Chronic kidney disease (CKD) and NAFLD: Time for awareness and screening
Authors: Giovanni Musso, James H Tabibian, Michael Charlton
Journal: Journal of Hepatology (2014)

Chronic kidney disease and associated mortality after liver transplantation – A time-dependent analysis using measured glomerular filtration rateJournal of HepatologyVol. 61Issue 2PreviewThe accuracy of creatinine-based estimated GFR (eGFR) in assessing the prevalence of chronic kidney disease (CKD) and associated mortality after liver transplantation (LTx) is unknown. Using measured GFR (mGFR) by iothalamate clearance, we determined the prevalence of the entire spectrum of renal dysfunction and the impact of CKD on mortality after LTx. Full-Text PDF Reply to: “Chronic kidney disease (CKD) and NAFLD: Time for awareness and screening”Journal of HepatologyVol. 62Issue 4PreviewWe appreciate the comments of Musso et al. related to our manuscript “Chronic kidney disease and associated mortality after liver transplantation - a time-dependent analysis using measured glomerular filtration rate” [1]. The authors call attention to the accumulating evidence of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) as a risk factor for chronic kidney disease (CKD). As NASH cirrhosis is emerging as the most common cause of liver transplantation (LT) [2], the incidence of subsequent CKD may increase. Full-Text PDF Open Access We read with interest the article by Allen et al. reporting on the high prevalence and associated mortality of chronic kidney disease (CKD), in patients who had undergone liver transplantation [[1]Allen A.M. Kim W.R. Therneau T.M. Larson J.J. Heimbach J.K. Rule A.D. Chronic kidney disease and associated mortality after liver transplantation–a time-dependent analysis using measured glomerular filtration rate.J Hepatol. 2014; 61: 286-292Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar]. We believe a thorough interpretation of these findings, which are consistent with recent liver transplant literature, should take into account the evolving aetiological spectrum of liver disease in both patients candidate for liver transplantation as well as in those with milder stage disease [[2]Singal A.K. Guturu P. Hmoud B. Kuo Y.F. Salameh H. Wiesner R.H. Evolving frequency and outcomes of liver transplantation based on etiology of liver disease.Transplantation. 2013; 95: 755-760Crossref PubMed Scopus (218) Google Scholar]: in either case, non-alcoholic steatohepatitis (NASH) is as an emerging risk factor for renal dysfunction, as compared with other aetiologies of cirrhosis. An analysis of the United Network Organ Sharing (UNOS) database, during the years 2002–2011, shows NASH-related cirrhosis as an increasing indication for simultaneous liver-kidney transplantation (SLKT) [[3]Singal A.K. Salameh H. Kuo Y.F. Wiesner R.H. Evolving frequency and outcomes of simultaneous liver kidney transplants based on liver disease etiology.Transplantation. 2014; 98: 216-221Crossref PubMed Scopus (55) Google Scholar]. A concerning observation was the reduced 5-year liver graft, kidney graft, and patient survival in NASH patients in comparison to transplantation for other causes of cirrhosis (HR of 2.50 (95% CI 1.10–5.80), 2.30 (1.10–5.10), and 2.20 (1.02–5.79) respectively), for loss of liver transplant, loss of kidney graft, and death. These findings are consistent with European data suggesting NASH as a risk factor for severe renal impairment after liver transplantation; Houlihan et al. [[4]Houlihan D.D. Armstrong M.J. Davidov Y. Hodson J. Nightingale P. Rowe I.A. et al.Renal function in patients undergoing transplantation for nonalcoholic steatohepatitis cirrhosis: time to reconsider immunosuppression regimens?.Liver Transpl. 2011; 17: 1292-1298Crossref PubMed Scopus (64) Google Scholar] reported more rapid loss of renal function in patients receiving a liver transplant for NASH-related cirrhosis in comparison to other aetiologies of cirrhosis (OR for incident CKD in NASH vs. controls of 2.43 (95% CI 1.05–5.63)) 2 years after liver transplantation, independent of BMI, diabetes, hypertension, hepatocellular carcinoma, and tacrolimus levels. Remarkably, 35% of patients transplanted for NASH-related cirrhosis progressed to stage 3b-4 CKD within 2 years after liver transplantation, compared to 10% of patients transplanted for other aetiologies of cirrhosis. The evidence connecting NAFLD to CKD is also emerging in the general population: we recently subjected studies, assessing the association of NAFLD with CKD, to meta-analysis [[5]Musso G. Gambino R. Tabibian J.H. Ekstedt M. Kechagias S. Hamaguchi M. et al.Association of non-alcoholic fatty liver disease with chronic kidney disease: a systematic review and meta-analysis.PLoS Med. 2014; 11: e1001680https://doi.org/10.1371/journal.pmed.1001680Crossref PubMed Scopus (439) Google Scholar], which included 33 studies (63,902 participants, 16 population-based and 17 hospital-based, 20 cross-sectional and 13 longitudinal). For 20 studies, individual participant data were obtained and NAFLD was defined by liver histology in 13 studies (2205 participants). NAFLD was associated with an increased prevalence (OR 2.12, 95% CI 1.69–2.66) and incidence (HR 1.79, 95% CI 1.65–1.95) of CKD. In non-cirrhotic biopsy-proven NAFLD patients, NASH was associated with a higher prevalence (OR 2.53, 95% CI 1.58–4.05) and incidence (HR 2.12, 95% CI 1.42–3.17) of CKD than simple steatosis. Similarly, NAFLD with advanced fibrosis was associated with a higher CKD prevalence (OR 5.20, 95% CI 3.14–8.61) and incidence (HR 3.29, 95% CI 2.30–4.71) than NAFLD with milder fibrosis stages. Remarkably, the severity of NAFLD was positively associated with CKD stages, with NASH and advanced fibrosis conferring a greater risk of developing stage 5 CKD (renal failure) than simple steatosis and milder fibrosis stages, respectively. In all analyses, the magnitude and direction of effects remained unaffected by diabetes status (present vs. absent) and after adjustment for other traditional risk factors for CKD (including age, obesity, metabolic syndrome components, smoking, hypertension, race). The prevalence of CKD, as well as NAFLD, is continuously rising in concert with the epidemic of its risk factors, including diabetes, obesity and metabolic syndrome. Although early recognition and treatment of CKD have been shown to reduce the staggering cost of CKD and related hospitalizations [[6]Black C. Sharma P. Scotland G. McCullough K. McGurn D. et al.Early referral strategies for management of people with markers of renal disease: a systematic review of the evidence of clinical effectiveness, cost-effectiveness and economic analysis.Health Technol Assess. 2010; 14: 1-184Crossref PubMed Scopus (153) Google Scholar], CKD often goes unrecognized, and in the Third National Health and Nutrition Survey (NHANES III), among all individuals with moderately decreased GFR (stage 3 CKD), the awareness approached 8.2% [[7]Coresh J. Byrd-Holt D. Astor B.C. Briggs J.P. Eggers P.W. et al.Chronic kidney disease awareness, prevalence, and trends among US adults, 1999 to 2000.J Am Soc Nephrol. 2005; 16: 180-188Crossref PubMed Scopus (695) Google Scholar]. Since current therapeutic options to reverse CKD in liver transplant recipients are limited, the findings discussed above emphasize the need for practicing hepatologists to recognize early CKD in chronic liver disease patients and in NAFLD in particular, to optimize the management of these patients by delaying renal disease progression. From a therapeutical stand-point, promising preliminary evidence from randomized trials suggest several available pharmacological classes provide incremental benefits on renal disease progression over others, with statins [[8]Athyros V.G. Tziomalos K. Gossios T.D. Griva T. Anagnostis P. Kargiotis K. et al.Safety and efficacy of long-term statin treatment for cardiovascular events in patients with coronary heart disease and abnormal liver tests in the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) Study: a post-hoc analysis.Lancet. 2010; 376: 1916-1922Abstract Full Text Full Text PDF PubMed Scopus (575) Google Scholar] and angiotensin receptor blockers slowing renal function decline and ameliorating proteinuria [[9]Hirata T. Tomita K. Kawai T. Yokoyama H. Shimada A. Kikuchi M. et al.Effect of Telmisartan or Losartan for Treatment of Nonalcoholic Fatty Liver Disease: Fatty Liver Protection Trial by Telmisartan or Losartan Study (FANTASY).Int J Endocrinol. 2013; 2013 (Article ID: 587140)Crossref PubMed Scopus (64) Google Scholar], in addition to the amelioration of markers of steatosis and liver histology in non-cirrhotic NASH [[10]Musso G. Cassader M. Rosina F. Gambino R. Impact of current treatments on liver disease, glucose metabolism and cardiovascular risk in non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of randomised trials.Diabetologia. 2012; 55: 885-904Crossref PubMed Scopus (470) Google Scholar]. Future trials should also evaluate the impact of experimental drugs on renal function, which is currently reported in less than 10% of available randomized trials in NASH. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.