Furosemide and Kidney Function

• Furosemide competes with chloride to bind to the Cl- binding site of the NKCC2 cotransporter
• Furosemide blocks transcellular transport of Na+, K+, and Cl-
  • Decreases reabsorption of Na+, K+, Cl-
  • Increases tubular solute concentration
  • Prevents water reabsorption, causing diuresis
  • Decreases osmolarity in the medullary interstitium
  • Disrupts the countercurrent multiplier system
  • Decreases the kidney’s ability to concentrate urine
• NKCC2 cotransporter contributes to the positive luminal potential because of K+ leakage into the lumen
• K+ leakage is facilitated by renal outer medullary K+ (ROMK) channels
• Positive luminal potential drives paracellular reabsorption of Ca2+and Mg2+
• Blocking of NKCC2 cotransporter:
  • Decreases interstitial K+ levels
  • Less positive luminal potential
  • Loss of force for paracellular transport of Ca2+ and Mg2+

Weak Inhibition of Carbonic Anhydrase

• Carbonic anhydrase facilitates the conversion of bicarbonate (HCO3-) and H+ into CO2 and H2O for reabsorption
• Furosemide reduces the reabsorption of bicarbonate
• Furosemide increases urinary excretion of HCO3- and phosphate in the proximal convoluted tubules

Polyuria

• Excessive diuresis caused by furosemide leads to increased urine production
• NKCC2 blockage prevents the transcellular reabsorption of Na+, K+, and Cl-
• There is a decrease in the osmolarity of the medullary interstitium, which lowers the interstitial osmotic gradient
• Water reabsorption is prevented, and water excretion via urine is increased
• Contributes to volume depletion

Hypovolemia

• Hypovolemia is a state of decreased blood volume (low plasma volume)
• This may lead to hypotension, which can trigger the RAAS system to regulate blood pressure, blood volume, and fluid balance
• There is decreased water and electrolyte reabsorption like in polyuria
• High solute concentration is found in the lumen, causing water to stay in the urine
• Reduced plasma volume and dehydration ensues

Hypernatremia

• Hypernatremia is shown as an elevated blood sodium concentration as a result of loss of free water

• Decreased Na+ reabsorption and increased Na+ excretion would intuitively lead to low serum Na+ concentrations

• Majority of Na+ reabsorption occurs in the PCT (60%), while only 25% is handled by the NKCC2 pump in the TALH

• Furosemide is a loop diuretic, hence, its action is limited to the reabsorption of sodium at the TALH

• Net loss of water is the dominant effect of Furosemide

  • Excretion of electrolyte-free water exceeds the increased natriuresis, leading to a higher concentration of sodium in the extracellular fluid
  • H2O concentration at ECF + ↑ Na+ concentration = Hypernatremia
  • Furosemide also decreases Urea permeability in the collecting ducts, exacerbating free H2O loss

Hypokalemia

• Hypokalemia is identified as low serum potassium
• NKCC2 blockage decreases K+ reabsorption
• ECF volume contraction triggers RAAS and a subsequent release of aldosterone
• This increases K+ excretion in the distal tubule and collecting duct through ROMK and BK channels
• Aldosterone-induced K+ excretion further decreases serum potassium levels and stimulates H+ secretion through H+-ATPase and H⁺/K⁺ exchanger, promoting metabolic alkalosis

Hypochloremia

• Hypochloremia is defined as low serum chloride

• NKCC2 blockage decreases Cl- reabsorption causing increased Cl- excretion in the urine and decreased concentration of Cl- in the blood

• Hypercalciuria is increased calcium excretion in the urine

• NKCC2 blockage decreases solute reabsorption, decreasing the positive (+) potential in the tubular lumen

• Positive luminal membrane drives paracellular Ca2+ (and Mg2+) reabsorption

• Decreased force for paracellular flux of Ca2+ in the TALH

• Lowered Ca2+ reabsorption and Increased Ca2+ excretion ensue

• The patient presents with increased Ca2+ concentration in urine

• Acute furosemide use may still be normocalcemic since the regulation of Ca2+ is more endocrine-based via hormones like PTH and calcitonin

• Chronic furosemide use causes hypocalcemia as stored Ca2+ is depleted

Hypomagnesemia

• Low serum magnesium is present
• There is a similar mechanism as hypercalciuria with decreased positive (+) potential in the tubular lumen
• Decreased force for paracellular flux of Mg2+ in the TALH
• Decreased paracellular Mg2+ reabsorption
• There are no other mechanisms for Mg2+ regulation

Hyperuricemia

• Elevated serum uric acid (urate) levels are diagnostic
• Furosemide directly blocks MRP4 (multidrug resistance protein 4), inhibiting uric acid secretion in the proximal tubule
• Diuretic-induced volume depletion increases uric acid reabsorption by proximal tubules
• Uric Acid Reabsorption Mechanism
  • Occurs in the proximal tubules
  • Mediated by:
  • Urate Transporter 1 (URAT1)
    • Located at the luminal membrane
    • Reabsorbs urate from tubular lumen into the cell

Metabolic Alkalosis

• The body's pH is elevated to greater than 7.45 indicative of metabolic alkalosis
• Inhibition of NKCC2 cotransporters in the TALH decreases ECF volume
• Volume depletion/contraction due to inhibited reabsorption of solutes and water concentrates ECF HCO₃, resulting in the elevation of plasma pH creating metabolic alkalosis

Salt Wasting

• Inhibition of Na+ in the TAL leads to salt wasting, which increases delivery of Na+ (and Cl-) to the more distal segments
• Na+ will be reabsorbed via epithelial Na+ channels (ENaC) as it exchanges for K+ and H+
• H+ secretion increases pH, leading to alkalosis
• High levels of Cl- in the urine also pulls K+ and H+, to increase their secretion

Activation of Renin-Angiotensin-Aldosterone System (RAAS)

• Reduced ECF volume results in low blood pressure, leading to activation of Renin-Angiotensin-Aldosterone System (RAAS)
• Effect of Angiotensin II
  • Potent stimulant of vasoconstriction
  • Stimulates Na+/H+ exchanger in the proximal convoluted tubule
  • Increased secretion of H+ into the lumen increases pH in the ECF
• Effect of Aldosterone
  • Stimulates type A intercalated cells, increasing secretion of H+ through H+-ATPase pump, increasing ECF pH due to H+ loss
  • Stimulates reabsorption of bicarbonate in the PCT, increasing ECF pH

Renal Correction of Alkalosis

• Alkalosis increases the HCO₃-/H+ ratio in the renal tubular fluid
• Increased HCO₃- in the ECF increases filtered load of HCO₃-, causing the excess to be secreted over H+ in the tubular fluid
• Excess will NOT be reabsorbed due to the lack of H+ that it can react with

Respiratory Acidosis

• Respiratory Acidosis is a compensatory mechanism of the body to metabolic alkalosis
• Metabolic alkalosis leads to alveolar hypoventilation to hold CO2, increasing arterial carbon dioxide tension (PaCO2)
• High concentrations of CO2 in ECF lowers pH, leading to respiratory acidosis

Urinalysis and Electrolyte Levels

• Urine is expected to be acidic (pH <5.5)
  • Net effect of the Extracellular Fluid Volume Contraction (ECFB) mechanism and Carbonic Anhydrase II (CAII) inhibition where the effect of decreased ECF volume prevails over CAll inhibition

Glomerular Filtration Rate (GFR)

Effects of furosemide on GFR are still conflicting, with several experimental studies having different results

• Blocked NKCC2 in thick ascending limb
• More Nat and Cl reach the macula densa in the distal convoluted tubule
• Afferent arteriole constriction is stimulated
• GFR decreases
• Modulated by angiotensin II, nitric oxide, bradykinin, thromboxane

Increase in GFR

• Furosemide and other loop diuretics are NKCC2 inhibitors
• NKCC2 is the primary salt sensor in the macula densa
• Tubuloglomerular feedback is inhibited
• Afferent arterioles constriction is inhibited
• GFR is increased
• Furosemide causes diuresis
• ECF volume loss
• Activates the RAAS system
• Angiotensin II will cause the vasoconstriction of efferent arteriole
• There is elevated GFR
• Aldosterone release corrects hypotension through increased Nat and water reabsorption in the principal cells of the DCT and collecting duct

Serum Calcium Level

• Acutely furosemide use will NOT cause any changes to the Ca2+ serum level

Other Diuretics to Counteract Furosemide

• Common contraindication for furosemide use includes patients with sulfonamide allergies because Furosemide has a sulfa group
• Thiazide Diuretics
  • Triggers blockage of Na+/Cl channels in the proximal segment of the distal convoluted tubule, preventing sodium from crossing the luminal membrane
  • Decreases action of Na+/K+ ATPase pump, inhibiting Na+/K+ exchange and retaining K+
  • Blockage of Na+/Cl channel increases flow of ions in the Na+/Cl channel, increasing calcium reabsorption in the interstitium
• Potassium-Sparing Diuretics
  • Offers adequate diuresis without risking electrolyte imbalance
  • Prevents overexcretion of K+ ions by interfering on the Na+/K+ exchange

Clinical Management of Furosemide Misuse

• Increased risk of dehydration and electrolyte imbalance
• Indicative presentation of dehydration: dry skin, electrolyte imbalance, increased risk

Liberal Fluid Intake

• Electrolyte-rich drinks should be consumed to replenish the body's sodium, potassium, and chloride levels and alleviate dehydration
• Avoid caffeinated drinks and alcohol as these increase the body's urine output
• Consumption of electrolyte-rich Food can aid in the process of kidney function
• Misuse of diuretics for non-medical reasons shown to increase the risk of dehydration and electrolyte imbalance

Renal Apnea

• Patient presented with metabolic alkalosis
• Hypoventilation occurs to compensate and regulate blood pH
• Leads to increased carbon dioxide in the blood thus respiratory acidosis
• In severe cases of metabolic alkalosis, hypoventilation may reach high rates
• Respiratory disturbances often seen with kidney disfunction