PHYSIOLOGY.ORG
Skip main navigation
Research Article

Therapeutic α-1-microglobulin ameliorates kidney ischemia-reperfusion injury

Published Online:20 Jun 2024https://doi.org/10.1152/ajprenal.00067.2024

Abstract

Download figureDownload PowerPoint

α-1-Microglobulin (A1M) is a circulating glycoprotein with antioxidant, heme-binding, and mitochondrial protection properties. The investigational drug RMC-035, a modified therapeutic A1M protein, was assessed for biodistribution and pharmacological activity in a broad set of in vitro and in vivo experiments, supporting its clinical development. Efficacy and treatment posology were assessed in various models of kidney ischemia and reperfusion injury (IRI). Real-time glomerular filtration rate (GFR), functional renal biomarkers, tubular injury biomarkers (NGAL and KIM-1), and histopathology were evaluated. Fluorescently labeled RMC-035 was used to assess biodistribution. RMC-035 demonstrated consistent and reproducible kidney protection in rat IRI models as well as in a model of IRI imposed on renal impairment and in a mouse IRI model, where it reduced mortality. Its pharmacological activity was most pronounced with combined dosing pre- and post-ischemia and weaker with either pre- or post-ischemia dosing alone. RMC-035 rapidly distributed to the kidneys via glomerular filtration and selective luminal uptake by proximal tubular cells. IRI-induced expression of kidney heme oxygenase-1 was inhibited by RMC-035, consistent with its antioxidative properties. RMC-035 also dampened IRI-associated inflammation and improved mitochondrial function, as shown by tubular autofluorescence. Taken together, the efficacy of RMC-035 is congruent with its targeted mechanism(s) and biodistribution profile, supporting its further clinical evaluation as a novel kidney-protective therapy.

NEW & NOTEWORTHY A therapeutic A1M protein variant (RMC-035) is currently in phase 2 clinical development for renal protection in patients undergoing open-chest cardiac surgery. It targets several key pathways underlying kidney injury in this patient group, including oxidative stress, heme toxicity, and mitochondrial dysfunction. RMC-035 is rapidly eliminated from plasma, distributing to kidney proximal tubules, and demonstrates dose-dependent efficacy in numerous models of ischemia-reperfusion injury, particularly when administered before ischemia. These results support its continued clinical evaluation.

REFERENCES

  • 1. Molitoris BA. Therapeutic translation in acute kidney injury: the epithelial/endothelial axis. J Clin Invest 124: 2355–2363, 2014. doi:10.1172/JCI72269.
    Crossref | PubMed | Web of Science | Google Scholar
  • 2. Hoste EAJ, Clermont G, Kersten A, Venkataraman R, Angus DC, De Baquer D, Kelum JA. RIFLE criteria for acute kidney injury are associated with hospital mortality in critically ill patients: a cohort analysis. Crit Care 10: R73, 2006. doi:10.1186/cc4915.
    Crossref | PubMed | Web of Science | Google Scholar
  • 3. Makris L, Spanou L. Acute kidney injury: definition, pathophysiology and clinical phenotypes. Clin Biochem Rev 37: 85–98, 2016.
    PubMed | Google Scholar
  • 4. Susantitaphong P, Cruz DN, Cerda J, Abulfaraj M, Alqahtani F, Koulouridis I, Jaber BL; Acute Kidney Injury Advisory Group of the American Society of Nephrology. World incidence of AKI: a meta-analysis. Clin J Am Soc Nephrol 8: 1482–1493, 2013 [Erratum in Clin J Am Soc Nephrol 9: 1148, 2014]. doi:10.2215/CJN.00710113.
    Crossref | PubMed | Web of Science | Google Scholar
  • 5. Vives M, Hernandez A, Parramon F, Estanyol N, Pardina B, Muñoz A, Alvarez P, Hernandez C. Acute kidney injury after cardiac surgery: prevalence, impact and management challenges. Int J Nephrol Renovasc Dis 12: 153–166, 2019. doi:10.2147/IJNRD.S167477.
    Crossref | PubMed | Web of Science | Google Scholar
  • 6. Thielmann M, Corteville D, Szabo G, Swaminathan M, Lamy A, Lehner LJ, Brown CD, Noiseux N, Atta MG, Squiers EC, Erlich S, Rothenstein D, Molitoris B, Mazer CD. Teprasiran, a small interfering RNA, for the prevention of acute kidney injury in high-risk patients undergoing cardiac surgery. Circulation 144: 1133–1144, 2021. doi:10.1161/CIRCULATIONAHA.120.053029.
    Crossref | PubMed | Web of Science | Google Scholar
  • 7. Bouma H, Mungroop HE, Fred de Geus A, Huisman DD, Nijsten MWN, Mariani MA, Scheeren TWL, Burgerhof JGM, Henning RH, Epema AH. Acute kidney injury classification underestimates long-term mortality after cardiac valve operations. Ann Thorac Surg 106: 92–98, 2018. doi:10.1016/j.athoracsur.2018.01.066.
    Crossref | PubMed | Web of Science | Google Scholar
  • 8. Vercaemst L. Hemolysis in cardiac surgery patients undergoing cardiopulmonary bypass: a review in search of a treatment algorithm. J Extra Corpor Technol 40: 257–267, 2008. doi:10.1051/ject/200840257.
    Crossref | PubMed | Google Scholar
  • 9. Vermeulen Windsant I, Snoeijs MG, Hanssen SJ, Altintas S, Heijmans JH, Koeppel TA, Schurink GWH, Buurman WA, Jacobs MJ. Hemolysis is associated with acute kidney injury during major aortic surgery. Kidney Int 77: 913–920, 2010. doi:10.1038/ki.2010.24.
    Crossref | PubMed | Web of Science | Google Scholar
  • 10. Duvigneau JC, Esterbauer H, Kozlov AV. Role of heme oxygenase as a modulator of heme-mediated pathways. Antioxidants (Basel) 8: 475, 2019. doi:10.3390/antiox8100475.
    Crossref | PubMed | Web of Science | Google Scholar
  • 11. Olsson MG, Olofsson T, Tapper H, Åkerström B. The lipocalin 1-microglobulin protects erythroid K562 cells against oxidative damage induced by heme and reactive oxygen species. Free Rad Res 42: 725–736, 2008. doi:10.1080/10715760802337265.
    Crossref | PubMed | Web of Science | Google Scholar
  • 12. Olsson MG, Nilsson EJC, Rutardottir S, Paczesny J, Pallon J, Åkerström B. Bystander cell death and stress response is inhibited by the radical scavenger a1-microglobulin in irradiated cell cultures. Radiation Res 174: 590–600, 2010. doi:10.1667/RR2213.1.
    Crossref | PubMed | Google Scholar
  • 13. May K, Rosenlöf L, Olsson MG, Centlow M, Mörgelin M, Larsson I, Cederlund M, Rutardottir S, Siegmund W, Schneider H, Åkerström B, Hansson SR. Perfusion of human placenta with hemoglobin introduces preeclampsia-like injuries that are prevented by a1-microglobulin. Placenta 32: 323–332, 2011. doi:10.1016/j.placenta.2011.01.017.
    Crossref | PubMed | Web of Science | Google Scholar
  • 14. Olsson MG, Allhorn M, Larsson J, Cederlund M, Lundqvist K, Schmidtchen A, Sörensen QE, Mörgelin M, Åkerström B. Up-regulation of A1M/α1-microglobulin in skin by heme and reactive oxygen species gives protection from oxidative damage. PLoS One 6: e27505, 2011. doi:10.1371/journal.pone.0027505.
    Crossref | PubMed | Google Scholar
  • 15. Åkerström B, Rosenlöf L, Hägerwall A, Rutardottir S, Ahlstedt J, Johansson ME, Erlandsson L, Allhorn M, Gram M. rA1M-035, a physicochemically improved human recombinant a1-microglobulin, has therapeutic effects in rhabdomyolysis-induced acute kidney injury. Antioxid. Redox Signal 30: 489–504, 2019. doi:10.1089/ars.2017.7181.
    Crossref | PubMed | Google Scholar
  • 16. Kristiansson A, Davidsson S, Johansson ME, Piel S, Elmér E, Hansson MJ, Åkerström B, Gram M. α1-Microglobulin (A1M) protects human proximal tubule epithelial cells from heme-induced damage in vitro. IJMS 21: 5825, 2020. doi:10.3390/ijms21165825.
    Crossref | PubMed | Google Scholar
  • 17. ClinicalTrials.gov. Efficacy and Safety of RMC-035 in Subjects at High Risk for Acute Kidney Injury Following Open-Chest Cardiac Surgery (AKITA) [Online]. Bethesda, MD: National Library of Medicine, 2021. https://www.clinicaltrials.gov/ct2/show/NCT05126303 [Accessed 14 September 2022].
    Google Scholar
  • 18. Molitoris BA, Wilson PD, Schrier RW, Simon FR. Ischemia induces partial loss of surface membrane polarity and accumulation of putative calcium ionophores. J Clin Invest 76: 2097–2105, 1985. doi:10.1172/JCI112214.
    Crossref | PubMed | Web of Science | Google Scholar
  • 19. McCurley A, Alimperti S, Campos-Bilderback SB, Sandoval RM, Calvino JE, Reynolds TL, Quigley C, Mugford JW, Polacheck WJ, Gomez IG, Dovey J, Marsh G, Huang A, Qian F, Weinreb PH, Dolinski BM, Moore S, Duffield JS, Chen CS, Molitoris BA, Violette SM, Crackower MA. Inhibition of αvβ5 integrin attenuates vascular permeability and protects against renal Ischemia-Reperfusion Injury. J Am Soc Nephrol 28: 1741–1752, 2017. doi:10.1681/ASN.2016020200.
    Crossref | PubMed | Web of Science | Google Scholar
  • 20. Rong S, Hueper K, Kirsch T, Greite R, Klemann C, Mengel M, Meier M, Menne J, Leitges M, Susnik N, Meier M, Haller H, Shushakova N, Gueler F. Renal PKC-ε deficiency attenuates acute kidney injury and ischemic allograft injury via TNF-α-dependent inhibition of apoptosis and inflammation. Am J Physiol Renal Physiol 307: F718–F726, 2014. doi:10.1152/ajprenal.00372.2013.
    Link | Web of Science | Google Scholar
  • 21. Schock-Kusch D, Sadick M, Henninger N, Kraenzlin B, Claus G, Kloetzer H-M, Weiss C, Pill J, Gretz N. Transcutaneous measurement of glomerular filtration rate using FITC-sinistrin in rats. Nephrol Dial Transplant 24: 2997–3001, 2009. doi:10.1093/ndt/gfp225.
    Crossref | PubMed | Web of Science | Google Scholar
  • 22. Hall AM, Crawford C, Unwin RJ, Duchen MR, Peppiatt-Wildman CM. Multiphoton imaging of the functioning kidney. J Am Soc Nephrol 22: 1297–1304, 2011. doi:10.1681/ASN.2010101054.
    Crossref | PubMed | Web of Science | Google Scholar
  • 23. Dunn KW, Sandoval RM, Kelly KJ, Dagher PC, Tanner GA, Atkinson SJ, Bacallao RL, Molitoris BA. Functional studies of the kidney of living animals using multicolor two-photon microscopy. Am J Physiol Cell Physiol 283: C905–C916, 2002. doi:10.1152/ajpcell.00159.2002.
    Link | Web of Science | Google Scholar
  • 24. Sandoval RM, Molitoris BA. Intravital multiphoton microscopy as a tool for studying renal physiology and pathophysiology. Methods 128: 20–32, 2017. doi:10.3389/fphys.2022.827280.
    Crossref | PubMed | Web of Science | Google Scholar
  • 25. Molitoris BA, Sandoval RM. Intravital multiphoton microscopy of dynamic renal processes. Am J Physiol Renal Physiol 288: F1084–F1089, 2005. doi:10.1152/ajprenal.00473.2004.
    Link | Web of Science | Google Scholar
  • 26. Rosin DL, Hall JP, Zheng S, Huang L, Campos-Bilderback S, Sandoval R, Bree A, Beaumont K, Miller E, Larsen J, Hariri G, Kaila N, Encarnacion IM, Gale JD, van Elsas A, Molitoris BA, Okusa MD. Human recombinant alkaline phosphatase (Ilofotase Alfa) protects against kidney ischemia-reperfusion injury in mice and rats through adenosine receptors. Front Med (Lausanne) 9: 931293, 2022. doi:10.3389/fmed.2022.931293.
    Crossref | PubMed | Web of Science | Google Scholar
  • 27. Liang J, Liu Y. Animal models of kidney disease: challenges and perspectives. Kidney360 4: 1479–1493, 2023. doi:10.34067/KID.0000000000000227.
    Crossref | PubMed | Google Scholar
  • 28. Thakar CV, Arrigain S, Worley S, Yared J-P, Paganini EP. A clinical score to predict acute renal failure after cardiac surgery. J Am Soc Nephrol 16: 162–168, 2005. doi:10.1681/ASN.2004040331.
    Crossref | PubMed | Web of Science | Google Scholar
  • 29. Chevalier RL. The proximal tubule is the primary target of injury and progression of kidney disease: role of the glomerulotubular junction. Am J Physiol Renal Physiol 311: F145–F161, 2016. doi:10.1152/ajprenal.00164.2016.
    Link | Web of Science | Google Scholar
  • 30. Basile DP, Anderson MD, Sutton TA. Pathophysiology of acute kidney injury. Compr Physiol 2: 1303–1353, 2012. doi:10.1002/cphy.c110041.
    Crossref | PubMed | Web of Science | Google Scholar
  • 31. Maack T, Johnson V, Kau ST, Figueiredo J, Sigulem D. Renal filtration, transport, and metabolism of low-molecular-weight proteins: a review. Kidney Int 16: 251–270, 1979. doi:10.1038/ki.1979.128.
    Crossref | PubMed | Web of Science | Google Scholar
  • 32. Weiss R, Meersch M, Wempe C, von Groote T, Agervald T, Zarbock A. Recombinant alpha-1-microglobulin (RMC-035) to prevent acute kidney injury in cardiac surgery patients: phase 1b evaluation of safety and pharmacokinetics. Kidney Int Rep 8: 980–988, 2023. doi:10.1016/j.ekir.2023.02.1071.
    Crossref | PubMed | Google Scholar
  • 33. Bergwik J, Kristiansson A, Allhorn M, Gram M, Åkerström B. Structure, functions, and physiological roles of the lipocalin α1-microglobulin (A1M). Front Physiol 12: 645650, 2021. doi:10.3389/fphys.2021.645650.
    Crossref | PubMed | Google Scholar
  • 34. Billings FT, Ball SK, Roberts LJ, Pretorius M. Postoperative acute kidney injury is associated with hemoglobinemia and an enhanced oxidative stress response. Free Rad Biol Med 50: 1480–1487, 2011. doi:10.1016/j.freeradbiomed.2011.02.011.
    Crossref | PubMed | Web of Science | Google Scholar
  • 35. Ralto KM, Parikh SM. Mitochondria in acute kidney injury. Semin Nephrol 36: 8–16, 2016. doi:10.1016/j.semnephrol.2016.01.005.
    Crossref | PubMed | Web of Science | Google Scholar
  • 36. Guerrero-Hue M, Rubio-Navarro A, Sevillano A, Yuste C, Gutierrez E, Palomino-Antolin A, Román E, Praga M, Egido J, Moreno JA. Adverse effects of the renal accumulation of haem proteins. Novel therapeutic approaches. Nefrologia 38: 13–26, 2018. doi:10.1016/j.nefro.2017.05.009.
    Crossref | PubMed | Google Scholar
  • 37. Tirapelli LF, Trazzi BFM, Bagnato VS, Tirapelli DPC, Kurachi C, Martins da Costa M, Tucci Jr S, Cologna AJ, Martins ACP. Histopathology and laser autofluorescence of ischemic kidneys of rats. Lasers Med Sci 24: 397–404, 2009. doi:10.1007/s10103-008-0578-7.
    Crossref | PubMed | Web of Science | Google Scholar
  • 38. Bugarski M, Martins JR, Haenni D, Hall AM. Multiphoton imaging reveals axial differences in metabolic autofluorescence signals along the kidney proximal tubule. Am J Physiol Renal Physiol 315: F1613–F1625, 2018. doi:10.1152/ajprenal.00165.2018.
    Link | Web of Science | Google Scholar
  • 39. Schaefer PM, Kalinina S, Rueck A, von Arnim CAF, von Einem B. NADH autofluorescence-A marker on its way to boost bioenergetic research. Cytometry 95: 34–46, 2019. doi:10.1002/cyto.a.23597.
    Crossref | PubMed | Google Scholar
  • 40. Olsson MG, Rosenlöf LW, Kotarsky H, Olofsson T, Leanderson T, Mörgelin M, Fellman V, Åkerström B. The radical-binding lipocalin A1M binds to a complex I subunit and protects mitochondrial structure and function. Antioxidants Redox Signaling 18: 2017–2028, 2013. doi:10.1089/ars.2012.4658.
    Crossref | PubMed | Web of Science | Google Scholar
  • 41. Tseng PY, Chen YT, Wang CH, Chiu KM, Peng YS, Hsu SP, Chen KL, Yang CY, Lee OKS. Prediction of the development of acute kidney injury following cardiac surgery by machine learning. Crit Care 24: 478, 2020. doi:10.1186/s13054-020-03179-9.
    Crossref | PubMed | Web of Science | Google Scholar
  • 42. Zarbock A, Koyner J, Boening A, Engelman D, Ronco C, Reusch M, Agervald T. Results of a randomized placebo-controlled double-blind adaptive Phase 2 study (AKITA) evaluating RMC-035 for the prevention of AKI in patients undergoing cardiac surgery. American Society of Nephrology, Kidney Week. Philadelphia, PA, November 1–5, 2023, p. TH-PO1160.
    Google Scholar
  • 43. McCullough PA, Bennett-Guerrero E, Chawla LS, Beaver T, Mehta RL, Molitoris BA, Eldred A, Ball G, Lee HJ, Houser MT, Khan S. ABT-719 for the prevention of acute kidney injury in patients undergoing high-risk cardiac surgery: a randomized phase 2b. Clinical Trial. JAHA 5: e003549, 2016. doi:10.1161/JAHA.116.003549.
    Crossref | PubMed | Google Scholar
  • 44. ClinicalTrials.gov. A Safety and Efficacy Trial of Multiple Dosing Regimens of ABT-719 for the Prevention of Acute Kidney Injury in Subjects Undergoing High Risk Cardiac Surgery [Online]. Bethesda, MD: National Library of Medicine, 2013. https://www.clinicaltrials.gov/ct2/show/NCT01777165 [Accessed 7 July 2021].
    Google Scholar
  • 45. ClinicalTrials.gov. QPI-1002 Phase 3 for Prevention of Major Adverse Kidney Events (MAKE) in Subjects at High Risk for AKI Following Cardiac Surgery [Online]. Bethesda, MD: National Library of Medicine, 2018. https://www.clinicaltrials.gov/ct2/show/NCT03510897 [Accessed 16 July 2021].
    Google Scholar
  • 46. van Till JWO, Nojima H, Kameoka C, Hayashi C, Sakatani T, Washburn TB, Molitoris BA, Shaw AD, Engelman DT, Kellum JA. The effects of peroxisome proliferator-activated receptor-delta modulator ASP1128 in patients at risk for acute kidney injury following cardiac surgery. Kidney Int Rep 8: 1407–1416, 2023. doi:10.1016/j.ekir.2023.04.004.
    Crossref | PubMed | Web of Science | Google Scholar
  • 47. ClinicalTrials.gov. Study to Prevent Acute Kidney Injury After Cardiac Surgery Involving Cardiopulmonary Bypass [Online]. Bethesda, MD: National Library of Medicine, 2016. https://www.clinicaltrials.gov/ct2/show/NCT02771509 [Accessed 15 July 2021].
    Google Scholar
Previous
Back to Top
Next
Download PDF