Evidence for the use of glomerulomegaly as a surrogate marker of glomerular damage and for alpha linolenic acid rich oils in the treatment of early obesity related glomerulopathy in a diet induced rodent model of obesity

Obesity related glomerulopathy (ORG) is a unique and emerging condition that can lead to renal failure. Early detection, aided by an earlier diagnostic marker, would improve patient outcomes; this could be facilitated by an accurate model. Such a model would be useful to examine interventions like dietary fatty acids, which are known to influence renal diseases in later stages. In this study, obese prone rats were provided high fat (55 per cent of energy) diets for 12 weeks to generate a model of diet-induced obesity. The rats were subsequently provided dietary oils with various levels of alpha linolenic acid (ALA) and linoleic acid (LA) for 8 weeks, as follows to  (g ALA to LA per 100 g oil) to  canola/flax (20 to 18), canola (8 to 18), soy (9 to 53), high oleic canola/canola (5 to 16), high-oleic canola (2 to 15), lard/soy (1 to 8), and safflower (0.2 to 73). The model developed obesity, glomerulomegaly, proteinuria, and scarce glomerular damage with an indolent course. Morphometry and histology revealed glomerulomegaly as the first renal structural alteration. The utility of this marker as a predictor for the presence of ORG and renal injury was evidenced by its correlation to visceral adiposity, proteinuria, change in proteinuria, and glomerular damage. Renal triglyceride ALA to LA was strongly correlated with dietary ALA to LA, and inversely associated with mean glomerular volume. The diet induced obese model accurately represents early ORG, and implicates glomerulomegaly as an early surrogate diagnostic marker. Early intervention with ALA rich dietary oils slowed glomerular enlargement; these findings warrant further clinical investigation to promote optimal patient outcomes. (Authors abstract)

Obesity related glomerulopathy (ORG) is an emerging epidemic because of the rising global prevalence of obesity. It has been estimated that from 1986 to 2000, the incidence of ORG biopsies increased 10 fold. The most common clinical and histologic characteristics of ORG are hyperfiltration, proteinuria, glomerulomegaly, and often the presence of focal segmental glomerulosclerosis; these obesity associated alterations in renal structure and function can lead to renal insufficiency. The diet induced obese (DIO) animal model might provide an accurate representation of ORG because it mimics the development of human obesity, as evidenced by visceral obesity, hyperleptinemia, hyperinsulinemia, and dyslipidemia. Leptin is positively correlated to body fat, and is associated with the presence of ORG. Leptin can induce stimulators of ORG onset, including inflammation, oxidative stress, transforming growth factor (TGF) production, insulin like growth factor  minus 1 and 2, connective tissue growth factor, platelet derived growth factor induced modulation of growth, and increased hydrostatic pressure within the kidney. Dietary intervention for ORG with the n3 fatty acid alpha linolenic acid (ALA) might be a viable treatment option, as evidenced by its influence on disease progression in the later stages of other renal diseases. Dietary sources of ALA might be reno protective because they reduce inflammation, cytokine production, and macrophage infiltration. The purpose of this study was to investigate the utility of the DIO rat as a model of ORG, and to examine the influence of diets containing various levels of ALA, linoleic acid (LA), and ALA to LA ratios on ORG progression.

The data indicate that the DIO model presents with characteristics of early ORG, as seen in humans. In this model, DIO rats developed obesity, proteinuria, glomerulomegaly, and scarce glomerulosclerosis, and had an absence of increased serum creatinine, interstitial fibrosis, and tubular defects—all with an indolent course of progression. As obesity progressed in the DIO model, the presence of glomerulomegaly increased, and appeared as the first indication of renal structural change before any significant indication of reduced renal function (increased serum creatinine) or glomerular or interstitial damage.  Using the DIO rat as a model of early ORG and glomerulomegaly as an indicator of the potential for further disease progression, the study provided evidence that dietary oils higher in ALA contributed to higher renal ALA to LA ratios, which are associated with renoprotection. The renal ALA to LA ratio was a stronger predictor of renoprotection than renal ALA levels. In contrast, dietary LA, renal LA, renal docosahexaenoic acid, and the level of dietary fat (25 per cent  vs. 55 per cent energy) did not appear to significantly influence renal pathology. The ALA to LA ratios that might be protective in ORG fall within the recommendations. However, the percentage of energy as ALA would be considerably higher than the current recommended intake, yet achievable with the addition, for example, of approximately 1.25 tablespoons of flax oil or 6.5 tablespoons of canola oil per day, based on a 2000 kilocalorie diet.  Thus, for future clinical trials, the creation of a 1 to 2 ALA to LA ratio and 4.4 per cent of total calories as ALA could be easily achieved with the use of ALA rich dietary oils.

In conclusion, this study provides evidence that further investigation of ORG can be facilitated with the DIO experimental model. Glomerulomegaly is a robust surrogate marker for the presence of early ORG and ORG progression, as shown in this model, and might be diagnostically useful in the clinical setting.  Dietary manipulation of ALA and LA intake was renoprotective in this model, and merits further exploration as a potential treatment for patients with early ORG. (Editors comments)