Renal Regulation of pH - MED 204

• Renal Regulation of pH is a course under the Renal System Module with code MED 204.
• Prof. Triona Ni Chonghaile & Dr. Patrick Walsh are the lecturers in February 2025.

Learning Objectives

• Need to be able to define pH, [H+], and what a buffer is.
• Need to recognise the role of the kidneys in maintaining pH balance.
• Need to describe urinary buffers.
• Must be able to define alkalosis and acidosis.
• Should summarise the causes of metabolic and respiratory acidosis and alkalosis.
• Compulsory to explain the compensatory response to metabolic and respiratory acidosis/alkalosis
• You should be able to describe the physiological effects of acidosis and alkalosis.

Blood pH

• Average blood pH is 7.4
• Normal range is 7.35 (venous) - 7.45 (arterial).
• Below 7.35, blood is acidotic; above 7.45, blood is alkalotic
• Range compatible with life is approximately 6.8 - 8.0
• Acid donates protons, and alkali (base) can accept.
• Stronger the acid, the greater percentage of molecules separate to free H+ and anions.
• 1 mmol of strong acid dissolves to produce 1 mmol of free H+.

Why is it Necessary to Maintain Plasma pH Constant?

• Cell pH of about 7 is necessary for normal cell function
• Enzyme functions in body are highly sensitive to hydrogen ion concentration ([H+]).
• Slight deviations in pH can change protein structure, enzyme activity, and nerve excitability.
• Metabolism in all tissues continuously produces CO2 at a rate of 15,000 mmol/day.
• Breakdown of food produces non-volatile acids, such as sulfuric and phosphoric acids from protein/meat breakdown.
• Metabolic intermediates, like lactic acid during heavy exercise, can alter pH.

Buffering H+

• Chemical buffers are the first line of defence to pH changes.
• Lungs can remove carbonic acid by eliminating CO2, with changes in the rate of ventilation.
• Kidneys regulate the amount of bicarbonate (HCO3-) reabsorbed and H+ secreted.

Buffering Acid in the Body

• The body has four buffer systems which are; the bicarbonate buffer system, the phosphate buffer system, the hemoglobin system, and plasma and cell proteins.
• A buffer is a mixture of 2 chemicals involved in a reversible reaction which minimizes pH change when acid/alkali is added

Normal Arterial Blood Plasma Acid-Base Values

Values to Remember

• [HCO3-] is maintained constant at 24 mmol/L by the kidneys.
• pCO2 is maintained constant at 40 mmHg by the lungs
• By maintaining pCO2 at 40 mmHg, [H2CO3] is maintained at 1.2 mmol/L.

Determinants of Blood pH: Henderson-Hasselbalch Equation

• Blood pH depends only on the ratio of [HCO3-] to [H2CO3] in plasma.
• Blood pH depends on the ratio of [HCO3-] to pCO2
• H2CO3 = pCO2 x 0.03 (0.03 = plasma solubility of CO2)
• pK for HCO3- = 6.10 at 37°C

How does the [HCO3-]/[H2CO3] Ratio Determine pH?

• Insert normal values for [HCO3-] and pCO2 into the Henderson-Hasselbalch equation giving pH = 7.4.
• pKa is the acid dissociation constant which is 6.1 at 37°C for carbonic acid.

The HCO3-/CO2 Buffering System is Remarkably Effective Because it is Open

• The equation states that CO2 + H2O <-> H2CO3 <-> H+ + HCO3-

Role of Kidneys in pH Balance

• Kidney controls pH of body fluids by Reabsorbing filtered bicarbonate, synthesis of new bicarbonate (HCO3-) and Tublar secretion of H+ (and its urinary buffering)
• The kidney filters 180 L a day x 24 mmol/L HCO3-

Reabsorption of HCO3-

• NBC1 is a sodium bicarbonate co-transporter
• Note that tublar cells are actually impermeable to HCO3-

2. Mechanism of Bicarbonate Synthesis

• Note, once all the filtered HCO3- has been reabsorbed additional excreted H+ is buffered using urinary buffers

H+ Secretion

• Most excreted H+ gains entry to tubular system from actively secreted H+
• H+ is secreted into the tubular filtrate by the proximal, distal and collecting tubules
• H+ secretion increases, when pH is low and decreases, when pH is high
• Also note that there are no mechanisms for reabsorbing H+
• H+ is so well buffered in plasma that almost no “free” H+ is filtered in glomerulus

Acid Excretion in Urine as...

• Titatrable acid: (Phosphate system) 33%
• Acid combined with ammonia (NH4+): 77%
• This is where H+ is buffered with filtrate buffers
• Phosphate (75% of titratable acid formed): Combination of H + with phosphate occurs mainly in proximal tubule, where HPO4 + H+ -> H2PO4
• Creatinine (25% titratable acid formed): Combination of H+ with creatinine occurs mainly in distal tubule.

Ammonia: Urinary Buffer

• Plasma does not normally contain NH3.
• PT cells glutamine = converted to NH3 and a-ketoglutarate.
• NH3 is lipid soluble - tubule lumen and combines with H⁺ to form NH₄ +.

Acidosis

• Acidosis is an abnormal process that tends to produce acidaemia.
• Acidosis / acidaemia is when pH < 7.35; [H+] > 45 nmol/L

Respiratory Acidosis

• pH < 7.35
• Primary defect is an increase in the pCO2
• The equation for Respiratory compensation states that CO2 + H2O → H2CO3 → H+ + HCO3
• It is an abnormal process characterised by CO2 accumulation
• Normally, lungs cannot blow off CO2 as rapidly as produced, but reduced CO2 diffusion, lung damage can cause this
• Respiratory acidosis is the most common acid-base abnormality and is mainly observed in critically ill patients
• In Respiratory acidosis, the level of volatile acids in plasma ↑, pH decreases
• Most of the chemical buffering in respiratory acidosis occurs within the cells, hence Reflex respiratory response

Compensatory Response to Respiratory Acidosis

• pCO2 has increased, therefore blood pH has fallen.
• The kidneys try to bring about a proportionate increase in the plasma [HCO3-], also known as renal compensation

Mechanism Of Renal Compensation in Respiratory Acidosis

• The following things occur during mechanism; Increased pCO2 in renal tubular cells, High Rate of H+ secretion (sequestered into urine by, NH3, and HPO42-), Rate of tubular synthesis of HCO3-↑ (CA) and Rate of HCO3- reabsorption increases
• This causes resulting Plasma [HCO3-] in renal Tubular cells to stabilized at a level above normal

Metabolic Acidosis

• The general equation for metabolic acidosis is CO2 + H2O ← H2CO3 ← H+ + HCO3
• Metabolic Acidosis is an abnormal process characterised by a gain of acid or a loss of HCO3
• As such, it can cause increased H+ and a reduced plasma pH
• Causes include uncontrolled diabetes mellitus with ketone bodies, ingestion of acidifying agents (e.g. NH4Cl), lactic acidosis, severe diarrhoea, loss of alkaline intestinal fluids and renal failure

Metabolic Acidosis in Diabetic Ketoacidosis

• In diabetes mellitus, the following equation results CO2 + H2O ← H2CO3 ← H+ + HCO3
• There is inadequate insulin so there is too little glucose use and an increased fat oxidation
• There is overproduction of ketone acid bodies (e.g. acetoacetic acid, pKa ~ 4-5)
• The severe acidemia impairs myocardial contractility (decreased cardiac output) and causes Arteriolar dilatation resulting in arterial BP decreasing
• As a consequence, the body has a Compensatory increase in ventilation and lowering of alveolar/arterial pCO2 shifts blood pH back to normal which presents as Labored, deep breathing in severe uncontrolled diabetes, "air hunger" (Kussmaul respiration)

Compensatory Response to Metabolic Acidosis

• Plasma [HCO3-] has decreased, therefore blood pH has fallen.
• Compensation is characterized by an Increased ventilation, rate of breathing and thereby a Proportionate decrease in the pCO2, and stabilized below normal
• This overall process is known as respiratory compensation.

Metabolic Acidosis & the Advantage of Respiratory Compensation

Some Consequences of Acidosis

• Changes in excitability of nerve and muscle cells (Plasma [K+] ↑, leads to hyperkalemia)
• CNS effects (Depression of CNS, disorientation, coma)
• Osteomalacia (Demineralisation of bones when chronic and due to release of basic phosphates/carbonates)
• Other effects (In respiratory acidosis, the pCO2↑ results in peripheral vasodilation)

Alkalosis

• This is an abnormal process that tends to produce alkalaemia
• It is characterised by the following, pH >7.45; [H+] < 35 nmol/L and either Respiratory or metabolic type

Respiratory Alkalosis

• General equation CO2 + H2O ← H2CO3 ← H+ + HCO3
• Is and abnormal process causing the loss of too much CO2, with ↓ and H⁺ ↓, hence pH increases
• It is Due to Alveolar hyperventilation (e.g. hysteria or anxiety or voluntary attempt)

Mechanism of Renal Compensation in Respiratory Alkalosis

• Characterised by a Decrease in pCO2 of renal tubular cells, H+ secretion decreases and only some HCO3- is reabsorbed
• and lower Rate of tubular synthesis of HCO3-
• The resulting Plasma [HCO3-] is that is stabilized at a level below normal

Metabolic Alkalosis

• Characterised by the equation CO2 + H2O ← H2CO3 ← H+ + HCO3 -Metabolic Alkalosis, is a gains Strong base or Increase in HCO3 or HCL loss [HCO3¯]uparrow, pHuparrow
• results as increased ingestions and decreased excretion. due to Intake and Loss imbalance
• The effects of Vomiting alkalosis increase plasma[H+ loss], thus causing[HCO3↑]

Compensatory Response to Metabolic Alkalosis

• Due to the following changes: Increased Plasma [HCO3], blood pH has increased and resultant Increase in pCO2
• The compensation in this state is a reduced chemoreceptive activit and lower rate of breathing

Some Consequences of Alkalosis

• Hyperexcitability of the Nervous system: (First peripheral effects, Tingling sensations and muscle twitches/spasms)
• Followed by Central effects and Irritability and confusion
• Note, if alkalosis is extreme: (hypocalcaemic tetany, impairment of respiratory muscles) can be a cause of death due to less free

Clinical Evaluation of Acid-Base Disturbances Requires a Comprehensive Study

1. Examine the pH to classify the disorder as either acidosis or alkalosis.
2. Next, If acidosis (Examine the value for pCO2) and determine its respiratory state
3. Finally If alkalosis: (Examine the value for pCO2) to determine its cause

Analysis of an Acid Base Disorder

• The analysis of an arterial blood sample can give valuable information about the nature/ origin
• ABG include values may be obtained (arterial blood for) pH, [HCO3-] or pCO2
• Measurement of plasma Na+, Cl- and HCO3 helps to determine the plasma anion gap

the Concept of Plasma Anion Gap and the Etiology of Metabolic Acidosis

• In a healthy person the anion gap falls in the range of 8-14 mEq/L
• This provides a means to measure whether an unmeasured anion is contributing to the metabolic acidosis
• in many forms of low blood pH (metabolic acidosis low) there is a high Gap
• These gaps is attributed to"unknown anions" (e.g lactic acid) which reduce H [HCO3].
• In several forms of metabolic acidosis, an organic anion is accumulated and this offset reduction is accompanied by increase gap causing a high anion gap e.g. like in Diabetic Ketoacidosis There may also be a high osmolar gap in some causes of gap e.g. methanol and ethylene glycol poisoning.

Recommended Further Reading

• Human Physiology, Sherwood, Ch. 15 (8th ed)
• Ganong’s Physiology, Ch. 35 (24th ed)
• Principles of critical care, Hall/Schmidt/Wood, Ch. 77 (3rd ed)
• Medical Physiology, Rhoades/Bell
• https://www.ncbi.nlm.nih.gov/books/NBK482291/