Renal Regulation of pH: MED 204 Notes

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Renal Regulation of pH: an Overview

• MED 204 details how the kidneys regulate pH
• The average blood pH is approximately 7.4
  • The normal range is 7.35 (venous) to 7.45 (arterial)
  • Below this range, blood is considered acidotic, and above it, alkalotic
  • Life is compatible within a pH range of roughly 6.8 to 8.0
• Acids donate protons, while alkalis (bases) accept them
• Stronger acids result in a higher percentage of molecules separating to free H+ and anions
  • 1 mmol of strong acid dissolving produces 1 mmol of free H+

Why Plasma pH Must Remain Constant

• A cell pH of about 7 is necessary for normal cell function
• Enzyme functions are highly sensitive to hydrogen ion concentration ([H+])
  • Slight pH deviations change protein structure, enzyme activity, and nerve excitability
• Metabolism in all tissues continuously produces CO2, about 15,000 mmol/day
• Food breakdown produces non-volatile acids
  • Breakdown of protein/meat releases sulphur and phosphorous that form sulphuric and phosphoric acids, which are non-carbonic acids
• Metabolic intermediates such as lactic acid during heavy exercise

Buffering Systems and the Role of Kidneys

• Chemical buffers are the first line of defense against pH changes
• Lungs remove carbonic acid by eliminating CO2, changing the rate of ventilation
• Kidneys regulate the amount of bicarbonate (HCO3-) reabsorbed and H+ secreted
• There are four buffer systems in the body
  • Bicarbonate buffer system
  • Phosphate buffer system
  • Hemoglobin system
  • Plasma and cell proteins
• Buffers minimize pH change when acid/alkali is added, involving a mix of 2 chemicals

Normal Arterial Blood Plasma Values

• Normal pH: 7.40 (range 7.35-7.45)
• Normal H+ concentration: 40 nmol/L (range 35-45)
• Normal pCO2: 40 mmHg (range 35-45)
• Normal HCO3- concentration: 24 mmol/L (range 22-26)
• HCO3- is kept constant at 24 mmol/L via the kidneys
• pCO2 is kept constant at 40 mmHg via the lungs
• Keeping pCO2 at 40 mmHg maintains H2CO3 at 1.2 mmol/L (40 x 0.03 = 1.2)

Henderson-Hasselbalch Equation

• pH = pK + Log [HCO3-] / [H2CO3]
• Blood pH depends on the ratio of [HCO3-] to [H2CO3] in plasma
• Blood pH relies on the ratio of [HCO3-] to pCO2 as well
  • H2CO3 = pCO2 x 0.03 (0.03 = plasma solubility of CO2)
• pK for HCO3- is 6.10 at 37°C
• pH = 6.10 + log [HCO3-] / 0.03 pCO2

Bicarbonate Buffering Effectiveness

• The HCO3-/CO2 system is effective because it is "open"

Kidney's Role in pH

• Kidneys control pH by reabsorbing filtered bicarbonate.
  • Approximately 180 L are filtered a day x 24 mmol/L HCO3-
• Kidneys also synthesize new bicarbonate (HCO3-), equivalent to what is consumed in buffering
• The kidney's regulate pH through tubular secretion of H+ and its urinary buffering

Bicarbonate Reabsorption

• Tubular cells are impermeable to HCO3-

Bicarbonate Synthesis

• After all filtered HCO3- has been reabsorbed net synthesis of bicarbonate occurs, and this is added to the blood
• H+ is secreted into the filtrate and buffered by urinary buffers

H+ Secretion

• Most excreted H+ actively secreted into the tubular system
• H+ secreted in the proximal, distal, and collecting tubules
• H+ secretion increases when pH is low (or CO2 high) and decreases when pH is high
• There are no mechanisms for reabsorbing H+
• Plasma buffers H+ so well that almost no "free" H+ is filtered in glomerulus.

Acid Excretion in Urine

• Excreted as titratable acid (33%) -Phosphate system
• Excreted as acid combined with ammonia (NH4+) (77%)
• Titratable acid involves H+ buffered with filtrate buffers.
  • Phosphate combines H+ with phosphate mainly in the proximal tubule
    • HPO4- + H+ -> H2PO4
  • Creatinine combines H + with creatinine in the distal tubule

Ammonia as a Urinary Buffer

• Plasma does not normally contain NH3
• PT cells convert glutamine into NH3 and α-ketoglutarate.
• NH3 is lipid soluble, combines with H+ in the tubule lumen to form NH4+

Acidosis

• Acidosis is an abnormal process that produces acidaemia
  • pH < 7.35 and [H+] > 45 nmol/L
• In respiratory acidosis:
  • pH < 7.35
  • The primary defect is an increase in pCO2.
• In metabolic acidosis:
  • pH < 7.35
  • The primary defect is a decrease in plasma [HCO3-]

Respiratory Acidosis

• Respiratory acidosis is characterized by CO2 accumulation, as the lungs cannot remove CO2 as rapidly as produced
• Causes of respiratory acidosis:
  • Depression of respiratory centre
  • Alveolar hypoventilation
  • Lung Damage
  • Reduced CO2 diffusion
• Respiratory acidosis is the most common acid-base abnormality in critically ill patients
• Volatile acids in plasma increase and pH decreases
• Chemical buffering in respiratory acidosis happens within cells
• The body triggers a reflex respiratory response

Compensatory Response to Respiratory Acidosis

• pCO2 increases, decreasing blood pH
• The kidneys increase plasma [HCO3-], known as renal compensation

Mechanism of Renal Compensation in Respiratory Acidosis

• Increase of pCO2 in renal tubular cells
• Increased rate of H+ secretion sequestered in urine by NH3 and HPO4(2-)
• Increased rate of tubular synthesis of HCO3-
• Increased rate of HCO3- reabsorption
  • Plasma [HCO3-] stabilized at a level above normal

Metabolic Acidosis

• Occurs when there is a gain of acid (other than H2CO3) or a loss of HCO3-
  • Causes [H+] increase and plasma pH decrease
  • Added H+ consumes HCO3-
  • Rapid acid infusion increases pCO2
• Causes of metabolic acidosis:
  • Uncontrolled diabetes mellitus -Ketone bodies
  • Ingestion of acidifying agents like NH4Cl
  • Lactic acidosis from tissue hypoxia
  • Severe diarrhoea
    • Loss of alkaline intestinal fluids
  • Renal failure reduces NH4+ production/excretion

Metabolic Acidosis in Diabetic Ketoacidosis

• Diabetes mellitus
  • Too little glucose use from inadequate insulin
  • Diversion of metabolism to fatty acid oxidation
  • Overproduction of ketone acid bodies (e.g., acetoacetic acid with pKa ~ 4-5)
• Results In Severe acidemia -Myocardial contractility is impaired reducing cardiac output -Arteriolar dilatation lowers arterial BP
• The body responds with compensatory increase in ventilation, the alveolar/arterial pCO2 causes shifting blood pH to normal -Labored deep breathing in severe uncontrolled diabetes, “air hunger" (Kussmaul respiration)

Compensatory Response to Metabolic Acidosis

• As plasma [HCO3-] decreases, blood pH falls
• The body increases ventilation and rate of breathing
• Proportionate decrease the pCO2 stabilizes the pH
• pCO2 stabilizes at levels below normal
• This is known as respiratory compensation

Advantage of Respiratory Compensation

• Respiratory compensation helps improve pH in metabolic acidosis

Consequences of Acidosis

• Changes the excitability of nerve and muscle cells by increasing plasma [K+], or hyperkalemia
• Depresses the CNS resulting in disorientation and coma
• Osteomalacia occurs when bones demineralizing, by gradually release of highly basic phosphates and carbonates
• Peripheral vasodilation can occur because pCO2 increases in respiratory acidosis

Alkalosis

• Alkalosis is the excess of base (or deficit of acid) in the blood
  • pH is higher than 7.45 and [H+] is lower than 35 nmol/L
• In respiratory alkalosis:
  • pH > 7.45
  • The primary defect is a decrease in pCO2
• In metabolic alkalosis:
  • pH > 7.45
  • The primary defect is an increase in plasma [HCO3-]

Respiratory Alkalosis

• Respiratory alkalosis is loss of too much CO2, with HCO3- and H+ decreasing and pH increasing
• Due to:
  • Alveolar hyperventilation from hysteria or anxiety
  • Voluntary effort
  • Direct stimulation of the medullary respiratory centre
  • Hypoxia from severe anaemia or high altitude
  • Certain neurotransmitters and hormones

Mechanism of Renal Compensation in Respiratory Alkalosis

• Decreased pCO2 of renal tubular cells
• H+ secretion decreases, the filtrate's HCO3- is not reabsorbed
• Decreased rate of tubular synthesis of HCO3.
• Plasma [HCO3-] stabilised at a level below normal.

Metabolic Alkalosis

• Metabolic alkalosis is characterized by a gain of strong base / HCO3-, or loss of an acid (other than carbonic acid)
• [HCO3-] increases while pH rises
• Due to:
  • Ingestion of antacids
  • Increased renal H+ loss from hyperaldosteronism or hypokalemia
  • Vomiting of gastric juices

Vomiting causes Alkalosis

• Vomiting leads to a loss of gastric H+
• Normally, gastric juice is secreted by parietal cells into lumen resulting in net gain of [HCO3-]
  • HCO3- is added to the plasma increasing HCO3 plasma and the H+ components reabsorbed neutralize this increase in the HCO3 plasma
• With H+ lost, plasma [HCO3-] remains elevated

Compensatory Response to Metabolic Alkalosis

• Plasma [HCO3] has increased, so blood pH has increased
• Lungs 'try to bring about' a proportionate increase in the pCO2 is increased
• The body uses respiratory compensation

Consequences of Alkalosis

• Hyperexcitability of the nervous system
  • First peripheral effect is Tingling sensations, Muscle twitches, muscle spasms
  • Finally, central effects are Irritability and confusion -If severe leads to hypocalcaemic tetany, due to less free calcium - more bound to albumin by change in pH., impairment of respiratory muscles
• A decrease in pCO2 causes cerebral ischaemia
  • Can cause dizziness and fainting from respiratory alkalosis

Clinical Evaluation of Acid-Base Disturbances

• Examine the pH to classify as acidosis or alkalosis
• If it is acidosis:
  • Examine the value for pCO2 - it will be high if respiratory
  • Examine the value for plasma [HCO3] - it will be low if metabolic
• If it is alkalosis:
  • Examine the value for pCO2 - it will be low if respiratory
  • Examine the value for plasma [HCO3] - it will be high if metabolic

Anion Gap

• In any body fluid, the sum of cations equals the sum of anions
  • [Na+] + [unmeasured cations] = [Cl-] + [HCO3-] + [unmeasured anions] -The "[unmeasured anions] or “anion gap” is calculated as [Na+] - [Cl-] - [HCO3-]." -A healthy person has an Anion Gap between falls 8-14 mEq/L." -Metabolic Anion causes of:
  • "Diabetic ketoacidosis."
  • "Lactic acidosis."
  • "Ethylene glycol poisoning, and chronic renal failure."
• If a patient has metabolic acidosis and normal Anion Gap then what's causing of HCO3 loss.

Osmolar gap explained

• The osmolar gap gap only present in metabolic acidosis if caused methanol and ethylene glycol poisoning
• It's the "difference between the measured plasma osmolarity and the estimated plasma osmolarity"

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