The Effects of n-3 Long-Chain Polyunsaturated Fatty Acid Supplementation on Biomarkers of Kidney Injury in Adults With Diabetes: Results of the GO-FISH trial

OBJECTIVE

Long-chain n-3 polyunsaturated fatty acid (n-3 PUFA) supplements may have renoprotective effects in patients with diabetes, but previous trials have been inconsistent. We performed a randomized controlled trial of n-3 PUFA supplementation on urine albumin excretion and markers of kidney injury in adults with type 2 diabetes.

RESEARCH DESIGN AND METHODS

We conducted a randomized, placebo-controlled, two-period crossover trial to test the effects of 4 g/day of n-3 PUFA supplementation on markers of glomerular filtration and kidney injury in adults with adult-onset diabetes and greater than or equal to trace amounts of proteinuria. Each period lasted 6 weeks and was separated by a 2-week washout. The main outcome was urine albumin excretion and, secondarily, markers of kidney injury (kidney injury molecule-1, N-acetyl β-d-glucosaminidase NAG], neutrophil gelatinase-associated lipocalin NGAL], and liver fatty acid–binding protein LFABP]), serum markers of kidney function (cystatin C, β₂-microglobulin, and creatinine), and estimated glomerular filtration rate (eGFR).

RESULTS

Of the 31 participants, 29 finished both periods. A total of 55% were male, and 61% were African American; mean age was 67 years. At baseline, mean BMI was 31.6 kg/m², median eGFR was 76.9 mL/min/1.73 m², and median 24-h urine albumin excretion was 161 mg/day. Compared with placebo, n-3 PUFA had nonsignificant effects on urine albumin excretion (−7.2%; 95% CI −20.6 to 8.5; P = 0.35) and significant effects on urine NGAL excretion (−16% −29.1 to −0.5%]; P = 0.04). There was no effect on serum markers of kidney function or eGFR. In subgroup analyses, there were significant decreases in 24-h urinary excretion of albumin, NGAL, LFABP, and NAG among participants taking medications that block the renin-angiotensin-aldosterone system (RAAS).

CONCLUSIONS

These results suggest a potential effect of n-3 PUFA supplementation on markers of kidney injury in patients with diabetes and early evidence of kidney disease. In the context of prior studies, these results provide a strong rationale for long-term trials of n-3 PUFA on chronic kidney disease progression.Diabetes is a leading cause of chronic kidney disease (CKD) (1). Treatments to slow the progression of CKD in diabetes include blocking the renin-angiotensin-aldosterone system (RAAS), implementing lower blood pressure (BP) treatment goals, and treating hyperglycemia (2). These therapies can also reduce urine protein excretion, a marker of disease severity. Indeed, maximal reduction of urine protein excretion has been proposed as a goal of drug therapy (3). Long-chain n-3 polyunsaturated fatty acid (n-3 PUFA) supplements may improve endothelial function, lower BP, and have independent antiproteinuric effects (4). However, evidence of benefit from supplementation with n-3 PUFA on urine protein excretion in the setting of diabetic kidney disease is inconsistent (5–11).New markers of kidney function and injury hold considerable promise as a means to evaluate the potential benefits of therapies designed to retard the progression of CKD. Biomarkers of tubulointerstitial kidney damage, including kidney injury molecule-1 (KIM-1), N-acetyl β-d-glucosaminidase (NAG), neutrophil gelatinase-associated lipocalin (NGAL), and liver fatty acid–binding protein (LFABP) may have greater sensitivity for identifying effects on kidney injury than total urine protein or albumin excretion, which reflect both kidney injury and hemodynamic effects (12,13). Novel serum markers, including β₂-microglobulin and cystatin C, may provide greater sensitivity for determining short-term effects of therapies on estimated glomerular filtration rate (eGFR) than traditional markers of filtration. These new markers of kidney function and injury might be especially useful in guiding the design of subsequent long-term trials.In this context, we conducted a randomized, controlled crossover trial to evaluate the efficacy of n-3 PUFA supplements on improving markers of kidney injury and function in adults with adult-onset diabetes and greater than or equal to trace amounts of proteinuria.