Pediatric Nephrology

, Volume 33, Issue 5, pp 779–787 | Cite as

Acute kidney injury: emerging pharmacotherapies in current clinical trials

  • Stefanie Woolridge Benoit
  • Prasad Devarajan
Educational Review


Acute kidney injury (AKI) is a significant source of morbidity and mortality in pediatric patients, affecting more than one quarter of critically ill children. Despite significant need, there are no targeted therapies to reliably prevent or treat AKI. Recent advances in our understanding of renal injury and repair signaling pathways have enabled the development of several targeted pharmaceuticals. Here we review emerging pharmacotherapies for AKI that are currently in clinical trials. Categorized by their general mechanism of action, the therapies discussed include anti-inflammatory agents (recAP, AB103, ABT-719), antioxidants (iron chelators, heme arginate), vasodilators (levosimendan), apoptosis inhibitors (QPI-1002), and repair agents (THR-184, BB-3, mesenchymal stem cells).


Acute kidney injury Acute renal failure Clinical trials Therapeutics Pediatric 


Compliance with ethical standards

Conflicts of interest

The authors declare no conflicts of interest.


No further disclosures.


  1. 1.
    Sutherland SM, Byrnes JJ, Kothari M, Longhurst CA, Dutta S, Garcia P, Goldstein SL (2015) AKI in hospitalized children: comparing the pRIFLE, AKIN, and KDIGO definitions. Clin J Am Soc Nephrol 10:554–561CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    McGregor TL, Jones DP, Wang L, Danciu I, Bridges BC, Fleming GM, Shirey-Rice J, Chen L, Byrne DW, Van Driest SL (2016) Acute kidney injury incidence in Noncritically ill hospitalized children, adolescents, and young adults: a retrospective observational study. Am J Kidney Dis 67:384–390CrossRefPubMedGoogle Scholar
  3. 3.
    Kaddourah A, Basu RK, Bagshaw SM, Goldstein SL (2017) Epidemiology of acute kidney injury in critically ill children and young adults. N Engl J Med 376:11–20CrossRefPubMedGoogle Scholar
  4. 4.
    Moffett BS, Goldstein SL (2011) Acute kidney injury and increasing nephrotoxic-medication exposure in noncritically-ill children. Clin J Am Soc Nephrol 6:856–863CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Goldstein SL (2012) Acute kidney injury in children and its potential consequences in adulthood. Blood Purif 33:131–137CrossRefPubMedGoogle Scholar
  6. 6.
    Chaturvedi S (2017) The path to chronic kidney disease following acute kidney injury: a neonatal perspective. Pediatr Nephrol 32:227–241CrossRefPubMedGoogle Scholar
  7. 7.
    Greenberg JH, Coca S, Parikh CR (2014) Long-term risk of chronic kidney disease and mortality in children after acute kidney injury: a systematic review. BMC Nephrol 15:184–184CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Hui-Stickle S, Brewer ED, Goldstein SL (2005) Pediatric ARF epidemiology at a tertiary care center from 1999 to 2001. Am J Kidney Dis 45:96–101CrossRefPubMedGoogle Scholar
  9. 9.
    Goldstein SL, Mottes T, Simpson K, Barclay C, Muething S, Haslam DB, Kirkendall ES (2016) A sustained quality improvement program reduces nephrotoxic medication-associated acute kidney injury. Kidney Int 90:212–221CrossRefPubMedGoogle Scholar
  10. 10.
    (2012) Section 3: Prevention and Treatment of AKI. Kidney Int Suppl 2:37–68Google Scholar
  11. 11.
    Matejovic M, Ince C, Chawla LS, Blantz R, Molitoris BA, Rosner MH, Okusa MD, Kellum JA, Ronco C (2016) Renal hemodynamics in AKI: in search of new treatment targets. J Am Soc Nephrol 27:49–58CrossRefPubMedGoogle Scholar
  12. 12.
    Okusa MD, Rosner MH, Kellum JA, Ronco C (2016) Therapeutic targets of human AKI: harmonizing human and animal AKI. J Am Soc Nephrol 27:44–48CrossRefPubMedGoogle Scholar
  13. 13.
    Humphreys BD, Cantaluppi V, Portilla D, Singbartl K, Yang L, Rosner MH, Kellum JA, Ronco C, for the Acute Dialysis Quality Initiative (ADQI) XIII Work Group (2016) Targeting endogenous repair pathways after AKI. J Am Soc Nephrol 27:990–998CrossRefPubMedGoogle Scholar
  14. 14.
    Rabb H, Griffin MD, DB MK, Swaminathan S, Pickkers P, Rosner MH, Kellum JA, Ronco C (2016) Inflammation in AKI: current understanding, key questions, and knowledge gaps. J Am Soc Nephrol 27:371–379CrossRefPubMedGoogle Scholar
  15. 15.
    Basile DP, Anderson MD, Sutton TA (2012) Pathophysiology of acute kidney injury. Compr Physiol 2:1303–1353PubMedPubMedCentralGoogle Scholar
  16. 16.
    Peters E, Heemskerk S, Masereeuw R, Pickkers P (2014) Alkaline phosphatase: a possible treatment for sepsis-associated acute kidney injury in critically ill patients. Am J Kidney Dis 63:1038–1048CrossRefPubMedGoogle Scholar
  17. 17.
    Peters E, Geraci S, Heemskerk S, Wilmer MJ, Bilos A, Kraenzlin B, Gretz N, Pickkers P, Masereeuw R (2015) Alkaline phosphatase protects against renal inflammation through dephosphorylation of lipopolysaccharide and adenosine triphosphate. Br J Pharmacol 172:4932–4945CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Pickkers P, Heemskerk S, Schouten J, Laterre P-F, Vincent J-L, Beishuizen A, Jorens PG, Spapen H, Bulitta M, Peters WH, van der Hoeven JG (2012) Alkaline phosphatase for treatment of sepsis-induced acute kidney injury: a prospective randomized double-blind placebo-controlled trial. Crit Care 16:R14CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Kaempfer R, Arad G, Levy R, Hillman D, Nasie I, Rotfogel Z (2013) CD28: direct and critical receptor for superantigen toxins. Toxins (Basel) 5:1531–1542CrossRefGoogle Scholar
  20. 20.
    Bulger EM, Maier RV, Sperry J, Joshi M, Henry S, Moore FA, Moldawer LL, Demetriades D, Talving P, Schreiber M, Ham B, Cohen M, Opal S, Segalovich I, Maislin G, Kaempfer R, Shirvan A (2014) A novel drug for treatment of necrotizing soft-tissue infections: a randomized clinical trial. JAMA Surg 149:528–536CrossRefPubMedGoogle Scholar
  21. 21.
    Star RA, Rajora N, Huang J, Stock RC, Catania A, Lipton JM (1995) Evidence of autocrine modulation of macrophage nitric oxide synthase by alpha-melanocyte-stimulating hormone. Proc Natl Acad Sci U S A 92:8016–8020CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    PA MC, Bennett-Guerrero E, Chawla LS, Beaver T, Mehta RL, Molitoris BA, Eldred A, Ball G, Lee HJ, Houser MT, Khan S (2016) ABT-719 for the prevention of acute kidney injury in patients undergoing high-risk cardiac surgery: a randomized phase 2b clinical trial. J Am Heart Assoc. doi: 10.1161/JAHA.116.003549
  23. 23.
    Leaf DE, Swinkels DW (2016) Catalytic iron and acute kidney injury. Am J Physiol Renal Physiol 311:F871–F876CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Walker VJ, Agarwal A (2016) Targeting iron homeostasis in acute kidney injury. Semin Nephrol 36:62–70CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Fraga CM, Tomasi CD, Damasio DC, Vuolo F, Ritter C, Dal-Pizzol F (2016) N-acetylcysteine plus deferoxamine for patients with prolonged hypotension does not decrease acute kidney injury incidence: a double blind, randomized, placebo-controlled trial. Crit Care 20:331CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Papneja K, Bhatt MD, Kirby-Allen M, Arora S, Wiernikowski JT, Athale UH (2016) Fanconi syndrome secondary to Deferasirox in Diamond-Blackfan anemia: case series and recommendations for early diagnosis. Pediatr Blood Cancer 63:1480–1483CrossRefPubMedGoogle Scholar
  27. 27.
    Chuang GT, Tsai IJ, Tsau YK, Lu MY (2015) Transfusion-dependent thalassaemic patients with renal Fanconi syndrome due to deferasirox use. Nephrology (Carlton) 20:931–935CrossRefGoogle Scholar
  28. 28.
    Dee CM, Cheuk DK, Ha SY, Chiang AK, Chan GC (2014) Incidence of deferasirox-associated renal tubular dysfunction in children and young adults with beta-thalassaemia. Br J Haematol 167:434–436CrossRefPubMedGoogle Scholar
  29. 29.
    Freedman MH, Boyden M, Taylor M, Skarf B (1988) Neurotoxicity associated with deferoxamine therapy. Toxicology 49:283–290CrossRefPubMedGoogle Scholar
  30. 30.
    Cases A, Kelly J, Sabater F, Torras A, Grino MC, Lopez-Pedret J, Revert L (1990) Ocular and auditory toxicity in hemodialyzed patients receiving desferrioxamine. Nephron 56:19–23CrossRefPubMedGoogle Scholar
  31. 31.
    Cohen AR, Galanello R, Piga A, DiPalma A, Vullo C, Tricta F (2000) Safety profile of the oral iron chelator deferiprone: a multicentre study. Br J Haematol 108:305–312CrossRefPubMedGoogle Scholar
  32. 32.
    Bolisetty S, Zarjou A, Agarwal A (2017) Heme Oxygenase 1 as a therapeutic target in acute kidney injury. Am J Kidney Dis 69:531–545CrossRefPubMedGoogle Scholar
  33. 33.
    Shiraishi F, Curtis LM, Truong L, Poss K, Visner GA, Madsen K, Nick HS, Agarwal A (2000) Heme oxygenase-1 gene ablation or expression modulates cisplatin-induced renal tubular apoptosis. Am J Physiol Renal Physiol 278:F726–F736CrossRefPubMedGoogle Scholar
  34. 34.
    Tracz MJ, Juncos JP, Croatt AJ, Ackerman AW, Grande JP, Knutson KL, Kane GC, Terzic A, Griffin MD, Nath KA (2007) Deficiency of heme oxygenase-1 impairs renal hemodynamics and exaggerates systemic inflammatory responses to renal ischemia. Kidney Int 72:1073–1080CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Thomas RA, Czopek A, Bellamy CO, SJ MN, Kluth DC, Marson LP (2016) Hemin preconditioning upregulates Heme Oxygenase-1 in deceased donor renal transplant recipients: a randomized, controlled, phase IIB trial. Transplantation 100:176–183CrossRefPubMedGoogle Scholar
  36. 36.
    Farmakis D, Alvarez J, Gal TB, Brito D, Fedele F, Fonseca C, Gordon AC, Gotsman I, Grossini E, Guarracino F, Harjola V-P, Hellman Y, Heunks L, Ivancan V, Karavidas A, Kivikko M, Lomivorotov V, Longrois D, Masip J, Metra M, Morelli A, Nikolaou M, Papp Z, Parkhomenko A, Poelzl G, Pollesello P, Ravn HB, Rex S, Riha H, Ricksten S-E, RHG S, Vrtovec B, Yilmaz MB, Zielinska M, Parissis J (2016) Levosimendan beyond inotropy and acute heart failure: evidence of pleiotropic effects on the heart and other organs: an expert panel position paper. Int J Cardiol 222:303–312CrossRefPubMedGoogle Scholar
  37. 37.
    Zager RA, Johnson AC, Lund S, Hanson SY, Abrass CK (2006) Levosimendan protects against experimental endotoxemic acute renal failure. Am J Physiol Renal Physiol 290:F1453–F1462CrossRefPubMedGoogle Scholar
  38. 38.
    Zhou C, Gong J, Chen D, Wang W, Liu M, Liu B (2016) Levosimendan for prevention of acute kidney injury after cardiac surgery: a meta-analysis of randomized controlled trials. Am J Kidney Dis 67:408–416CrossRefPubMedGoogle Scholar
  39. 39.
    Devarajan P (2006) Update on mechanisms of ischemic acute kidney injury. J Am Soc Nephrol 17:1503–1520CrossRefPubMedGoogle Scholar
  40. 40.
    Yan M, Tang C, Ma Z, Huang S, Dong Z (2016) DNA damage response in nephrotoxic and ischemic kidney injury. Toxicol Appl Pharmacol 313:104–108CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Molitoris BA, Dagher PC, Sandoval RM, Campos SB, Ashush H, Fridman E, Brafman A, Faerman A, Atkinson SJ, Thompson JD, Kalinski H, Skaliter R, Erlich S, Feinstein E (2009) siRNA targeted to p53 attenuates ischemic and Cisplatin-induced acute kidney injury. J Am Soc Nephrol 20:1754–1764CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Chawla LS, Eggers PW, Star RA, Kimmel PL (2014) Acute kidney injury and chronic kidney disease as interconnected syndromes. N Engl J Med 371:58–66CrossRefPubMedGoogle Scholar
  43. 43.
    Tsujimura T, Idei M, Yoshikawa M, Takase O, Hishikawa K (2016) Roles and regulation of bone morphogenetic protein-7 in kidney development and diseases. World J Stem Cells 8:288–296CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Vukicevic S, Basic V, Rogic D, Basic N, Shih MS, Shepard A, Jin D, Dattatreyamurty B, Jones W, Dorai H, Ryan S, Griffiths D, Maliakal J, Jelic M, Pastorcic M, Stavljenic A, Sampath TK (1998) Osteogenic protein-1 (bone morphogenetic protein-7) reduces severity of injury after ischemic acute renal failure in rat. J Clin Invest 102:202–214CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Morrissey J, Hruska K, Guo G, Wang S, Chen Q, Klahr S (2002) Bone morphogenetic protein-7 improves renal fibrosis and accelerates the return of renal function. J Am Soc Nephrol 13(Suppl 1):S14–S21PubMedGoogle Scholar
  46. 46.
    Tampe D, Zeisberg M (2014) Potential approaches to reverse or repair renal fibrosis. Nat Rev Nephrol 10:226–237CrossRefPubMedGoogle Scholar
  47. 47.
    Sugimoto H, LeBleu VS, Bosukonda D, Keck P, Taduri G, Bechtel W, Okada H, Carlson W Jr, Bey P, Rusckowski M, Tampe B, Tampe D, Kanasaki K, Zeisberg M, Kalluri R (2012) Activin-like kinase 3 is important for kidney regeneration and reversal of fibrosis. Nat Med 18:396–404CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Organ SL, Tsao M-S (2011) An overview of the c-MET signaling pathway. Ther Adv Med Oncol 3(1 Suppl):S7–S19CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Ono K, Matsumori A, Shioi T, Furukawa Y, Sasayama S (1997) Enhanced expression of hepatocyte growth factor/c-met by myocardial ischemia and reperfusion in a rat model. Circulation 95:2552–2558CrossRefPubMedGoogle Scholar
  50. 50.
    Zhou D, Tan RJ, Lin L, Zhou L, Liu Y (2013) Activation of hepatocyte growth factor receptor, c-met, in renal tubules is required for renoprotection after acute kidney injury. Kidney Int 84:509–520CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Tan RJ, Zhou D, Liu Y (2016) Signaling crosstalk between tubular epithelial cells and interstitial fibroblasts after kidney injury. Kidney Dis (Basel) 2:136–144CrossRefGoogle Scholar
  52. 52.
    Gong R, Rifai A, Tolbert EM, Biswas P, Centracchio JN, Dworkin LD (2004) Hepatocyte growth factor ameliorates renal interstitial inflammation in rat remnant kidney by modulating tubular expression of macrophage chemoattractant protein-1 and RANTES. J Am Soc Nephrol 15:2868–2881CrossRefPubMedGoogle Scholar
  53. 53.
    Narayan P, Duan B, Jiang K, Li J, Paka L, Yamin MA, Friedman SL, Weir MR, Goldberg ID (2016) Late intervention with the small molecule BB3 mitigates postischemic kidney injury. Am J Physiol Renal Physiol 311:F352–F361CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Peired AJ, Sisti A, Romagnani P (2016) Mesenchymal stem cell-based therapy for kidney disease: a review of clinical evidence. Stem Cells Int 2016:4798639PubMedPubMedCentralGoogle Scholar
  55. 55.
    Tögel FE, Westenfelder C (2012) Kidney protection and regeneration following acute injury: progress through stem cell therapy. Am J Kidney Dis 60:1012–1022CrossRefPubMedGoogle Scholar
  56. 56.
    Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group (2012) KDIGO clinical practice guideline for acute kidney injury. Kidney Int Suppl 2:1–138CrossRefGoogle Scholar

Copyright information

© IPNA 2017

Authors and Affiliations

  1. 1.Cincinnati Children’s Hospital Medical CenterCincinnatiUSA

Personalised recommendations