAAP financial measures provides useful supplementary information to and facilitates additional analysis by investors. The Company uses certain non-GAAP financial measures to enhance an investor's overall understanding of the financial performance and prospects for the future of the Company's normal and recurring business activities by facilitating comparisons of results of normal and recurring business operations among current, past and future periods. The Company believes that FCF provides a further measure of the Company's liquidity. The Company believes its debt leverage ratio provides a supplemental operating metric for the full year period as it compares the amount of cash generated by our operations for the year. The Company uses the non-GAAP financial measures set forth in the news release in connection with its own budgeting and financial planning internally to evaluate the performance of the business, including to allocate resources and to evaluate results relative to incentive compensation targets. The non-GAAP financial measures are in addition to, not a substitute for, or superior to, measures of financial performance prepared in accordance with GAAP. About Amgen Amgen discovers, develops, manufactures and delivers innovative medicines to help millions of patients in their fight against some of the world's toughest diseases. More than 40 years ago, Amgen helped to establish the biotechnology industry and remains on the cutting-edge of innovation, using technology and human genetic data to push beyond what's known today. Amgen is advancing a broad and deep pipeline that builds on its existing portfolio of medicines to treat cancer, heart disease, osteoporosis, inflammatory diseases and rare diseases. In 2024, Amgen was named one of the "World's Most Innovative Companies" by Fast Company and one of "America's Best Large Employers" by Forbes, among other external recognitions. Amgen is one of the 30 companies that comprise the Dow Jones Industrial Average ® , and it is also part of the Nasdaq-100 Index ® , which includes the largest and most innovative non-financial companies listed on the Nasdaq Stock Market based on market capitalization. For more information, visit Amgen.com and follow Amgen on X , LinkedIn , Instagram , YouTube and Threads . Forward-Looking Statements This news release contains forward-looking statements that are based on the current expectations and beliefs of Amgen . All statements, other than statements of historical fact, are statements that could be deemed forward-looking statements, including any statements on the outcome, benefits and synergies of collaborations, or potential collaborations, with any other company (including BeiGene, Ltd. or Kyowa Kirin Co., Ltd.), the performance of Otezla ® (apremilast) (including anticipated Otezla sales growth and the timing of non-GAAP EPS accretion), our acquisitions of Teneobio, Inc. , ChemoCentryx, Inc. , or Horizon (including the prospective performance and outlook of Horizon's business, performance and opportunities and any potential strategic benefits, synergies or opportunities expected as a result of such acquisition, and any projected impacts from the Horizon acquisition on our acquisition-related expenses going forward), as well as estimates of revenues, operating margins, capital expenditures, cash, other financial metrics, expected legal, arbitration, political, regulatory or clinical results or practices, customer and prescriber patterns or practices, reimbursement activities and outcomes, effects of pandemics or other widespread health problems on our business, outcomes, progress, and other such estimates and results. Forward-looking statements involve significant risks and uncertainties, including those discussed below and more fully described in the Securities and Exchange Commission reports filed by Amgen , including our most recent annual report on Form 10-K and any subsequent periodic reports on Form 10-Q and current reports on Form 8-K. Unless otherwise noted, Amgen is providing this information as of the date of this news release and does not undertake any obligation to update any forward-looking statements contained in this document as a result of new information, future events or otherwise. No forward-looking statement can be guaranteed and actual results may differ materially from those we project. Our results may be affected by our ability to successfully market both new and existing products domestically and internationally, clinical and regulatory developments involving current and future products, sales growth of recently launched products, competition from other products including biosimilars, difficulties or delays in manufacturing our products and global economic conditions. In addition, sales of our products are affected by pricing pressure, political and public scrutiny and reimbursement policies imposed by third-party payers, including governments, private insurance plans and managed care providers and may be affected by regulatory, clinical and guideline developments and domestic and international trends toward managed care and healthcare cost containment. Furthermore, our research, testing, pricing, marketing and other operations are subject to extensive regulation by domestic and foreign government regulatory authorities. We or others could identify safety, side effects or manufacturing problems with our products, including our devices, after they are on the market. Our business may be impacted by government investigations, litigation and product liability claims. In addition, our business may be impacted by the adoption of new tax legislation or exposure to additional tax liabilities. If we fail to meet the compliance obligations in the corporate integrity agreement between us and the U.S. government, we could become subject to significant sanctions. Further, while we routinely obtain patents for our products and technology, the protection offered by our patents and patent applications may be challenged, invalidated or circumvented by our competitors, or we may fail to prevail in present and future intellectual property litigation. We perform a substantial amount of our commercial manufacturing activities at a few key facilities, including in Puerto Rico, and also depend on third parties for a portion of our manufacturing activities, and limits on supply may constrain sales of certain of our current products and product candidate development. An outbreak of disease or similar public health threat, such as COVID-19, and the public and governmental effort to mitigate against the spread of such disease, could have a significant adverse effect on the supply of materials for our manufacturing activities, the distribution of our products, the commercialization of our product candidates, and our clinical trial operations, and any such events may have a material adverse effect on our product development, product sales, business and results of operations. We rely on collaborations with third parties for the development of some of our product candidates and for the commercialization and sales of some of our commercial products. In addition, we compete with other companies with respect to many of our marketed products as well as for the discovery and development of new products. Discovery or identification of new product candidates or development of new indications for existing products cannot be guaranteed and movement from concept to product is uncertain; consequently, there can be no guarantee that any particular product candidate or development of a new indication for an existing product will be successful and become a commercial product. Further, some raw materials, medical devices and component parts for our products are supplied by sole third-party suppliers. Certain of our distributors, customers and payers have substantial purchasing leverage in their dealings with us. The discovery of significant problems with a product similar to one of our products that implicate an entire class of products could have a material adverse effect on sales of the affected products and on our business and results of operations. Our efforts to collaborate with or acquire other companies, products or technology, and to integrate the operations of companies or to support the products or technology we have acquired, may not be successful. There can be no guarantee that we will be able to realize any of the strategic benefits, synergies or opportunities arising from the Horizon acquisition, and such benefits, synergies or opportunities may take longer to realize than expected. We may not be able to successfully integrate Horizon, and such integration may take longer, be more difficult or cost more than expected. A breakdown, cyberattack or information security breach of our information technology systems could compromise the confidentiality, integrity and availability of our systems and our data. Our stock price is volatile and may be affected by a number of events. Our business and operations may be negatively affected by the failure, or perceived failure, of achieving our environmental, social and governance objectives. The effects of global climate change and related natural disasters could negatively affect our business and operations. Global economic conditions may magnify certain risks that affect our business. Our business performance could affect or limit the ability of our Board of Directors to declare a dividend or our ability to pay a dividend or repurchase our common stock. We may not be able to access the capital and credit markets on terms that are favorable to us, or at all. CONTACT: Amgen , Thousand Oaks Elissa Snook, 609-251-1407 (media) Justin Claeys, 805-313-9775 (investors) Amgen Inc. Consolidated Statements of Income - GAAP (In millions, except per-share data) (Unaudited) Three months ended December 31, Twelve months ended December 31, 2024 2023 2024 2023 Revenues: Product sales $    8,716 $    7,833 $  32,026 $  26,910 Other revenues 370 363 1,398 1,280 Total revenues 9,086 8,196 33,424 28,190 Operating expenses: Cost of sales 3,112 3,112 12,858 8,451 Research and development 1,724 1,534 5,964 4,784 Selling, general and administrative 1,878 2,274 7,096 6,179 Other 61 5 248 879 Total operating expenses 6,775 6,925 26,166 20,293 Operating income 2,311 1,271 7,258 7,897 Other income (expense): Interest expense, net (747) (821) (3,155) (2,875) Other (expense) income, net (782) 402 506 2,833 Income before income taxes 782 852 4,609 7,855 Provision for income taxes 155 85 519 1,138 Net income $       627 $       767 $    4,090 $    6,717 Earnings per share: Basic $      1.17 $      1.43 $      7.62 $    12.56 Diluted $      1.16 $      1.42 $      7.56 $    12.49 Weighted-average shares used in calculation of earnings per share: Basic 537 535 537 535 Diluted 542 540 541 538 Amgen Inc. Consolidated Balance Sheets - GAAP (In millions) December 31, December 31, 2024 2023 (Unaudited) Assets Current assets: Cash and cash equivalents $              11,973 $              10,944 Trade receivables, net 6,782 7,268 Inventories 6,998 9,518 Other current assets 3,277 2,602 Total current assets 29,030 30,332 Property, plant and equipment, net 6,543 5,941 Intangible assets, net 27,699 32,641 Goodwill 18,637 18,629 Other noncurrent assets 9,930 9,611 Total assets $              91,839 $              97,154 Liabilities and Stockholders' Equity Current liabilities: Accounts payable and accrued liabilities $              19,549 $              16,949 Current portion of long-term debt 3,550 1,443 Total current liabilities 23,099 18,392 Long-term debt 56,549 63,170 Long-term deferred tax liabilities 1,616 2,354 Long-term tax liabilities 2,349 4,680 Other noncurrent liabilities 2,349 2,326 Total stockholders' equity 5,877 6,232 Total liabilities and stockholders' equity $              91,839 $              97,154 Shares outstanding 537 535 Amgen Inc. GAAP to Non-GAAP Reconciliations (Dollars in millions) (Unaudited) Three months ended December 31, Twelve months ended December 31, 2024 2023 2024 2023 GAAP cost of sales $       3,112 $       3,112 $      12,858 $       8,451 Adjustments to cost of sales: Acquisition-related expenses (a) (1,576) (1,834) (7,122) (3,842) Certain net charges pursuant to our restructuring and cost-savings initiatives — — — (36) Total adjustments to cost of sales (1,576) (1,834) (7,122) (3,878) Non-GAAP cost of sales $       1,536 $       1,278 $       5,736 $       4,573 GAAP cost of sales as a percentage of product sales 35.7 % 39.7 % 40.1 % 31.4 % Acquisition-related expenses (a) (18.1) (23.4) (22.2) (14.3) Certain net charges pursuant to our restructuring and cost-savings initiatives 0.0 0.0 0.0 (0.1) Non-GAAP cost of sales as a percentage of product sales 17.6 % 16.3 % 17.9 % 17.0 % GAAP research and development expenses $       1,724 $       1,534 $       5,964 $       4,784 Adjustments to research and development expenses: Acquisition-related expenses (b) (26) (28) (86) (55) Certain net charges pursuant to our restructuring and cost-savings initiatives — (12) — (29) Total adjustments to research and development expenses (26) (40) (86) (84) Non-GAAP research and development expenses $       1,698 $       1,494 $       5,878 $       4,700 GAAP research and development expenses as a percentage of product sales 19.8 % 19.6 % 18.6 % 17.8 % Acquisition-related expenses (b) (0.3) (0.3) (0.2) (0.2) Certain net charges pursuant to our restructuring and cost-savings initiatives 0.0 (0.2) 0.0 (0.1) Non-GAAP research and development expenses as a percentage of product sales 19.5 % 19.1 % 18.4 % 17.5 % GAAP selling, general and administrative expenses $       1,878 $       2,274 $       7,096 $       6,179 Adjustments to selling, general and administrative expenses: Acquisition-related expenses (c) (59) (510) (314) (648) Certain net charges pursuant to our restructuring and cost-savings initiatives — — — (13) Total adjustments to selling, general and administrative expenses (59) (510) (314) (661) Non-GAAP selling, general and administrative expenses $       1,819 $       1,764 $       6,782 $       5,518 GAAP selling, general and administrative expenses as a percentage of product sales 21.5 % 29.0 % 22.2 % 23.0 % Acquisition-related expenses (c) (0.6) (6.5) (1.0) (2.4) Certain net charges pursuant to our restructuring and cost-savings initiatives 0.0 0.0 0.0 (0.1) Non-GAAP selling, general and administrative expenses as a percentage of product sales 20.9 % 22.5 % 21.2 % 20.5 % GAAP operating expenses $       6,775 $       6,925 $      26,166 $      20,293 Adjustments to operating expenses: Adjustments to cost of sales (1,576) (1,834) (7,122) (3,878) Adjustments to research and development expenses (26) (40) (86) (84) Adjustments to selling, general and administrative expenses (59) (510) (314) (661) Certain net charges pursuant to our restructuring and cost-savings initiatives (d) (40) (2) (36) (185) Certain other expenses (e) (21) (3) (212) (694) Total adjustments to operating expenses (1,722) (2,389) (7,770) (5,502) Non-GAAP operating expenses $       5,053 $       4,536 $      18,396 $      14,791 Three months ended December 31, Twelve months ended December 31, 2024 2023 2024 2023 GAAP operating income $       2,311 $       1,271 $       7,258 $       7,897 Adjustments to operating expenses 1,722 2,389 7,770 5,502 Non-GAAP operating income $       4,033 $       3,660 $      15,028 $      13,399 GAAP operating income as a percentage of product sales 26.5 % 16.2 % 22.7 % 29.3 % Adjustments to cost of sales 18.1 23.4 22.2 14.4 Adjustments to research and development expenses 0.3 0.4 0.2 0.3 Adjustments to selling, general and administrative expenses 0.6 6.5 1.0 2.6 Certain net charges pursuant to our restructuring and cost-savings initiatives (d) 0.5 0.1 0.1 0.7 Certain other expenses (e) 0.3 0.1 0.7 2.5 Non-GAAP operating income as a percentage of product sales 46.3 % 46.7 % 46.9 % 49.8 % GAAP interest expense, net $        (747) $        (821) $      (3,155) $      (2,875) Adjustments to interest expense, net: Interest expense on acquisition-related debt (f) — 19 — 807 Non-GAAP interest expense, net $        (747) $        (802) $      (3,155) $      (2,068) GAAP other (expense) income, net $        (782) $          402 $          506 $       2,833 Adjustments to other (expense) income, net Interest income and other expenses on acquisition-related debt (f) — (18) — (625) Net losses (gains) from equity investments (g) 875 (217) 182 (1,522) Total adjustments to other (expense) income, net 875 (235) 182 (2,147) Non-GAAP other income, net $            93 $          167 $          688 $          686 GAAP income before income taxes $          782 $          852 $       4,609 $       7,855 Adjustments to income before income taxes: Adjustments to operating expenses 1,722 2,389 7,770 5,502 Adjustments to interest expense, net — 19 — 807 Adjustments to other income, net 875 (235) 182 (2,147) Total adjustments to income before income taxes 2,597 2,173 7,952 4,162 Non-GAAP income before income taxes $       3,379 $       3,025 $      12,561 $      12,017 GAAP provision for income taxes $          155 $            85 $          519 $       1,138 Adjustments to provision for income taxes: Income tax effect of the above adjustments (h) 537 404 1,544 846 Other income tax adjustments (i) (192) (7) (236) (1) Total adjustments to provision for income taxes 345 397 1,308 845 Non-GAAP provision for income taxes $          500 $          482 $       1,827 $       1,983 GAAP tax as a percentage of income before taxes 19.8 % 10.0 % 11.3 % 14.5 % Adjustments to provision for income taxes: Income tax effect of the above adjustments (h) 0.7 6.1 5.1 2.0 Other income tax adjustments (i) (5.7) (0.2) (1.9) 0.0 Total adjustments to provision for income taxes (5.0) 5.9 3.2 2.0 Non-GAAP tax as a percentage of income before taxes 14.8 % 15.9 % 14.5 % 16.5 % GAAP net income $          627 $          767 $       4,090 $       6,717 Adjustments to net income: Adjustments to income before income taxes, net of the income tax effect 2,060 1,769 6,408 3,316 Other income tax adjustments (i) 192 7 236 1 Total adjustments to net income 2,252 1,776 6,644 3,317 Non-GAAP net income $       2,879 $       2,543 $      10,734 $      10,034 Note: Numbers may not add due to rounding Amgen Inc. GAAP to Non-GAAP Reconciliations (In millions, except per-share data) (Unaudited) The following table presents the computations for GAAP and non-GAAP diluted earnings per share: Three months ended December 31, 2024 Three months ended December 31, 2023 GAAP Non-GAAP GAAP Non-GAAP Net income $           627 $        2,879 $           767 $        2,543 Weighted-average shares for diluted EPS 542 542 540 540 Diluted EPS $          1.16 $          5.31 $          1.42 $          4.71 Twelve months ended December 31, 2024 Twelve months ended December 31, 2023 GAAP Non-GAAP GAAP Non-GAAP Net income $        4,090 $      10,734 $        6,717 $      10,034 Weighted-average shares for diluted EPS 541 541 538 538 Diluted EPS $          7.56 $        19.84 $        12.49 $        18.65 (a) The adjustments related primarily to noncash amortization of intangible assets and fair value step-up of inventory acquired from business acquisitions. (b) For the three and twelve months ended December 31, 2024, the adjustments related primarily to acquisition-related costs related to our Horizon acquisition. For the three months ended December 31, 2023, the adjustments related primarily to acquisition-related costs related to our Horizon acquisition. For the twelve months ended December 31, 2023, the adjustments related primarily to noncash amortization of intangible assets acquired from business acquisitions. (c) For the three and twelve months ended December 31, 2024 and 2023, the adjustments related primarily to acquisition-related costs related to our Horizon acquisition. (d) For the three and twelve months ended December 31, 2024 and 2023, the adjustments related to separation costs associated with our restructuring plan and other cost-savings initiatives. (e) For the twelve months ended December 31, 2024, the adjustments related primarily to impairment charges for IPR&D intangible assets related to our Teneobio, Inc. acquisition from 2021. For the twelve months ended December 31, 2023, the adjustments related primarily to a net IPR&D intangible asset impairment charge for AMG 340. (f) For the three and twelve months ended December 31, 2023, the adjustments included (i) interest expense and income on senior notes issued in March 2023 and (ii) debt issuance costs and other fees related to our bridge credit and term loan credit agreements, incurred prior to the closing of our acquisition of Horizon. (g) For the three and twelve months ended December 31, 2024, the adjustments related primarily to our BeiGene equity fair value adjustment. For the twelve months ended December 31, 2023, the adjustments related primarily to our BeiGene equity fair value adjustment. (h) The tax effect of the adjustments between our GAAP and non-GAAP results takes into account the tax treatment and related tax rate(s) that apply to each adjustment in the applicable tax jurisdiction(s). Generally, the tax impact of adjustments, including the amortization of intangible assets and acquired inventory, gains and losses on our investments in equity securities and expenses related to restructuring and cost-savings initiatives, depends on whether the amounts are deductible in the respective tax jurisdictions and the applicable tax rate(s) in those jurisdictions. Due to these factors, the effective tax rate for the adjustments to our GAAP income before income taxes for the three and twelve months ended December 31, 2024, was 20.7% and 19.4%, respectively, compared to 18.6% and 20.3% for the corresponding periods of the prior year. (i) The adjustments related to certain acquisition items, prior period and other items excluded from GAAP earnings. Amgen Inc. Reconciliations of Cash Flows (In millions) (Unaudited) Three months ended December 31, Twelve months ended December 31, 2024 2023 2024 2023 Net cash provided by operating activities $    4,771 $       538 $    11,490 $      8,471 Net cash used in investing activities (402) (27,089) (1,046) (26,204) Net cash (used in) provided by financing activities (1,407) 2,754 (9,415) 21,048 Increase (decrease) in cash and cash equivalents 2,962 (23,797) 1,029 3,315 Cash and cash equivalents at beginning of period 9,011 34,741 10,944 7,629 Cash and cash equivalents at end of period $   11,973 $   10,944 $    11,973 $    10,944 Three months ended December 31, Twelve months ended December 31, 2024 2023 2024 2023 Net cash provided by operating activities $    4,771 $       538 $    11,490 $      8,471 Capital expenditures (371) (249) (1,096) (1,112) Free cash flow $    4,400 $       289 $    10,394 $      7,359 Amgen Inc. Reconciliation of GAAP Net Income to EBITDA and Debt Leverage Ratio Calculation (Dollars in millions) (Unaudited) Twelve months ended December 31, 2024 GAAP Net Income $                                   4,090 Depreciation and amortization 5,592 Interest expense, net 3,155 Provision for income taxes 519 EBITDA (a) $                                 13,356 As of December 31, 2024 Current portion of long-term debt $                                   3,550 Long-term debt 56,549 Total GAAP Debt $                                 60,099 As of December 31, 2024 Total GAAP Debt $                                 60,099 EBITDA $                                 13,356 Debt leverage ratio 4.5 (a) 2024 EBITDA includes amortization of inventory step-up of $2.4 billion and net losses from equity investments of $182 million. Amgen Inc. Reconciliation of GAAP EPS Guidance to Non-GAAP EPS Guidance for the Year Ending December 31, 2025 (Unaudited) GAAP diluted EPS guidance $ 10.89 — $ 12.14 Known adjustments to arrive at non-GAAP*: Acquisition-related expenses (a) 9.06 — 9.11 Non-GAAP diluted EPS guidance $ 20.00 — $ 21.20 * The known adjustments are presented net of their related tax impact, which amount to approximately $1.54 per share. (a) The adjustments include noncash amortization of intangible assets and fair value step-up of inventory acquired in business acquisitions. Our GAAP diluted EPS guidance does not include the effect of GAAP adjustments triggered by events that may occur subsequent to this press release such as acquisitions, asset impairments, litigation, changes in fair value of our contingent consideration obligations and changes in fair value of our equity investments. Reconciliation of GAAP Tax Rate Guidance to Non-GAAP Tax Rate Guidance for the Year Ending December 31, 2025 (Unaudited) GAAP tax rate guidance 11.0 % — 12.5 % Tax rate of known adjustments discussed above 3.5 % — 4.0 % Non-GAAP tax rate guidance 15.0 % — 16.0 % View original content to download multimedia: https://www.prnewswire.com/news-releases/amgen-reports-fourth-quarter-and-full-year-2024-financial-results-302367906.html SOURCE Amgen

黄鑫 中国药科大学多靶标天然药物全国重点实验室新药筛选与药效评价中心副研究员、硕士生导师。2000 年、2004 年和 2013 年分别获中国药科大学药物分析学理学学士、硕士和博士学位，2004 年留校工作至今。2015—2016年到美国加州大学旧金山分校进行博士后访问学者研究。主持3项国家自然科学基金，参与了多项国家自然科学基金和国家重大新药创制项目研究，并主持和参与多项新药开发相关的校企课题研究。现已发表文章 60 余篇。主要从事药物体内分析和中药毒效相关性研究，利用现代分析技术，多学科结合，研究机体内源性物质和外源药物的体内行为变化与毒性、药效之间的关系，揭示有毒药物的毒效相关性。 维生素 D-维生素 D 受体轴在慢性肾病中的作用PPS  孙娟，崔雪扬，王鹤霏，江振洲，黄鑫 * （中国药科大学多靶标天然药物全国重点实验室新药筛选与药效评价中心，江苏 南京 210009） [摘要]：全球超过10% 的人口受到慢性肾病（chronic kidney disease, CKD）的威胁。大量研究证据表明，低水平的维生素 D 与CKD 的进展和不良预后存在联系。随着研究的深入，维生素 D 及维生素 D 受体（vitamin D receptor, VDR）在 CKD 中的作用越来越受到关注。目前，提高 CKD 患者维生素 D 的水平或使用 VDR 激动剂成为 CKD 的治疗手段。对维生素 D 的合成与代谢，VDR 的分布、功能与调控，维生素 D 与 CKD 之间的联系以及维生素 D-VDR 轴对 CKD 的保护机制 4 个方面进行综述，以期为 CKD 的疾病预防和治疗提供一定的理论依据及研究思路。 慢性肾病（chronic kidney disease，CKD）的特点是肾功能逐渐丧失，最终导致终末期肾病（endstagerenal disease，ESRD）。CKD 是全球公共卫生问题，我国超过 1 亿人受其影响，然而目前对于CKD 产生的原因及进展机制仍不完全清楚。 CKD 的发展过程中伴随着体内维生素 D 的缺乏和矿物质代谢紊乱。近 20 年来，维生素 D 及其受体（vitamin D receptor，VDR）的研究热度呈逐年上升的趋势，约 3% 的小鼠和人类基因组直接或间接受到维生素 D 和 VDR 的调控 [1]。低水平的维生素 D 与 CKD 的进展和死亡率相关，维生素 D 缺乏成为 CKD 的独立危险因素 [2]。  维生素 D 主要通过其活性形式 1，25(OH)2D 与 VDR 结合发挥作用。维生素 D 及 VDR 通过影响蛋白尿、炎症和氧化应激等方面对 CKD 患者发挥一定的治疗作用 [3-4]。维生素 D 类似物（如骨化三醇、帕立骨化醇和度骨化醇等）已成为临床中治疗肾病的药物之一 [5]。本文就维生素 D 的合成与代谢，VDR 的分布、功能与调控，维生素 D 与 CKD 之间的联系以及维生素 D-VDR 轴对 CKD 的保护机制 4 个方面展开综述，以期为 CKD 患者的疾病预防及治疗提供参考。 1 维生素 D 的合成与代谢 维生素 D 是类固醇类激素，有 2 种主要的形式：维生素 D2 和维生素 D3。机体可以通过摄入蘑菇、牛奶和鱼等获取外源性维生素 D，但机体中约 80%的维生素 D 来源于皮肤受到的光照作用。紫外线 B 可以使存在于表皮和真皮细胞质膜中的 7-脱氢胆固醇（7-dehydrocholesterol，7-DHC）迅速转化为前维生素 D3，后者进行非酶异构化转化为维生素 D3。长时间暴露于阳光下不会导致维生素 D3 中毒，原因在于前维生素 D3 和维生素 D3 会与生物惰性甾醇（速甾醇、7-DHC、超甾醇和 5，6-反式维生素 D3 等）发生可逆光异构化 [6]。  机体内大部分维生素 D 会与维生素 D 结合蛋白（vitamin D-binding protein，VDBP）紧密结合，其中 10% ~ 15% 与白蛋白结合，游离形式的循环维生素 D 不到 1%[7]。维生素 D 首先被 VDBP 运送到肝脏，在肝脏中经 25-羟化酶代谢为 25(OH)D。由于 25(OH)D 半衰期长，其在血液中的浓度成为反映体内维生素 D 含量的标准。Cyp2r1 敲除小鼠血浆中25(OH)D 的含量相较于野生型小鼠降低了 50%，表明 CYP2R1 是生成 25(OH)D 的主要 25-羟化酶 [8]。CYP2R1 是存在于微粒体中的代谢酶，主要分布于肝脏，其次它也在肾脏、睾丸和棕色脂肪等器官或组织中表达。CYP2R1 的表达具有性别差异性，研究发现雄性小鼠中睾丸是第 2 高表达器官，而雌性小鼠中肾脏是第 2 高表达器官 [9]。  在肝脏中完成第 1 步羟化后，VDBP 将 25(OH)D 运送至肾脏进行第 2 步羟化代谢。在近端肾小管细胞内 25(OH)D 经 1α -羟化酶代谢为具有生物活性的1，25(OH)2D。CYP27B1 是负责将 25(OH)D 转化为 1，25(OH)2D 唯一的 1α -羟化酶，主要存在于肾脏近端小管线粒体中 [10]。1，25(OH)2D 通过发生慢速的基因组反应（激活或抑制含有维生素 D 反应元件的靶基因）和快速的非基因组反应（启动膜相关信号转导）参与细胞内信号转导 [11]。  在肾脏中，25(OH)D 除了通过 CYP27B1 转化为 1，25(OH)2D 外， 还可以被 CYP24A1（线粒体内膜细胞色素 P450 酶）代谢。该酶不仅可以羟基化 25(OH)D，还可以羟基化 1，25(OH)2D，但其更偏向 1，25(OH)2D 的代谢 [10]。体内 1，25(OH)2D 的水平主要由 CYP27B1 和 CYP24A1 决定，甲状旁腺激素（parathyroid hormone，PTH）、成纤维细胞生长因子 23（fibroblast growth factor，FGF23）、1，25(OH)2D、钙离子、磷酸盐和一些细胞因子是CYP27B1 和 CYP24A1 的关键调节因子 [12-13] （见图 1）。 2 VDR 的分布、功能与调控 VDR 作为配体激活的转录因子，属于核受体超家族的一员。它分布在肾脏、肠道、免疫细胞、生殖器官、内分泌腺和皮肤等部位 [14]。在肾脏中，VDR 主要在近端和远端肾小管上皮细胞、足细胞和集合管上皮细胞中表达，肾小球和黄斑区的系膜细胞中也有分布 [15]。VDR 的表达在少数肾脏疾病如多囊肾 [16] 中上调，但在大多数肾脏疾病如急性肾损伤 [17]、糖尿病肾病 [18] 和狼疮性肾炎 [19] 中下调。 VDR 是分子量约 50 000 的单链多肽，由 6 个功能域组成，其中 E 域负责与配体结合 [20]。VDR编码基因定位在 12 号染色体的长臂上，包含 11 个外显子，跨度约 75 000 bp[15]。VDR 通过调节靶基因的转录介导基因组反应，在维生素 D 的生物学效应（包括钙磷稳态、细胞生长与分化和免疫调节等）中起到核心作用。配体与 VDR 结合后，VDR和维甲酸 X 受体（retinoid-X receptor，RXR）发生异二聚化，复合物发生核转位与靶基因启动子区域的维生素 D 反应元件（vitamin D response element，VDRE）的不同 DNA 序列结合，导致靶基因被反式激活或抑制 [21]（见图 2）。除经典配体维生素 D 外，胆汁酸（主要是石胆酸及其代谢物）也被证明是 VDR 的内源性配体 [20]。VDR 的表达除了受到其配体的影响外，还受到环境因素（如年龄、阳光照射、饮食等）、遗传因素、细菌代谢产物（如丁酸盐）和疾病的影响 [15, 20, 22]。 3 维生素 D 与 CKD 之间的联系 蛋白尿或肾小球滤过率（glomerular filtration rate，GFR）每 1.73 m² 低于 60  mL · min-1 达 3 个月及以上时可被诊断为 CKD。根据 GFR 将 CKD 分为5 个阶段，ESRD 也被称为肾衰竭，是 CKD 最严重的结果，该阶段的患者只能通过透析或肾移植来维持生命。维生素 D 作为多功能激素，在体内的水平与 CKD 患者的疾病进程密切相关，维生素 D 或类似物已成为治疗 CKD 的潜在药物。 3.1 CKD 患者维生素 D 缺乏的判断标准 维生素 D 缺乏是全球性的健康问题，全球超过10 亿人口受其影响。目前对于维生素 D 缺乏的标准尚未达成一致定论，但大多数学者的判断标准为血液中 25(OH)D 的质量浓度低于 20 mg · L-1 为维生素 D 缺乏，20 ~ 29 mg · L-1 为维生素 D 不足，高于 30 mg · L-1 为维生素 D 正常 [23]。若以此作为判断标准，维生素 D 缺乏和不足在 CKD 患者中很普遍，维生素 D 缺乏的 CKD 患者高达 80%[24]，并且随着疾病进程的发展维生素 D 缺乏的风险加大。CKD 患者维生素 D 缺乏原因与营养摄入不足、户外活动减少、蛋白尿、维生素 D 合成和代谢异常、尿毒症等因素有关 [2]。有报道称，接受透析的 ESRD 患者体内 CYP24A1 mRNA表达上调，但患者血清中低含量的 24，25(OH)2D 与该发现相矛盾 [25]。Dai 等 [26] 给出的解释为：1）底物25(OH)D 缺乏；2）24，25(OH)2D 的清除率增加；3）CYP24A1 的基因表达上调不代表其活性的增加。不过，这些解释尚有待进一步的研究来证实。 3.2 CKD 患者维生素 D 的补充   根据“肾脏疾病预后质量倡议（Kidney Disease Outcomes Quality Initiative，KDOQI）”发布的指南，所有血清 25(OH)D 水平低于 30 mg · L-1 的 CKD 患者应补充维生素 D[23]。临床研究数据表明，补充维生素 D 使体内 25(OH)D 的质量浓度至少保持 30 mg · L-1 对 CKD 患者的健康有益，但不宜超过 50 mg · L-1 [27]。原因是过量的维生素 D 容易引发高钙血症，早期会产生恶心、厌食、腹泻等症状，后期则引发骨痛、嗜睡、头痛、心律不齐甚至肾结石等不良反应 [28]。临床上采取的方案是每天、每周或每月补充维生素D 或维生素 D 类似物（如帕立骨化醇）以提升 CKD患者体内 25(OH)D 的水平。 4 维生素 D 及 VDR 对 CKD 的保护机制 活性维生素 D 的使用与 CKD 进展减缓和生存率提高相关 [29-30]，它能够改善 CKD 患者的蛋白尿、肾脏炎症和肾脏纤维化，具体的作用机制总结如下（见表 1）。 4.1 抗炎 受损的免疫系统和持续的炎症是导致 CKD 发生和发展的重要因素 [47]。维生素 D 在调控先天性和适应性免疫系统中起到重要作用，被称为免疫系统的调节剂。VDR 存在于 T 淋巴细胞、B 淋巴细胞、巨噬细胞、早幼粒细胞和树突状细胞等免疫细胞中 [14]，其中一些免疫细胞（如巨噬细胞、树突状细胞、T淋巴细胞）可表达 CYP27B1 以合成 1，25(OH)2D 进行下游信号转导，从而实现局部免疫反应 [48]。维生素 D 在临床应用中表现出良好的抗炎能力，体现在对银屑病、炎症性肠病、1 型糖尿病和类风湿性关节炎等炎症性疾病均有良好的治疗效果 [49]。 维生素 D 及其受体激动剂在 CKD 中同样具有潜在的抗炎能力，这部分归因于对核因子κB（nuclear factor-κB，NF-κB）信号通路的调控。VDR 能够抑制核因子 κB 抑制蛋白（nuclear factor-κB inhibitory protein，IκBα）降解并阻止 p65/p50 核转位来抑制NF-κB 通路激活 [50-51]。CKD 患者使用帕立骨化醇治疗 12 周可以减少炎症因子的产生 [31]。Brito 等 [32] 将单核细胞暴露在尿毒症患者血清中，与健康个体的血清相比，尿毒症患者血清孵育的单核细胞中 Toll 样受体 4（Toll-like receptor 4，TRL4）、白细胞介素（interleukin，IL）-6、肿瘤坏死因子-α（tumor necrosis factor α，TNF-α）、IL-10、抗菌肽和单核细胞趋化蛋白 -1（monocyte chemoattractant protein-1，MCP-1）的表达升高，补充维生素 D 能够降低 TRL4、抗菌肽和 MCP-1 的表达。维生素 D还能调节巨噬细胞分化，它可以促使巨噬细胞从促炎的 M1 表型向抗炎的 M2 表型转化来改善肾小球损伤 [33]。 4.2 抑制肾素-血管紧张素系统 肾素-血管紧张素系统（renin-angiotensin system，RAS）主要由肾素、血管紧张素原（angiotensinogen，AGT）、血管紧张素转化酶（angiotensin converting enzyme，ACE）、血管紧张素（angiotensin，Ang）及其相应的受体构成。RAS 能够影响 CKD 的进展，靶向 RAS 的药物如血管紧张素转换酶抑制剂（angiotensin converting enzyme inhibitors，ACEIs）和 血 管 紧 张 素 受 体 阻 滞 剂（angiotensin receptor blockers，ARBs）已被证明可以改善肾小球硬化、肾小管间质纤维化和蛋白尿 [52]。靶向 RAS 的药物与维生素 D 联用已被多项临床试验证明对 CKD 具有协同治疗效果 [3, 53]。  维生素 D 通过影响肾素、肾素受体、AGT、血管紧张素Ⅱ 1 型受体（angiotensin Ⅱ type 1 receptor，AT1R）和 ACE 的表达来负调控 CKD 期间被激活的 RAS。VDR 的缺失会导致小鼠体内肾素表达上调，维生素 D 的活性形式 1，25(OH)2D 能够激活 VDR，且与 VDR 结合后，能够抑制肾素基因启动子区域环磷酸腺苷反应元件的活性，从而直接抑制肾素基因的表达 [34, 54]。帕立骨化醇能够抑制慢性肾功能衰竭模型（chronic renal failure，CRF）大鼠体内 AGT、AT1R 和肾素受体的表达，改善肾小球和肾小管间质损伤、蛋白尿以及肾功能恶化 [35]。对2 ~ 3期CKD比格犬补充维生素D，与对照组相比，维生素 D 能够使血清中 ACE 的活性显著降低 [36]。 4.3 抑制上皮-间质转化   肾纤维化是绝大多数 CKD 患者发展至 ESRD的病理特征 [55]，主要表现为间质纤维化。上皮-间质转化（epithelial mesenchymal transition，EMT）被认为是肾纤维化的驱动因素。上皮细胞转分化为间充质细胞的过程称为 EMT，维生素 D 具有抑制EMT 的作用。转化生长因子 β（transforming growth factor β，TGF-β）可以诱导发生 EMT，帕立骨化醇可以显著抑制 CRF 大鼠体内升高的 TGF-β，有效地减轻了 CRF 诱导的肾间质纤维化 [37]。Chang 等 [38]发现 1，25(OH)2D3 能够通过抑制磷脂酰肌醇 3-激酶（phosphatidylinositol 3-kinase，PI3K）/蛋白激酶 B（protein kinase B，AKT）/ β -连环蛋白通路，下调硫酸吲哚酚（典型的尿毒症毒素）引起的人肾小管上皮细胞中 EMT 相关蛋白的表达。  E-钙黏蛋白是粘附连接的主要成分，它可使细胞保持固定形态和结构以使细胞粘附在一起。当发生 EMT 时，E-钙黏蛋白会丢失。Tan 等 [39] 发现帕立骨化醇通过上调 VDR 恢复单侧输尿管梗阻（unilateral ureteral obstruction，UUO）小鼠肾脏中 E 钙黏蛋白的表达，并抑制肌成纤维细胞的标志分子α平滑肌肌动蛋白（α-smoothmuscle actin，α-SMA）、转化生长因子β 受体 1（transforming growth factorβreceptor 1，TGF-βR1）及 TGF-β 的表达，表明维生素 D 靶向 EMT 对维持肾小管上皮的完整性至关重要。Snail 基因是启动 EMT 的主要基因，帕里骨化醇能够显著抑制 Snail 的表达，体现了维生素 D 在抑制 EMT 中的关键作用 [39]。  4.4 抑制肾小管上皮细胞凋亡 糖尿病肾病（diabetic nephropathy，DN）和急性肾损伤（acute kidney injury，AKI）都存在肾小管上皮细胞凋亡的病理特征，肾小管上皮细胞凋亡是触发肾小管萎缩及肾损伤的潜在机制 [40-41]。p53上调凋亡调节因子（p53 upregulated modulator of apoptosis，PUMA）和微小RNA-155（microRNA-155，miR-155）是 VDR 抑制肾小管细胞凋亡的关键靶点，其中 PUMA 抑制 B 细胞淋巴瘤 2（B-cell lymphomato-2，BCL-2） 的 活 性，miR-155 则促进BCL-2 mRNA 降解并抑制 BCL-2 的蛋白翻译。而维生素 D-VDR 轴可通过抑制 NF-κB 引起的 PUMA 和miR-155 的上调来改善 AKI[40]。此外，维生素 D-VDR轴还能抑制 p38 丝裂原活化蛋白激酶（p38 mitogenactivatedprotein kinase，p38 MAPK）凋亡信号通路， 下 调 促 凋 亡 蛋 白 BCL-2 相 关 X 蛋白（BCL2-associatedX protein，BAX）和上调抗凋亡蛋白BCL-2 的表达，从而减少肾小管上皮细胞凋亡的数量 [41]。  维生素 D 还可以通过影响内质网应激（endoplasmic reticulum stress，ERS）来抑制肾小管上皮细胞凋亡 [42]。活化转录因子 4（activating transcription factor 4，ATF4）是 ERS 的关键蛋白， 它 可 以 激 活 下 游 C/EBP 同源蛋白（C/EBP homologous protein，CHOP） 的表达。CHOP 通过负调控 BCL-2 的表达，导致 BAX 从细胞质转运至线粒体，引发细胞凋亡。Tang 等 [42] 发现 VDR 通过下调 ATF4 及 CHOP 的表达减轻 AKI 小鼠的肾小管上皮细胞凋亡。  4.5 促进肾细胞自噬 自噬为溶酶体依赖的过程，通过形成双层自噬体吞噬受损的蛋白质和细胞器，之后与溶酶体融合，降解和回收营养物质，以维持细胞稳态。足细胞是构成肾小球滤过屏障的重要组成部分，足细胞损伤会引发蛋白尿并最终导致肾功能下降。维生素 D-VDR 轴通过上调自噬相关蛋白 3（autophagyrelatedprotein 3，ATG3）的表达，减少自噬降解底物 p62 的积累来增强自噬，抑制 DN 小鼠足细胞狭缝隔膜向紧密连接的转变 [43]。此外，维生素 D 还能上调自噬体关键成分自噬相关蛋白16-1（autophagyrelatedprotein 16-1，ATG16L1）的表达来恢复足细胞受损的自噬通量，减轻足细胞损伤 [44]。Li 等 [45]发现 VDR 通过激活钙/钙调蛋白依赖性蛋白激酶激酶 2（calcium/calmodulin dependent protein kinase kinase 2，CAMKK2）-AMP 活化蛋白激酶（AMPactivatedprotein kinase，AMPK）信号通路，显著改善 DN 小鼠肾小管上皮细胞的自噬缺陷。 4.6 修复肠道屏障 肠道屏障是阻碍致病菌和毒素的先天性屏障，一旦受损会引发细菌易位诱发全身炎症反应。CKD 期间尿素浓度的增加会改变肠道屏障，从而加速 CKD 的进程 [56]。紧密连接是细胞与细胞间接触最顶端区域的上皮细胞间连接，是液体和溶质通过细胞间隙的主要屏障。它主要由膜蛋白和胞浆蛋白组成，其中闭合蛋白、咬合蛋白和连接黏附分子构成膜蛋白，闭合小环蛋白（zonula occluden，ZO）-1 构成胞浆蛋白。 维生素 D 能直接调控多种闭合蛋白的表达，其中 Claudin-2，Claudin-5 和 Claudin-15 是 VDR 的靶基因 [57-59]。紧密连接是肠道屏障的重要组成，维生素 D 可上调 ZO-1，Occludin 和 Claudin-1 的表达改善敌草快引起的肠道屏障损伤 [46]。 5 结语 维生素 D 除了调节钙磷水平，其免疫调节、抗炎、抗氧化和抗肿瘤等骨骼外的效应也备受关注。肾脏作为产生活性形式维生素 D 的主要器官，肾功能的恶化会导致维生素 D 代谢逐渐失调。由于维生素 D 对于维持肾功能正常至关重要，维生素 D 代谢的失调会进一步加剧肾功能的恶化，从而形成恶性循环，这可能是 CKD 进展及其并发症（如血管疾病、认知障碍和全身炎症）的驱动因素之一。  最新的研究发现激活 VDR 能够抑制铁死亡 [18] 和上调谷胱甘肽过氧化物酶 3（glutathione peroxidase 3，GPX3）[60] 的表达来改善肾功能。此外，VDR 激动剂在联合用药中具有良好的临床应用前景，李明艳等 [61] 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