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Lecture 28

PSL301H1 Lecture 28: L28 Excreting Wastes & Hormone Functions

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Michelle French

Lecture 28 Excreting Wastes and Hormone Functions Silverthorn 7E: pp. n/a Case Study 8: Uremia Paul is a 65-year-old man who lives alone. He has been diabetic for 25 years and seldom sees his doctor. He comes to the ER, complaining of severe fatigue and weakness, poor appetite, nausea and vomiting, swelling of his feet and ankles, severe itching of his skin, poor memory, difficulty sleeping, and twitching muscles. • Diabetes is most common cause of end-stage kidney failure in North America A physical exam confirmed edema and hypertension (180/110), paleness, confusion and poor memory, involuntary muscle movements, and his breath smells like urine. Lab Results: Blood Test Paul Normal Range • Normal blood pressure is 115/70 (or 120/80) Creatinine 1450 µmol/L < 120 µmol/L • Elevated serum creatinine, urate, potassium (deathly) Urea 75 mmol/L < 75 mmol/L • Profoundly low hemoglobin and bicarbonate (kidney has to Urate 900 µmol/L < 450 µmol/L regenerate bicarbonate) Hemoglobin 50 g/L 140-160 g/L Potassium 8.5 mmol/L 2.5-5 mmol/L Bicarbonate 14 mmol/L 25 mmol/L Calcium 1.6 mol/L 2.2-2.6 mol/L Parathyroid hormone 100 pmol/L 1-7 pmol/L Uremia is a syndrome consisting of symptoms, clinical signs, and laboratory changes due to severe kidney failure. • GFR < 15 mL/min (normal is 120mL/min), so 10-12% of normal kidney function • Most common cause is diabetes mellitus • More of the problems in uremia are readily explained through understanding kidney physiology Fatigue and weakness: decreased oxygen delivery and decreased muscle mass • Anemia (low hemoglobin) • Reduced erythropoietin secretion by the damaged kidney – in response to low oxygen • Reduced oxygen carrying capacity of blood • Uremia (acidosis) reduces muscle mass – cannot regenerate bicarbonate, so progressive acidemia • Most common symptom is fatigue Hypertension and edema: • Due to impaired sodium excretion by damaged kidney • In part due to severely reduced GFR • Signs of sodium excess: o Expanded extracellular fluid volume (ECF), edema (IF), hypertension (IV) High Levels of urea, creatinine, and urate: • Entirely due to decreased excretion in urine because of low glomerular filtration rate • High risk of gout (urate) • Levels of urea and creatinine in blood enable diagnosis of severe kidney failure Estimated GFR is only 3 mL/min (normal is 90-110 mL/min) Case Study 8: Uremia Cont’d… Hyperkalemia: • Serum potassium 8.5 (normal 3.5-5) • Contributes to muscle dysfunction – changes membrane potential • Risk of series heart problems – cardiac arrhythmias • Due to impaired excretion of potassium by damaged kidney and severely low GFR – reabsorbed and passively secreted Low bicarbonate: • Metabolic acidosis • Low blood bicarbonate 14 (normal 25) • Due to impaired ammonium excretion by the damaged kidney (generation and H + secretion) – cannot make ammonium without functioning PCT and CD to trap ammonium in the lumen • May contribute to loss of appetite Low blood calcium level, high blood PTH level: consequence of impaired 1,25-diOH vitamin D • Failure of kidney to synthesize 1,25-diOH vitamin D • Reduced calcium absorption from the gut • Hypocalcemia o Stimulates PTH secretion • High PTH decalcifies bones, predisposing to bone fractures Biochemical phenotype of disordered mineral metabolism in CKD. ▪ Decline in GFR ▪ High FGF 23, high PTH, low vitamin D ▪ High phosphate, because if you don’t filter it, you can’t excrete it But, we don’t understand everything! • There are still symptoms that are poorly explained o Confusion, poor appetite, muscle twitching, nausea, vomiting, sleep disturbance, itching • Due to accumulation of a variety of nitrogenous waste products due to low GFR and perhaps bacterial metabolites • If untreated, ultimately leads to coma and death • Treatment options are kidney dialysis or kidney transplantation 2 What is urea? The term uremia is derived from urea. • Uremia is associated with marked impairment of kidney function, and the Nitrogenous Wastes Excreted by the Kidney accumulation of urea • Nitrogenous wastes contain a nitrogen group • Urea • Urea is dominant nitrogenous compound excreted by the kidney • Creatinine • Ureic acid • Chicken, eggs, cheese, steak, or protein supplements  converted to amino acids in digestive tract Urea: Protein Intake • Used to synthesize proteins or can be degraded in the liver – amino group is • Food rich in protein converted to amino acids removed and converted to urea • Two fates of amino acids o Used to synthesize proteins o Degraded in liver • Amino group removed and converted to urea Overview of Protein Metabolism Transport and fate of major carbohydrate and amino acid substrates • Protein comes in, degraded to amino acids, delivered to and metabolism. There is little free glucose in muscle, since it’s rapidly liver where they enter a pool where they can be assembled phosphorylated upon entry. into proteins • An important protein that is synthesized is albumin, in the liver – it confers oncotic pressure that serves to retain water in the vascular compartment • Amino acids then secreted by liver or delivered to other tissues where they can make proteins or return to the liver pool and can also be broken down into glucose where they can be stored or delivered to other organs • There is a small amount of protein that isn’t broken down into amino acids, but is sent to the liver and converted into urea then sent to the kidney to be excreted Proteins to Urea • 75% of proteins we intake form an amino acid pool • Transamination reaction takes a-keto acid and adds an amino acid to form glutamate • Oxidative deamination protduces a-ketoglutarate and ammonium o Ammonium is a very toxic chemical, so it combines with2CO during the urea cycle to form urea • Ammonium and ammonia is a product of degradation of amino acids o Ammonium is toxic so must be secreted to urea 3 Urea Generation from Ammonia and Protein (Amino Acids) • Ammonia enters urea cycle and as urea movoes through, urea • Ammonia generated from amino acid breakdown is highly toxic o Converted to urea in liver is a byproduct of degradation of arginine • Ammonium generated from amino acid breakdown is toxic • Urea is non-toxic and is excreted in the urine • It’s converted into urea in the liver, which is a nitrogen containing compound • Urea is excreted in the urine Dietary Intake of Protein Each day, we eat 70-120 g of protein. • We generate 200-800 mmol/day of urea • As we metabolize proteins, we generate urea and we excrete it in the kidney What about urea excretion by the kidney? Nephron Handling of Urea • Kidney excretes end metabolite • As kidney function declines, urea concentration in the blood begins to rise • Urea is freely filtered at glomerulus, and enters proximal tubule • By the time urea enters the junction at the collecting duct, there’s about 110-70% of the original filtered load • As urea moves down the collecting duct, there’s regulated transport out of lumen so that we excrete 30-50% of the filtered load • Body generates urea, it’s filtered, it passes through the nephron and about 30-50% of all urea filtered is excreted in the urine • Production and excretion leads to steady state urea concentration in the plasma 4 Nephron Handling of Urea • Urea is freely filtered • As it comes down the descending limb, there are AQP channels and some channels that are permeable so some moves into the interstitium • When it goes up thick ascending limb, there is no extra reabsorption of urea, just removal of salt and water o You end up with about filtered load of urea • Cortical collecting duct isn’t permeable to urea, but at the inner medullary collecting duct, there are urea transporters that allow urea to move around • This is why we have freely filtered urea that comes down into the inner medullary collecting duct, it enters the interstitium and into the thin ascending limb – recycling of urea leads to final 30-50% of filtered load • As GFR declines, ability to recycle urea becomes impaired and urea concentration increases Urea Transport Across an IMCD Cell • With AVP circulating, it interacts with its receptor, activates adenylyl cyclase which increases cAMP leading to increased water channels being inserted • Activated kinases phosphorylate urea transporters and allow urea to enter the cell and exit from another urea transporter • With high urea concentration, we reabsorb water but also urea • Urea recycles within medulla and contributes tointerstitial concentrating mechanism Summary: Urea Excretion • Only about 30-50% of the filtered load is excreted • Readily filtered • Minimal reabsorption • Urea excretion = 200-800 mmol/day Note: urea in high levels doesn’t cause symptoms, but ammonia in high levels causes o Directly related to protein intake symptoms – a decrease in level of consciousness, impaired consciousness and even • Each urea has two nitrogen atoms seizures (in liver failure, because you don’t have functional urea cycle, so urea doesn’t get made and ammonia accumulates) • Regulated by ADH Learning Catalytics 1. Which of the following statements is true? a. Urea excretion is related to total dietary protein intake – end metabolite of transamination reaction of amino acids; people used to think that urea caused uremia and restricted protein intake to restrict urea that was made and limited symptoms (untrue) b. Urea is not freely filtered but secreted by the distal convoluted tubule – it is freely filtered, secreted by collecting duct via AVP c. Urea is transported across cell membranes by a sodium cotransport protein – urea channels that bind and translocate urea across membrane d. The urea cycle in the liver generates urea from ammonia – urea cycle metabolizes ammonia and turns into urea (detoxification) 5 Kidney is an Endocrine Organ • Renin • Kidney produces hormones – renin in response to low blood pressure and volume • Erythropoietin • Calcium and phosphate balance Endocrine Function: Erythropoietin • Cells in interstitial space make erythropoietin • If you stain kidney, you see EPO within interstitial cells of the kidney (between tubules) • EPO is made by interstitial cells in the kidney which tend to reside right at the cortical medullary junction • Any time you have hypoxia or low hemoglobin concentration, oxygen tension of CM junction falls, • It’s a good place to test oxygen because of the energy requirements
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