Renal Physiology

Renal Physiology PART THREE Renal Acid-Base Balance

Acid • An acid is when hydrogen ions accumulate in a solution. • It becomes more acidic • [H+] increases = more acidity • CO2 is an example of an acid. HCl 2 7 H + Cl- H + Cl- pH H + Cl- H + Cl- H + Cl- As concentration of hydrogen ions increases, pH drops

Base • A base is chemical that will remove hydrogen ions from the solution • Bicarbonate is an example of a base. 2 7 NaOH Na+ OH- H + Cl- H + Cl- pH Na+ OH- Acids and basis neutralize each other H + Cl- H + Cl- Na+ OH- H + Cl- Na+ OH-

A change of 1 pH unit corresponds to a 10-fold change in hydrogen ion concentration 2 7 Na+ Cl- pH Na+ Cl- H+ H2O OH- Na+ Cl- Na+ Cl-

Acids are being created constantly through metabolism • Protein breakdown produces phosphoric acid • Anaerobic respiration of glucose produces lactic acid • Fat metabolism yields organic acids and ketone bodies • Carbon dioxide is also an acid. Transporting CO2 as bicarbonate leads to a release of H+ (an acid)

Acid/Base Balance • There is a pH differential between arterial blood (pH=7.4) and intracellular fluid (pH = 7.0). • Most metabolic reactions liberate H+, and a buffer system is needed to maintain physiological pH.

Buffers • “Buffers are solutions which can resist changes in pH when acid or alkali is added.”

Acids must be buffered, transported away from cells, and eliminated from the body.These are the most important buffers. Phosphate:important renal tubular buffer HPO4- + H+ H2PO4 Ammonia:important renal tubular buffer NH3 + H+ NH4+ Proteins:important intracellular and plasma buffers H+ + Hb HHb Bicarbonate: most important Extracellular buffer and is also another important renal tubular buffer. H2O + CO2 H2CO3 H+ + HCO3-

BUFFERING SYSTEMS BUFFERS USED BY THE BUFFERING SYSTEMS Phosphate Phosphate Respiratory System Bicarbonate Bicarbonate Bicarbonate Blood Proteins Ammonia Kidneys

Phosphate Buffer System • It is mainly an intracellular buffer and a renal tubular buffer. • Its concentration in plasma is very low. • The phosphate buffer system operates in the internal fluid of all cells. This buffer system consists of dihydrogen phosphate ions (H2PO4-) as hydrogen-ion donor (acid) and hydrogen phosphate ions (HPO42-) as hydrogen-ion acceptor (base). These two ions are in equilibrium with each other as indicated by the chemical equation below. H2PO4- H+ + HPO42- • If additional hydrogen (H+) ions enter the cellular fluid, they are consumed in the reaction with HPO42-, and the equilibrium shifts to the left. If additional hydroxide (OH-) ions enter the cellular fluid, they react with H2PO4-, producing HPO42-, and shifting the equilibrium to the right.

Ammonia Buffer System • Important renal tubule buffer. • Excess H+ can be picked up by the ammonia system in a complicated set of reactions. • The kidney makes ammonia by breaking down glutamine (an amino acid). • Ammonium is secreted into the filtrate while the good products are reabsorbed.

Ammonia as a Buffer

Protein buffer system • Most important buffer system in body cells. Also important in the blood. • There are 16 histidine (amino acid) residues in albumin and 38 histidines residues in hemoglobin. • These amino acids can accept a H+ and act as a buffer in the RBC’s and plasma.

BICARBONATE BUFFER SYSTEM • Most important buffer system in the plasma • Accounts for 65% of the buffering capacity in plasma • Accounts for 40% of the buffering capacity in the whole body

Bicarbonate as a Buffer

Phosphate and Bicarbonate Buffers • The phosphate buffer is very effective but not found in high concentrations in all tissues. • The bicarbonate buffer is also very effective and there are high levels of bicarbonate in all tissues that contain carbonic anhydrase (red blood cells, kidney, pancreas, stomach and brain): carbonic anhydraseH2O + CO2 H2CO3 HCO3(-) + H+

Buffering Capacity in Body • 52% of the buffering capacity is in cells • 5% is in RBCs • 43% of the buffering capacity is in the extracellular space • of which 40% by bicarbonate buffer, 1% by proteins and 1% by phosphate buffer system

Buffering Systems • The three different buffering systems are: 1) Respiratory buffering system • Uses bicarbonate 2) Blood buffering system • Uses bicarbonate, phosphate, and protein 3) Renal buffering system • Uses bicarbonate, phosphate, and ammonia

Respiratory Buffering System • The respiratory buffering system uses bicarbonate. The respiratory system controls CO2 levels, while the kidney can excrete bicarbonate. • Hyperventilation leads to loss of CO2 and creates alkaline conditions, while hypoventilation creates acid conditions. • Peripheral receptors detect CO2 concentration changes and send the appropriate signal to the respiratory system. • When CO2 builds up, a central receptor increases ventilation.

Blood Buffering System • The blood buffering system uses three different chemical buffers: phosphate, bicarbonate and proteins. The phosphate buffer is not abundant in blood. Blood contains a high concentration of proteins.

Renal Buffering System • The renal buffer system uses bicarbonate, phosphate and ammonium. In the kidneys, the bicarbonate buffer may increase plasma pH in three ways: secrete H+, "reabsorb" bicarbonate, or produce new bicarbonate. • H+ secretion occurs mostly in the proximal tubule by the carbonic anhydrase reaction. • In acidic conditions, CO2 diffuses inside tubular cells and is converted to carbonic acid, which the dissociates to yield a H+ which is then secreted into the lumen by the Na+/H+ shuttle.

Buffering is good, but it is a temporary solution. Excess acids and bases must be eliminated from the body gas aqueous H2O + CO2 H2CO3 H+ + HCO3- Kidneys can remove excess non-gas acids and bases Lungs eliminate carbon dioxide

Excessive Acids and Bases can cause pH changes---denature proteins • Normal pH of body fluids is 7.40 • Alkalosis (alkalemia) – arterial blood pH rises above 7.45 • Acidosis (acidemia) – arterial pH drops below 7.35 • Acidosis: • Too much acid • Too little base • Alkalosis • Too much base • Too little acid

Compensation for deviation • Lungs (only if not a respiratory problem) • If too much acid (low pH)—respiratory system will ventilate more (remove CO2) and this will raise pH back toward set point • If too little acid (high pH)—respiratory will ventilate less (trap CO2 in body) and this will lower pH back toward set point • Kidneys • If too much acid (low pH)—intercalated cells will secrete more acid into tubular lumen and make NEW bicarbonate (more base) and raise pH back to set point. • If too little acid/excessive base (high pH)- proximal convoluted cells will NOT reabsorb filtered bicarbonate (base) and will eliminate it from the body to lower pH back toward normal.

Acid-Base Balance • How would your ventilation change if you had excessive acid? • You would hyperventilate • How would your ventilation change if you had excessive alkalosis? • Your breathing would become shallow

How can the kidneys control acids and bases? • Bicarbonate is filtered and enters nephron at Bowman’s capsule • Proximal convoluted tubule • Can reabsorb all bicarbonate (say, when you need it to neutralize excessive acids in body) OR • Can reabsorb some or NONE of the bicarbonate (maybe you have too much base in body and it needs to be eliminated)

How can the kidneys control acids and bases? • Acidosis • Intercalated cells • Secrete excessive hydrogen • Secreted hydrogen binds to buffers in the lumen (ammonia and phosphate bases) • Secretion of hydrogen leads to formation of bicarbonate HPO4- NH3

What would happen if the respiratory system had a problem with ventilation?Respiratory Acidosis and Alkalosis Normal PCO2 fluctuates between 35 and 45 mmHg • Respiratory Alkalosis (less than 35mmHg- lowered CO2) • Hyperventilation syndrome/ psychological (fear, pain) • Overventilation on mechanical respirator • Ascent to high altitudes • Fever • Respiratory Acidosis (elevated CO2 greater than 45mmHg) • Depression of respiratory centers via narcotic, drugs, anesthetics • CNS disease and depression, trauma (brain damage) • Interference with respiratory muscles by disease, drugs, toxins • Restrictive, obstructive lung disease (pneumonia, emphysema)

Metabolic acidosis Bicarbonate levels below normal (22 mEq/L) Metabolic alkalosis bicarbonate ion levels higher (greater than 26mEq/L) What if your metabolism changed? • Excessive loss of acids due to loss of gastric juice during vomiting • Excessive bases due to ingestion, infusion, or renal reabsorption of bases • Intake of stomach antacids • Diuretic abuse (loss of H+ ions) • Severe potassium depletion • Steroid therapy • Ingestion, infusion or production of more acids (alcohol) • Salicylate overdose (aspirin) • Diarrhea (loss of intestinal bicarbonate) • Accumulation of lactic acid in severe Diabetic ketoacidosis • starvation

How can you tell if the acid-base imbalance is from a kidney disorder or a lung disorder? Acidosis: pH < 7.4 - Metabolic: HCO3- Or normal - respiratory:pCO2 Alkalosis: pH > 7.4 - Metabolic: HCO3- - respiratory:pCO2 Or normal

pH Imbalances • Acidosis • Can be metabolic or respiratory • Alkalosis • Can be metabolic or respiratory

Acidosis • Acidosis is excessive blood acidity caused by an overabundance of acid in the blood or a loss of bicarbonate from the blood (metabolic acidosis), or by a buildup of carbon dioxide in the blood that results from poor lung function or slow breathing (respiratory acidosis).

Acidosis • Blood acidity increases when people ingest substances that contain or produce acid or when the lungs do not expel enough carbon dioxide. • People with metabolic acidosis have nausea, vomiting, and fatigue and may breathe faster and deeper than normal. • People with respiratory acidosis have headache and confusion, and breathing may appear shallow, slow or both. • Tests on blood samples show there is too much acid. • Doctors treat the cause of the acidosis.

Respiratory acidosis • Respiratory acidosis is due to an accumulation of CO2 in the blood stream. This pushes the carbonic anhydrase reaction to the right, generating H+: carbonic anhydraseCO2 H2CO3 HCO3(-) + H+

Respiratory acidosis • Cause • The increase in CO2 in the blood is often caused by hypoventilation. • This can be caused by asthma, COPD, and overuse of sedatives, barbiturates, or narcotics such as valium, heroin, or other drugs which make you sleepy. • It can also be caused by other things wrong with the lungs: an accident where the breathing muscles are damaged (causing decreased ventilation), airway obstruction, or lung disease (pneumonia, cystic fibrosis, emphysema, etc.).

Respiratory acidosis • Compensation • Even if the peripheral receptors sense the change in pH, the lungs are unresponsive. • The kidneys will compensate by secreting H+. • If H+ excretion cannot restore the balance, the kidneys will also generate bicarbonate. • Since the primary abnormality is an increase in pCO2, the compensatory response is intracellular buffering of hydrogen (by hemoglobin) and renal retention of bicarbonate, which takes several days to occur.

Respiratory acidosis • Symptoms • May have no symptoms but usually experience headache, nausea, vomiting, and fatigue. • Breathing becomes deeper and slightly faster (as the body tries to correct the acidosis by expelling more carbon dioxide). • As the acidosis worsens, people begin to feel extremely weak and drowsy and may feel confused and increasingly nauseated. • Eventually, blood pressure can fall, leading to shock, coma, and death. • The most common clinical intervention is IV bicarbonate and applying an oxygen mask.

Respiratory acidosis • Treatment • Treatment is aimed at the underlying disease, and may include: • Bronchodilator drugs to reverse some types of airway obstruction • Noninvasive positive-pressure ventilation (sometimes called CPAP or BiPAP) or a breathing machine, if needed • Oxygen if the blood oxygen level is low • Treatment to stop smoking

Metabolic acidosis • Metabolic acidosis is the gain of acid or the loss of bicarbonate. • Cause • Usual causes are the generation of ketone bodies in uncontrolled diabetes mellitus, diarrhea (loss of bicarbonate), excess protein consumption (breakdown products are amino ACIDS), or excess alcohol consumption: (alcohol formaldehyde acetic acid). • Can also be caused by ingestion of an acid (aspirin, ethanol, or antifreeze). • Exercise creates a milder, transient metabolic acidosis because of the production of lactic acid.

Metabolic acidosis • Compensation • The body will compensate with hyperventilation and increased bicarbonate reabsorption in the kidney. • Since the primary abnormality is a decrease in HCO3, the compensatory response includes extracellular buffering (by bicarbonate), intracellular buffering (by phosphate and proteins), respiratory compensation and renal hydrogen excretion. • Metabolic acidosis stimulates an increase in ventilation (reducing pCO2). • This hyperventilation is called Kussmaul's respiration.

Metabolic acidosis • Symptoms • Most symptoms are caused by the underlying disease or condition that is causing the metabolic acidosis. • Metabolic acidosis itself usually causes rapid breathing. • Confusion or lethargy may also occur. • Severe metabolic acidosis can lead to shock or death. • In some situations, metabolic acidosis can be a mild, chronic (ongoing) condition.

Metabolic acidosis • Treatment is give i.v. of sodium bicarbonate. • The HCO3- deficit can be calculated by using the following equation: • HCO3- deficit = deficit/L (desired serum HCO3- - measured HCO3-) x 0.5 x body weight (volume of distribution for HCO3-) • This provides a crude estimate of the amount of HCO3- that must be administered to correct the metabolic acidosis; the serum HCO3- level or pH should be reassessed frequently.

Alkalosis • Alkalosis is excessive blood alkalinity caused by an overabundance of bicarbonate in the blood or a loss of acid from the blood (metabolic alkalosis), or by a low level of carbon dioxide in the blood that results from rapid or deep breathing (respiratory alkalosis).

Alkalosis • People may have irritability, muscle twitching, or muscle cramps, or even muscle spasms. • Blood is tested to diagnose alkalosis. • Metabolic alkalosis is treated by replacing water and electrolytes. • Respiratory alkalosis is treated by slowing breathing.

Respiratory alkalosis • Respiratory alkalosis is generally caused by hyperventilation, usually due to anxiety. The primary abnormality is a decreased pCO2. • Cause • Caused from a decrease in CO2 in the blood because the lungs are hyperventilating (anxiety, but not panting). • Fever or aspirin toxicity may also cause respiratory alkalosis.

Respiratory alkalosis • Compensation • The body will reduce the breathing rate, and the kidney will excrete bicarbonate.

Respiratory alkalosis • Compensation • The compensatory response to a respiratory alkalosis is initially a release of hydrogen from extracellular and intracellular buffers. • This is followed by reduced hydrogen excretion by the kidneys. • This results in decreased plasma bicarbonates. • In chronic respiratory alkalosis, compensation can lead to pH returning to normal.

Respiratory alkalosis • Symptoms • Irritability • Muscle twitching • Muscle cramps

Respiratory alkalosis • Treatment • Treatment for hyperventilation is to breathe into a paper bag for a while, as the person breathes carbon dioxide back in after breathing it out. • For severe cases, need to replace the water and electrolytes (sodium and potassium).

Metabolic alkalosis • Metabolic alkalosis is due to the gain of base or the loss of acid. The primary abnormality is an increased HCO3. • Cause • Caused from an increase in bicarbonate in the blood because of ingestion of excess bicarbonate in the form of an antacid (Tums), eating excess fruits (vegetarian diets and fad diets*), loss of acid from vomiting, or loss of potassium from diuretics.

Renal Physiology