7.4 Renal Ion & Acid-Base Regulation

Sodium, Potassium, and Aldosterone

Sodium balance is the dominant determinant of ECF volume. The kidney filters ~25,000 mmol of Na+ per day and reabsorbs all but ~1-2%. Segmental handling: proximal tubule ~65%, thick ascending limb ~25%, distal convoluted tubule ~5%, collecting duct ~2-3% under hormonal control. The final adjustment occurs in collecting duct principal cells: apical ENaC reabsorbs Na+, basolateral Na+/K+-ATPase extrudes it, and K+ is secreted through ROMK into the lumen. Aldosterone, secreted by the adrenal zona glomerulosa, increases ENaC expression and Na+/K+-ATPase activity, producing Na+ retention, K+ secretion, and a small H+ secretion. Atrial natriuretic peptide (ANP) opposes aldosterone by increasing natriuresis.

Potassium balance is regulated by both internal redistribution (insulin, beta-2 agonists, and acid-base status shift K+ into cells) and renal excretion. Hyperkalemia stimulates aldosterone directly via adrenal glomerulosa K+ channels, increasing K+ secretion. Hypokalemia reduces aldosterone and K+ secretion and promotes H+ secretion, often producing metabolic alkalosis.

Calcium and Phosphate

Filterable Ca2+ is ~60% of total plasma calcium (the rest is protein-bound or complexed). Most Ca2+ reabsorption is paracellular in the proximal tubule (~65%) and thick ascending limb (~25%), driven by the lumen-positive potential. The distal convoluted tubule (~8-10%) is the hormonally regulated site: parathyroid hormone (PTH) increases apical TRPV5 channel insertion, cytosolic calbindin-D28k, and basolateral Ca2+-ATPase and Na+/Ca2+ exchanger, promoting Ca2+ reabsorption. Loop diuretics can cause hypercalciuria (loss of lumen-positive potential); thiazides increase DCT Ca2+ reabsorption and can cause hypercalcemia.

Phosphate is freely filtered and largely reabsorbed (~80%) in the proximal tubule via NaPi-2a and NaPi-2c cotransporters. PTH inhibits these cotransporters, producing phosphaturia—a key feature of primary hyperparathyroidism. Fibroblast growth factor 23 (FGF23) from osteocytes also inhibits NaPi and reduces 1-alpha-hydroxylase, lowering calcitriol.

The Renin-Angiotensin-Aldosterone System (RAAS)

The RAAS responds to decreased renal perfusion, decreased NaCl delivery at the macula densa, and increased sympathetic tone. Steps:

1. Renin is released from juxtaglomerular (JG) cells of the afferent arteriole.
2. Renin cleaves circulating angiotensinogen (from the liver) to angiotensin I (10 amino acids).
3. Angiotensin-converting enzyme (ACE), mostly in pulmonary capillaries, cleaves angiotensin I to angiotensin II (8 amino acids).
4. Angiotensin II has four key effects: (a) efferent arteriolar constriction (preserves GFR), (b) stimulates aldosterone release from the adrenal zona glomerulosa, (c) stimulates ADH and thirst via the hypothalamus, and (d) increases proximal tubule Na+ reabsorption directly.
5. Aldosterone acts on principal cells to retain Na+ and water, expanding ECF volume and restoring perfusion.

ACE inhibitors (e.g., lisinopril) and ARBs (e.g., losartan) block this system, lowering GFR in stenotic kidneys but reducing hyperfiltration injury in diabetes. Renin inhibitors (aliskiren) act upstream.

Acid-Base Regulation

The kidney maintains plasma bicarbonate (~24 mEq/L) and pH (~7.40) by two processes:

Bicarbonate Reabsorption (Proximal Tubule)

Filtered HCO3- is reclaimed almost completely (~85% in proximal tubule, ~10% in thick ascending limb, ~5% in collecting duct). Mechanism in the proximal tubule:

1. Apical Na+/H+ exchanger (NHE3) secretes H+ into the lumen.
2. H+ combines with filtered HCO3- to form H2CO3, which is converted by brush-border carbonic anhydrase IV to H2O and CO2 that diffuse back into the cell.
3. Intracellular carbonic anhydrase II regenerates H+ and HCO3-.
4. HCO3- exits basolaterally via the Na+-HCO3- cotransporter (NBCe1).

Carbonic anhydrase inhibitors (acetazolamide) block this, causing bicarbonaturia and metabolic acidosis.

New Bicarbonate Generation (Distal Nephron)

Type A intercalated cells secrete H+ via H+-ATPase and H+/K+-ATPase on the apical membrane. Secreted H+ is buffered in the urine by two main buffers:

• Titratable acid (mostly phosphate, HPO4^2-/H2PO4-): accounts for ~40 mEq/day.
• Ammonium (NH4+): proximal tubule cells produce NH3 from glutamine via glutaminase; NH3 diffuses into the lumen and traps H+ as NH4+, which is reabsorbed in the thick ascending limb and recycled, amplifying the medullary NH3 gradient. NH4+ excretion accounts for ~60 mEq/day and increases severalfold in chronic acidosis.

Compensatory Responses

The body defends pH through three lines: chemical buffers (minutes), respiratory compensation (minutes to hours), and renal compensation (hours to days).

The anion gap = Na+ − (Cl- + HCO3-), normal 8-12 mEq/L. High anion gap metabolic acidosis (MUDPILES: methanol, uremia, DKA, propylene glycol, iron/INH, lactic acidosis, ethylene glycol, salicylates) indicates addition of unmeasured anions. Normal anion gap (hyperchloremic) acidosis results from GI or renal bicarbonate loss (diarrhea, renal tubular acidosis).

Renal Tubular Acidosis (RTA)

• Type 1 (distal) RTA: impaired H+ secretion in alpha-intercalated cells; urine pH >5.5 despite acidosis; associated with nephrocalcinosis.
• Type 2 (proximal) RTA: impaired HCO3- reabsorption; bicarbonaturia, hypokalemia; urine pH >5.5 until HCO3- falls, then <5.5.
• Type 4 RTA: hypoaldosteronism or aldosterone resistance; hyperkalemia distinguishes it from types 1 and 2.

Per the PA-CAT Bulletin of Information, rev. 20240815, the Renal Physiology group explicitly lists acid-base regulation and ion handling; expect questions on RAAS ordering, bicarbonate handling, buffer systems, and compensation patterns.