Renal Control of Acid-Base Balance

• The urology module covers the renal control of acid and base balance.

Objectives Overview

• Determine the normal range of plasma pH.
• Identify clinical effects of acidemia and alkalemia.
• Explain the carbon dioxide/hydrogen carbonate buffer system and the factors influencing pCO2 and [HCO3-].
• Use values to identify respiratory acidemia (acidosis) and alkalemia (alkalosis), and metabolic acidosis and alkalosis.
• Diagram the cellular mechanisms of reabsorption of HCO3- in the proximal tubule.
• Diagram the cellular mechanisms of H+ excretion in the distal tubule.
• Describe the mechanism of buffering of H+ in urine, explain the concept of titratable acid, and the role of NH4+.
• Explain the interactions between the acid-base status and plasma [K+].
• Relate renal control of acid-base balance and control of plasma volume.
• List common causes of metabolic alkalosis, specifically the effects of persistent vomiting.
• List the main classes of metabolic acidosis and the role of anion-gap measurements in distinguishing between them.

Functions of Kidneys

• Excrete waste products of metabolism, including urea and creatinine.
• Recover essential filtered molecules like glucose and amino acids.
• Synthesize erythropoietin and D3.
• Play an essential homeostatic role by adjusting body balance of water and salts, controlling plasma volume and osmolarity.
• Control plasma pH by filtering and variably recovering hydrogen carbonate and actively secreting hydrogen ions.

Normal Plasma pH

• Normal range: 7.38-7.42.
• Alkalemia (Alkalosis) occurs when pH is greater than 7.42.
• Acidemia (Acidosis) occurs when pH is less than 7.38.

Alkalemia

• Lowers free calcium and increases the excitability of nerves.
• Paraesthesia and tetany may appear if pH is greater than 7.45.
• Mortality rate is 45% if pH is 7.55.
• Mortality rate is 80% if pH is 7.65.

Acidemia

• Affects many enzymes.
• Results in reduced cardiac and skeletal muscle contractility, reduced glycolysis in many tissues, and reduced hepatic function.
• Increases plasma potassium.
• Is severe below pH 7.1.
• Is life-threatening below pH 7.0.

Henderson-Hasselbalch Equation

• pH=pK+ log ([HCO3-]/pCO2x 0.23
• pK= 6.1
• log 20 = 1.3
• pH=6.1+log (25 mM/1.2mM
• pH=6.1+log 20
• pH=6.1 + 1.3 = 7.4

Plasma pH and Acid-Base Balance

• pH depends on the ratio of [HCO3-] to pCO2.
• HCO3- is controlled by the kidney and disturbed by metabolic diseases.
• CO2 is determined by respiration, controlled by chemoreceptors, and disturbed by respiratory disease.

Ventilation and Acid-Base Balance

• Hypoventilation leads to hypercapnia, causing plasma pH to fall, and results in respiratory acidemia (acidosis).
• Hyperventilation leads to hypocapnia, causing plasma pH to rise, and results in respiratory alkalaemia (alkalosis).
• Hyperventilating >hypocapnia > acidosis > hyperkalmia

Chemoreceptors

• Central chemoreceptors control pCO2 within tight limits.
• Respiratory changes correct respiratory disturbances of pH.
• Peripheral chemoreceptors enable changes in respiration driven by changes in plasma pH.

Role of the Kidneys

• Plasma pH depends on the ratio of [HCO3-] to pCO2, not on their absolute values.
• Changes in pCO2 can be compensated for by changes in HCO3-.
• The kidney controls HCO3-.
• Respiratory acidemia (acidosis) is compensated for by the kidneys increasing [HCO3-].
• Respiratory alkalaemia (alkalosis) is compensated for by the kidneys decreasing [HCO3-].

Metabolic Changes of ABB (Acid-Base Balance)

• If tissues produce acid, this reacts with HCO3-.
• A fall in [HCO3-] leads to a fall in pH, resulting in metabolic acidosis.
• This can be compensated for by changing ventilation through peripheral chemoreceptors, where increased ventilation lowers pCO2 and restores pH toward normal.
• If plasma [HCO3-] rises (e.g. after vomiting), plasma pH rises, leading to metabolic alkalosis.
• This can only be partially compensated for by decreasing ventilation.

Summary of Changes

• Plasma pH depends on the ratio of [HCO3-] to pCO2.
• Respiratory-driven changes in pH are compensated for by the kidney.
• Metabolic changes in pH are compensated for by breathing.

Renal Control of Acid-Base Balance

• Kidneys correct metabolic disturbances of pH by variable excretion and creation of HCO3-.
• Large quantities of HCO3- are filtered each day, approximately 4500 mmol.
• HCO3- must be easily lost.
• Increased [HCO3-] requires both recovery of all filtered HCO3- and new HCO3- generation.

Recovery of Bicarbonate

• 80-90% of filtered bicarbonate recovery occurs in the proximal tubule through a similar mechanism in the thick ascending limb of the loop of Henle:
  • Na+ is reabsorbed from the lumen into the tubular cell via the Na+/H+ antiporter.
  • H+ is secreted into the lumen, where it combines with HCO3- to form H2O and CO2 and enters the tubular cell.
  • CO2 and H2O in the tubular cell combine to form H+ and HCO3- using the enzyme carbonic anhydrase.
  • Basolaterally, HCO3- is transported into the capillaries, and Na+ is transported out using the Na+/K+ ATPase pump.

Generation of New Bicarbonate

• Metabolic activity of the kidney produces large quantities of CO2 which can react with water generate HCO3- to enter plasma and H+ to enter urine.
• H+ is actively pumped out to the lumen, where it is buffered by phosphate and ammonia generated from glutamine reaction.
• Ammonia increases 10 times when there is a high need to generate bicarbonate for example in sever acidosis

Acid Excretion

• Minimum urine pH reaches 4.5, with [H+] of 0.04mM.
• There is no excretion of HCO3-.
• Some H+ is buffered by phosphate, which is considered titratable acid.
• The remaining H+ attaches to ammonia as ammonium.
• Total acid secretion is 50-100 mM H+ per day.
• Keeps plasma [HCO3-] normal.

Cellular Responses to Acidosis

• Enhanced H+/Na+ exchange, leading to full recovery of all filtered HCO3-.
• Enhanced ammonium production in the proximal tubule.
• Increased activity of H+/ATP-ase in the distal tubule.
• Increased capacity to export HCO3- from tubular cells to ECF.

Metabolic Acidosis

• A condition of low bicarbonate where acids, produced metabolically, generate H+ and an anion (lactate, ketones).
• H+ reacts with HCO3- to produce CO2 that is breathed out.
• H+ + HCO3- = H2CO3 dissociates to CO2+H2O
• HCO3- is replaced by the anion from the acid.

The Anion Gap

• Indicates whether any HCO3- has been replaced with something other than Cl-.
• Calculated as the difference between ([Na+] + K) and ([Cl-] + [HCO3-]).
  • Example: 140 + 4 = 100 + 25 + A-
  • (A-) represents unaccounted anions.
• Normal range: 14-19mM.
• Increased if anions from metabolic acid have replaced plasma HCO3-.
• Renal problems can sometimes reduce [HCO3-] without increasing the anion gap if it is replaced with Cl-.

Renal Correction

• A fall in tubular cell intracellular pH stimulates acid secretion and HCO3- recovery, increasing plasma [HCO3-].

Metabolic Alkalosis

• Bicarbonate increases under conditions such as persistent vomiting, which is very easy to correct.
• Bicarbonate infusions excreted rapidly
• The rise in intracellular pH reduces both H+ excretion and bicarbonate recovery.
• When there is volume depletion the capacity to lose HCO3- is less, because of high rates of recovery of Na+favouring HCO3-recovery as well

Acid-Base Disturbances and Potassium

• Metabolic acidosis is associated with hyperkalemia except for 3 conditions
  • K+ moves out of cells.
  • More K+ reabsorption in the distal nephron.
• Metabolic alkalosis is associated with hypokalemia.
  • K+ moves into cells.
  • There is less K+ reabsorption.
• Hypokalemia creates an acidic intracellular environment in tubule cells prompting H+ excretion and HCO3 recovery, leading to further metabolic alkalosis.
• Hyperkalemia creates an alkaline intracellular environment prompting to HCO3- excretion creating metabolic acidosis

Overall Acid-Base Balance

• Normally, the body produces acid without depleting [HCO3-].
• The kidneys recover all filtered [HCO3-] through sodium-dependent reabsorption.
• The cells of the distal tubule generate HCO3- and H+ from intracellular CO2, the H+ is buffered in urine by phosphate and ammonia.

This module explores the renal control of acid and base balance, including normal plasma pH and the effects of acidemia and alkalemia. It covers buffer systems, reabsorption mechanisms, H+ excretion, and the role of titratable acid and NH4+. It also addresses interactions with plasma [K+] and common causes of metabolic imbalances.