Mary Nelligan Flashcards
What part(s) of the nephron are mostly responsible for potassium handling?
Reabsorption: PCT (65%), Thick Ascending LOH (30%)
Secretion: Principal cells of DCT + Collecting duct/tubules
Explain the mechanism of potassium reabsorption and secretion
Reabsorption
(1) Proximal convoluted tubule
- Reabsorption is generally via passive diffusion paracellularly, driven by (i) Solvent drag with water reabsorption (ii) electrochemical gradient between lumen and interstitial fluid which is maintained through the Na+/K+ ATPase pumps on basolateral side.
(2) Thick Asc LOH
- Reabsorption is active transport of potassium via NKCC2 channels on apical side of epithelial cell.
- Some K+ ions will leak back into tubular lumen via ROMK channels in order to maintain normal NKCC2 function.
-Other K+ ions will diffuse into interstitial fluid via K+ channels.
Secretion
- Potassium is pumped from interstitial fluid into the prinicpal cells, against its concentration gradient, via Na+/K+ ATPase pumps.
-Potassium then diffuses out into lumen down its concentration gradient for excretion in urine.
Describe how the PCT manages acid-base balance.
In the PCT, Thick LOH
-Co2 from the tubular fluid/ blood enters the epithelial cells. Intracellular carbonic anhydrase produces H2CO3 which dissociates into H+ and HCO3-
-H+ ions are secreted at apical membrane via a sodium-hydrogen counter-transporter. This is upregulated by Angiotensin II.
-HCO3 is reabsorbed into interstitial fluid through the basolateral membrane via a bicarbonate-chloride exchanger and a bicarb-sodium symporter.
-H+ that is secreted into the lumen can re-combine with HCO3- to form H2CO3- which can dissociate into CO2 and H20. CO2 can then enter the cell to participate in the H+ and HCO3- production again. This allows for the cycle to continue and for efficient bicarb recovery.
-The Na+/K+ ATPase pump on the basolateral side is essential for maintaining the electrochemical gradient. It actively transports sodium out of the cell and potassium into the cell, which helps drive the secondary active transport mechanisms and maintain the gradients necessary for the movement of bicarbonate and hydrogen ions
Explain how the distal nephron functions in acid-base homeostasis
*The Type A intercalated cells of the collecting duct are responsible for approximately 5-10% of acid-base handling in the kidneys, fine-tuning the acidity of excreted urine based on the homeostatic needs of the body.
*In the cells, CO2 combines with H2O to form H2CO3 (carbonic acid), catalyzed by the enzyme carbonic anhydrase.
*H2CO3 dissociates into H⁺ and HCO3⁻.
*H⁺ ions are actively secreted into the tubular fluid via two mechanisms:
o H⁺ ATPase pumps protons directly into the lumen.
o H⁺/K⁺ ATPase exchanges H⁺ for K⁺, allowing potassium reabsorption.
*HCO3⁻ is reabsorbed into the interstitial fluid via the HCO3⁻/Cl⁻ exchanger (anion exchanger, AE1) on the basolateral membrane. Chloride (Cl⁻) flows into the cell to balance the charge, enabling bicarbonate reabsorption.
Name the different forms of calcium in the plasma and briefly describe each.
Ionized Calcium (Ca²⁺): This is the free, biologically active form of calcium that constitutes about 50% of total plasma calcium. It is crucial for various physiological functions, including muscle contraction, blood clotting, and neurotransmitter release.
Protein-Bound Calcium: Approximately 40% of plasma calcium is bound to plasma proteins, primarily albumin. This form is not biologically active but can be released into the ionized form as needed.
Calcium Complexed with Anions: About 10% of plasma calcium is bound to anions such as phosphate, sulfate, and citrate. This form is also not biologically active but plays a role in maintaining calcium balance and availability
What parts of the nephron handle calcium? Describe this
PCT (65%), Thick Asc LOH (25%), DCT+CT (10%)
(1) PCT
- mostly via paracellular route via solvent drag
- some via transcellular route down its electrochemical gradient and pumped out by calcium-ATPase pumps as well as via sodium-calcium exhanger.
-PTH not very active on PCT
(2) Thick Asc LOH
-50% transcellular route as above - PTH acts to increase activity of calcium-sodium exchanger.
-50% paracellular- passive diffusion due to lumen being more positively charged relative to interstitial fluid.
(3) DCT + CD
- Transcellular down ECG and pumped out via calcium ATPase and calcium-sodium exhanger
-PTH increases luminal calcium channels + actiity of exchangers.
Name the enzyme that converts 25-hydroxyvitamin D to 1,25-dihydroxycholecalciferol (its biologically active form).
1-alpha-hydroxylase (in the kidney)
How does calcitriol promote calcium absorption in the small intestine?
(1) Increases expression of calcium-binding proteins on the intestinal epithelial cells, such as calbindin
(2) Increases formation and activity of calcium channels and calcium-ATPase pumps in the epithelial brush border.
Describe the physiological effects of calcitonin on serum calcium levels.
- Produced by parafollicular (C-cells) of the thyroid gland.
-Opposes the effects of PTH, aiming to reduce serum calcium levels.
(i) binds to and Inhibits osteoclast activity which inhibits bone demineralisation.
(ii) Decreases calcium reabsorption in the kidney, particularly in the distal nephron, by reducing its permeability to calcium ions.
Why does hyperparathyroidism occur commonly in CKD
- CKD can result in loss of 1-alpha-hydroxylase activity thereby causing reduced calcitriol formation (active vit D). This causes reduced absorption of calcium from the intestine causing hypocalcaemia.
- The resulting hypocalcaemia disinhibits the parathyroid glands which begin hyper-secreting parathyroid hormone in an attempt to return serum calcium levels to normal. This is acheived through stimulating osteoclast bone demineralisation and increasing tubular reabsorption of calcium (However reabsorption capabilities may be impaired in CKD leading to loss of calcium in urine).
- Hyperphosphatemia can occur as a result of reduced GFR and impaired ability of nephron to excrete phosphate as (as it should under PTH activity). The high levels of phosphate then act to bind to ionised calcium in the blood rendering it biologically inactive, thereby lowering ionised serum calcium levels.
- The result of all this is chronic hypersecretion of PTH i.e. secondary hyperparathyroidism which can result it osteodystrophy.
Define secondary hyperparathyroidism and outline 3 main aetiologies.
SHPT is the elevation of PTH secondary to hypocalcaemia. The disease is frequently associated with chronic kidney disease, however vitamin D deficiency is the most common cause.
- Chronic kidney disease resulting in loss of calcitriol production -> hypocalcaemia.
- Malabsorption of calcium in the gut e.g. Crohn’s disease or coeliac disease -> hypocalcaemia.
- Low exposure to sun light
Reduced vitamin D synthesis in the skin (cholecalciferol) -> hypocalcaemia. - Hypercalciuria secondary to loop diuretics
How might secondary hyperparathyroidism be managed in CKD?
- Lower serum phosphate levels to normal range
- Usually through dietary restrictions on phosphate-rich foods.
-Phosphate binders may be used if dietary approach is not adequate - Vitamin D supplementation
-Ergocalciferol or Cholecalciferol
-Can help restore calcium levels without giving calcium salts. - Calcium levels
- Can use calcium salts such as calcium carbonate, acetate, gluconate or chloride if severe and persistent hypocalcaemia. - Persistent PTH
- Calcimimetics can be used to bind to calcium-sensing receptors in parathyroid glands thereby suppressing PTH release.
Define tertiary hyperparathyroidism
Tertiary hyperparathyroidism is the persistent, autonomous secretion of PTH in the absence of the original inciting stimulus, which occurs as a result of long-standing secondary hyperparathyroidism. The para-thyroid glands are therefore refractory to the normal feedback mechanisms which control it. This results in hypercalcaemia.
What type of hormone is erythropoeitin and where in the kidney is it produced?
What type of anaemia is associated with CKD?
EPO is a glycoprotein hormone produced by the interstitial peritubular cells in the cortex and outer medulla.
Normocytic normochromic anaemia.
What might be given to compensate for loss of EPO production?
Erythropoiesis-stimulating agents such as erythropoeitin alfa (every 1-2 wks) or darbepoetin alfa (every 2-4 weeks).
These are generally reserved for those with a Hb <10 g/dL
What are normal Hb levels ?
Men 13.5-18 g/dL
Women 12-15 g/dL
Describe the autoregulation system intrinsic to the kidney that maintains GFR despite fluctuations in systemic MAP
Autoregulation is achieved via the tubuloglomerular feedback system.
This acts to maintain near to normal renal blood flow and therefore GFR between MAP ranges of 80-170mmHg.
-Reduced renal blood flow/ GFR results in reduced NaCl filtration.
-Low NaCl is sensed by macula densa cells of distal tubule which respond in the following way:
(i) Vasodilates afferent arteriole to increase hydrostatic pressure in glomerular capillaries.
(ii) Stimulates the release of Renin from juxtaglomerular cells, which kicks of RAAS thereby producing angiotensin II
(iii)Angiotensin II vasoconstricts the efferent arteriole thereby further increasing hydrostatic pressure within the glomerular capillaries.
This restores normal GFR, normal NaCl filtration which therefore causes negative feedback loop to dampen this cycle.
Where are the cell bodies located for the sympathetic nerves innervating the kidney?
lateral horns of grey matter from T10-11 (lesser splanchnic) and T12 (least splanchnic). These preganglionic fibres synapse at aorticorenal and coeliac ganglia from where post-ganglionic fibres reach the kidney via renal plexus.
SNS:
-vasoconstricts afferent and efferent arterioles thereby reducing GFR
-stimulates renin release
-increases sodium and water reabsorption by the tubules
What part of the nephron is most responsible for sodium handling? How does it do it?
PCT reabsorbs 65-70% of filtered sodium.
(i) Na+/K+ ATPase pump on basolateral membrane creates an electrochemical gradient that allows for diffusion of sodium into cell at apical end down its electrochemical gradient. This is then pumped out at the BL side by this pump.
(ii) The Na+/H+ antiporter also transports sodium into the cell - this antiporter is upregulated by angiotensin II.
(iii) The sodium is reabsorbed into the peritubular capillaries from the interstitial fluid through a combination of hydrostatic and colloid pressures.
Name 3 hormones that regulate sodium handling in the kidney
(1) Angiotensin II
- Increase sodium reabsorption in the PCT through upregulating Na+/H+ antiporter activity.
-Vasoconstricts the efferent arteriole to increase GFR
-Indirectly acts by stimulating aldosterone release.
(2) Aldosterone
- Increases sodium reabsorption at collect tubule
- Released from adrenal gland in response to angiotensin II and high potassium levels.
- Increases synthesis of sodium channels (ENAC) and Na+/K+ ATPase pumps.
(3) Atrial natriuretic peptide
- Decreases sodium reabsorption and increases sodium and water excretion.
- Released from cardiac muscle fibres in response to high atrial pressures.
- Vasodilates afferent and vasocontricts efferent to increase GFR
How does PTH act to increase serum calcium levels normally?
(1) Stimulates 1-alpha hydroxylase to increase production of 1,25-dihydroxycholecalciferol in the kidneys which will promote calcium reabsorption in the intestine.
(2) Stimulates bone demineralisation through upregulation of osteoclast activity via RANK-L expression and inhibition of OPG release.
(3) Increases proliferation of osteoclasts moving towards a net bone resorption.
(4) Stimulates the reabsorption of calcium in the renal tubules
(5) Promotes the excretion of phosphate by the renal tubules.
