Renal Physiology, Electrolytes, and Acid-Base

Renal Reasoning Map

Renal physiology starts with Starling forces across the glomerular capillary. GFR is favored by glomerular capillary hydrostatic pressure and opposed by Bowman's space hydrostatic pressure and plasma oncotic pressure. Renal plasma flow is determined by renal arterial pressure and total renal vascular resistance. Filtration fraction equals GFR divided by RPF. Afferent arteriolar constriction lowers pressure entering the glomerulus, decreasing both RPF and GFR; filtration fraction often falls or is unchanged. Afferent dilation raises RPF and GFR.

Efferent arteriolar constriction backs pressure into the glomerular capillary, decreasing RPF and increasing filtration fraction; at moderate levels it maintains or raises GFR, but severe efferent constriction lowers GFR because plasma oncotic pressure rises rapidly along the capillary and renal blood flow becomes too low. NSAIDs reduce prostaglandin-mediated afferent dilation and can lower GFR, especially in volume depletion.

ACE inhibitors and angiotensin receptor blockers dilate the efferent arteriole and can lower GFR in bilateral renal artery stenosis, where angiotensin II is needed to maintain filtration pressure.

Autoregulation keeps GFR relatively stable across usual blood pressure ranges. The myogenic response constricts afferent arterioles when stretch increases. Tubuloglomerular feedback occurs at the macula densa, which senses NaCl delivery through NKCC2. High NaCl delivery indicates excessive filtration and triggers adenosine-mediated afferent constriction plus reduced renin. Low NaCl delivery, sympathetic stimulation, and reduced afferent pressure increase renin release from juxtaglomerular cells. Renin converts angiotensinogen to angiotensin I; ACE converts angiotensin I to angiotensin II.

Angiotensin II constricts efferent arterioles, stimulates aldosterone from zona glomerulosa, increases proximal sodium-hydrogen exchange, stimulates ADH and thirst, and increases systemic vascular resistance. Aldosterone acts on principal cells to increase ENaC and Na/K ATPase activity, increasing sodium reabsorption and potassium secretion, and on alpha-intercalated cells to increase hydrogen secretion.

ADH acts on V2 receptors in collecting duct principal cells, inserting aquaporin-2 and increasing water reabsorption; high ADH also increases urea permeability in the inner medullary collecting duct, strengthening the medullary gradient.

Nephron segment transporters are repeatedly tested. The proximal tubule reabsorbs about two thirds of filtered sodium and water iso-osmotically and nearly all filtered glucose and amino acids under normal conditions. Carbonic anhydrase enables bicarbonate reclamation: filtered bicarbonate combines with secreted hydrogen to form carbonic acid, which becomes CO2 and water in the lumen; CO2 enters the cell and is converted back to bicarbonate for basolateral exit.

The proximal tubule also reabsorbs phosphate through sodium-phosphate cotransporters inhibited by PTH, and it secretes organic acids and bases such as PAH and many drugs. Fanconi syndrome is generalized proximal tubule dysfunction causing glucosuria with normal serum glucose, aminoaciduria, phosphaturia, bicarbonaturia, and proximal renal tubular acidosis.

The thin descending limb is permeable to water and concentrates tubular fluid. The thick ascending limb reabsorbs sodium, potassium, and chloride through NKCC2, is impermeable to water, and dilutes tubular fluid. Potassium recycling through ROMK creates a lumen-positive potential that drives paracellular magnesium and calcium reabsorption. Loop diuretics inhibit NKCC2, causing natriuresis, hypokalemic metabolic alkalosis, increased calcium excretion, increased magnesium excretion, ototoxicity risk, and loss of medullary concentrating ability.

The early distal convoluted tubule reabsorbs sodium and chloride through NCC and is water impermeable. Thiazides inhibit NCC, causing hypokalemic metabolic alkalosis, hyponatremia, hyperuricemia, hyperglycemia, and increased calcium reabsorption. PTH increases calcium reabsorption in the distal tubule and phosphate excretion in the proximal tubule.

The collecting duct fine-tunes electrolytes and water. Principal cells reabsorb sodium through ENaC and secrete potassium; aldosterone increases both. Amiloride and triamterene block ENaC, while spironolactone and eplerenone antagonize mineralocorticoid receptors. These potassium-sparing diuretics can cause hyperkalemia and metabolic acidosis. Alpha-intercalated cells secrete hydrogen through H ATPase and H/K ATPase and generate new bicarbonate, important in metabolic acidosis. Beta-intercalated cells secrete bicarbonate during alkalosis.

Type 1 distal renal tubular acidosis is impaired hydrogen secretion, causing urine pH above 5.5, hypokalemia, calcium phosphate kidney stones, and metabolic acidosis. Type 2 proximal RTA is impaired bicarbonate reabsorption, often with Fanconi syndrome. Type 4 RTA is hypoaldosteronism or aldosterone resistance, causing hyperkalemic non-anion gap metabolic acidosis.

Electrolyte disorders become easier when tied to water handling and hormones. Hyponatremia usually reflects excess water relative to sodium. SIADH causes euvolemic hyponatremia with inappropriately concentrated urine and high urine sodium because ADH is high despite low plasma osmolality. Diabetes insipidus causes polyuria with dilute urine; central DI improves with desmopressin, while nephrogenic DI does not and can be caused by lithium, hypercalcemia, or hypokalemia.

Hyperkalemia depolarizes cells but inactivates sodium channels, producing muscle weakness and cardiac conduction abnormalities; insulin, beta agonists, and alkalosis shift potassium into cells, while aldosterone, distal sodium delivery, and flow promote renal potassium secretion. Hypokalemia hyperpolarizes cells, impairs urinary concentrating ability, and favors metabolic alkalosis because hydrogen shifts into cells and renal ammoniagenesis rises.

Glomerular disease is organized by nephritic versus nephrotic patterns. Nephritic syndromes are inflammatory, with hematuria, dysmorphic RBCs, RBC casts, oliguria, hypertension, and variable proteinuria. Poststreptococcal glomerulonephritis follows infection and has granular immune complex deposits with low complement. IgA nephropathy causes episodic hematuria soon after mucosal infection due to mesangial IgA deposition.

Rapidly progressive glomerulonephritis has crescents from fibrin and macrophages in Bowman's space and can be due to anti-GBM antibodies, immune complexes, or pauci-immune ANCA-associated vasculitis. Goodpasture disease causes linear IgG against type IV collagen in glomerular and alveolar basement membranes, producing hematuria and pulmonary hemorrhage. Nephrotic syndromes cause heavy proteinuria, hypoalbuminemia, edema, hyperlipidemia, and lipiduria because the filtration barrier loses charge or structural selectivity.

Minimal change disease causes podocyte foot process effacement and is classically steroid responsive. Focal segmental glomerulosclerosis is segmental sclerosis of some glomeruli and is associated with HIV, heroin use, obesity, sickle cell disease, and reduced nephron mass. Membranous nephropathy has subepithelial immune deposits, often anti-PLA2R, malignancy, hepatitis, or lupus associated. Diabetic nephropathy produces mesangial expansion, nodular glomerulosclerosis, and arteriolar hyalinosis of both afferent and efferent arterioles.

Tubulointerstitial and urinary tract pathology often presents with location clues. Acute tubular necrosis follows ischemia or toxins and causes muddy brown granular casts, intrinsic acute kidney injury, and impaired concentrating ability; fractional excretion of sodium is usually high after established tubular injury. Acute interstitial nephritis is a hypersensitivity reaction, often to drugs, with fever, rash, eosinophilia, sterile pyuria, and WBC casts. Papillary necrosis is associated with sickle cell disease, diabetes, analgesic overuse, pyelonephritis, and obstruction.

Pyelonephritis is infection of renal pelvis and parenchyma, causing fever, flank pain, WBC casts, and possibly abscesses; reflux and obstruction predispose. Cystitis causes dysuria, frequency, urgency, and suprapubic pain without casts. Urolithiasis depends on solute chemistry: calcium oxalate stones are radiopaque and envelope shaped; struvite stones form with urease-positive organisms, alkaline urine, and staghorn calculi; uric acid stones are radiolucent and occur in acidic urine; cystine stones are hexagonal and occur with impaired dibasic amino acid transport.

Acid-base analysis should be systematic. First identify pH, then the primary change in bicarbonate or Pco2, then expected compensation. Metabolic acidosis is divided by anion gap: high anion gap reflects addition of acid, such as lactic acidosis, ketoacidosis, renal failure, or toxins; normal anion gap reflects bicarbonate loss or impaired renal acid excretion, such as diarrhea or RTA. Winter's formula estimates respiratory compensation in metabolic acidosis: expected Pco2 equals 1.5 times bicarbonate plus 8, plus or minus 2.

Metabolic alkalosis is often from vomiting, diuretics, mineralocorticoid excess, or volume contraction; maintenance requires impaired bicarbonate excretion, usually from low effective arterial volume, chloride depletion, hypokalemia, or aldosterone. Respiratory acidosis reflects hypoventilation; acute compensation raises bicarbonate slightly, while chronic compensation is larger due to renal bicarbonate retention. Respiratory alkalosis reflects hyperventilation from anxiety, pain, pregnancy, sepsis, high altitude, or liver disease; chronic compensation lowers bicarbonate through renal excretion.

Compensation never overshoots, so a normal pH with abnormal Pco2 and bicarbonate suggests a mixed disorder.