Nonalcoholic Fatty Liver Linked to Kidney Disease in Diabetic Patients

By Judith Groch
VERONA, 31 may 2008-- For patients with type 2 diabetes, non-alcoholic fatty livers may lead to chronic kidney disease, an observational study found.
The risk for chronic kidney disease was 69% higher for diabetic patients with non-alcoholic fatty liver disease than for diabetic patients without the liver disorder, Giovanni Targher, M.D., of the University of Verona, and colleagues here and at the University of Colorado reported online in the Journal of the American Society of Nephrology.
Non-alcoholic fatty liver prevalence has been estimated to be in the 15% to 30% range in the general population in various countries and appears to be increasing, the researchers said. However, there has been little information about the association between the fatty liver disease and the risk of developing diabetic nephropathy.
Treating earlier stages of nephropathy in diabetic patients could slow the progression of the kidney disorder to end-stage renal disease. Thus, early detection of precursors and risk factors for chronic kidney disease is very important, Dr. Targher and colleagues wrote.
Their study included 1,760 outpatients with type 2 diabetes and normal or near-normal kidney function and without overt proteinuria.
Patients were followed for 6.5 years (through December 2006) for the occurrence of chronic kidney disease (overt proteinuria and/or estimated GFR< 60 ml/min per 1.73 m2).
The participants were recruited from the Valpolicella Heart Diabetes Study cohort, a prospective observational study to evaluate associations between diabetes and chronic vascular complications.
Patients with other common causes of fatty liver, such as alcohol abuse, chronic viral hepatitis, and use of potentially liver-toxic medications were excluded.
During follow-up, 547 participants developed incident chronic kidney disease, with a yearly risk of about 4.5%, the researchers said.
Nonalcoholic fatty liver disease, diagnosed by liver ultrasound and exclusion of other common causes of chronic liver disease, was associated with a moderately increased risk for the kidney disorder (hazard ratio 1.69, 95% confidence interval 1.3 to 2.6, P<0.001).
Adjustments for gender, age, BMI, waist circumference, blood pressure, smoking, diabetes duration, glycosylated hemoglobin, lipids, baseline estimated GFR, microalbuminuria, and medications (hypoglycemic, lipid-lowering, antihypertensive, or antiplatelet drugs) did not appreciably attenuate this association (HR 1.49, 95% CI 1.1 to 2.2, P < 0.01).
The annual cumulative incidence of 4.5% per year was comparable to that previously described in other Italian and European populations with diabetes and similar baseline characteristics.
The underlying biologic mechanisms by which fatty liver disease may increase the risk for chronic kidney disease in type 2 diabetes are poorly understood, the investigators said. The most obvious explanation is that the findings simply reflect the coexistence of underlying known risk factors.
However, they said, the findings were independent of numerous baseline risk factors, so that it is conceivable that nonalcoholic fatty liver may confer an excess risk beyond these known risk factors and that fatty liver itself in diabetic patients may be involved in the pathogenesis of chronic kidney disease.
The possible molecular mediators may include the release of some pathogenic factors from the liver, including elevated advanced glycosylated end products, increased reactive oxygen species, elevated C-reactive protein, TNF-α, TGF-β1, and other proinflammatory cytokines.
Importantly, several studies have shown that these potential mediators of vascular and/or renal injury are remarkably higher in diabetic or obese patients with fatty liver disease and are thought to be pathogenic factors for the progression of chronic kidney disease.
In addition, they said, the liver disease may worsen whole-body insulin resistance and hyperglycemia, which may in turn contribute to the progression of kidney disease. This was supported by the observation in this study that HbA1c was higher in patients with fatty liver than in those without it.
Study limitations included the use of an estimated GFR to define chronic kidney disease. Also, the fatty liver diagnosis was based on ultrasound diagnosis and exclusion of secondary causes of chronic liver disease but was not confirmed by biopsy. Whether these observations can be extended to nonwhite patients and other ethnic groups remains to be determined.
It is not known whether treating fatty liver disease will ultimately prevent progression to chronic kidney disease, the researchers said.
However, they wrote, it is notable that interventions effective in preventing or delaying the progression to chronic kidney disease in patients with diabetes, such as weight reduction or treatment with angiotensin receptor blockers or insulin-sensitizing agent, may also be effective for fatty liver disease.
Further prospective studies are required to confirm the reproducibility of these results and whether the findings can be extended to nonwhite ethnic groups, they concluded.
No financial conflicts were reported.
Primary source: Journal of the American Society of NephrologySource reference:Targher G, et al "Increased risk of CKD among type 2 diabetics with nonalcoholic fatty liver disease" J Am Soc Nephrol 2008; DOI: 10.1681/ASN.2007101155.