Step 1 · Renal

Nephron Transport

Name: Nephron Transport
Creator: Veli Bakalov, MD

Segment by segment: the transporters, the diuretics that block them, and the medullary gradient

Renal·Physiology·5 min read·9 high-yield points·Reviewed by Veli Bakalov, MD @HemeOncBuddy

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The PCT reabsorbs ~65% of filtered Na⁺ and water isotonically, all glucose and amino acids, most HCO₃⁻ (carbonic anhydrase, NHE3), and most phosphate (PTH blocks phosphate reabsorption → phosphaturia).
Glucose is reabsorbed by SGLT2 with a transport maximum: glucosuria starts above ~200 mg/dL and transporters saturate (Tm ~375 mg/min) near 350–375 mg/dL; splay reflects nephron heterogeneity.
The thin descending limb is water-permeable only (concentrates filtrate); the thick ascending limb (NKCC2) is water-impermeable, the diluting segment, and its lumen-positive potential drives paracellular Ca²⁺ and Mg²⁺ reabsorption.
Loop diuretics block NKCC2 and increase Ca²⁺ excretion (hypercalcemia therapy); thiazides block NCC in the early DCT and decrease Ca²⁺ excretion (stone prevention).
Principal cells: aldosterone drives ENaC, Na⁺/K⁺-ATPase, and ROMK (Na⁺ retention, K⁺ and H⁺ secretion); ADH acts on V2 receptors to insert aquaporin-2 and raise urea permeability.
α-Intercalated cells secrete H⁺ (H⁺-ATPase) and reabsorb HCO₃⁻ and K⁺.
Spironolactone/eplerenone block the aldosterone receptor and amiloride/triamterene block ENaC; both are K-sparing and risk hyperkalemia.
Countercurrent multiplication (TAL single effect + hairpin loop) builds a medulla up to ~1200 mOsm; vasa recta countercurrent exchange and urea recycling preserve it.
Inulin TF/P rises along the nephron (marks water removal); Na⁺ TF/P stays ~1.0 in the PCT; TF/P below 1 means the solute is reabsorbed faster than water.

The proximal tubule: bulk reabsorption

"65% plus everything." The proximal convoluted tubule (PCT) reabsorbs ~65% of filtered Na⁺ and water isotonically, all filtered glucose and amino acids, most HCO₃⁻, and most phosphate. The apical Na⁺/H⁺ exchanger (NHE3) drives much of this: secreted H⁺ combines with filtered HCO₃⁻, luminal carbonic anhydrase converts it to CO₂ and water that enter the cell, and intracellular carbonic anhydrase regenerates HCO₃⁻ for return to blood. Angiotensin II stimulates NHE3, and PTH inhibits phosphate reabsorption here, causing phosphaturia. The PCT also secretes organic acids and bases, including PAH and many drugs.

Glucose transport maximum. Glucose enters PCT cells by Na⁺-coupled SGLT2, a carrier with a transport maximum (Tm). Glucosuria begins once plasma glucose exceeds ~200 mg/dL (the threshold), and all transporters saturate (Tm ~375 mg/min) near 350–375 mg/dL. The gradual bend between the two ("splay") reflects nephron heterogeneity. SGLT2 inhibitors (the -gliflozins) block this carrier to cause deliberate glucosuria.

~200 mg/dLPlasma glucose at which glucosuria begins

~375 mg/minGlucose Tm: all transporters saturated

~1200 mOsmMaximal medullary (and urine) osmolality

TF/P ratios. The tubular fluid/plasma concentration ratio tracks handling along the tubule. Inulin TF/P rises steadily because water is reabsorbed and inulin is left behind, so it marks water removal. Na⁺ TF/P stays ~1.0 in the PCT because reabsorption there is isotonic. A TF/P below 1 (glucose, amino acids, HCO₃⁻ in the early PCT) means the solute is reabsorbed faster than water.

Fanconi syndrome. Generalized PCT failure produces glucosuria with normal plasma glucose, aminoaciduria, phosphaturia, and bicarbonaturia (proximal renal tubular acidosis).

Loop of Henle and the medullary gradient

Two limbs, opposite permeabilities. The thin descending limb is permeable to water only, so filtrate concentrates as it descends into the hyperosmotic medulla. The ascending limb is impermeable to water but reabsorbs solute, so it dilutes the filtrate.

Thick ascending limb (TAL). The Na⁺-K⁺-2Cl⁻ cotransporter (NKCC2) reabsorbs ~25% of filtered Na⁺ without water, making the TAL the "diluting segment." K⁺ leaks back into the lumen through ROMK, creating a lumen-positive potential that drives paracellular reabsorption of Ca²⁺ and Mg²⁺. Loop diuretics (furosemide) block NKCC2 and abolish that potential, so Ca²⁺ and Mg²⁺ are wasted, which is why a loop diuretic plus IV fluids treats hypercalcemia.

Countercurrent multiplication. Active NaCl transport by the TAL into the interstitium (the "single effect"), repeated along the loop's hairpin geometry, multiplies a small horizontal gradient into a large vertical one: the medullary interstitium reaches up to ~1200 mOsm at the papilla. The hairpin vasa recta preserve the gradient by countercurrent exchange, and urea recycling from the inner medullary collecting duct adds to it.

TAL pumps NaCl outThe single effect
Medulla turns hyperosmoticUp to ~1200 mOsm
Descending limb loses waterFiltrate concentrates
ADH opens AQP2Concentrated urine

Building and using the medullary gradient

Loop diuretics wash out the medullary gradient, impairing both urine concentration and dilution.

Distal tubule and collecting duct

Distal convoluted tubule (DCT). The early DCT reabsorbs ~5% of filtered Na⁺ with Cl⁻ through the Na⁺-Cl⁻ cotransporter (NCC) and is impermeable to water, diluting the filtrate further. PTH stimulates Ca²⁺ reabsorption here. Thiazides block NCC; the fall in intracellular Na⁺ enhances basolateral Na⁺/Ca²⁺ exchange, so Ca²⁺ reabsorption rises and urinary Ca²⁺ falls (hypocalciuria), which helps prevent calcium stones.

Principal cells. They reabsorb Na⁺ through ENaC, secrete K⁺ through ROMK, and reabsorb water through aquaporin-2. Aldosterone inserts and activates ENaC, the basolateral Na⁺/K⁺-ATPase, and ROMK, producing Na⁺ (and water) retention with K⁺ and H⁺ secretion; excess causes hypokalemia and metabolic alkalosis. ADH (vasopressin) binds V2 receptors (Gs → cAMP), inserting aquaporin-2 to concentrate the urine, and raises inner medullary urea permeability to strengthen the gradient.

α-Intercalated cells. They secrete H⁺ through an apical H⁺-ATPase and reabsorb HCO₃⁻ and K⁺ (H⁺/K⁺-ATPase), completing urinary acidification.

The filtrate's journey

Segment	Key transporters	Water permeability	Job and regulation
PCT	NHE3, SGLT2, carbonic anhydrase	High (isotonic)	~65% Na⁺; all glucose and amino acids; most HCO₃⁻
Thin descending limb	Aquaporin-1	High	Water out; filtrate concentrates
Thick ascending limb	NKCC2, ROMK	None	~25% Na⁺; dilutes; builds gradient; paracellular Ca²⁺, Mg²⁺
Early DCT	NCC	None	~5% Na⁺; PTH-driven Ca²⁺ reabsorption
Collecting duct	ENaC, ROMK, AQP2; H⁺-ATPase	ADH-dependent	Fine-tuning of Na⁺, K⁺, H⁺, water by aldosterone and ADH

Diuretics and their inherited mimics

One drug, one transporter. Loop and thiazide diuretics deliver extra Na⁺ to the collecting duct, where ENaC reabsorption drives K⁺ and H⁺ secretion; together with volume-driven aldosterone release, this explains their hypokalemia and metabolic alkalosis. K-sparing diuretics act at the collecting duct itself, so they retain K⁺ instead.

The diuretic map

Diuretic	Site	Target	Characteristic effects
Acetazolamide	PCT	Carbonic anhydrase	HCO₃⁻ diuresis, hyperchloremic metabolic acidosis
Mannitol	PCT, descending limb	Osmotic (holds water in lumen)	Used for ↑ ICP; risk of pulmonary edema
Loop (furosemide)	TAL	NKCC2	↑ Ca²⁺ and Mg²⁺ excretion; hypokalemia; ototoxicity
Thiazides	Early DCT	NCC	↓ Ca²⁺ excretion; hypokalemia, hyponatremia, hyperglycemia, hyperuricemia
Spironolactone, eplerenone	Collecting duct	Aldosterone receptor	Hyperkalemia; gynecomastia (spironolactone)
Amiloride, triamterene	Collecting duct	ENaC	Hyperkalemia

Calcium separates the two big diuretics: loops raise urinary Ca²⁺ (hypercalcemia therapy), thiazides lower it (stone prevention).

Inherited mimics. Bartter syndrome (NKCC2 or related TAL defects) looks like chronic loop diuretic use: hypokalemia, metabolic alkalosis, hypercalciuria. Gitelman syndrome (NCC defect) looks like thiazide use: hypokalemia, metabolic alkalosis, hypocalciuria, and hypomagnesemia. Liddle syndrome, a gain-of-function ENaC mutation, is the reverse of amiloride: hypertension, hypokalemia, and metabolic alkalosis with low aldosterone, treated with amiloride.