Renal and Acid Base

Transport Mechanisms

Glomerular filtration, renal blood flow and clearance

Glomerular filtration rate (GFR)

GFR is the volume of filtrate formed by both kidneys per minute.

• Typical adult value: approximately 125 mL/min, or about 180 L/day.
• GFR depends on the net filtration pressure and the filtration coefficient (\(K_f\)).
• The filtration barrier restricts cells and most large proteins while allowing water and small solutes to pass.

The Simplified GFR Equation

Filtered Load

Dehydration

Regulation of water balance

• Osmoreceptors and thirst: detect changes in plasma osmolality and stimulate thirst/ADH responses.
• ADH (vasopressin): increases water permeability in collecting ducts through V2 receptors and aquaporin-2 insertion.
• RAAS: promotes Na⁺ retention and helps preserve extracellular volume and blood pressure.
• ANP/BNP: promote natriuresis and oppose excessive volume expansion.

Clinical fluid-shift patterns

Clinical correlation: Primary adrenal insufficiency can produce hypotension, hyponatremia, hyperkalemia and metabolic acidosis due to deficient aldosterone, alongside cortisol deficiency.

Kidney Anatomy

Nephron overview

The nephron is the functional unit of the kidney. It filters plasma, reabsorbs useful substances, secretes selected solutes and produces urine.

Renal blood supply

Renal circulation follows this general sequence:

Renal artery → segmental arteries → interlobar arteries → arcuate arteries → cortical radiate arteries → afferent arterioles → glomerular capillaries → efferent arterioles → peritubular capillaries or vasa recta → venous drainage.

Remember: The glomerulus is unusual because it lies between two arterioles.

• Afferent arteriole: brings blood into the glomerulus.
• Efferent arteriole: carries blood away from the glomerulus.
• Peritubular capillaries: support reabsorption and secretion, particularly around cortical nephrons.
• Vasa recta: supply juxtamedullary nephrons and preserve the medullary osmotic gradient.

Juxtaglomerular apparatus (JGA)

The JGA regulates GFR and systemic blood pressure through tubuloglomerular feedback and renin release.

Tubuloglomerular feedback

1. Increased NaCl delivery to the macula densa indicates relatively high tubular flow/GFR.
2. Signals cause afferent arteriolar constriction.
3. Glomerular capillary pressure and GFR decrease toward baseline.
4. Low NaCl delivery tends to promote afferent dilation and renin release.

The JGA therefore helps stabilize filtration despite changes in systemic pressure.

Renal clearance

Clearance is the hypothetical volume of plasma completely cleared of a substance per unit time.

Clearance markers

Important distinction: Creatinine clearance is clinically convenient, but inulin clearance is the classic reference method for measuring GFR.

Filtration, reabsorption and secretion

• Filtration: blood → tubular lumen.
• Reabsorption: tubular lumen → blood.
• Secretion: blood → tubular lumen.
• Excretion: the final amount appearing in urine.

Fractional excretion

Fractional excretion (FE) is the percentage of a filtered substance that is ultimately excreted.

Segmental tubular transport

Transport maximum and renal threshold

Glucose handling: Normally, filtered glucose is reabsorbed in the PCT. When the filtered load exceeds tubular reabsorptive capacity, glucose appears in urine.

Segment-by-segment transport table

Proximal convoluted tubule (PCT)

• Reabsorbs roughly 65–70% of filtered Na⁺ and water under usual conditions.
• Reabsorbs nearly all filtered glucose and amino acids under normal plasma conditions.
• Reabsorbs most filtered bicarbonate.
• Secretes H⁺, organic acids/bases and many drugs.
• Reabsorption is largely iso-osmotic: water follows solute.

Exam tip: The PCT is the major site of bulk reabsorption.

Loop of Henle

Descending limb

• Highly permeable to water.
• Relatively less permeable to NaCl.
• Water leaves the tubule into the increasingly hyperosmotic medulla.
• Tubular fluid becomes more concentrated.

Thick ascending limb

• Reabsorbs Na⁺, K⁺ and 2Cl⁻ through the NKCC2 cotransporter.
• Is essentially impermeable to water.
• Dilutes tubular fluid while contributing to the medullary osmotic gradient.
• The lumen-positive electrical potential supports paracellular Ca²⁺ and Mg²⁺ reabsorption.

Remember: The thick ascending limb is the diluting segment.

Early distal convoluted tubule

• Reabsorbs NaCl through the NCC cotransporter.
• Is relatively impermeable to water.
• Participates in calcium balance; PTH increases calcium reabsorption.

Late distal tubule and collecting duct

Two major cell types regulate final electrolyte and acid-base composition.

Aldosterone increases Na⁺ reabsorption and K⁺ secretion, while promoting H⁺ secretion in appropriate conditions.

ADH increases collecting-duct water permeability by inserting aquaporin-2 channels into the apical membrane of principal cells.

Urine concentration, dilution and free-water clearance

Countercurrent multiplication

The loop of Henle creates a corticomedullary osmotic gradient, allowing the kidney to produce concentrated urine when water conservation is required.

• The descending limb loses water.
• The thick ascending limb reabsorbs NaCl but not water.
• Repeated transport along the loop multiplies the small local osmotic differences into a large medullary gradient.

Countercurrent exchange

The vasa recta preserve the medullary gradient by exchanging water and solutes with the surrounding interstitium.

Difference to memorize:

Role of urea

• Urea recycling contributes to the high osmolarity of the inner renal medulla.
• ADH increases inner medullary collecting-duct permeability to urea.
• Urea moves into the medulla and can recycle through the loop of Henle, supporting urine concentration.

ADH and urine concentration

When plasma osmolality rises or effective circulating volume falls, ADH release increases.

1. ADH binds V2 receptors on collecting-duct principal cells.
2. Gs activates adenylate cyclase.
3. cAMP and protein kinase A signaling promote aquaporin-2 insertion.
4. Water is reabsorbed down the medullary osmotic gradient.
5. Urine volume falls and urine becomes concentrated.

When ADH is low, collecting ducts remain relatively water-impermeable, allowing dilute urine to be produced.

Concentrated versus dilute urine

Free-water clearance

Free-water clearance estimates whether the kidney is excreting water in excess of solute or conserving water.

Clinical patterns

Exam tip: Central DI is due to inadequate ADH production/release; nephrogenic DI is due to renal resistance to ADH.

Renin–angiotensin–aldosterone system (RAAS)

RAAS sequence

1. Reduced renal perfusion, reduced NaCl delivery to the macula densa or sympathetic β₁ stimulation promotes renin release.
2. Renin converts angiotensinogen (from the liver) into angiotensin I.
3. ACE converts angiotensin I into angiotensin II.
4. Angiotensin II increases vascular tone and stimulates aldosterone release.

Major actions of angiotensin II

Aldosterone

Aldosterone acts mainly on principal cells of the late distal nephron and collecting duct.

• Increases ENaC activity and Na⁺/K⁺-ATPase expression/activity.
• Increases Na⁺ reabsorption.
• Increases K⁺ secretion.
• Can increase H⁺ secretion indirectly and through effects on intercalated cells.

Net effect: Sodium retention, expansion of extracellular volume and support of blood pressure, with increased urinary K⁺ loss.

Regulation of aldosterone

• Increased by: angiotensin II and elevated plasma K⁺.
• ACTH: has a smaller, generally permissive or transient effect.
• Decreased by: suppression of RAAS, including volume expansion and natriuretic signaling.

Pressure natriuresis

Increased arterial pressure promotes renal sodium and water excretion, helping oppose sustained increases in blood pressure.

• RAAS promotes sodium retention and supports blood pressure.
• ANP promotes natriuresis and vasodilatory effects, opposing excessive volume expansion.

ACE inhibitors: renal physiology connection

ACE inhibition reduces angiotensin II and aldosterone effects.

• Efferent arteriolar dilation reduces intraglomerular pressure.
• GFR may fall, particularly in patients dependent on angiotensin II to maintain filtration.
• Hyperkalemia can occur because aldosterone activity falls.

MCQ tip: ACE inhibitors can increase creatinine and potassium. Bilateral renal artery stenosis is a classic setting in which a significant fall in GFR may occur.

Electrolyte handling by the nephron

Sodium handling

The kidney filters a large amount of sodium daily and reabsorbs nearly all of it.

These percentages are approximate and vary with physiologic conditions.

Potassium balance

Potassium distribution is critical because changes in extracellular K⁺ affect membrane excitability, particularly in cardiac and skeletal muscle.

• Most body potassium is intracellular.
• The kidneys regulate long-term K⁺ balance.
• The PCT and thick ascending limb reabsorb much of the filtered K⁺.
• Final urinary K⁺ excretion is regulated mainly by secretion in the distal nephron.

Calcium, phosphate and magnesium

Urea

• Filtered at the glomerulus.
• Undergoes substantial tubular reabsorption and recycling.
• Contributes to medullary hyperosmolality and urine concentration.

Renal acid–base physiology

Normal blood pH

Normal arterial blood pH is approximately 7.35–7.45.

The bicarbonate buffer system is central to extracellular acid-base regulation.

Major buffer systems

How the kidneys regulate pH

The kidneys maintain acid-base balance through three main processes:

1. Reabsorbing filtered bicarbonate.
2. Secreting H⁺ into tubular fluid.
3. Generating new bicarbonate while excreting net acid, mainly as ammonium and titratable acid.

Important: Reclaiming filtered bicarbonate prevents its loss; excreting net acid allows the body to add new bicarbonate to the blood.

Bicarbonate reabsorption

Most filtered bicarbonate is reclaimed in the PCT.

1. Tubular cells secrete H⁺ into the lumen.
2. H⁺ combines with filtered HCO₃⁻ to form carbonic acid.
3. Luminal carbonic anhydrase facilitates conversion to CO₂ and H₂O.
4. CO₂ enters the tubular cell.
5. Intracellular reactions regenerate HCO₃⁻, which returns to blood.

The secreted H⁺ is effectively recycled during this process; therefore, bicarbonate reclamation alone does not represent net acid excretion.

Ammonium and titratable acid

Intercalated cells

Minimum urine pH

The source highlights a minimum urine pH of approximately 4.5 under normal physiologic conditions. The kidney cannot excrete unlimited free H⁺ in urine; buffers such as phosphate and ammonia are essential.

Anion gap and metabolic acid-base disorders

Anion gap

The anion gap helps identify unmeasured anions, particularly in metabolic acidosis.

A commonly used normal range is approximately 8–12 mEq/L when potassium is excluded, although laboratory ranges vary.

High versus normal anion gap metabolic acidosis

Compensation rules

Compensation reduces the pH disturbance but does not generally return pH fully to normal. A value outside the expected compensation range suggests an additional primary disorder.

Classic acid-base scenarios

Renal tubular acidosis (RTA)

RTA refers to metabolic acidosis caused by impaired renal acid handling, typically with a normal anion gap.

MCQ tip: Hyperkalemia strongly points toward type 4 RTA in the appropriate clinical setting.

Diuretics

Sites of action

Diuretic memory cues

• PCT: carbonic anhydrase inhibitors.
• Thick ascending limb: loop diuretics.
• Early DCT: thiazides.
• Collecting duct: potassium-sparing drugs.

Remember: Loop diuretics inhibit NKCC2; thiazides inhibit NCC. These are different transporters in different nephron segments.