Pharm Exam 2 - from notes - Renal Physiology and Anatomy

Renal Physiology and Anatomy

• Kidneys regulate salt and water balance, which affects cardiac output, blood pressure, and perfusion.
• The kidneys also maintain acid-base balance.
• Kidneys filter around 180 liters daily, reabsorbing approximately 178 liters.
• Kidneys remove toxins and metabolites and produce hormones like renin, erythropoietin, and vitamin D.
• Key anatomical structures of the kidneys include the cortex, medulla, renal artery and vein, and ureter.
• The nephron, located in both the cortex and medulla, is the functional unit of the kidney.
• The glomerulus, a capillary collection within Bowman's capsule, filters plasma, with hydrostatic and osmotic pressures influencing filtration.
• Tubule components consist of the proximal convoluted tubule, loop of Henle, distal convoluted tubule, and collecting duct.
• Renal blood flow receives 25% of cardiac output, which is 1-1.2 liters per minute.
• Blood flows from the renal artery to lobar, interlobar, arcuate, and interlobular arteries, then to the afferent arteriole, glomerulus, efferent arteriole, and eventually to the renal vein and IVC.

Auto-regulation and Hormonal Influence

• Auto-regulation maintains renal blood flow with a mean arterial pressure (MAP) between 80-180.
• The kidneys vasodilate or vasoconstrict to maintain perfusion.
• Filtration may stop below a MAP of 50.
• Afferent arterioles mediate auto-regulation via vasodilation or vasoconstriction.
• Aldosterone, from the adrenal cortex, promotes distal reabsorption of sodium and water and secretion of potassium.
• Hyperkalemia strongly triggers aldosterone release.
• Antidiuretic hormone (ADH) increases water permeability in the distal tubule and collecting duct to reabsorb water.
• The Renin-Angiotensin System involves angiotensinogen from the liver being converted to angiotensin I, then to angiotensin II by ACE (from the lungs).
• Angiotensin II causes vasoconstriction, sodium and water reabsorption, potassium secretion, and ADH release.
• Atrial Natriuretic Peptides (ANP) promote natriuresis and diuresis, responding to atrial stretch.
• ANP decreases sodium reabsorption and produces vasodilation.
• Renal Prostaglandins maintain renal blood flow during ischemia, with most causing vasodilation.

Acid-Base Balance

• Kidneys regulate plasma and urine pH, with urine pH typically a little over 4.5.
• Bicarbonate reabsorption is a primary function.
• On the apical border, sodium and hydrogen exchange occurs and hydrogen combines with bicarbonate to form carbonic acid, which is then broken down by carbonic anhydrase into water and CO2.
• Water and CO2 diffuse back into the cell.
• Bicarbonate is transported with sodium via a co-transporter and exchanged for chloride.
• Alpha intercalated cells in the collecting duct use a hydrogen pump to excrete hydrogen, buffered by hydrogen phosphate.

Renal Processes

• Filtration involves the passive movement of water and small molecules into the filtrate.
• Red blood cells and large proteins should not be filtered unless there is renal injury.
• Reabsorption involves the movement of substances from the filtrate back into the plasma.
• Secretion involves the movement of substances from the plasma into the filtrate.
• Excretion involves the elimination of substances from the body.

Diuretics

• Diuretics inhibit sodium reabsorption, promoting urinary loss of sodium and water.
• They are used for hypertension, heart failure, kidney disease, and liver disease.

Classes of Diuretics

• Carbonic Anhydrase Inhibitors (Acetazolamide) block carbonic anhydrase enzymes in the proximal tubule and collecting duct, reducing hydrogen ions intracellularly in exchange for sodium.
• Carbonic Anhydrase Inhibitors decrease reabsorption of sodium, bicarbonate, and water, leading to natriuresis, diuresis, and alkaline urine, with side effects of metabolic acidosis, hypokalemia, hyperchloremia, and kidney stones.
• Osmotic Diuretics (Mannitol) are inert substances freely filtered by the glomerulus, increasing osmolarity of plasma and filtrate.
• Osmotic Diuretics decrease water reabsorption with side effects like increased plasma volume, potential for pulmonary edema, hypovolemia with long-term use, hypokalemia, and hyponatremia, with a general dose of 0.25 to 2 grams per kilo IV.
• Loop Diuretics (Furosemide) block the sodium-potassium-2-chloride co-transporter in the thick ascending limb of the loop of Henle.
• Loop Diuretics decrease reabsorption of sodium, potassium, chloride, and water, leading to natriuresis, diuresis, and hypokalemia, with side effects of hypokalemia, hyponatremia, hypocalcemia, hypomagnesemia, metabolic alkalosis, hypotension, and ototoxicity.
• Thiazide Diuretics (Hydrochlorothiazide) block the sodium-chloride co-transporter in the distal convoluted tubule, which increase excretion of sodium, chloride, and water and increase reabsorption of calcium.
• Thiazide Diuretics cause side effects like hypokalemia, hyponatremia, hypercalcemia, hyperuricemia, metabolic alkalosis, and hyperglycemia.
• Potassium-Sparing Diuretics decrease sodium and water reabsorption in the collecting duct, without increasing potassium excretion.
• Potassium-Sparing Diuretics: ENaC Blockers (Triamterene, Amiloride) block sodium channels, and Aldosterone Receptor Antagonists (Spironolactone, Eplerenone) inhibit aldosterone binding.
• Potassium-Sparing Diuretics cause side effects like hyperkalemia, hyponatremia, metabolic acidosis, dehydration, hypotension, and gynecomastia.

Anesthetic Considerations

• It's usually okay to hold diuretics, especially thiazides for hypertension, but continue if needed for severe heart failure.
• Assess fluid volume status and electrolytes, especially potassium.
• Maintain renal blood flow, correct hypovolemia, minimize vasodilators, treat pain and stress, and avoid nephrotoxic agents intraoperatively.

Body Fluid Compartments and Composition

• Total Body Water (TBW) averages 42 liters in a 70 kg person.
• TBW varies based on sex, age, and body composition (muscle ~75% water, adipose ~10% water).
• TBW is divided into intracellular and extracellular spaces.
• Extracellular space is approximately 1/3 of TBW and is divided into interstitial fluid (~80%) and plasma (~20%).
• Intracellular space is rich in potassium and phosphate.
• Extracellular space is rich in sodium and chloride and includes transcellular spaces like cerebrospinal fluid (CSF).
• Plasma composition consists primarily of water, plasma proteins (albumin, globulins), salts, O2, CO2, nutrients, waste products, hormones, vitamins, and blood cells.
• Plasma proteins are for oncotic pressure, pH balance, and drug binding.
• Small ions move freely between plasma and interstitial fluid, whilst proteins and macromolecules do not move freely due to tight junctions between endothelial cells and the glycocalyx layer.
• Endothelial cells lining vessels have varying degrees of tightness: continuous endothelium (tight junctions), fenestrated endothelium (larger gaps/pores), and discontinuous endothelium (large spaces).
• Fenestrations are induced for absorption.
• Inflammation can damage the glycocalyx layer and tight junctions, increasing permeability and allowing larger molecules and proteins to move across, increasing albumin movement.

Monitoring Intravascular Volume Status

• Standard monitors include a non-invasive blood pressure cuff and heart rate monitoring.
• Advanced monitors include an arterial line, cardiac output monitor, and central line with CVP.
• The risk of volume changes should be assessed based on the surgery and patient comorbidities to decide on the level of monitoring needed.
• Static parameters reflect one moment in time and include blood pressure and heart rate.
• Compensatory mechanisms can mask hypovolemia, especially in young patients, and beta-blockers can mask tachycardia.
• Dynamic parameters assess fluid responsiveness to guide fluid therapy, particularly in invasive surgeries with large blood losses or fluid shifts.
• Respiratory Variation measures variation in arterial blood pressure waveform or pulse oximetry during mechanical ventilation.
• Positive pressure ventilation increases intrathoracic pressure, potentially compressing vessels and reducing venous return.
• Variation >10-12% suggests hypovolemia and fluid responsiveness.
• Pulse Pressure Variation is calculated using max and min pulse pressure values.
• Systolic Pressure Variation is calculated using max and min systolic pressure values.
• Spontaneous ventilation, low tidal volumes, high PEEP, open thoracic surgery, increased intra-abdominal pressure, tamponade, arrhythmias, and right heart failure limit accuracy.
• High doses of vasoactive infusions can also affect the Frank-Starling curve.
• The Expiratory Occlusion Test stops ventilation for 15 seconds to assess preload changes.
• Ultrasound uses Esophageal Doppler or echocardiography to measure chamber volume and function.
• Non-invasive Technologies include Pleth variability index (PVI) using pulse oximetry, pulse wave analysis, and CO2 rebreathing.
• Increasing lactate levels may indicate decreased tissue perfusion.

Intravenous Fluids

• Crystalloids contain electrolytes and low molecular weight molecules, but no proteins and are classified by osmolality relative to plasma (isotonic, hypertonic, hypotonic).
• Isotonic Solutions have a similar osmolality to plasma, used in anesthesia.
• Balanced Crystalloids mirror plasma electrolyte levels.
• Isotonic Solutions should not cause fluid movement in or out of cells and are used for volume replacement and drug/blood product administration.
• Strong Ion Difference (SID) is the difference between strong cations (sodium, potassium) and anions (chloride) and has a normal SID ~ 40.
• In healthy patients, only 20-25% Isotonic Solutions remains intravascularly, with effects lasting ~30 minutes, increasing in effectiveness in dehydrated or hemorrhaging patients.
• Historically Isotonic Solutions were used liberally, but now trending towards restrictive approaches.
• Hypotonic Crystalloids have a lower osmolality; they cause water to shift into cells and are used to treat solute-free water deficits and for maintenance.
• Hypertonic Solutions have a higher osmolality causing water to shift out of cells and are used to remove excess water from cells.
• Colloids contain large molecular weight particles/macromolecules (e.g., proteins, starches).
• Colloids help retain fluid in the vascular space.
• Albumin is naturally derived, available in 5% and 25% concentrations, increasing serum albumin and colloidal osmotic pressure, and is expensive.
• Hydroxyethyl Starches (HES) are synthetic and associated with bleeding, kidney injuries, and adverse events.
• Hydroxyethyl Starches (HES) have a black box warning limits use, especially in critically ill patients and can persist in tissues, causing renal dysfunction and pruritus.
• Crystalloids are typically the first choice for IV fluid replacement, with Colloids being used when fluid restriction is necessary.

Hypovolemia and Hypervolemia

• Hypovolemia can be caused by fasting, bowel prep, diuretics, inflammatory disorders, hemorrhage, surgical bleeding, patient positioning, and positive pressure ventilation.
• Hypovolemia is treated with a crystalloid bolus of 250-500 mL in adults, then reassess.
• Hypervolemia can be caused by excess fluid administration, heart failure, renal failure, and anesthetics.
• Hypervolemia causes risks like tissue perfusion impairment, oxygen exchange issues, edema, and dilutional coagulopathy.

Goal-Directed Fluid Therapy (GDFT)

• Goal-Directed Fluid Therapy Optimizes volume status before vasopressors are used.
• Protocols may involve initial fluid administration followed by boluses based on dynamic parameters.

Blood Physiology and Transfusion

• Blood Components are 45% cells (primarily red blood cells/hematocrit) and 55% plasma (water, proteins, nutrients).
• Blood Cell Production occurs in the bone marrow, liver, and spleen.
• Red Blood Cells (Erythrocytes) have a flexible shape and contain hemoglobin for O2 binding.
• Anemia is a reduction in red blood cell count or hemoglobin due to hemorrhage, marrow failure, dietary deficiencies, or kidney disease.
• Iron is absorbed in the diet, transported by transferrin, and is essential for erythrocyte production.
• Blood Types are based on antigens on cell surfaces, and Rh factor is an inherited protein on red blood cells.
• Red Blood Cell Storage causes biochemical changes, including depletion of ATP and 2,3-DPG, with older cells having decreased O2 delivery and increased inflammatory response.
• General Transfusion Thresholds are Hemoglobin 7-8 g/dL, Cardiac Patients have a higher threshold of 9-10 g/dL, and Young, Healthy Patients have a lower threshold of 6 g/dL.
• Administration requires large-bore IV access, following protocol for checking blood products to avoid errors, using filters to remove aggregates and leukocytes, and keeping blood products cold until use.
• Normal saline is used for dilution, avoiding dextrose-containing or hypotonic solutions.

Blood Products

• Plasma (FFP) contains coagulation factors and is used to replace volume and coagulation factors with a dose of 10-15 mL/kg.
• Cryoprecipitate (Cryo) is a protein fraction from frozen plasma rich in factors I, VIII, XIII, used to increase fibrinogen, with a dose of 1 unit per 10 kg.
• Platelets have a lifespan of 8-12 days and are transfused to increase platelet count.
• Adverse Effects of Transfusion include inflammatory response, infection, TACO (volume overload), and TRALI (acute lung injury).

Massive Transfusion

• Massive Transfusion is the transfusion of >10 units of blood in 24 hours.
• Pathophysiology involves extensive vascular and tissue injury leading to endothelialopathy, coagulopathy, inflammation, and multi-organ dysfunction.
• Management prioritizes blood products over crystalloids, monitoring coagulation profiles and using thromboelastography (TEG) or rotational thromboelastometry (ROTEM) for goal-directed management.
• The Transfusion Ratio is 1:1:1 ratio of FFP, platelets, and red blood cells.
• Goals are PT 150 x 10^9/L and hemoglobin 8-10 g/dL.
• Calcium Replacement using calcium chloride or gluconate to address hypocalcemia.
• Liver transplant, cardiac surgery, and obstetric patients may require massive transfusion.
• The goal fibrinogen in obstetric patients is >200 mg/dL.
• Uterotonics are used in postpartum hemorrhage to increase uterine smooth muscle contraction.

Sodium

• The majority of sodium is in the extracellular fluid, with a higher plasma concentration of around 135 to 145 mEq/L.
• Sodium is important for osmotic balance and volume, nerve impulse conduction, and muscle contraction.
• Most sodium comes from diet or IV fluids.
• Kidneys are the primary determinant of sodium balance, with most filtered sodium being reabsorbed.
• The renin-angiotensin-aldosterone system, antidiuretic hormone, and the sympathetic nervous system are involved in sodium handling.
• Excretion is stimulated by parathyroid and natriuretic peptides, triggering natriuresis.
• Hyponatremia (low sodium levels) can be hypervolemic, hypovolemic, or euvolemic, with symptoms including cerebral edema or confusion, nausea, vomiting, and muscle cramps, and treatment depends on the underlying cause.
• Hypernatremia is usually due to water loss or osmotic diuresis, with symptoms including signs of dehydration or fluid excess, cellular death, altered mental status, and seizure, and treatment depends on the underlying cause.

Potassium

• The majority of potassium is intracellular, with low plasma levels of 3.5 to about 5.
• Potassium functions include membrane excitability, kidney function, vasodilation, inhibition of thrombus formation and platelet activation, and influence on osmotic pressure.
• Kidneys are the primary determinant of potassium and actively secrete it into the urine.
• Aldosterone, glucocorticoids, and vasopressin increase secretion, while catecholamines decrease secretion in the collecting ducts.
• Acidosis decreases potassium secretion, while alkalosis increases potassium secretion
• Hypokalemia is primarily caused by diuretics, beta agonists, insulin, antibiotics, catecholamines, and GI losses, with symptoms including muscle weakness, cramps, and dysrhythmias.
• Hypokalemia treatment involves determining the cause and potassium replacement via PO or IV administration, typically at 10 mEq/hour peripherally or 20 mEq/hour through a central line, with cautious replacement required for patients with diminished potassium regulation.
• Hyperkalemia is usually due to potassium redistribution or inhibition of secretion by the kidneys.
• Drugs affecting hyperkalemia levels include succinylcholine, aldosterone antagonists, beta antagonists, and non-steroidal drugs, with symptoms including peaked T-waves, widened QRS.
• Hyperkalemia treatment often involves calcium to stabilize the heart, sodium bicarbonate, insulin and glucose, K-exalate, beta agonists, and loop diuretics.

Magnesium

• The majority of magnesium is intracellular, with a low plasma concentration of about 1.7 to 2.4.
• Magnesium functions in protein synthesis, nucleic acid stability, neuromuscular function (muscle relaxation), and is an antiarrhythmic, vasodilates, stabilizes the blood-brain barrier, and can decrease anesthetic requirements.
• Most magnesium comes from diet or supplements, with the kidneys helping to regulate levels.
• Hypomagnesemia is usually caused by dietary deficiency or malabsorption, Renal losses can occur through diuretics or nephropathy, with symptoms including cardiac and neuromuscular symptoms.
• Hypermagnesemia can result from excessive supplemental magnesium administration, with symptoms including a wider QRS, conduction block or asystole, hypotension, respiratory depression, muscle paralysis, and narcosis.
• Treatment for hypermagnesemia is calcium gluconate, diuretics, or dialysis.
• Magnesium is indicated for preeclampsia, dysrhythmias, cardiopulmonary bypass, and asthma patients, and also has anti-nociceptive effects.

Calcium

• Over 99% of calcium is in the skeleton.
• Serum levels are about 8.5 to 10.5 mg/dL, or 4.5 to 5.5 mEq.
• Ionized calcium (51% of plasma level) is the form that produces physiologic effects, with a normal level of 2 to 2.5 mEq/L.
• Acidosis increases ionized calcium levels, while alkalosis decreases them.
• Protein-bound calcium (40%) binds to albumin, which means that low albumin states can decrease total plasma calcium.
• Functions include musculoskeletal strength and contraction, neuromuscular transmission, contractility in the heart, rhythm, vascular motor tone, coagulation, and intracellular signaling.
• The endocrine system controls calcium regulation through vitamin D, parathyroid hormone, and calcitonin.
• Bone acts as a reservoir.
• Hypocalcemia can be due to a decrease in albumin or vitamin D or disorders like hypoparathyroidism, citrate binding, with symptoms including neuromuscular excitability and dysrhythmias.
• Treatment includes calcium chloride or calcium gluconate, with caution to avoid rapid IV push for either.
• Hypercalcemia is usually related to hyperparathyroidism, cancer, or excess dietary supplementation, with symptoms including GI relaxation and a shortened QT.
• The goal is to promote the kidneys to get rid of calcium by giving IV fluids and loop diuretics.

Phosphate

• The majority of phosphate is intracellular, particularly in bone and soft tissue, with a plasma level of about 3 to 4.5.
• Functions in energy metabolism, intracellular signaling, immune system regulation, coagulation cascade regulation, and as a buffer for acid-base balance.
• There is an interplay between phosphate and calcium.
• Hypophosphatemia permits an increase in serum calcium, with symptoms including profound skeletal muscle weakness.
• Hyperphosphatemia is quite rare.

Hemostasis

• Hemostasis involves procoagulation.
• Injury to a blood vessel initiates a cascade of effects to plug the hole and prevent blood loss.

Primary Hemostasis

• Primary hemostasis involves the formation of a platelet plug.
• Primary hemostasis includes three phases: adhesion, activation, and aggregation.
• Endothelial cells break to expose collagen for adhesion.
• Endothelial cells release von Willebrand factor (vWF), which helps platelets adhere to the sub-endothelial collagen layer.
• Von Willebrand disease results in increased bleeding time because platelets has a difficult time adhering to the collagen layer.
• Thrombin (Factor IIa) binds to thrombin receptors on the platelet, which changes the platelet's shape for activation.
• Mediators like thromboxane A2 and adenosine diphosphate (ADP) are released.
• Thromboxane A2 uncovers a fibrinogen receptor for aggregation.
• Fibrinogen binds and helps to link the platelets.
• Prostacyclin inhibits platelet aggregation to avoid occluding the vessel.

Secondary Hemostasis

• Secondary hemostasis involves the coagulation cascade and clotting factors to form a more stable clot.
• Clotting factors are produced by the liver.
• Factors II, VII, IX, and X are vitamin K dependent.
• Secondary hemostasis follows a three-phase model: initiation, amplification, and propagation.
• Initiation (Extrinsic Pathway) is initiated by damage exterior to the vascular compartment.
• Thromboplastin (Factor III) is released, which activates Factor VII.
• Factor III and VII form a complex with calcium (Factor IV) on the platelet surface, activating Factor X.
• Amplification (Intrinsic Pathway) is where damage to the interior of the vessel increases activity.
• Factor XII is converted to XIIa, which activates XI, which activates IX.
• Factor IX forms a complex with VIII and calcium on the platelet surface, which activates Factor X.
• Propagation (Final Common Pathway) occurs when Factor Xa forms a complex with activated Factor V and calcium.
• This converts prothrombin into thrombin.
• Thrombin (Factor IIa) converts fibrinogen to fibrin.
• Factor XIII then helps to form a stable clot.

Coagulation Testing

• APTT evaluates the intrinsic and final common pathways.
• PT evaluates the extrinsic and final common pathways.
• INR provides equivalency across different labs and reagents used for prothrombin time.
• ACT monitors heparinization or protamine antagonization.
• Prolonged PT can be seen with decreased factors VII and V, warfarin use, or liver dysfunction.
• Prolonged PTT can be seen in hepatic dysfunction, leukemia, intrinsic factor or vitamin K deficiencies, or heparin use.

Anticoagulants

• Anticoagulants are used for cardiovascular procedures, preventing clots, cardiovascular disease, and arrhythmias.
• Heparin (Unfractionated) binds reversibly to antithrombin III, increasing its activity, inhibiting thrombin and factors Xa, XIIa, XIa, and IXa.
• IV administration provides immediate onset, while subcutaneous administration takes 1-2 hours.
• Heparin resistance may be related to antithrombin III deficiency.
• Major sites of action are factors Xa and IIa, and the intrinsic pathway.
• A possible adverse effect is heparin-induced thrombocytopenia (HIT).
• Low Molecular Weight Heparin causes greater inhibition of Factor Xa than Factor IIa, has less protein binding, is more predictable in effectiveness, and is cleared by the kidneys.
• Protamine does not effectively neutralize Low Molecular Weight Heparin.
• Warfarin inhibits vitamin K epoxide reductase, which converts vitamin K dependent factors into their active form and is monitored via PT and INR.
• Fondaparinux is a synthetic anticoagulant that inhibits Factor Xa indirectly.
• Direct Thrombin Inhibitors are parenteral drugs that directly inhibit Factor IIa.
• Dabigatran is an oral direct thrombin inhibitor where the manufacturer advises against regional anesthesia.
• Direct Factor Xa Inhibitors are used to reduce stroke and DVT prophylaxis.
• Aspirin irreversibly acetylates cyclooxygenase, preventing thromboxane A2 formation.
• Clopidogrel (Plavix) binds to the P2Y12 receptor, inhibiting ADP binding.
• Kengrealor is a direct-acting P2Y12 inhibitor in IV form with a short half-life.
• Glycoprotein IIb/IIIa Antagonists block fibrinogen from linking platelets.

Physiology of Anticoagulation

• Activated antithrombin III binds to Factors IIa and Xa and partially inhibits Factors IX, XI, and XII, and is synthesized by the liver and requires heparin as a cofactor.
• Plasminogen is converted to plasmin by tissue-type plasminogen activator (tPA).
• Plasmin helps break down clots.
• Protein C is activated by thrombin and thrombomodulin complex and has anti-inflammatory processes.
• Protein S binds to Factors Va and VIIIa.

Procoagulants/Antifibrinolytics

• Antifibrinolytics reduce the risk of bleeding and the need for transfusion.
• Aminocaproic Acid (Amicar) is synthetic and inhibits conversion of plasminogen to plasmin.
• Tranexamic Acid (TXA) inhibits conversion of plasminogen to plasmin, and can directly inhibit activated plasmin in high doses.
• TXA is administered IV or topically.
• Aprotinin inhibits plasmin.
• Protamine is a polypeptide base that inactivates heparin molecules via acid-base neutralization.
• DDAVP increases the release of endogenous stores of von Willebrand factor and Factor VIII from endothelial cells.
• Fibrinogen is needed for stable clot formation and is replaced via cryoprecipitate or fibrinogen concentrate.
• Recombinant Activated Factor VII forms a complex with tissue factor.
• Topical Hemostatic Agents are used by surgeons to assist in local hemostasis.