Kidney Function, Regulation, and pH Balance

Kidney Function and Regulation

Observations and Mechanisms

• The kidney plays a crucial role in maintaining homeostasis by:
  • Conserving electrolytes and water.
  • Controlling blood pressure (BP).
  • Maintaining a remarkably constant filtration rate (GFR).
  • Holding osmolarity within a tight range.
• Key mechanisms involved in kidney function:
  • Vasopressin (AVP) signals from the hypothalamus to the kidney.
  • Angiotensin II regulates vasoconstriction, among other functions.
  • Aldosterone regulates salt and water balance.

Aquaporins and Water Permeability

• Aquaporins are crucial for water permeability in the Loop of Henle.
• Water moves through aquaporins in the descending loop, allowing water reabsorption.
• The ascending loop is impermeable to water due to the absence of aquaporins.
• High urea concentration is present.
• Variable reabsorption occurs in the collecting duct.

Vasopressin (AVP) and Urine Concentration

• $+AVP \rightarrow$ concentrated urine.
• No AVP $\rightarrow$ dilute urine.
• Diabetes insipidus:
  • Characterized by excessive urination ("diabetes") and extreme thirst.
  • No elevated glucose levels ("insipidus"), indicating insulin is not the primary issue.
  • Much less common (1:25,000) than diabetes mellitus (1:10).
  • Cause: Either no AVP production (central) or insensitivity to AVP (nephrogenic).

Hypothalamus and Vasopressin Release

• The hypothalamus regulates vasopressin release through osmo- and baroreceptors.
• High blood osmolarity triggers thirst and AVP release, leading to water retention.
• Low blood pressure potentiates osmolarity-induced AVP release.
• AVP neurons integrate blood pressure and osmolality information.
• A 10% decrease in blood volume/pressure or a 10% increase in plasma osmolality can affect AVP release.
• The brainstem cardiovascular control center (CVCC) also plays a role.

Glomerular Filtration Rate (GFR) Regulation

• GFR needs to be remarkably consistent for proper kidney function.
• The nephron must "know" if GFR has changed.
• When blood pressure drops, the tubule switches back.
• When blood pressure rises, the tubule also compensates.

Juxtaglomerular Complex and GFR Control

• The macula densa senses tubule flow rate and regulates GFR via paracrine signaling.
• The juxtaglomerular complex consists of:
  • Macula densa.
  • Granular cells.
  • Arteriole smooth muscle.

Paracrine Signals and GFR Feedback

• Paracrine signals, including adenosine, ATP, and nitric oxide, are involved in GFR feedback regulation.
• High GFR leads to increased $[NaCl]$ in the tubule.
• Na+, Cl- entry and cilia bending in macula densa (MD) cells.
• Afferent arteriole constriction results in reduced GFR.
• Faster filtrate flow velocity occurs with high blood pressure.

Renin-Angiotensin System (RAS)

• The renin-angiotensin system (RAS) has widespread effects.
• Increased GFR: Efferent arteriole constriction.
• Body-wide vasoconstriction via Angiotensin receptors.
• Low GFR activates RAS.
• Low blood pressure activates RAS.
• Integrated response (brain, endocrine).

Angiotensin II Effects on GFR

• Angiotensin II responds to low BP and low GFR.
• Angiotensin II has a more potent effect on the efferent arteriole than the afferent arteriole.
• Thus, RAS increases GFR.
• Low GFR $\rightarrow$ AngII $\rightarrow$ Increased PH in Glomerulus $\rightarrow$ Increased GFR.

Clinical Relevance of RAS

• ACE blockers and AngR antagonists are used to treat hypertension.
• Decreased BP/GFR results in body-wide Renin production.
• Angiotensin receptors are present in various tissues.
• ACE inhibitor: Captopril, derived from Jararaca pit viper.

Anti-Hypertensive Treatments

• Anti-hypertensive treatments are highly prescribed in America, many targeting the RAS system.
• Examples include: Ang II blockers, Beta-blockers.
  • U.S. Anti-hypertensive Drugs Market Size, by Drug Class, 2020-2030 (USD Billion) is valued at $7.9B$.
• Common drug classes:
  • Calcium Channel Blockers
  • Beta-adrenergic Blockers
  • ACE Inhibitors (Captopril & successors)
  • Vasodilators
  • Diuretics
  • Others

Atrial Natriuretic Peptide (ANP)

• Atrial natriuretic peptide (ANP) counters RAS activity.
• ANP:
  • Inhibits release of renin, aldosterone, and vasopressin.
  • Acts in the brainstem to decrease sympathetic outflow.
• BNP (“brain” naturetic peptide):
  • Ventricular stretch receptors cause its release.
  • Increases during heart failure, acting as a biomarker.
  • Antagonizes most actions of RAS but doesn’t act on arterioles directly.

Aldosterone and Potassium Regulation

• RAAS: Aldosterone promotes Na+ reabsorption and K+ secretion.
• Hyperkalemia promotes aldosterone synthesis – $[K^+]$ dysregulation risks cardiac arrhythmia.
• Low Na+ ( $\rightarrow$ low blood volume) – Swelling cells, low blood pressure.

Adrenal Gland Hormones

• Adrenal glands produce multiple hormones.
  • Capsule -> Adrenal Cortex -> secretes steroid hormones.
    • Zona glomerulosa -> Aldosterone
    • Zona fasciculata -> Glucocorticoids
    • Zona reticularis -> Sex hormones
  • Adrenal medulla -> secretes catecholamines (Esp. epinephrine).

Steroid Hormone Synthesis

• All steroids are derived from cholesterol, and the adrenal cortex processes it.
• Key enzymes in steroid synthesis include:
  * Aldosterone synthase
  * Cholesterol side-chain cleavage enzyme
  * 17α-hydroxylase
  * 17,20 lyase
  * 21-hydroxylase
  * 11β-hydroxylase
  * Aromatase
  * 5α-reductase

Aldosterone Mechanism

• Steroid hormones bind transcription factors, directing mRNA synthesis.
• Aldosterone binds to the mineralocorticoid receptor (MR).

Aldosterone and Sodium Reabsorption

• Aldosterone promotes Na+ reabsorption in the distal tubule.
• Increased permeability in the early phase:
  • ENaC: leak Na channel.
  • ROMK: leak K channel.
• Increased channels and pumps in the late phase: transcription-dependent.
  • Retained sodium, more water reabsorption.
  • K+ lost as a byproduct.
  • Hyperkalemia also activates these P cells.

Coordinated Regulation of pH

• Lungs and kidneys coordinate pH regulation.
• Respiration can rapidly regulate pH.
• Regulation of bicarbonate levels allows regulation of pH by the kidneys.
• $P<em>{CO</em>2}$ directly alters plasma pH.
• The proximal tubule regulates $[HCO_3^-]$.
• Distal tubulates $[H^+]$ at the expense of $[K^+]$.
• Majority of $CO_2$ transported as dissolved bicarbonate (~70%).
• $CO<em>2 + H</em>2O \rightleftharpoons H^+ + HCO_3^-$.

Factors Causing Changes in pH

• Dissolved $CO_2$.
• Dietary acids (fatty acids, amino acids).
• Ketoacidosis (diabetics use fats & proteins to generate energy).
• Lactic acid.
• Acidosis:
  • Neurons become less excitable.
  • Respiratory depression and/or coma may result.
• Alkalosis:
  • Neurons become hyperexcitable.
  • Numbness or tingling, muscle twitches, tetanus.
• These are due to a $K^+/H^+$ antiporter, leading to changes in $[K^+]$.

Bicarbonate Regulation by Proximal Kidney

• Na/K ATPase.
• Net effect: $HCO_3^-$ returns from filtrate to blood, $H^+$ excreted.

Distal Tubule Responses to pH Imbalance

• Reabsorption of $K^+$ in acidosis $\rightarrow$ NS depression.
• Loss of $K^+$ in alkalosis $\rightarrow$ Hyperexcitability.

Kidney Responses to Acid-Base Disturbances

• ∆Reabsorption rate of bicarbonate.
• ∆Reabsorption or secretion rate of $H^+$.
• Multiple locations & mechanisms:
  • Proximal tubule: $Na^+/H^+$ antiporter, $Na^+/NH<em>4^+$ antiporter, $Na^+/HCO</em>3^-$ symporter.
  • Intercalated cells of distal tubule: $H^+$ ATPase, $H^+/K^+$ antiporter, $HCO_3^-/Cl^-$ antiporter.

Compensation for pH Imbalance

• Pneumonia.
  • Less $CO<em>2$ transfer $\rightarrow$ increased $P</em>{CO_2}$ $\rightarrow$ Decreased pH (acidosis).
  • Increased $HCO_3^-$ reabsorption will shift equilibrium left $\rightarrow$ Corrects pH (increases).

Analysis of pH Imbalances

• Is the pH increased or decreased? $\rightarrow$ Alkalosis or Acidosis.
• Is $P<em>{CO</em>2}$ increased or decreased?
• Is $HCO_3^-$ increased or decreased?
• Metabolic or respiratory?
• Which is the primary symptom, and which is compensatory?

Davenport Diagram and Henderson-Hasselbalch Equation

• The Davenport diagram illustrates the interrelationship between pH, $P<em>{CO</em>2}$, and $[HCO_3^-]$.
• $pH = 6.1 + log \frac{[HCO<em>3^-]}{P</em>{CO_2} \times 0.03}$
• The Henderson-Hasselbalch equation relates $P<em>{CO</em>2}$ to pH.

ACE2 and Angiotensin Peptides

• Substrates identified for ACE2 include Ang I and Ang II.
• ACE2 has been implicated in Ang-(1-7) formation, playing a key role in vasodilation and antiproliferative effects.
• ACE2 is a negative regulator of the RAS, counterbalancing the functions of ACE1.
• ACE2 is expressed predominantly in the heart, kidneys, and testes, and at lower levels in various tissues.

ACE2 and SARS-CoV-2

• SARS-CoV-2 uses the ACE2 receptor for entry and the serine protease TMPRSS2 for S protein priming.
• Key questions include:
  • Do ACE/AT drugs have any effect on Covid-19 outcomes?
  • Does destruction of ACE2+ cells affect the CV system?
  • Why are lungs most affected?
  • Are other tissues infected, or are impacts on them secondary?

Lung Vulnerability and ACE2 Expression

• The lung's large surface area makes it susceptible to inhaled viruses.
• 83% of ACE2-expressing cells were alveolar epithelial type II cells (AECII).