Renal System
The main function of the kidneys is water regulation and balance of inorganic ions. However, they are also involved in removal of metabolic waste products and drugs from the blood and their excretion in urine, as well as gluconeogenesis and endocrine functions. In patients with kidney disease, the build up of waste is serious but extracellular fluid volume and composition disturbances are a much more pressing issue.
The nephron is known as the functional unit of the kidney. Ther are approximately 2.5 million in the kidneys. The two functional components are the tubular and the vascular component. The tubular component contains the filtrate which eventually becomes urine, whereas the vascular component is the nephron’s blood supply.
The glomerular filtrate drains into the Bowman’s capsule and then into the proximal convoluted tubule (PCT). The glomerular endothelium contains pores to allow small molecules to pass through but prevent the passage of larger proteins and cells. Passage of proteins/cells is also prevented by negatively charged podocytes and the basement membrane.
Macula densa are specialised cells in the DCT which sense the glomerular flow rate by sodium ion concentration.
The juxtaglomerular apparatus includes pressure sensitive juxtaglomerular cells which secrete renin. The apparatus helps to regulate renal blood glow, glomerular flow rate and indirectly modulates sodium ion balance and systemic blood pressure.
Glomerular flow rate is controlled by the diameters of the afferent and efferent arterioles, as well as sympathetic vasoconstrictor nerves, ADH and the renin-angiotensin-aldosterone system. Autoregulation is important as it maintains blood supply (and GFR as a result) and prevents high pressure surges from damaging the kidneys. The blood supply is unique in that it contains both upstream and downstream arterioles.
The kidneys act as a long-term blood pressure control by controlling blood volume. Reduction in renal pressure leads to intrarenal distribution of pressure, and increased absorption of salt and water.
Decreased pressure in the renal arterioles and sympathetic activity causes renin to be produced, leading to angiotensin II production.
What does aldosterone do?
- Stimulates sodium ion reabsorption and potassium ion excretion by the renal tubule
- Exerts indirect -ve feedback on the RAAS by increasing effective circulating volume and lowering plasma [K+]
- Conserves [Na+] and water as well as presenting large [K+} fluctuations
What does angiotensin II do? Angiotensin II causes direct constriction of renal arterioles and stimulates synthesis of aldosterone from the adrenal cortex, causing sodium to be absorbed and intravascular blood volume to increase. It also enhances tubuloglomerular feedback by making the macula densa more sensitive, enhances Na-H exchangers and sodium channel functions to promote sodium reabsorption, stimulates thirst and ADH release by acting upon the hypothalamus and is involved in renal hypertrophy.
Low blood pressure -> renin production by kidney -> liver produce angiotensin I -> angiotensin I-> II in lungs -> adrenal gland produces aldosterone -> pressure increase. The RAA system is primarily important In controlling blood pressure and is released in response to reduced blood flow. Renal/renovascular disease may result in inappropriate RAAS activation.
The release of renin is stimulated by decreased blood pressure (sympathetic effects on JGA), decreased [NaCl] at the macula densa, or decreased renal perfusion pressure detected by renal baroreceptors. Renin release is the lead factor in controlling levels of angiotensin II.
Effecting circulating volume is the circulating blood, usually between 5 and 10 litres in volume. ECV sensors are found in the carotid sinus, aortic arch, renal afferent arteriole and the atria. Efferent pathways controlling the ECV are the RAAS, ADH, atrial natriuretic peptide and the sympathetic nervous system. The heart and blood vessels are short term effectors of ECV and the kidney is the long term ECV effector. In the short term, blood pressure is affected and sodium ion excretion is affected in the long term.
SLIDE 16 - Low ECV triggers 4 parallel effector pathways which act on the kidney, leading to either changes in haemodynamics or in sodium ion transport by renal tubule cells
Plasma osmolality is the solute concentration present in the plasma and is valued at 250 milli-osmoles +/-10. Hypothalamic osmoreceptors detect ant changes. Efferent pathways are the ADH and thirst pathway. The effector organ for the ADH pathway is the kidney and excretion of water from the renal system is affected. The effector organ of the thirst pathway is the brain, causing the individual to increase their water intake by drinking.
LOOK AT SLIDE 15 AND FIGURE OUT WHAT’S GOING ON
Drugs which affect the renal system can be used to treat high blood pressure. Diuretics are provided as short term solutions to rapidly offload fluid eg in the case of a pulmonary edema and are typically used as a secondary treatment alongside another drug. Sympatholytics oppose the downstream effects of postganglionic nerve firing in any effector organs innervated by the sympathetic nervous system. Drugs which directly act on the RAAS may be used, as well as calcium ion channel blockers or direct-acting vasodilators
All diuretics prevent reabsorption of water INDIRECTLY, typically by preventing sodium ion reabsorption. Loop diuretics = furosemide supplemented with spironolactone/amiloride. Thiazides = Bendroflumethiazide. Potassium sparing diuretics don’t act directly on sodium ions.
Furosemide acts on the loop of Henle by inhibiting the Na+/K+/2Cl- co-transporter. Thiazides are most commonly used and inhibit the DCT NaCl transporters. This transporter typically reabsorbs around 5% of filtered sodium so thiazides are less effective at producing diuresis and natriuresis than loop diuretics. Potassium sparing diuretics are inhibitors of distal tubule sodium ion channels or antagonists of aldosterone receptors. One of the issues with diuretics Is that they can cause hypokalaemia (loss of potassium) which can lead to heart issues.
i) Angiotensinogen, synthesized in liver (+ glucocorticoids and estrogens), is the substrate for renin, an arterial enzyme.
ii) Renin acts upon angiotensinogen to produce angiotensin I.
iii) Hypertension associated with these hormones may be due in part to increased levels of angiotensinogen. Since it circulates at about the same Km (binding affinity) for renin, small changes would markedly affect the generation of angiotensin I.
iv) Angiotensin-Converting Enzyme (ACE), a glycoprotein found in lung, endothelial cells and plasma, removes 2 carboxy-terminal amino acids from angiotensin I to form angiotensin II.
v) Various antagonistic peptide analogues of angiotensin II and drugs like Captopril (a suicide substrate that inhibits ACE) are used to treat renin-dependent hypertension.
Angiotensin II increases blood pressure by causing vasoconstriction of the arterioles and is the most potent vasoactive substance known.
Angiotensin Iinhibits renin release in a short feedback loop and is a potent stimulator of aldosterone production. Aldosterone increases Na+ and H2O retention
Any combination of factors that decreases fluid volume (dehydration, decreased blood pressure, fluid or blood loss) or decreases in NaCl concentration (low Na+ intake) stimulates renin release.
This system is so sensitive that even a change from lying down to sitting up will increase renin secretion and lead to Na+ and H2O retention via aldosterone.
Aldosterone inhibitors include spironolactone and eplerenone. They bind competitively to the aldosterone receptor and promote sodium ion and water excretion in the collecting tubule and duct.