1. Biochemical aspects of the kidney function František Duška

2. Overview Functions of exploded nephron Internal environment and the kidneys –isovolumia –isoionia –isohydria Excretion of nitrogen waste (urea and ammonia) Kidney as an endocrine and metabolic organ

3. Nefron

4. Glomerular filtration I. Blood plasm is strained through a molecular sieve composed of: –capillary endothelium –basal membrane: colagen IV., glycoproteins –podocyte processes Basal membrane is negatively charged, foreclosing albumin to pass through.

5. Glomerular filtration II. 20% of flowing plasma is filtered (2 ml/s), i.e. 160-180 l daily Primary urine: –is identical with plasma, but... –contains only a small amounts of proteins (α2 and β2 microglobulin, lysozyme) which are than resorbed in tubules

6. Proteinuria...means pathological presence of protein in definitive urine (i.e. > 0.15 g/24 hr.)...is common sign of glomerular impairment: –mechanical: non-selective proteinuria –charge loss: albuminuria “Tubular proteinuria“: the presence of proteins normally filtered, which are not resorbed in tubules Extrarenal causes: myoglobine, Hb etc..

7. Tubules - sophisticated analytical laboratory Tubules analyse urine and excrete or save back substances according to body needs, using: –tubular resorption (back to plasma) –tubular secretion Many active transporters - huge energy demands Hormonal regulation (ADH, aldosteron)

8. Proximal tubule …is a site of obligatory (hormone- independent) resorption of: –most Na +, Cl-, K +, 70% of water –all filtered glucose and amino acids –bicarbonate Actively resorbed Na + is followed by Cl - and water Secondary active transport of Glc and AA

10. The loop of Henle Function: –resorption of futher 20% of filtrated volume –creation of hyperosmolar environment in the kidney medulla Counter-current multiplication system – descending limb is freely permeable for water – ascending limb has Na + K + 2Cl - co-transporter

11. Distal tubule Aldosterone-dependent Na + resorption and K + excretion Further resorption of 0 - 5% filtered water Aldosterone: –increases Na + and fluid conserving in the body –insreases K + excretion in the distal tubule – acts by inducing Na + K + ATPase of bazolateral membrane

12. Collecting tubule …determines definitive urine final volume and osmolality ADH increases tubule wall permeability for water, thus concentrating urine – in the presence of ADH water is passively moved to hyperosmotic intersticium –otherwise urine pass the kidney medulla unchanged (hypoosmotic)

14. Water metabolism - obligatory resorption From180 l of primary urine daily: –60-70% (110-130 l) is resorbed in the proximal tubule – 20% (40 l) is resorbed in counter-current systém of Henle’s loop – remains 20 l of hypotonic urine incomming to the distal tubule… …and here excreted volume is to be regulated.

15. Regulation of urine volume and osmolality … 20 - 30 l of hypoosmotic urine daily come to the distal tubule, where... Aldosteron - conserves sodium, increases kalium excretion (Na + / K + exchange) ADH - conserves water Definitive urine: 0.5 - 24 l daily (normally 1-2 l), 100 - 1400mosm/l, according to body needs to maintain plasma volume

16. Disturbancies of urine volume and osmolality Polyuria = > 3 l/24 hours –osmotic diuresis –water diuresis Oliguria = < 0.5 l/24 hours Anuria = < 0.1 l/24 hours Izostenuria

17. Izoionia - ion concentration stability Na + active transport is a force for water, glucose and chloride resorption K + : – resorbed in proximal tubule –excreted in distal tubule (aldosterone) –antiport with Na +, competition with H + Ca 2+ and phosphate: PTH and vit. D

18. The kidney (and lung) is the most important organ for maintaining acid-base balance. Protecting the internal environment against acid overload.

19. Izohydria I. proximal tubule Bicarbonate reabsorption H + secretion Carboanhydrase H + excretion depends on pCO 2

20. H + secretion into the distal tubule H + ATPase performs H + transport Aldosteron increases H + secretion H + in the urine –reacts with NH 3 (glutaminase, GDH) –reacts with HPO 4 2- Urine pH varies between 4.5 - 8.0

21. Nitrogen-containing compouds excretion Urea: –is synthesized in liver –passivly passes th¨rough the membranes –plays a role in the counter-current mechanism Ammonia, an important urine buffer, rises from glutamine (and glutamate) Creatinine comes from muscles, is neither resorbed nor excreted in tubules. It is thus useful for glomerular filtration rate calculations.

22. The kidney as an endocrine organ Renin-angiotensin system, kalikrein-kinin and prostaglandins have especially an influence on haemodynamics (see physiology) Erytropoetin The role in vit. D3 metabolism: final hydroxylation on the 1 position gives a rise to an active form of vitamine D: calcitriol (1,25 - dihydroxycholecalciferol)

23. The role in intermediary metabolism Tubular epithelium is the most active Active transports are energized by lactate, glutamine and FA oxidation Most of the pathways ¨need oxygen. Important organ of gluconeogenesis (and ketogenesis?) during starvation Glutamine...

24. Renal failure Hyperkalemia Urea and creatinine plasma levels rise Acidosis (phosphate and sulphate accumulation) Chronic renal impairment: anaemia (APO), bone disorders (Ca) Volume changes

25. Review The kidney is important for maintaining stability of internal environment (volume, ion composition and pH) …excrete nitrogen from the body. … are a source of several hormones … are a target organ for several hormones … have an influence on ABB, circulation, bone, intermediary metabolism, erythropoesis etc...… have an influence on ABB, circulation, bone, intermediary metabolism, erythropoesis etc...