Renal Regulation of pH

Renal Regulation of pH: Overview

• The lecture covers renal regulation of pH, including the role of kidneys, urinary buffers, and causes and effects of acidosis and alkalosis.

Learning Objectives

• Define pH, [H+], and what a buffer is.
• Recognize the kidneys' role in maintaining pH balance.
• Describe urinary buffers.
• Define alkalosis and acidosis.
• Summarize causes of metabolic/respiratory acidosis and alkalosis
• Explain compensatory responses to metabolic/respiratory acidosis/alkalosis
• Describe the physiological effects of acidosis and alkalosis.

Blood pH

• Average blood pH is 7.4.
• The normal blood pH range is 7.35 (venous) to 7.45 (arterial).
• Blood pH below 7.35 is acidotic, above 7.45 is alkalotic.
• The pH range compatible with life is approximately 6.8 to 8.0.
• Acid donates protons, while alkali(base) accepts protons.
• A stronger acid results in greater separation of molecules to free H+ and anions.
• 1 mmol of strong acid dissolving produces 1 mmol of free H+.

Importance of Maintaining Constant Plasma pH

• Cell pH of about 7 is necessary for normal cell function.
• Enzyme functions are highly sensitive to hydrogen ion concentration [H+].
• Slight deviations in pH can change protein structure, enzyme activity, and nerve excitability.

Causes of pH Change

• Metabolism in all tissues continuously produces CO2, approximately 15,000 mmol/day.
• Food breakdown produces non-volatile acids like sulfuric and phosphoric acids from protein/meat.
• Metabolic intermediates, such as lactic acid during heavy exercise, cause pH change.

Buffering H+

• Chemical buffers are the first line of defence against pH changes.
• The lungs remove carbonic acid by eliminating CO2 and changing the rate of ventilation.
• The kidneys regulate the amount of bicarbonate (HCO3-) reabsorbed and H+ secreted.

Buffering Acid in the Body

• The body has four buffer systems: bicarbonate, phosphate, hemoglobin, and plasma/cell proteins.
• A buffer minimizes pH change when acid/alkali is added, involving a mix of 2 chemicals in reversible reaction.

Normal Arterial Blood Plasma Acid-Base Values

• Normal arterial blood pH is 7.40 (range 7.35-7.45).
• Normal arterial [H+] is 40 nmol/L (range 35-45).
• Normal arterial pCO2 is 40 mmHg (range 35-45).
• Normal aterial [HCO3-] is 24 mmol/L (range 22-26).

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 (40 x 0.03 = 1.2).

Determinants of Blood pH: Henderson-Hasselbalch Equation

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

How the [HCO3-]/[H2CO3] Ratio Determines pH

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

Remarkable Effectiveness of the HCO3-/CO2 Buffering System

• The HCO3-/CO2 buffering system is effective because it's open.

Role of Kidneys in pH Balance

• Kidneys control pH of body fluids via reabsorbing filtered bicarbonate.
• 180 L of fluid is filtered a day x 24 mmol/L HCO3

Reabsorption of Bicarbonate (HCO3-)

• Tubular cells are impermeable to HCO3-.

Net Synthesis of Bicarbonate and Urinary Buffering

• When all filtered bicarbonate has been reabsorbed, the basic reaction results in net synthesis of bicarbonate which is added to the blood.
• H+ is secreted into the filtrate and is buffered by urinary buffers.

Mechanisms of Bicarbonate Synthesis

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

H+ Secretion

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

Acid Excretion in Urine

• Acid is excreted in urine as titratable acid (33%) and as acid combined with ammonia (NH4+) (77%).
• H+ is buffered with filtrate buffers known as titratable acids.
• Phosphate (75% of titratable acid) combines with H+ mainly in the proximal tubule.
• Creatinine (25% of titratable acid) combines with H+ mainly in the distal tubule.

Ammonia: Urinary Buffer

• Plasma normally doesn't contain NH3.
• PT cells turn glutamine into NH3 and α-ketoglutarate.
• NH3 is lipid soluble and combines with H+ in the tubule lumen to form NH4+.

Acidosis

• Acidosis is an abnormal process that tends to produce acidaemia.
• Acidaemia has a serum pH less than 7.35 and [H+] greater than 45 nmol/L.

Respiratory Acidosis

• Respiratory acidosis has a pH less than 7.35, with the primary defect an increase in pCO2.
• It is characterized by CO2 accumulation because the lungs cannot blow off CO2.
• Causes include depression of the respiratory center and alveolar hypoventilation.
• It could also be due to lung damage or a reduced CO2 diffusion.
• Respiratory acidosis, the most common acid-base abnormality, is seen in critically ill patients.
• The level of volatile acids in plasma increases and pH decreases.
• Reflex respiratory response

Compensatory Response to Respiratory Acidosis

• In response to increased pCO2 and fallen blood pH, the kidneys attempt to raise plasma [HCO3-]. This is called renal compensation.

Mechanism of Renal Compensation in Respiratory Acidosis

• There is an increase of pCO2 in renal tubular cells.
• The rate of H+ secretion increases, sequestered in urine by NH3 and HPO42-
• The rate of tubular synthesis of HCO3- increases as does HCO3 reabsorption.
• Plasma [HCO3-] stabilized at a level above normal.

Metabolic Acidosis

• Metabolic acidosis features a serum pH less than 7.35, with the primary defect a decrease in plasma [HCO3-].
• The abnormal process is characterized by a gain of acid (other than H2CO3) or a loss of HCO3-.
• Increases H+ and decreases plasma pH.
• Added H+ consumes HСО3-.
• Causes include uncontrolled diabetes mellitus and ingestion of acidifying agents.
• Other causes are lactic acidosis/tissue hypoxia, loss of alkaline intestinal fluids, and renal failure (diminished NH4+ production/excretion).

Metabolic Acidosis in Diabetic Ketoacidosis

• Diabetes mellitus leads to inadequate insulin and glucose use alongside fatty acid oxidation.
• Excessive ketone acid bodies are produced.
• Severe acidemia results, impairing myocardial contractility and lowering arterial BP.
• Compensatory increase in ventilation and lowering of alveolar/arterial pCO2 shifts blood pH back to normal.
• Labored, deep breathing in severe uncontrolled diabetes is "air hunger" (Kussmaul respiration).

Compensatory Response to Metabolic Acidosis

• Decreased plasma [HCO3-] is offset by increased ventilation and breathing rate.
• Proportionate decrease in pCO2, stabilised at levels below normal.
• This is called respiratory compensation.

Metabolic Acidosis & The Advantage of Respiratory Compensation

• In no compensation, [HCO3-] is 18 mmol/l and [H2CO3] is 1.2 mmol/l resulting in pH 7.28.
• With compensation, [HCO3-] is 18 mmol/l and [H2CO3] is 1.1 mmol/l resulting in pH 7.31.

Consequences of Acidosis

• Acidosis changes the excitability of nerve and muscle cells, raising plasma [K+] and causing hyperkalemia.
• CNS effects include depression, disorientation, and coma.
• Osteomalacia happens because bones demineralize due to gradual release of phosphates/carbonates.
• pCO2 rising in respiratory acidosis leads to peripheral vasodilation.

Alkalosis

-Defines acid-base imbalance where body fluids are too basic (alkaline) causing alkalaemia.

Respiratory Alkalosis

• Defined as pH above 7.45. Primary defect is a decrease in the pCO2.
• It results from losing too much CO2 and decreasing HCO3 and H+, increasing pH.
• Causes include alveolar hyperventilation, voluntary effort, and neurotransmitters/hormones.

Mechanism of Renal Compensation in Respiratory Alkalosis

• There is a decrease in pCO2 of renal tubular cells.
• H+ secretion decreases, with only some of the HCO3- of the filtrate being reabsorbed.
• HCO3- decreases as does plasma [HCO3-].

Metabolic Alkalosis

• Process characterized by a gain of a strong base or HCO3 or decreased acid.
• [HCO3-] increases and is pH increases.
• Causes include ingesting antacids or vomiting gastric juices.

The Effect of Vomiting: Alkalosis

• Normally gastric juice is a mix of 0.1 M HCI secreted by parietal cells into lumen.
• Causes a temporary raised [HCO3].
• Occurs because reabsorption of gastric H+ components increases [HCO3].
• With vomiting, loss of H+ can increase [HCO3].

Compensatory Response to Metabolic Alkalosis

• Increased plasma [HCO3] increases blood pH.
• Causes an increased chemoreceptor activity, lowered breathing rate, and stabilised pCO2.
• The lungs try to increase pCO2, described as respiratory compensation.

Consequences of Alkalosis

• Hyperexcitability of the nervous system, beginning with peripheral effects like tingling and spasms.
• Central effects include irritability and confusion.
• Respiratory alkalosis can trigger hypocalcaemic tetany, respiratory muscle impairment, and even death.
• Decrease in pCO2 due to decreased free calcium levels can cause cerebral ischaemia, leading to dizziness and fainting.

Clinical Evaluation of Acid-Base Disturbances

• First, examine the pH to classify the disorder as acidosis or alkalosis.
• In acidosis, pCO2 is high if respiratory, while plasma [HCO3] is low if metabolic.
• In alkalosis, pCO2 is low if respiratory, while plasma [HCO3] is high if metabolic.

Analysis of an Acid Base Disorder

• The analysis of an arterial blood sample can give valuable information.
• Values may be obtained for arteria blood pH, [HCO3-] and pCO2 (ABG - arterial blood gas analysis).
• Use plasma Na+, Cl, and HCO3 to determine the plasma anion gap

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

• In any body fluid, the sum of anions and cations are equal.
• Calculate by anion gap = [Na+] - [CI] - [HCO3-].
• In healthy individuals it lies within 8 to 14 mEq/L

If metabolic acidosis is present & the Anion Gap is high

• Check to see if it present it the unmeasured anion causing loss of HCO3
• Could present as "unknown anion" such as Lactic acid resulting in low HCO3 levels