Tubular biomarkers:Insights into fluid-electrolyte disorders and kidney disease

Chronic kidney disease (CKD) affects approximately 9% of the global population and is a major risk factor for cardiovascular morbidity and mortality. Current CKD staging relies on glomerular markers such as estimated glomerular filtration rate (eGFR) and albuminuria, while tubular damage, an independent predictor of kidney failure, remains underrecognized. This thesis investigates tubular biomarkers as tools to better understand kidney physiology, kidney disease progression, and cardiovascular risk, with a primary focus on urinary prostaglandin E2 (PGE2) and epidermal growth factor (EGF). In the first part of this thesis, we examined the role of PGE2 in water and electrolyte homeostasis. Using a kidney tubule-specific EP3 knockout mouse model, we found no evidence for a major role of tubular EP3 in water or sodium handling. In a population-based cohort, higher urinary PGE2 and its metabolite PGEM were associated with lower serum sodium levels, particularly among thiazide users, supporting a role for PGE2 in water reabsorption and hyponatremia. Furthermore, across CKD patients, the general population, and healthy volunteers receiving potassium loading, higher plasma potassium concentrations were consistently associated with higher urinary PGE2 and PGEM excretion, providing novel evidence for a role of PGE2 in kaliuresis and suggesting its potential relevance in hyperkalemia risk assessment. In the second and third parts, we evaluated tubular biomarkers in the general population and in autosomal dominant polycystic kidney disease (ADPKD). In participants of the Rotterdam Study, a general population cohort, higher urinary PGE2 and PGEM excretion were independently associated with incident CKD, faster eGFR decline, and increased cardiovascular and all-cause mortality. Lower urinary EGF excretion reflected reduced tubular mass, was associated with hypertension and lower serum magnesium, and predicted incident CKD. In patients with autosomal dominant polycystic kidney disease (ADPKD), higher urinary PGE2 and PGEM excretion were associated with more severe disease and faster progression, while phosphate wasting independently predicted adverse renal outcomes. Together, these findings highlight the clinical relevance of tubular biomarkers in kidney physiology, CKD progression, and ADPKD, supporting their potential role in risk stratification and therapeutic targeting.