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   Pancreatitis: inflammation of the pancreas is most often not infectious in nature, it is from gallstones obstructing pancreatic outflow, or alcohol having direct toxic effects and decreasing the sphincter of Oddi motility  51: Liver and Biliary System, Large Intestines (Nguyen)    ...

   Pancreatitis: inflammation of the pancreas is most often not infectious in nature, it is from gallstones obstructing pancreatic outflow, or alcohol having direct toxic effects and decreasing the sphincter of Oddi motility  51: Liver and Biliary System, Large Intestines (Nguyen)     Liver  Portal system transports blood from the intestines to the liver, where the portal system turns into sinusoidal capillaries  Kupffer cells are phagocytes (macrophages) that sample the portal blood, cleansing it of pathogens and debris that escapes the intestinal lumen. Damage to the kupffer cells may lead to sepsis  Liver has portal vein blood supply, and arterial blood supply, the blood it receives gets detoxified, metabolites get processed into excretabile forms, albumin and clotting factors are synthesized, and bile gets made.  The liver is the site of gluconeogenesis, and is a glycogen storage area. Because of this, in liver failure, hypoglycemia is common.  Drugs we take orally go to the liver and immediately undergo first pass metabolism  Cholesterol 7alpha hydroxylase is rate limiting step of cholesterol -> bile Bile flow  Hepatocytes release bile into the bile canaliculi, which feed into bile ducts.  Right bile duct + left bile duct = common hepatic duct  Common hepatic duct + cystic duct= common bile duct  Cystic duct drains gallbladder  Common bile duct meets with the main pancreatic duct, forming the hepatopancreatic ampulla, which empties into the duodenum via sphincter of Oddi  CCK relaxes the sphincter of Oddi, remember it is released by I-cells in response to fat, it allows emulsifying agents to enter  This anatomical relationship is why gallstones lead to pancreatitis Clinical Correlations  Hepatic Encephalopathy: Liver failure impairs ammonia metabolism, increasing the circulating ammonia levels in the blood. The increased ammonia will go to the brain, be converted into glutamine, can cause symptoms of confusion, and coma. The root of the problem is liver damage increasing circulating ammonia, treat by reducing ammonia  Gilbert’s Syndrome: bilirubin is a component of bile. In Gilbert’s syndrome there is a defect in metabolism of bilirubin(no glucuronidation) leading to increased unconjugated bilirubin  Dubin-Johnson Syndrome: defect in hepatocyte excretion of bilirubin into bile canaliculi, defective MRP2 gene, increased conjugated bilirubin  Ileal Resection: Bile salts get reabsorbed by the ileum after fat digestion and recycled. If the ileum is removed, the bile salts will not be reabsorbed, leading to impaired fat digestion and steatorrhea. Large Intestine  Haustral contractions slowly push chyme through the large colon, where it reabsorbs water(mostly in the right colon) fecal waste is stored in the left colon  Large intestine secretes bicarb to neutralize the acids produced by the rich bacterial population, and mucus to protect the lumen from fecal abrasions  Mass movements are propulsive movements, intense prolonged peristaltic contractions, forces contents toward the rectum  Gastrocolic reflex occurs when the stomach is activated by food, initiating a mass movement in the colon  Defecation: caused by relaxation of both internal and external anal sphincters, and increase in abdominal pressure. Internal sphincter is parasympathetically relaxed, external sphincter is voluntarily relaxed 52: Overview of Renal Physiology (Zagvazdin)           Blood → Kidney → filtration at glomerulus → filtrate flows through nephron → collecting duct → ureters → bladder → urethra (void) Kidney: Excretory (Filter Blood), Secretory (Homeostasis of Body Fluids), Endocrine (Hormones) Calcitriol: Vitamin D (active form)  Gut: Increases Ca+ and Phosphate absorption  Kidney: Increases Ca+ reabsorption Erythropoietin: low pO2 → stimulates bone marrow to increase RBC synthesis Renin: released w/ low AFFERENT arteriole BP; activates RAAS system (increase BP) Renalase: break down catecholamines Capsule (Superficial) → Cortex (Salty) → Medulla (IM: very salty) Nephron: Functional Unit of Kidney Filtrate:  Afferent arteriole → glomerulus → bowman’s → PCT → thin descending limb of loop → thin ascending loop → thick ascending limb → DCT → collecting duct  Collecting ducts: conglomerate papillary ducts → drain into renal papilla → minor calyx → major calyces → renal pelvis → ureters Nephron types:  Cortical (most) Juxtamedullary (best when need to conserve water)  Loop descends deep into medulla Corticomedullary gradient  Cortex: Interstitial osmolarity is 290  Medulla: Interstitial osmolarity is 1200 (very salty)  Filtrate travels into medulla → water reabsorbed → filtrate concentrated (needs higher interstitial osmolarity to pull water out the deeper it goes) Urine formation:  Filtration: glomerulus  Reabsorption: renal tubule lumen, back into blood  Secretion: blood into the lumen (not from filtration)  Excretion: end product (Filtration PLUS Secretion MINUS Reabsorption)  Remember, F and S are in the excretion tubule lumen, that would equal what is excreted, BUT we have to account for what is     Filtration > Excretion = Reabsorption occurred Filtration < Excretion = Secretion occurred Filtered load of a substance = GFR x plasma concentration of that substance  Filtered concentration over time! Excretion rate = Urine flow x urine concentration of that substance  Excretion of a substance over time! 53: Body Fluids (Zagvazdin)                  60% body weight is water, 40% of that water is ICF; 20% of that water is ECF  ECF: 75% interstitial fluid; 25% plasma Plasma: 55% of blood volume RBCs: 45% of blood volume Transcellular fluid: CSF, GI fluids, aqueous humor (this is smallest body fluid compartment) Nephrotic syndrome:  ↓ proteins in urine leads to:  ↓ albumin in blood, which leads to:  ↓ osmotic pressure, causing:  ↑ edema ICF: High in K+, Phosphate, Proteins, Mg ECF: Na+, Ca+, Cl-, Bicarb Oliguria: low urine (<500mL in a day) Anuria: no urine Polyuria: way too much peeing lol Urinalysis:  Colorless: ↑ output and ↓ osmolarity  Cloudy: leukocyte and bacteria (infection!)  Red-brown without RBCs: hemoglobin or myoglobin Rhabdomyolysis: muscle wasting (Coca-Cola urine)  Urine dipstick + for blood (heme)  Myoglobinuria and elevated plasma creatinine kinase to confirm  As muscles lyse, their intracellular contents are released to blood Intravascular hemolysis (RBC destruction): can cause hemoglobinuria due to haptoglobin saturation when so much hemoglobin is released Urine casts: crystal-like structures of Tamm-Horsfall protein Specific gravity: concentrating ability of urine Protein concentration: SHOULD be negative or trace on dipstick Decreased kidney function:  Elevated creatinine in blood (less clearance of muscle metabolism products; decreased GFR)  Elevated BUN (less urea clearance, decreased GFR) 54 and 55: Glomerular Filtration Rate and Renal Blood Flow I-II (Zagvazdin)     Blood → afferent arteriole → glomerulus filtration → capillary through endothelial cells → negatively charged basement membrane → between podocyte foot processes → bowman’s capsule  Basement membrane is negatively charged as a protective mechanism to NOT FILTER out albumin (we need it!) Mesangial cells: present in glomerulus, modified smooth muscle cells (respond to vasoactive substances)  Diabetic nephropathy: mesangial cells proliferate to the point that blood flow and filtration is impeded Granular cells: juxtaglomerular cells; release renin to increase BP  In close relationship to the afferent arteriole, sending flow incoming toward the kidney  Sympathetic input is targeted at the granular cells Macula dense: part of the juxtaglomerular apparatus that senses filtrate flow; can stimulate granular cells  Filtered:  Plasma substances get filtered (besides protein)  Water, ions, glucose, amino acids (small and lack large negative charge)  NOT filtered:                  Blood cells (normally)  Larger, negatively charged molecules Tamm-Horsfall protein: synthesized in renal tubules, normally found in urine  Only trace amounts of proteins should be found in urine analysis  High amounts of proteinuria (>3g/day) cause decreased oncotic pressure  Nephrotic syndrome is profound proteinuria (periorbital edema) Nephritic: blood (hematuria) HTN, oliguria, slightly elevated proteinuria Nephrotic: profound proteinuria, edema, hypoalbuminemia, hyperlipidemia  Minimal change disease: effacement of podocytes on electron microscopy Glomerulonephritis: casts, RBC casts, hematuria, mesangial contraction and proliferation, WBCs in glomerulus Decreased GFR:  Acute drop: often reversible, due to inflammation (proliferation of mesangial cells), infection, drugs  Chronic drop: chronic kidney disease (CKD Stage 1-5; 5 being end-stage kidney disease)  Normal GFR is about 100; end-stage CKD GFR is about 15 Hydrostatic and oncotic forces in the glomerular capillary mediate GFR  Net filtration pressure = plasma hydrostatic pressure – bowman’s space hydrostatic pressure – plasma oncotic pressure  Net filtration decreases as the capillary gets closer to the efferent arteriole Afferent dilation and efferent constriction will increase GFR the most Afferent constriction or renal artery stenosis will decrease RBF, decreasing GFR Efferent stenosis: buildup and backflow, increasing GFR RBF: Plasma (55%) and RBCs (45%)  RBCs: Hematocrit  Renal Plasma Flow = RBF x (1-Ht)  Ht = 0.45 GFR = FF x RPF  FF: Filtration fraction Control Mechanisms:  Neural control: sympathetic nerves  Hormonal control: angiotensin  Intrinsic control: autoregulation  Ensures RBF and GFR remain relatively constant despite changes in BP Hydrostatic pressure: DROPS along length of afferent and efferent arterioles  Constant across glomerular capillary Oncotic pressure: CONSTANT across afferent and efferent arterioles  INCREASES across glomerular capillary GFR: Amount of filtrate produced per unit of time  Normal: 100-120 mL/min  GFR = Kf x NFP  Creatinine:  Freely filtered; NOT reabsorbed; SLIGHTLY secreted  High in plasma means low GFR (kidney not filtering properly)  Overestimates GFR because creatinine is slightly secreted  Inulin Clearance:  Only filters (no S or R)  HIGH BUN: indicator of low GFR (urea not being filtered out) AKI: Sudden drop in GFR  Prerenal azotemia  ↓ blood flow to kidney  ↑ BUN (azotemia means nitrogen in blood)  Examples: Atherosclerosis and ischemic nephropathy  Stenosis of left renal artery  Postrenal azotemia  ↓ urine outflow from kidney (obstruction)  Examples: kidney stones  Chronic renal failure  Results in uremia: chronically elevated BUN  GFR below 60 is when clinical manifestations begin    Proximal Tubule:  Na reabsorption: ACTIVE process  Glucose, amino acids, and phosphate are co-transported with the sodium across apical membrane  Na/K ATPase drives reabsorption of molecules and ions across basolateral membrane  Na/H pump counter transport drive secretion of H+  Chloride transport:  Paracellularly  Driven by transepithelial potential difference  Water:  Osmosis (high oncotic pressure in proximal peritubular capillary)  Water follows salt!  Fluid in proximal tubule remains isotonic because of this mechanism  Solvent drag: along with osmotic water flow, it takes ions like K+ and Ca+ with it  Bicarb reabsorption: linked to H+ secretion (involves carbonic anhydrase)  As H+ is secreted, bicarb and H combine and carbonic anhydrase converts H2CO3 into water and CO2, which can pass through the membrane!  Carbonic Anhydrase Inhibitors:  Glaucoma treatment: inhibit the formation of aqueous humor  Suppresses bicarbonate reabsorption  Lead to acidosis (elevated H+)  Fanconi’s Syndrome:  Impaired reabsorption in proximal tubule  Water, glucose, amino acids, bicarb, and phosphate wasted in urine instead of being reabsorbed Loop of Henle:  High permeability to water and low permeability to Na or Cl (no active transport)  Water loss (only if osmolarity of interstitial fluid is higher than that of the filtrate)  Descending limb:  Filtrate enters: isotonic  Water leaves the most here  Ascending limb:  Filtrate enters is hyperosmotic  Filtrate leaves is hyposmotic  Decrease is due to active reabsorption of ions along the way!  Na/K/Cl transported in ascending limb drive the transport  Leads to paracellular reabsorption of Ca and Mg through an electrochemical gradient Diuretics:  Treat high BP: promote water loss in urine  Decrease water leads to decreased volume and BP  Classes:  Loop Diuretics: Loop of Henle (block Na/K/Cl Pump)  Furosemide result in excess loss of K (hypokalemia) and decreased paracellular transport of Ca and Mg (hypercalciuria)  Bartter Syndrome: mutation in Na/K/Cl cotransporter: hypokalemia, hypercalciuria, polyuria 56 and 57: Tubular Transport – Reabsorption and Secretion I and II (Zagvazdin)       Paracellular: between cells  Via diffusion and the electrochemical gradient Transcellular: through cells  Via ion channels and transporters Carrier mediated: either primary or secondary active transport  Na/K ATPase: major source for primary active transport PCT:  Most reabsorption and section (brush border w/ microvilli; large SA w mitochondria → active transport of molecules is easy here) DCT:  Fine tuning  Tightly regulated by hormones Loop of Henle:  Descending: ONLY water is reabsorbed  Ascending: ONLY solutes are reabsorbed    Thiazide Diuretics: Early DCT (block NaCl channels)  Hypokalemia and hypocalciuria  INCREASE CA+ reabsorption (loop decreases it)  Gitelman Syndrome mimics these diuretics! K Sparing Diuretics: collecting duct (blocking K secretion)  Glucose:  Only reabsorbed in PCT  SHOULD be NO glucose in urine!!!  Glucosuria: glucose threshold met and kidney cannot keep with reabsorption!  Diabetes Mellitus:  High blood glucose levels: Glucosuria  Acts like an osmotic diuretic; activates osmoreceptors (polydipsia)  High glucose impedes water reabsorption (polyuria) Distal Tubule!     Fine tuning balance of Na, K, and water (regulated by ADH and aldosterone) Two cell types:  Principal cells: Secrete K and Reabsorb Na  Intercalated cells: Reabsorb K and Secrete H  Alpha cells: H secretion (a for acid)  Beta cells: Bicarb secretion (b for bicarb) Aldosterone: stimulates Na/K ATPase, promotes Na reabsorption and K secretion (works on principal cells) ADH: makes cells more permeable to water (antidiuretic) 58: Water Balance and Control of Body Fluid Osmolality (Zagvazdin)   Hormones to conserve fluid volume:  ADH (antidiuretic hormone)  RAAS (renin-angiotensin-aldosterone system) Hormones to reduce fluid volume:  ANP (atrial natriuretic peptide) 59 and 60: Sodium, Potassium Balance (Zagvazdin)          Plasma osmolarity is maintained at about 290; urine concentrations can range from 50 to 1200  Kidneys manage ECF osmolarity by concentrating or diluting urine! Estimate plasma osmolarity with 2Na HIGH water intake: urine is diluted (diuresis) LOW water intake: urine is concentrated (antidiuresis) Urine volume depends on plasma ADH level Urea recycling: 50% of the urea filtered is reabsorbed by the PCT; when ADH is high, additional urea is reabsorbed in the collecting duct (helps draw out more water!) Antidiuretic Hormone:  Released into the blood from the hypothalamus when osmoreceptors register an increase in ECF osmolarity  Largest effect: collecting duct of nephron  Binds V2 receptors on the basolateral membrane and increases apical aquaporin channels (cAMP created)  Other actions:  Acting on Na/K/Cl channels in the thick ascending loop, increasing Na reabsorption  Adding apical urea transporters in the collecting duct, increasing urea reabsorption.  Reabsorbing these solutes increases the corticomedullary gradient, aiding in water reabsorption.  The increased water reabsorption does not dilute the interstitial osmolarity because the water is transported away by peritubular capillaries and vasa recta.  Increased plasma osmolarity is the most sensitive, major stimulus for ADH secretion  ADH will increase when there is a drop in blood pressure, in response to angiotensin 2, in pain, heat, stress, nausea, vomiting (need to hold onto fluid!)  ADH decreases in response to ANP, cold temperatures, alcohol (too much fluid!)  Diabetes insipidus: ADH Deficiency; constant diuresis; polydipsia; polyuria; hypovolemia  Central: lack of production of ADH, low plasma ADH; treat w/ desmopressin  Nephrogenic: problem at kidney, ADH receptors either nonfunctional or absent (desmopressin will not help)  SIADH: Inappropriate excess of ADH (water retention and hyponatremia)  Dilute plasma, concentrate urine  Ecstasy: Intense thirst; hyponatremia, cerebral edema, brain herniation    Sodium and Potassium balance is controlled by RAAS and ANP: opposing systems  RAAS: Responds to low blood volume/low blood pressure  Wants to increase CO, vasoconstrict, reabsorb sodium, reabsorb H2O, increase thirst  ANP: Responds to high blood volumes in heart  Wants to vasodilate afferent arteriole, vasoconstrict efferent, increase GFR, decrease Na and H2O reabsorption, decrease CO, peripheral vasodilation Atrial Natriuretic Peptide  Released when blood volumes stretch the right atrium: wants to reduce BP  Increases:  GFR  Decreases:  Renin  Aldosterone  ADH  Promotes negative Na balance RAAS: Increases BP; promotes positive Na balance  Renin release from juxtaglomerular cells  Angiotensinogen: liver  ACE enzyme: lungs and blood vessels  Aldosterone: adrenal cortex  ADH: hypothalamus 1. Renin is released when there is low afferent arteriole pressure, when there is low filtrate flow (sensed by macula densa), or sympathetic input. Renin can be falsely elevated leading to secondary HTN (ex. renal artery stenosis). Secretion of renin is rate limiting step in RAAS 2. Renin cleaves angiotensinogen into angiotensin 1(inactive) 3. Angiotensin 1 is converted to angiotensin 2(active) by the ACE enzyme. 4. Angiotensin 2 does many things including vasoconstriction, Na reabsorption in proximal convoluted tubule (influencing Na/H antiport), stimulates aldosterone production, and stimulates ADH production. 5. Aldosterone is a mineralocorticoid that acts on the distal and collecting tubules, increases basolateral Na/K ATPase activity driving sodium reabsorption BP Clinical Correlations:  Hypertension is the most important modifiable risk factor for stroke  Venom of Latin American pit vipers causes drastic hypotension because it blocks the angiotensin converting enzyme (ACE)  Medications have been made to mimic these molecules->captopril was the first ACE inhibiting hypertensive drug. ACE inhibitors end in -pril  ACE inhibitors are associated with a bradykinin-induced cough, vasodilation occurs in the lungs. Angiotensin receptor blockers (ARBs) were developed to provide the same BP lowering effects without the cough.  ARBs are antagonists to AT1 receptors. They end -sartan. Examples are valsartan and losartan.  Other options to decrease BP are beta-blockers, B blockage at the kidney will inhibit sympathetic renin release  Aliskiren is a direct renin blocker, reducing effective renin reduces both angiotensin 1 and angiotensin 2 Aldosterone and Clinical Correlations:  Major stimuli for release are: angiotensin 2, and high plasma K+  Stimulates basolateral Na/K ATPase at the collecting duct. Stimulates production of apical Na channels (ENaC), and extra Na/K ATPases  Aldosterone increases Na reabsorption, H secretion, K secretion  Amiloride is a potassium sparing diuretic that targets ENaC Channels  Spironolactone is a potassium sparing diuretic that targets the mineralocorticoid receptor aldosterone binds to  Fludrocortisone is the injectable mimic of aldosterone for a patient with hypoaldosteronism  Conn’s syndrome: primary hyperaldosteronism.    Tumor of the adrenal gland causing hypersecretion of aldosterone. High plasma aldosterone, low plasma renin, HTN, hypernatremia, hypokalemia, metabolic alkalosis Renal artery stenosis: secondary hyperaldosteronism.  Activation of RAAS due to low kidney perfusion, prerenal azotemia. Decreased Fraction of excreted sodium. Increasing BP even though BP is already high.         Addison’s disease:  Hypoactive adrenal gland, low cortisol and aldosterone  Patient lose weight, dehydrate, and hypovolemic  Hyperkalemia and hyponatremia Hyporeninemic hypoaldosteronism: Atrophy of juxtaglomerular cells Liddle’s syndrome: hyperactive ENaC channels, increasing sodium reabsorption; HTN and hypokalemia; unresponsive to spironolactone but RESPONSIVE to Amiloride Potassium:  PCT: reabsorbs K  Ascending Loop: Na/K/Cl reabsorbs K  DCT:  K secretion: principal cells  K reabsorption: alpha intercalated cells  Balance: linked to acid base balance  Acidosis: decreased K secretion  Alkalosis: increased K secretion  Excessive insulin: hypokalemia  Cell lysis: hyperkalemia (i.e. Crush syndrome and Rhabdomyolysis) Hyper/hypokalemia  Hyperkalemia is most DANGEROUS electrolyte abnormality  EKG: peaked T wave  Nausea, weakness, paresthesias  Causes: renal failure, K-sparing diuretics, hypoaldosteronism, tissue damage, severe acidosis  Give sodium bicarb for acidosis induced hyperkalemia  Hypokalemia: EKG: inverted T waves  Causes: hypomagnesemia, insulin elevation, diarrhea, hyperaldosteronism, loop and thiazide diuretics 61: Acid Base Balance (Zagvazdin)     Increase in CO2 or decrease in HCO3 ---> acidosis Increase in HCO3 or decrease in CO2 ----> alkalosis Respiratory Acid-Base Disorders --> change in CO2 due to inadequate lung ventilation  Compensation is via the kidneys  Respiratory Acidosis  Increase in PCO2 ----> usually due to decreased ventilation rate  Ex: obstructive lung disease like asthma or COPD (remember it is hard to breathe air out in these diseases meaning you are expelling less CO2 and therefore it builds up in the body)  Respiratory Alkalosis  Decrease in PCO2 -----> usually due to increased ventilation rate  Ex: anxiety causes you to hyperventilate leading to more expulsion of CO2 from the body and therefore for alkalosis Metabolic Acid-Base Disorders ---> change in HCO3  Compensation is via lungs or kidneys or both  Metabolic Acidosis  Loss of bicarb or gain of H  Ex: diabetic ketoacidosis causes an excess gain of H or diarrhea can cause an excess loss of HCO3  Metabolic Alkalosis  Gain of bicarb or loss of H   Ex: vomiting causes a loss of stomach acid leading to a loss of H Compensation  Alpha Intercalated Cells  Responds to metabolic acidosis by increasing the secretion of H+ to the kidney ---> excreting more H+  Remember in these cells H+ secretion is linked with K+ reabsorption  Therefore increasing H+ secretion ---> hyperkalemia and vice versa  Beta Intercalated cells  Responds to metabolic alkalosis by increasing the secretion of HCO3 to the kidney ---> excreting more HCO3  Sodium bicarb can be used to treat severe metabolic acidosis  Not used in mild cases or respiratory acidosis  In acute respiratory acidosis there will be no compensation from the kidney because the kidney takes a long time to respond  Kidney compensation is therefore only in chronic acid-base disorders Bicarb Reabsorption and H+ Secretion  Bicarb Reabsorption: Primarily takes place in the proximal tubule  Remember: bicarb cannot be reabsorbed, it must first be broken down into H20 and C02 by carbonic anhydrase  H+ Secretion: Happens is the proximal and distal tubules  H+ trapping via buffers  Phosphate: Secreted H+ is bound to Na2HPO4 and secreted in the urine  Ammonia: Secreted H+ ions combine with NH3 forming NH4 which is excreted in the urine Renal Tubular Acidosis  Four types of RTA  Type 1: Distal hypokalemic acidosis  Damage to alpha intercalated cells in distal tubule ---> can no longer secrete H+ ---> acidosis  Type 2: Proximal hypokalemic  Damage to proximal tubule cannot form/reabsorb bicarb ---.> acidosis  Ex: Fanconi’s Syndrome  Can be caused by carbonic anhydrase inhibitors  Type 3: Mixed of type 1 and 2  Type 4: Distal hyperkalemic  Na/K pump damage that causes Na to stay out and K+ to stay in.  Since this pump is linked to the K+/H pump then there is no H+ secretion ---> H+ builds up ---> acidosis  Ex: Hyperaldosteronism Anion Gap: Difference in plasma anions and cations (the gap!)  Ideal is 0, but normal = 8-16  [Na] – ([Cl] + [HCO3]) = Anion Gap  Used to diagnose types of metabolic acidosis  Anion gap metabolic acidosis: metabolic acidosis due to an increase in unmeasured organic acids  Ex: diabetic ketoacidosis is due to an increase in ketones which are not measure by the blood tests ---> increased anion gap  High anion gap metabolic acidosis = GOLD MARK  Glycols, oxoproline, L-lactate, D-lactate, methanol, aspirin, renal failure, ketones  Normal anion gap metabolic acidosis: metabolic acidosis where no organic acids have accumulated  Ex: diarrhea is due to a loss in bicarb ---> the anion gap stays normal because of the accumulation of Cl that happens 62: Calcium, Phosphate, and Magnesium Balance (Zagvazdin)      Calcium  Normal is between 9 and 10.5 --> tightly regulated  Acidosis: increased excretion  Alkalosis: decreased excretion Phosphate levels are opposite the levels of Calcium  When phosphate levels are high, it binds free calcium, decreasing Ca levels  When Ca levels are high there is less phosphate available to bind it Calcium and Phosphate balance is regulated by:  Parathyroid hormone  Vitamin D  Calcitonin Calcium Transport  In the early proximal tubule:  Ca is reabsorbed via the solvent drag  Late proximal tubule  Ca is reabsorbed via active transport ---> Ca ATPase Diuretics:  Loop diuretics inhibit calcium reabsorption by blocking the Na/Cl/K pump which causes there to be no solvent drag ---> no reabsorption    Thiazide diuretics inhibit the Na/Cl transporter which stops the Na/K transported, this increases the activity of Na/Ca transporter to feed the Na/K pump Parathyroid Hormone  Functions:  Increase plasma Calcium by stimulating osteoclasts to resorb bone and the kidneys to reabsorb Ca  Stimulates calcitriol production ---> increased Ca absorption in GI tract  Decreases plasma phosphate level by increasing phosphate excretion by kidneys  Stimulated by low Ca levels  Hypoparathyroidism  Leads to low calcium levels ---> causes increased excitability of neurons --->Trousseau’s and Chvostek signs  Trousseau’s sign = muscle spasms of upper extremity induced by blood pressure cuff  Chvostek Sign = contraction of facial muscles due to facial nerve tapping  Hyperparathyroidism  Leads to high calcium levels ---> “stones, bones, groans and psychiatric moans”  Primary  Caused most commonly by a parathyroid secreting adenoma  Can lead to osteoporosis due to increased bone resorption  Secondary  Caused by renal failure ---> kidney cannot excrete phosphate --> phosphate binds Ca decreasing its concentration ---> PTH is secreted in response to low free Ca levels  Can lead to renal osteodystrophy ---> breakdown of bone in renal failure due to excess activation of osteoclasts by PTH ---> forms brown tumors Hypo and Hyperphosphatemia  Hyperphosphatemia  Can be caused by renal failure bc renal tubule cannot excrete phosphate appropriately  Leads to decreased calcitriol production --> decreases GI absorption of Ca  Phosphate binders and low phosphate diets are used in chronic renal failure patients to combat hyperphosphatemia and hyperparathyroidism  Hypophosphatemia  Common in malnourished alcoholics and veterans  Glucose causes release of insulin which shifts phosphate into the cells further exacerbating hypophosphatemia  When phosphate goes into the cells it is made into ATP and used for processes like glycolysis  Phosphate in the nephron  Majority of reabsorption happens in proximal tubule via Na active cotransport  Reabsorption of phosphate has a set rate  If there is a slight increase in phosphate levels the kidney will markedly increase the excretion of phosphate and vice versa  This is accomplished via phosphatoins like FGF-23 which inhibit the reabsorption of phosphate Magnesium  Magnesium is primarily reabsorbed in the thick ascending limb of the loop of Henle  Diuretics:  Loop diuretics inhibit magnesium reabsorption by decreasing the solvent drag  Therefore loop diuretics can cause hypomagnesemia, hypokalemia, and hypocalcemia  Hypercalcemia can also decrease Mg reabsorption bc it competes with Mg for solvent drag paracellular route. If too much Ca then Mg gets left behind  Thiazide diuretics cause excess loss of Mg by increased flow of filtrate (washout) and through blocking of Mg channels in the distal tubule  Gitleman’s Syndrome: genetic defect in Na/Cl cotransporter in distal tubule. This transporter is linked to the Mg channel, by blocking it you block Mg  Hypomagnesemia  Causes fatigue, muscle weakness and cardiac problems  Most commonly caused by Diuretics 63: Renal Physiology Applications (Zagvazdin)  Excretory: remove waste products  Clearance = volume of plasma that is cleared from a substance ( = filtration + secretion – reabsorption)  Kidney stones (urolithiasis): form at the renal papilla and can obstruct the flow of urine/removal of waste  Become symptomatic once they leave the kidney  High protein diet and low fluid intake are risk factors Renal Corpuscle contains Bowman’s Capsule, Glomerulus and Mesangial Cells Regulatory: maintain homeostasis of body fluids  Total body water is divided into 4 compartments --> intracellular, interstitial, plasma and transcellular  Transcellular: smallest compartment  INTRAcellular ions = Na, Cl, HCO3, Ca  EXTRAcellular ions = K, Mg, PO4 and Proteins  Rhabdomyolysis ---> breakdown of muscle cells causes Myoglobin and CK to rise as well as intracellular ion levels bc when the muscle cell lyses it releases its intracellular contents  Hemoglobin Casts ---> glomerulonephritis  WBC Casts ---> infection/pyelonephritis Juxtaglomerular Apparatus: granular cells, macula densa, and external mesangial cells  Macula densa senses flow of filtrate  Granular releases renin Endocrine: release calcitriol, erythropoietin, renin, and renalase Creatinine is a marker of renal health  BUN is also a measure of renal health; increase BUN ---> decrease GFR  GFR and Hydrostatic pressure in glomerulus are determined by the diameter of the afferent and afferent arterioles  Constrict afferent arteriole ---> decrease RBF ---> decreases GFR and hydrostatic pressure  Constrict efferent arteriole ---> flow backs up and slows down ---> increase GFR and hydrostatic pressure  NFP = Ph - Pbs - Po  GFR = Kf x NFP  NFP decreases along the length of the glomerular capillary because oncotic pressure goes up along the length and hydrostatic pressure remains the same along the length of the capillary Nephrotic Syndrome: Profound proteinuria, hypoalbuminemia, edema, hyperlipidemia Nephritic Syndrome: Hematuria, oliguria, and minimal proteinuria Glucosuria ---> diabetes Thiazide and Loop diuretics cause hypokalemia  Bartter Syndrome = mimics loop diuretics ---> mutation in Na/Cl/K transporter (BARTER IN THE LOOP)  Gitelman Syndrome = mimics thiazide diuretics (GIT THOSE THIAS) Potassium diuretics cause hyperkalemia  Inhibit Na and K transport in the collecting duct by blocking ENACs and Mineralocorticoid receptors  More or less aldosterone antagonists            64: Acid Base Applications (Riskin) 65: Genitourinary Physiology (Nguyen)    Male Hypogonadism: check testosterone and FSH levels, both stimulate sertoli cells for spermatogenesis  Symptoms: decreased sexual function, decreased bone mass, anemia  Treatment: testosterone replacement therapy patches  Side effects of this therapy can include increased hematocrit, balding and acne Micturition  Urine is stored in the bladder, when it accumulates it stretches the detrusor muscle, stimulating the pelvic  nerve(S2-S4) to trigger the micturition reflex  2 receptors, M3 and B3.  M3 is parasympathetic causing contraction of the detrusor muscle.  B3 is sympathetic causing relaxation of the muscle.  Sympathetic innervation comes from the hypogastric nerve.  There are two urethral sphincters, inner and outer.  The inner urethral sphincter has sympathetic innervation using alpha 1 receptors.  Sympathetic stimulation via the hypogastric nerve will cause contraction of the internal sphincter preventing urination  The outer urethral sphincter is under voluntary control via the pudendal nerve.  If stimulated it decreases sphincter tone promoting urination.  The ability to control the outer urethral sphincter occurs between ages 2-3, until then there is a simplified micturition reflex Incontinence  Overflow: hypoactive detrusor  Bladder completely fills to the point bladder pressure > sphincter pressure, constant dribbling leakage. Example is following spinal cord injury.  Give cholinergic to enhance detrusor contraction  Urge: hyperactive detrusor  Spastic contraction of detrusor gives constant sensation of needing to void.  Example is Parkinson’s.  Give Antimuscarinic to reduce the contractions Benign prostatic hyperplasia: proliferation of cells in the transitional and periurethral zones of the prostate, leading to incomplete voiding and increased urgency.  Increased exposure to testosterone increases hyperplasia.  Treat with 5 alpha reductase inhibitors (finasteride, Dustaride) or alpha 1 antagonists(Tamsulosin)  Stress: due to weak pelvic floor muscles unable to handle increases in abdominal pressure, incontinence when sneezing, coughing, lifting objects.  Example is pregnancy.  Prescribe Kegel exercises. Erection  Sexual stimulation causes production of nitric oxide in endothelial cells of penis, activating guanylyl cyclase and increasing cGMP concentrations.  cGMP relaxes the smooth muscle of corpus cavernosum, causing dilation and erection  cGMP is broken down by phosphodiesterase-5.  Take PDE-5 inhibitors such as sildenafil, tadalafil, vardenafil to assist with penile dysfunction  Parasympathetic induces erection, sympathetic induces ejaculation. Point and Shoot Female Reproductive  Granulosa cells are stimulated by FSH: production of estradiol (Granny Feeds Extra)  Theca cells are stimulated by LH: production of progesterone (That Little Progesterone!)  Parasympathetic leads to female sexual arousal, sympathetic inhibits female sexual arousal     66: Physiology Applications (Nguyen)                   Multiple sclerosis: autoimmune; degradation of oligodendrocytes, loss of myelination in CNS  Difficulty walking when affects the basal ganglia or cerebellum Myasthenia gravis: autoimmune attack against ACh receptors at the neuromuscular junction.  Progressive weakness throughout the day that improves with rest Duchenne Muscular Dystrophy: lack of or abnormal mutation in the dystrophin protein that anchors actin to the cell membrane.  Contracting the muscle will lead to cell membrane damage, progressively worsening weakness Pericardial tamponade: accumulation of fluid in the pericardial space that inhibits ventricular filling; muffled heart sounds, JVD and hypotension.  Treat with pericardiocentesis to increase preload Aortic stenosis: stiffening of the aortic valve, can be from calcification  Increased afterload, decreased stroke volume, decreased ejection fraction Myocardial infarction: occlusion of a coronary artery leading to ischemia and necrosis of the myocardium, inhibiting its function Renal artery stenosis: atherosclerosis leading to decreased renal perfusion pressure and activation of RAAS.  Sodium and H2O reabsorption will lead to HTN Kidney stones: consequence of dehydration, jagged stones can lodge in the ureter and damage epithelial cells causing extreme pain.  May cause microscopic hematuria Diabetic nephropathy: glucose will be found in the urine.  Glycosylation of basement membrane and increased HBA1c make the glomerulus more permeable to glucose and albumin Acute respiratory acidosis: Increase in arterial CO2 leading to acidosis Asthma: type of obstructive lung disease characterized by bronchospasm and mucus production.  Bronchospasm is triggered by allergens and irritants and excess exercise.  Bronchospasm increases the airway resistance, making exhalation more difficult, and wheezing noticeable.  Decrease in FEV1/FVC ratio Carbon monoxide poisoning: carbon monoxide binds hemoglobin at higher affinity than oxygen.  Lack of oxygen binding sites lead to decreases in arterial PO2, and hypoxia Pulmonary embolism: occlusion of a branch of the pulmonary artery, the alveoli supplied by this branch become physiologic dead space as there is no gas exchange, they are ventilated but not perfused Acute mountain sickness: arterial hypoxia leads to increases ventilation, dropping arterial CO2 creating cerebral vasodilation, leading to headache.  Hypoxia also disrupts sleep Parkinson’s: progressive degenerative motor disease caused by damage to the substantia nigra.  Low dopamine causes increased inhibition of movement.  Symptoms are bradykinesia(slow movements) postural instability, impaired balance Alzheimer's: neurodegenerative disorder leading to impaired memory, progressing to dementia and cognitive decline Epilepsy: excessive activity in a cluster of neurons, symptoms are determined by which area of the brain is hyperactive.  Seizures can be brought on by trauma, fever, neurotransmitter imbalances, abnormal brain development Grave’s disease: autoimmune disorder stimulating the thyroid gland to increase production of T3/T4.      Enlargement of the thyroid gland and elevated thyroid hormone will be observed.  Exophthalmos: protrusion of the eyeballs Hashimoto’s: autoimmune disease against the thyroid gland reducing the production of thyroid hormone.  Destruction of thyroid follicles Hyperparathyroidism: mostly from adenoma, excessive production of PTH increases bone resorption, disrupting calcium regulation and reducing bone strength. Addison’s: hypoactive adrenal cortex can be caused by damage or removal, leads to low cortisol levels and may also present with low aldosterone levels.  Hypoglycemia, fatigue, weight loss, and weakness are symptoms Conn’s: tumor of the adrenal gland leading to increases aldosterone production.  Will cause hypertension, hypokalemia, metabolic alkalosis Pheochromocytoma: tumor of the adrenal medulla leading to excess catecholamine production (epi, norepi).  Stimulates sympathetic nervous system increasing blood pressure, increasing heart rate