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L3 Renal Physiology 2

Renal Physiology Lecture 2: Nephron Processes — Extraction

This lecture covers how the nephron processes blood to make urine, working through the four functional segments in sequence. It starts with glomerular filtration (the barrier, the driving forces, and how filtration rate is measured and regulated), then moves to the renal blood supply and its intrinsic and extrinsic control, and finishes with tubular handling (reabsorption versus secretion, the routes solutes take across the epithelium, and the segment-specific roles of the proximal tubule, loop of Henle, distal tubule, and collecting duct).

Division of Labour in the Nephron

  • The four segments each do a distinct job: glomerulus filters, proximal tubule does bulk reabsorption, distal tubule fine-tunes electrolytes, collecting duct fine-tunes water reabsorption.
  • A fifth concept added later: the loop of Henle puts salt into the medulla to create the gradient that drives water movement in the collecting duct. Fit this into the sequence above.
  • The core problem reabsorption solves: about 180 L/day is filtered but only about 1.5 L/day of urine is produced, so reabsorption (plus some secretion) recovers nearly everything.

Glomerular Filtration: What Happens

  • Glomerular filtration is a specialised ultrafiltration, with roughly 100x the permeability of normal capillaries, producing a plasma-like filtrate.
  • Know the what/from/via/to: filtered = plasma water and small solutes; retained = blood cells and proteins; from the glomerular capillary lumen, via the filtration barrier, to Bowman’s capsule.
  • Molecular weight cut-offs: around 100,000 (uncharged) and 70,000 for negatively charged molecules. Understand why the negative cut-off is lower (charge repulsion, see barrier below).
  • Scale of filtration: about 180 L/day, or 125 mL/min.

The Glomerular Filtration Barrier (three layers)

  • Know the three layers in order and what each contributes:
    • Fenestrations of glomerular capillary endothelial cells: act as a size barrier.
    • Basement membrane (shared by capillary and podocytes): carries negative charge, which restricts proteins.
    • Filtration slits between podocyte foot processes: size-selective via the slit diaphragm (nephrins).
  • Understand: filtration is both size-selective and charge-selective, and the two properties come from different layers.

Forces Driving Filtration

  • Filtration is determined by the pressure gradient between glomerular capillary and Bowman’s space, the permeability of the capillary, and its surface area.
  • Kf (ultrafiltration coefficient) bundles permeability and surface area, and is about 100x that of systemic capillaries.
  • Know the Starling equation as applied here: Net filtration pressure = glomerular hydrostatic pressure − Bowman’s capsule pressure − glomerular oncotic pressure.
  • Know the slide’s example values: 60 − 18 − 32 = 10 mmHg net filtration pressure.
  • Understand the renal vessel pressure profile: pressure stays high through the glomerular capillaries (favouring filtration) and drops sharply across the efferent arteriole.
  • GFR = amount of fluid filtered across the glomerulus per unit time; typically 180 L/day or 125 mL/min.
  • It is tightly regulated (intrinsic and extrinsic), varies between people, is expressed as about 70 mL/min per 1.73 m² body surface area, and declines slowly from age 30. Single-nephron GFR (SNGFR) is given as 60 nL/min.
  • Know the derived quantities:
    • Renal plasma flow (RPF) = RBF × (1 − Hct), estimated with PAH.
    • Filtration fraction = GFR/RPF, about 20%.
    • Filtered load = GFR × plasma concentration of the solute.
    • Clearance = UV/P, which indicates how the kidney handles a substance and can be calculated for any substance.

Clearance to Estimate GFR

  • Understand the logic: if a substance is filtered but neither reabsorbed nor secreted, then amount filtered = amount excreted, so GFR × P = U × V, which rearranges to GFR = UV/P = clearance.
  • Creatinine fits this well enough to estimate GFR via creatinine clearance. Inulin is better but must be injected.

Renal Blood Supply

  • Know the magnitudes: 20 to 25% of cardiac output (compare brain 13%, heart 4%); 1 to 1.2 L/min, roughly 400 mL/100g/min; 90% goes to cortex, 1% to inner medulla.
  • The high flow is for filtration, not for the kidney’s own metabolic demand.
  • Know the vascular sequence: renal artery, afferent arteriole, glomerular capillaries, efferent arteriole, peritubular capillaries, renal vein.
  • Understand why glomerular capillaries sit between two arterioles: this maintains high pressure for filtration and allows easy control of flow by adjusting either arteriole.

Autoregulation (Intrinsic Control)

  • Purpose: keep RBF and GFR relatively constant across a range of blood pressures. Understand the autoregulation curve: RBF and GFR are roughly flat over a mid-range of mean arterial pressure.
  • Two mechanisms:
    • Myogenic: stretch of vascular smooth muscle causes it to contract.
    • Tubuloglomerular feedback via the macula densa.
  • Understand the direction of effects in tubuloglomerular feedback:
    • Less NaCl reaching the distal tubule → less NaCl into macula densa cells → afferent vasodilation → raises GFR. Angiotensin II adds efferent constriction (the efferent is most sensitive), also raising GFR.
    • More NaCl at the distal tubule → afferent vasoconstriction → lowers GFR.
  • Understand the effect of constricting or dilating each arteriole on glomerular capillary pressure (PGC) and GFR: constrict afferent → lower PGC and GFR; constrict efferent → raise PGC and GFR; dilate efferent → lower PGC and GFR; dilate afferent → raise PGC and GFR.
  • Understand the negative-feedback loop diagram: a fall in arterial pressure lowers glomerular hydrostatic pressure and GFR, which lowers macula densa NaCl, raising renin and angiotensin II, which raises efferent resistance and lowers afferent resistance to restore glomerular pressure.

Extrinsic Control of Renal Blood Flow

  • This operates outside the range or capacity of autoregulation, and during systemic events such as cold and bleeding.
  • Know the listed mediators: sympathetic innervation, angiotensin II, prostaglandins, plus NO, endothelin, bradykinins, natriuretic peptides, glucocorticoids, adenosine, ATP, and arteriolar endothelial cells.
  • Sympathetic innervation: acts on afferent and efferent arterioles, minimal when ECF volume is normal, mainly α1 on the afferent, and reduces RBF and GFR.
  • Angiotensin II: acts systemically and locally, constricts both arterioles, with the efferent more sensitive (the “low dose” effect).
  • Prostaglandins: limited role at rest in health; produced locally during volume depletion, stress, SNS, and angiotensin II activity; they modulate SNS and AngII inputs to attenuate vasoconstriction and prevent renal ischaemia, and matter more with age. Understand the clinical link: NSAIDs inhibit prostaglandins and can cause renal ischaemia.

Tubular Handling: Reabsorption vs Secretion

  • All tubule segments reabsorb to varying degrees, and some also secrete.
  • Know the three classification groups:
    • Only reabsorbed (not secreted): glucose, water, Na⁺, Cl⁻, PO₄³⁻, Ca²⁺.
    • Only secreted (not reabsorbed): organic cations (monoamines such as dopamine and histamine, drugs such as morphine) and organic anions (endogenous compounds such as bile salts, drugs such as penicillin).
    • Both secreted and reabsorbed: K⁺, NH₃, H⁺, HCO₃, urea. Of these, the first four are regulated to homeostatic requirements while urea handling is not regulated.

Tubular Epithelium and Transport Routes

  • Know the epithelial features: variety of cell types, cells joined by tight junctions, microvilli (brush border) to increase surface area.
  • Know the orientation terms: apical side = tubule lumen (“urine side”); basolateral side = interstitium (“blood side”); plus the lateral interstitial spaces.
  • Understand the two transport routes:
    • Paracellular: between cells, a single barrier, no transport proteins, limited selectivity, permeability set by tight-junction “tightness.” This is the “leaky” bulk-reabsorption route (e.g. proximal tubule).
    • Transcellular: through cells, crossing two barriers (apical and basolateral), usually using membrane transport proteins, so highly selective and amenable to hormonal control.

Proximal Tubule

  • The main site of reabsorption (“bulk reabsorption”). Know the fractions: about 65% of sodium, water, and chloride; all filtered glucose; almost all amino acids; about 90% of K⁺, plus PO₄ and Ca; and half the urea. It also secretes organic acids, drugs, and H⁺.
  • Understand the Na⁺-driven mechanism: the basolateral Na-K-ATPase keeps intracellular Na⁺ low, so Na⁺ moves down its gradient into the cell at the apical side. Many solutes (glucose, amino acids) are coupled to this Na⁺ movement (secondary active transport). Reabsorption is partly paracellular and isosmotic, and transcellular reabsorption is driven by Na⁺ reabsorption.
  • Understand the glucose transport maximum (Tm): at normal filtered loads all glucose is reabsorbed and none appears in urine; when plasma glucose is high (e.g. diabetes) the filtered load exceeds reabsorptive capacity and glucose spills into the urine. Understand the renal glucose handling graph (filtered, reabsorbed, and excreted curves with the Tm plateau).
  • Understand bicarbonate handling: filtered HCO₃ is not directly reabsorbed; instead a new HCO₃ is synthesised in the tubule cell to replace the filtered ion, with H⁺ secreted at the same time.

Loop of Henle

  • Know the thick ascending limb properties: water-impermeable, with energy-dependent removal of NaCl (the NaK2Cl transporter) and urea from the filtrate.
  • Understand the consequence: this makes the medullary interstitium hyperosmotic (the hyperosmotic medullary gradient, HOMG) and leaves the filtrate dilute. Water is then reabsorbed in the collecting duct as required.

Distal Tubule and Collecting Duct

  • Function: fine-tune electrolytes, pH, and water. They reabsorb most of the remaining NaCl (about 10%) and water (about 15%), and secrete K⁺ and H⁺.
  • Know the hormonal control: sodium reabsorption by aldosterone, water reabsorption by ADH.
  • Understand the daily handling diagram: 180 L water and 27,000 mmol Na⁺ are filtered, progressively reduced through the segments, with the final 0.5 to 30 L water and about 200 mmol Na⁺ excreted depending on ADH and aldosterone.

Self-Test Checklist

  • Can you state which process each of the four (five) nephron segments performs?
  • Can you name the three filtration barrier layers and what each one selects for?
  • Can you write the net filtration pressure equation and plug in the slide’s values?
  • Can you define GFR, RPF, filtration fraction, filtered load, and clearance?
  • Can you derive GFR = UV/P from first principles, and explain why creatinine is used over inulin in practice?
  • Can you quote the renal blood flow figures and explain why flow is so high?
  • Can you explain both autoregulatory mechanisms and predict the effect on PGC and GFR of constricting or dilating each arteriole?
  • Can you walk through tubuloglomerular feedback in both directions?
  • Can you list the extrinsic mediators and explain the NSAID and renal ischaemia link?
  • Can you sort solutes into reabsorbed-only, secreted-only, and both?
  • Can you contrast paracellular and transcellular transport?
  • Can you state the proximal tubule reabsorption fractions and explain how Na⁺ drives the rest?
  • Can you explain the glucose Tm and why glucosuria appears in diabetes?
  • Can you explain how filtered bicarbonate is handled (and why it is not simple reabsorption)?
  • Can you explain how the loop of Henle creates the HOMG and why that matters for the collecting duct?
  • Can you state what aldosterone and ADH each control in the distal nephron?

Graph View