Acid base homeostasis and associated disorders

• Transport of O2 to the tissues
• In the lungs, where the concentration of O2 is high (hence high pO2) the hemoglobin gets fully saturated (loaded) with O2 . Conversely, at the tissue level, where the O2 concentration is low (hence low pO2 ), the oxyhemoglobin releases (unloads) its O2 for cellular respiration. This is often mediated by binding O2 to myoglobin which serves as the immediate reservoir and supplier of O2 to the tissues.
• Transport of CO2
• 1. 10% CO2 is transported as dissolved form
• 2. 15% CO2 is transported as Carbamino- Hemoglobin.

R–NH2 + CO2 -------🡪R–NH–COOH

• 3. 75% CO2 is transported as bicarbonate

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Acid base homeostasis

• The normal pH of the blood is maintained in the narrow range of 7.35–7.45, i.e. slightly alkaline.
• The pH of intracellular fluid is rather variable. Thus, for erythrocytes the pH is 7.2, while for skeletal muscle, it may be as low as 6.0.
• Maintenance of blood pH is an important homeostatic mechanism of the body. In normal circumstances, the regulation is so effective that the blood pH varies very little.
• Changes in blood pH will alter the intracellular pH which, in turn, influence the metabolism e.g. distortion in protein structure, enzyme activity etc.
• It is estimated that the blood pH compatible to life is 6.8–7.8.
• (For a good understanding of acid-base balance, adequate knowledge on acids, bases, pH and buffers is essential.

Production of acids by the body

• The metabolism of the body is accompanied by an overall production of acids.
• These include the volatile acids like carbonic acid (most predominant, about 20,000 mEq/day) or nonvolatile acids (about 80 mEq/day) such as lactic acid, sulfuric acid, phosphoric acid etc.
• Carbonic acid is formed from the metabolic product CO2 ;
• lactic acid is produced in anaerobic metabolism;
• sulfuric acid is generated from proteins (sulfur containing amino acids);
• phosphoric acid is derived from organic phosphates (e.g. phospholipids).
• All these acids add up H+ ions to the blood. A diet rich in animal proteins results in more acid production by the body that ultimately leads to the excretion of urine which is profoundly acidic.

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Production of bases by the body

• The formation of basic compounds in the body, in the normal circumstances, is negligible.
• Some amount of bicarbonate is generated from the organic acids such as lactate and citrate.
• A vegetarian diet has a tendency for a net production of bases. This is due to the fact that vegetarian diet produces salts of organic acids such as sodium lactate which can utilize H+ ions produced in the body.
• For this reason, a vegetarian diet has an alkalizing effect on the body. This is reflected by the excretion of neutral or slightly alkaline urine by these subjects.
• The carbonic acid, being volatile, is eliminated as CO2 by the lungs. The fixed acids are buffered and later on the H+ are excreted by the kidney.

Maintenance of blood pH

• The body has developed three lines of defense to regulate the body's acid -base balance and maintain the blood pH (around 7.4).
• I Blood buffers
• II Respiratory mechanism
• III Renal mechanism.

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I. Buffer

• A buffer may be defined as a solution of a weak acid (HA) and its salt (BA) with a strong base.
• Buffer action : magnitude of buffer that can resist changes in pH by one unit when small amount of acid or base is added.
• The buffer resists the change in pH by the addition of acid or alkali and the buffering capacity is dependent on the absolute concentration of salt and acid.
• It should be borne in mind that the buffer cannot remove H+ ions from the body. It temporarily acts as a shock absorbent to reduce the free H+ ions. The H +ions have to be ultimately eliminated by the renal mechanism.

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• Henderson-Hasselbalch equation,
• pH = pKa + log [salt] /[acid]
• When [base] = [acid]; then pH = pKa

Bicarbonate Buffer System

• The most important buffer system in the plasma is the bicarbonate-carbonic acid system (NaHCO3 /H2 CO3 ). It accounts for 65% of buffering capacity in plasma and 40% of buffering action in the whole body.
• The base constituent, bicarbonate (HCO3–), is regulated by the kidney (metabolic component).
• While the acid part, carbonic acid (H2 CO3 ), is under respiratory regulation (respiratory component).
• The normal bicarbonate level of plasma is 24 mmol/L. The normal pCO2 of arterial blood is 40 mm of Hg. The normal carbonic acid concentration in blood is 1.2 mmol/L(40mmHg x 0.03 solubility constant). The pKa for carbonic acid is 6.1.
• Substituting these values in the Henderson Hasselbalch’s equation,
• pH = pKa + log[HCO3-]/[H2Co3]
• 7.4 = 6.1 + log 24/ 1.2
• = 6.1 + log 20
• =6.1+1.3

• Bicarbonate represents the alkali reserve and it has to be sufficiently high to meet the acid load.
• If it was too low to give a ratio of 1, all the HCO3– would have been exhausted within a very short time; and buffering will not be effective.
• So, under physiological circumstances, the ratio of 20 (a high alkali reserve) ensures high buffering efficiency against acids.

Phosphate buffer system

• Sodium dihydrogen phosphate and disodium hydrogen phosphate (Na2HPO4 – NaH2PO4 ) constitute the phosphate buffer.
• It is mostly an intracellular buffer and is of less importance in plasma due to its low concentration. With a pK of 6.8 (close to blood pH 7.4), the phosphate buffer would have been more effective, had it been present in high concentration.
• It is estimated that the ratio of base to acid for phosphate buffer is 4 compared to 20 for bicarbonate buffer.

Protein buffer system :

• The plasma proteins and hemoglobin together constitute the protein buffer system of the blood.
• The buffering capacity of proteins is dependent on the pK of ionizable groups of amino acids. The imidazole group of histidine (pK = 6.7) is the most effective contributor of protein buffers. The plasma proteins account for about 2% of the total buffering capacity of the plasma.

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II. Respiratory mechanism for pH regulation

• Respiratory system provides a rapid mechanism for the maintenance of acid-base balance. This is achieved by regulating the concentration of carbonic acid (H2 CO3 ) in the blood i.e. the denominator in the bicarbonate buffer system.
• The large volumes of CO2 produced by the cellular metabolic activity endanger the acid-base equilibrium of the body. But in normal circumstances, all of this CO2 is eliminated from the body in the expired air via the lungs, as summarized below.
• H2Co3🡨--------------------------------🡪H20 + Co2
• Carbonic Anhydrase
• The rate of respiration (or the rate of removal of CO2 ) is controlled by a respiratory centre, located in the medulla of the brain. This centre is highly sensitive to changes in the pH of blood.
• Any decrease in blood pH causes hyperventilation to blow off CO2 , thereby reducing the H2CO3 concentration. Simultaneously, the H+ ions are eliminated as H2O.
• Respiratory control of blood pH is rapid but only a short term regulatory process, since hyperventilation cannot proceed for long

Action of Hemoglobin

• i. The hemoglobin serves to transport the CO2 formed in the tissues, with minimum change in pH (isohydric transport).
• ii. Side by side, it serves to generate bicarbonate or alkali reserve by the activity of the carbonic anhydrase system. Due to lack of aerobic metabolic pathways, RBC produce very little CO2 . The plasma CO2 diffuses into the RBC along the concentration gradient where it combines with water to form H2 CO3 . This reaction is catalysed by carbonic anhydrase (also called carbonate dehydratase).
• In the RBC, H2CO3 dissociates to produce H+ and HCO3- . The H+ ions are trapped and buffered by hemoglobin. As the concentration of HCO3- increases in the RBC, it diffuses into plasma along with the concentration gradient, in exchange for Cl− ions, to maintain electrical neutrality. This phenomenon, referred to as chloride shift, helps to generate bicarbonate.
• Carbonic anhydrase
• CO2 + H2O --------------------🡪H2CO3
• H2CO3----------------🡪 HCO3- + H+
• H+ + Hb---------------🡪HHb

• iii. The reverse occurs in the lungs during oxygenation and elimination of CO2 . When the blood reaches the lungs, the bicarbonate re-enters the erythrocytes by reversal of chloride shift. It combines with H+ liberated on oxygenation of hemoglobin to form carbonic acid which dissociates into CO2 and H2O. CO2 is thus eliminated by the lungs.
• HHb + O2-------------🡪 HbO2 + H+
• HCO3– + H+ ---------------🡪H2CO3
• H2CO3----------------------🡪 H2O + CO2

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• iv. The activity of the carbonic anhydrase (also called carbonate dehydratase) increases in acidosis and decreases with decrease in H+ concentration.

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III. Renal mechanism for pH regulation

• The role of kidneys in the maintenance of acid-base balance of the body (blood pH) is highly significant. The renal mechanism tries to provide a permanent solution to the acid-base disturbances. This is in contrast to the temporary buffering system and a short term respiratory mechanism, described above.
• Normal urine has a pH around 6; this pH is lower than that of extracellular fluid (pH = 7.4). This is called acidification of urine. In other words, the H+ ions generated in the body in the normal circumstances, are eliminated by acidified urine.
• The pH of the urine may vary from as low as 4.5 to as high as 9.8, depending on the amount of acid excreted. The major renal mechanisms for regulation of pH are:

Carbonic anhydrase and renal regulation of pH

• The enzyme carbonic anhydrase (inhibited by acetazolamide) is of central importance in the renal regulation of pH which occurs by the following mechanisms.
• 1. Excretion of H+ ions
• 2.Reabsorption of bicarbonate
• 3. Excretion of titratable acid
• 4. Excretion of ammonium ions

1. Excretion of H+ ions �

• This process occurs in the proximal convoluted tubules.
• ii. The CO2 combines with water to form carbonic acid, with the help of carbonic anhydrase. The H2 CO3 then ionizes to H+ and bicarbonate.
• iii. The hydrogen ions are secreted into the tubular lumen; in exchange for Na+ reabsorbed. These Na+ ions along with HCO3– will be reabsorbed into the blood.
• iv. There is net excretion of hydrogen ions, and net generation of bicarbonate. So this mechanism serves to increase the alkali reserve.

2.Reabsorption of bicarbonate �

• i. This is mainly a mechanism to conserve base. There is no net excretion of H+.
• ii. The cells of the PCT have a sodium hydrogen exchanger. When Na+ enters the cell, hydrogen ions from the cell are secreted into the luminal fluid. The hydrogen ions are generated within the cell by the action of carbonic anhydrase.
• iii. The hydrogen ions secreted into the luminal fluid is required for the reabsorption of filtered bicarbonate.
• iv. Bicarbonate is filtered by the glomerulus. This is completely reabsorbed by the proximal convoluted tubule, so that the urine is normally bicarbonate free.
• v. The bicarbonate combines with H+ in tubular fluid to form carbonic acid. It dissociates into water and CO2 . The CO2 diffuses into the cell, which again combines with water to form carbonic acid.
• vi. In the cell, it again ionizes to H+ that is secreted into lumen in exchange for Na+. The HCO3– is reabsorbed into plasma along with Na+.
• vii. Here, there is no net excretion of H+ or generation of new bicarbonate. The net effect of these processes is the reabsorption of filtered bicarbonate which is mediated by the Sodium-Hydrogen exchanger. This mechanism prevents the loss of bicarbonate through urine.

3. Excretion of titratable acid �

• i. In the distal convoluted tubules net acid excretion occurs. Hydrogen ions are secreted by the distal tubules and collecting ducts by hydrogen ion-ATPase located in the apical cell membrane. The hydrogen ions are generated in the tubular cell by a reaction catalyzed by carbonic anhydrase. The bicarbonate generated within the cell passes into plasma.
• ii. The term titratable acidity of urine refers to the number of milliliters of N/10 NaOH required to titrate 1 liter of urine to pH 7.4. This is a measure of net acid excretion by the kidney.
• iii. The major titratable acid present in the urine is sodium acid phosphate. As the tubular fluid passes down the renal tubules more and more H+ are secreted into the luminal fluid so that its pH steadily falls. The process starts in the proximal tubules, but continues up to the distal tubules.
• iv. Due to the Na+ to H+ exchange occurring at the renal tubular cell boarder, the Na2HPO4 (basic phosphate) is converted to NaH2PO4 (acid phosphate). As a result, the pH of tubular fluid falls.
• v. The acid and basic phosphate pair is considered as the urinary buffer. The maximum limit of acidification is pH 4.5. This process is inhibited by carbonic anhydrase inhibitors like acetazolamide.

4. Excretion of ammonium ions�

• i. This predominantly occurs at the distal convoluted tubules. This would help to excrete H+ and reabsorb HCO3– .
• ii. This mechanism also helps to trap hydrogen ions in the urine, so that large quantity of acid could be excreted with minor changes in pH. The excretion of ammonia helps in the elimination of hydrogen ions without appreciable change in the pH of the urine.
• iii. The Glutaminase present in the tubular cells can hydrolyze glutamine to ammonia and glutamic acid. The NH3 (ammonia) diffuses into the luminal fluid and combines with H+ to form NH4 +(ammonium ion). The glutaminase activity is increased in acidosis. So large quantity of H+ ions are excreted as NH4 + in acidosis.
• NH4+ is a major urine acid. It is estimated that about half to two-thirds of body acid load is eliminated in the form of NH4+ ions. For this reason, renal regulation viaNH4+ excretion is very effective to eliminate large quantities of acids produced in the body. This mechanism becomes predominant particularly in acidosis.

• iv. Since it is a positively charged ion, it can accompany negatively charged acid anions; so Na+ and K+ are conserved.
• v. Normally, about 70 mEq/L of acid is excreted daily; but in condition of acidosis, this can rise to 400 mEq/ day.
• vi. The enhanced activity of glutaminase and increased excretion of NH4 + take about 3–4 days to set in under conditions of acidosis. But once established, it has high capacity to eliminate acid.
• vii. Ammonia is estimated in urine, after addition of formaldehyde. The titratable acidity plus the ammonia content will be a measure of acid excreted from the body. Maximum urine acidity reached is 4.5.

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Disorders of acid-base balance

• The body has developed an efficient system for the maintenance of acid-base equilibrium with a result that the pH of blood is almost constant (7.4). The blood pH compatible to life is 6.8–7.8, beyond which life cannot exist.
• For a better understanding of the disorders of acid-base balance, the Henderson-Hasselbalch equation must be frequently consulted.
• pH= pKa+log [HCO3-]/H2CO3
• It is evident from the above equation that the blood pH (H+ ion concentration) is dependent on the relative concentration (ratio) of bicarbonate (HCO3- ) and carbonic acid (H2 CO3 ).

The acid-base disorders are mainly classified as �

• 1. Acidosis—a decline in blood pH
• (a) Metabolic acidosis—due to a decrease in bicarbonate.
• (b) Respiratory acidosis—due to an increase in carbonic acid.
• 2. Alkalosis—a rise in blood pH
• (a) Metabolic alkalosis—due to increase in bicarbonate.
• (b) Respiratory alkalosis—due decrease in carbonic acid

The most important clinical causes/disease states that result in acid-base disorders are as

Metabolic acidosis could occur due to diabetes mellitus (ketoacidosis), lactic acidosis, renal failure etc.

Respiratory acidosis is common in severe asthma and cardiac arrest.

Vomiting and hypokalemia may result in metabolic alkalosis while

hyperventilation and severe anemia may lead to respiratory alkalosis.

Metabolic acidosis

• The primary defect in metabolic acidosis is a reduction in bicarbonate concentration which leads to a fall in blood pH. The bicarbonate concentration may be decreased due to its utilization in buffering H+ ions, loss in urine or gastrointestinal tract or failure to be regenerated.
• The most important cause of metabolic acidosis is due to an excessive production of organic acids which combine with NAHCO3-and deplete the alkali reserve.
• Excess acid production (e.g. lactic acid, ketoacidosis)
• Loss of bicarbonate (e.g. diarrhea, renal tubular acidosis)
• NAHCO3- +organic acids---------🡪Na salts of organic acids+ CO2
• Metabolic acidosis is commonly seen in severe uncontrolled diabetes mellitus which is associated with excessive production of acetoacetic acid and β hydroxybutyric acid (both are organic acids)

Compensation of metabolic acidosis

• The acute metabolic acidosis is usually compensated by hyperventilation of lungs. This leads to an increased elimination of CO2 from the body (hence H2CO3 ↓). but respiratory compensation is only short-lived.
• Renal compensation sets in within 3–4 days and the H+ ions are excreted as NH4+ ions.

Respiratory acidosis

• The primary defect in respiratory acidosis is due to a retention of CO2 (H2 CO3 ↑).
• There may be several causes for respiratory acidosis which include depression of the respiratory centre (overdose of drugs), pulmonary disorders (bronchopneumonia) and breathing air with high content of CO2 .
• The renal mechanism comes for the rescue to compensate respiratory acidosis. More HCO3- is generated and retained by the kidneys which adds up to the alkali reserve of the body. The excretion of titratable acidity and NH4+ is elevated in urine.
• Acute respiratory acidosis (compensation takes few hours)
• Chronic respiratory acidosis (compensation takes 3-5 days)
• Secondary compensation hyperventilation

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Metabolic alkalosis

• The primary abnormality in metabolic alkalosis is an in increase in concentration of HCO3- . This may occur due to excessive vomiting (resulting in loss of H+) or an excessive intake of sodium bicarbonate for therapeutic purposes (e.g. control of gastric acidity).
• Cushing's syndrome (hypersecretion of aldosterone) causes increased retention of Na+ and loss of K+ from the body.
• Metabolic alkalosis is commonly associated with low K+ concentration (hypokalemia). In severe K+ deficiency, H+ ions are retained inside the cells to replace missing K+ ions. In the renal tubular cells, H+ ions are exchanged (instead of K+) with the reabsorbed Na+. Paradoxically, the patient excretes acid urine despite alkalosis.
• The respiratory mechanism initiates the compensation by hypoventilation to retain CO2 (hence H2 CO3 ↑).
• This is slowly taken over by renal mechanism which excretes more HCO3- and retains H+.

Respiratory alkalosis

• The primary abnormality in respiratory alkalosis is a decrease in H2CO3 concentration. This may occur due to prolonged hyperventilation resulting in increased exhalation of CO2 by the lungs.
• Hyperventilation is observed in conditions such as hysteria, hypoxia, raised intracranial pressure, excessive artificial ventilation and the action of certain drugs (salicylate) that stimulate respiratory centre.
• The renal mechanism tries to compensate by increasing the urinary excretion of HCO3-.

Anion gap

• For a better understanding of acid-base disorders, adequate knowledge of anion gap is essential.
• The total concentration of cations and anions (expressed as mEq/l) is equal in the body fluids. This is required to maintain electrical neutrality.
• The commonly measured electrolytes in the plasma are Na+, K+, Cl− and HCO3- .
• Na+ and K+ together constitute about 95% of the plasma cations. Cl− and HCO3- are the major anions, contributing to about 80% of the plasma anions.
• The remaining 20% of plasma anions (not normally measured in the laboratory) include proteins, phosphate, sulfate, urate and organic acids.

• Anion gap is defined as the difference between the total concentration of measured cations (Na+ and K+) and that of measured anion (Cl− and HCO3-).
• The anion gap (A−) in fact represents the unmeasured anions in the plasma which may be calculated as follows, by substituting the normal concentration of electrolytes (mEq/l)
• Na+ + K+ = Cl- + HCO3- + A-
• 136+ 4 = 100 + 25 + A-
• A- = 15 mEq/L
• The anion gap in a healthy individual is around 15 mEq/l (range 8–18 mEq/l). Acid-base disorders are often associated with alterations in the anion gap.

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Arterial blood gas analysis

• The assessment of acid-base status is usually done by the arterial blood gas (ABG) analyzer, which measures pH, pCO2 and pO2 directly, by means of electrodes.
• Arterial blood is used to measure the acid-base parameters.
• ii. In the absence of a blood gas analyzer, venous blood may be collected under paraffin (to eliminate contact with air).
• Bicarbonate is estimated by Henderson-Hasselbalch equation .
• From the values of Na+, K+, Cl– and HCO3–, the anion gap is calculated.
• Most of the critical care analyzers estimate the blood gas, electrolytes and calculate the anion gap.

Body fluid and electrolyte Homeostasis

• The maintenance of extracellular fluid volume and pH are closely interrelated.
• Body is composed of about 60–70% water. (men 55–70%, women 45–60%). The women and obese individuals have relatively less water which is due to the higher content of stored fat in an anhydrous form.
• Distribution of water in different body water compartments depends on the solute content of each compartment.
• Osmolality of the intra- and extracellular fluid is the same, but there is marked difference in the solute content.

Water intake

• Exogenous water
• Ingested water and beverages, water content of solid foods-constitute the exogenous source of water. Water intake is highly variable which may range from 0.5–5 litres. It largely depends on the social habits and climate.
• The major factors controlling the intake are thirst and the rate of metabolism. The thirst center located in the hypothalamus is stimulated by an increase in the osmolality of blood, leading to increased intake.
• Endogenous water
• The metabolic water produced within the body is the endogenous water. This water (300–350 ml/day) is derived from the oxidation of foodstuffs.
• It is estimated that During oxidation of foodstuffs, 1 g carbohydrate produces 0.6 mL of water, 1 g protein releases 0.4 mL water and 1 g fat generates 1.1 mL of water. Intake of 1000 kcal produces 125 mL water.

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Water output

• Water losses from the body are variable. There are four distinct routes for the elimination of water from the body—urine, skin, lungs and feces.
• Urine This is the major route for water loss from the body. In a healthy individual, the urine output is about 1–2 l/day.
• Water loss through kidneys although highly variable, is well regulated to meet the body demands—to get rid of water or to retain.
• It should, however, be remembered that man cannot completely shut down urine production, despite there being no water intake. This is due to the fact that some amount of water (about 500 ml/day) is essential as the medium to eliminate the waste products from the body.

• Skin
• Loss of water (450 ml/day) occurs through the body surface by perspiration. This is an unregulated process by the body which mostly depends on the atmospheric temperature and humidity. The loss is more in hot climate.
• Fever causes increased water loss through the skin. It is estimated that for every 1°C rise in body temperature, about 15% increase is observed in the loss of water (through skin)
• Lungs
• During respiration, some amount of water (about 400 ml/day) is lost through the expired air. The lat er is saturated with water and expelled from the body.
• In hot climates and/or when the person is suffering from fever, the water loss through lungs is increased. The loss of water by perspiration (via skin) and respiration (via lungs) is collectively referred to as insensible water loss.

• Feces
• Most of the water entering the gastrointestinal tract is reabsorbed by the intestine. About 150 ml/day is lost through feces in a healthy individual.
• Fecal loss of water is tremendously increased in diarrhea. A summary of the water intake and output is as;

Electrolyte balance

• Electrolytes are the compounds which readily dissociate in solution and exist as ions i.e. positively and negatively charged particles. For instance, NaCl does not exist as such, but it exists as cation (Na+) and anion (Cl−). �The concentration of electrolytes are expressed as milliequivalents (mEq/l) rather than milligrams.
• Electrolyte composition of body fluids
• Electrolytes are well distributed in the body fluids in order to maintain the osmotic equilibrium and water balance.
• The total concentration of cations and anions in each body compartment (ECF or ICF) is equal to maintain electrical neutrality.

Osmolarity and osmolality of body fluids

• There are two ways of expressing the concentration of molecules with regard to the osmotic pressure.
• 1. Osmolarity : The number of moles (or millimoles) per liter of solution.
• 2. Osmolality : The number of moles (or millimoles) per kg of solvent.
• If the solvent is pure water, there is almost no difference between osmolarity and osmolality. However, for biological fluids (containing molecules such as proteins), the osmolality is more commonly used. This is about 6% greater than osmolarity.
• Osmolality of plasma Osmolality is a measure of the solute particles present in the fluid medium. The osmolality of plasma is in the range of 285–295 milliosmoles/ kg. This is maintained by kidney. Sodium and its associated anions make the largest contribution (−90%) to plasma osmolality. Osmolality is generally measured by Osmometer.

• For practical purposes, plasma osmolality can be computed from the concentrations (mmol/l) of Na+, K+, urea and glucose as follows
• 2(Na+) + 2(K+) + Urea + Glucose
• The factor 2 is used for Na+ and K+ ions to account for the associated anion concentration (assuming complete ionization of the molecules). Since plasma Na+ is the most predominant contributor to osmolality, the above calculation is further simplified as follows
• Plasma Osmolality (mmol/Kg) = 2x Na+ (mmol/L)
• The above calculation holds good only if plasma concentration of glucose and urea are in the normal range. This calculation, however, will not be valid in severe hyperproteinemia and lipemia.

Osmolality of ECF and ICF

• Movement of water across the biological membranes is dependent on the osmotic pressure differences between the intracellular fluid (ICF) and extracellular fluid (ECF).
• In a healthy state, the osmotic pressure of ECF, mainly due to Na+ ions, is equal to the osmotic pressure of ICF which is predominantly due to K+ ions. As such, there is no net passage of water molecules in or out of the cells, due to this osmotic equilibrium.

Regulation of water and electrolyte balance

• Electrolyte and water balance are regulated together and the kidneys play a predominant role in this regard. The regulation is mostly achieved through the hormones aldosterone, ADH and renin-angiotensin.

ADH

• It is indeed surprising to know that about 180 litres of water is filtered by the glomeruli into the renal tubules everyday. However, most of this is reabsorbed and only 1–2 litres is excreted as urine.
• Water excretion by the kidney is tightly controlled by vasopressin also known as antidiuretic hormone (ADH) of the posterior pituitary gland.
• The secretion of ADH is regulated by the osmotic pressure of plasma. An increase in osmolality promotes ADH secretion that leads to an increased water reabsorption from the renal tubules (less urine output).
• On the other hand, a decrease in osmolality suppresses ADH secretion that results in reduced water reabsorption from the renal tubules (more urine output).
• Plasma osmolality is largely dependent on the sodium concentration, hence sodium indirectly controls the amount of water in the body.
• Diabetes insipidus is a disorder characterized by the deficiency of ADH which results in an increased loss of water from the body

Aldosterone

• It is a mineralocorticoid produced by adrenal cortex. Aldosterone increases Na+ reabsorption by the renal tubules at the expense of K+ and H+ ions. The net effect is the retention of Na+ in the body.
• Renin-angiotensin
• The secretion of aldosterone is controlled by renin-angiotensin system. Decrease in the blood pressure (due to a fall in ECF volume) is sensed by juxtaglomerular apparatus of the nephron which secrete renin.
• Renin acts on angiotensinogen to produce angiotensin I. The latter is then converted to angiotensin II which stimulates the release of aldosterone. Aldosterone and ADH coordinate with each other to maintain the normal fluid and electrolyte balance.

Atrial natriuretic factor (ANF)

• Atrial natriuretic factor (ANF) ANF or atriopeptin is a 28-amino acids containing peptide.
• It is produced in the atrium of heart in response to increased blood volume, elevated blood pressure and high salt intake.
• ANF acts on kidneys to increase GFR, sodium excretion and urine output.
• Thus ANF opposes the actions of renin and aldosterone (which increase salt retention and blood pressure).

Na+ concentration and ECF

• It is important to realise that Na+ and its anions (mainly Cl−) are confined to the extracellular fluid. And the retention of water in the ECF is directly related to the osmotic effect of these ions (Na+ and Cl−).
• Therefore, the amount of Na+ in the ECF ultimately determines its volume. Dietary intake and electrolyte balance
• Generally, the consumption of a well-balanced diet supplies the body requirement of electrolytes.
• Thirst, however, may regulate electrolyte intake also.
• In hot climates, the loss of electrolyte is usually higher. Sometimes it may be necessary to supplement drinking water with electrolytes.

Disturbances in Fluid and Electrolyte Balance

• Abnormalities in fluid and electrolyte balance can be expressed in terms of tonicity.
• When the effective osmolality is increased, the body fluid is called hypertonic and when osmolality is decreased the body fluid is called hypotonic.
• Dehydration
• Dehydration is a condition characterized by water depletion in the body. It may be due to insufficient intake or excessive water loss or both. Dehydration is generally classified into two types.
• 1. Due to loss of water alone.
• 2. Due to deprivation of water and electrolytes.

Causes of dehydration

• Dehydration may occur as a result of diarrhea, vomiting, excessive sweating, fluid loss in burns, adrenocortical dysfunction, kidney diseases (e.g. renal insufficiency), deficiency of ADH (diabetes insipidus) etc.
• Characteristic features of dehydration There are three degrees of dehydration—mild, moderate and severe.
• The salient features of dehydration are given hereunder
• 1. The volume of the extracellular fluid (e.g. plasma) is decreased with a concomitant rise in electrolyte concentration and osmotic pressure.
• 2. Water is drawn from the intracellular fluid that results in shrunken cells and disturbed metabolism e.g. increased protein breakdown.
• 3. ADH secretion is increased. This causes increased water retention in the body and consequently urine volume is very low.
• 4. Plasma protein and blood urea concentrations are increased.
• 5. Water depletion is often accompanied by a loss of electrolytes from the body (Na+, K+etc.).
• 6. The principal clinical symptoms of severe dehydration include increased pulse rate, low blood pressure, sunken eyeballs, decreased skin turgor, lethargy, confusion and coma.

Treatment

• The treatment of choice for dehydration is intake of plenty of water. In the subjects who cannot take orally, water should be administered intravenously in an isotonic solution (usually 5% glucose).
• If the dehydration is accompanied by loss of electrolytes, the same should be administered by oral or intravenous routes. This has to be done by carefully monitoring the water and electrolyte status of the body

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Osmotic imbalance and dehydration in cholera

• Cholera is transmitted through water and foods, contaminated by the bacterium Vibrio cholerae.
• This bacterium produces a toxin which stimulates the intestinal cells to secrete various ions (Cl−, Na+, K+, etc.) into the intestinal lumen. These ions collectively raise the osmotic pressure and suck the water into lumen. This results in diarrhea with a heavy loss of water (5–10 liters/day).
• If not treated in time, the victims of cholera will die due to dehydration and loss of dissolved salts.
• Thus, cholera and other forms of severe diarrhea are the major killers of young children in many developing countries.
• Oral rehydration therapy (ORT) is commonly used to treat cholera and other diarrheal diseases.

Overhydration

• Overhydration or water intoxication is caused by excessive retention of water in the body.
• This may occur due to excessive intake of large volumes of salt free fluids, renal failure, overproduction of ADH etc.
• Overhydration is observed after major trauma or operation, lung infections etc.
• Water intoxication is associated with dilution of ECF and ICF with a decrease in osmolality.
• The clinical symptoms include headache, lethargy and convulsions. The treatment advocated is stoppage of water intake and administration of hypertonic saline.

Hyponatremia :

• This is a condition in which the serum sodium level falls below the normal.
• Hyponatremia may occur due to diarrhea, vomiting, chronic renal diseases, adrenocortical insufficiency (Addison's disease).
• Administration of salt free fluids to patients may also cause hyponatremia. This is due to overhydration.
• Decreased serum sodium concentration is also observed in edema which occurs in cirrhosis or congestive heart failure.
• The manifestations of hyponatremia include reduced blood pressure and circulatory failure.
• 2. Hypernatremia : This condition is characterized by an elevation in the serum sodium level. The symptoms include increase in blood volume and blood pressure.

• It may occur due to hyperactivity of adrenal cortex (Cushing's syndrome), prolonged administration of cortisone, ACTH and/or sex hormones.
• Loss of water from the body causing dehydration, as it occurs in diabetes insipidus, results in hypernatremia.
• Rapid administration of sodium salts also increases serum sodium concentration.
• It may be noted that in pregnancy, steroid and placental hormones cause sodium and water retention in the body, leading to edema. In edema, along with water, sodium concentration in the body is also elevated.
• Administration of diuretic drugs increases the urinary output of water along with sodium. In the patients of hypertension and congestive cardiac failure salt (Na+) restriction is advocated.

Hypokalemia

• Decrease in the concentration of serum potassium is observed due to overactivity of adrenal cortex (Cushing's syndrome), prolonged cortisone therapy, intravenous administration of K+-free fluids, treatment of diabetic coma with insulin, prolonged diarrhea and vomiting.
• The symptoms of hypokalemia include irritability, muscular weakness, tachycardia(heart is beating faster than normal), cardiomegaly(Enlargement of heart) and cardiac arrest. Changes in the ECG are observed (flattened waves with inverted T wave).

Hyperkalemia �

• Increase in the concentration of serum potassium is observed in renal failure, adrenocortical insufficiency (Addison's disease), diabetic coma, severe dehydration, intravenous administration of fluids with excessive potassium salts.
• The manifestations of hyperkalemia include depression of central nervous system, mental confusion, numbness(loss of feel), bradycardia(usually below 60 beats per minute of heart in adults) with reduced heart sounds and, finally, cardiac arrest.
• Changes in ECG are also observed (elevated T wave)

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