Editorial for ‘Alimentary, Pharmacology & Therapeutics’
Re: ‘Improvement in liver histology due to lifestyle modification is independently associated with improved kidney function in patients with non-alcoholic steatohepatitis: results from a post hoc analysis of a clinical trial’ Vilar-Gomez et al. 2016
TREATING THE LIVER TO TREAT THE KIDNEY
Fiona Gifford MBChB*
Neeraj Dhaun PhD*†
* Department of Renal Medicine, Royal Infirmary of Edinburgh
†University/British Heart Foundation Centre of Research Excellence, University of Edinburgh, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh. EH16 4TJ
Correspondence to: Dr Fiona Gifford
Department of Renal Medicine
Royal Infirmary of Edinburgh
51 Little France Crescent
Edinburgh
EH16 4SA
Tel: +44(0)1312421626
Email:
Word count: 645
Figures: 1
Pages: 8
Chronic kidney disease (CKD) is increasingly common with a current estimated global prevalence of 8-16%.1It is a significant cause of morbidity and mortality.1Importantly, renal impairment is an independent predictor of outcome in myocardial infarction, strokeand peripheral vascular disease.2Similarly, it isindependently associated with increased morbidity and mortality in acute3and chronic4liver disease, as well as in liver transplantion,5explaining its importance in prognostic stratification.
A recent meta-analysis revealed an increased prevalence of CKDin patients with non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and advanced fibrosis.6 This was independent of major confounders such as obesity, insulin resistance and the metabolic syndrome. The authors suggested that one mechanism to explain their findings might be the release of kidney damaging pro-inflammatory and pro-coagulant mediatorsfrom the diseased liver. However, whereas a parallel injury in the kidney to that in the liver is well recognised(Figure 1), there remain few data that show therapy directed towards the liver – other than liver transplantation –independently benefits the kidney.
In the current issue of the Journalthe study by Vilar-Gomez and colleagues advances our understanding of the nature of the renal impairment associated with NAFLD.7 They present a post hoc analysis of their recently published cohort study where 12 months of lifestyle modification (exercise and weight loss)led to resolution of steatohepatitis, a reduction in NAFLD activity score and fibrosis regression in patients with biopsy proven NASH.8Interestingly, here they show that these non-pharmacological manoeuvres also improved estimated glomerular filtration rate (eGFR).The observed improvement in eGFR was greatest (~8ml/min/1.73m2) in those who demonstrated an improvement in fibrosis, the subgroup at greatest risk of CKD.6 A smaller, but significant, increasein eGFR (~2ml/min/1.73m2) was seen in patients with NASH resolution. These improvements were seen even after controlling for factors such as liver disease severity, baseline eGFR, comorbidity and weight loss.
Current guidelines define CKD as an eGFR that is maintained at <60ml/min/1.73m2for 3 or more months.9As a result in many clinical settings the actual eGFR, if >60ml/min/1.73m2, is not reported. In this study, >95% of subjects had an eGFR of >60ml/min/1.73m2and so the increases in eGFR observed here may not be apparent in the clinic. Furthermore, it remains unclear whether these eGFR improvements, which are even greater than those seen following the introduction of an angiotensin converting enzyme (ACE) inhibitor (the current standard of care for CKD patients),10 translate to better outcomes for patients with NAFLD.
Of note, the largest increase in eGFR was observed in those with the lowest baseline eGFR. This is also the case with ACE inhibitors.10The authors excluded those with significant renal dysfunction (eGFR<40ml/min/1.73m2) who one might argue have the most to gain. This group should certainly be the focus of future research. Also, as recognised by the authors, it is unfortunate that there are no data on proteinuria. This defines CKD regardless of eGFR and is incrementally and independently associated with clinical outcomes.11Finally, although the authors state they accounted for drug prescriptions during and within the 3 months preceding the study in their analysis,it is unclear whether agents such as ACE inhibitors and HMG-coenzyme A reductase inhibitors (‘statins’) which have longer term benefits for the kidney10,12might have impacted the outcomes seen.
This intriguing work suggests that treating the liver also treats the kidney. However, its reproducibility in a real-world setting with both time and financial constraints remains unclear. Furthermore, the mechanisms for these benefits should be explored further. One possibility includes the release of extracellular vesicles by the liver.13In theUS, an estimated64 million people have NAFLD/NASH with predicted annual medical costs of around $94 billion.14As the prevalence of obesity and NAFLD soars, appropriate screening and early effective interventions are essential to reduce the financial and societal burden of both NAFLD and the kidney disease with which it is associated.
References
1.Jha V, Garcia-Garcia G, Iseki K, et al. Chronic kidney disease: global dimension and perspectives. Lancet 2013; 382: 260-72.
2.Bax L, Algra A, Mali WP, et al. Renal function as a risk indicator for cardiovascular events in 3216 patients with manifest arterial disease. Atherosclerosis 2008; 200: 184-90.
3.Moore JK, Love E, Craig DG, et al. Acute kidney injury in acute liver failure: a review. Expert Rev Gastroenterol Hepatol 2013; 7: 701-12.
4.Tsien CD, Rabie R, Wong F. Acute kidney injury in decompensated cirrhosis. Gut 2013; 62: 131-7.
5.Nair S, Verma S, Thuluvath PJ. Pretransplant renal function predicts survival in patients undergoing orthotopic liver transplantation. Hepatology 2002; 35: 1179-85.
6.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.
7.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 2016.
8.Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, et al. Weight Loss Through Lifestyle Modification Significantly Reduces Features of Nonalcoholic Steatohepatitis. Gastroenterology 2015; 149: 367-78.
9.NICE. Chronic kidney disease in adults: assessment and management. 2014. - classification-of-chronic-kidney-disease-2 (accessed 16 Nov 2016).
10.Ruggenenti P, Perna A, Benini R, et al. In chronic nephropathies prolonged ACE inhibition can induce remission: dynamics of time-dependent changes in GFR. Investigators of the GISEN Group. Gruppo Italiano Studi Epidemiologici in Nefrologia. J Am Soc Nephrol 1999; 10: 997-1006.
11.Tonelli M, Klarenbach SW, Lloyd AM, et al. Higher estimated glomerular filtration rates may be associated with increased risk of adverse outcomes, especially with concomitant proteinuria. Kidney Int 2011; 80: 1306-14.
12.Geng Q, Ren J, Song J, et al. Meta-analysis of the effect of statins on renal function. Am J Cardiol 2014; 114: 562-70.
13.Herrera Sanchez MB, Bruno S, Grange C, et al. Human liver stem cells and derived extracellular vesicles improve recovery in a murine model of acute kidney injury. Stem Cell Res Ther 2014; 5: 124.
14.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: 1577-86.
Figure legend
Figure 1. Potential mechanisms for liver-mediated renal disease
Blue arrow; direction of potential harm, upwardpointing arrow; increased, downwardpointing arrow; decreased,ApoB; apolipoprotein B,HDL; high-density lipoprotein, small dense LDL; small dense low-density lipoprotein, PAI-1; plasminogen activator inhibitor-1, CRP; C-reactive protein,IL-6; interleukin 6, TNF-; tumour necrosis factor alpha.
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Figure 1. Potential mechanisms for liver-mediated renal disease
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