#4592 A HIGH PROTEIN DIET INDUCES DEPRESSION-LIKE BEHAVIOR IN CKD RODENT MODELS
Authors: Lauriola Mara , Dejongh Sander , Farré Ricard , Meijers Björn 
Published: June 2023

Abstract

Background and Aims
The prevalence of depression among patients with Chronic Kidney Disease (CKD) is higher than the general population. Around 21-27% of CKD patients is estimated to be affected by depression. Several studies hypothesized that mood disorders may be due to reduced family support, older age, low educational status and low quality of life. However, adults with CKD are also known to exhibit altered tryptophan metabolism causing reduced plasma levels of tryptophan and elevated kynurenine and kynurenic acid. Moreover, CKD patients show increased levels of indoxyl sulfate and indole-3-acetic acid, two protein-bound uremic toxins deriving from the gut microbiome metabolism of tryptophan. We postulate that depression is not just due to reduced quality of life but also to a biological reason. In addition, we hypothesize that a high protein diet may influence tryptophan metabolism and therefore affect depression symptoms.

Method
Eighteen Sprague-Dawley male rats (Janvier, Le Genest- St Isle, France), 7-8 weeks old, were induced with CKD utilizing 5/6 nephrectomy and were randomly assigned to a low protein (n = 10) or a high protein (n = 8) diet. A sham-operated control group for each diet was used (n = 7 respectively). The splash test was adopted to assess depressive symptoms in rats. In short, the splash test is a behavioral test consisting in sprinkling a 10% sucrose solution on the dorsal coat of a rat. Latency (time before the initiation of grooming) and duration of grooming were recorded for 5 min and used as an indication of self-care behavior. Delayed and reduced grooming is considered as a depression-like behavior of rats. Blood and urine creatinine were determined with standard laboratory techniques. Total plasmatic concentrations of tryptophan, kynurenine, kynurenic acid and indoxyl sulfate were measured using LC-MS/MS.

Results
The latency before the starting of the grooming behavior was significantly higher (p = .0499) in CKD rats on a high protein diet compared to sham rats on the same diet while no difference was seen between the low protein groups. CKD rats reported significantly higher plasma levels of indoxyl sulfate and kynurenic acid and reduced tryptophan. Interestingly, kynurenic acid plasma levels were significantly reduced when administering a low protein diet to CKD rats (p = .0025). Among CKD rats, the latency to the grooming behavior was correlated with plasmatic levels of creatinine clearance (Spearman r = -.57, p value = .019), indoxyl sulfate (Spearman r = .64, p value = .007), and kynurenic acid (Spearman r = .63, p value = .009). The total grooming time was shorter in both CKD groups compared to the sham rats, but not significantly (p = .4881 and p = .4312, respectively).

Conclusion
These results suggest that biological factors contribute to depression onset and that the decline of kidney function and the accumulation of uremic toxins are potential risk factors for depression. Dietary interventions such as a low protein diet, are potential strategies to lower the plasmatic levels of uremic toxins which may alleviate depressive-like symptoms.