Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Association of metabolic dysfunction-associated fatty liver disease with kidney disease

Abstract

Non-alcoholic fatty liver disease (NAFLD) is characterized by the accumulation of fat in more than 5% of hepatocytes in the absence of excessive alcohol consumption and other secondary causes of hepatic steatosis. In 2020, the more inclusive term metabolic (dysfunction)-associated fatty liver disease (MAFLD) — defined by broader diagnostic criteria — was proposed to replace the term NAFLD. The new terminology and revised definition better emphasize the pathogenic role of metabolic dysfunction and uses a set of definitive, inclusive criteria for diagnosis. Diagnosis of MAFLD is based on evidence of hepatic steatosis (as assessed by liver biopsy, imaging techniques or blood biomarkers and scores) in persons who are overweight or obese and have type 2 diabetes mellitus or metabolic dysregulation, regardless of the coexistence of other liver diseases or excessive alcohol consumption. The known association between NAFLD and chronic kidney disease (CKD) and our understanding that CKD can occur as a consequence of metabolic dysfunction suggests that individuals with MAFLD — who by definition have fatty liver and metabolic comorbidities — are at increased risk of CKD. In this Perspective article, we discuss the clinical associations between MAFLD and CKD, the pathophysiological mechanisms by which MAFLD may increase the risk of CKD and the potential drug treatments that may benefit both conditions.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1: Similarities and differences between NAFLD and MAFLD.
Fig. 2: PNPLA3 rs738409 polymorphism and potential shared pathogenic mechanisms in NAFLD and CKD.
Fig. 3: Potential mechanisms implicated in the gut–liver–kidney axis.

References

  1. Chalasani, N. 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 142, 1592–1609 (2012).

    PubMed  Google Scholar 

  2. Younossi, Z. M. et al. Global epidemiology of nonalcoholic fatty liver disease — meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 64, 73–84 (2016).

    PubMed  Google Scholar 

  3. Sarin, S. K. et al. Liver diseases in the Asia-Pacific region: a Lancet Gastroenterology & Hepatology Commission. Lancet Gastroenterol. Hepatol. 5, 167–228 (2020).

    PubMed  Google Scholar 

  4. Targher, G., Chonchol, M. B. & Byrne, C. D. CKD and nonalcoholic fatty liver disease. Am. J. Kidney Dis. 64, 638–652 (2014).

    PubMed  Google Scholar 

  5. Musso, G. et al. Association of non-alcoholic fatty liver disease with chronic kidney disease: a systematic review and meta-analysis. PLoS Med. 11, e1001680 (2014).

    PubMed  PubMed Central  Google Scholar 

  6. Mantovani, A. et al. Nonalcoholic fatty liver disease increases risk of incident chronic kidney disease: a systematic review and meta-analysis. Metabolism 79, 64–76 (2018).

    CAS  PubMed  Google Scholar 

  7. Wijarnpreecha, K. et al. Nonalcoholic fatty liver disease and albuminuria: a systematic review and meta-analysis. Eur. J. Gastroenterol. Hepatol. 30, 986–994 (2018).

    PubMed  Google Scholar 

  8. Mantovani, A. et al. Non-alcoholic fatty liver disease and risk of incident chronic kidney disease: an updated meta-analysis. Gut https://doi.org/10.1136/gutjnl-2020-323082 (2020).

    Article  PubMed  Google Scholar 

  9. Sun, D. Q. et al. Higher liver stiffness scores are associated with early kidney dysfunction in patients with histologically proven non-cirrhotic NAFLD. Diabetes Metab. 46, 288–295 (2020).

    CAS  PubMed  Google Scholar 

  10. Paik, J. et al. Chronic kidney disease is independently associated with increased mortality in patients with nonalcoholic fatty liver disease. Liver Int. 39, 342–352 (2019).

    PubMed  Google Scholar 

  11. Yilmaz, Y. et al. Microalbuminuria in nondiabetic patients with nonalcoholic fatty liver disease: association with liver fibrosis. Metabolism 59, 1327–1330 (2010).

    CAS  PubMed  Google Scholar 

  12. Onnerhag, K., Dreja, K., Nilsson, P. M. & Lindgren, S. Increased mortality in non-alcoholic fatty liver disease with chronic kidney disease is explained by metabolic comorbidities. Clin. Res. Hepatol. Gastroenterol. 43, 542–550 (2019).

    PubMed  Google Scholar 

  13. Eslam, M. et al. A new definition for metabolic dysfunction-associated fatty liver disease: an international expert consensus statement. J. Hepatol. 73, 202–209 (2020).

    PubMed  Google Scholar 

  14. Brunt, E. M. et al. Concurrence of histologic features of steatohepatitis with other forms of chronic liver disease. Mod. Pathol. 16, 49–56 (2003).

    PubMed  Google Scholar 

  15. Eslam, M., Sanyal, A. J. & George, J., International Consensus Panel. MAFLD: a consensus-driven proposed nomenclature for metabolic associated fatty liver disease. Gastroenterology 158, 1999–2014.e1 (2020).

    CAS  PubMed  Google Scholar 

  16. Wong, V. W. et al. Impact of the new definition of metabolic associated fatty liver disease on the epidemiology of the disease. Clin. Gastroenterol. Hepatol. 19, 2161–2171.e5 (2021).

    CAS  PubMed  Google Scholar 

  17. Sun, D. Q. et al. MAFLD and risk of CKD. Metabolism 115, 154433 (2021).

    CAS  PubMed  Google Scholar 

  18. Targher, G. Concordance between MAFLD and NAFLD diagnostic criteria in ‘real-world’ data. Liver Int. 40, 2879–2880 (2020).

    PubMed  Google Scholar 

  19. Schaffner, F. & Thaler, H. Nonalcoholic fatty liver disease. Prog. Liver Dis. 8, 283–298 (1986).

    CAS  PubMed  Google Scholar 

  20. Zelman, S. The liver in obesity. AMA 90, 141–156 (1952).

    CAS  Google Scholar 

  21. Cortez-Pinto, H., Camilo, M. E., Baptista, A., De Oliveira, A. G. & De Moura, M. C. Non-alcoholic fatty liver: another feature of the metabolic syndrome? Clin. Nutr. 18, 353–358 (1999).

    CAS  PubMed  Google Scholar 

  22. Marceau, P. et al. Liver pathology and the metabolic syndrome X in severe obesity. J. Clin. Endocrinol. Metab. 84, 1513–1517 (1999).

    CAS  PubMed  Google Scholar 

  23. Dunn, W. et al. Modest alcohol consumption is associated with decreased prevalence of steatohepatitis in patients with non-alcoholic fatty liver disease (NAFLD). J. Hepatol. 57, 384–391 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Kwon, H. K., Greenson, J. K. & Conjeevaram, H. S. Effect of lifetime alcohol consumption on the histological severity of non-alcoholic fatty liver disease. Liver Int. 34, 129–135 (2014).

    CAS  PubMed  Google Scholar 

  25. Ascha, M. S. et al. The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology 51, 1972–1978 (2010).

    PubMed  Google Scholar 

  26. Mitchell, T. et al. Type and pattern of alcohol consumption is associated with liver fibrosis in patients with non-alcoholic fatty liver disease. Am. J. Gastroenterol. 113, 1484–1493 (2018).

    PubMed  Google Scholar 

  27. Mohanty, S. R. et al. Influence of ethnicity on histological differences in non-alcoholic fatty liver disease. J. Hepatol. 50, 797–804 (2009).

    PubMed  Google Scholar 

  28. Hashimoto, E. & Tokushige, K. Prevalence, gender, ethnic variations, and prognosis of NASH. J. Gastroenterol. 46(Suppl 1), 63–69 (2011).

    PubMed  Google Scholar 

  29. Wang, T. Y., George, J. & Zheng, M. H. Metabolic (dysfunction) associated fatty liver: more evidence and a bright future. Hepatobiliary Surg. Nutr. https://doi.org/10.21037/hbsn-21-352 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Zheng, K. I. et al. From NAFLD to MAFLD: a “redefining” moment for fatty liver disease. Chin. Med. J. 133, 2271–2273 (2020).

    PubMed  PubMed Central  Google Scholar 

  31. Younossi, Z. M. et al. From NAFLD to MAFLD: Implications of a premature change in terminology. Hepatology 73, 1194–1198 (2020).

    Google Scholar 

  32. Chen, F. et al. Lean NAFLD: a distinct entity shaped by differential metabolic adaptation. Hepatology 71, 1213–1227 (2020).

    CAS  PubMed  Google Scholar 

  33. Frey, S. et al. Prevalence of NASH/NAFLD in people with obesity who are currently classified as metabolically healthy. Surg. Obes. Relat. Dis. 16, 2050–2057 (2020).

    PubMed  Google Scholar 

  34. Yamamura, S. et al. MAFLD identifies patients with significant hepatic fibrosis better than NAFLD. Liver Int. 40, 3018–3030 (2020).

    CAS  PubMed  Google Scholar 

  35. Huang, S. C. et al. Clinical and histologic features of patients with biopsy-proven metabolic dysfunction-associated fatty liver disease. Gut Liver 15, 451–458 (2021).

    PubMed  PubMed Central  Google Scholar 

  36. Lin, S. et al. Comparison of MAFLD and NAFLD diagnostic criteria in real world. Liver Int. 40, 2082–2089 (2020).

    PubMed  Google Scholar 

  37. Mak, L. Y., Yuen, M. F. & Seto, W. K. Letter regarding “A new definition for metabolic dysfunction-associated fatty liver disease: an international expert consensus statement”. J. Hepatol. 73, 1573–1574 (2020).

    PubMed  Google Scholar 

  38. Zheng, K. I., Sun, D. Q., Jin, Y., Zhu, P. W. & Zheng, M. H. Clinical utility of the MAFLD definition. J. Hepatol. 74, 989–991 (2021).

    PubMed  Google Scholar 

  39. Yilmaz, Y., Byrne, C. D. & Musso, G. A single-letter change in an acronym: signals, reasons, promises, challenges, and steps ahead for moving from NAFLD to MAFLD. Expert Rev. Gastroenterol. Hepatol. 15, 345–352 (2021).

    CAS  PubMed  Google Scholar 

  40. Angulo, P. et al. Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology 149, 389–397.e10 (2015).

    PubMed  Google Scholar 

  41. Hagstrom, H. et al. Fibrosis stage but not NASH predicts mortality and time to development of severe liver disease in biopsy-proven NAFLD. J. Hepatol. 67, 1265–1273 (2017).

    PubMed  Google Scholar 

  42. Yeung, M. W. et al. Advanced liver fibrosis but not steatosis is independently associated with albuminuria in Chinese patients with type 2 diabetes. J. Hepatol. 68, 147–156 (2017).

    Google Scholar 

  43. Zhang, H. J., Wang, Y. Y., Chen, C., Lu, Y. L. & Wang, N. J. Cardiovascular and renal burdens of metabolic associated fatty liver disease from serial US national surveys, 1999–2016. Chin. Med. J. 134, 1593–1601 (2021).

    PubMed  PubMed Central  Google Scholar 

  44. Deng, Y., Zhao, Q. & Gong, R. Association between metabolic associated fatty liver disease and chronic kidney disease: a cross-sectional study from NHANES 2017-2018. Diabetes Metab. Syndr. Obes. 14, 1751–1761 (2021).

    PubMed  PubMed Central  Google Scholar 

  45. Vespasiani-Gentilucci, U. et al. Promoting genetics in non-alcoholic fatty liver disease: combined risk score through polymorphisms and clinical variables. World J. Gastroenterol. 24, 4835–4845 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Pirazzi, C. et al. PNPLA3 has retinyl-palmitate lipase activity in human hepatic stellate cells. Hum. Mol. Genet. 23, 4077–4085 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Xu, R., Tao, A., Zhang, S., Deng, Y. & Chen, G. Association between patatin-like phospholipase domain containing 3 gene (PNPLA3) polymorphisms and nonalcoholic fatty liver disease: a HuGE review and meta-analysis. Sci. Rep. 5, 9284 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Tilson, S. G. et al. Modeling PNPLA3-Associated NAFLD using human-induced pluripotent stem cells. Hepatology 74, 2998–3017 (2021).

    CAS  PubMed  Google Scholar 

  49. Pirazzi, C. et al. Patatin-like phospholipase domain-containing 3 (PNPLA3) I148M (rs738409) affects hepatic VLDL secretion in humans and in vitro. J. Hepatol. 57, 1276–1282 (2012).

    CAS  PubMed  Google Scholar 

  50. Hellemans, K., Grinko, I., Rombouts, K., Schuppan, D. & Geerts, A. All-trans and 9-cis retinoic acid alter rat hepatic stellate cell phenotype differentially. Gut 45, 134–142 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Bruschi, F. V. et al. The PNPLA3 I148M variant modulates the fibrogenic phenotype of human hepatic stellate cells. Hepatology 65, 1875–1890 (2017).

    CAS  PubMed  Google Scholar 

  52. Targher, G. et al. Relationship between PNPLA3 rs738409 polymorphism and decreased kidney function in children With NAFLD. Hepatology 70, 142–153 (2019).

    CAS  PubMed  Google Scholar 

  53. Oniki, K. et al. Influence of the PNPLA3 rs738409 polymorphism on non-alcoholic fatty liver disease and renal function among normal weight subjects. PLoS One 10, e0132640 (2015).

    PubMed  PubMed Central  Google Scholar 

  54. Marzuillo, P. et al. Nonalcoholic fatty liver disease and eGFR levels could be linked by the PNPLA3 I148M polymorphism in children with obesity. Pediatr. Obes. 14, e12539 (2019).

    PubMed  Google Scholar 

  55. Mantovani, A. et al. Association between PNPLA3rs738409 polymorphism decreased kidney function in postmenopausal type 2 diabetic women with or without non-alcoholic fatty liver disease. Diabetes Metab. 45, 480–487 (2019).

    CAS  PubMed  Google Scholar 

  56. Sun, D. Q. et al. PNPLA3 rs738409 is associated with renal glomerular and tubular injury in NAFLD patients with persistently normal ALT levels. Liver Int. 40, 107–119 (2020).

    CAS  PubMed  Google Scholar 

  57. Mantovani, A. et al. PNPLA3 I148M gene variant and chronic kidney disease in type 2 diabetic patients with NAFLD: clinical and experimental findings. Liver Int. 40, 1130–1141 (2020).

    CAS  PubMed  Google Scholar 

  58. Gellert-Kristensen, H., Nordestgaard, B. G., Tybjaerg-Hansen, A. & Stender, S. High risk of fatty liver disease amplifies the alanine transaminase-lowering effect of a HSD17B13 variant. Hepatology 71, 56–66 (2020).

    CAS  PubMed  Google Scholar 

  59. Luukkonen, P. K. et al. Hydroxysteroid 17-beta dehydrogenase 13 variant increases phospholipids and protects against fibrosis in nonalcoholic fatty liver disease. JCI Insight 5, e132158 (2020).

    PubMed Central  Google Scholar 

  60. Di Sessa, A. et al. Pediatric non-alcoholic fatty liver disease and kidney function: effect of HSD17B13 variant. World J. Gastroenterol. 26, 5474–5483 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Sun, D. Q. et al. The HSD17B13 rs72613567 variant is associated with lower levels of albuminuria in patients with biopsy-proven nonalcoholic fatty liver disease. Nutr. Metab. Cardiovasc. Dis. 31, 1822–1831 (2021).

    CAS  PubMed  Google Scholar 

  62. Luo, F., Oldoni, F. & Das, A. TM6SF2: a novel genetic player in nonalcoholic fatty liver and cardiovascular disease. Hepatol. Commun. https://doi.org/10.1002/hep4.1822 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  63. Musso, G., Cassader, M., Paschetta, E. & Gambino, R. TM6SF2 may drive postprandial lipoprotein cholesterol toxicity away from the vessel walls to the liver in NAFLD. J. Hepatol. 64, 979–981 (2016).

    CAS  PubMed  Google Scholar 

  64. Musso, G., Cassader, M. & Gambino, R. PNPLA3 rs738409 and TM6SF2 rs58542926 gene variants affect renal disease and function in nonalcoholic fatty liver disease. Hepatology 62, 658–659 (2015).

    PubMed  Google Scholar 

  65. Marzuillo, P. et al. Transmembrane 6 superfamily member 2 167K allele improves renal function in children with obesity. Pediatr. Res. 88, 300–304 (2020).

    CAS  PubMed  Google Scholar 

  66. Mancina, R. M. et al. The MBOAT7-TMC4 Variant rs641738 increases risk of nonalcoholic fatty liver disease in individuals of European descent. Gastroenterology 150, 1219–1230.e6 (2016).

    CAS  PubMed  Google Scholar 

  67. Thabet, K. et al. The membrane-bound O-acyltransferase domain-containing 7 variant rs641738 increases inflammation and fibrosis in chronic hepatitis B. Hepatology 65, 1840–1850 (2017).

    CAS  PubMed  Google Scholar 

  68. Koo, B. K. et al. Association between a polymorphism in MBOAT7 and chronic kidney disease in patients with biopsy-confirmed nonalcoholic fatty liver disease. Clin. Gastroenterol. Hepatol. 18, 2837–2839.e2 (2020).

    CAS  PubMed  Google Scholar 

  69. Sliz, E. et al. NAFLD risk alleles in PNPLA3, TM6SF2, GCKR and LYPLAL1 show divergent metabolic effects. Hum. Mol. Genet. 27, 2214–2223 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Boger, C. A. et al. Association of eGFR-related loci identified by GWAS with incident CKD and ESRD. PLoS Genet. 7, e1002292 (2011).

    PubMed  PubMed Central  Google Scholar 

  71. Hishida, A. et al. GCK, GCKR polymorphisms and risk of chronic kidney disease in Japanese individuals: data from the J-MICC Study. J. Nephrol. 27, 143–149 (2014).

    CAS  PubMed  Google Scholar 

  72. Simons, P. et al. Association of common gene variants in glucokinase regulatory protein with cardiorenal disease: a systematic review and meta-analysis. PLoS One 13, e0206174 (2018).

    PubMed  PubMed Central  Google Scholar 

  73. Di Costanzo, A. et al. Nonalcoholic Fatty Liver Disease (NAFLD), but not its susceptibility gene variants, influences the decrease of kidney function in overweight/obese children. Int. J. Mol. Sci. 20, 4444 (2019).

    PubMed Central  Google Scholar 

  74. Xia, M., Zeng, H., Wang, S., Tang, H. & Gao, X. Insights into contribution of genetic variants towards the susceptibility of MAFLD revealed by the NMR-based lipoprotein profiling. J. Hepatol. 74, 974–977 (2021).

    CAS  PubMed  Google Scholar 

  75. Raj, D., Tomar, B., Lahiri, A. & Mulay, S. R. The gut-liver-kidney axis: Novel regulator of fatty liver associated chronic kidney disease. Pharmacol. Res. 152, 104617 (2020).

    CAS  PubMed  Google Scholar 

  76. Meijers, B., Evenepoel, P. & Anders, H. J. Intestinal microbiome and fitness in kidney disease. Nat. Rev. Nephrol. 15, 531–545 (2019).

    PubMed  Google Scholar 

  77. Mafra, D. et al. Food as medicine: targeting the uraemic phenotype in chronic kidney disease. Nat. Rev. Nephrol. 17, 153–171 (2021).

    PubMed  Google Scholar 

  78. Tan, X. et al. Trimethylamine N-oxide aggravates liver steatosis through modulation of bile acid metabolism and inhibition of farnesoid X receptor signaling in nonalcoholic fatty liver disease. Mol. Nutr. Food Res. 63, e1900257 (2019).

    PubMed  Google Scholar 

  79. Ravid, J. D., Kamel, M. H. & Chitalia, V. C. Uraemic solutes as therapeutic targets in CKD-associated cardiovascular disease. Nat. Rev. Nephrol. 17, 402–416 (2021).

    CAS  PubMed  Google Scholar 

  80. Tang, W. H. et al. Gut microbiota-dependent trimethylamine N-oxide (TMAO) pathway contributes to both development of renal insufficiency and mortality risk in chronic kidney disease. Circ. Res. 116, 448–455 (2015).

    CAS  PubMed  Google Scholar 

  81. Herman-Edelstein, M., Weinstein, T. & Levi, M. Bile acid receptors and the kidney. Curr. Opin. Nephrol. Hypertens. 27, 56–62 (2018).

    CAS  PubMed  Google Scholar 

  82. Wang, X. X. et al. A dual agonist of farnesoid X receptor (FXR) and the G protein-coupled receptor TGR5, INT-767, reverses age-related kidney disease in mice. J. Biol. Chem. 292, 12018–12024 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Jiao, N. et al. Suppressed hepatic bile acid signalling despite elevated production of primary and secondary bile acids in NAFLD. Gut 67, 1881–1891 (2018).

    CAS  PubMed  Google Scholar 

  84. Morrison, D. J. & Preston, T. Formation of short chain fatty acids by the gut microbiota and their impact on human metabolism. Gut Microbes 7, 189–200 (2016).

    PubMed  PubMed Central  Google Scholar 

  85. Wang, S. et al. Quantitative reduction in short-chain fatty acids, especially butyrate, contributes to the progression of chronic kidney disease. Clin. Sci. 133, 1857–1870 (2019).

    CAS  Google Scholar 

  86. Andrade-Oliveira, V. et al. Gut bacteria products prevent AKI induced by ischemia-reperfusion. J. Am. Soc. Nephrol. 26, 1877–1888 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Pluznick, J. L. et al. Olfactory receptor responding to gut microbiota-derived signals plays a role in renin secretion and blood pressure regulation. Proc. Natl Acad. Sci. USA 110, 4410–4415 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Chambers, E. S. et al. Effects of targeted delivery of propionate to the human colon on appetite regulation, body weight maintenance and adiposity in overweight adults. Gut 64, 1744–1754 (2015).

    CAS  PubMed  Google Scholar 

  89. Zhou, D. et al. Sodium butyrate reduces high-fat diet-induced non-alcoholic steatohepatitis through upregulation of hepatic GLP-1R expression. Exp. Mol. Med. 50, 1–12 (2018).

    PubMed  PubMed Central  Google Scholar 

  90. Chambers, E. S. et al. The effects of dietary supplementation with inulin and inulin-propionate ester on hepatic steatosis in adults with non-alcoholic fatty liver disease. Diabetes Obes. Metab. 21, 372–376 (2019).

    CAS  PubMed  Google Scholar 

  91. Zhao, Z. H. et al. Sodium butyrate supplementation inhibits hepatic steatosis by stimulating liver kinase B1 and insulin-induced gene. Cell Mol. Gastroenterol. Hepatol. 12, 857–871 (2021).

    PubMed  PubMed Central  Google Scholar 

  92. Chambers, E. S., Morrison, D. J. & Frost, G. Control of appetite and energy intake by SCFA: what are the potential underlying mechanisms? Proc. Nutr. Soc. 74, 328–336 (2015).

    CAS  PubMed  Google Scholar 

  93. Zhang, S. et al. Dietary fiber-derived short-chain fatty acids: a potential therapeutic target to alleviate obesity-related nonalcoholic fatty liver disease. Obes. Rev. 22, e13316 (2021).

    CAS  PubMed  Google Scholar 

  94. Giorgio, V. et al. Intestinal permeability is increased in children with non-alcoholic fatty liver disease, and correlates with liver disease severity. Dig. Liver Dis. 46, 556–560 (2014).

    PubMed  Google Scholar 

  95. Shi, K. et al. Gut bacterial translocation may aggravate microinflammation in hemodialysis patients. Dig. Dis. Sci. 59, 2109–2117 (2014).

    CAS  PubMed  Google Scholar 

  96. Sanchez-Lozada, L. G. et al. Uric acid activates aldose reductase and the polyol pathway for endogenous fructose and fat production causing development of fatty liver in rats. J. Biol. Chem. 294, 4272–4281 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Xu, K. et al. Gender effect of hyperuricemia on the development of nonalcoholic fatty liver disease (NAFLD): a clinical analysis and mechanistic study. Biomed. Pharmacother. 117, 109158 (2019).

    CAS  PubMed  Google Scholar 

  98. Ding, R. B., Bao, J. & Deng, C. X. Emerging roles of SIRT1 in fatty liver diseases. Int. J. Biol. Sci. 13, 852–867 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Hasegawa, K. et al. Renal tubular Sirt1 attenuates diabetic albuminuria by epigenetically suppressing Claudin-1 overexpression in podocytes. Nat. Med. 19, 1496–1504 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Ralto, K. M., Rhee, E. P. & Parikh, S. M. NAD+ homeostasis in renal health and disease. Nat. Rev. Nephrol. 16, 99–111 (2020).

    CAS  PubMed  Google Scholar 

  101. Sato, Y. et al. The case for uric acid-lowering treatment in patients with hyperuricaemia and CKD. Nat. Rev. Nephrol. 15, 767–775 (2019).

    CAS  PubMed  Google Scholar 

  102. Steiger, S., Ma, Q. & Anders, H. J. The case for evidence-based medicine for the association between hyperuricaemia and CKD. Nat. Rev. Nephrol. 16, 422 (2020).

    PubMed  Google Scholar 

  103. Kurella, M., Lo, J. C. & Chertow, G. M. Metabolic syndrome and the risk for chronic kidney disease among nondiabetic adults. J. Am. Soc. Nephrol. 16, 2134–2140 (2005).

    PubMed  Google Scholar 

  104. Singh, A. K. & Kari, J. A. Metabolic syndrome and chronic kidney disease. Curr. Opin. Nephrol. Hypertens. 22, 198–203 (2013).

    CAS  PubMed  Google Scholar 

  105. Chen, J. et al. The metabolic syndrome and chronic kidney disease in U.S. adults. Ann. Intern. Med. 140, 167–174 (2004).

    PubMed  Google Scholar 

  106. Stojsavljevic, S., Gomercic Palcic, M., Virovic Jukic, L., Smircic Duvnjak, L. & Duvnjak, M. Adipokines and proinflammatory cytokines, the key mediators in the pathogenesis of nonalcoholic fatty liver disease. World J. Gastroenterol. 20, 18070–18091 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Ix, J. H. & Sharma, K. Mechanisms linking obesity, chronic kidney disease, and fatty liver disease: the roles of fetuin-A, adiponectin, and AMPK. J. Am. Soc. Nephrol. 21, 406–412 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Mantovani, A. et al. Non-alcoholic fatty liver disease and risk of incident diabetes mellitus: an updated meta-analysis of 501 022 adult individuals. Gut 70, 962–969 (2021).

    CAS  PubMed  Google Scholar 

  109. Spoto, B., Pisano, A. & Zoccali, C. Insulin resistance in chronic kidney disease: a systematic review. Am. J. Physiol. Renal Physiol. 311, F1087–F1108 (2016).

    CAS  PubMed  Google Scholar 

  110. Guerreiro, G. T. S., Longo, L., Fonseca, M. A., de Souza, V. E. G. & Alvares-da-Silva, M. R. Does the risk of cardiovascular events differ between biopsy-proven NAFLD and MAFLD? Hepatol. Int. 15, 380–391 (2021).

    PubMed  Google Scholar 

  111. Gupta, A. & Quigg, R. J. Glomerular diseases associated with hepatitis B and C. Adv. Chronic Kidney Dis. 22, 343–351 (2015).

    PubMed  Google Scholar 

  112. Eslam, M. et al. The Asian Pacific Association for the Study of the Liver clinical practice guidelines for the diagnosis and management of metabolic associated fatty liver disease. Hepatol. Int. 14, 889–919 (2020).

    PubMed  Google Scholar 

  113. Alicic, R. Z., Cox, E. J., Neumiller, J. J. & Tuttle, K. R. Incretin drugs in diabetic kidney disease: biological mechanisms and clinical evidence. Nat. Rev. Nephrol. 17, 227–244 (2021).

    CAS  PubMed  Google Scholar 

  114. Kang, A. & Jardine, M. J. SGLT2 inhibitors may offer benefit beyond diabetes. Nat. Rev. Nephrol. 17, 83–84 (2021).

    CAS  PubMed  Google Scholar 

  115. DeFronzo, R. A., Reeves, W. B. & Awad, A. S. Pathophysiology of diabetic kidney disease: impact of SGLT2 inhibitors. Nat. Rev. Nephrol. 17, 319–334 (2021).

    CAS  PubMed  Google Scholar 

  116. Marton, A. et al. Organ protection by SGLT2 inhibitors: role of metabolic energy and water conservation. Nat. Rev. Nephrol. 17, 65–77 (2021).

    CAS  PubMed  Google Scholar 

  117. Sloan, L. A. Review of glucagon-like peptide-1 receptor agonists for the treatment of type 2 diabetes mellitus in patients with chronic kidney disease and their renal effects. J. Diabetes 11, 938–948 (2019).

    PubMed  PubMed Central  Google Scholar 

  118. Patel Chavez, C., Cusi, K. & Kadiyala, S. The emerging role of glucagon-like peptide-1 receptor agonists for the management of NAFLD. J. Clin. Endocrinol. Metab. https://doi.org/10.1210/clinem/dgab578 (2021).

    Article  PubMed Central  Google Scholar 

  119. American Diabetes, A. 9. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes-2021. Diabetes Care 44, S111–S124 (2021).

    Google Scholar 

Download references

Acknowledgements

The authors’ work was supported by grants from the National Natural Science Foundation of China (82070588, 82000690), High Level Creative Talents from the Department of Public Health in Zhejiang Province, Project of New Century 551 Talent Nurturing in Wenzhou and a Project of Science and Technology Development Fund in Wuxi (N20202001). D.-Q.S. is supported in part by grants from the Youth Research Project Fund from Wuxi Municipal Health Commission (Q201932), Top-notch Talents from Young and Middle-Age Health Care in Wuxi (BJ2020026). G.T. is supported in part by grants from the University School of Medicine of Verona, Verona, Italy. C.D.B. is supported in part by the Southampton NIHR Biomedical Research Centre (IS-BRC-20004), UK.

Author information

Authors and Affiliations

Authors

Contributions

R.-F.W., Z.-Y.B. and D.-Q.S. researched data for the article. T.-Y.W., G.T., C.D.B., D.-Q.S. and M.-H.Z. wrote the manuscript. All authors contributed substantially to the discussion of the content and reviewed and/or edited the manuscript before submission.

Corresponding authors

Correspondence to Dan-Qin Sun or Ming-Hua Zheng.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Nephrology thanks Manuel Praga, Yusuf Yilmaz and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Wang, TY., Wang, RF., Bu, ZY. et al. Association of metabolic dysfunction-associated fatty liver disease with kidney disease. Nat Rev Nephrol 18, 259–268 (2022). https://doi.org/10.1038/s41581-021-00519-y

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41581-021-00519-y

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing