The impact of insulin resistance and NAFLD after liver transplantation on patient survival and development of chronic kidney disease

Česká verzia

Authors: Irena Míková ¹ ; D. Erhartová Kyselová ^1,2 ; K. Dvořáková ¹ ; M. Dezortová ³ ; M. Hájek ³ ; M. Cahová ⁴ ; H. Daňková ⁴ ; V. Lánská ⁵ ; Julius Špičák ¹ ; Pavel Trunečka ¹
Authors place of work: Klinika hepatogastroenterologie, Institut klinické a experimentální medicíny, Praha ¹; Fyziologický ústav 1. LF UK, Praha ²; Pracoviště radiodiagnostiky a intervenční radiologie, Institut klinické a experimentální medicíny, Praha ³; Centrum experimentální medicíny, Institut klinické a experimentální medicíny, Praha ⁴; Oddělení datových analýz, statistik a umělé inteligence OI, Institut klinické a experimentální medicíny, Praha ⁵
Published in the journal: Gastroent Hepatol 2022; 76(5): 429-441
Category: Hepatology: original article
doi: https://doi.org/10.48095/ccgh2022429

Summary

Introduction: Insulin resistance (IR) is a hallmark of non-alcoholic fatty liver disease (NAFLD), which has been associated with worse long-term survival and more frequent occurrence of chronic kidney disease (CKD) than in patients without NAFLD. The aim of our study was to evaluate the impact of NAFLD and IR on survival and renal function in patients after liver transplantation (LT). Methods: Our prospective study included 96 LT candidates who were observed after LT. We evaluated patient survival and occurrence of CKD (defined as estimated glomerular filtration [eGFR] ≤1.00 mL/s/1.73 m² or overt proteinuria) 5 years after LT and at the end of follow-up. Clinical, laboratory, MR and elastographic evaluation before and 1 year after LT were performed as well as liver biopsy 1 year after LT. Results: Of the factors present 1 year after LT, higher ALT (P = 0.021), ALP (P = 0.012) and everolimus treatment (P = 0.025) increased the risk of death at the end of follow-up, borderline significance was found also for higher waist circumference (P = 0.058), AST (P = 0.059), HOMA-IR (P = 0.056) and presence of fibrosis stage ≥3 in biopsy (P = 0.055). In addition to the presence of CKD 1 year after LT (P <0.001), other independent posttransplant risk factors of CKD 5 years after LT included presence of IR defined as HOMA-IR ≥3 (OR 4.33; 95% CI 1.25–15.04; P = 0.021) and higher serum high-molecular-weight (HMW) adiponectin (OR 1.25; 95% CI 1.03–1.50; P = 0.021). Of the factors present 1 year after LT, diabetes treated by antidiabetics (P = 0.008), higher serum levels od triglycerides (P = 0.031), C-peptide (P = 0.022) and leptin (P = 0.002) and lower total bilirubin (P = 0.006) were associated with lower eGFR at the end of follow-up. We observed a trend towards higher eGFR levels in patients treated with everolimus (P = 0.055). We did not observe an impact of grade of steatosis and presence of steatohepatitis on biopsy 1 year after LT on survival or renal functions. Conclusion: Presence of IR 1 year after LT independently increased the risk of CKD 5 year after LT. Patients with higher HOMA-IR 1 year after LT had a trend towards worse survival at the end of follow-up.

Keywords:

liver transplantation – non-alcoholic fatty liver disease – insulin resistance – chronic kidney disease – survival

Zdroje

1. Gaggini M, Morelli M, Buzzigoli E et al. Non-alcoholic fatty liver disease (NAFLD) and its connection with insulin resistance, dyslipidemia, atherosclerosis and coronary heart disease. Nutrients 2013; 5 (5): 1544–1560. doi: 10.3390/nu5051544.

2. Muniyappa R, Lee S, Chen H et al. Current approaches for assessing insulin sensitivity and resistance in vivo: advantages, limitations, and appropriate usage. Am J Physiol Endocrinol Metab 2008; 294 (1): E15–26. doi: 10.1152/ajpendo.00645.2007.

3. Wallace TM, Matthews DR. The assessment of insulin resistance in man. Diabet Med 2002; 19 (7): 527–534. doi: 10.1046/j.1464-5491.2002.00745.x.

4. Younossi Z, Stepanova M, Afendy M et al. Changes in the prevalence of the most common causes of chronic liver diseases in the United States from 1988 to 2008. Clin Gastroenterol Hepatol 2011; 9 (6): 524–530. doi: 10.1016/ j.cgh.2011.03.020.

5. Magri CJ, Fava S, Galea J. Prediction of insulin resistance in type 2 diabetes mellitus using routinely available clinical parameters. Diabetes Metab Syndr Clin Res Rev 2016; 10 (2): S96–S101. doi: 10.1016/j.dsx.2016.03.002.

6. Calori G, Lattuada G, Ragogna F et al. Fatty liver index and mortality: The cremona study in the 15th year of follow-up. Hepatology 2011; 54 (1): 145–152. doi: 10.1002/hep.24356.

7. Ekstedt M, Hagström H, Nasr P et al. 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.

8. Liu Y, Zhong GC, Tan HY et al. Nonalcoholic fatty liver disease and mortality from all causes, cardiovascular disease, and cancer: a meta-analysis. Sci Rep 2019; 9 (1): 11124. doi: 10.1038/s41 598-019-47687-3.

9. Sōoderberg C, Stål P, Askling J et al. Decreased survival of subjects with elevated liver function tests during a 28-year follow-up. Hepatology 2010; 51 (2): 595–602. doi: 10.1002/hep.23314.

10. Hejlova I, Honsova E, Sticova E et al. Prevalence and risk factors of steatosis after liver transplantation and patient outcomes. Liver Transplant 2016; 22 (5): 644–655. doi: 10.1002/lt.24393.

11. Galvin Z, Rajakumar R, Chen E et al. Predictors of De Novo Nonalcoholic Fatty Liver Disease After Liver Transplantation and Associated Fibrosis. Liver Transpl 2019; 25 (1): 56–67. doi: 10.1002/lt.25338.

12. Narayanan P, Mara K, Izzy M et al. Recurrent or De Novo Allograft Steatosis and Long-term Outcomes After Liver Transplantation. Transplantation 2019; 103 (1): e14–e21. doi: 10.1097/TP.0000000000002317.

13. Gitto S, De Maria N, Di Benedetto F et al. De-novo nonalcoholic steatohepatitis is associated with long-term increased mortality in liver transplant recipients. Eur J Gastroenterol Hepatol 2018; 30 (7): 766–773. doi: 10.1097/MEG.0000000000001105.

14. Targher G, Chonchol M, Zoppini G et al. Risk of chronic kidney disease in patients with non-alcoholic fatty liver disease: is there a link? J Hepatol 2011; 54 (5): 1020–1029. doi: 10.1016/j.jhep.2010.11.007.

15. 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 (3): 444–450. doi: 10.1007/ s00125-007-0897-4.

16. Madero M, Sarnak MJ. Creatinine-based formulae for estimating glomerular filtration rate: is it time to change to chronic kidney disease epidemiology collaboration equation? Curr Opin Nephrol Hypertens 2011; 20 (6): 622–630. doi: 10.1097/MNH.0b013e32834ba210.

17. Orlando R, Mussap M, Plebani M et al. Diagnostic value of plasma cystatin C as a glomerular filtration marker in decompensated liver cirrhosis. Clin Chem 2002; 48 (6 Pt 1): 850–858.

18. Guo D, Wang H, Liu J et al. Prediction of chronic kidney disease after orthotopic liver transplantation: development and validation of a nomogram model. BMC Nephrol 2022; 23 (1): 33. doi: 10.1186/s12882-021-02650-1.

19. Li Y, Li B, Wang W et al. Risk factors for new-onset chronic kidney disease in patients who have received a liver transplant. Exp Ther Med 2018; 15 (4): 3589–3595. doi: 10.3892/etm.2018. 5823.

20. Lamattina JC, Foley DP, Mezrich JD et al. Chronic kidney disease stage progression in liver transplant recipients. Clin J Am Soc Nephrol 2011; 6 (8): 1851–1857. doi: 10.2215/CJN.00650111.

21. Kang GW, Lee IH, Ahn KS et al. One-Year Follow-up of the Changes in Renal Function After Liver Transplantation in Patients Without Chronic Kidney Disease. Transplant Proc 2016; 48 (4): 1190–1193. doi: 10.1016/j.transproceed.2016.02. 013.

22. Fussner LA, Charlton MR, Heimbach JK et al. The impact of gender and NASH on chronic kidney disease before and after liver transplantation. Liver Int 2014; 34 (8): 1259–1266. doi: 10.1111/liv.12381.

23. 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.

24. Levey AS, Stevens LA, Schmid CH et al. A new equation to estimate glomerular filtration rate. Ann Intern Med 2009; 150 (9): 604–612. doi: 10.7326/0003-4819-150-9-200905050-00006.

25. Zima T, Racek J, Ryšavá R et al. Doporučení k diagnostice chronického onemocnění ledvin (odhad glomerulární filtrace a vyšetřování proteinurie). Klin Biochem Metab 2021; 29 (2): 94–103.

26. Flegal KM, Kit BK, Orpana H et al. Association of all-cause mortality with overweight and obesity using standard body mass index categories: a systematic review and meta-analysis. JAMA 2013; 309 (1): 71–82. doi: 10.1001/jama.2012.113905.

27. Tancredi M, Rosengren A, Svensson A-M et al. Excess Mortality among Persons with Type 2 Diabetes. N Engl J Med 2015; 373 (18): 1720–1732. doi: 10.1056/NEJMoa1504347.

28. Pelaez-Jaramillo MJ, Cardenas-Mojica AA et al. Post-Liver Transplantation Diabetes Mellitus: A Review of Relevance and Approach to Treatment. Diabetes Ther 2018; 9 (2): 521–543. doi: 10.1007/s13300-018-0374-8.

29. Parekh J, Corley DA, Feng S. Diabetes, hypertension and hyperlipidemia: prevalence over time and impact on long-term survival after liver transplantation. Am J Transplant 2012; 12 (8): 2181––2187. doi: 10.1111/j.1600-6143.2012.04077.x.

30. Terjimanian MN, Harbaugh CM, Hussain A et al. Abdominal adiposity, body composition and survival after liver transplantation. Clin Transplant 2016; 30 (3): 289–294. doi: 10.1111/ctr.12688.

31. De Simone P, Fagiuoli S, Cescon M et al. Use of Everolimus in Liver Transplantation: Recommendations From a Working Group. Transplantation 2017; 101 (2): 239–251. doi: 10.1097/TP.0000000000001438.

32. Ueno T, Hiwatashi S, Saka R et al. Everolimus Rescue Treatment for Chronic Rejection After Pediatric Living Donor Liver Transplantation: 2 Case Reports. Transplant Proc 2018; 50 (9): 2872–2876. doi: 10.1016/j.transproceed.2018.03.079.

33. Faggiano A, Malandrino P, Modica R et al. Efficacy and Safety of Everolimus in Extrapancreatic Neuroendocrine Tumor: A Comprehensive Review of Literature. Oncologist 2016; 21 (7): 875–886. doi: 10.1634/theoncologist.2015-0420.

34. Roberts MS, Angus DC, Bryce CL et al. Survival after liver transplantation in the United States: a disease-specific analysis of the UNOS database. Liver Transplant 2004; 10 (7): 886–897. doi: 10.1002/lt.20137.

35. Giusto M, Berenguer M, Merkel C et al. Chronic kidney disease after liver transplantation: pretransplantation risk factors and predictors during follow-up. Transplantation 2013; 95 (9): 1148–1153. doi: 10.1097/TP.0b013e3182884890.

36. Kalisvaart M, Schlegel A, Trivedi PJ et al. Chronic Kidney Disease After Liver Transplantation: Impact of Extended Criteria Grafts. Liver Transplant 2019; 25 (6): 922–933. doi: 10.1002/lt.25468.

37. Ojo AO, Held PJ, Port FK et al. Chronic renal failure after transplantation of a nonrenal organ. N Engl J Med 2003; 349 (10): 931–940. doi: 10.1056/NEJMoa021744.

38. Kim JY, Akalin E, Dikman S et al. The variable pathology of kidney disease after liver transplantation. Transplantation 2010; 89 (2): 215–221. doi: 10.1097/TP.0b013e3181c353e5.

39. Stevens LA, Coresh J, Greene T et al. Assessing kidney function – measured and estimated glomerular filtration rate. N Engl J Med 2006; 354 (23): 2473–2483. doi: 10.1056/NEJMra054415.

40. Adebayo D, Morabito V, Davenport A et al. Renal dysfunction in cirrhosis is not just a vasomotor nephropathy. Kidney Int 2015; 87 (3): 509–515. doi: 10.1038/ki.2014.338.

41. Chang Y, Ryu S, Sung E et al. Nonalcoholic fatty liver disease predicts chronic kidney disease in nonhypertensive and nondiabetic Korean men. Metabolism 2008; 57 (4): 569–576. doi: 10.1016/j.metabol.2007.11.022.

42. 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 (8): 1564–1570. doi: 10.1681/ASN. 2007101155.

43. Singal AK, Hasanin M, Kaif M et al. 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.

44. Houlihan DD, Armstrong MJ, Davidov Y et al. Renal function in patients undergoing transplantation for nonalcoholic steatohepatitis cirrhosis: time to reconsider immunosuppression regimens? Liver Transplant 2011; 17 (11): 1292–1298. doi: 10.1002/lt.22382.

45. Northup PG, Argo CK, Bakhru MR et al. Pretransplant predictors of recovery of renal function after liver transplantation. Liver Transplant 2010; 16 (4): 440–446. doi: 10.1002/lt.22008.

46. Iglesias J, Frank E, Mehandru S et al. Predictors of renal recovery in patients with pre-orthotopic liver transplant (OLT) renal dysfunction. BMC Nephrol 2013; 14: 147. doi: 10.1186/14 71-2369-14-147.

47. Trunečka P, Klempnauer J, Bechstein WO et al. The Effect of Donor Age and Recipient Characteristics on Renal Outcomes in Patients Receiving Prolonged-Release Tacrolimus After Liver Transplantation: Post-Hoc Analyses of the DIAMOND Study. Ann Transplant 2019; 24: 319–327. doi: 10.12659/AOT.913103.

48. Huang JW, Yen CJ, Chiang HW et al. Adiponectin in peritoneal dialysis patients: a comparison with hemodialysis patients and subjects with normal renal function. Am J Kidney Dis 2004; 43 (6): 1047–1055. doi: 10.1053/j.ajkd. 2004.02.017.

49. Liu M, Liu F. Regulation of adiponectin multimerization, signaling and function. Best Pract Res Clin Endocrinol Metab 2014; 28 (1): 25–31. doi: 10.1016/j.beem.2013.06.003.

50. Zoccali C, Mallamaci F, Tripepi G et al. Adiponectin, metabolic risk factors, and cardiovascular events among patients with end-stage renal disease. J Am Soc Nephrol 2002; 13 (1): 134–141. doi: 10.1681/ASN.V131134.

51. Przybyciński J, Dziedziejko V, Puchałowicz K et al. Adiponectin in Chronic Kidney Disease. Int J Mol Sci 2020; 21 (24): 9375. doi: 10.3390/ijms 21249375.

52. Wu ZJ, Cheng YJ, Gu WJ et al. Adiponectin is associated with increased mortality in patients with already established cardiovascular disease: a systematic review and meta-analysis. Metabolism 2014; 63 (9): 1157–1166. doi: 10.1016/j.metabol.2014.05.001.

53. Menon V, Li L, Wang X et al. Adiponectin and mortality in patients with chronic kidney disease. J Am Soc Nephrol 2006; 17 (9): 2599–2606. doi: 10.1681/ASN.2006040331.

54. Song SH, Oh TR, Choi HS et al. High serum adiponectin as a biomarker of renal dysfunction: Results from the KNOW-CKD study. Sci Rep 2020; 10 (1): 5598. doi: 10.1038/s41598-020-62465-2.

55. Chudek J, Adamczak M, Karkoszka H et al. Plasma adiponectin concentration before and after successful kidney transplantation. Transplant Proc 2003; 35 (6): 2186–2189. doi: 10.1016/j.trans proceed.2003.08.001.

56. Banu S, Jabir NR, Manjunath CN et al. C-peptide and its correlation to parameters of insulin resistance in the metabolic syndrome. CNS Neurol Disord Drug Targets 2011; 10 (8): 921–927. doi: 10.2174/187152711799219271.

57. Wolf G, Chen S, Han DC et al. Leptin and renal disease. Am J Kidney Dis 2002; 39 (1): 1–11. doi: 10.1053/ajkd.2002.29865.

58. Wolf G, Hamann A, Han DC et al. Leptin stimulates proliferation and TGF-beta expression in renal glomerular endothelial cells: potential role in glomerulosclerosis. Kidney Int 1999; 56 (3): 860–872. doi: 10.1046/ j.1523-1755.1999.00626.x.

59. Vítek L, Jirsa M, Brodanová M et al. Gilbert syndrome and ischemic heart disease: a protective effect of elevated bilirubin levels. Atherosclerosis 2002; 160 (2): 449–456. doi: 10.1016/ s0021-9150 (01) 00601-3.

60. Vítek L, Novotný L, Sperl M et al. The inverse association of elevated serum bilirubin levels with subclinical carotid atherosclerosis. Cerebrovasc Dis 2006; 21 (5–6): 408–414. doi: 10.1159/000091966.

61. Temme EH, Zhang J, Schouten EG et al. Serum bilirubin and 10-year mortality risk in a Belgian population. Cancer Causes Control 2001; 12 (10): 887–894. doi: 10.1023/a: 1013794407325.

62. Horsfall LJ, Rait G, Walters K et al. Serum bilirubin and risk of respiratory disease and death. JAMA 2011; 305 (7): 691–697. doi: 10.1001/jama. 2011.124.

63. Chin HJ, Cho HJ, Lee TW et al. The mildly elevated serum bilirubin level is negatively associated with the incidence of end stage renal disease in patients with IgA nephropathy. J Korean Med Sci 2009; 24 (1): S22–S29. doi: 10.3346/jkms.2009.24.S1.S22.

64. Shin HS, Jung YS, Rim H. Relationship of serum bilirubin concentration to kidney function and 24-hour urine protein in Korean adults. BMC Nephrol 2011; 12: 29. doi: 10.1186/1471-2369- 12-29.

65. Boon AC, Bulmer AC, Coombes JS et al. Circulating bilirubin and defense against kidney disease and cardiovascular mortality: mechanisms contributing to protection in clinical investigations. Am J Physiol Renal Physiol 2014; 307 (2): F123–F136. doi: 10.1152/ajprenal.00039.2014.

66. Bhuiyan AR, Srinivasan SR, Chen W et al. Association of serum bilirubin with pulsatile arterial function in asymptomatic young adults: the Bogalusa Heart Study. Metabolism 2008; 57 (5): 612–616. doi: 10.1016/j.metabol.2007.12.003.

67. Adin CA, Croker BP, Agarwal A. Protective effects of exogenous bilirubin on ischemia-reperfusion injury in the isolated, perfused rat kidney. Am J Physiol Renal Physiol 2005; 288 (4): F778–F784. doi: 10.1152/ajprenal.00215.2004.

68. Deetman PE, Zelle DM, Homan van der Heide JJ et al. Plasma bilirubin and late graft failure in renal transplant recipients. Transpl Int 2012; 25 (8): 876–881. doi: 10.1111/j.1432-2277.2012.01515.x.

69. Bulmer AC, Blanchfield JT, Toth I et al. Improved resistance to serum oxidation in Gilbert’s syndrome: a mechanism for cardiovascular protection. Atherosclerosis 2008; 199 (2): 390–396. doi: 10.1016/j.atherosclerosis.2007.11.022.

70. De Simone P, Nevens F, De Carlis L et al. Everolimus with reduced tacrolimus improves renal function in de novo liver transplant recipients: a randomized controlled trial. Am J Transplant 2012; 12 (11): 3008–3020. doi: 10.1111/j.1600- 6143.2012.04212.x.

71. Maurel P, Prémaud A, Carrier P et al. Evaluation of Longitudinal Exposure to Tacrolimus as a Risk Factor of Chronic Kidney Disease Occurrence Within the First-year Post-Liver Transplantation. Transplantation 2021; 105 (7): 1585–1594. doi: 10.1097/TP.0000000000003384.

72. Sherman DS, Fish DN, Teitelbaum I. Assessing renal function in cirrhotic patients: problems and pitfalls. Am J Kidney Dis 2003; 41 (2): 269–278. doi: 10.1053/ajkd.2003.50035.