We have generated a mouse model with an ADTKD disease-causing UMOD mutation, that displays: defective uric acid excretion; urinary concentrating defects; renal failure; defective uromodulin trafficking, maturation and secretion; renal fibrosis; interstitial immune cell infiltration; and ER stress with upregulation of the UPR in the TAL. Here, UMOD is linked to autosomal dominant medullary cystic kidney disease with or without hyperuricemia.