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Foundational Sciences · Physiology
Renal Physiology: Nephron Transport & Clearance
A Step 1-focused walk through nephron segment transport (transporters, % Na⁺ reabsorbed, diuretic sites) and the clearance framework (GFR, RPF, FF, TF/P, glucose titration, free-water clearance), tied to the hormonal loops and channelopathies the boards test. Emphasis on the exact numbers, curves, and mechanism-to-disease correlations.
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The nephron as a reabsorption assembly line
The kidneys filter roughly 180 L/day and excrete only ~1.5 L — meaning ~99% of filtrate is reclaimed, segment by segment. Every apical transporter you must know is ultimately powered by the basolateral Na⁺/K⁺-ATPase, which keeps intracellular Na⁺ low and drives secondary-active transport at the lumen.
Organize the tubule into three jobs:
- Bulk isosmotic reabsorption — the proximal convoluted tubule (PCT) reclaims ~2/3 of everything.
- Building the medullary gradient — the loop of Henle separates salt from water (countercurrent multiplier).
- Fine, hormone-tuned adjustment — the distal convoluted tubule (DCT) and collecting duct set final Na⁺, K⁺, H⁺, Ca²⁺, and water.
Clearance is the quantitative overlay that converts a urine sample into whole-organ function — it tells you GFR, renal plasma flow, and exactly how each solute is handled.
Clearance & flow — the must-know numbers
- Clearance: C = (U × V) / P (mL/min) — the volume of plasma completely cleared of a substance per minute.
- Inulin clearance = GFR (freely filtered, neither reabsorbed nor secreted). Normal GFR ≈ 100–125 mL/min.
- Creatinine clearance slightly OVERestimates GFR — creatinine is minimally secreted by the PCT.
- PAH clearance = effective renal plasma flow (RPF) — filtered plus secreted (~90% cleared in one pass). eRPF ≈ 600 mL/min.
- RBF = RPF / (1 − Hct) ≈ 1000–1200 mL/min (~20–25% of cardiac output).
- Filtration fraction: FF = GFR / RPF ≈ 20%.
- Filtered load = GFR × plasma concentration. Net Excretion = Filtered − Reabsorbed + Secreted.
Nephron segments, transporters & diuretic sites
| Segment | Na⁺ reabsorbed | Key apical transporter | H₂O permeable? | Drug / target |
|---|---|---|---|---|
| PCT | ~65–67% | NHE3 (Na⁺/H⁺), SGLT2 (glucose), Na-Pᵢ, Na-AA | Yes (isosmotic) | Acetazolamide (carbonic anhydrase → HCO₃⁻ loss) |
| Thin descending limb | — | passive H₂O efflux; solute-impermeable | Very high | Mannitol (osmotic) |
| Thick ascending limb (TAL) | ~25% | NKCC2 (Na-K-2Cl) | Impermeable | Loop diuretics (furosemide); "diluting segment" |
| Early DCT | ~5% | NCC (Na-Cl); TRPV5 (PTH-driven Ca²⁺) | Impermeable | Thiazides |
| Collecting duct | ~3–5% | ENaC (principal, aldosterone); AQP2 (ADH) | ADH-dependent | Amiloride (ENaC), spironolactone (aldo R) |
TF/P ratios, the glucose curve & free-water clearance
TF/P (tubular fluid / plasma) ratios track handling along the tubule:
- TF/P inulin rises to ~3 by the end of the PCT because inulin isn't reabsorbed — as ~67% of water leaves, its concentration triples. Formula: TF/P inulin = 1 / (fraction of water remaining).
- [TF/P]ₓ ÷ [TF/P]inulin = fraction of filtered X remaining. If this ratio < 1, X was net reabsorbed; > 1, net secreted.
- TF/P Na⁺ ≈ 1.0 through the PCT (reabsorption is isosmotic).
Glucose titration curve (classic Step 1 graph):
- Filtered load = GFR × plasma glucose. Below threshold, reabsorption (SGLT2) matches filtration → no glucosuria.
- Threshold ≈ 200 mg/dL; transport maximum (Tm) ≈ 375 mg/min (saturation).
- Splay = glucosuria appears before Tm because nephrons are heterogeneous and the transporter's affinity is low.
- Pregnancy lowers the threshold (↑GFR) → benign glucosuria.
Free-water clearance: C_H₂O = V − C_osm, where C_osm = (U_osm × V) / P_osm.
- Positive C_H₂O = dilute urine / net water excretion (water loading, diabetes insipidus).
- Negative C_H₂O = concentrated urine / net water conservation (dehydration, ADH acting, SIADH).
Glomerular hemodynamics — arterioles set GFR, RPF & FF
- Afferent constriction (e.g., NSAIDs block vasodilatory prostaglandins): ↓GFR, ↓RPF, FF ~ unchanged.
- Efferent constriction (Angiotensin II, physiologic dose): ↑GFR, ↓RPF, ↑FF.
- Efferent dilation (ACE inhibitors / ARBs): ↓GFR, ↑RPF, ↓FF → can precipitate acute kidney injury in bilateral renal artery stenosis.
- ↑Plasma oncotic pressure (dehydration/hypergammaglobulinemia): ↓GFR. ↓Plasma protein: ↑GFR. Ureteral obstruction (↑Bowman hydrostatic): ↓GFR.
- ↑FF → ↑peritubular oncotic pressure → ↑PCT Na⁺/H₂O reabsorption (basis of AT II–driven Na⁺ retention).
- Autoregulation keeps GFR/RBF nearly constant over MAP ~80–180 mmHg via the myogenic reflex + tubuloglomerular feedback (macula densa senses ↑NaCl → adenosine → afferent constriction).
Hormones acting on the nephron
| Hormone | Site | Action |
|---|---|---|
| Aldosterone | Principal + α-intercalated cells (CD) | Principal: ↑ENaC + Na⁺/K⁺-ATPase → Na⁺ reabsorption & K⁺ secretion; α-intercalated: ↑H⁺-ATPase → H⁺ secretion |
| ADH (vasopressin, V2) | Collecting duct | Inserts AQP2 → water reabsorption; ↑urea reabsorption (UT-A1) in medullary CD |
| PTH | PCT + DCT | PCT: inhibits Na-Pᵢ → phosphaturia, ↑1α-hydroxylase; DCT: ↑Ca²⁺ reabsorption (TRPV5) |
| Angiotensin II | PCT + efferent arteriole | ↑NHE3 (Na⁺/HCO₃⁻ reabsorption, "contraction alkalosis"); constricts efferent → ↑FF |
| ANP / BNP | Afferent + efferent art., CD | Dilates afferent and constricts efferent → ↑GFR; inhibits Na⁺ reabsorption & renin → natriuresis |
Tubular channelopathies = "built-in diuretics"
Mechanism → vignette. Each inherited defect mimics a diuretic acting at that segment.
- Bartter syndrome — loss of NKCC2 / ROMK / ClC-Kb in the TAL = "congenital loop diuretic." Childhood onset: hypokalemic metabolic alkalosis + hyperCalciuria (± nephrocalcinosis), normal-to-low BP.
- Gitelman syndrome — loss of NCC in the DCT = "congenital thiazide." Milder/later: hypokalemic metabolic alkalosis, HYPOcalciuria, HYPOmagnesemia, normal BP.
- Liddle syndrome — ENaC gain-of-function (channel stuck open): unregulated Na⁺ retention → HTN, hypokalemia, metabolic alkalosis, but LOW renin AND LOW aldosterone. Treat with amiloride/triamterene (block ENaC directly) — spironolactone won't work.
- Contrast: Conn (primary hyperaldosteronism) gives the same electrolytes but HIGH aldosterone with low renin; AME (apparent mineralocorticoid excess) — 11β-HSD2 deficiency or licorice — lets cortisol activate the mineralocorticoid receptor → identical picture with low aldosterone.
ADH disorders — reading water handling
ADH sets collecting-duct water permeability (AQP2). Follow serum Na⁺, urine osmolality, and free-water clearance.
- Central DI (no ADH) vs Nephrogenic DI (V2 receptor unresponsive — lithium [most common], hypercalcemia, hypokalemia, demeclocycline): both → dilute urine, high free-water clearance, hypernatremia/polyuria. Water-deprivation + desmopressin (DDAVP): urine osmolality rises with DDAVP in central DI, fails to rise in nephrogenic DI.
- SIADH — inappropriate ADH → water retention → euvolemic hyponatremia with inappropriately concentrated urine (high U_osm, negative free-water clearance). Causes: small cell lung carcinoma, CNS disease, drugs (carbamazepine, SSRIs, cyclophosphamide). Correct hyponatremia slowly to avoid osmotic demyelination syndrome.
- Bonus PCT vignette: generalized proximal failure = Fanconi syndrome → glucosuria (with normal serum glucose), aminoaciduria, phosphaturia, type 2 (proximal) RTA. Causes: Wilson disease, multiple myeloma, tenofovir, expired tetracyclines, lead.
High-yield mnemonics (the real ones)
- Calcium & diuretics: "Loops Lose calcium (hyperCalciuria); thiaZides hold on (hypoCalciuria)." → thiazides treat Ca²⁺ stones & osteoporosis; loops treat hypercalcemia.
- Bartter vs Gitelman: Bartter hits the loop — higher up, more severe, hypercalciuria (like a loop diuretic). Gitelman = Gentler, DCT/thiazide-like, hypocalciuria + low Mg²⁺.
- Liddle → aMILoride: "Liddle loves amiLoride" — block ENaC directly (spironolactone fails).
- ADH = "Add Water" — V2 → aquaporins → water reabsorption.
- SGLT2 = "sweet pee" — SGLT2 inhibitors ("-gliflozins") deliberately cause glucosuria.
- Tracers: "PAH = Plasma flow (RPF); inulin = filtration (GFR)."
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