Non-alcoholic fatty liver and chronic kidney disease: Retrospect, introspect, and prospect

Table 1 Incidence and prevalence of chronic kidney disease in patients with varying degrees of non-alcoholic fatty liver disease severity

Ref.	Year	n	NAFLD diagnostic modalities	Conclusion(s)
Musso et al[12]. A meta-analysis of 33 studies	2014	63902	Liver biopsy, abdominal ultrasound, elevated liver enzymes	(1) 20 cross-sectional studies: Nearly two-fold increased risk of CKD in patients with NAFLD (OR 2.12, 95%CI 1.69-2.66); (2) 11 longitudinal studies: 1.8-fold increased risk of CKD in patients with NAFLD (HR 1.79, 95%CI 1.65–1.95); and (3) advanced fibrosis associated with increased prevalence (OR 5.20, 95%CI 3.14-8.61) and incidence (HR 3.29, 95%CI 2.30-4.71) of CKD in patients with NAFLD
Mantovani et al[13]. A meta-analysis of 9 studies	2018	96595	Abdominal ultrasound; FLI; serum GGT	Incidence of CKD: (1) 1.4-fold increased long-term risk (HR 1.37, 95%CI 1.20–1.53) in patients with NAFLD with a median follow-up period of 5.2 years; and (2) 1.5-fold increased risk (HR 1.50, 95%CI 1.25-1.74) in patients with severe NAFLD (defined as NFS ≥ -1.455 or serum GGT ≥ 109 U/L)
Park et al[14]. Retrospective Cohort with Propensity Score Matching (1:3)	2019	262619	ICD-9	Incidence of CKD: 1.4-fold increased risk (aHR 1.41; 95%CI, 1.36-1.46) in patients with NAFLD after adjusting for demographics, baseline covariates, and ACEi/ARB use; Risk of incident CKD increases as the severity of NAFLD increases: (1) compensated cirrhosis (aHR, 1.47; 95%CI 1.36-1.59); and (2) decompensated cirrhosis (aHR, 2.28; 95%CI 2.12-2.46)

NAFLD: Non-alcoholic fatty liver disease; CKD: Chronic kidney disease; HR: Hazard ratio; FLI: Fatty liver index; GGT: Gamma glutamyl transferase; NFS: NAFLD fibrosis score; CI: Confidence interval; OR: Odds ratio; ACEi: Angiotensin-converting enzyme inhibitor; ARB: Angiotensin receptor blocker; ICD-9: International classification of disease-9.

Table 2 Summary of studies assessing non-hepatic risk factors for chronic kidney disease in patients with non-alcoholic fatty liver disease

Ref.	Risk factor(s)	Year	n	Comparison	Findings
Önnerhag et al[147]	Older age	2019	120	Biopsy-proven NAFLD vs non-NAFLD	Higher prevalence of CKD in patients ≥ 55 years old
Targher et al[20]	Diabetes mellitus	2008	2103	NAFLD and T2DM vs T2DM only	Patients with NAFLD and T2DM independently associated with increased risk of CKD (OR 1.87; 95%CI 1.3-4.1, P = 0.020)
Targher et al[33]	Diabetes mellitus	2010	301	NAFLD and T1DM vs T1DM only	Patients with NAFLD and T1DM independently associated with increased risk of CKD
Jang et al[29]	Elevated baseline eGFR, HTN, and current smoking	2018	1525	NAFLD vs Non-NAFLD	The decline in eGFR associated with NAFLD appeared to be stronger among patients who were current smokers, hypertensive, and lower eGFR at baseline

NAFLD: Non-alcoholic fatty liver disease; CKD: Chronic kidney disease; T2DM: Type 2 diabetes mellitus; OR: Odds ratio; CI: Confidence interval; T1DM: Type 1 Diabetes Mellitus; eGFR: Estimated glomerular filtration rate; HTN: Hypertension.

Table 3 Summary of studies assessing non-invasive scoring systems for advanced fibrosis to assess risk for chronic kidney disease in patients with nonalcoholic fatty liver disease

Ref.	Year	n	Scoring system(s) assessed	Results
Ciardullo et al[82]	2020	2770	APRI, FIB-4, FLI, NFS	NAFLD-related fibrosis as measured with FIB-4 associated with CKD (P < 0.01)
Hsieh et al[6]	2020	11376	NFS	Higher NFS associated with impaired eGFR (P < 0.0001)
Choi et al[81]	2019	11836	APRI, BARD, FIB-4, FLI	FIB-4 (P = 0.0258) most precise in predicting kidney dysfunction
Önnerhag et al[79]	2019	144	APRI, BARD, NFS, FIB-4	High-risk NFS (P < 0.001), FIB-4 (P < 0.001), APRI (P = 0.008) predict CKD
Wijarnpreecha et al[80]	2018	4142	APRI, BARD, NFS, FIB-4	High/intermediate probability of liver fibrosis on NFS (AUC = 0.75) and FIB-4 (AUC = 0.77) independently predict CKD
Huh et al[23]	2017	6238	FLI	NAFLD cut-off for NAFLD is an independent RF for CKD (P < 0.0001)

NFS: Nonalcoholic fatty liver disease fibrosis score; FIB-4: Fibrosis-4 index; APRI: Aspartate aminotransferase to platelet ratio index; FLI: Fatty liver index; CKD: Chronic kidney disease; eGFR: Estimated glomerular filtration rate; AUC: Area under the curve; RF: Risk factor; BARP: Biologically-oriented Alveolar Ridge Preservation; NAFLD: Nonalcoholic fatty liver disease.

Table 4 Summary of Interventions for patients with nonalcoholic fatty liver disease and chronic kidney disease

Intervention	Ref.	Year	n	Findings	Recommendation
Decreasing WHR	Chon et al[43]. 12-yr prospective cohort	2020	6137	A decrease in the WHR of more than 5% in patients with NAFLD leads to a significantly reduced risk of CKD development, even in non-obese patients	Serial Monitoring WHR may be beneficial in identifying patients with NAFLD at risk of developing CKD and reduction can ameliorate the progression
Weight loss	Vilar-Gomez et al[94]. Post-hoc analysis	2017	261	Improvement in liver histology due to weight loss linked to improved renal outcomes, even after adjusting for medication profile, diabetes, and hypertension	Advocate for weight loss
SGLT2 Inhibitors	Shimizu et al[96]. RCT	2019	57	SGLT inhibitor (Dapagliflozin) improved liver steatosis in patients with T2DM and NAFLD and attenuates liver fibrosis in patients with NAFLD-related advanced fibrosis	Although data is not sufficient, consider using SGLT2 inhibitors in T2DM patients with NAFLD and CKD
	Perkovic et al[95]. CREDENCE trial	2019	4401	SGLT2 inhibitor (Canagliflozin) decreased the risk of renal failure in patients with T2DM and CKD
GLP-1	Armstrong et al[100]. LEAN trial	2016	52	Liraglutide led to weight loss, glycemic control, and histological resolution of NASH	GLP-1’s in NASH is considered effective in improving components of MetS, however, long-term studies are needed to determine NASH-related outcomes
	Tuttle et al[101]. AWARD-7 trial	2018	577	Once-weekly dulaglutide is associated with reduced decline in eGFR, while being as effective as insulin in achieving glycemic control	GLP-1 is a safe option for patients with CKD and is associated with slower progression of CKD
Coenzyme Q10	Farhangi et al[109] and Farsi et al[110]. RCT	2014[109] and 2016[110]	44[109] and 41[110]	100 mg of oral CoQ10/d improve biochemical variables of NAFLD after 4 wk[109] and 12 wk[110] of treatment	Due to lack of data in patients with both NAFLD and CKD, the benefit of CoQ10 supplementation is unknown; however, in separate trials with regards to both NAFLD and CKD, CoQ10 supplementation is beneficial
	Yeung et al[111]. RCT	2015	15	Oral CoQ10 supplementation in patients with CKD showed significant improvement in serum creatinine when compared to placebo

WHR: Waist-to-hip ratio; NAFLD: Nonalcoholic fatty liver disease; CKD: Chronic kidney disease; SGLT2: Sodium-glucose co-transporter-2; RCT: Randomized controlled trial; T2DM: Type 2 Diabetes Mellitus; GLP-1: Glucagon-like peptide receptor agonist; NASH: Non-alcoholic steatohepatitis.