Ketogenic Diet and Progression of Kidney Disease in Animal Models of Nephropathic Cystinosis

Background: Nephropathic cystinosis is a rare inherited lysosomal storage disorder caused by mutations in the CTNS gene that encodes for cystinosin, a lysosomal cystine/H + symporter. From the standpoint of the kidneys, patients develop early-onset renal Fanconi syndrome and progressive chronic kidney disease. Current therapy with cysteamine delays but does not prevent kidney failure, and has significant side effects that limit adherence and reduce the quality of life of patients. Methods: We have tested biochemically and histologically the effects of ketogenic diet on kidney disease of two animal models of nephropathic cystinosis. Results: When Ctns -/- mice were fed with ketogenic diet from 3 to 12 months of age, we observed significant nearly complete prevention of Fanconi syndrome, including low molecular weight proteinuria, glycosuria and polyuria. Compared to wild-type animals, BUN at 12 months was higher in cystinotic mice fed with standard diet (P<0.001), but not with ketogenic diet. At sacrifice, kidneys of knock out mice fed with ketogenic diet appeared macroscopically similar to those of wild type animals, which was reflected microscopically by a significant reduction of interstitial cell infiltration (CD3 and CD68 positive cells, P<0.01), of interstitial fibrosis (Masson and α-SMA staining, P< 0.001), and of apoptosis (cleaved caspase 3 levels; P<0.001), and by indirect evidence of restoration of a normal autophagic flux (SQSTM1/p62 and LC3-II expression, P<0.05). Beneficial effects of ketogenic diet on tubular function were also observed after mice were fed with this ketogenic diet from the age of 6 months to the age of 15 months, after they had developed proximal tubular dysfunction. Although slightly less pronounced, these results were replicated in Ctns -/- rats fed with ketogenic diet from 2 to 8 months of life. Conclusions: These results indicate significant mitigation of the kidney phenotype in cystinotic animals fed with ketogenic diet.