Metabolic Function Of The Kidney

Urine Formation Filtration Reabsorption Secretion GFR  125 ml/min = 180 litres per day Urine Formation Rate: 1 ml/min (1.5 L/day)

Metabolic Function Of The Kidney Excretion: (non-volatile) metabolic end products (e.g. urea, uric acid, creatinine, NH4+) and “foreign” solutes (e.g. some drugs) fluids & electrolytes Balance Metabolic conversions Acid-base balance Production and secretion of enzymes (e.g., renin) & hormones (Vit. D & erythropoietin)

Energy supply for The Kidney

The kidney tissue represents less than 0.5% of the body weight

It recieves 25% of the cardiac output and 10% of O2 consumption. COP body weight

It recieves 25% of the cardiac output and 10% of O2 consumption. WHY? body weight This is required for the synthesis of ATP needed to reabsorb most of the solutes filtered through glomerular membranes.

Very Low Energy Reserves Glycogen Phosphocreatine Neutral lipids Very Low Energy Reserves So kidney must get its energy requirement from circulating substrates.

Substrates used by kidney for energy production ? Fed State Starvation

Substrates used by kidney for energy production Fed State Oxidation Glucose Lactate

Substrates used by kidney for energy production blood lactate glucose Starvation Blood fatty acid & ketone body concentrations major kidney fuels during starvation.

Carbohydrate metabolism in the kidney Gluconeogenesis , Glucose Oxidation Glycolysis, Citric acid cycle HMS Fructose metabolism

KIDNEY & GLUCOSE HOMEOSTASIS

Regarding glucose homeostasis, the kidney can be considered as 2 organs due to the differences in the distribution of various enzymes in renal medulla and renal cortex. Renal cortex Renal medulla Glucose synthesis Glucose utilization

Cells of the Renal Medulla have considerable glucose-phosphorylating enzymes (hexokinase), glycolytic enzyme activity, So, can take up, phosphorylate and metabolize glucose through glycolysis, depend on glucose as a major source of energy The cells don’t have glucose-6-phosphatase and other gluconeogenic enzymes. they can form glycogen, but cannot release free glucose into the circulation.

Cells of the renal cortex the cells have gluconeogenic enzymes, have little phosphorylating enzymes, cannot synthesize appreciable concentrations of glycogen under normal conditions, So, we can say that 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 and lactate, followed by glycerol. While alanine is preferentially used by the liver

Renal glucose metabolism in the postprandial conditions After meal ingestion There is decrease in gluconeogenesis glucose is mainly utilized by brain, liver & muscles. Renal glucose uptake is < 10% of the ingested glucose. Renal gluconeogenesis paradoxically increases &it accounts for 50% of the endogenous glucose release. DIABETES CARE, VOLUME 24, NUMBER 2, FEBRUARY 2001

Renal gluconeogenesis paradoxically increases WHY? postprandially due to: Postprandial increases in sympathetic nervous system activity availability of gluconeogenic precursors (e.g., lactate and amino acids). This increase in renal gluconeogenesis help liver glycogen repletion by suppression of hepatic glucose release.

Hormonal control of renal gluconeogenesis Insulin: Decreases renal gluconeogenesis by: Shunting precursors away from gluconeogenic pathway and diverting them into the oxidative pathway. Decreasing renal free fatty acid uptake Glucagon: has no effect on renal gluconeogenesis *The mechanism is mediated through free fatty acids released during lipolysis accompanying hypoglycemia. Epinephrine: has more effect on renal gluconeogenesis than hepatic gluconeogenesis (may be due to the rich autonomic innervations of the kidney).

After a 60-h fasting Early increase in glucose release is mainly caused by hepatic glycogenolysis, later it is mainly a result of gluconeogenesis. Renal glucose uptake is reduced . Renal glucose release increased

After a 60-h fasting Hepatic glucose release decreased by 25% So, liver cannot compensate for the kidney to preserve normoglycemia in patients with renal insufficiency during prolonged fasting. This may explain why patients with renal failure develop hypoglycemia.

Lipid metabolism in kidney The kidney has active glycerol kinase enzyme It is a site for B-Oxidation. synthesis of carnitine . ketolysis. denovo synthesis of cholesterol denovo synthesis of fatty acids.

Protein metabolism in the kidney: The Kiney is a site for urea synthesis. site for creatine formation glycine & arginine. Oxidative deamination and transdeamination of individual amino acids. Oxidative deamination catalyzed by : Amino acid oxidases Transdeamination (L-Glutamate dehydrogenase) major site for the action of glutaminase enzyme with its great role in acidosis.

Synthesis of creatine: Amidine group from arignine Guanidnoacetate is first formed in kidneys from arginine and glycine, then it is methylated to form creatine in liver.

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Ammonia Formation f

Other Metabolic Function Of The Kidney Ammonia Production In The Kidney In the renal tubules by the action of the enzymes: glutaminase and L-glutamate dehydrogenase. It combines with H+ to form ammonium ions: NH3 + H+ ↔NH4+

NH3 + H+ ↔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 and is trapped in the lumen to be excreted in urine with other anions such as phosphate, chloride and sulphate. NH4+ production in the tubular lumen accounts for about 60 % excretion of hydrogen ions associated with nonvolatile acids.

The H+ required for NH4+ formation comes from: Glomerular filtrate The effect of carbonic anhydrase enzyme during the synthesis of carbonic acid in the tubular cells, these H+ are 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 systemic acidosis

Production of Erythropoietin (EPO) 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 renal insufficiency.

Active vitamin D One of the major metabolic function of the kidney is formation of the active form of vitamin D. The key regulatory enzyme in vitamin D formation is the 1ά-hydroxylase enzyme

In renal failure patients and hemodialysis the formation of vitamin D is greatly diminished leading to hyperparathyroidism.

RAS Changes in renin ultimately alter the output of this system, principally the hormones angiotensin II and aldosterone. Each hormone acts via multiple mechanisms, but both increase the kidney's absorption of sodium chloride, thereby expanding the extracellular fluid compartment and raising blood pressure.