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Open Access 01-12-2022 | Acute Kidney Injury | Research

Limited clinical utility for GWAS or polygenic risk score for postoperative acute kidney injury in non-cardiac surgery in European-ancestry patients

Authors: Daniel B. Larach, Adam Lewis, Lisa Bastarache, Anita Pandit, Jing He, Anik Sinha, Nicholas J. Douville, Michael Heung, Michael R. Mathis, Jonathan D. Mosley, Jonathan P. Wanderer, Sachin Kheterpal, Matthew Zawistowski, Chad M. Brummett, Edward D. Siew, Cassianne Robinson-Cohen, Miklos D. Kertai

Published in: BMC Nephrology | Issue 1/2022

Abstract

Background

Prior studies support a genetic basis for postoperative acute kidney injury (AKI). We conducted a genome-wide association study (GWAS), assessed the clinical utility of a polygenic risk score (PRS), and estimated the heritable component of AKI in patients who underwent noncardiac surgery.

Methods

We performed a retrospective large-scale genome-wide association study followed by a meta-analysis of patients who underwent noncardiac surgery at the Vanderbilt University Medical Center (“Vanderbilt” cohort) or Michigan Medicine, the academic medical center of the University of Michigan (“Michigan” cohort). In the Vanderbilt cohort, the relationship between polygenic risk score for estimated glomerular filtration rate and postoperative AKI was also tested to explore the predictive power of aggregating multiple common genetic variants associated with AKI risk. Similarly, in the Vanderbilt cohort genome-wide complex trait analysis was used to estimate the heritable component of AKI due to common genetic variants.

Results

The study population included 8248 adults in the Vanderbilt cohort (mean [SD] 58.05 [15.23] years, 50.2% men) and 5998 adults in Michigan cohort (56.24 [14.76] years, 49% men). Incident postoperative AKI events occurred in 959 patients (11.6%) and in 277 patients (4.6%), respectively. No loci met genome-wide significance in the GWAS and meta-analysis. PRS for estimated glomerular filtration rate explained a very small percentage of variance in rates of postoperative AKI and was not significantly associated with AKI (odds ratio 1.050 per 1 SD increase in polygenic risk score [95% CI, 0.971–1.134]). The estimated heritability among common variants for AKI was 4.5% (SE = 4.5%) suggesting low heritability.

Conclusion

The findings of this study indicate that common genetic variation minimally contributes to postoperative AKI after noncardiac surgery, and likely has little clinical utility for identifying high-risk patients.

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Zeng X, McMahon GM, Brunelli SM, Bates DW, Waikar SS. Incidence, outcomes, and comparisons across definitions of AKI in hospitalized individuals. Clin J Am Soc Nephrol. 2014;9(1):12–20. https://doi.org/10.2215/CJN.02730313.CrossRefPubMed

Wang HE, Muntner P, Chertow GM, Warnock DG. Acute kidney injury and mortality in hospitalized patients. Am J Nephrol. 2012;35(4):349–55. https://doi.org/10.1159/000337487.CrossRefPubMedPubMedCentral

Susantitaphong P, Cruz DN, Cerda J, et al. World incidence of AKI: a meta-analysis. Clin J Am Soc Nephrol. 2013;8(9):1482–93. https://doi.org/10.2215/CJN.00710113.CrossRefPubMedPubMedCentral

Hsu RK, McCulloch CE, Dudley RA, Lo LJ, Hsu CY. Temporal changes in incidence of dialysis-requiring AKI. J Am Soc Nephrol. 2013;24(1):37–42. https://doi.org/10.1681/ASN.2012080800.CrossRefPubMed

Walsh M, Devereaux PJ, Garg AX, et al. Relationship between intraoperative mean arterial pressure and clinical outcomes after noncardiac surgery: toward an empirical definition of hypotension. Anesthesiology. 2013;119(3):507–15. https://doi.org/10.1097/ALN.0b013e3182a10e26.CrossRefPubMed

Bihorac A, Yavas S, Subbiah S, et al. Long-term risk of mortality and acute kidney injury during hospitalization after major surgery. Ann Surg. 2009;249(5):851–8. https://doi.org/10.1097/SLA.0b013e3181a40a0b.CrossRefPubMed

O'Connor ME, Kirwan CJ, Pearse RM, Prowle JR. Incidence and associations of acute kidney injury after major abdominal surgery. Intensive Care Med. 2016;42(4):521–30. https://doi.org/10.1007/s00134-015-4157-7.CrossRefPubMed

Pickering JW, James MT, Palmer SC. Acute kidney injury and prognosis after cardiopulmonary bypass: a meta-analysis of cohort studies. Am J Kidney Dis. 2015;65(2):283–93. https://doi.org/10.1053/j.ajkd.2014.09.008.CrossRefPubMed

Vaught AJ, Ozrazgat-Baslanti T, Javed A, Morgan L, Hobson CE, Bihorac A. Acute kidney injury in major gynaecological surgery: an observational study. BJOG. 2015;122(10):1340–8. https://doi.org/10.1111/1471-0528.13026.CrossRefPubMed

10.

Wilson FP, Yang W, Feldman HI. Predictors of death and dialysis in severe AKI: the UPHS-AKI cohort. Clin J Am Soc Nephrol. 2013;8(4):527–37. https://doi.org/10.2215/CJN.06450612.CrossRefPubMed

11.

Uchino S, Kellum JA, Bellomo R, et al. Acute renal failure in critically ill patients: a multinational, multicenter study. JAMA. 2005;294(7):813–8. https://doi.org/10.1001/jama.294.7.813.CrossRefPubMed

12.

Hoste EA, Schurgers M. Epidemiology of acute kidney injury: how big is the problem? Crit Care Med. 2008;36(4 Suppl):S146–51. https://doi.org/10.1097/CCM.0b013e318168c590.CrossRefPubMed

13.

Gonzalez Sanchidrian S, Deira Lorenzo JL, Mucino Bermejo MJ, et al. Survival and renal recovery after acute kidney injury requiring dialysis outside of intensive care units. Int Urol Nephrol. 2020;52(12):2367–77. https://doi.org/10.1007/s11255-020-02555-2.CrossRefPubMed

14.

Khwaja A. KDIGO clinical practice guidelines for acute kidney injury. Nephron Clin Pract. 2012;120(4):c179–84. https://doi.org/10.1159/000339789.CrossRefPubMed

15.

Matheny ME, Miller RA, Ikizler TA, et al. Development of inpatient risk stratification models of acute kidney injury for use in electronic health records. Med Decis Mak. 2010;30(6):639–50. https://doi.org/10.1177/0272989X10364246.CrossRef

16.

Forni LG, Dawes T, Sinclair H, et al. Identifying the patient at risk of acute kidney injury: a predictive scoring system for the development of acute kidney injury in acute medical patients. Nephron Clin Pract. 2013;123(3–4):143–50. https://doi.org/10.1159/000351509.CrossRefPubMed

17.

Drawz PE, Miller RT, Sehgal AR. Predicting hospital-acquired acute kidney injury--a case-controlled study. Ren Fail. 2008;30(9):848–55. https://doi.org/10.1080/08860220802356515.CrossRefPubMed

18.

Kheterpal S, Tremper KK, Heung M, et al. Development and validation of an acute kidney injury risk index for patients undergoing general surgery: results from a national data set. Comparative study research support, non-U.S. Gov't validation studies. Anesthesiology. 2009;110(3):505–15. https://doi.org/10.1097/ALN.0b013e3181979440.CrossRefPubMed

19.

Wuttke M, Li Y, Li M, et al. A catalog of genetic loci associated with kidney function from analyses of a million individuals. Nat Genet. 2019;51(6):957–72. https://doi.org/10.1038/s41588-019-0407-x.CrossRefPubMedPubMedCentral

20.

Graham SE, Nielsen JB, Zawistowski M, et al. Sex-specific and pleiotropic effects underlying kidney function identified from GWAS meta-analysis. Nat Commun. 2019;10(1):1847. https://doi.org/10.1038/s41467-019-09861-z.CrossRefPubMedPubMedCentral

21.

Zhao B, Lu Q, Cheng Y, et al. A genome-wide association study to identify single-nucleotide polymorphisms for acute kidney injury. Am J Respir Crit Care Med. 2017;195(4):482–90. https://doi.org/10.1164/rccm.201603-0518OC.CrossRefPubMedPubMedCentral

22.

Stafford-Smith M, Li YJ, Mathew JP, et al. Genome-wide association study of acute kidney injury after coronary bypass graft surgery identifies susceptibility loci. Kidney Int. 2015;88(4):823–32. https://doi.org/10.1038/ki.2015.161.CrossRefPubMedPubMedCentral

23.

Westphal S, Stoppe C, Gruenewald M, et al. Genome-wide association study of myocardial infarction, atrial fibrillation, acute stroke, acute kidney injury and delirium after cardiac surgery - a sub-analysis of the RIPHeart-study. BMC Cardiovasc Disord. 2019;19(1):26. https://doi.org/10.1186/s12872-019-1002-x.CrossRefPubMedPubMedCentral

24.

Larach DB, Engoren MC, Schmidt EM, Heung M. Genetic variants and acute kidney injury: a review of the literature. J Crit Care. 2018;44:203–11. https://doi.org/10.1016/j.jcrc.2017.11.019.CrossRefPubMed

25.

Little J, Higgins JP, Ioannidis JP, et al. Strengthening the reporting of genetic association studies (STREGA): an extension of the STROBE statement. Research support, non-U.S. Gov't. Hum Genet. 2009;125(2):131–51. https://doi.org/10.1007/s00439-008-0592-7.CrossRefPubMed

26.

Elixhauser A, Steiner C, Harris DR, Coffey RM. Comorbidity measures for use with administrative data. Med Care. 1998;36(1):8–27. https://doi.org/10.1097/00005650-199801000-00004.CrossRefPubMed

27.

Mathis MR, Naik BI, Freundlich RE, et al. Preoperative risk and the association between hypotension and postoperative acute kidney injury. Anesthesiology. 2020;132(3):461–75. https://doi.org/10.1097/ALN.0000000000003063.CrossRefPubMed

28.

Zhong X, Yin Z, Jia G, et al. Electronic health record phenotypes associated with genetically regulated expression of CFTR and application to cystic fibrosis. Genet Med. 2020;22(7):1191–200. https://doi.org/10.1038/s41436-020-0786-5.CrossRefPubMedPubMedCentral

29.

Douville NJ, Surakka I, Leis A, et al. Use of a polygenic risk score improves prediction of myocardial injury after non-cardiac surgery. Circ Genom Precis Med. 2020;13(4):e002817. https://doi.org/10.1161/CIRCGEN.119.002817.CrossRefPubMedPubMedCentral

30.

Yang J, Lee SH, Goddard ME, Visscher PM. GCTA: a tool for genome-wide complex trait analysis. Research support, non-U.S. Gov't. Am J Hum Genet. 2011;88(1):76–82. https://doi.org/10.1016/j.ajhg.2010.11.011.CrossRefPubMedPubMedCentral

31.

Manichaikul A, Wang XQ, Sun L, et al. Genome-wide association study of subclinical interstitial lung disease in MESA. Respir Res. 2017;18(1):97. https://doi.org/10.1186/s12931-017-0581-2.CrossRefPubMedPubMedCentral

32.

Wang Y, Chung DH, Monteleone LR, et al. RNA binding candidates for human ADAR3 from substrates of a gain of function mutant expressed in neuronal cells. Nucleic Acids Res. 2019;47(20):10801–14. https://doi.org/10.1093/nar/gkz815.CrossRefPubMedPubMedCentral

33.

Oguro R, Kamide K, Katsuya T, et al. A single nucleotide polymorphism of the adenosine deaminase, RNA-specific gene is associated with the serum triglyceride level, abdominal circumference, and serum adiponectin concentration. Exp Gerontol. 2012;47(2):183–7. https://doi.org/10.1016/j.exger.2011.12.004.CrossRefPubMed

34.

Sung YJ, de Las FL, Schwander KL, Simino J, Rao DC. Gene-smoking interactions identify several novel blood pressure loci in the Framingham heart study. Am J Hypertens. 2015;28(3):343–54. https://doi.org/10.1093/ajh/hpu149.CrossRefPubMed

35.

Li J, Hu X, Su M, Shen H, Qiu W, Tian Y. CDK5RAP3 participates in autophagy regulation and is Downregulated in renal Cancer. Dis Markers. 2019;2019:6171782. https://doi.org/10.1155/2019/6171782.CrossRefPubMedPubMedCentral

36.

Lin JX, Yoon C, Li P, et al. CDK5RAP3 as tumour suppressor negatively regulates self-renewal and invasion and is regulated by ERK1/2 signalling in human gastric cancer. Br J Cancer. 2020;123(7):1131–44. https://doi.org/10.1038/s41416-020-0963-y.CrossRefPubMedPubMedCentral

37.

Zhao JJ, Pan K, Li JJ, et al. Identification of LZAP as a new candidate tumor suppressor in hepatocellular carcinoma. PLoS One. 2011;6(10):e26608. https://doi.org/10.1371/journal.pone.0026608.CrossRefPubMedPubMedCentral

38.

Zhuo ML, Huang Y, Chen JZ, et al. Endothelium-specific overexpression of human IC53 downregulates endothelial nitric oxide synthase activity and elevates systolic blood pressure in mice. Cardiovasc Res. 2009;84(2):292–9. https://doi.org/10.1093/cvr/cvp204.CrossRefPubMedPubMedCentral

39.

Zhu Y, Cui J, Liu J, Hua W, Wei W, Sun G. Sp2 promotes invasion and metastasis of hepatocellular carcinoma by targeting TRIB3 protein. Cancer Med. 2020;9(10):3592–603. https://doi.org/10.1002/cam4.2977.CrossRefPubMedPubMedCentral

40.

Alghamdi M, Bashiri FA, Abdelhakim M, et al. Phenotypic and molecular spectrum of pyridoxamine-5′-phosphate oxidase deficiency: a scoping review of 87 cases of pyridoxamine-5′-phosphate oxidase deficiency. Clin Genet. 2021;99(1):99–110. https://doi.org/10.1111/cge.13843.CrossRefPubMed

41.

Canadas-Garre M, Anderson K, Cappa R, et al. Genetic susceptibility to chronic kidney disease - some more pieces for the heritability puzzle. Front Genet. 2019;10:453. https://doi.org/10.3389/fgene.2019.00453.CrossRefPubMedPubMedCentral

42.

Oprea AD, Lombard FW, Liu WW, et al. Baseline pulse pressure, acute kidney injury, and mortality after noncardiac surgery. Anesth Analg. 2016;123(6):1480–9. https://doi.org/10.1213/ANE.0000000000001557.CrossRefPubMed

Title: Limited clinical utility for GWAS or polygenic risk score for postoperative acute kidney injury in non-cardiac surgery in European-ancestry patients
Authors: Daniel B. Larach
Adam Lewis
Lisa Bastarache
Anita Pandit
Jing He
Anik Sinha
Nicholas J. Douville
Michael Heung
Michael R. Mathis
Jonathan D. Mosley
Jonathan P. Wanderer
Sachin Kheterpal
Matthew Zawistowski
Chad M. Brummett
Edward D. Siew
Cassianne Robinson-Cohen
Miklos D. Kertai
Publication date: 01-12-2022
Publisher: BioMed Central
Keywords: Acute Kidney Injury
Acute Kidney Injury
Published in: BMC Nephrology / Issue 1/2022
Electronic ISSN: 1471-2369
DOI: https://doi.org/10.1186/s12882-022-02964-8

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Conclusion

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