Lakhasly

Nonalcoholic fatty liver disease (NAFLD), which is strongly and bidirectionally asso ciated with metabolic syndrome and its individual features, encompasses a spectrum of liver diseases ranging from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis

(NASH) and carries the risk of developing cirrhosis and hepatocellular carcinoma in a pro portion of cases [1].The latter entity exhibits glomerular hypertrophy, focal dilatation of the afferent arteriole and glomerular perihilar capillaries, and perihilar segmental sclerosis; mildly increased mesangial matrix and the thickening of glomerular basement membranes (i.e., diabetes-like features), interstitial fibrosis, foot process effacement, and hypertrophy of podocyte cell bodies may also occur [20].The pathogenesis of NAFLD involves a profound perturbation of metabolic homeostasis; a reprogramming of the interplay be tween hepatocytes, sinusoidal endothelial cells, and hepatic stellate cells; a rearrangement of the liver immune landscape; and a remodeling of the hepatic microvasculature and stromal microenvironment [7].Interestingly, the metabolic pathways, cellular phenomena, and molecular mediators involved in NAFLD and CKD are similar to each other and include insulin resistance, ectopic fat deposition, and the activation of the insulin/PI3K/Akt/mTOR and transforming growth factor-pathways [20,23].To date, however, there are no systematic studies evaluating kidney histology among patients with NAFLD and, usually, in such cases a reference is rather made to the functional classification of CKD stages based on the estimated glomerular f iltration rate (eGFR) and proteinuria, both in clinical practice and in the research arena [11].New insights into liver cell-cell interactions will define the molecular pathways that culminate in hepatic fibrogenesis and identify

novel targets to interrupt disease progression to adverse clinical outcomes [10].These severe liver-related outcomes usually result from the progression of NAFLD diagnosed as NASH, although a subgroup of NAFLD patients diagnosed as NAFLmayalsodevelop liver fibrosis, indicating a propensity for progression [1].

Nonalcoholic fatty liver disease (NAFLD), which is strongly and bidirectionally asso
ciated with metabolic syndrome and its individual features, encompasses a spectrum of
liver diseases ranging from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis

(NASH) and carries the risk of developing cirrhosis and hepatocellular carcinoma in a pro
portion of cases [1]. These severe liver-related outcomes usually result from the progression
of NAFLD diagnosed as NASH, although a subgroup of NAFLD patients diagnosed as
NAFLmayalsodevelop liver fibrosis, indicating a propensity for progression [1]. To date,
NAFLDhas become the most common chronic liver disease worldwide, affecting up to
~30%of adults in the general population, up to ~70% of patients with type 2 diabetes (T2D),
and almost all patients with severe obesity [2–6]. The pathogenesis of NAFLD involves
a profound perturbation of metabolic homeostasis; a reprogramming of the interplay be
tween hepatocytes, sinusoidal endothelial cells, and hepatic stellate cells; a rearrangement of the liver immune landscape; and a remodeling of the hepatic microvasculature and
stromal microenvironment [7]. A key effect of persistent metabolic stress on the liver is the

activation of hepatic stellate cells and the development of liver fibrosis, which typically
dictates the natural course of NAFLD [8,9]. New insights into liver cell–cell interactions
will define the molecular pathways that culminate in hepatic fibrogenesis and identify

novel targets to interrupt disease progression to adverse clinical outcomes [10].
Chronic kidney disease (CKD) is the shared outcome of a variety of etiologies that
impair the functional renal reserve, resulting in a gradual loss of function [11] and eventu
ally causing end-stage renal disease in a subset of individuals [11]. The global estimated
prevalence of CKD is approximately 10% [12–15], resulting in nearly 1.2 million deaths and
28 million years of life lost each year [12]. In high-income countries, CKD tends to be most
often associated with metabolic disorders, such as T2D, obesity, and hypertension [16,17].
In low-income and middle-income countries, infectious diseases and environmental toxins
are also commonly associated with CKD [18]. Given the close interconnection of CKD with
metabolic disorders, the prototypical examples of pathophenotypes in NAFLD-related CKD
maybediabetic nephropathy and nephropathy in the obese. The former entity features the
thickening of the glomerular basement membrane, the fusion of foot processes, the loss
of podocytes with the denuding of the glomerular basement membranes, and mesangial
matrix expansion [19]. The latter entity exhibits glomerular hypertrophy, focal dilatation of
the afferent arteriole and glomerular perihilar capillaries, and perihilar segmental sclerosis;
mildly increased mesangial matrix and the thickening of glomerular basement membranes
(i.e., diabetes-like features), interstitial fibrosis, foot process effacement, and hypertrophy
of podocyte cell bodies may also occur [20]. These features classically characterize the most
severe cases of CKD. To date, however, there are no systematic studies evaluating kidney
histology among patients with NAFLD and, usually, in such cases a reference is rather
made to the functional classification of CKD stages based on the estimated glomerular
f
iltration rate (eGFR) and proteinuria, both in clinical practice and in the research arena [11].
The spectrum of similarities between NAFLD and CKD is impressive: both are
common conditions (implying that their association is probable), both exhibit sexual di
morphism [21], and both are associated with an increased risk of major cardiovascular
events [22]. Interestingly, the metabolic pathways, cellular phenomena, and molecular
mediators involved in NAFLD and CKD are similar to each other and include insulin
resistance, ectopic fat deposition, and the activation of the insulin/PI3K/Akt/mTOR and
transforming growth factor-pathways [20,23]. However, conflicting with these simi
larities, in both clinical and research settings NAFLD is either diagnosed based on liver
histology or with imaging techniques and serum