The Oxalate-Kidney-Brain Axis: Calcium Oxalate Crystal Nephropathy as a Hidden, Treatable Cause of Dilutional Hyponatremia and DSM-5 Mimicking Neuropsychiatric Syndromes

Abstract: DSM-5 criteria for autism spectrum disorder (ASD) and schizophrenia-spectrum disorders are purely syndromal and biomarker-free, creating diagnostic heterogeneity and missed treatable etiologies. We synthesize evidence that chronic low-grade calcium-oxalate nephropathy in genetically or metabolically susceptible “stone-formers” impairs renal free-water excretion, producing dilutional (euvolemic) hyponatremia. Even mild, fluctuating hyponatremia disrupts cerebral osmolyte balance and glutamate signaling, generating fatigue, social withdrawal, cognitive fog, sensory hypersensitivity, repetitive behaviors, and psychosis-like phenomena that fulfill DSM-5 thresholds. This oxalate-kidney-brain axis integrates (1) established hyperoxaluria in ASD cohorts (plasma oxalate 3-fold elevated), (2) crystal-induced tubulointerstitial injury and fibrosis, (3) documented impairment of urinary dilution in tubulointerstitial disease, (4) bidirectional hyponatremia–stone risk (persistent hyponatremia OR 6.25), and (5) clinical reports of hyponatremia inducing organic brain syndromes indistinguishable from primary psychiatric illness. Simple, low-cost interventions—low-oxalate diet, oxalate-degrading probiotics (e.g., Oxalobacter formigenes or engineered strains), potassium citrate, and serial sodium monitoring—could be trialed immediately. Positive response would represent a paradigm shift from lifelong psychotropics to metabolic root-cause correction in a definable subset of patients. We provide a testable screening protocol and call for rapid prospective studies. Keywords: oxalate nephropathy, dilutional hyponatremia, autism spectrum disorder, schizophrenia, calcium oxalate stones, tubulointerstitial nephritis, metabolic psychiatry, glutamate-oxalate axis