Renal Regulation and Acid-Base Balance

Renal Ion Regulation

Overview of Renal Ion Regulation

• Plasma Na⁺ Regulation
    - Regulation of plasma volume

• Plasma K⁺ Regulation
    - Influences cell excitability

• Plasma Ca²⁺ Regulation
    - Affects cell excitability & signaling

• Plasma HCO₃^- Regulation
    - Renal contribution to pH regulation

Regulation of Plasma Volume

• Long-term Regulation of Blood Pressure
    - Distribution of body H₂O between compartments is determined by the number of osmotically active particles (“osmolytes”).
    - Na⁺ and Cl^- are the major extracellular fluid (ECF) osmolytes.
    - Regulation of ECF volume is thus equivalent to the regulation of ECF Na⁺ content.
      - Passive movement of Cl^- ions follows the active transport of Na⁺ ions.
      - Water follows Na⁺ and Cl^- due to osmosis.
    - Changes in Na⁺ content within interstitial fluid (ISF) lead to changes in plasma Na⁺ content, consequently affecting plasma volume.
      - Since the plasma (vascular) compartment is in ionic equilibrium with ISF, regulation of Na⁺ content is achieved by monitoring plasma volume via low and high-pressure baroreceptors and ultimately controlling Na⁺ reabsorption in the cortical collecting duct.

Plasma Volume Control System

• Sensors:
    - High-pressure receptors located in large arteries.
    - Low-pressure receptors located in large veins & atria.
    - Juxtaglomerular apparatus (JGA) smooth muscle cells in kidneys.

• Integrator:
    - JGA smooth muscle cells.

• Effectors:
    - Principal cells in the cortical collecting duct.
    - Drinking and salt-eating behavior.

Juxtaglomerular Apparatus (JGA)

• Components:
    - Afferent arteriolar smooth muscle cells
    - Macula densa cells, which are specialized smooth muscle cells.
      - Secrete the enzyme renin, which senses tubular [NaCl] and signals locally to smooth muscle cells.

Renin-Angiotensin-Aldosterone System

• Rapid Change (secs/mins):
    - Increased plasma [renin] leads to:
      - Increased plasma [angiotensin II]
      - Increased plasma [aldosterone]
      - Increased plasma volume / Mean Arterial Pressure (MAP)
    - Angiotensin converting enzyme (ACE) inhibitors act here.

• Slow Change (hours):
    - Thirst mechanisms activated.

Plasma K⁺ Regulation

Importance of Plasma [K⁺]

• Plasma / ISF [K⁺] is the primary determinant of the resting membrane potential of excitable cells.
    - Normal ECF [K⁺] is approximately 4 mM.
    - Hyperkalemia: If plasma [K⁺] > 5.5 mM
      - Causes membrane depolarization of excitable cells.
      - Symptoms may include muscle spasticity, seizures, ventricular fibrillation, and ultimately death.
    - Hypokalemia: If plasma [K⁺] < 3.5 mM
      - Causes membrane hyperpolarization of excitable cells.
      - Symptoms may include muscle weakness, cardiac arrhythmias, and ultimately death.
    - Normal Range: Plasma [K⁺] is between 3.5 mM and 5.5 mM.

Renal Regulation of K⁺ Excretion

• An excess of K⁺ ions is usually present in the diet, necessitating the elimination of some K⁺.

• K⁺ is excreted by secretion into the cortical collecting duct.

• K⁺ secretion is regulated by the adrenal cortical hormone aldosterone.

Secretion Mechanism of K⁺ in Cortical Collecting Duct

• Outlines the cell structure involved:
    - Tubular lumen → Cortical collecting duct cells → Interstitial fluid
    - Mechanisms involve tight junctions, the basolateral membrane, and luminal membrane characteristics.
    - K⁺ leak channels allow for diffusion and are influenced by sodium channels for Na⁺.

Effects of Increased Potassium Intake

• Higher potassium intake leads to:
    - Increased plasma potassium, stimulating the adrenal cortex.
    - This results in increased aldosterone secretion; plasma [K⁺] has a direct effect on aldosterone-secreting cells.
    - Increased plasma aldosterone increases the number of Na/K pumps in the cortical collecting ducts, enhancing potassium secretion and excretion.

Plasma Ca²⁺ Regulation

Importance of Plasma [Ca²⁺]

• Ca²⁺ is critical for cell excitability and signal transduction.

• Normal plasma [Ca²⁺] is approximately 1 mM.

• Plasma [Ca²⁺] is sensed by parathyroid hormone (PTH) cells.

Effects of Ca²⁺ Levels

• Ca²⁺ levels are modulated by three target tissues (effectors):
    - Gut: Increases absorption of Ca²⁺ indirectly via calcitriol.
    - Bone: Influences deposition and resorption of Ca²⁺.
    - Kidney: Regulates calcium excretion.

Acid-Base Balance

Major Plasma Buffer System

• The main plasma buffer system is the H₂CO₃/HCO₃^- system with the following reaction:
    - $CO_2 + H_2O <br>ightleftharpoons H_2CO_3 <br>ightleftharpoons HCO_3^{-} + H^{+}$

• Carbonic anhydrase is an enzyme crucial for these reactions.

• Normal Mean Plasma pH: 7.40
    - pH < 7.35 indicates clinical acidosis.   - pH > 7.45 indicates clinical alkalosis.
    - Therefore, the normal pH range is between 7.35 – 7.45.

Renal Maintenance of Plasma HCO₃^-

• The kidneys maintain plasma [bicarbonate] by secreting H⁺ into the nephron lumen.

• In addition to eliminating CO₂, tissue metabolism produces H⁺ from non-volatile acids (e.g., lactic acid) necessitating further H⁺ secretion by kidneys.

HCO₃^- Regulation Process

1. Normally, all filtered HCO₃^- is reabsorbed from the filtrate by secreting H⁺ into the tubule.

2. When eliminating non-volatile acids, the kidneys secrete additional H⁺ into the tubule, producing new plasma HCO₃^-, which replaces the HCO₃^- consumed in buffering.

3. Metabolic Alkalosis: Kidneys eliminate excess HCO₃^-.

Quantifying Plasma pH Changes

• Henderson-Hasselbalch Equation:
    - $pH = pK + ext{log} rac{[HCO_3^{-}]}{[CO_2]}$

• Example calculation with known values:
    - $pH = 6.1 + ext{log} rac{24 mM}{(0.03 mM/mmHg) imes 40 mmHg} = 7.40$

Mechanism of HCO₃^- Reabsorption

• Involves:
    - Active transport driving the entire process facilitated diffusion.
    - Actions of players include apical H⁺ pumps and basolateral bicarbonate ion transporters facilitated by carbonic anhydrase.

Secretion Process for Additional H⁺

• This occurs when:
    - Plasma [HCO₃^-] decreases, triggering the diffusion of HCO₃^- into plasma and driving the overall process to enhance buffer capacity.

Acid/Base Imbalances

Identifying and Compensating for Imbalances

• Respiratory Acidosis (hypoventilation):
    - Compensated by increased H secretion by kidneys.
    - Characterized by PCO₂ > 40 mmHg.

• Respiratory Alkalosis (hyperventilation):
    - Compensated by decreased H secretion by kidneys.
    - Characteristics include PCO₂ < 40 mmHg.

• Metabolic Acidosis (various causes):
    - Compensated by increased H secretion by kidneys.
    - Compensated by hyperventilation, leading to PCO₂ < 40 mmHg.

• Metabolic Alkalosis (various causes):
    - Compensated by decreasing H secretion by kidneys.
    - Compensated by hypoventilation, leading to PCO₂ > 40 mmHg.

Diagnosing Acid/Base Imbalances

• Respiratory Acidosis: Indicates hypoventilation; confirmed by PCO₂ IDing > 40 mmHg.

• Respiratory Alkalosis: Indicates hyperventilation; confirmed by PCO₂ IDing < 40 mmHg.

• Metabolic Acidosis:
    - Requires metabolic disturbance compensation, confirmed by increased H secretion and hyperventilation leading PCO₂ < 40 mmHg.

• Metabolic Alkalosis:
    - Requires metabolic disturbance compensation, confirmed by decreased H secretion and hypoventilation leading PCO₂ > 40 mmHg.