Biochemical aspects of the kidney function

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+ • Ca2+ 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 pCO2

20. H+ secretion into the distal tubule • H+ ATPase performs H+ transport • Aldosteron increases H+ secretion • H+ in the urine • reacts with NH3 (glutaminase, GDH) • reacts with HPO42- • 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...