Chapter 24. The kidney.

The main function is to maintain the constancy of the interior environment by eliminating waste products and by regulating the volume, electrolyte content and pH of the extracellulair fluid in the face of varying dietary intake and varying environmental demands. The kidneys receive about of the cardiac output. 1. The structure and function of the nephron.

Each nephron consists of a glomerulus, proximal tubule- comprising convoluted and straight segments, loop of Henle, distal convoluted tubule and collecting ducts. The glomerulus comprises a tuft of capillaires projecting into a dilated end of renal tubule. 1.1.1 The blood supply tot he nephron. The special characteristic of having two capillary beds in series with each other. The afferent arteriole of each cortical nephron branches to form the glomerulus; branches to form a second capillary network in the cortex. By contrast, efferent arterioles of juxtamedullary nephrons lead to vessel loops that pass deep into the medulla with the thin loops of Henle. These loops are called vasa recta and play a key role in counter-current exchange. 1.1.2 juxtaglomerular apparatus. A conjunction of afferent arteriole, efferent arteriole and distal convoluted tubule near the glomerulus forms the juxtaglomerular apparatus. There are specialised cells in both the afferente arteriole and in the tubule. Macula densa cells, respond to change in the rate of flow and the composition of tubule fluid, and they control renin release. Other mediators also influence renine secretion, including beta2-anta, vasodilator prostaglandins and feedback inhibition ang-II acting on At1-receptors.

1.1.3. Glomerular filtration. Fluid is driven from the capillaries into the tubular sapsule by hydrodynamic force opposed by the oncotic pressure of the plasma proteins to which glomerular capillaries are impermeable. 1.2. Tubular function. The apex of each tubular cell is surrounded by a tight junction. This is a specialised region of membrane that separates the intercellular space from the lumen. The movement of ions and water across the epithelium can occur through cells and between cells. 1.2.1. Proximal convoluted tubule. The epithelium is leaky, being permeable to ions and water, and permitting passive flow in either direction. The most important mechanism for Na+ entry into tubular cells from the filtrate occurs by Na+/H+ exchange. Intracellular carbonic anyhydrase is essential for production for H+, and transported out of cells into the interstitium and thence into the blood by a Na+/K+ ATPase. Both Na+/H+ and Na+/K+ are instances antiport-systems. Bicarbonate is normally completely reabsorbed in the proximal tubule. This is achieved by combination with protons, yielding carbonic acid, which dissociated to form carbon dioxide and water, followed by passive reabsorption of the dissolved carbon dioxide.

Plaatje: Cells are depicted as an orange bored round the yellow tubular lumen. Mechanisms of ion absorption at the apical margin of the tubule cell: 1.) Na+/H+ exchange; 2.) Na+/K+/2Clcotransport; 3.) Na+/Cl- cotransport; 4.) Na+ entry through sodium channels. Sodium is pumped out of the cells into the interstitium by the Na+/K+ ATPase in the basolateral margin of the tubular cells. The numbers in the boxes give concentration of ions as millimoles per liter of filtrate, and the percentage of filtered ions still remaining in the tubular fluid at the sites specified.

Plaatje proximale tubule: Sodium ions are absorbed and H+ secreted at the lumenal surface by an antiport mechanism (a). The primary active transport mechanism is the Na+ pump (p).

1.2.2. The loop of Henle. Consists of a descending and an ascending portion. Up to 30% of filtered Na+ is reabsorbed by this part of the nephron, which enables the kidney to excrete urine that is either more or less concentrated than plasma. - Descending limb: permeable to water, which exits passively because the interstitial fluid of the medulla is kept hypertonic. - Ascending limb: has a very low water permeability, the tight junctions are really tight, enabling the build-up of a substantial concentration gradient across the wall of the tubule. 20-30% of filtered Na+ is reabsorbed. There is active reabsorption of NaCl, unaccompanied by water. Ions move into the cell acros by a Na+/K+/2Cl- symporter. Reabsorption of salt is not balanced by reabsorption of water, so tubular fluid is hypotonic with respect to plasma. 1.2.3. Distal tubule. In the early distal tubule, NaCl reabsorption fruther dilutes the tubular fluid. Transport is driven by Na+/K+ ATPase. This lowers cytoplasmic Na+ concentration, and consequently Na+ enters the cell from the lumen down its concentration gradient, accompanied by Cl-. PTH and calcitriol both increas Ca2+ reabsorption. 1.2.4. Collecting tubule and collecting duct. Collecting tubules include principal cells, which reabsorb Na+ and secrete K+ and two populations of intercalated cells, alfa and beta, which secrete acid and base. The tight junctions are impermeable to water and ions. It is under independent hormonal control: absorption of NaCL by aldosterone, and absorption of water by ADH. Aldosterone enhances Na+ reabsorption and promotes K+ excretion. It promotes Na+ reabsorption by: - A rapid effect, stimulating Na+/H+ exchange; - A delayed effect, via nuclear receptors; - Long-term effects, by increasing the number of basolateral Na+ pumps. ADH is secreted by the posterior pituitary and binds V2 receptors in the basolateral membranes, increasing expression of aquaporin. This renders this part of the nephron permeable to water, allowing passive reabsorption of water as the collecting duct traverses the hyperosmotic region of the medulla and hence the excretion of concentrated urine. In the absence of ADH collecting duct epithelium is impermeable to

water. Athanol inhibits the secretion of ADH, causing water diuresis as a kind of transient diabetes inspidus. DUS! Na+/K+ ATPase in the basolateral membrane is the main active transporter. It provides the gradients for passive transporters in the apical membranes. 60-70% of the filtered Na+ and > 90% of HCO3 is absorbed in the proximal tubule. The thick ascending limb of Henles loop is impermeable to water; 20-30% of filtered NaCl is actively reabsorbed in this segment. Ions are reabsorbed from tubular fluid bij Na+/K+/2Cl- cotransporter in the apical membranes of the thick ascending limb ( hier werken diuretica op in). Filtrate is diluted as it traverses the thick ascending limb as ions are reabsorbed, so that it is hypotonic when it leaves. Na+/Cl- cotransport (inhibited by thiazide) reabsorbs 5-10% of filtered Na+ in the distal tubule. K+ is secreted into tubulair fluid in the distal tubule and the collecting tubules and the collecting ducts. In the absence of ADH, collecting tubules have low permeability to salt and water. Na+ is reabsorbed from collecting duct through epithelial sodium channels. 1.3.1 Acid-base balance. Carbonic anyhydrase is essential for acid-base control both because of its lumenal and cellular roles in the proximal tubule. 1.3.2. Potassium balance. Extracellular K+ is tightly controlled through regulation of K+ excretion by the kidney. Potassium ions are transported into collecting duct cells from blood and interstitial fluid by Na+/K+ ATPase and leak into the lumen through a K+ selective ion channel. Thus K+ secretion is coupled Na+ reabsorption. Consequently K+ is lost when: - More Na+ reaches the collecting duct; - Na+ reabsorption in the collecting duct is increased directly; K+ is retained when: - Na+ reabsorption in the collecting duct is decreased. 1.3.3. Natriuretic peptides. Nedogenous A, B and C natriuretic peptides are involed in the regulation of Na+ excretion. They are released from the heart in response to stretch (A+B), from endothelium (C) from brain (B). They activate particulate form of guanylate cyclase, and cause natriuresis both by renal haemodynamic effects. The tubular actions include the inhibition of angiotensin-II and of the action of ADH. Prostaglandings and renal function. Modulate its haemodynamic and excretory functions. Vasodilator and natriuretic. Factors that stimulate their synthesis include ischaemia, angio-II, ADH and bradykinin. 2.0. Drugs acting on the kidney. 2.1. Diuretics. Increase the excretion of Na+ and water. They decrease the reabsorption of Na+ and Clfrom the filtrate. Because a very large proportion of salt (NaCl) and water that passes into the tubule in the glomerulus is reabsorbed, a small decrease in reabsorption can cause a marked increase in Na+ excretion. 2.1.1. Diuretics acting directly on cells of the nephron. Affect those parts of the nephron where solute reabsorption occurs. Most Na+ absorption occurs in the proximal tubule -> anyhydrase inhibitors though are not particularly potent.

This is because they inhibit NaHCO3 rather than NaCl absorption.

The main therapeuticallyu usefull diuretics act on the: - Thick ascending loop of Henle; - Early distal tubule; - Collecting tubules and ducts. 2.1.2. Diuretics acting on the proximal tubule. carbonic anhydrase inhibitors increase excretion of bicarbonate with accompanying Na+, K+ and water. These agents are now not used as diuretics, but are still used in the treatment of glaucoma to reduce formation of aqueous humour. 2.1.3. Loop diuretics. Are the most powerful diuretics, capable of causing the excretion of 15-25% of filtered Na+. They also have incompletely understood vascular actions. Loop diuretics increase the delivery of Na+ to the distal nephron, causing loss of H+ and K+. Because Cl- but not HCO3- is lost in the urine, the plasma concentration of HCO3- increases as plasma volume is reduced. They are readily absorbed from the gastrointestinal tract. Given orally, they act within 1 hour. They are strongly bound to plasma protein, and so do not pass directly into the glomerular filtrate. They reach their site of action by being secreted in the proximal tubule by the organic transport mechanism. In nephrotic syndrome loop diuretics become bound to albumin in the tubular fluid, and consequently are not available to act on the Na+/K+/2Cl- carrier. Unwanted effects: excessive Na+ loss and diuresis are common, and can cause hypovolaemia and hypotension. Potassium loss, resulting in low plasma K+, and metabolic alkalosis. If necessary, hypokalaemia can be averted or treated by concomitant use of K+-sparing diuretics.
Plaatje ascending limb of Henles loop: the sodium pump (P) is the main primary active transport mechanism, and Na+, K+ and Cl- enter by cotransport system (C1). Chloride leaves the cell both trough basolateral chloride channels and by an electroneutral K+/Clcotransport system (C2). Some K+ returns to the lumen via potassium channels in the apical membrane, and some Na+ is absorbed paracelluarly trough zonula occludens.

2.1.4. Diuretics acting on the distal tubule. Thiazides are less powerful than loop diuretics but are preferred in treating uncomplicated hypertension. They are better tolerated than loop diuretics. They bind to the Cl- site of the distal tubular Na+/Cl- cotransport system, inhibiting its action and causing natriuresis with loss of sodium and chloride ions. The resulting contraction in blood volume stimulates rennin secretion, leading to angiotensin formation and aldosterone secretion. Thiazides reduces Ca2+ excretion. They have an incompletely understood vasodilator action and can cause hyperglycaemia. When used in the treatment of hypertension the initial fall in blood pressure results from decreased blood volume caused by diuresis, but the later phase is also related to an action on vascular smooth muscle. Thiazides have a paradoxical effect in diabetes inspidus, where they reduce the volume of urine by interfering with the production of hypotonic fluid in the distal tubule, and hence reduce the ability of the kidney to secrete hypotonic urine. They can be taken orally and are all excreted in urine, mainly by tubular excretion. Mild unwanted effects are common. These re-enact the features of Gitelmans syndrome, are disorder due to an inactivating mutation in the thiazide-sensitive Na+/Cl- cotransporter in the distal tubule. The clinical features are milder but as in Barterrs syndrome include renal salt loss, low blood pressure and hypokalaemic metabolic alkalosis; hypocalciuria is a feature, in contrast to Bartters syndrome, and hypomagnesaemia is characteristic. It can also give erectile dysfunction!
Plaatje distal tubule: the sodium pump (p) in the basolateral membrane is the primary active transport mechanism. Sodium and chloride ions enter by an electroneutral carrier (c1). Some Cl- is transported out of the cel by K+/Cl- contransport carrier (c2); some leaves the cell trhough chloride channels. Some K+ is transported out of the cell by the cotransport carrier (c2) and some passes back into the tubule lumen through the potassium channels.

2.1.5. Aldosterone antagonists.

Have very limited diuretic action when used singly , because distal Na+/k+ exchange accounts fro reabsorption of only 2% of filtered Na+. They do have marked antihypertensive effects, prolong survival in selected patients with heart failure and can prevent hypokalaemia when combined with loop diuretics or with thiazides. They compete with aldosterone for its intracellular receptors, thereby inhibiting distal Na+ retention and K+ secretion. Aldosterone antagonist predispose hyperkalaemia, which potentially fatal. Potassium supplement must not be co prescribed. They are used in patients with impaired renal function. Triameterene and amiloride. Like alodsterone antagonists, only have limited diuretic efficacy, because they also act on the distal nephron, where only small fraction of Na+ reabsorption occurs. They act on the collecting tubules and collecting ducts, inhibiting Na+ reasorption by blocking luminal sodium channels and decreasing K+ excretion. They can be given with K+-losing diuretics. Main unwanted effect, hyperkalaemia.

Plaatje collecting tubule: The cells are impermeable to water in the absence of ADH, and to Na+ in the absence of aldosterone. Aldosteorne acts on a nuclear receptor within the tubule cell and on membrane receptors. Chloride ions exit the tubule through the paracellular pathway. Potassium ions are added to the filtrate, as H+. The Na+ pump (p) in the basolateral membrane is main source of energy ion movement.

2.1.6. Diuretics that act indirectly by modifying the content of the filtrate. Osmotic diuretics: Are pharmacologically inert substances that are filtered in the

glomerulus but not reabsorbed by the nephron, they must constitute an appreciable fraction of the osmolarity of the tubular fluid. A larger volume of fluid remains within the proximal tubule. This has the secondary effect of reducing Na+ reabsportion. They are not useful in treating conditions such as heart failure associated with Na+ retention but much more limited therapeutic indications. 3.0 Drugs that alter the PH of the urine. 3.1. Agents that increase urinary PH. Citrate is metabolized via the Krebs cycle with generation of bicarbonate, which is excreted to give an alkaline urine. Alkalinisation is important in preventing certain weak acid drugs with limited aquous solubility. Sodium bicarbonate is sometimes used to treat salicylate overdose. DUS! Normally < 1% of filtred Na+ is excreted. Diuretics increase the excretion of salt and water. Loop diuretics, thiazides and K+-sparing diuretics are the main therapeutic drugs. Loop diuretics cause copious urine production. They inhibit the Na+/K+/2Cl- cotransporter in the thick ascending loop of Henle. They are used to treat heart failure and other disease complicated by salt and water retention. Hypovolaemia and hypokalaemia are important unwanted effects. Thiazides are less potent than loop diuretics. They inhibit the Na+/2CL- cotransporter in the distal convoluted tubule. They are used to treat hypertension. Erectile dysfunction is an important adverse effect. Hypokalaemia and other metabolic effects can occur. 4.1. Drugs that alter the excretion of organic molecules. Uric acid passes freely into the glomerular filtrate, and most is then reabsorbed in the proximal tubule while small amount is secreted into the tubule. The secretory mechanism is generally inhibited by low doses of drugs affect uric acid excretion, whereas higher doses are needed to bock reabsorption. Such drugs therefore tend to cause retention of uric acid at low doses, while promoting its excretion at higher doses. 5.1. Drug used in renal failure. 5.1.1. Hyperhosphatataemia. Phosphate causes vascular smooth muscle cell differentiation into osteoblast-like cells able to sustain mineralization. Hyperphosphataemia is common in renal failure. It may asymptomatic, but an acute increase in plasma phosphate causes symptoms by causing acute hypocalcaemia. Large calcium phosphate deposits around joints limit mobility but otherwise cause surprisingly few symptoms. Phosphate binders: approximately half of patient on chronic haemoldialysis are treated with such drugs. Calcium-containing phosphoate binding agents are widely used. They are contraindicated in hypercalcaemia or hypercalciuria but until recently have been believed to be otherwise safe.