Nonalcoholic Fatty Liver Disease And Chronic Kidney Disease: A Review Of Links And Risks

Keywords: nonalcoholic fatty liver disease, chronic kidney disease, mortality, metabolic syndrome, gut-liver axis, gut-kidney axis, liver-kidney axis

Introduction: Nonalcoholic fatty liver disease (NAFLD) is defined by the presence of hepatic steatosis with a spectrum of severity including nonalcoholic fatty liver (NAFL), nonalcoholic steatohepatitis (NASH) with and without fibrosis, and cirrhosis. NAFL is also referred to as simple steatosis; that is, there is increased fat accumulation in hepatocytes but no significant inflammation, injury, or fibrosis. NASH is defined histologically by the presence of steatosis, lobular inflammation, and liver cell injury with hepatocyte ballooning.1 Chronic kidney disease (CKD) is defined by the Kidney Disease Improving Global Outcomes (KDIGO) work group as abnormalities of kidney structure or function for greater than three months with implications for health.2 Glomerular filtration rate (GFR) is a marker of kidney function with five categories (G1: ≥90; G2: 60–89; G3a: 45–59; G3b: 30–44; G4: 15–29; G5<15 mL/min/ 1.73 m2 ) where CKD is defined by GFR<60 mL/min/1.73 m2. Albumin-to-creatinine ratio (ACR) is one of the markers of kidney damage with three categories (A1:<30; a2:="" a3:="">300 mg/g) with the threshold >30 mg/ g defining CKD. Staging of CKD includes categorization based on decreased GFR and increased ACR, and these both play an important role in risk categorization and prognostication.2 Increasing rates of both NAFLD and CKD are expected with the rising trends in diabetes (DM) and obesity alongside the aging population.3 NAFLD is quickly rising to be the leading cause of liver transplantation and the most rapidly increasing indication for simultaneous liver-kidney transplants.

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The Link Between NAFLD and CKD: Common Risk Factors and Shared Mechanisms NAFLD is a multiorgan disease and has been strongly associated with type 2 DM, CVD, and CKD.23 A causal relationship between NAFLD and CKD is difficult to prove given their many shared risk factors including IR, DM, HTN, dyslipidemia, and obesity. Numerous shared risks and pathogenetic mechanisms carry out similar processes of injury with the interplay between the organs. The association between MetS and CKD is not surprising given that the two leading causes of CKD, DM, and HTN, are also components of MetS. The presence of MetS is significantly associated with decreased eGFR<60 mL/ min/1.73 m2 (OR: 1.55, CI: 1.34–1.8) which includes a contribution from each individual component of MetS and the greatest risk if all five components of MetS are present (OR: 1.96, CI: 1.71–2.24, p<0.01).28 Furthermore, the reversal or resolution of an individual MetS component leads to a reduced risk of CKD.

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Treatment Strategies in Coexistent NAFLD and CKD Development of therapeutics to improve both NAFLD and CKD has been forthcoming given the link between the two conditions including overlapping risks and poor outcomes. The targets for therapies are based on the proposed pathogenic mechanisms shared between the two disease entities, particularly modification of cardiometabolic risk factors and reducing IR. Additional strategies for therapeutics under investigation for NAFLD include decreasing FFA delivery to the liver and increased disposal of FFA from the liver. Sodium-glucose co-transporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1RA) are two groups of medications approved for use in DM that have additional benefits for NASH and protective effects on cardiovascular and renal outcomes.50 SGLT2 inhibitors are recommended to prevent the progression of CKD in diabetic patients, particularly for those with ACR >200 mg/g or GFR 25–60 mL/min/1.73 m2. 50 Meta-analysis of three RCTs comparing the use of SGLT2 inhibitors to standard-of-care diabetic treatment showed a significant decrease in hepatic steatosis determined by magnetic resonance imaging (MRI) (−2.2, CI: −3.67 to −0.74, p=0.003) and degree of fibrosis determined by FIB-4 scores (−0.06, CI: −0.1 to−0.02, p=0.01) despite no significant difference in the degree of glucose control between groups.

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Conclusion:

Both NAFLD and CKD are rising rapidly as important public health concerns alongside the increasing rates of obesity, MetS, and DM. A causal association between NAFLD and CKD may not be possible given the observational nature of studies to date. Nonetheless, there is strong supporting evidence of the increased prevalence and incidence of CKD in NAFLD, including greater severity in NASH and advanced fibrosis. NAFLD and CKD have similar impacts on outcomes, most notably cardiovascular morbidity and mortality. Thus, early recognition and screening for CKD in NAFLD patients is important to allow for the earlier implementation of relevant strategies. The desire for improvement of renal function alongside a histologic resolution of NASH may suggest a population that would benefit from clinical trial enrollment for NASH and fibrosis reversal as there is currently no medication approved by the regulatory agencies for this purpose.

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References

1. Kleiner DE, Brunt EM, Van Natta M, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41(6):1313–1321. doi:10.1002/hep.20701

2. Stevens PE, Levin A. Evaluation and management of chronic kidney disease: synopsis of the kidney disease: improving global outcomes 2012 clinical practice guideline. Ann Intern Med. 2013;158 (11):825–830. doi:10.7326/0003-4819-158-11-201306040-00007

3. Gregg EW. Secular trends in cardiovascular disease risk factors according to body mass index in US adults. JAMA. 2005;293 (15):1868. doi:10.1001/jama.293.15.1868

4. Singal AK, Hasanin M, Kaif M, Wiesner R, Kuo YF. Nonalcoholic steatohepatitis is the most rapidly growing indication for simultaneous liver-kidney transplantation in the United States. Transplantation. 2016;100(3):607–612. doi:10.1097/TP.0000000000000945

5. Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease-metaanalytic assessment of prevalence, incidence, and outcomes. Hepatology. 2016;64(1):73–84. doi:10.1002/hep.28431

6. Estes C, Razavi H, Loomba R, Younossi Z, Sanyal AJ. Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in the burden of the disease. Hepatology. 2018;67 (1):123–133. doi:10.1002/hep.29466

7. Younossi ZM, Blissett D, Blissett R, et al. The economic and clinical burden of nonalcoholic fatty liver disease in the United States and Europe. Hepatology. 2016;64(5):1577–1586. doi:10.1002/hep.28785

8. Ekstedt M, Hagstrom H, Nasr P, et al. The fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up. Hepatology. 2015;61(5):1547–1554. doi:10.1002/hep.27368

9. Hill NR, Fatoba ST, Oke JL, et al. The global prevalence of chronic kidney disease – a systematic review and meta-analysis. PLoS One. 2016;11(7):e0158765. doi:10.1371/journal.pone.0158765

10. Elshahat S, Cockwell P, Maxwell AP, Griffin M, O’Brien T, O’Neill C. The impact of chronic kidney disease on developed countries from a health economics perspective: a systematic scoping review. PLoS One. 2020;15(3):e0230512. doi:10.1371/journal. pone.0230512

11. Go AS, Chertow GM, Fan D, Mcculloch CE, Hsu C-Y. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004;351(13):1296–1305. doi:10.1056/NEJMoa041031

12. Foreman KJ, Marquez N, Dolgert A, et al. Forecasting life expectancy, years of life lost, and all-cause and cause-specific mortality for 250 causes of death: reference and alternative scenarios for 2016–40 for 195 countries and territories. Lancet. 2018;392 (10159):2052–2090. doi:10.1016/S0140-6736(18)31694-5

13. Bikbov B, Purcell CA, Levey AS, et al. Global, regional, and national burden of chronic kidney disease, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2020;395 (10225):709–733. doi:10.1016/S0140-6736(20)30045-3

14. Levey AS, De Jong PE, Coresh J, et al. The definition, classification, and prognosis of chronic kidney disease: a KDIGO Controversies Conference report. Kidney Int. 2011;80(1):17–28. doi:10.1038/ ki.2010.483

15. Targher G, Byrne CD, Lonardo A, Zoppini G, Barbui C. Nonalcoholic fatty liver disease and risk of incident cardiovascular disease: a meta-analysis. J Hepatol. 2016;65(3):589–600. doi:10.1016/j. jeep.2016.05.013

16. Paik J, Golabi P, Younoszai Z, Mishra A, Trimble G, Younossi ZM. Chronic kidney disease is independently associated with increased mortality in patients with nonalcoholic fatty liver disease. Liver Int. 2019;39(2):342–352. doi:10.1111/liv.13992

17. Targher G, Chonchol MB, Byrne CD. CKD and Nonalcoholic Fatty Liver Disease. Am J Kidney Dis. 2014;64(4):638–652. doi:10.1053/j. asked.2014.05.019

18. Musso G, Gambino R, Tabibian JH, et al. Association of non-alcoholic fatty liver disease with chronic kidney disease: a systematic review and meta-analysis. PLoS Med. 2014;11(7): e1001680. doi:10.1371/journal.pmed.1001680

19. Mantovani A, Petracca G, Beatrice G, et al. Non-alcoholic fatty liver disease and risk of incident chronic kidney disease: an updated meta-analysis. Gut. 2020;gutjnl-2020-2323. doi:10.1136/gutjnl-2020- 323082

20. A JN, Joo SK, Koo BK, Kim JH, Oh S, Kim W. Portal inflammation predicts renal dysfunction in patients with nonalcoholic fatty liver disease. Hepatol Int. 2020;14(5):798–807. doi:10.1007/s12072-020-10063-9

21. Targher G, Bertolini L, Rodella S, Lippi G, Zoppini G, Chonchol M. Relationship between kidney function and liver histology in subjects with nonalcoholic steatohepatitis. Clin J Am Soc Nephrol. 2010;5 (12):2166–2171. doi:10.2215/CJN.05050610

22. Vilar-Gomez E, Calzadilla-Bertot L, Friedman SL, et al. Improvement in liver histology due to lifestyle modification is independently associated with improved kidney function in patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2017;45 (2):332–344. doi:10.1111/apt.13860

23. Byrne CD, Targher G. NAFLD: a multisystem disease. J Hepatol. 2015;62(1 Suppl):S47–S64. doi:10.1016/j.jhep.2014.12.012

24. Alberti KG, Eckel RH, Grundy SM, et al. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation. 2009;120(16):1640–1645.

25. Golabi P, Otgonsuren M, de Avila L, Sayiner M, Rafiq N, Younossi ZM. Components of metabolic syndrome increase the risk of mortality in nonalcoholic fatty liver disease (NAFLD). Medicine (Baltimore). 2018;97(13):e0214. doi:10.1097/MD.0000000000010214

26. Lonardo A, Nascimbeni F, Mantovani A, Targher G. Hypertension, diabetes, atherosclerosis, and NASH: cause or consequence? J Hepatol. 2018;68(2):335–352. doi:10.1016/j.jhep.2017.09.021

27. Marchesini G, Bugianesi E, Forlani G, et al. Nonalcoholic fatty liver, steatohepatitis, and metabolic syndrome. Hepatology. 2003;37 (4):917–923. doi:10.1053/jhep.2003.50161

28. Thomas G, Sehgal AR, Kashyap SR, Srinivas TR, Kirwan JP, Navaneethan SD. Metabolic syndrome and kidney disease: a systematic review and meta-analysis. Clin J Am Soc Nephrol. 2011;6(10):2364–2373. doi:10.2215/CJN.02180311

29. Park S, Lee S, Kim Y, et al. Reduced risk for chronic kidney disease after recovery from metabolic syndrome: a nationwide population-based study. Kidney Res Clin Pract. 2020;39 (2):180–191. doi:10.23876/j.krcp.20.016

30. Luukkonen PK, Zhou Y, Sädevirta S, et al. Hepatic ceramides dissocial steatosis and insulin resistance in patients with non-alcoholic fatty liver disease. J Hepatol. 2016;64(5):1167–1175. doi:10.1016/j. jeep.2016.01.002