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Mantovani et al. Hepatoma Res 2020;6:78 I http://dx.doi.org/10.20517/2394-5079.2020.75 Page 13 of 22

T2DM and NAFLD had an increased risk of incident CKD (defined as CKD stage ≥ 3 and/or overt
proteinuria) as compared to those without NAFLD over a mean follow-up period of 6.5 years [149] . Recently,
in a meta-analysis involving 9 cohort studies with a total of nearly 100,000 patients with and without
T2DM, Mantovani et al. [150] confirmed that NAFLD was independently associated with an increased risk of
incident CKD. Interestingly, when the authors performed a subgroup analysis, they found that the risk of
incident CKD in patients with NAFLD was greater in patients with T2DM (random effects hazard ratio 1.56,
95% confidence interval 1.07-2.05) than in patients with no T2DM (random effects hazard ratio 1.35, 95%
confidence interval 1.16-1.54) [150] .

Accumulating data also suggest that NAFLD patients with CKD tend to have a worse prognosis and
an increased overall mortality as well, when compared to those with NAFLD but without CKD [148] . For
instance, in a cohort study enrolling 11,695 patients, Paik et al. [151] documented that the presence of both
CKD and NAFLD was associated with an increased risk for overall mortality (hazard ratio 2.34, 95%
confidence interval 1.91-2.87). Interestingly, in that study, the severity of CKD was even associated with
higher risk of mortality in patients with NAFLD [151] . Specifically, the presence of NAFLD with advanced
CKD stages (from stage 3B to stage 5) was associated with a nearly 5-fold (hazard ratio 4.80, 95%
confidence interval 2.40-9.71) increased risk of death when compared to absence of CKD, whereas the
presence of NAFLD with intermediate CKD stages (from stage 2 to stage 3A) was associated with a 2.3-fold
(95% confidence interval 1.70-3.15) increased risk of death [151] . Although further studies are needed, it is
possible that the difference in overall mortality observed by Paik et al. [151] might be related to the presence
of specific metabolic features, including T2DM. Önnerhag et al. [152] corroborated this hypothesis in an
observational study involving 120 patients with biopsy-diagnosed NAFLD.

Recently, some observational studies that enrolled patients with and without T2DM have documented that
PNPLA3 rs738409 (I148M protein variant), which is the most important variant associated with NAFLD
and its severe forms, is independently associated with an increased risk of CKD [145,148] . For instance, in
a recent study of 157 Italian patients with T2DM, who underwent liver ultrasound and kidney function
assessment, Mantovani et al. [153] reported that the association of I148M homozygosity with higher risk
of CKD was independent of liver disease severity and other confounders. Interestingly, in that study, the
authors also found that PNPLA3 mRNA expression was greatest in liver and renal cortex, especially in
podocytes, thereby suggesting that PNPLA3 I148M variant might exert adverse effects on the kidney [153] .

Association between NAFLD and distal symmetric polyneuropathy in patients with diabetes
mellitus
Several observational studies, although not all [154,155] , have documented a significant association between
NAFLD and prevalent distal symmetric polyneuropathy in patients with T2DM [22,39,71] . This association
persisted even after adjustment for many cardiometabolic risk factors and other potential confounders.
Interestingly, in a recent cross-sectional study involving approximately 400 outpatients with T2DM
(mean age 68 years, 52% male) attending 5 Italian diabetes centers, who underwent liver ultrasonography,
[71]
FibroScan® and evaluation of microvascular diabetic complications, Lombardi et al. documented
that significant fibrosis (i.e., LSM ≥ 7.0/6.2 kPa with M/XL probes) was independently associated with
increased prevalence of microvascular diabetic complications, including distal symmetric polyneuropathy
(3% in patients with LSM < 7.0/6.2 kPa vs. 14% in patients with LSM ≥ 7.0/6.2 kPa). Contrariwise, in a
retrospective study of 927 Asian patients with T2DM, Kim et al. [155] did not observe a significant difference
in the prevalence of diabetic peripheral neuropathy among patients with and without NAFLD.

Collectively, these data suggest that diabetic patients with NAFLD should be evaluated for the presence of
distal symmetric polyneuropathy, along with other hepatic and extrahepatic complications. In addition,
the issue of whether the increased risk of microvascular complications in diabetic patients with NAFLD is