Portal inflammation predicts renal dysfunction in patients with nonalcoholic fatty liver disease

Abstract

Background

The association between nonalcoholic fatty liver disease (NAFLD) and renal function changes remains inconclusive. We explored whether the histological severity of NAFLD is associated with early deterioration of renal function.

Methods

Patients with biopsy-proven NAFLD were prospectively followed for renal function monitoring. A renal outcome was defined as a ≥ 50% increase in serum creatinine, a < 30% decrease in the estimated glomerular filtration rate (eGFR) or an eGFR < 45 mL/min/1.73 m2.

Results

Among 455 NAFLD patients, 221 (48.6%) had nonalcoholic steatohepatitis (NASH), and no difference in baseline eGFR was found between NASH and NAFL patients. During a median follow-up of 32 months, a renal outcome occurred in 15 patients; the incidence rate was 12.3 per 1,000 person-years. Compared with NAFL, NASH did not increase the risk of renal outcomes. Among the histological components of NAFLD, lobular inflammation (≥ 2), fibrosis (≥ F3), and portal inflammation (≥ 3) significantly increased the risk of renal outcomes in the crude analysis (HR 3.35, 95% CI 1.10–9.11; HR 3.25, 95% CI 1.12–8.84; and HR 7.73, 95% CI 2.86–22.22). After adjustment for risk factors for renal dysfunction, including sex, age, diabetes, hypertension, and chronic kidney disease, only portal inflammation significantly increased the risk of renal outcomes (HR 5.88, 95% CI 1.87–18.42, p = 0.002).

Conclusions

Portal inflammation predicts early deterioration of renal function in patients with biopsy-proven NAFLD. Individualized monitoring of renal function based on the histological severity of NAFLD may be helpful for early identification of long-term renal outcomes.

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References

  1. 1.

    Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology. Gastroenterology 2012;142:1592–609.

    Article  Google Scholar 

  2. 2.

    Rinella ME. Nonalcoholic fatty liver disease: a systematic review. JAMA 2015;313:2263–73.

    CAS  Article  Google Scholar 

  3. 3.

    Rafiq N, Bai C, Fang Y, et al. Long-term follow-up of patients with nonalcoholic fatty liver. Clin Gastroenterol Hepatol 2009;7:234–8.

    Article  Google Scholar 

  4. 4.

    Soderberg C, Stal P, Askling J, et al. Decreased survival of subjects with elevated liver function tests during a 28-year follow-up. Hepatology 2010;51:595–602.

    Article  Google Scholar 

  5. 5.

    Armstrong MJ, Adams LA, Canbay A, Syn WK. Extrahepatic complications of nonalcoholic fatty liver disease. Hepatology 2014;59:1174–97.

    CAS  Article  Google Scholar 

  6. 6.

    Targher G, Chonchol MB, Byrne CD. CKD and nonalcoholic fatty liver disease. Am J Kidney Dis 2014;64:638–52.

    Article  Google Scholar 

  7. 7.

    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:e1001680.

    Article  Google Scholar 

  8. 8.

    Targher G, Bertolini L, Rodella S, et al. Non-alcoholic fatty liver disease is independently associated with an increased prevalence of chronic kidney disease and proliferative/laser-treated retinopathy in type 2 diabetic patients. Diabetologia 2008;51:444–50.

    CAS  Article  Google Scholar 

  9. 9.

    Targher G, Bertolini L, Chonchol M, et al. Non-alcoholic fatty liver disease is independently associated with an increased prevalence of chronic kidney disease and retinopathy in type 1 diabetic patients. Diabetologia 2010;53:1341–8.

    CAS  Article  Google Scholar 

  10. 10.

    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;5:2166–71.

    CAS  Article  Google Scholar 

  11. 11.

    Ruggenenti P, Cravedi P, Remuzzi G. Mechanisms and treatment of CKD. J Am Soc Nephrol 2012;23:1917–28.

    CAS  Article  Google Scholar 

  12. 12.

    Liu Y. Renal fibrosis: new insights into the pathogenesis and therapeutics. Kidney Int 2006;69:213–7.

    CAS  Article  Google Scholar 

  13. 13.

    Torres DM, Harrison SA. NAFLD: Predictive value of ALT levels for NASH and advanced fibrosis. Nat Rev Gastroenterol Hepatol 2013;10:510–1.

    CAS  Article  Google Scholar 

  14. 14.

    Studenski SA, Peters KW, Alley DE, et al. The FNIH sarcopenia project: rationale, study description, conference recommendations, and final estimates. J Gerontol A Biol Sci Med Sci 2014;69:547–58.

    Article  Google Scholar 

  15. 15.

    Brunt EM, Kleiner DE, Wilson LA, Belt P, Neuschwander-Tetri BA, Network NCR. Nonalcoholic fatty liver disease (NAFLD) activity score and the histopathologic diagnosis in NAFLD: distinct clinicopathologic meanings. Hepatology 2011;53:810–20.

    CAS  Article  Google Scholar 

  16. 16.

    Levey AS, Inker LA, Matsushita K, et al. GFR decline as an end point for clinical trials in CKD: a scientific workshop sponsored by the National Kidney Foundation and the US Food and Drug Administration. Am J Kidney Dis 2014;64:821–35.

    Article  Google Scholar 

  17. 17.

    Hwang JH, Lee JP, Kim CT, et al. Urinary periostin excretion predicts renal outcome in IgA nephropathy. Am J Nephrol 2016;44:481–92.

    CAS  Article  Google Scholar 

  18. 18.

    Heinze G, Schemper M. A solution to the problem of monotone likelihood in Cox regression. Biometrics 2011;57:114–9.

    Article  Google Scholar 

  19. 19.

    Jia G, Di F, Wang Q, et al. Non-alcoholic fatty liver disease is a risk factor for the development of diabetic nephropathy in patients with type 2 diabetes mellitus. PLoS One 2015;10:e0142808.

    Article  Google Scholar 

  20. 20.

    Yan LH, Mu B, Guan Y, et al. Assessment of the relationship between non-alcoholic fatty liver disease and diabetic complications. J Diabetes Investig 2016;7:889–94.

    CAS  Article  Google Scholar 

  21. 21.

    Targher G, Chonchol M, Bertolini L, et al. Increased risk of CKD among type 2 diabetics with nonalcoholic fatty liver disease. J Am Soc Nephrol 2008;19:1564–70.

    CAS  Article  Google Scholar 

  22. 22.

    Adams LA, Lymp JF, St Sauver J, et al. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology 2005;129:113–21.

    Article  Google Scholar 

  23. 23.

    Sinn DH, Kang D, Jang HR, et al. Development of chronic kidney disease in patients with non-alcoholic fatty liver disease: a cohort study. J Hepatol 2017;67:1274–80.

    Article  Google Scholar 

  24. 24.

    Jang HR, Kang D, Sinn DH, et al. Nonalcoholic fatty liver disease accelerates kidney function decline in patients with chronic kidney disease: a cohort study. Sci Rep 2018;8:4718.

    Article  Google Scholar 

  25. 25.

    Koo BK, An JN, Joo SK, et al. Association between a polymorphism in MBOAT7 and chronic kidney disease in patients with biopsy-confirmed nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2019. https://doi.org/10.1016/j.cgh.2019.09.017.

    Article  PubMed  Google Scholar 

  26. 26.

    Targher G, Chonchol M, Zoppini G, Abaterusso C, Bonora E. Risk of chronic kidney disease in patients with non-alcoholic fatty liver disease: is there a link? J Hepatol 2011;54:1020–9.

    CAS  Article  Google Scholar 

  27. 27.

    Tanaka S, Tanaka T, Nangaku M. Hypoxia as a key player in the AKI-to-CKD transition. Am J Physiol Renal Physiol. 2014;307:F1187–195.

    CAS  Article  Google Scholar 

  28. 28.

    Ruiz S, Pergola PE, Zager RA, Vaziri ND. Targeting the transcription factor Nrf2 to ameliorate oxidative stress and inflammation in chronic kidney disease. Kidney Int 2013;83:1029–41.

    CAS  Article  Google Scholar 

  29. 29.

    Khwaja A. KDIGO clinical practice guidelines for acute kidney injury. Nephron Clin Pract 2012;120:c179–84.

    PubMed  Google Scholar 

  30. 30.

    An JN, Hwang JH, Kim DK, Lee H, Ahn SY, Kim S, et al. Chronic kidney disease after acute kidney injury requiring continuous renal replacement therapy and its impact on long-term outcomes: a multicenter retrospective cohort study in Korea. Crit Care Med 2017;45:47–57.

    Article  Google Scholar 

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Funding

This study was supported by the National Research Foundation of Korea grant funded by the Korea Government (MEST) (2016R1D1A1B04934590) and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute funded by the Ministry of Health & Welfare, Republic of Korea (HI17C0912). The funders played no role in the design of the study, collection, analysis, or interpretation of the data, preparation of the manuscript, or the decision to submit the article for publication.

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Correspondence to Won Kim.

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Conflict of interest

Jung Nam An, Sae Kyung Joo, Bo Kyung Koo, Jung Ho Kim, Sohee Oh and Won Kim do not have any relevant conflict of interest or other financial disclosures.

Ethical approval

This study was approved by the Institutional Review Board of Seoul National University Boramae Medical Center (16-2014-86) and was carried out in accordance with the guidelines of the 2013 Declaration of Helsinki. All study participants provided informed consent prior to recruitment into the registry.

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An, J.N., Joo, S.K., Koo, B.K. et al. Portal inflammation predicts renal dysfunction in patients with nonalcoholic fatty liver disease. Hepatol Int (2020). https://doi.org/10.1007/s12072-020-10063-9

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Keywords

  • Nonalcoholic fatty liver disease
  • Nonalcoholic steatohepatitis
  • Histology
  • Severity
  • Portal inflammation
  • Lobular inflammation
  • Fibrosis
  • Renal function
  • Early deterioration
  • Risk factors