Fig 1, Targher et al AJKD, ©National Kidney Foundation.

Targher et al recently published a review in AJKD that discussed the potential link between non-alcoholic fatty liver disease (NAFLD) and chronic kidney disease (CKD). We know the common causes of CKD include diabetes and hypertension; however, NAFLD is now being recognized as a possible cause.

What is NAFLD?

NAFLD is essentially an umbrella term that includes the entire spectrum of liver injury ranging from steatosis, to steatohepatitis, and finally cirrhosis. It is a histologic diagnosis, and excludes liver disease from other entities (alcohol, viruses like Hepatitis B/C, autoimmune, hemochromatosis, toxic insults, etc). NAFLD is one of the most prevalent causes of chronic liver disease worldwide, and has become the third most common indication for liver transplantation in the United States during the last decade. It is often asymptomatic and no standard treatment exists. So what is the approach to a patient with NAFLD? As with managing CKD, the key is “risk factor modification.” Hence, the focus is on losing weight, exercise, and dietary adjustment.

Does NAFLD cause CKD?

Targher and colleagues reviewed studies that analyzed possible association (and perhaps a causal role) between NAFLD and CKD. Several large, cross-sectional studies reported higher prevalence of CKD in patients with NAFLD. This held true for patients with and without diabetes. The association persisted even after adjusting for traditional CKD-related risk factors.

The role of NAFLD in causing incident CKD is more controversial. It is unclear whether NAFLD is an innocent bystander in CKD development, or actually has a causative role. While it seems plausible that NAFLD is associated with CKD given the shared pertinent risk factors (eg, obesity, dyslipidemia, etc), there is mounting evidence that NAFLD could instead be a mediator in CKD development. A 6.5 year long prospective study in Italian diabetics with NAFLD did report an increased risk of incident CKD independent of BMI, hemoglobin A1C level, smoking, etc.

Marker or Mediator?

How does NAFLD lead to CKD? It is hard to identify a mechanism given both NAFLD’s and CKD’s relationship with abdominal obesity and insulin resistance, but certain putative mechanisms have been proposed. Abdominal obesity does not just reflect an adverse quantity of adipose tissue; it is also characterized by inflamed visceral adipose mass (the source of pro-inflammatory adipokines). The liver becomes not just the target of consequent systemic inflammation (which would be a pure association with CKD), but is also an active source of pathogenic mediators (hepatokines) and worsening insulin resistance, factors that amplify kidney damage.

Hence, changes induced in the liver from the effects of adipokines could make it complicit in CKD development. Nonalcoholic steatohepatitis (NASH, a subcategory of NAFLD) is especially known to release pro-inflammatory, pro-fibrogenic, pro-coagulant, and pro-oxidant factors, all of which could contribute to CKD. Interestingly, angiotensinogen release from the liver is increased in NASH as well. Lastly, low levels of two plasma proteins, adiponectin (an anti-inflammatory adipokine) and fetuin-A (a protein secreted by the liver that regulates adiponectin levels, and a factor that has received intense attention in the nephrology world as a potent inhibitor of vascular and systemic calcification) have been postulated to play a role in this “cross-talk” between the liver, kidneys, and fat, that eventually leads to both liver and kidney damage.

Clinical Implications

As mentioned above, no specific treatment exists for NAFLD. Interventional trials studying potential treatments have focused on everything ranging from diet and exercise, to drugs like metformin, thiazolidinediones, and vitamin E, and even bariatric surgery. Statins have been tried as well, although without convincing evidence. Patients with preexisting NAFLD/NASH have not been shown to be at increased risk of statin-induced hepatotoxicity.

From a renal perspective, some of these interventions that target insulin resistance and cardio-metabolic risk factors should have a salutary effect on CKD development/progression. Angiotensin receptor blockers, drugs we often prescribe, have been shown to have a potential role in improving insulin sensitivity and even improving NAFLD stage.

An important question given this information is whether patients with NAFLD should be screened for CKD? Does the link between NAFLD and CKD impact clinical practice? Let us know your thoughts!

Dr. Veeraish Chauhan
eAJKD Contributor

To view the article abstract or full-text (subscription required), please visit AJKD.org.