Bartter & Gitelman

Both are tubular salt-wasting disorders → RAAS activation → secondary hyperaldosteronism --> ↑ Na⁺ reabsorption at collecting duct → ↑ K⁺ wasting (hypokalemia), & H+ excretion (alkalosis) are common, but they’re NOT the same.

• BARTTER = Furosemide phenotype => (loop of Henle, high urine calcium)

• GITELMAN = Thiazide phenotype => (DCT, low urine calcium, low Mg)

This mechanism is exactly same as: 1. vomiting + 2. diuretics + 3. Bartter + 4. Gitelman (4 DDs) => all look similar: metabolic alkalosis + hypokalemia + low/normal BP.

Bartter (Loop defect)

• Metabolic alkalosis + hypokalemia + high urine Ca + normal BP

• defective Na-K-2Cl (NKCC2) in the thick ascending limb --> More Na reaches the distal nephron --> The macula densa detects “low NaCl delivery" --> That triggers: ↑ COX-2 → ↑ PGE₂ --> PGE₂ massively stimulates Renin release --> RAAS storm --> ENaC in the collecting duct absorbs Na in exchange for K⁺ and H⁺ → hypokalemia + metabolic alkalosis

• Indomethacin helps Bartter (↓ PGE→ ↓ renin → ↓ aldosterone → ↓ K wasting); Stops inappropriate macula densa stimulation. Basically, Bartter is a PGE₂-driven hyper-reninemic state.

• Because Bartter physiologically mimics a chronic high-dose loop diuretic state --> polyurea and volume depletion is the clinical clues

Mechanism of high urine calcium in Bartter: Normally NKCC2 transporter pulls Na⁺, K⁺, & 2 Cl⁻ from the tubular lumen → into the tubular cell. But here’s the problem: There isn’t enough K⁺ in the lumen to keep NKCC2 working continuously. Therefore, the cell returns K⁺ to the lumen through ROMK channels (Renal outer medullary potassium channel) - This is called K⁺ recycling (Positive lumen charge created by ROMK cycling of K⁺). When K⁺ is pushed back into the lumen, the tubular lumen becomes positively charged. This positive electrical gradient pushes other positively charged ions (Ca²⁺, Mg²⁺, Na⁺) across the tight junctions (paracellular pathway) into the blood. Basically, ROMK recycles K⁺ → lumen becomes positive → Ca²⁺ gets sucked into the blood. In Bartter, the NKCC2 transporter is defective→ Less K⁺ enters the cell→ Less K⁺ is available to recycle→ ROMK cannot pump K⁺ out→ No positive lumen charge→ Ca²⁺ is no longer reabsorbed→ Ca²⁺ gets wasted in urine → hypercalciuria → nephrocalcinosis. That's why: Bartter = high urine calcium

Gittleman (DCT defect)

• Metabolic alkalosis + hypokalemia + low urine Ca + low serum Mg

• Thiazide-sensitive sodium-chloride cotransporter NCC defect (DCT) → ↓ NaCl reabsorption → mild RAAS activation (Chronic but mild ECV depletion --> Juxtaglomerular cells sense ↓ renal perfusion

→ mild RAAS activation) → hypokalemia + metabolic alkalosis + ↓ Mg + ↓ Ca (urine Ca ↓). The NaCl wasting in Gitelman is not as brutal as Bartter; therefore, RAAS activation is compensatory but not explosive. Aldosterone ↑ enough to produce hypokalemia + alkalosis. But not enough sodium retention to raise BP--> So normotension or low BP persists. Gitelman activates RAAS, but not enough to overcome Na loss → no hypertension.

• Less Na⁺ enters the DCT cell from the lumen --> Cell becomes Na-hungry--> to compensate, the DCT cell increases activity of the basolateral Na⁺/Ca²⁺ exchanger (NCX) --> It pulls Na⁺ from blood → into the cell & pushes Ca²⁺ from the cell into the blood --> This lowers intracellular Ca²⁺ → Ca²⁺ gets pulled across the apical channel from the urine --> Result: More Ca²⁺ is reabsorbed → less Ca²⁺ lost in urine

• Magnesium replacement is mandatory in Gitelman. 

• Hypokalemia + Hypomagnesemia => Gittleman until proven otherwise

• Mechanism of low magnesium in Gittleman; The DCT is the main regulatory site for Mg reabsorption in the kidney. The channel responsible = TRPM6. NCC doesn’t work → less Na⁺ enters the DCT cell from the lumen --> The DCT cell becomes “electrically quiet” and less active (TRPM6 expression/activity is tied to NCC function), When NCC is low → TRPM6 downregulates--> Mg gets spilt in urine--> persistent hypomagnesemia--> Magnesium normally blocks ROMK channels in the collecting duct → prevents excessive K⁺ secretion, When Mg is low: ROMK becomes overactive-->K⁺ pours out into urine, So in Gitelman: Hypomagnesemia drives hypokalemia (This is the classic real-world mistake — giving potassium again and again with no result)

Liddle (CT defect)

• Metabolic alkalosis + hypokalemia + low aldosterone

• Overactive ENaC (collecting duct) → Na retention independent of aldosterone → hypertension + hypokalosis + alkalosis with low renin & low aldosterone.

• Treat with amiloride (not spironolactone).

SAME (Syndrome of Apparent Mineralocorticoid Excess)

• Metabolic alkalosis + hypokalemia + low aldosteronism

• 11β-HSD2 deficiency → cortisol behaves like aldosterone → hypertension + hypokalosis + alkalosis with low renin & low aldosterone.

• Liquorice toxicity is the acquired version.

Hypoaldosteronism / Type 4 RTA

• Metabolic acidosis + hyperkalemia + low aldosterone

• Low aldosterone or low response → ↓ Na reabsorption + ↓ K secretion → hyperkalemia + mild metabolic acidosis + normal/low BP.

• Unlike Bartter/Gitelman.

Gordon (Reverse of Gittleman)

• Overactive NCC (DCT) → Na retention → hypertension + hyperkalemia + metabolic acidosis with low renin.

• Reverse of Gitelman. Treat with thiazides.