Download In renal insufficiency

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
Fluids &
Electrolytes
Balance
Metabolic
Conversions
Excretion of Metabolic
End Products
e.g. ammonia, urea,
creatinine, uric acid & some
‘foreign’ molecules as drugs
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
25% of
COP
Kidney tissue represents
less than 0.5% of the body weight
body
weight
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
Fed State
Starvation
Glucose oxidation
Fatty acids
Glycolysis
oxidation
&
&
citric acid cycle
ketone bodies
degradation
(ketolysis)
Carbohydrate Metabolism
in the kidney
,
Glucose oxidation
Gluconeogenesis
Glycolysis,
citric acid cycle
&
PPP
Synthesis of glucose from noncarbohydrate sources
as lactate, glycerol & amino acids
(esp. glutamine)
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
Glucose synthesis
Renal medulla
Glucose utilization
Cells of the cortex have considerable amounts
gluconeogenic enzymes,
BUT: have little hexokinase
Cells of the medulla have considerable amounts of
hexokinase (of glycolysis). So, they can take up,
phosphorylate & metabolize glucose through glycolysis
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
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).
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:
123445-
b-oxidation of fatty acids
Synthesis of carnitine : for transport of FA to mitochondria for oxidation
De-novo synthesis of fatty acids
Degradation of ketone bodies (Ketolysis)
De-novo synthesis of cholesterol
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:
1.
2.
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
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)
In Tubules of kidney
Decrease Na+ excretion
Increase K+ excretions
Renin
(synth. by kidney)
Angiotensin I
Hypernatremia
hypokalemia
Angiotensin Converting Enzyme
(ACE)
Angiotensin II
Increase BP
simulate aldesterone release (from adrenal cortex)