The nephron

Loop diuretics block NKCC2 and abolish the lumen-positive potential that drives paracellular Ca2+ and Mg2+ reabsorption in the thick ascending limb, so both are lost in the urine (hence frusemide after saline for hypercalcaemia). Thiazides block NCC in the distal tubule; the resulting volume contraction increases proximal Na+-linked Ca2+ reabsorption and the DCT cells extrude more Ca2+ via NCX1, so urinary calcium falls and serum calcium drifts up. That is why thiazides treat calcium stones and can unmask primary hyperparathyroidism.

Aldosterone increases ENaC in principal cells. Na+ entry makes the lumen electronegative, which pulls K+ out through ROMK and H+ out through the alpha-intercalated cell H+-ATPase (which aldosterone also stimulates directly). Hypokalaemia then upregulates the H+/K+-ATPase, worsening the alkalosis. The same triad of hypertension, hypokalaemia and alkalosis appears with Liddle syndrome, liquorice and Cushing syndrome; Bartter and Gitelman syndromes give the hypokalaemic alkalosis without the hypertension because they are salt-wasting.

Downstream of a stenosis, glomerular capillary pressure is held up only by angiotensin II constricting the efferent arteriole. Remove that with an ACE inhibitor or ARB and the efferent dilates, net filtration pressure collapses and creatinine climbs. In other patients a creatinine rise of up to about 30% after starting is tolerated; a larger or continuing rise should prompt stopping the drug and imaging the renal arteries.

The thick ascending limb pumps NaCl out but is impermeable to water, so at any level the interstitium is about 200 mOsm/kg more concentrated than ascending fluid (the single effect). Descending fluid flows the opposite way and is water-permeable, so it equilibrates with that interstitium and delivers ever-saltier fluid to the ascending limb, which then pumps from a higher baseline; stacking this along the loop builds 300 to 1200 mOsm/kg. Urea recycled from the inner medullary collecting duct adds to the deepest osmolality, and the vasa recta exchange rather than dissipate it. The collecting duct then simply equilibrates with the gradient when ADH inserts AQP2.

The macula densa senses NaCl reaching the end of the thick ascending limb through NKCC2. Too much: adenosine constricts the afferent arteriole and GFR falls. Too little: prostaglandins and nitric oxide dilate it and renin is released. NSAIDs remove the prostaglandin arm, so when perfusion is marginal the afferent cannot dilate and pre-renal AKI follows, especially with an ACE inhibitor and a diuretic on board. In diabetes, proximal SGLT2 overactivity starves the macula densa of NaCl and causes hyperfiltration; SGLT2 inhibitors restore distal delivery, re-engage TGF, lower intraglomerular pressure and slow nephropathy, at the cost of a small initial eGFR dip.

Acetazolamide: proximal carbonic anhydrase, weak (under 5%), bicarbonaturia. Mannitol: proximal tubule and descending limb, osmotic. Loop diuretics: NKCC2 in the thick ascending limb, up to 20-25% of filtered Na+ (the high-ceiling drugs). Thiazides: NCC in the early distal tubule, 3-5%. Amiloride and triamterene (ENaC) and spironolactone and eplerenone (mineralocorticoid receptor): collecting duct, up to about 3% but potassium-sparing. Vaptans: V2 receptor, water only. Loop and thiazide drugs are protein-bound and must be secreted by proximal OAT to reach their luminal targets, which is why they lose potency in CKD and nephrotic syndrome.

Type 1 (distal): alpha-intercalated H+ secretion fails, so urine pH stays above 5.5 despite acidosis, with hypokalaemia, hypercalciuria and nephrocalcinosis. Type 2 (proximal): bicarbonate reclamation fails, so urine pH falls below 5.5 once serum HCO3- has dropped below the new threshold; hypokalaemia, often part of Fanconi syndrome. Type 4: aldosterone deficiency or resistance gives hyperkalaemia with mild acidosis and urine pH below 5.5, typically an older diabetic on an ACE inhibitor, spironolactone or trimethoprim.