University of Arkansas for Medical Sciences College of Medicine Little Rock, Arkansas, United States
Background: Genetic glomerulopathies such as Alport syndrome have limited treatment options and typically progress to advanced chronic kidney disease (CKD). Impaired renal function leads to systemic bioaccumulation of indoxyl sulfate and other uremic toxins. Observational studies have linked indoxyl sulfate with the development of CKD-related cardiovascular disease, and elevated plasma indoxyl sulfate concentration predicts CKD progression in children. The effect of indoxyl sulfate on the progression of kidney disease due to Alport syndrome has not been investigated. Objective: The objective of this research study was to test the hypothesis that indoxyl sulfate exposure accelerates the progression of CKD and development of CKD-related cardiovascular disease in a mouse model of Alport syndrome. Design/Methods: Male and female Col4a3 knockout (Col4a3KO) mice were exposed to indoxyl sulfate via administration of the toxin in drinking water starting at 4 weeks of age. Weight and urine albumin/creatinine ratio were measured weekly. At 8 weeks of age, mice were euthanized for measurement of BUN and evaluation of renal pathology using standard histologic techniques. Cardiac size and histology were also evaluated. Survival analysis was used to assess the effect of indoxyl sulfate exposure on mortality. Results: In female Col4a3KO mice, indoxyl sulfate exposure led to slower weight gain. However, there was no effect on albuminuria, biochemical markers of kidney function, renal histopathology, or survival. Male Col4a3KO mice exposed to indoxyl sulfate had elevated BUN at 8 weeks of age compared to unexposed controls (108.9 +/- 8.1 mg/dL vs 73.3 +/- 19.4 mg/dL; p = 0.02), which was associated with more severe renal histopathology. Cardiac sized was also increased in indoxyl sulfate exposed 8-week-old Col4a3KO males compared to unexposed controls (6.4 +/- 0.4 mg/g vs 5.4 +/- 0.7 mg/g; p = 0.04). However, there was no difference in weight gain or severity of albuminuria. Overall, indoxyl sulfate exposure led to a reduced lifespan in male Col4a3KO mice compared to controls (survival time of 62 +/- 6 days vs 71 +/- 3 days; p = 0.04)
Conclusion(s): Indoxyl sulfate exposure leads to more severe renal disease and may contribute to the development of cardiovascular disease in male Col4a3KO mice, whereas females appear to be largely protected from the deleterious effects of this uremic toxin.
