Bob Delaney Flashcards

1
Q

Describe the movement of ions/molecules across the membrane of the PCT

A

70% water, sodium and potassium
100% glucose + amino acids
80% of bicarbonate
50% urea + Chloride
Variable calcium, phosphate, magnesium

On the basolateral side of tubular epithelial cells, Na+/K+ ATPase pumps maintain high levels of intracellular K+ and low levels of intracellular Na+ which creates an electrochemical gradient.

sodium-glucose/amino acids symporters allow for glucose/AA’s to enter with sodium. Glucose enters blood stream via facilitated diffusion transporters. Sodium is pumped out via ATPase pump.

Chloride enters apical end, swapped for a base. This chloride travels out into blood stream driven by the leakage of K+ back out through the basolateral end down the gradient created by ATPase pump.

Carbonic anhydrase produce H2CO3 which produces H+ and HCO3. Bicarb diffuses into blood via facilitated diffusion, H+ enters lumen via and Na+/H+ antiporter.

Increased osmotic pressure into the blood causes movement of water paracellularly from lumen into blood.

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2
Q

List 3 causes of intra-renal AKI

A
  1. Acute tubular necrosis
    -> Death/necrosis of the tubular epithelial cells resulting in sloughing of cells into urine forming muddy casts on urinalysis
  2. Acute Interstitial Nephritis
    -> Immune reaction to an agent such as drugs, infections or due to auto-immune condition can result in immune attack of the tubules and interstitial tissue causing renal impairment.
  3. Acute Glomerulonephritis
    ->immune-led damage to the glomerulus leading to glomerular dysfunction
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3
Q

Explain possible causes of hyperkalemia in AKI

A

“In AKI, hyperkalemia can occur for several reasons:

(1) Reduced GFR decreases the kidney’s ability to filter potassium, leading to its retention in the blood.

(2) The impaired ability of the distal nephron to secrete potassium into the urine results in further potassium accumulation.

(3) Tissue breakdown, such as in rhabdomyolysis, can cause a significant release of intracellular potassium into the bloodstream.

(4) Metabolic acidosis, often due to impaired bicarbonate reabsorption and hydrogen ion excretion, causes hydrogen ions to move into cells in exchange for potassium, leading to an increase in serum potassium levels.

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4
Q

Explain the relevance of FeNa for diagnosis of AKI

A

This test measures how much sodium is being excreted in the urine relative to the amount filtered by the kidneys.

FeNa <1% typically indicates pre-renal AKI, where the kidney is under-perfused but the tubular function is still intact. The low FeNa suggests that the kidneys are conserving sodium (and water) in response to reduced blood flow, indicating the tubules are functioning properly to retain sodium.

FeNa >2% suggests intrinsic (intra-renal) AKI, such as acute tubular necrosis (ATN). Here, the kidney tubules are damaged and unable to reabsorb sodium effectively, leading to excessive sodium loss in the urine.

FeNa between 1-2% is less specific and may indicate mixed causes of AKI or evolving renal injury.

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5
Q

Explain the expected BUN: Creatinine ratio findings in pre-renal AKI. How might this compare to intrinsic and post renal AKI?

A

In pre-renal AKI, the BUN
ratio is typically elevated above 20:1. This is due to decreased renal perfusion, which reduces the glomerular filtration of both urea and creatinine, leading to their accumulation in the blood.

However, in response to underperfusion, the kidneys reabsorb more water and sodium to preserve volume. This increased water reabsorption also enhances the reabsorption of urea in the collecting duct, while creatinine is not reabsorbed.

As a result, BUN levels rise disproportionately compared to creatinine, increasing the BUN
ratio above the normal range of 10-20:1.

Intrinsic AKI: Both are elevated but the ratio may be normal because the kidneys have lost filtration and reabsorption capability and so neither rises to a greater extend than the other.

Post-renal: The ratio may be elevated due to increased pressure within the tubules due to obstruction causing BUN to be forced out into the intersitium.

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6
Q

Compare expected urine osmolality findings between pre-renal and intrinsic renal AKI

A

Pre-renal: Urine osmolality would be high because there is increased water resabsorption by the nephron.

Intrinsic renal: Low urine osmolality because there is loss of resabsorption abilities in the nephron and so water is lost in the urine.

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7
Q

What are the clinical signs of acute tubular necrosis and why?

A

Signs of fluid depletion or overload and hypotension or hypertension may be present, depending on the extent of the disease and the underlying cause. Pre-renal AKI, commonly caused by hypoperfusion due to hypovolemia, may present initially with signs of fluid depletion and hypotension. However, as ATN develops, fluid overload and edema become more likely due to reduced GFR and the kidneys’ impaired ability to excrete sodium and water, leading to fluid retention in the blood

Hyperkalemia and acidosis: The tubules have lost secretory capabilities and so potassium remains elevated in blood. Additionally, the inability to reabsorb HCO3 and secrete H+ results in acidosis. The elevated H+ ions can cause intracellular K+ to move out of cell in exchange for H+ further precipitating hyperkalemia.

Oliguria or anuria: Reduced GFR can occur due to tubular lumen blockage following cast formation from necrotic epithelial cells which have shed off into the lumen thereby occluding it.

Low urine osmolality: the tubules have lost ability to concentrate urine.

FeNa >2%: Tubules have lost ability to reabsorb sodium which is then lost in the urine.

BUN: Creatinine ratio: normal to low: Reduced GFR coupled with reduced ability of tubules to reabsorb urea means that both components rise in the blood but may not rise disproportionately to each other.

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8
Q

List 5 indications for RRT

A

A E I O U

Acidosis
Electrolyte imbalance
Intoxication/Poisoning
Overload (fluid)
Uremic complications (e.g. Pericarditis, encephalopathy, pulmonary edema)

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9
Q

Explain why hyperkalemia occurs in ATN

A

(1) Tubular epithelial cells cannot effectively reabsorb sodium in exchange for potassium secretion- this leads to potassium retention in the blood.

(2) Metabolic acidosis which arises due to low HCO3- can cause H+ ions to shift intracellularly which causes K+ ions to shift extracellularly into blood.

(3) Rhabdomyolysis, which is itself a potential cause of ATN, can cause release of intracellular K+ into the blood following skeletal muscle breakdown

(4) Necrotic debris that slough into tubular lumen can back up fluid and increase pressures within bowman’s capsule. This reduces GFR meaning less K+ is filtered and is instead retained in blood.

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10
Q

urinalysis in ATN would show what?

A

High urinary sodium (cant reabsorb)

Low urine osmolality (cant reabsorb water i.e. cant concentrate urine i.e. urine very dilute) < 500 mOsm/kg

muddy brown casts (if severe)

FeNa > 2%

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11
Q

Explain how severe vomiting causes contraction alkalosis

A

(1) Prolonged vomiting leads to a loss of H⁺ and Cl⁻ from the stomach. This means less H⁺ enters the duodenum, reducing the need for pancreatic bicarbonate (HCO₃⁻) to neutralize the acid. As a result, more bicarbonate is retained in the bloodstream, contributing to metabolic alkalosis.

(2) Dehydration from vomiting decreases kidney perfusion, activating the RAAS.

Angiotensin II promotes increased sodium (Na⁺) and bicarbonate reabsorption in the proximal tubule, raising blood bicarbonate levels.

Aldosterone increases potassium (K⁺) excretion, leading to hypokalemia. Hypokalemia causes K⁺ to shift from cells into the ECF, in exchange for H⁺ moving into cells, further decreasing H⁺ in the blood and worsening the alkalosis.

(3) ECF contraction from volume loss concentrates bicarbonate in the blood, worsening the alkalosis due to the reduced dilution of HCO₃

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12
Q

Discuss the differences in ion and water permeability between the descending and ascending limbs of the loop of Henle, and how these differences contribute to the overall process of urine formation and concentration.

A
  • The descending limb is permeable to water but impermeable to ions (solutes)
  • The ascending limb is impermeable to water but permeable to ions (solutes).
  • These differences in permeabilities creates the counter-current multiplier system to aid in urine concentration.
  • The ascending limb produces a hypertonic medullary interstitial space which causes the movement of water through osmotic gradient out of the descending limb for reabsorption. Na+/K+/2Cl transporter is that responsible for ion reabsorption in ascending limb (thick part).
  • This creates a hypertonic filtrate as it descends towards the hump of the loop of henle.
  • As it ascends through the ascending limb it becomes more hypotonic as ions are pumped out into the intersitial space.
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13
Q

Describe the role of the proximal diluting segment of the distal convoluted tubule in the maintenance of sodium and water balance.

A
  • This segment reabsorbs sodium (Na⁺) actively via sodium-chloride (Na⁺/Cl⁻) co-transporters on the apical membrane of the tubular cells. This occurs without concurrent water reabsorption, due to the water impermeability of the early DCT. This characteristic leads to the “diluting” effect, where the filtrate becomes more hypotonic as sodium is reabsorbed without water.
  • Contribution to Sodium Balance: By fine-tuning the amount of sodium that continues downstream, the proximal diluting segment indirectly influences the final sodium content in the urine, which is crucial for maintaining sodium homeostasis in the body.
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14
Q

What is the role of juxtaglomerular apparatus?

A
  • The juxtaglomerular apparatus (JGA) is composed of juxtaglomerular cells located adjacent to the afferent and efferent arterioles, macula densa cells in the distal convoluted tubule (DCT) and mesangial cells adjacent to glomerulus
  • The macula densa cells monitor sodium-chloride levels, which serve as a surrogate indicator for the glomerular filtration rate (GFR). When sodium-chloride levels are low, indicating a low GFR, the macula densa cells signal the juxtaglomerular cells to release renin. Renin initiates the renin-angiotensin-aldosterone system (RAAS), in which angiotensin II stimulates efferent arteriole vasoconstriction, raising glomerular hydrostatic pressure and thereby increasing GFR.
  • Additionally, RAAS promotes sodium and water retention to support blood volume and blood pressure. When sodium levels in the DCT return to normal, the macula densa cells stop stimulating renin release, thus regulating the system via negative feedback.
  • The mesangial cells mediate glomerular vessel diameter by mediating contraction and relaxation of vascular smooth muscle
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15
Q

Explain the effect of RAAS on potassium excretion.

A
  • RAAS results in increased angiotensin II levels which increase the secretion and release of aldosterone from the adrenal cortex.
  • Aldosterone works to increase sodium reabsorption in the principal cells of the late distal tubule and collecting ducts which subsequently causes obligatory potassium secretion and excretion.
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16
Q

Describe MOA of ADH in collecting duct?

A
  • ADH, released from the posterior pituitary, binds to V2 receptors on principal cells in the collecting duct. This action triggers the insertion of aquaporin-2 channels into the apical membrane, allowing water to be reabsorbed from the tubular fluid back into the bloodstream. This process is essential for concentrating urine and maintaining body water balance, especially during dehydration(Bob Delaney).
17
Q

Identify two differences between the thick ascending and thin descending limbs of the Loop of Henle in terms of permeability and ion transport.

A
  • Permeability to Water: The thin descending limb is permeable to water, allowing water reabsorption into the hypertonic medulla, whereas the thick ascending limb is impermeable to water.
  • Ion Transport: The thick ascending limb actively reabsorbs ions, including sodium, potassium, and chloride, through the Na⁺/K⁺/2Cl⁻ cotransporter. The thin descending limb does not engage in active ion transport
18
Q

Explain why serum creatinine alone is insufficient to reliably assess GFR in acute kidney injury (AKI).

A
  • In AKI, serum creatinine levels can lag behind actual changes in GFR due to the time needed for creatinine to accumulate in the blood, making it less accurate during rapid declines in kidney function. Additionally, creatinine production is constant, but in acute settings, factors like hydration status and fluctuating kidney function can distort its accuracy. Therefore, other markers and direct measurements, such as urine output and fluid balance, are often used alongside serum creatinine(
19
Q

Why does a decrease in renal perfusion pressure trigger the release of renin from the juxtaglomerular cells?

A
  • When renal perfusion pressure drops, juxtaglomerular cells detect this change and release renin as part of the renin-angiotensin-aldosterone system (RAAS). Renin acts to raise blood pressure by converting angiotensinogen to angiotensin I, which is later converted to angiotensin II. Angiotensin II causes vasoconstriction and stimulates aldosterone release, increasing blood volume and pressure to improve renal perfusion
20
Q

List 5 causes of pre-renal AKI

A

(1) Heart failure causing reduced effective blood volume causing hypoperfusion of kidneys

(2) Massive haemorrhage causing hypovolemic shock and hypoperfusion

(3) Renal artery stenosis

(4) Severe burns

(5) Embolus or thrombosis of renal artery

(6) NSAIDs causing reduced prostaglandin-induced vasodilation of afferent arteriole –> vasoconstriction of afferent

21
Q

Describe how aminoglycosides cause nephrotoxicity

A

Aminoglycosides are filtered across the glomerulus and can enter the epithelial cells of the PCT via endocytosis

They can then concentrate in lysosomes or organelles including the mitochondria and golgi apparatus.

This results in mitochondrial dysfunction and the production of reactive oxygen species which can cause cellular death leading to acute tubular necrosis

22
Q

List 4 causes of acute tubular necrosis

A

(1) Nephrotoxic ATN –> PCT
–> Aminoglycosides
–> Contrast dye
–> NSAIDs
–> ACE-inhibitors

(2) Ischemic ATN –> PCT and thick ascending LOH
–> Prolonged pre-renal AKI i.e. dehydration, heart failure, haemorrhage
–> Sepsis
–> Pyelonephritis
–> Microangiopathies e.g. in DM

23
Q

How is AKI diagnosed

A

Any of the following

(1) Urine output < 0.5ml/kg/hr for 6 hours

(2) Serum Creatinine > 1.5x normal level for 7 days

(3) Creatinine rises by >0.3mg/dL in 48 hours

24
Q

Describe the pathophysiology of acute tubular necrosis

A

*Ischemic or nephrotoxic damage results in death of tubular epithelial cells -> particularly in the PCT and thick ascending limb

*Cells slough off and fall into the tubular lumen thereby obstructing filtrate flow.
*Obstruction disturbs the pressure gradient across the glomerular capillaires, opposing hydrostatic pressure and reducing the glomerular filtration rate.

*Creatinine and blood urea nitrogen begin to rise in the blood causing azotemia.
*Urinary output falls,

*Dead epithelial cells form casts which are excreted as typical muddy-brown casts.

25
Q

define azotemia

A

Azotemia refers to an elevated level of nitrogenous waste products (primarily creatinine and blood urea nitrogen (BUN)) in the blood. It is commonly a sign of impaired kidney function or kidney failure.

26
Q

Name 4 prognostic indicators for AKI

A
  1. Stage and severity –> Stage 2 and 3 are higher risk of poorer outcomes including need for dialysis
  2. Co-morbidity e.g. Heart failure and diabetes
  3. Underlying cause of AKI –> intrinsic AKI can be associated with more long-term complications.
  4. Age and functional status –> elderly have lower renal reserve with less ability to recover fully from an AKI