7 Metabolic Functions of the Kidney Excretion of MetabolicEnd Productse.g. ammonia, urea, creatinine, uric acid & some ‘foreign’ molecules as drugsFluids & ElectrolytesBalanceMetabolicConversionsAcid-basebalanceEnzyme production & Endocrinal role1- Production of certain enzymes (e.g. renin)2- Endocrinal roles:Activation of vitamin DProduction of erythropoietin
8 Kidneys receive 25 % of the cardiac output & 10 % of O2 consumption Kidney tissue representsless than 0.5% of the body weightbodyweight25% ofCOPThis is required for the synthesis of ATP needed to reabsorb most of the solutes filtered through glomerular membranes
9 Glycogen Phosphocreatine (CP) Lipids are very low energy stores Sokidney must get its energy requirement fromcirculating fuel substrates(as glucose, fatty acids & ketone bodies)
10 Substrates used by kidney for energy production StarvationFed StateGlucose oxidationGlycolysis&citric acid cycleFatty acidsoxidation&ketone bodiesdegradation(ketolysis)
11 Carbohydrate Metabolism in the kidneyGluconeogenesisSynthesis of glucose from non-carbohydrate sourcesas lactate, glycerol & amino acids (esp. glutamine)Glucose oxidation,Glycolysis,citric acid cycle&PPPFructose metabolism
12 Kidney & glucose homeostasis The kidney can be considered as 2 organs due to the differences inthe distribution of various enzymes in renal medulla & renal cortexRenal cortexRenal medullaGlucose synthesisGlucose utilizationCells of the cortex have considerable amounts gluconeogenic enzymes,BUT: have little hexokinaseSo, the release of glucose by the normal kidneyis exclusively, a result of renal corticalgluconeogenesis .The most important substrates for renal gluconeogenesis are glutamine, lactate & glycerolCells of the medulla have considerable amounts of hexokinase (of glycolysis). So, they can take up, phosphorylate & metabolize glucose through glycolysisBUT: don’t have gluconeogenic enzymesThey can form glycogen (limited amounts), but cannot release free glucose into the circulation.
13 Hormonal control of renal gluconeogenesis InsulinDecreases renal gluconeogenesis by:Shunting precursors away from gluconeogenic pathway & diverting them into the oxidativepathways (glycolysis & PPP)Epinephrine:has more effect on stimulating renal gluconeogenesis than hepatic gluconeogenesis (may be due to the rich autonomic innervations of the kidney).*The mechanism is mediated through free fatty acids released during lipolysis accompanying hypoglycemia.Glucagonhas no effect on renal gluconeogenesis
14 Kidney & Glucose Metabolism in Fasting Early fasting (first hours):Source of glucose in blood is mainly by liver glycogenolysis18 – 60 hours of fasting:Source of blood glucose is mainly gluconeogenesis (in liver & kidneys)After 60 hours of fasting:Liver gluconeogenesis release is decreased by 25%So, liver cannot compensate for the kidney to preserve normal blood glucose levelsin patients with renal insufficiency during prolonged fasting.This may explain why patients with renal failure develop hypoglycemia
15 Lipid Metabolism in the Kidney Lipid metabolic pathways occur in the kidneys:1- b-oxidation of fatty acids2- Synthesis of carnitine : for transport of FA to mitochondria for oxidation3- De-novo synthesis of fatty acids4- Degradation of ketone bodies (Ketolysis)4- De-novo synthesis of cholesterol5- Activation of glycerol to glycerol 3-phosphate (by glycerol kinase)
16 Protein Metabolism in the Kidney Amino acid metabolic pathways occur in the kidneys:1- Excretion of ammonia & urea to urineAmmonia & urea are products of amino acid metabolism2- Degradation of glutamine by glutaminase enzymeGlutamine produced in most organs (from amino acid metabolism) aredegraded into glutamate & ammonia in the kidney.Ammonia produced is important in acid base balance3- Amino acids deamination4- Creatine synthesis (first step) from amino acids glycine & arginine
17 Synthesis of Creatine by kidneys & liver 2Methylation of guanido acetic acid to creatinein the liver1Formation of guanido acetic acidFrom amino acids glycine & argenineIn the kidney
18 Ammonia metabolism & acid base balance in the kidney Ammonia (NH3) is produced in cells of renal tubules:By the enzymes:Glutaminase (as discussed before)Glutamate dehydrogenaseIn the tubular lumen, NH4+ is produced from ammonia (NH3) & H+ :Ammonia (NH3) + Hydrogen ions (H+ ) = Ammonium ions (NH4+ )This reaction is favored at the acid pH of urine.The formed NH4+ in the tubular lumen can not easily cross the cell membranes & istrapped in the lumen to be excreted in urine with other anions such as phosphate, chloride &sulphate.(forming ammonium phosphate, ammonium chloride & ammonium sulphates).NH4+ production in the tubular lumen accounts for about 60% excretion of hydrogen ions associated with nonvolatile acids.
19 Source of H+ required for NH4+ formation: Glomerular filtrateThe effect of carbonic anhydrase enzyme during the synthesis of carbonic acid in the tubular cells, H+ is secreted into the lumen by the Na+/ H+ exchanger.In renal insufficiency, the kidneys are unable to produce enough NH3 to buffer the nonvolatile acids leading to metabolic acidosis
20 Production of Erythropoietin It is a glycoprotein hormone that controls erythropoiesis.It is produced by the renal cortex in response to low oxygen levels in the bloodIn renal insufficiency:There is decreased production of erythropoietin, leading to anemia which isone of the major features in cases of renal insufficiency.
21 Activation of vitamin D in the Kidney Renal 1a hydroxylaseThe key regulatory enzyme in vitamin D activation is the 1a hydroxylase enzyme producedby the kidney.Vitamin D3 (cholecalceferol) is hydroxylated in the liver to 25 hydroxycholecalciferol (25 HCC)Then, the renal 1a hydroxylase converts 25 HCC to 1, 25 dihydroxycholecalceferol (1, 25DHCC), which is the active form of vitamin D.The main physiological role of active vitamin D (1, 25 DHCC) is promoting calcification ofbones (adding calcium) mainly through increasing calcium absorption from GIT.In renal insufficiency,Active vitamin D is not sufficient ending in renal rickets (poor calcification of bones).The resulting hypocalcemia due to vitamin D deficiency may end in hyperparathydroidismi.e. increased production of the parathyroid hormone (PTH).
23 Role of the Kidney in Electrolytes Balance Electrolyte balance (Na+ & K+)BY: Renin-Angiotensin SystemAngiotensinogen (in liver, inactive)Renin(synth. by kidney)Angiotensin IAngiotensin Converting Enzyme(ACE)Angiotensin IIsimulate aldesterone release (from adrenal cortex)In Tubules of kidneyDecrease Na+ excretionIncrease K+ excretionsHypernatremiahypokalemiaIncrease BP