Urine Formation Filtration Reabsorption Secretion GFR 125 ml/min = 180 litres per day Urine...

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)

Acid-base balance

Production and secretion of enzymes (e.g., renin) & hormones (Vit. D & erythropoietin)

Excretion: (non-volatile) metabolic end products (e.g. urea, uric acid, creatinine, NH4+) and “foreign” solutes (e.g. some drugs)

Metabolic conversions

fluids & electrolytes Balance

Metabolic Function Of The Kidney

Energy supply for The Kidney

The kidney tissue represents less than 0.5% of the body

weight

body weight0.5%

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

25% ofCOP

body weight

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

• This is required for the synthesis of ATP needed to reabsorb most of the solutes filtered through glomerular membranes.

body weight

WHY?

Very Low Energy Reserves

kidney must get its energy requirement from circulating

substrates.

• Glycogen • Phosphocreatine• Neutral lipids

So

Substrates used by kidney for energy production

Fed State Starvation ?

Substrates used by kidney for energy production

Fed State Oxidation

Lactate Glucose

Substrates used by kidney for energy production

Starvation blood lactate glucose

Blood fatty acid & ketone body concentrations

major kidney fuels during starvation.

Glycolysis,Citric acid cycle

HMS

,

• Glucose Oxidation

• Gluconeogenesis

• Fructose metabolism

Carbohydrate metabolism in the kidney

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 medullaRenal cortex

Glucose utilization Glucose synthesis

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

Renal gluconeogenesis paradoxically increases &it accounts for 50% of the endogenous glucose release.

Renal glucose uptake is < 10% of the ingested glucose.

glucose is mainly utilized by brain, liver & muscles.

DIABETES CARE, VOLUME 24, NUMBER 2, FEBRUARY 2001

Renal gluconeogenesis paradoxically increases

due to:• Postprandial increases in sympathetic

nervous system activity • availability of gluconeogenic

precursors (e.g., lactate and amino acids).

WHY?

This increase in renal gluconeogenesis help liver glycogen repletion by suppression of hepatic glucose release.

postprandially

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

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

It is a site for• B-Oxidation.• synthesis of carnitine .

• ketolysis.

• denovo synthesis of cholesterol• denovo synthesis of fatty acids.

The kidney has active glycerol kinase enzyme

Protein metabolism in the kidney:

The Kiney is a site for

urea synthesis.

Oxidative deamination and transdeamination of individual amino acids.

major site for the action of glutaminase enzyme with its great role in acidosis.

site for creatine formation glycine & arginine.

L-glutamic aciddehydrogenase

NADP(NAD)

COOH

CHNH2

CH2

CH2

COOHNADPH+H

COOH

C

CH2

CH2

COOH

NH

NH3

COOH

C

CH2

CH2

COOH

O

NADH+H+

H2O

Iminoacid

R-CH-COOH R-C-COOHAmino acid oxidaseNH2

NH

Flavin Flavin-H2

H2O

H2O2 O2

1/2 O2

H2O

CatalaseR-C-COOH

-Ketoacid

Aminoacid Iminoacid

O

NH3

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.

12

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:

1. Glomerular filtrate2. 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.