Comprehensive Renal Physiology Study Notes

Kidney Functions: General Overview

• Maintains overall homeostasis by controlling:

  • Volume of extracellular & intracellular fluid

  • Fluid osmolality

  • Acid–base balance

  • Electrolyte concentrations

  • Removal of metabolic wastes & xenobiotics

• Endocrine roles:

  • Converts vitamin D to its active form (calcitriol)

  • Synthesizes erythropoietin (EPO) & renin

• Excretes specific ions/substances: \text{H}^+,\;\text{NH}_4^+,\;\text{K}^+,\;\text{uric acid}

• About \dfrac{1}{5} of renal blood flow is filtered through glomeruli

Vitamin D Metabolism in the Kidney

• Circulating 25-hydroxy-vitamin D (calcidiol) bound to DBP enters renal cortex

• Two competing enzymes in proximal tubule mitochondria:

  • 1-α-hydroxylase → 1,25-(OH)_2D (calcitriol) when \text{PTH} is high / [\text{Ca}^{2+}] is low

  • 24-hydroxylase → 24,25-(OH)_2D when calcitriol levels are high (negative feedback)

• Excess calcitriol further catabolised to 1,24,25-(OH)_3D and finally calcitroic acid for urinary excretion

Erythropoietin Production

• Hypoxia → pericytes in renal cortex/outer medulla ↑EPO gene expression

• Drives hematopoietic stem-cell differentiation toward erythroid lineage:

  • BFU-E → CFU-E (EPO-dependent) → pro-, basophilic, polychromatophilic, orthochromatophilic erythroblasts → reticulocytes → mature RBCs

• Transcription factors: GATA-1, KLF-1 promote erythroid genes; PU.1 antagonises erythropoiesis

Long-Term Arterial Pressure Control: Renal–Body Fluid System

• Fundamental concept: arterial pressure is determined by intersection of renal output curve & extracellular fluid volume

• Sequence when ECFV ↑:

  1. ↑Blood volume → ↑Mean circulatory filling pressure → ↑Venous return

  2. ↑Cardiac output (CO) → autoregulation ↑total peripheral resistance (TPR)

  3. ↑Arterial pressure → kidneys ↑urinary output (pressure diuresis) → returns volume & pressure to baseline

• Graphically, renal output curve intersects vascular function curve to establish steady-state \text{MAP}

Autoregulation of GFR & RBF

• GFR ≈ 125\;\text{mL/min} = 180\;\text{L/day} remains constant over physiological pressures (~80-180 mmHg)

• Key feedback components:

  • Juxtaglomerular apparatus (macula densa + JG cells + extraglomerular mesangium)

  • Regulation of afferent & efferent arteriolar resistance

Juxtaglomerular Apparatus (JGA)

• Macula densa (late thick ascending limb/early DCT):

  • Senses tubular \text{NaCl} & flow; detects low pressure via mechanosensors; β-adrenergic sensitive

• Juxtaglomerular (granular) cells (afferent/efferent arteriole walls):

  • Store & release renin; modified smooth muscle

• Extraglomerular mesangial cells: relay signals between macula densa & arterioles

• Stimuli & responses:

  • Low \text{NaCl}, low BP, or sympathetic (β-1) → afferent vasodilation + renin release → ↑GFR & RAAS activation

Renin–Angiotensin–Aldosterone System (RAAS)

• Cascade:
  \text{Angiotensinogen (liver)}\xrightarrow{\text{Renin (kidney)}}\text{Ang I}\xrightarrow{\text{ACE (lung/endothelium)}}\text{Ang II}

• Ang II actions:

  • Potent arteriolar vasoconstriction (esp. efferent) → ↑TPR & GFR maintenance

  • Stimulates adrenal zona glomerulosa → aldosterone

  • Enhances sympathetic activity & central thirst

  • Promotes ADH release from posterior pituitary

• Overall: water & sodium retention → ↑ECFV → ↑MAP

Aldosterone

• Secreted from adrenal cortex (zona glomerulosa) via Ang II, high [\text{K}^+], ACTH, stress

• Cellular effects in late DCT & cortical collecting duct:

  1. ↑Na⁺/K⁺-ATPase activity (basolateral)

  2. ↑ENaC & ROMK channel expression (luminal)

  • Plasma: ↑[\text{Na}^+], ↓[\text{K}^+] → water follows Na⁺ → ↑blood volume

  • Urine: ↓Na⁺, ↑K⁺, ↓volume

• Secondary effects: stimulates ADH, augments BP, contributes to gluconeogenesis & anti-inflammatory actions (via cortisol crossover)

Antidiuretic Hormone (ADH / Vasopressin)

• Released from posterior pituitary (supraoptic/paraventricular nuclei) in response to ↑plasma osmolality or ↓BP

• Binds V2 receptors on principal cells (late DCT & collecting ducts) → inserts aquaporin-2 channels → ↑water reabsorption

• Permits independent control of water vs. solute excretion → crucial for osmolarity regulation

Sympathetic Regulation

• Afferent & efferent arterioles richly innervated; norepinephrine & epinephrine:

  • Constrict arterioles

  • Stimulate β-1 receptors on JG cells → renin release

  • Net ↓GFR during severe activation (e.g., hemorrhage) + Na⁺ retention

Macroscopic Kidney Anatomy

• Cortex: outer layer; contains corpuscles, PCT/DCT, peritubular capillaries; site of ultrafiltration & EPO production

• Medulla: pyramids; hypertonic; loops of Henle & collecting ducts create concentration gradient; high O₂ consumption (~80 % reabsorbed here)

• Papilla (apex) empties urine into minor calyces; NSAID toxicity → papillary necrosis

• Blood supply (arterial): renal → segmental → interlobar → arcuate → interlobular → afferent arteriole → glomerulus → efferent arteriole → peritubular/vasa recta

Nephron Numbers & Types

• ~1\,000\,000 nephrons per kidney; non-regenerative

• Cortical nephrons: short loops; majority

• Juxtamedullary nephrons: long loops; vital for concentration via countercurrent multiplier

Glomerular Filtration

• Filtration barrier: fenestrated endothelium + negatively charged basement membrane + podocyte slit diaphragms

• Pressures (typical):

  • P_G (glomerular hydrostatic) ≈ 60\;\text{mmHg}

  • \pi_G (oncotic) ≈ 32\;\text{mmHg}

  • P_B (Bowman’s capsule) ≈ 18\;\text{mmHg}

  • Net filtration: PG - (\piG + P_B) = 10\;\text{mmHg}

• Filtrate resembles plasma minus large proteins (albumin repelled by negative charge)

• Plasma volume filtered ~60× daily

Proximal Convoluted Tubule (PCT)

• Reabsorbs ~65\% of filtered load; processes are iso-osmotic

• Substances reabsorbed nearly completely: glucose, amino acids, lactate

• Major transporters:

  • Luminal SGLT 1/2 (Na⁺-glucose co-transport)

  • Basolateral Na⁺/K⁺-ATPase drives secondary active transport

• Transport Maximum for glucose (TmG): \approx 375\;\text{mg/min} (plasma ~180 mg/dL → glucosuria beyond)

• Threshold ≠ Tm (heterogeneity among nephrons)

Loop of Henle & Countercurrent Multiplier

• Descending thin limb: permeable to \text{H}_2\text{O}; impermeable to solutes → filtrate becomes hyperosmotic

• Ascending limb (thin & thick):

  • Impermeable to water

  • Reabsorbs NaCl (NKCC2, Na⁺/K⁺-ATPase) → dilutes tubular fluid; raises medullary interstitium osmolarity (up to 1200\;\text{mOsm/L})

• Establishes corticomedullary gradient; vasa recta (countercurrent exchanger) preserves gradient

Distal Convoluted Tubule (DCT)

• Early DCT (“diluting segment”): further NaCl reabsorption via NCC; impermeable to water; macula densa present

• Late DCT & cortical collecting duct:

  • Principal cells: aldosterone-sensitive Na⁺ reabsorption & K⁺ secretion; ADH-regulated water permeability

  • Intercalated cells: \text{H}^+ secretion (alpha) & \text{HCO}_3^- secretion (beta) → acid-base balance

• By end of DCT, ~99\% of solutes reabsorbed (under normal hormone levels)

Medullary Collecting Duct

• Permeable to water only in presence of ADH

• Urea transporters (UT-A1/3) recycle urea → augments medullary gradient

• Secrete \text{H}^+; reabsorb \text{HCO}_3^- → final urine acidification

Tubular Secretion

• Occurs mainly in PCT & DCT for organic acids/bases, H⁺, K⁺, creatinine, drugs (e.g., penicillin)

• Allows rapid elimination of foreign substances even when protein-bound in plasma

Waste Products & Metabolic Pathways

• Urea: from hepatic urea cycle (carbamoyl-phosphate synthetase, OTC, ASS, ASL, arginase) → filtered & partially reabsorbed/recycled

• Creatinine:

  • Derived from creatine/phosphocreatine (AGAT in kidney; GAMT in liver)

  • Constant non-enzymatic conversion (~1.6 %/day) → excretion ~14.6\;\text{mmol/24 h}; useful GFR marker (slight secretion)

• Bilirubin: heme → biliverdin → bilirubin → conjugated by UGT1A1 → bile → intestinal urobilinogen → stercobilin (feces); minimal renal excretion unless conjugated bilirubin elevated

Urine Formation Equation

\text{Excretion} = \text{Filtration} - \text{Reabsorption} + \text{Secretion}

• Filtration at glomerulus → reabsorption/secretion along tubules → excretion via papilla → calyces → pelvis → ureter → bladder → urethra

Solute Concentration Principles

• If water reabsorption > solute → tubular solute concentration ↑ (e.g., inulin, creatinine)

• If solute reabsorption > water → tubular solute concentration ↓ (e.g., glucose, amino acids)

Key Numbers, Formulas & Definitions

• Normal GFR categories (CKD staging):

  • G1 \ge 90, G2 = 60-89, G3a = 45-59, G3b = 30-44, G4 = 15-29, G5 < 15\;\text{mL/min/1.73 m}^2

• Mean arterial pressure (simplified): BP = PR \times CO (or BP = TPR \times CO)

• Filtration fraction ≈ \dfrac{GFR}{RPF} \approx 0.2

• Plasma volume filtered/day ≈ 3\;\text{L} \times 60 = 180\;\text{L}

• Medullary osmotic gradient: cortex \approx 300\;\text{mOsm/L} → inner medulla \approx 1200\;\text{mOsm/L}

Clinical & Pharmacological Connections

• NSAID-induced papillary necrosis due to medullary ischemia

• ACE inhibitors/ARBs: ↓Ang II → efferent dilation → ↓GFR; renoprotective in proteinuric CKD

• SGLT2 inhibitors (e.g., empagliflozin): block proximal Na-glucose co-transport → glucosuria, natriuresis, ↓hyperfiltration

• Diuretics act at specific nephron segments (loop, thiazide, K⁺-sparing, carbonic anhydrase inhibitors)

Ethical & Practical Implications

• Early CKD detection via GFR & albuminuria prevents progression

• Balance of RAAS blockers vs. renal perfusion critical in elderly/dehydrated

• EPO misuse in sports → polycythemia & thrombotic risk

Summary Flow of Urine Formation

1. Filtration: glomerulus → Bowman’s space

2. PCT: bulk iso-osmotic reabsorption

3. Loop of Henle: countercurrent multiplier; sets gradient

4. DCT: fine-tuning of ions; macula densa feedback

5. Collecting ducts: hormonal control of water & urea; acid-base regulation

6. Excretion: papilla → calyces → pelvis → ureter → bladder → urethra

(End of notes)