Biochemistry of kidney

Functions of the Kidney Regulation of the water and electrolyte content of the body. Regulation of the water and electrolyte content of the body. Retention of substances vital to the body Retention of substances vital to the body Maintenance of acid/base balance. Maintenance of acid/base balance. Excretion of waste products, water soluble toxic substances and drugs. Excretion of waste products, water soluble toxic substances and drugs. Endocrine functions Endocrine functions

Urine is formed as a result of a three phase process Glomerular fitration Glomerular fitration Selective (active) and passive reabsorption Selective (active) and passive reabsorption Secretion Secretion

Glomerular filtration Filtration takes place through the semipermeable walls of the glomerular capillaries Filtration takes place through the semipermeable walls of the glomerular capillaries The driving hydrostatic pressure is provided by arterial pressure The driving hydrostatic pressure is provided by arterial pressure About 20% of renal plasma flow is filtered each minute (~ 125 ml/min) GFR About 20% of renal plasma flow is filtered each minute (~ 125 ml/min) GFR Result is glomerular filtrate GF (primary urine) Result is glomerular filtrate GF (primary urine) (~ 150 l). (~ 150 l).

Reabsorption In the proximal and distal tubule, the GF becomes highly concentrated as the result of the removal of water. In the proximal and distal tubule, the GF becomes highly concentrated as the result of the removal of water. At the same time, many other low molecular weight constituents are rebsorbed by active transport – glucose, AA and organic and inorganic ions At the same time, many other low molecular weight constituents are rebsorbed by active transport – glucose, AA and organic and inorganic ions

Secretion Some of the substances that have to be excreted from the body are released into urine in the kidney by active transport – H+ and K+ ions, urea, creatinine and drugs. Some of the substances that have to be excreted from the body are released into urine in the kidney by active transport – H+ and K+ ions, urea, creatinine and drugs.

Proximal Tubule Reabsorbs 60% of all solute (100% of glucose and AA, 90% of bicarbonate, % of inorganic phosphate and water. Reabsorbs 60% of all solute (100% of glucose and AA, 90% of bicarbonate, % of inorganic phosphate and water.

Loop of Henle Next reabsorption of NaCl Next reabsorption of NaCl In descending loop of Henle In descending loop of Henle - resorption of water by osmosis - increasing of osmolarity (hypertonic) In ascending loop of Henle In ascending loop of Henle - active transport of NaCl out of the tubule - decreasing of osmolarity (hypotonic)

Distal Tubule and Collecting Ducts Aldosterone promotes Na+ ions and water reabsorption Aldosterone promotes Na+ ions and water reabsorption Excretion of H+ ions Excretion of H+ ions The final concentration of urine depends upon antidiuretic hormone (ADH). The final concentration of urine depends upon antidiuretic hormone (ADH).

Energy for the transport ATP is derived from the oxidative metabolism of glucose, lactate, pyruvate, fatty acids, glycerol, citrate and AA absorbed from the blood. ATP is derived from the oxidative metabolism of glucose, lactate, pyruvate, fatty acids, glycerol, citrate and AA absorbed from the blood.

Constituents of the urine Organic constituents Organic constituents Inorganic constituents Inorganic constituents

Organic constituents grams/day urea20 – 30 creatinin 1 – 1,5 uric acid 0,3 – 2,0 hippurate 0,15 glucose < 0,16 ketone bodies< 3 aminoacids< 1 – 3 proteins< 0,15 Inorganic constituents mmol/day Cl – 240 Na – 150 K + 60 – 80 SO – 60 NH – 50 HPO – 40 Ca 2+ 4 – 11 Mg 2+ 3 – 6

Proton secretion The tubule cells absorb CO2 from the blood and then hydrate it to carbonic acid (carbonate dehydratase). The tubule cells absorb CO2 from the blood and then hydrate it to carbonic acid (carbonate dehydratase). Carbonic acid then dissociates to HCO3- and H+. Carbonic acid then dissociates to HCO3- and H+. H+ is exported to the urine by an ATP- driven membrane-localised transport system, while HCO3- returns to the blood. H+ is exported to the urine by an ATP- driven membrane-localised transport system, while HCO3- returns to the blood.

Ammonia excretion Ammonia is produced enzymatically from glutamine and other AA. Ammonia is produced enzymatically from glutamine and other AA. NH3 combines with secreted H+ ions to form a nondiffusible ammonium ion (NH4+) which is excreted in the urine. NH3 combines with secreted H+ ions to form a nondiffusible ammonium ion (NH4+) which is excreted in the urine. Ammonia production is increased by a severe metabolic acidosis. Ammonia production is increased by a severe metabolic acidosis.

Recycling of the calcium and phosphate ions Parathormone (parathyrin) Parathormone (parathyrin) Calcitonin Calcitonin Calcitriol Calcitriol

Parathormone PTH (parathyrin) A peptide hormone produced by parathyroid gland A peptide hormone produced by parathyroid gland - stimulates the absorption of calcium in the kidney - at the same time inhibits the resorption of phosphate The overal effect of elevated PTH levels is The overal effect of elevated PTH levels is - an increase in plasma calcium level - decline in plasma phosphate level

Calcitonin A peptide produced in C cells of the thyroid gland A peptide produced in C cells of the thyroid gland Inhibits the reabsorption of both calcium and phosphate Inhibits the reabsorption of both calcium and phosphate The result is an overal decline in the plasma level of either ion The result is an overal decline in the plasma level of either ion With to respect to calcium reabsorption, calcitonin is an antagonist of PTH With to respect to calcium reabsorption, calcitonin is an antagonist of PTH

Calcitriol Steroid hormone, formed in the kidneys Steroid hormone, formed in the kidneys It has stimulatory effect on the reabsorption of both calcium and phosphate ions It has stimulatory effect on the reabsorption of both calcium and phosphate ions

Reabsorption of sodium ions Aldosterone (steroid hormone) stimulates Na+ retention Aldosterone (steroid hormone) stimulates Na+ retention Atrial natriuretic peptide (ANP), a hormone from the atrium of the heart inhibits retention of Na+. Atrial natriuretic peptide (ANP), a hormone from the atrium of the heart inhibits retention of Na+. Both hormones probably affect Na+/K+ - ATPase Both hormones probably affect Na+/K+ - ATPase

Atrial Natriuretic Peptide (ANP) ANP is released when arterial pressure is increased (in heart failure) or fluid overload. ANP is released when arterial pressure is increased (in heart failure) or fluid overload. It promotes loss of Na+ and Cl- ions and water chiefly by increasing GFR. It promotes loss of Na+ and Cl- ions and water chiefly by increasing GFR.

Antidiuretic Hormon (ADH) ADH increases the water permeability of the distal tubule and collecting duct, thus increasing the concentration of urine. ADH increases the water permeability of the distal tubule and collecting duct, thus increasing the concentration of urine. In contrast when secretion of ADH is inhibited, it allows dilute urine to be formed. This occures mainly, when plasma sodium concentration falls such as following drinking large quantities of water. In contrast when secretion of ADH is inhibited, it allows dilute urine to be formed. This occures mainly, when plasma sodium concentration falls such as following drinking large quantities of water. This fall is detected by osmoreceptors in the hypothalamus. This fall is detected by osmoreceptors in the hypothalamus.

Gluconeogenesis Chief substrate is glutamine Chief substrate is glutamine Other substrates are AA, lactose, glycerol or fructose (all are obtained from the blood plasma) Other substrates are AA, lactose, glycerol or fructose (all are obtained from the blood plasma) The ammonia derived from this AA serve to buffer the pH of the urine. The ammonia derived from this AA serve to buffer the pH of the urine. Gluconeogenesis is induced by cortisol Gluconeogenesis is induced by cortisol

Glucose recycling Is an energy dependent process Is an energy dependent process Is independent of gluconeogenesis Is independent of gluconeogenesis Glucose uptake occurs as compulsatory cotransport with Na+ ions Glucose uptake occurs as compulsatory cotransport with Na+ ions It is driven by the concentration gradient of Na+ between the urine and interior of the cells (secondary active transport) It is driven by the concentration gradient of Na+ between the urine and interior of the cells (secondary active transport)

Hormones of the kidney Erythropoietin Erythropoietin Calcitriol Calcitriol Angiotensin Angiotensin

Erythropoietin Polypeptide hormon that is formed predominantly by the kidney (also by the liver) Polypeptide hormon that is formed predominantly by the kidney (also by the liver) It controls the differentiation of the bone marrow stem cells It controls the differentiation of the bone marrow stem cells The release is stimulated by hypoxia (low pO2) The release is stimulated by hypoxia (low pO2) The hormon ensures that the bone marrow cells are converted to erythrocytes, so that their concentration in the blood increases The hormon ensures that the bone marrow cells are converted to erythrocytes, so that their concentration in the blood increases

Calcitriol 1-alpha,25-dihydroxycholecalciferol is a steroid-related hormon involved in calcium homeostasis. 1-alpha,25-dihydroxycholecalciferol is a steroid-related hormon involved in calcium homeostasis. It is formed in the liver from calcidiol by hydroxylation at C-1 It is formed in the liver from calcidiol by hydroxylation at C-1 The activity of hydroxylase (calcidiol-1- monooxygenase) is regulated by the hormone parathyrin (parathormone). The activity of hydroxylase (calcidiol-1- monooxygenase) is regulated by the hormone parathyrin (parathormone).

Renin – angiotensin system Renin is an enzyme which converts the plasma protein angiotensinogen to angiotensin I. Renin is an enzyme which converts the plasma protein angiotensinogen to angiotensin I. Angiotensin converting enzyme (ACE) which is formed in the lungs converts angiotensin I to angiotensin II which causes vasoconstriction and an increase in blood pressure. Angiotensin converting enzyme (ACE) which is formed in the lungs converts angiotensin I to angiotensin II which causes vasoconstriction and an increase in blood pressure. Angiotensin II also stimulates the aldosterone production (water and sodium retention which together increase blood volume). Angiotensin II also stimulates the aldosterone production (water and sodium retention which together increase blood volume).

Renin increases the production of angiotensin II which is released when there is fall in intravascular volume and dehydration. This leads to: Constriction of the efferent arteriole to maintain GFR, by increasing the filtration pressure in the glomerules. Constriction of the efferent arteriole to maintain GFR, by increasing the filtration pressure in the glomerules. Release of aldosterone. Release of aldosterone. Increased release of ADH. Increased release of ADH. Thirst Thirst The opposite occurs when fluid overload occurs. The opposite occurs when fluid overload occurs.