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Pediatric Nephrology
Published in: Pediatric Nephrology 5/2018

01-05-2018 | Educational Review

Acute kidney injury: emerging pharmacotherapies in current clinical trials

Authors: Stefanie Woolridge Benoit, Prasad Devarajan

Published in: Pediatric Nephrology | Issue 5/2018

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Abstract

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).
Literature
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 10:554–561CrossRefPubMedPubMedCentral
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 67:384–390CrossRefPubMed
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 376:11–20CrossRefPubMed
4.
Moffett BS, Goldstein SL (2011) Acute kidney injury and increasing nephrotoxic-medication exposure in noncritically-ill children. Clin J Am Soc Nephrol 6:856–863CrossRefPubMedPubMedCentral
5.
Goldstein SL (2012) Acute kidney injury in children and its potential consequences in adulthood. Blood Purif 33:131–137CrossRefPubMed
6.
Chaturvedi S (2017) The path to chronic kidney disease following acute kidney injury: a neonatal perspective. Pediatr Nephrol 32:227–241CrossRefPubMed
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 15:184–184CrossRefPubMedPubMedCentral
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 45:96–101CrossRefPubMed
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 90:212–221CrossRefPubMed
10.
(2012) Section 3: Prevention and Treatment of AKI. Kidney Int Suppl 2:37–68
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 27:49–58CrossRefPubMed
12.
Okusa MD, Rosner MH, Kellum JA, Ronco C (2016) Therapeutic targets of human AKI: harmonizing human and animal AKI. J Am Soc Nephrol 27:44–48CrossRefPubMed
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 27:990–998CrossRefPubMed
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 27:371–379CrossRefPubMed
15.
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 63:1038–1048CrossRefPubMed
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 172:4932–4945CrossRefPubMedPubMedCentral
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:R14CrossRefPubMedPubMedCentral
19.
Kaempfer R, Arad G, Levy R, Hillman D, Nasie I, Rotfogel Z (2013) CD28: direct and critical receptor for superantigen toxins. Toxins (Basel) 5:1531–1542CrossRef
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 149:528–536CrossRefPubMed
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 92:8016–8020CrossRefPubMedPubMedCentral
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.
24.
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 20:331CrossRefPubMedPubMedCentral
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 63:1480–1483CrossRefPubMed
27.
Chuang GT, Tsai IJ, Tsau YK, Lu MY (2015) Transfusion-dependent thalassaemic patients with renal Fanconi syndrome due to deferasirox use. Nephrology (Carlton) 20:931–935CrossRef
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 167:434–436CrossRefPubMed
29.
Freedman MH, Boyden M, Taylor M, Skarf B (1988) Neurotoxicity associated with deferoxamine therapy. Toxicology 49:283–290CrossRefPubMed
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 56:19–23CrossRefPubMed
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 108:305–312CrossRefPubMed
32.
Bolisetty S, Zarjou A, Agarwal A (2017) Heme Oxygenase 1 as a therapeutic target in acute kidney injury. Am J Kidney Dis 69:531–545CrossRefPubMed
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–F736CrossRefPubMed
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 72:1073–1080CrossRefPubMedPubMedCentral
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 100:176–183CrossRefPubMed
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 222:303–312CrossRefPubMed
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–F1462CrossRefPubMed
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 67:408–416CrossRefPubMed
39.
Devarajan P (2006) Update on mechanisms of ischemic acute kidney injury. J Am Soc Nephrol 17:1503–1520CrossRefPubMed
40.
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 20:1754–1764CrossRefPubMedPubMedCentral
42.
Chawla LS, Eggers PW, Star RA, Kimmel PL (2014) Acute kidney injury and chronic kidney disease as interconnected syndromes. N Engl J Med 371:58–66CrossRefPubMed
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 8:288–296CrossRefPubMedPubMedCentral
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 102:202–214CrossRefPubMedPubMedCentral
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–S21PubMed
46.
Tampe D, Zeisberg M (2014) Potential approaches to reverse or repair renal fibrosis. Nat Rev Nephrol 10:226–237CrossRefPubMed
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 18:396–404CrossRefPubMedPubMedCentral
48.
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 95:2552–2558CrossRefPubMed
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 84:509–520CrossRefPubMedPubMedCentral
51.
Tan RJ, Zhou D, Liu Y (2016) Signaling crosstalk between tubular epithelial cells and interstitial fibroblasts after kidney injury. Kidney Dis (Basel) 2:136–144CrossRef
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 15:2868–2881CrossRefPubMed
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–F361CrossRefPubMedPubMedCentral
54.
Peired AJ, Sisti A, Romagnani P (2016) Mesenchymal stem cell-based therapy for kidney disease: a review of clinical evidence. Stem Cells Int 2016:4798639PubMedPubMedCentral
55.
Tögel FE, Westenfelder C (2012) Kidney protection and regeneration following acute injury: progress through stem cell therapy. Am J Kidney Dis 60:1012–1022CrossRefPubMed
56.
Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group (2012) KDIGO clinical practice guideline for acute kidney injury. Kidney Int Suppl 2:1–138CrossRef
Metadata
Title
Acute kidney injury: emerging pharmacotherapies in current clinical trials
Authors
Stefanie Woolridge Benoit
Prasad Devarajan
Publication date
01-05-2018
Publisher
Springer Berlin Heidelberg
Published in
Pediatric Nephrology / Issue 5/2018
Print ISSN: 0931-041X
Electronic ISSN: 1432-198X
DOI
https://doi.org/10.1007/s00467-017-3695-3

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