tubular secretion

**Definition:** Movement of solutes from peritubular capillary blood across the tubular epithelium into the lumen. Excretion = Filtration − Reabsorption + Secretion.

**Sites and key transporters** - **Proximal tubule (S2/S3 segments):** - *Organic anion transporters (OAT1/OAT3, basolateral; MRP2/URAT, apical)* secrete weak acids: penicillins, cephalosporins, loop and thiazide diuretics, NSAIDs, salicylates, methotrexate, uric acid, PAH. - *Organic cation transporters (OCT2 basolateral; MATE1/2-K, P-gp apical)* secrete weak bases: creatinine (partly), cimetidine, trimethoprim, dopamine, choline, procainamide, metformin, cisplatin. - **Distal nephron:** - *Principal cells* secrete K+ (via ROMK and BK channels), driven by aldosterone and increased distal flow/Na+ delivery. - *Alpha-intercalated cells* secrete H+ (H+-ATPase, H+/K+-ATPase), which generates new HCO3−. This is the basis of acid–base regulation and ammonium excretion. - *Proximal tubule* also secretes H+ through the Na+/H+ exchanger (NHE3).

**Clinical significance and high-yield associations** - **Clearance concepts:** If clearance > GFR (inulin), net secretion occurs. PAH is filtered and nearly completely secreted, so PAH clearance ≈ effective renal plasma flow (~600–700 mL/min). Creatinine is slightly secreted, so creatinine clearance slightly overestimates GFR. Trimethoprim and cimetidine block creatinine secretion, raising serum creatinine without a true GFR change. - **Drug interactions (competition for transporters):** - *Probenecid* inhibits OAT, which reduces penicillin secretion and prolongs its half-life. It also reduces urate secretion, which is why it is a uricosuric at high doses. - *Cilastatin* inhibits renal dipeptidase, so it is not a secretion inhibitor. It protects imipenem from metabolism. - *Methotrexate* toxicity increases with NSAIDs, penicillins, and probenecid. - *Loop and thiazide diuretics* must be secreted into the lumen to reach their luminal targets (NKCC2, NCC). Reduced secretion in CKD or with competing organic acids (NSAIDs) blunts the diuretic response. - **Uric acid:** Handled by filtration, reabsorption, secretion, and post-secretory reabsorption. Low-dose salicylates and lactate or ketoacids (via competition) decrease urate secretion and cause hyperuricemia. - **Potassium:** - Hyperaldosteronism, loop and thiazide diuretics, and high distal flow increase K+ secretion, causing hypokalemia. - Spironolactone, amiloride, triamterene, and trimethoprim reduce K+ secretion, causing hyperkalemia. - **Acid–base:** Type 1 (distal) RTA is a defect in alpha-intercalated cell H+ secretion. It causes a non-anion gap metabolic acidosis with urine pH >5.5, hypokalemia, and calcium phosphate stones. Type 4 RTA (hypoaldosteronism) causes decreased K+ and H+ secretion, leading to hyperkalemia. - **Weak acid/base trapping:** Alkalinizing urine with bicarbonate traps weak acids (salicylates, phenobarbital) in the lumen. Acidifying urine (e.g., with ammonium chloride) enhances excretion of weak bases (amphetamines, PCP). - **Saturation:** Secretion is carrier-mediated, so it shows a transport maximum (Tm) and can be saturated or competitively inhibited. - **Age:** Tubular secretory capacity is immature in neonates, so doses of renally secreted drugs (e.g., penicillins) are lower, and it declines with age.

**Memory aids:** "PAH is secreted, inulin is not." "Probenecid Prolongs Penicillin." Secreted weak acids and bases are handled by separate transporter families (OAT vs OCT).