Together, these data support that MANF upregulation in ER-stressed TAL cells is indispensable for maintaining autophagic activity, and that loss of MANF in mutant TALs exacerbates autophagy inhibition and mutant UMOD accumulation, further intensifying kidney injury in ADTKD-UMOD. Here, UMOD is linked to autosomal dominant medullary cystic kidney disease with or without hyperuricemia.