Mary Nelligan

Question 1

What part(s) of the nephron are mostly responsible for potassium handling?

Answer 1

Reabsorption: PCT (65%), Thick Ascending LOH (30%)

Secretion: Principal cells of DCT + Collecting duct/tubules

Question 2

Explain the mechanism of potassium reabsorption and secretion

Answer 2

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.

Question 3

Describe how the PCT manages acid-base balance.

Answer 3

In the PCT, Thick LOH

-Intracellular carbonic anhydrase produces H2CO3 which dissociates into H+ and HCO3-

-H+ ions are secreted at apical membrane via a sodium-hydrogen counter-transporter.

-HCO3 is reabsorbed into interstitial fluid through the basolateral membrane via a bicarbonate-chloride exchanger and a bicarb-sodium symporter.

-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

Question 4

Name the different forms of calcium in the plasma and briefly describe each.

Answer 4

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

Question 5

What parts of the nephron handle calcium? Describe this

Answer 5

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.

Question 6

Name the enzyme that converts 25-hydroxyvitamin D to 1,25-dihydroxycholecalciferol (its biologically active form).

Answer 6

1-alpha-hydroxylase (in the kidney)

Question 7

How does calcitriol promote calcium absorption in the small intestine?

Answer 7

(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.

Question 8

Why does hyperparathyroidism occur commonly in CKD

Answer 8

1. 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.
2. 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).
3. 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.
4. The result of all this is chronic hypersecretion of PTH i.e. secondary hyperparathyroidism which can result it osteodystrophy.

Question 9

Define secondary hyperparathyroidism and outline 3 main aetiologies.

Answer 9

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.

1. Chronic kidney disease resulting in loss of calcitriol production -> hypocalcaemia.
2. Malabsorption of calcium in the gut e.g. Crohn’s disease or coeliac disease -> hypocalcaemia.
3. Low exposure to sun light
   Reduced vitamin D synthesis in the skin (cholecalciferol) -> hypocalcaemia.

Question 10

How might secondary hyperparathyroidism be managed in CKD?

Answer 10

1. 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
2. Vitamin D supplementation
   -Ergocalciferol or Cholecalciferol
   -Can help restore calcium levels without giving calcium salts.
3. Calcium levels
   - Can use calcium salts such as calcium carbonate, acetate, gluconate or chloride if severe and persistent hypocalcaemia.
4. Persistent PTH
   - Calcimimetics can be used to bind to calcium-sensing receptors in parathyroid glands thereby suppressing PTH release.

Question 11

Define tertiary hyperparathyroidism

Answer 11

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.

Question 12

What type of hormone is erythropoeitin and where in the kidney is it produced?

What type of anaemia is associated with CKD?

Answer 12

EPO is a glycoprotein hormone produced by the interstitial peritubular cells in the cortex and outer medulla.

Normocytic normochromic anaemia.

Question 13

What might be given to compensate for loss of EPO production?

Answer 13

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

Question 14

What are normal Hb levels ?

Answer 14

Men 13.5-18 g/dL

Women 12-15 g/dL

Question 15

Describe the autoregulation system intrinsic to the kidney that maintains GFR despite fluctuations in systemic MAP

Answer 15

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.

Question 16

Where are the cell bodies located for the sympathetic nerves innervating the kidney?

Answer 16

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

Question 17

What part of the nephron is most responsible for sodium handling? How does it do it?

Answer 17

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.

Question 18

Name 3 hormones that regulate sodium handling in the kidney

Answer 18

(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

Question 19

How does PTH act to increase serum calcium levels normally?

Answer 19

(1) Stimulates 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) Stimulates the reabsorption of calcium in the renal tubules

(4) Promotes the excretion of phosphate by the renal tubules.

Question 20

How does calcitriol (active vit D) promote calcium absorption in the gut?

Answer 20

1. Promotes the expression of calcium binding proteins such as calbindin in the intestinal epithelium
2. Promotes the synthesis of calcium-stimulated ATPase pumps in the intestinal epithelial cells.

Question 21

What causes the acidosis in CKD (3 things)

Answer 21

1. Impaired acid secretory mechanisms
   - The kidneys ability to excrete H+ ions becomes impaired resulting in accumulation of H+ ions in the blood.
   -Bicarbonate in the blood acts to buffer the excess H+ but eventually gets depleted.
2. Impaired bicarb reabsorption
   -Reduced ability of nephron the reabsorb bicarbonate further hinders the buffering capacity and causes metabolic acidosis.
3. Impaired ammoniogenesis
   - Ammonia (NH3) is produced from glutamine by the kidney tubules as a means of neutralising acid loads.
   -It is secreted by the PCT into the lumen to neutralise H+ ions, forming ammonium (NH4) which is then excreted.
   -Reduced ammonia production therefore results in reduced ammonium excretion meaning a net increase in H+ ions in the blood, further precipitating acidosis

Question 22

What is the single most significant factor in improving the prognosis of progressive renal disease?

Answer 22

Control of hypertension

Question 23

Define chronic kidney disease

Answer 23

CKD is the result of progressive scarring resulting from any type of kidney disease whereby alterations in the function of intact nephrons become maladaptive over time causing further scarring. This eventually results in end-stage renal failure where glomeruli, tubules, interstitium and blood vessels are sclerosed, regardless of the primary site of disease.

Question 24

Describe 5 morphological features of CKD

Answer 24

1. Glomerular scarring/ glomerulosclerosis/hyalinosis due to deposition of plasma proteins and collegen matrix, with obliteration of the glomeruli seen in later stage disease.
2. Interstitial fibrosis with atrophy and drop out of renal tubules/ loss of peritubular capillary network
3. Hypertensive changes in arteries is seen as thick walled arteries with narrowing of the vessel lumen.
4. Inflammatory infiltrates may be seen to invade the fibrotic interstitial tissue.
5. Shrunken, often symmetrically contracted kidneys which are red-brown in colour with a granular surface.

Question 25

Describe the 4 main histological alterations seen in glomerular disease

Answer 25

1. Hypercellularity
   - increase in number of cells in the glomerulus due to proliferation of mesangial and endothelial cells +/- leucocyte infiltration
2. Basement membrane thickening
   -Deposition of immune complexes in the basement membrane.
   -Fibrin, amyloid or abnormal fibrillary proteins may also deposit.
   -Seen in membranous glomerulopathy.
3. Hyalinosis and sclerosis
   - Hyalinosis of glomerulus occurs due to accumulation of material such as plasma proteins following capillary wall injury
   - seen in focal segmental glomerulosclerosis.
   -Sclerosis of the glomerulus occurs when extracellular collagenous matrix accumulates in the glomerulus
4. Crescent formation
   - Accumulation of proliferating parietal cells and infiltrating leukocytes within the glomerulus following an immune or inflammatory injury.

Question 26

list 5 systems affected by uremia

Answer 26

1. Gastro-intestinal
   - Uremic gastropathy/gastroenteritis
2. Cardiovascular
   -Uremic fibrinous pericarditis
   -Pericardial effusion
3. Nervous system
   -Peripheral neuropathy
   -Asterixis
   -Low mood
4. Respiratory
   -Pulmonary oedema
   -Pleuritis
5. Integumentary (skin)
   -Pruritis
   -Uremic frost
   -Calciphylaxis causing ulceration

Question 27

Why are ACE inhibitors beneficial in slowing progression of renal failure but why are they not suitable in advanced disease?

Answer 27

ACE inhibitors can slow the rate of progression of renal disease through lowering hypertension both systemically but also within the glomerulus.

ACEI’s act by inhibiting the conversion of angiotensin I to II by ACE. This prevents vasoconstriction of the efferent arteriole thereby lowering intraglomerular pressure.

This helps offset the complications of long-term hypertension within the kidney such as hyperplastic arteriolosclerosis as well as preventing sustained hyperfiltration in the functioning nephrons thereby preventing proteinuria.

ACE’Is are not suitable in late stage renal failure due to the risk of hyperkalemia caused by its inhibtion of aldosterone production and secretion. Aldosterone normally functions to up regulate potassium secretion (and sodium reabsorption).

As well as this, they reduce GFR due to their effects of reducing glomerular hydrostatic pressure which can cause accumulation of K+ in the blood.

Question 28

What is meant by “adjusted calcium” and how and why is it calculated?

Answer 28

Corrected or adjusted calcium is derived in order to determine how much ionized calcium in present in the blood. This is important because this is the biologically active form.

It is important to determine because Total serum calcium levels may appear low in patients with hypoalbuminemia because the portion of calcium bound to albumin (roughly 40% of total calcium) is lost.

Corrected ca2+ (mmol/L) = unadjusted ca2+ (mmol/L) + 0.02 x (40 - serum albumin g/L)

Question 29

Define and distinguish between Nephrotic syndrome and Nephritic syndrome

Answer 29

Nephrotic syndrome refers to excessive proteinuria (>3.5g/L/day), hypoalbuminemia, hyperlipidemia and lipiduria. It results from damage to the glomerular filtration barrier often from primary glomerular diseases such as minimal change disease, Focal segmental glomerulosclerosis, membranous nephropathy. Hyperlipidemia can result from increased lipid production by the liver as well as derranged lipid transport proteins as a result of the hypoalbuminemia.

Nephritic syndrome is a condition involving haematuria, mild to moderate proteinura (<3.5g/L/day), hypertension, oliguria and red cell casts in urine (indicating glomerular damage). It is caused by inflammatory glomerular pathologies such as post-strep glomerulonephritis which cause inflammatory infiltrate and capillary wall injuries allowing for passage of blood into filtrate. There is a reduction in GFR as well as increased sodium + water retention (RAAS ) which causes the oliguria.

Question 30

Explain why proteinuria occurs in CKD

Answer 30

There are 2 main reasons why proteinuria occurs in CKD and it can depend on the stage of the disease and the primary cause and site of damage within the kidney.

1. In early stage CKD, proteinuria can occur due to adaptive mechanisms of functioning nephrons whereby they begin hyperfiltrating to compensate for overall net reduction in GFR. This is achieved through vasoconstriction of efferent arteriole to increase intraglomerular pressures. This in itself lead to increased glomerular permeability leading to protein filtration.
2. In later stage disease, structural damage to the glomerulus can give rise to proteinuria due to the sustained high pressures within the glomerulus caused by prolonged adaptive mechanisms as well as glomerular pathologies themselves resulting in loss of glomerular filtration barrier.

Question 31

List 3 ACEI’s and 3 common side effects

Answer 31

Enalapril, Lisinopril, Ramipril

1. Hyperkalemia due to inhibition of aldosterone production leading to reduced potassium secretion.
2. Dry cough due to increased concentrations of substance P, prostaglandins, kinins and TXA2 as a result of ACE inhibition.
3. Hypotension due to excessive vasodilation

Question 32

Describe the pathogenesis of osteitis fibrosa cystica.

Answer 32

OFC is associated with hyperparathryoidism.

High PTH levels increase osteoclast activity which begin resorbing bone, hollowing out osteons with desposition of collegenous matrix adjacent to trabeculae.

Eventually, Trabecular bone is resorbed and marrow is replaced by loose fibrous tissue and woven bone.

Cystic degeneration occurs leading to bone destabalisation. Hemosiderin-laden macrophages and giant cells can be seen histologically, forming what is called a “brown tumour”.

Question 33

Name 5 bone diseases associated with renal disease

Answer 33

1. Osteitis fibrosa cystica (most common)
2. Mixed bone disease
3. Osteomalacia (due to aluminium overload in bone caused by dialysis - prolongs mineralisation lag time)
4. Adynamic bone disease (excessive suppression of PTH-> reduced osteoblasts/osteoid, bone instability and accumulation of old bone)
5. Osteopenia- commonly due to glucocorticoid use after renal transplant (increase osteoclast activity)

Question 34

Describe polycystic kidney disease

Answer 34

PCKD is an inherited disorder characterised by the development of multiple cysts in the kidney which expand and destroy the kidney parenchyma.

It can be classified into 2 forms:

(1) Adult onset PCKD which is autosomal dominant caused by mutations in genes encoding for polycystin 1 + 2. Commonly associated with signs of CKD including fluid overload and HTN.

(2) Childhood onset PCKD which is autosomal recessive caused by muations in genes encoding fibrocystin. Commonly associated with pulmonary insufficiency, hepatomegaly, fluid overload.

Question 35

Describe the role of FGF 23

Answer 35

FGF23 is a phosphatonin, a glycoprotein hormone primarily produced by osteocytes that plays a key role in serum phosphate and vitamin D homeostasis.

It reduces serum phosphate levels by binding to its FGF receptor which reduces expression of sodium-phosphate cotransporters in the prox tubules, reducing phosphate reabsorption.

It also regulates vitamin D levels by inhibiting 1-alpha-hydroxylase production in the kidneys, preventing the formation of calcitriol (active vitamin D).

FGF23 levels are elevated in chronic kidney disease (CKD) to offset phosphate retention in the blood.

Question 36

Define CKD including two characteristic abnormalities other than elevated serum urea and creatinine that may be seen in this condition.

Answer 36

• Chronic kidney disease (CKD) describes a chronic reduction in kidney function, GFR < 60ml/min/1.73m2, sustained over three months. It tends to be permanent and progressive. It is the end result of progressive scarring from any type of kidney disease which eventually results in end stage renal failure.
• Two characteristic abnormalities associated with CKD, apart from elevated serum urea and creatinine levels, include:
  o Proteinuria: The presence of excess protein in the urine, which can indicate damage to the kidney’s filtering units (glomeruli) as well as hyperfiltration response in remaining nephrons.
  o Electrolyte Imbalances: Commonly seen imbalances include hyperkalemia (elevated potassium levels) and metabolic acidosis, resulting from the kidneys’ reduced ability to excrete potassium and regulate acid-base balance.

Question 37

Explain the relationship between hypertension and CKD

Answer 37

• Hypertension can result in damage to the glomeruli, particularly if it is chronically elevated or if there is an acute rise in blood pressure as seen in malignant/accelerated hypertension.
• The most common manifestations of hypertension in the kidney are hyaline and hyperplastic glomerulosclerosis, the latter being associated with acute BP rises.
• Both of these conditions involve thickening of the glomerular walls and narrowing of the lumen and can result in glomerular scarring , nephrosclerosis and/or necrotising arterolitis. This impairs the glomerular filtration barrier  proteinuria.
• Conversely, CKD can cause hypertension as reduced kidney function results in inability to maintain fluid homeostasis. This can precipitate high blood volumes resulting in hypertension.

Question 38

Explain the effect of CKD on hemoglobin concentrations.

Answer 38

• CKD results in a reduced hemoglobin concentration due to loss of EPO production. EPO is a glycoprotein hormone produced by the interstitial peritubular cells in the cortex and outer medulla.
• Along with GM-CSD and IL-3, EPO is responsible for stimulating erythropoiesis in the bone marrow and thus the production of RBC’s. The resulting normocytic normochromic anemia causes reduced Hb levels since hemoglobin is found in RBC’s.

Question 39

What effect does chronic renal failure have on serum phosphate?

Answer 39

Chronic kidney disease results in hyperphosphatemia due to phosphate retention from reduced GFR. Elevated phosphate levels decrease serum calcium by binding to free calcium, leading to hypocalcemia, which stimulates secondary hyperparathyroidism. Elevated PTH levels attempt to increase serum calcium by mobilizing calcium and phosphate from bones. However, while PTH would normally help excrete phosphate in the kidneys, this compensatory mechanism is impaired in CKD, resulting in persistent hyperphosphatemia.