Renin-Angiotensin-Aldosterone System (RAAS)😊

Lactic Acidosis

Types of Lactic acidosis	Notes
Type A	• Hypoperfusion / hypoxia Examples • Shock • Cardiac failure • Severe anemia • Carbon monoxide toxicity • Cyanide toxicity
Type B	• metabolic causes with normal oxygenation Examples • Malignancy • Renal failure • Hepatic failure • Drugs: metformin, ethanol, ethylene glycol, methanol • Diabetes mellitus • Seizures • Severe malaria / cholera

Renin-Angiotensin-Aldosterone System (RAAS)

• Initiated: In response to low BP.

Clinical Relevance:

• Overactive RAAS → Hypertension

• Treatment of HTN:
• ACE inhibitors

• Direct renin blockers: 
• Aliskiren (blocks renin directly).

Calculation of GFR

Cockcroft and Gault Equation

• Creatinine clearance = (140 - Age) x Body weight x 0.8 (if female)
  72 x S. creatinine

Problems with Cockcroft and Gault Equation

Advantages of CKD-EPI and MDRD Equations

• Calculate GFR directly.

• Use standardized methods for creatinine estimation.

• Based on isotope dilution mass spectroscopy.

• Have replaced weight with race in calculations.

Erythropoietin Source

• Note:
• Renin → JG cells
• Erythropoietin → Peritubular capillary cells

Clearance

Urinary Amount =

• Filtration + Secretion - Reabsorption.

Problems with Creatinine

• More muscle mass = more creatinine.
• Not dependent on obesity.

• Time gap between AKI and Creatinine rise
• 24 to 48 hours

• Overestimates GFR.

• Physiologically, rise after 40 years

• False ↑↑ when using drugs like trimethoprim and cimetidine
• Compete with Creatinine for tubular secretion

Other markers

Graphs Illustrating Nephron Handling

Clearance Sequence (Highest → Lowest):

• PAH > Creatinine > Inulin > Urea > Sodium/Potassium > Glucose.

• PCI → UCN → HGA

Inulin Clearance

• Filtration Rate = GFR = 125 ml/min
  Plasma Concentration

Substances

Secretion of Para-Amino Hippuric Acid (PAH)

• 1. Early part of excretion:
• Curve is more steep.
• Involves both Filtration + secretion.

• 2. Late part of excretion:
• Curve becomes less steep.
• Only Filtration.

Saturation of SGLT-2 (Glucose Reabsorption)

Maximum transport capacity (TmG) of SGLT-2

• At 200 mg/dL of plasma glucose
• 375 mg/min of glucose is reabsorbed.

• Saturation occurs.

• Excess glucose is excreted (glycosuria).

Splay

• Occurs due to:
• Diverse/heterogeneous nephrons.
• Each nephron has different TmG.

• Causes early appearance of glucose in urine before actual TmG.

Graph: TF/P Ratio vs Proximal Tubule Length

• TF/P = Tubular Fluid / Plasma concentration ratio

Key Concepts

Water Reabsorption and ADH Action

Mechanism of ADH Action (on collecting duct cells):

• Most potent stimulus for ADH secretion.
• Plasma osmolality > 280 mOsm/L

• MOA
• Acts on collecting duct cells → bind V2 receptors.
• Activate V2 receptor (basolateral) → ↑ cAMP
• ↑↑ cAMP → AQP2-containing vesicles fuse with luminal membrane → water enters cell from tubular lumen

• Water exits to blood via AQP3/AQP4 (basolateral, constitutive, not ADH-regulated).

Diabetes Insipidus

ㅤ	Central/Neurogenic DI	Nephrogenic DI
ADH secretion	Low plasma ADH	ㅤ
ADH action	ㅤ	↓↓ [d/t mutation of V2 receptor gen]
ADH injection	Reduces urine volume.	• Does not reduce urine volume. • Urine osmolality remains low

Countercurrent System

Kidney mechanism

• Countercurrent multiplication → Loop of Henle

• Countercurrent exchange → Vasa recta

Requirements (4):

1. Two parallel tubes

2. Opposite flow

3. Close proximity

4. Selective permeability

Other countercurrent systems (MCQ-relevant):

• True countercurrent:
• Kidney (Loop of Henle)
• Testes (Pampiniform plexus)
• Intestinal villi
• Skin (heat exchange)

• Not true countercurrent:
• Lungs → Crosscurrent
• Liver

Medullary Hyperosmolarity

• Medullary Hyperosmolarity
• Enables ADH-dependent water reabsorption in collecting ducts

• Note
• highest osmolality with
• Inner medulla
• Longer LOH (up to 1200 mOsm).

ㅤ	Long LOH	Short LOH
Includes	Juxtamedullary nephron,  Cortical nephron.	ㅤ
%	15%	85%
Role	Responsible for concentration & dilution of urine	ㅤ

ADH (Vasopressin)

• Receptor: V2 receptors (Basolateral membrane of CD).

• Mechanism: ↑ cAMP → ↑ Expression of Aquaporin 2 (Luminal membrane).

• Result: Reabsorption of salt-free water utilizing medullary hyperosmolarity.

1. Medullary Hypertonicity

2. Loop of Henle: Countercurrent Multiplier

• Input: Isotonic fluid (300 mOsm/L) from PCT

• Function: Concentrates and dilutes urine

• Note: Outer medullary osmolality remains 290 mOsm.

3. Vasa Recta: Countercurrent Exchanger

• Structure: Blood vessels running alongside LOH.

• Mechanism: Acts as a countercurrent exchange system.

• Urea Role:
• Maintain interstitial osmolality created by LOH.
• Reabsorbed from inner medullary collecting duct.
• Recycled via Vasa Recta.

4. Collecting Duct (CD)

• Water Reabsorption:
• H2O exits to medulla via AQP2-4.
• Regulated by ADH.

• Urea Reabsorption:
• Occurs in Inner Medulla.
• Moves to interstitium via UT-A1.

5. Urea recycling:

• Goal: Keeps Urea within medullary interstitium to maintain high osmolality gradient.

Step	Location	Transporter
Entry	Descending limb of Vasa Recta	UT-B
Exit	Ascending limb of Vasa Recta	UT-B
Re-entry	Thin Descending Limb of LOH	UT-A2

Filtration Fraction

Ion Reabsorption

Note

• Hormone Responsible for Calcium absorption
• PTH and Vit D → Upregulate TRPV 5 in DCT

• Ion responsible for Calcium and Magnesium (Divalent ions)
• K+ → Ascending LOH

Bartter Syndrome

• AR inheritance

• Defect:
• Na⁺-K⁺-2Cl⁻ cotransporter (TAL of LoH) OR
• Barttin channel

• Consequences:
• Polyuria, salt wasting
• ↑Ca²⁺ excretion → Nephrocalcinosis
• Activation of RAAS →↑ Na+, H2O reabsorption → Normal/low BP
• Hypokalemic hypochloremic metabolic alkalosis

Reabsorption in PCT

Proportional Reabsorption of Filtered Substances

Chloride (Cl⁻) Reabsorption:

• Cl⁻ ↑↑ in concentration in lumen
• Due to preferential Na⁺ absorption in the early PCT.

• Cl⁻ is reabsorbed in the later parts of the PCT.

Class	MOA & Site	Enzyme	Effects
Carbonic Anhydrase Inhibitors /	PCT	Block carbonic anhydrase (Fanconi) ↳ Fanil acid ozhich ↳ Hypokalemic Metabolic acidosis	Acidazolomide ↳ Sulfa drug ↳ Hypokalemia ↳ Acidosis (HCO₃⁻ loss)
Loop Diuretics	TAL	Block Na+-K+-2Cl- pump/ Chloride channel (Barttin) (Bartter syndrome)	Loop diuretics → all low • Hyponatremia • Hypokalemia • Gout • Hypochloremia • Hypocalcemia • Indirect vasodilators ↳ (↑ prostaglandins). Hypokalemic hypochloremic metabolic alkalosis + ↑Ca²⁺ excretion (Nephrocalcinosis)
Thiazides	DCT	Block Na-Cl cotransporter (Gitelman syndrome) Gitel man → Gita maggy (magnesium) undakk	• Hyponatremia • Hypokalemia • Gout • Postural Hypotension • Hyperglycemia • Hypercalcemia • Hypomagnesemia • Direct vasodilators ↳ open K+ channels Hypokalemic metabolic alkalosis + Hypomagnesemia
Osmotic Diuretics	PCT & loop	Solute-free water loss	ㅤ
Potassium-Sparing Diuretics	ㅤ	ㅤ	ㅤ
Spironolactone/ Eplerenone:	CD	Block aldosterone.	• Hyponatremia • Hyperkalemia • Gynecomastia
Amiloride	CD	Blocks ENaC (Liddle syndrome) ↳ SCNN1B/G genes ↳ AD inheritance ↳ Little Hypertensive	• Hyponatremia • Hyperkalemia • Alkalosis + HTN

Mnemonic: FABulous Glittering Liquid

• Gordon
• Opp of Gitelman

• Psudo-hypoaldosteronism
• Opp to Liddle

Cystometrogram

Aquaporins

Applied Aspect

Vaptans (conivaptan): 

• Vasopressin receptor blockers
• ↑↑ pure water excretion in urine.

Vasopressin escape

• In SIADH

• Kidney escapes ADH effect by downregulation of Aqp-2.

Factors Affecting ADH Secretion

• ↑↑ ADH Secretion 
• Painful stimuli
• Nausea and vomiting
• ↑ osmotic pressure
• ↓ ECF volume

• ↓↓ ADH Secretion
• Alcohol (inhibits ADH)
• ↓ osmotic pressure
• ↑ ECF volume

Actions Mediated by Vasopressin Receptors

Free Water Clearance

Natriuretic Peptides

Aldosterone escape:

• Kidneys escape effect of aldosterone in hyperaldosteronism.

• ↑↑ aldosterone → ↑↑ Na+ & H2O reabsorption → ↑↑ BP
• but no edema
• d/t ANP: Pressure diuresis

Aldosterone

• t½: 20 mins.

Site 1: Primarily in Principal Cell (CD)

• Collecting duct

• Aldosterone acts on Mineralocorticoid Receptor (MR)
• MR (Inactive) → Aldosterone binding → Active MR → ↑↑ activity of

Specific Channels	Function
ENaC	↑ Na⁺ reabsorption
ROMK (Renal Outer Medullary K⁺ channel)	↑ K⁺ secretion
Na⁺-K⁺ ATPase (basolateral membrane):	Pumps 3 Na⁺ out and 2 K⁺ into the cell → maintaining gradient.

• Overall: Na⁺ reabsorption & K⁺ secretion.

Site 2: Type A Intercalated Cell (DCT)

• ↑ H⁺ secretion via H⁺-ATPase

• Overall: H⁺ secretion and HCO₃⁻ reabsorption ⇒ Metabolic alkalosis

MR sites:

• Kidneys, colon, hippocampus, salivary glands, sweat glands.

Factors Regulating Aldosterone Synthesis

• Hyperkalemia → Stimulates aldosterone release.

• ACTH → Increases aldosterone transiently.

Intercalated cells

Dominant Cell	Site	Process	Result
Type A intercalated	• DCT	A Attract B H⁺ secreted, HCO₃⁻ reabsorbed	In Acidosis → ↑ plasma HCO₃⁻
Type B intercalated	• Late DCT • Cortical collecting duct	B Repel B H⁺ reabsorbed, HCO₃⁻ secreted	In Alkalosis → ↓ plasma HCO₃⁻ (excreted)

Bicarbonate Excretion

• Proximal Tubule (85%)
• via Na⁺/H⁺ exchanger (NHE3)

• Type B intercalated cells
• Actively secrete HCO₃⁻ via pendrin
• Pendrin = major transporter for HCO₃⁻ excretion.