Metabolic Functions of The Kidney

Urine Formation Filtration Reabsorption Secretion Glomerular Filtration Rate (GFR) = 125 ml/min = 180 L / day Urine Formation Rate = 1 ml/min = 1.5 L / day

Metabolic Functions of the Kidney Excretion of Metabolic End Products e.g. ammonia, urea, creatinine, uric acid & some ‘foreign’ molecules as drugs Fluids & Electrolytes Balance Metabolic Conversions Acid-base balance Enzyme production & Endocrinal role 1- Production of certain enzymes (e.g. renin) 2- Endocrinal roles: Activation of vitamin D Production of erythropoietin

Kidneys receive 25 % of the cardiac output & 10 % of O2 consumption Kidney tissue represents less than 0.5% of the body weight body weight 25% of COP This is required for the synthesis of ATP needed to reabsorb most of the solutes filtered through glomerular membranes

Glycogen Phosphocreatine (CP) Lipids are very low energy stores So kidney must get its energy requirement from circulating fuel substrates (as glucose, fatty acids & ketone bodies)

Substrates used by kidney for energy production Starvation Fed State Glucose oxidation Glycolysis & citric acid cycle Fatty acids oxidation & ketone bodies degradation (ketolysis)

Carbohydrate Metabolism in the kidney Gluconeogenesis Synthesis of glucose from non-carbohydrate sources as lactate, glycerol & amino acids (esp. glutamine) Glucose oxidation , Glycolysis, citric acid cycle & PPP Fructose metabolism

Kidney & glucose homeostasis The kidney can be considered as 2 organs due to the differences in the distribution of various enzymes in renal medulla & renal cortex Renal cortex Renal medulla Glucose synthesis Glucose utilization Cells of the cortex have considerable amounts gluconeogenic enzymes, BUT: have little hexokinase So, the release of glucose by the normal kidney is exclusively, a result of renal cortical gluconeogenesis . The most important substrates for renal gluconeogenesis are glutamine, lactate & glycerol Cells of the medulla have considerable amounts of hexokinase (of glycolysis). So, they can take up, phosphorylate & metabolize glucose through glycolysis BUT: don’t have gluconeogenic enzymes They can form glycogen (limited amounts), but cannot release free glucose into the circulation.

Hormonal control of renal gluconeogenesis Insulin Decreases renal gluconeogenesis by: Shunting precursors away from gluconeogenic pathway & diverting them into the oxidative pathways (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. Glucagon has no effect on renal gluconeogenesis

Kidney & Glucose Metabolism in Fasting Early fasting (first 12 -18 hours): Source of glucose in blood is mainly by liver glycogenolysis 18 – 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 levels in patients with renal insufficiency during prolonged fasting. This may explain why patients with renal failure develop hypoglycemia

Lipid Metabolism in the Kidney Lipid metabolic pathways occur in the kidneys: 1- b-oxidation of fatty acids 2- Synthesis of carnitine : for transport of FA to mitochondria for oxidation 3- De-novo synthesis of fatty acids 4- Degradation of ketone bodies (Ketolysis) 4- De-novo synthesis of cholesterol 5- Activation of glycerol to glycerol 3-phosphate (by glycerol kinase)

Protein Metabolism in the Kidney Amino acid metabolic pathways occur in the kidneys: 1- Excretion of ammonia & urea to urine Ammonia & urea are products of amino acid metabolism 2- Degradation of glutamine by glutaminase enzyme Glutamine produced in most organs (from amino acid metabolism) are degraded into glutamate & ammonia in the kidney. Ammonia produced is important in acid base balance 3- Amino acids deamination 4- Creatine synthesis (first step) from amino acids glycine & arginine

Synthesis of Creatine by kidneys & liver 2 Methylation of guanido acetic acid to creatine in the liver 1 Formation of guanido acetic acid From amino acids glycine & argenine In the kidney

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 dehydrogenase In 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 & is trapped 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.

Source of H+ required for NH4+ formation: Glomerular filtrate The 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

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 blood In renal insufficiency: There is decreased production of erythropoietin, leading to anemia which is one of the major features in cases of renal insufficiency.

Activation of vitamin D in the Kidney Renal 1a hydroxylase The key regulatory enzyme in vitamin D activation is the 1a hydroxylase enzyme produced by 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, 25 DHCC), which is the active form of vitamin D. The main physiological role of active vitamin D (1, 25 DHCC) is promoting calcification of bones (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 hyperparathydroidism i.e. increased production of the parathyroid hormone (PTH).

Activation of vitamin D

Role of the Kidney in Electrolytes Balance Electrolyte balance (Na+ & K+) BY: Renin-Angiotensin System Angiotensinogen (in liver, inactive) Renin (synth. by kidney) Angiotensin I Angiotensin Converting Enzyme (ACE) Angiotensin II simulate aldesterone release (from adrenal cortex) In Tubules of kidney Decrease Na+ excretion Increase K+ excretions Hypernatremia hypokalemia Increase BP