Top

Published in:

01-12-2020 | Acute Kidney Injury | Research article

Genetic variation implicates plasma angiopoietin-2 in the development of acute kidney injury sub-phenotypes

Authors: Pavan K. Bhatraju, Max Cohen, Ryan J. Nagao, Eric D. Morrell, Susanna Kosamo, Xin-Ya Chai, Robin Nance, Victoria Dmyterko, Joseph Delaney, Jason D. Christie, Kathleen D. Liu, Carmen Mikacenic, Sina A. Gharib, W. Conrad Liles, Ying Zheng, David C. Christiani, Jonathan Himmelfarb, Mark M. Wurfel

Published in: BMC Nephrology | Issue 1/2020

Abstract

Background

We previously identified two acute kidney injury (AKI) sub-phenotypes (AKI-SP1 and AKI-SP2) with different risk of poor clinical outcomes and response to vasopressor therapy. Plasma biomarkers of endothelial dysfunction (tumor necrosis factor receptor-1, angiopoietin-1 and 2) differentiated the AKI sub-phenotypes. However, it is unknown whether these biomarkers are simply markers or causal mediators in the development of AKI sub-phenotypes.

Methods

We tested for associations between single-nucleotide polymorphisms within the Angiopoietin-1, Angiopoietin-2, and Tumor Necrosis Factor Receptor 1A genes and AKI- SP2 in 421 critically ill subjects of European ancestry. Top performing single-nucleotide polymorphisms (FDR < 0.05) were tested for cis-biomarker expression and whether genetic risk for AKI-SP2 is mediated through circulating biomarkers. We also completed in vitro studies using human kidney microvascular endothelial cells. Finally, we calculated the renal clearance of plasma biomarkers using 20 different timed urine collections.

Results

A genetic variant, rs2920656C > T, near ANGPT2 was associated with reduced risk of AKI-SP2 (odds ratio, 0.45; 95% CI, 0.31–0.66; adjusted FDR = 0.003) and decreased plasma angiopoietin-2 (p = 0.002). Causal inference analysis showed that for each minor allele (T) the risk of developing AKI-SP2 decreases by 16%. Plasma angiopoietin-2 mediated 41.5% of the rs2920656 related risk for AKI-SP2. Human kidney microvascular endothelial cells carrying the T allele of rs2920656 produced numerically lower levels of angiopoietin-2 although this was not statistically significant (p = 0.07). Finally, analyses demonstrated that angiopoietin-2 is minimally renally cleared in critically ill subjects.

Conclusion

Genetic mediation analysis provides supportive evidence that angiopoietin-2 plays a causal role in risk for AKI-SP2.

Available only for authorised users

Clermont G, Acker CG, Angus DC, Sirio CA, Pinsky MR, Johnson JP. Renal failure in the ICU: comparison of the impact of acute renal failure and end-stage renal disease on ICU outcomes. Kidney Int. 2002;62:986–96.PubMed

Ishani A, Xue JL, Himmelfarb J, Eggers PW, Kimmel PL, Molitoris BA, et al. Acute kidney injury increases risk of ESRD among elderly. J Am Soc Nephrol JASN. 2009;20:223–8.PubMed

Coca SG, Yusuf B, Shlipak MG, Garg AX, Parikh CR. Long-term risk of mortality and other adverse outcomes after acute kidney injury: a systematic review and meta-analysis. Am J Kidney Dis Off J Natl Kidney Found. 2009;53:961–73.

Chawla LS, Eggers PW, Star RA, Kimmel PL. Acute kidney injury and chronic kidney disease as interconnected syndromes. N Engl J Med. 2014;371:58–66.PubMed

Stafford-Smith M, Li Y-J, Mathew JP, Li Y-W, Ji Y, Phillips-Bute BG, et al. Genome-wide association study of acute kidney injury after coronary bypass graft surgery identifies susceptibility loci. Kidney Int. 2015;88:823–32.PubMedPubMedCentral

Zhao B, Lu Q, Cheng Y, Belcher JM, Siew ED, Leaf DE, et al. A genome-wide association study to identify single-nucleotide polymorphisms for acute kidney injury. Am J Respir Crit Care Med. 2016;195:482–90.

Barasch J, Zager R, Bonventre JV. Acute kidney injury: a problem of definition. Lancet Lond Engl. 2017;389:779–81.

Copeland KT, Checkoway H, McMichael AJ, Holbrook RH. Bias due to misclassification in the estimation of relative risk. Am J Epidemiol. 1977;105:488–95.PubMed

Siroux V, González JR, Bouzigon E, Curjuric I, Boudier A, Imboden M, et al. Genetic heterogeneity of asthma phenotypes identified by a clustering approach. Eur Respir J. 2014;43:439–52.PubMed

10.

Bhatraju PK, Zelnick LR, Herting J, Katz R, Mikacenic C, Kosamo S, et al. Identification of acute kidney injury sub-phenotypes with differing molecular signatures and response to vasopressin therapy. Am J Respir Crit Care Med. 2018;199:863–72.

11.

Russell JA, Walley KR, Singer J, Gordon AC, Hébert PC, Cooper DJ, et al. Vasopressin versus norepinephrine infusion in patients with septic shock. N Engl J Med. 2008;358:877–87.PubMed

12.

Wu X, Guo R, Chen P, Wang Q, Cunningham PN. TNF induces caspase-dependent inflammation in renal endothelial cells through a rho- and myosin light chain kinase-dependent mechanism. Am J Physiol Renal Physiol. 2009;297:F316–26.PubMed

13.

Xu C, Chang A, Hack BK, Eadon MT, Alper SL, Cunningham PN. TNF-mediated damage to glomerular endothelium is an important determinant of acute kidney injury in sepsis. Kidney Int. 2014;85:72–81.PubMed

14.

Cunningham PN, Dyanov HM, Park P, Wang J, Newell KA, Quigg RJ. Acute renal failure in Endotoxemia is caused by TNF acting directly on TNF Receptor-1 in kidney. J Immunol. 2002;168:5817–23.PubMed

15.

Han S, Lee S-J, Kim KE, Lee HS, Oh N, Park I, et al. Amelioration of sepsis by TIE2 activation-induced vascular protection. Sci Transl Med. 2016;8:335ra55.PubMed

16.

Parikh SM. The Angiopoietin-Tie2 signaling Axis in systemic inflammation. J Am Soc Nephrol JASN. 2017;28:1973–82.PubMed

17.

Wei Y, Tejera P, Wang Z, Zhang R, Chen F, Su L, et al. A missense genetic variant in LRRC16A/CARMIL1 improves acute respiratory distress syndrome survival by attenuating platelet count decline. Am J Respir Crit Care Med. 2017;195:1353–61.PubMedPubMedCentral

18.

Trinder M, Genga KR, Kong HJ, Blauw LL, Lo C, Li X, et al. Cholesteryl Ester transfer protein influences high-density lipoprotein levels and survival in Sepsis. Am J Respir Crit Care Med. 2019;199:854–62.PubMed

19.

Reilly JP, Wang F, Jones TK, Palakshappa JA, Anderson BJ, Shashaty MGS, et al. Plasma angiopoietin-2 as a potential causal marker in sepsis-associated ARDS development: evidence from Mendelian randomization and mediation analysis. Intensive Care Med. 2018;44:1849–58.PubMedPubMedCentral

20.

Bhatraju PK, Mukherjee P, Robinson-Cohen C, O’Keefe GE, Frank AJ, Christie JD, et al. Acute kidney injury subphenotypes based on creatinine trajectory identifies patients at increased risk of death. Crit Care Lond Engl. 2016;20:372.

21.

National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network, Matthay MA, Brower RG, Carson S, Douglas IS, Eisner M, et al. Randomized, placebo-controlled clinical trial of an aerosolized β₂-agonist for treatment of acute lung injury. Am J Respir Crit Care Med. 2011;184:561–8.

22.

National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (Ards) Clinical Trials Network, Wheeler AP, Bernard GR, Thompson BT, Schoenfeld D, Wiedemann HP, et al. pulmonary-artery versus central venous catheter to guide treatment of acute lung injury. N Engl J Med 2006;354:2213–2224.

23.

Rice TW, Wheeler AP, Thompson BT, de Boisblanc BP, Steingrub J, Rock P, et al. Enteral omega-3 fatty acid, gamma-linolenic acid, and antioxidant supplementation in acute lung injury. JAMA. 2011;306:1574–81.PubMedPubMedCentral

24.

Gong MN, Zhou W, Williams PL, Thompson BT, Pothier L, Christiani DC. Polymorphisms in the mannose binding lectin-2 gene and acute respiratory distress syndrome. Crit Care Med. 2007;35:48–56.PubMedPubMedCentral

25.

Liu KD, Glidden DV, Eisner MD, Parsons PE, Ware LB, Wheeler A, et al. Predictive and pathogenetic value of plasma biomarkers for acute kidney injury in patients with acute lung injury. Crit Care Med. 2007;35:2755–61.PubMedPubMedCentral

26.

Liu K-L, Lee K-T, Chang C-H, Chen Y-C, Lin S-M, Chu P-H. Elevated plasma thrombomodulin and angiopoietin-2 predict the development of acute kidney injury in patients with acute myocardial infarction. Crit Care Lond Engl. 2014;18:R100.

27.

Siew ED, Matheny ME, Ikizler TA, Lewis JB, Miller RA, Waitman LR, et al. Commonly used surrogates for baseline renal function affect the classification and prognosis of acute kidney injury. Kidney Int. 2010;77:536–42.PubMed

28.

Howie BN, Donnelly P, Marchini J. A flexible and accurate genotype imputation method for the next generation of genome-wide association studies. PLoS Genet. 2009;5:e1000529.PubMedPubMedCentral

29.

Marchini J, Howie B. Genotype imputation for genome-wide association studies. Nat Rev Genet. 2010;11:499–511.PubMed

30.

Lee PH, Bergen SE, Perlis RH, Sullivan PF, Sklar P, Smoller JW, et al. Modifiers and subtype-specific analyses in whole-genome association studies: a likelihood framework. Hum Hered. 2011;72:10–20.PubMedPubMedCentral

31.

Bhatraju P, Hsu C, Mukherjee P, Glavan BJ, Burt A, Mikacenic C, et al. Associations between single nucleotide polymorphisms in the FAS pathway and acute kidney injury. Crit Care Lond Engl. 2015;19:368.

32.

Yeboah J, Delaney JA, Nance R, McClelland RL, Polak JF, Sibley CT, et al. Mediation of cardiovascular risk factor effects through subclinical vascular disease: the multi-ethnic study of atherosclerosis. Arterioscler Thromb Vasc Biol. 2014;34:1778–83.PubMedPubMedCentral

33.

Kosuke Imai, Luke Keele, Teppei Yamamoto. Identification, Inference and Sensitivity Analysis for Causal Mediation Effects. JSTOR. 2010;25:51–71.

34.

Skol AD, Scott LJ, Abecasis GR, Boehnke M. Joint analysis is more efficient than replication-based analysis for two-stage genome-wide association studies. Nat Genet. 2006;38:209–13.PubMed

35.

Higgins SJ, Purcell LA, Silver KL, Tran V, Crowley V, Hawkes M, et al. Dysregulation of angiopoietin-1 plays a mechanistic role in the pathogenesis of cerebral malaria. Sci Transl Med. 2016;8:358ra128.PubMedPubMedCentral

36.

Pulvers JN, Journiac N, Arai Y, Nardelli J. MCPH1: a window into brain development and evolution. Front Cell Neurosci. 2015 [cited 2019 Mar 19];9. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4376118/.

37.

Lieb W, Chen M-H, Larson MG, Safa R, Teumer A, Baumeister SE, et al. Genome-wide association study for endothelial growth factors. Circ Cardiovasc Genet. 2015;8:389–97.PubMed

38.

Meyer NJ, Li M, Feng R, Bradfield J, Gallop R, Bellamy S, et al. ANGPT2 genetic variant is associated with trauma-associated acute lung injury and altered plasma angiopoietin-2 isoform ratio. Am J Respir Crit Care Med. 2011;183:1344–53.PubMedPubMedCentral

39.

Jongman RM, van Klarenbosch J, Molema G, Zijlstra JG, de Vries AJ, van Meurs M. Angiopoietin/Tie2 Dysbalance is associated with acute kidney injury after cardiac surgery assisted by cardiopulmonary bypass. PLoS One. 2015;10:e0136205.PubMedPubMedCentral

40.

Robinson-Cohen C, Katz R, Price BL, Harju-Baker S, Mikacenic C, Himmelfarb J, et al. Association of markers of endothelial dysregulation Ang1 and Ang2 with acute kidney injury in critically ill patients. Crit Care Lond Engl. 2016;20:207.

41.

David S, Park J-K, van Meurs M, Zijlstra JG, Koenecke C, Schrimpf C, et al. Acute administration of recombinant Angiopoietin-1 ameliorates multiple-organ dysfunction syndrome and improves survival in murine sepsis. Cytokine. 2011;55:251–9.PubMed

42.

Kümpers P, Hafer C, David S, Hecker H, Lukasz A, Fliser D, et al. Angiopoietin-2 in patients requiring renal replacement therapy in the ICU: relation to acute kidney injury, multiple organ dysfunction syndrome and outcome. Intensive Care Med. 2010;36:462–70.PubMed

43.

Yuan HT, Khankin EV, Karumanchi SA, Parikh SM. Angiopoietin 2 is a partial agonist/antagonist of Tie2 signaling in the endothelium. Mol Cell Biol. 2009;29:2011–22.PubMedPubMedCentral

44.

Kim DH, Jung YJ, Lee AS, Lee S, Kang KP, Lee TH, et al. COMP-angiopoietin-1 decreases lipopolysaccharide-induced acute kidney injury. Kidney Int. 2009;76:1180–91.PubMed

45.

Felcht M, Luck R, Schering A, Seidel P, Srivastava K, Hu J, et al. Angiopoietin-2 differentially regulates angiogenesis through TIE2 and integrin signaling. J Clin Invest. 2012;122:1991–2005.PubMedPubMedCentral

46.

Fiedler U, Reiss Y, Scharpfenecker M, Grunow V, Koidl S, Thurston G, et al. Angiopoietin-2 sensitizes endothelial cells to TNF-alpha and has a crucial role in the induction of inflammation. Nat Med. 2006;12:235–9.PubMed

47.

Higgins SJ, De Ceunynck K, Kellum JA, Chen X, Gu X, Chaudhry SA, et al. Tie2 protects the vasculature against thrombus formation in systemic inflammation. J Clin Invest. 2018;128:1471–84.PubMedPubMedCentral

48.

Zacho J, Tybjaerg-Hansen A, Jensen JS, Grande P, Sillesen H, Nordestgaard BG. Genetically elevated C-reactive protein and ischemic vascular disease. N Engl J Med. 2008;359:1897–908.PubMed

49.

Emerging Risk Factors Collaboration; Kaptoge S, Di Angelantonio E, Lowe G, Pepys MB, Thompson SG, Collins R, Danesh J. C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis. Lancet. 2010;375(9709):132-40. https://doi.org/10.1016/S0140-6736(09)61717-7.

Title: Genetic variation implicates plasma angiopoietin-2 in the development of acute kidney injury sub-phenotypes
Authors: Pavan K. Bhatraju
Max Cohen
Ryan J. Nagao
Eric D. Morrell
Susanna Kosamo
Xin-Ya Chai
Robin Nance
Victoria Dmyterko
Joseph Delaney
Jason D. Christie
Kathleen D. Liu
Carmen Mikacenic
Sina A. Gharib
W. Conrad Liles
Ying Zheng
David C. Christiani
Jonathan Himmelfarb
Mark M. Wurfel
Publication date: 01-12-2020
Publisher: BioMed Central
Keywords: Acute Kidney Injury
Acute Kidney Injury
Biomarkers
Published in: BMC Nephrology / Issue 1/2020
Electronic ISSN: 1471-2369
DOI: https://doi.org/10.1186/s12882-020-01935-1

ACC 2024 Congress Coverage

Heart Failure Video

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Genetic variation implicates plasma angiopoietin-2 in the development of acute kidney injury sub-phenotypes

Abstract

Background

Methods

Results

Conclusion

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2020

Exploring reasons for state-level variation in incidence of dialysis-requiring acute kidney injury (AKI-D) in the United States

Removal of large middle molecules via haemodialysis with medium cut-off membranes at lower blood flow rates: an observational prospective study

Variation in contrast-associated acute kidney injury prophylaxis for percutaneous coronary intervention: insights from the Veterans Affairs Clinical Assessment, Reporting, and Tracking (CART) program

Effect of donor non-muscle myosin heavy chain (MYH9) gene polymorphisms on clinically relevant kidney allograft dysfunction

Development and validation of hybrid Brillouin-Raman spectroscopy for non-contact assessment of mechano-chemical properties of urine proteins as biomarkers of kidney diseases

Associations of urological malignancies with renal progression and mortality in advanced chronic kidney disease: a propensity-matched cohort study

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page