Nephrology
High-yield nephrology for USMLE Step 2/3 — glomerular disease, AKI and tubular pathology, electrolyte disorders, acid-base mastery, hyperkalemia, hypernatremia, RAAS pharmacology, and renovascular hypertension, extracted from Divine Intervention and organized for exam performance.
- Minimal change disease (MCD): Most common cause of nephrotic syndrome in children. T-cell mediated destruction of podocyte foot processes → selective proteinuria (mostly albumin). No antibodies involved.
- Clinical clues: 5–10 year old child with facial puffiness, periorbital edema, weight gain (7+ lbs). No hematuria, no hypertension. Urinalysis shows massive proteinuria. First step = urinalysis, not biopsy.
- Microscopy triad: Light microscopy → normal. Immunofluorescence → negative (no antibodies). Electron microscopy → podocyte foot process effacement (the defining finding).
- Selective vs non-selective proteinuria: MCD = selective (albumin only, negative charge barrier lost). Other nephrotic diseases = non-selective (lose antithrombin III → hypercoagulability, IgG → infection risk).
- Treatment: Corticosteroids. Excellent prognosis — does not progress to ESRD. Will relapse but responds to steroids repeatedly.
- Next step algorithm: Child + edema + weight gain → urinalysis → proteinuria → diagnose nephrotic syndrome → treat empirically with steroids → biopsy only if steroid-resistant.
Nephrotic vs Nephritic — Master Comparison
| Feature | Nephrotic | Nephritic |
|---|---|---|
| Proteinuria | >3.5 g/day (massive) | <3.5 g/day (mild–moderate) |
| Hematuria | Absent or minimal | Present — RBC casts = pathognomonic |
| Edema | Marked (low oncotic pressure) | Mild–moderate |
| Hypertension | Absent or mild | Prominent (GFR drops → Na retention) |
| Albumin | Low (<3.5 g/dL) | Normal or mildly low |
| Lipids | Hyperlipidemia + lipiduria (fatty casts) | Normal |
| Mechanism | Permeability barrier lost (podocyte) | Inflammatory cell infiltration (glomerulus) |
Glomerular Disease Diagnosis by Microscopy
| Disease | Type | Light Microscopy | IF | EM |
|---|---|---|---|---|
| Minimal Change Disease | Nephrotic | Normal | Negative | Foot process effacement |
| FSGS | Nephrotic | Segmental sclerosis in some glomeruli | IgM, C3 in sclerotic areas | Foot process effacement |
| Membranous GN | Nephrotic | GBM thickening, "spike and dome" | Granular IgG, C3 (subepithelial) | Subepithelial deposits |
| Diabetic GN | Nephrotic | Kimmelstiel-Wilson nodules | Nodular mesangial deposits | GBM thickening |
| MPGN | Nephrotic/Nephritic | "Tram-track" GBM splitting | C3 ± IgG (subendothelial) | Subendothelial deposits |
| Post-strep GN | Nephritic | Hypercellular, "lumpy bumpy" | Granular IgG, C3 ("starry sky") | Subepithelial "humps" |
| IgA Nephropathy | Nephritic | Mesangial hypercellularity | IgA mesangial deposits | Mesangial deposits |
| Goodpasture / Anti-GBM | Nephritic | Crescentic GN | Linear IgG (smooth) | No immune deposits |
| ANCA-associated GN | Nephritic | Crescentic (pauci-immune) | Negative (pauci-immune) | No deposits |
| Lupus Nephritis | Nephritic | Variable; "wire loop" in class IV | "Full house" IgG/IgM/IgA/C3/C1q | Subendothelial deposits |
Post-strep GN: Recent throat or skin infection → nephritic syndrome 2–3 weeks later. Low C3. Anti-DNase B titer elevated. Resolves spontaneously.
IgA Nephropathy: Hematuria within 24–48 hours of URI (synpharyngitic) — not weeks later. Normal complement (C3 normal).
Goodpasture: Linear IF + lung hemorrhage + anti-GBM antibodies + crescentic GN. Treat with plasmapheresis + cyclophosphamide.
Complications of Nephrotic Syndrome (Non-Selective Proteinuria)
- Hypercoagulability: Lose antithrombin III → DVT, renal vein thrombosis (classic). Also lose protein C and S.
- Infection risk: Lose IgG → susceptibility to encapsulated organisms (Strep pneumo). Give pneumococcal vaccine.
- Hyperlipidemia: Liver upregulates VLDL/LDL synthesis to compensate for low oncotic pressure. Lipiduria = oval fat bodies + maltese crosses under polarized light.
- Edema mechanism: Low albumin → low oncotic pressure → fluid leaks from capillaries → ascites, pleural effusion, peripheral edema (pitting, dependent).
- Renal Tubular Acidosis (RTA) — the framework: All RTAs = normal anion gap metabolic acidosis (NAGMA) + hyperchloremia. The difference is the site of the defect and the urine pH.
- Type 1 (distal) RTA: Cannot acidify urine (alpha-intercalated cells fail to secrete H+). Urine pH >5.5 despite acidosis. Causes: Sjogren's, amphotericin B, SLE. Complication: nephrocalcinosis, nephrolithiasis (calcium phosphate stones in alkaline urine). Treat: oral bicarb.
- Type 2 (proximal) RTA: Cannot reabsorb bicarb in proximal tubule. Urine pH initially >5.5, then acidifies normally once threshold is passed. Causes: carbonic anhydrase inhibitors (acetazolamide), Fanconi syndrome, multiple myeloma, Wilson disease, tenofovir. Treat: large doses of bicarb.
- Type 4 RTA (hypoaldosterone state): ONLY RTA with hyperkalemia. Normal anion gap metabolic acidosis + hyperkalemia = Type 4. Cause: any low aldosterone state — Addison's, ACE inhibitors, ARBs, spironolactone, amiloride, triamterene, NSAIDs, TMP-SMX, tacrolimus, cyclosporine.
- AKI classification: Pre-renal (↓ perfusion, FENa <1%, BUN:Cr >20:1, urine osmolality >500) → Intrinsic (ATN, GN, AIN; FENa >2%, granular casts) → Post-renal (obstruction; relieve urgently).
- ATN casts: Muddy brown granular casts = hallmark. Causes: ischemia (shock, sepsis) or nephrotoxins (aminoglycosides, IV contrast, cisplatin, myoglobin from rhabdomyolysis).
RTA Master Table
| Type | Site of Defect | Urine pH | K+ | Key Causes | Complication |
|---|---|---|---|---|---|
| Type 1 (Distal) | Alpha-intercalated cells — cannot secrete H+ | >5.5 (always alkaline) | Low | Sjogren's, amphotericin B, SLE, lithium | Nephrocalcinosis, calcium phosphate stones |
| Type 2 (Proximal) | Proximal tubule — cannot reabsorb HCO3− | Initially >5.5, then <5.5 | Low | Acetazolamide, Fanconi, MM, Wilson's, tenofovir | Rickets/osteomalacia (Fanconi loses phosphate) |
| Type 3 | Carbonic anhydrase II deficiency (rare) | Variable | Low | Rare genetic | Osteopetrosis |
| Type 4 (Hypoaldo) | Collecting duct — aldosterone deficiency/resistance | <5.5 (can acidify) | HIGH | Addison's, ACEi, ARB, spironolactone, TMP-SMX, NSAIDs, tacrolimus | Hyperkalemia → arrhythmia |
Type 4 is the ONLY RTA with hyperkalemia. If you see NAGMA + hyperkalemia on a vignette, the answer is Type 4 RTA from a hypoaldosterone state. This is mechanistically identical to what happens with Addison's disease, ACE inhibitors, ARBs, spironolactone, amiloride, triamterene, TMP (trimethoprim — blocks ENaC same as amiloride), NSAIDs (block prostacyclin → reduce K secretion), and calcineurin inhibitors (block Na-K-ATPase).
AKI — Classification and Urinary Findings
| Category | Cause | FENa | BUN:Cr | Urine Osm | Urine Na | Casts |
|---|---|---|---|---|---|---|
| Pre-renal | Hypovolemia, low CO, NSAID, ACEi in bilateral RAS | <1% | >20:1 | >500 mOsm/kg | <20 mEq/L | Hyaline casts |
| ATN (intrinsic) | Ischemia, aminoglycosides, contrast, cisplatin, rhabdo | >2% | <20:1 | <350 mOsm/kg | >40 mEq/L | Muddy brown granular casts |
| AIN | NSAIDs, penicillin, rifampin, PPIs, cimetidine | >2% | Variable | Variable | Variable | WBC casts, eosinophiluria |
| Post-renal | BPH, stones, malignancy, retroperitoneal fibrosis | Variable | >20:1 | Variable | Variable | None specific |
Rhabdomyolysis — The Triple Threat
- Cause → AKI: Myoglobin (brown urine, no RBCs on dipstick) → tubular toxicity → ATN. Muddy brown casts.
- Cause → Hyperkalemia: Massive K+ release from damaged muscle cells → risk of fatal arrhythmia.
- Cause → Hypocalcemia: Calcium deposits in injured muscle → low serum calcium → Chvostek/Trousseau signs. Paradoxically, can rebound to hypercalcemia during recovery as calcium releases.
- Treatment: Aggressive IV hydration with normal saline (goal urine output 200–300 mL/hr). Avoid contrast and nephrotoxins.
Proximal tubule loses: glucose (glucosuria with normal blood glucose), phosphate (hypophosphatemia → rickets/osteomalacia), amino acids, uric acid, bicarb (Type 2 RTA). Causes: multiple myeloma (light chains toxic), Wilson's disease, tenofovir, lead poisoning, outdated tetracycline. Key NBME clue: normal glucose but glycosuria + metabolic acidosis.
- Drug-induced nephrolithiasis: Acyclovir → crystalline nephropathy (flank pain in patient treated for herpes/shingles). Indinavir (HIV PI) → radiolucent stones. Topiramate → crystalline nephropathy + cognitive slowing ("dumb it down drug"). Loop diuretics → calciuria → calcium stones. Thiazides → ↓ urine calcium → REDUCE stone risk.
- Conn syndrome (primary hyperaldosteronism) — diagnosis algorithm: Resistant HTN + hypokalemia + metabolic alkalosis → check PAC:PRA ratio. Ratio >30 = Conn syndrome. Ratio <20 = renal artery stenosis / fibromuscular dysplasia.
- Salt suppression test: Saline infusion → normal = aldosterone suppresses. Conn = aldosterone fails to suppress. Diagnostic for Conn syndrome.
- Adrenal vein sampling: After confirming Conn, differentiate unilateral adenoma vs bilateral hyperplasia. One side high + other side low = adenoma → unilateral adrenalectomy. Both high = bilateral hyperplasia → medical therapy (spironolactone or eplerenone).
- Fibromuscular dysplasia vs renal artery stenosis: FMD = media affected (not intima), young women, string-of-beads on angiography. RAS = intimal atherosclerosis, older patients, smoking = #1 risk factor. Both → high renin → high aldosterone → hypokalemia + metabolic alkalosis.
Kidney Stone Types — USMLE Breakdown
| Stone Type | % of Stones | pH | Radiopaque? | Key Associations | Treatment |
|---|---|---|---|---|---|
| Calcium oxalate | Most common (~70%) | Any | Yes | Hyperoxaluria (Crohn's, fat malabsorption), hypercalciuria, low citrate | Increase fluids, thiazides, potassium citrate |
| Calcium phosphate | ~10% | Alkaline >6.5 | Yes | Type 1 RTA, hyperparathyroidism | Treat underlying cause |
| Uric acid | ~10% | Acidic <5.5 | No (radiolucent) | Gout, high protein diet, tumor lysis, Lesch-Nyhan | Alkalinize urine, allopurinol |
| Struvite (triple phosphate) | ~15% | Alkaline >7 | Yes (staghorn) | Urease-producing bacteria (Proteus, Klebsiella, Pseudomonas) | Antibiotics + surgical removal |
| Cystine | Rare | Acidic | Weakly | Cystinuria (autosomal recessive, SLC3A1/SLC7A9 mutation) | Alkalinize urine, D-penicillamine, tiopronin |
Thiazides (e.g., hydrochlorothiazide) increase calcium reabsorption at the distal convoluted tubule → reduce urinary calcium excretion → protect against calcium stones. This is the opposite of loop diuretics, which waste calcium. Give thiazides to patients with recurrent calcium nephrolithiasis and hypercalciuria.
Conn Syndrome Diagnosis Pathway
- Step 1: Suspect Conn in any patient with resistant HTN (failed ≥3 drugs) + hypokalemia + metabolic alkalosis.
- Step 2: Check plasma aldosterone concentration (PAC) to plasma renin activity (PRA) ratio. PAC:PRA >30 → Conn. PAC:PRA <20 → secondary hyperaldosteronism (renal artery stenosis, FMD).
- Step 3: Salt suppression test — give IV saline. In Conn, aldosterone does not suppress. This is diagnostic.
- Step 4: Adrenal vein sampling to lateralize (unilateral adenoma vs bilateral hyperplasia).
- Treatment: Unilateral adenoma → laparoscopic adrenalectomy. Bilateral hyperplasia → spironolactone or eplerenone (aldosterone antagonists). Eplerenone does NOT cause gynecomastia (no androgen receptor blockade). Spironolactone does.
Renal artery stenosis: Intimal layer (atherosclerosis). Older patients. Smoking = #1 risk factor. String-of-beads NOT seen — irregular narrowing.
Fibromuscular dysplasia: Medial layer. Young women. Non-atherosclerotic. Classic "string-of-beads" appearance on angiography. Association with spontaneous coronary artery dissection and carotid FMD.
- Pseudohyperkalemia: K+ = 7 but patient is asymptomatic with normal EKG → hemolyzed sample. Recheck before treating. 98% of body's K+ is intracellular.
- Causes by mechanism — Na-K-ATPase inhibition: Digoxin (direct pump inhibitor), calcineurin inhibitors (cyclosporine, tacrolimus), pentamidine, beta blockers (block beta-2 → less pump activation → K stays extracellular). Metabolic acidosis (H+ drives K+ out of cells electroneutrally).
- Causes by mechanism — aldosterone deficiency: Addison's disease, 21-hydroxylase deficiency (CAH), ACE inhibitors, ARBs, spironolactone/eplerenone, NSAIDs (inhibit COX-2 → less prostacyclin → less K secretion at distal nephron). All → Type 4 RTA.
- Causes by mechanism — ENaC blockade: Amiloride, triamterene, TMP-SMX (trimethoprim blocks ENaC = acts like amiloride). ENaC in collecting duct principal cell drives K+ secretion when Na+ enters.
- EKG progression: Peaked T waves → widened QRS → sinusoidal wave → asystole. Treatment must follow this sequence: calcium gluconate → insulin + glucose → nebulized albuterol → sodium bicarb → diuretics (if kidneys work) → sodium polystyrene sulfonate (Kayexalate) → hemodialysis (most effective).
- Hyperkalemic periodic paralysis: Autosomal dominant (chromosome 17). Sodium channels slow to close after exercise → excess Na+ influx displaces K+ extracellularly → paralysis after exercise. Elevated K+ after exercise + weakness = the exam vignette.
Hyperkalemia Causes — Organized by Mechanism
| Mechanism | Examples | Rationale |
|---|---|---|
| Pseudohyperkalemia | Hemolyzed sample, prolonged tourniquet | RBC/muscle breakdown releases intracellular K+. Normal EKG = clue. |
| Renal failure / missed dialysis | CKD, end-stage renal disease | Kidneys are the primary K+ excretion organ |
| Hypoaldosteronism | Addison's, 21-hydroxylase def., ACEi, ARB, spironolactone, NSAIDs | Aldosterone drives K+ secretion via principal cell ENaC/ROMK |
| ENaC blockade | Amiloride, triamterene, TMP (trimethoprim) | Blocks sodium entry → no electrochemical gradient for K+ exit |
| Na-K-ATPase inhibition | Digoxin, cyclosporine, tacrolimus, pentamidine, beta-blockers (beta-2) | Pump normally takes 3 Na+ out, 2 K+ in. Inhibition = K stays outside. |
| Cell lysis / rhabdomyolysis | Crush injury, burns, marathon, ecstasy, chemotherapy (tumor lysis), succinylcholine, NMS, MH | Intracellular K+ floods extracellular space |
| Metabolic acidosis | Any acidosis | H+ enters cells → K+ exits to maintain electroneutrality |
| Insulin deficiency | Octreotide (suppresses insulin), DKA | Insulin activates Na-K-ATPase → K+ enters cells. Loss → K stays outside. |
Treatment of Hyperkalemia — Step-by-Step
- Step 1 — Stabilize myocardium: Calcium gluconate or calcium chloride. Does NOT lower K+. Raises threshold potential → reduces arrhythmia risk. Works in minutes. Give if EKG changes present.
- Step 2 — Redistribute K+ into cells: Regular insulin (10 units IV) + glucose (D50 or D5W). Insulin activates Na-K-ATPase → K+ enters cells. Give glucose to prevent hypoglycemia. Works in 15–30 min. Also: nebulized albuterol (beta-2 agonist activates Na-K-ATPase).
- Step 3 — Alkalinize (optional): Sodium bicarb raises pH → H+ leaves cells → K+ enters cells. Most useful in concurrent metabolic acidosis.
- Step 4 — Eliminate K+ from body: Loop diuretics (if kidneys work). Sodium polystyrene sulfonate (Kayexalate) — binds K+ in gut. Patiromer or sodium zirconium cyclosilicate (newer potassium binders, fewer GI side effects).
- Most effective K+ removal: Hemodialysis. Classic exam answer when asked "most effective rapid lowering of serum potassium."
Succinylcholine causes depolarization → Na+ rushes into skeletal myocytes → K+ displaced extracellularly. Safe in most patients. CONTRAINDICATED in burn patients, crush injuries, rhabdomyolysis, denervation injuries, prolonged immobilization — because these patients have already released intracellular K+ and succinylcholine can cause fatal hyperkalemia. Use a non-depolarizing agent (vecuronium, rocuronium) instead.
- Anion gap formula: AG = Na − (Cl + HCO3−). Normal = 12 ± 2 mEq/L. Represents the unmeasured anions (albumin, phosphate, sulfate).
- High anion gap metabolic acidosis (HAGMA): An acid (e.g., lactic acid) is introduced. The acid dissociates into H+ (consumed by HCO3− → HCO3− drops) + anion (e.g., lactate — adds to unmeasured anions). Chloride does NOT rise. AG widens because HCO3− falls without a compensatory Cl− rise.
- Normal anion gap metabolic acidosis (NAGMA): HCO3− is lost directly (diarrhea, RTA). Body compensates by retaining Cl− to maintain electroneutrality. Cl− rises as HCO3− falls → AG stays normal (12). Hyperchloremia = hallmark of NAGMA.
- MUDPILES mnemonic for HAGMA: Methanol, Uremia (CKD), DKA/alcoholic ketoacidosis, Propylene glycol/Paraldehyde, Isoniazid/Iron, Lactic acidosis (sepsis, metformin), Ethylene glycol, Salicylates. Rhabdomyolysis + renal failure also cause HAGMA.
- Classic NAGMA causes: Diarrhea, renal tubular acidosis (Types 1, 2, 4), carbonic anhydrase inhibitors (acetazolamide), adrenal insufficiency. Hyperalimentation and ureterosigmoidostomy are rare causes.
- Counterbalancing rule: In HAGMA, the anion of the added acid (lactate, ketone, salicylate) counterbalances the lost HCO3−. In NAGMA, Cl− counterbalances — body has no exogenous anion to use.
Anion Gap — The Mechanics
The body maintains electroneutrality: cations = anions. The major extracellular cation is sodium. The major anions are chloride, bicarbonate, and unmeasured anions (albumin, phosphate, sulfate, organic acids). The anion gap quantifies the unmeasured anions: AG = Na − (Cl + HCO3−) = ~12 mEq/L.
When a new acid (e.g., lactic acid) is added: H+ buffers HCO3− → HCO3− falls. Cl− stays the same. The acid's anion (lactate) fills the gap where HCO3− was → AG rises. This is HAGMA.
When HCO3− is lost (diarrhea, RTA): No exogenous anion is introduced. Body retains Cl− to maintain electroneutrality → Cl− rises. AG stays normal. This is NAGMA.
HAGMA Causes — MUDPILES Expanded
| Cause | Anion Responsible | Key Clinical Clue |
|---|---|---|
| Methanol | Formate | Blindness + osmol gap; antifreeze ingestion |
| Uremia (CKD) | Phosphate, sulfate, organic acids | BUN ↑↑, Cr ↑↑, eGFR <15 |
| DKA | Ketones (acetoacetate, beta-hydroxybutyrate) | Type 1 DM, glucose >250, ketones in urine |
| Alcoholic ketoacidosis | Ketones | Binge drinking, normal or low glucose, high ETOH |
| Lactic acidosis | Lactate | Sepsis/septic shock, metformin in renal failure, ischemia |
| Ethylene glycol | Oxalate, glycolate | Osmol gap, calcium oxalate crystals in urine, AKI |
| Salicylates | Salicylate | Respiratory alkalosis + metabolic acidosis (mixed) |
| Isoniazid/Iron | Lactic acid (INH blocks lactate metabolism) | Seizures with INH; liver failure with Fe overdose |
When you have HAGMA, calculate delta-delta = (AG − 12) / (24 − HCO3−). If delta-delta is 1–2 = pure HAGMA. If >2 = concurrent metabolic alkalosis (HCO3− is higher than expected — not all HCO3− was consumed). If <1 = concurrent NAGMA (HCO3− is lower than expected — additional HCO3− lost). This unmasks hidden mixed disorders.
Osmol gap = measured osmolality − calculated osmolality. Calculated = 2(Na) + glucose/18 + BUN/2.8. Normal <10. If osmol gap >10 in a patient with HAGMA → think methanol or ethylene glycol. These alcohols add osmoles without appearing in standard anion calculations.
- Step 1 — pH: pH <7.35 = acidosis. pH >7.45 = alkalosis. Always start here.
- Step 2 — Primary disorder: Acidosis + high pCO2 = respiratory acidosis. Acidosis + low HCO3− = metabolic acidosis. Alkalosis + low pCO2 = respiratory alkalosis. Alkalosis + high HCO3− = metabolic alkalosis.
- Step 3 (metabolic acidosis) — Winter's formula: Expected pCO2 = 1.5 × HCO3− + 8 (± 2). If actual pCO2 is within that range = perfect compensation, only one disorder. If actual pCO2 is below range = concurrent respiratory alkalosis (overcompensated). If actual pCO2 is above range = concurrent respiratory acidosis.
- Key compensation rule: Compensation can NEVER normalize the pH back to 7.35–7.45 or overshoot. If pH looks normal with obvious primary disorder present, there is a concurrent opposite disorder (e.g., mixed metabolic acidosis + metabolic alkalosis canceling each other out).
- Compensation direction: Metabolic acidosis → respiratory compensation (hyperventilate, blow off CO2 → ↓ pCO2). Metabolic alkalosis → respiratory compensation (hypoventilate → ↑ pCO2). Respiratory acidosis → metabolic compensation (kidneys retain HCO3− → ↑ HCO3−). Respiratory alkalosis → metabolic compensation (kidneys excrete HCO3− → ↓ HCO3−).
- Anion gap calculation: Calculate AG = Na − (Cl + HCO3−). >12 = HAGMA. Normal = NAGMA. Pair with pCO2 and Winter's formula to identify mixed disorders.
Step-by-Step ABG Interpretation
- Step 1: Look at pH. <7.35 = acidosis. >7.45 = alkalosis.
- Step 2: Identify primary disorder (pCO2 or HCO3−, whichever matches the pH direction).
- Step 3 (if metabolic acidosis): Calculate Winter's formula. Expected pCO2 = (1.5 × HCO3−) + 8 ± 2.
- Compare actual pCO2 to expected range: Within range = metabolic acidosis only. Below range = metabolic acidosis + respiratory alkalosis. Above range = metabolic acidosis + respiratory acidosis.
- Step 4: Calculate anion gap. If AG >12 → HAGMA (think MUDPILES). If AG normal → NAGMA (think diarrhea, RTA, acetazolamide).
- Step 5: If HAGMA present, calculate delta-delta to check for concurrent metabolic alkalosis or additional NAGMA.
Compensation Formulas — Complete Reference
| Primary Disorder | Compensatory Response | Formula |
|---|---|---|
| Metabolic acidosis | Respiratory (↓ pCO2) | Expected pCO2 = 1.5 × HCO3− + 8 (± 2) [Winter's] |
| Metabolic alkalosis | Respiratory (↑ pCO2) | Expected pCO2 = 0.7 × HCO3− + 21 (± 2) |
| Acute respiratory acidosis | Metabolic (↑ HCO3−) | HCO3− rises 1 mEq/L per 10 mmHg rise in pCO2 |
| Chronic respiratory acidosis | Metabolic (↑ HCO3−) | HCO3− rises 3.5 mEq/L per 10 mmHg rise in pCO2 |
| Acute respiratory alkalosis | Metabolic (↓ HCO3−) | HCO3− falls 2 mEq/L per 10 mmHg fall in pCO2 |
| Chronic respiratory alkalosis | Metabolic (↓ HCO3−) | HCO3− falls 5 mEq/L per 10 mmHg fall in pCO2 |
On USMLE exams: if you have a primary metabolic acidosis (pH <7.35), the compensatory respiratory alkalosis cannot bring pH back to ≥7.35. If the pH looks normal or high in a patient with clear HCO3− abnormality, there is a CONCURRENT opposite primary process normalizing the pH. This is the key to identifying mixed acid-base disorders.
Patient: pH 7.28, HCO3− = 14, pCO2 = 40.
Step 1: pH <7.35 = acidosis. Step 2: HCO3− low = metabolic acidosis.
Step 3: Expected pCO2 = (1.5 × 14) + 8 = 21 + 8 = 29 ± 2 → range 27–31.
Actual pCO2 = 40. That is ABOVE the range.
Answer: Metabolic acidosis + concurrent respiratory acidosis.
- Hypernatremia = serum Na >145 mEq/L. Symptoms usually begin when Na >160. Underlying principle: concentration = mass/volume. Any scenario where water is lost faster than sodium = hypernatremia.
- Hypovolemic hypernatremia (most common): Loss of hypotonic solution (more water than sodium lost). Causes: sweating (sweat is hypotonic), osmotic diarrhea (lactose intolerance, mannitol), inadequate water intake (elderly, stroke). Urine Na <20 if cause is extrarenal (kidneys conserve). Urine Na >40 if intrarenal (mannitol, osmotic diuresis). Treat: isotonic saline first to restore volume, then half-normal saline to correct sodium.
- Euvolemic hypernatremia: Loss of free water only. No sodium loss. Extracellular volume maintained as intracellular fluid shifts out. Cause = diabetes insipidus (central: no ADH; nephrogenic: kidneys don't respond to ADH). Treat: free water (D5W or oral water).
- Hypervolemic hypernatremia (rare): Hypertonic sodium administration exceeds water gain. Causes: sodium bicarb resuscitation, large hypertonic saline infusion, Conn syndrome (without access to water), seawater ingestion, soy sauce overdose. Treat: diuretics + free water.
- Correction rule: Do NOT correct hypernatremia too fast. Maximum rate: 0.5 mEq/L/hr (or ~10 mEq/L/day). Rapid correction → cerebral edema → herniation and death. Mechanism: brain generates idiogenic osmoles during hypernatremia. Rapid dilution → water floods into brain cells → swelling.
- Hyponatremia correction trap: Overcorrecting hyponatremia → osmotic demyelination syndrome (central pontine myelinolysis). Overcorrecting hypernatremia → cerebral edema. Know which direction kills which way.
Hypernatremia — Classification and Treatment
| Type | Volume Status | Mechanism | Common Causes | Treatment |
|---|---|---|---|---|
| Hypovolemic | Depleted | Hypotonic fluid loss (lose more water than Na) | Sweating, osmotic diarrhea, inadequate intake (elderly, stroke), mannitol | Step 1: Normal saline (restore volume). Step 2: Half-NS or D5W (correct Na) |
| Euvolemic | Normal | Free water loss only; ICF shifts to ECF | Central DI (no ADH), nephrogenic DI (Li+, demeclocycline, hypercalcemia) | D5W or oral free water (replenish free water) |
| Hypervolemic | Expanded | Hypertonic Na gain exceeds water gain | Hypertonic NaHCO3 resuscitation, Conn syndrome, seawater, soy sauce | Loop diuretic + free water |
Why Half-Normal Saline is a Bad Volume Expander
Half-normal saline (0.45% NaCl) is hypotonic. When infused IV, it reduces extracellular osmolality → water shifts into cells → only ~25% stays in the extracellular compartment. You need 4 liters of half-NS to expand by 1 liter of effective extracellular volume. Therefore: fix volume depletion with isotonic saline first, then correct sodium concentration with hypotonic fluid.
Diabetes Insipidus — Central vs Nephrogenic
| Central DI | Nephrogenic DI | |
|---|---|---|
| Mechanism | Posterior pituitary / hypothalamus fails to produce ADH | Kidneys fail to respond to ADH (V2 receptor/aquaporin-2 problem) |
| Causes | Head trauma, neurosurgery, sarcoidosis, Sheehan's, idiopathic | Lithium (#1 drug cause), demeclocycline, hypercalcemia, hypokalemia, sickle cell |
| Urine osmolality | Low (<200 mOsm/kg) | Low (<200 mOsm/kg) |
| Water deprivation test | Urine does not concentrate | Urine does not concentrate |
| Desmopressin (ADH analog) response | Urine concentrates (responds) | No response |
| Treatment | Intranasal desmopressin (DDAVP) | Thiazide diuretic + low-sodium diet (paradoxical → ↓ GFR → ↑ proximal reabsorption). Amiloride for lithium-induced. |
When the brain is chronically exposed to hypernatremia, cells generate their own intracellular osmoles (idiogenic osmoles — taurine, glycine, myo-inositol) to prevent shrinkage. These osmoles persist even after serum Na is corrected. If you correct hypernatremia too quickly, the extracellular fluid becomes hypotonic relative to the brain → water rushes into brain cells → cerebral edema → transtentorial herniation → death. Max correction: 10 mEq/L per day.
Despite tasting salty, sweat contains far more water than sodium — it is a hypotonic fluid. The same is true for diarrhea in osmotic states. Losing large volumes of hypotonic fluid (water > sodium lost) → hypernatremia even though sodium is also being lost. The denominator (water) shrinks faster than the numerator (sodium mass) → concentration rises.
- Renal cell carcinoma (RCC): #1 risk factor = smoking. Hematuria + flank pain + palpable mass = classic triad. Lytic bone metastases. Diagnosis: CT abdomen/pelvis with IV contrast. Do NOT biopsy — perform radical nephrectomy (ROTA rule: RCC, Ovarian, Testicular, Adrenal cancers — biopsy is organ removal). Treat with IL-2 analogs (immunotherapy).
- RCC paraneoplastic syndromes: Ectopic EPO → polycythemia. PTHrP → hypercalcemia. Hypertension (via renin production). VHL association: chromosome 3, autosomal dominant, bilateral RCC + hemangioblastomas (posterior fossa, produce EPO) + pancreatic cysts + pheochromocytoma.
- BPH management: DHT (from testosterone via 5-alpha reductase) drives prostate growth. Short-term: alpha-1 blockers (tamsulosin → selective alpha-1A in prostate; terazosin/doxazosin → also vasodilate → orthostatic hypotension). Long-term: 5-alpha reductase inhibitors (finasteride, dutasteride) → ↓ DHT → prostate shrinks over months. Refractory: TURP (transurethral resection of prostate).
- SGLT2 inhibitors (gliflozins): Block SGLT2 in proximal tubule → glycosuria → weight loss + BP reduction. Improve survival in HFrEF (independent of diabetes). Side effects: UTI, genital mycotic infections, Fournier's gangrene (necrotizing fasciitis of perineum — surgical debridement + IV antibiotics). Avoid in poor renal function (eGFR <30).
- Fournier's gangrene: Polymicrobial necrotizing fasciitis of the perineum. Risk factors: diabetes + SGLT2 inhibitors. Bluish discoloration of perineum + fever + high WBC = emergency. Treatment: surgical debridement + broad-spectrum IV antibiotics.
RCC vs Bladder Cancer — Differentiation
| Renal Cell Carcinoma | Bladder Cancer (TCC) | |
|---|---|---|
| Hematuria | Painless, often gross | Painless, gross hematuria most common presentation |
| Flank pain | Yes (mass effect) | No (unless obstructing ureter) |
| Bone mets | Lytic lesions — classic exam clue | Rare in early disease |
| Risk factors | Smoking #1, VHL, obesity | Smoking #1, aniline dyes, cyclophosphamide, schistosomiasis (squamous cell) |
| Imaging | CT abdomen/pelvis with contrast | Cystoscopy (bladder mass visualization) |
| Treatment | Radical nephrectomy (no biopsy first) | TURBT + BCG intravesical therapy (non-invasive). Cystectomy (invasive). |
BPH Drug Comparison
| Drug Class | Examples | Mechanism | Key Side Effects |
|---|---|---|---|
| Alpha-1A selective blocker | Tamsulosin, silodosin | Relax smooth muscle at bladder neck and prostate urethra | Retrograde ejaculation (minimal BP effect) |
| Non-selective alpha-1 blocker | Terazosin, doxazosin, prazosin | Relax prostate AND vascular smooth muscle | Orthostatic hypotension, syncope (especially with PDE5 inhibitors) |
| 5-alpha reductase inhibitor | Finasteride, dutasteride | Block conversion of testosterone → DHT → ↓ prostate size | Sexual dysfunction, decreased libido, gynecomastia. Takes 3–6 months for effect. |
Survival benefit in heart failure (HFrEF): Dapagliflozin, empagliflozin improve outcomes even without diabetes. Added to ACEi/ARB + beta blocker + aldosterone antagonist regimen.
Avoid if: eGFR <30 (no glycosuria → no benefit). Recent ketoacidosis (risk of euglycemic DKA).
Never combine with: Poor renal function or volume-depleted states — worsens renal outcomes.
Genital mycoses: Glucose in urine → Candida overgrowth in perineal area. More common in women.
- Renin release triggers: (1) Low sodium delivery to macula densa → senses low perfusion pressure. (2) Beta-1 adrenergic stimulation (sympathetic activation). (3) Low blood flow to afferent arteriole (renal artery stenosis, hypovolemia). NSAIDs can ↑ renin by constricting afferent arteriole (loss of prostacyclin-mediated dilation).
- Angiotensin II actions: (1) Powerful vasoconstriction via AT1 receptor → ↑ SVR → ↑ BP. (2) Proximal tubule Na+ reabsorption. (3) Zona glomerulosa → aldosterone release → principal cell ENaC → Na+ reabsorption + K+ secretion + H+ secretion. (4) Posterior pituitary → ADH release → aquaporin-2 → water reabsorption. (5) Cardiac hypertrophy and fibrosis (cardiac remodeling).
- ACE is in pulmonary capillaries: Converts Ang I → Ang II there. Pulmonary capillaries also break down serotonin (explains why carcinoid → right-sided heart disease only — serotonin metabolized before reaching left heart).
- ACE inhibitors (side effects): Block ACE → ↑ bradykinin → dry nonproductive cough (most common side effect, 10–15% of patients). Angioedema (rare but life-threatening — also bradykinin mediated). Switch to ARB if cough is intolerable. ARBs do NOT raise bradykinin.
- ANP/BNP (counter-RAAS): Atria make ANP, ventricles make BNP. Released with wall stretch → ↓ renin, inhibit ENaC → natriuresis + vasodilatation (via cGMP/protein kinase G → myosin light chain phosphatase → smooth muscle relaxation). Neprilysin breaks down ANP/BNP. Sacubitril (neprilysin inhibitor) + valsartan (ARB) = entresto → improves survival in HFrEF.
- ACE level in sarcoidosis: Granulomas in lung contain activated macrophages that express ACE → ↑ serum ACE. Useful diagnostic marker for sarcoidosis.
RAAS Cascade — Complete Pathway
| Step | Source | Key Fact |
|---|---|---|
| Low Na/flow → renin released | Juxtaglomerular (JG) cells, afferent arteriole | Macula densa = sodium sensor adjacent to JG cells |
| Renin cleaves angiotensinogen → Ang I | Liver makes angiotensinogen | Renin is the rate-limiting step of the RAAS |
| Ang I → Ang II (pulmonary capillaries) | Pulmonary ACE | Ang I levels high in pulmonary artery, low in pulmonary vein |
| Ang II → vasoconstriction | AT1 receptor on vascular smooth muscle | Most potent vasoconstrictor in the body |
| Ang II → proximal Na+ reabsorption | Proximal tubule | Increases NHE3 (Na-H exchanger) activity |
| Ang II → aldosterone (zona glomerulosa) | Adrenal cortex | Aldosterone: ENaC (Na in) → ROMK (K out) + alpha-IC (H+ out) |
| Ang II → ADH (posterior pituitary) | Hypothalamic/pituitary axis | ADH acts on V2 receptors → aquaporin-2 insertion → water reabsorption |
| Ang II → cardiac remodeling | Cardiac myocytes, fibroblasts | Mechanism for ACEi/ARB benefit in CHF — blocks hypertrophy + fibrosis |
ACE Inhibitors vs ARBs — Key Differences
| ACE Inhibitors (e.g., lisinopril, enalapril) | ARBs (e.g., losartan, valsartan) | |
|---|---|---|
| Mechanism | Block ACE → ↓ Ang II, ↑ bradykinin | Block AT1 receptor → ↓ Ang II effects. Bradykinin unaffected. |
| Cough | Yes — 10–15% (bradykinin accumulation) | No (bradykinin not affected) |
| Angioedema | Yes (rare but life-threatening) | Rare, but can occur (cross-reactivity ~30%) |
| Potassium | ↑ K+ (↓ aldosterone) | ↑ K+ (same mechanism) |
| Creatinine | ↑ Cr mildly (efferent dilation → ↓ GFR) | Same — minor ↑ Cr expected. Major ↑ = bilateral RAS. |
| Heart failure | Improve survival | Improve survival (valsartan + sacubitril best combo) |
| Contraindication | Bilateral renal artery stenosis, pregnancy (teratogenic — oligohydramnios, renal agenesis) | Same contraindications |
1. Beta blockers (metoprolol succinate, carvedilol, bisoprolol)
2. ACE inhibitors or ARBs (reduce cardiac remodeling, ↓ preload and afterload)
3. Aldosterone antagonists (spironolactone/eplerenone — after ACEi + BB are optimized, EF <35%)
4. SGLT2 inhibitors (dapagliflozin, empagliflozin)
5. Sacubitril/valsartan (ARNI — replaces ACEi in HFrEF EF <40%)
6. ICD: Prior MI with EF ≤30%, or Class II–III HF with EF ≤35%
7. Hydralazine + isosorbide dinitrate (BiDil): Black patients intolerant of ACEi/ARB
ANP → binds receptor → activates guanylate cyclase → GTP → cGMP → activates protein kinase G (PKG) → PKG phosphorylates myosin light chain phosphatase (activates it) → myosin light chains dephosphorylated → smooth muscle relaxation → vasodilation. This is how ANP causes natriuresis AND vasodilation simultaneously. Neprilysin inhibitors (sacubitril) block ANP breakdown → prolonged ANP effects.
- ACE inhibitor expected renal effects (minor, acceptable): Creatinine rises 10–20% (efferent arteriole dilates → ↓ GFR). K+ rises mildly (↓ aldosterone → ↓ K+ excretion). Metabolic acidosis (↓ aldosterone → retain H+). These are expected and acceptable. Do not stop ACE inhibitor for minor bumps.
- ACE inhibitor → major GFR drop = bilateral renal artery stenosis signal: If creatinine rises dramatically (e.g., 1.1 → 2.5+ mg/dL) after ACEi, suspect bilateral RAS. In bilateral RAS, patients depend on angiotensin II to constrict the efferent arteriole to maintain GFR against poor afferent perfusion. ACEi removes this compensatory mechanism → GFR crashes.
- Bilateral RAS pathophysiology: Both afferent arterioles hypoperfused → massive renin release → high Ang II → efferent constriction sustains GFR. Add ACEi → dilate efferent → GFR tanks → acute kidney injury. This is why bilateral RAS is an absolute contraindication to ACEi/ARB.
- Electrolyte changes with ACE inhibitor: ↓ Aldosterone → (1) ↓ Na+ reabsorption → slight volume depletion. (2) ↑ K+ (hyperkalemia). (3) ↑ H+ retention → metabolic acidosis. These three together = Type 4 RTA pharmacology.
- Tumor lysis syndrome electrolytes: Massive cell lysis → ↑ K+ (hyperkalemia), ↑ phosphate (hyperphosphatemia), ↑ uric acid (hyperuricemia → gout + AKI), ↓ calcium (hypocalcemia — calcium bound to phosphate). Treat prophylactically with allopurinol + aggressive IV fluids ± rasburicase (uricase).
Glomerular Capillary Hemodynamics — The Core Concept
Glomerular capillaries are fed by the afferent arteriole (blood in) and drained by the efferent arteriole (blood out). GFR is determined by the hydrostatic pressure inside the glomerular capillaries.
- ↑ Efferent resistance (Ang II): Blood can't leave easily → hydrostatic pressure ↑ → ↑ GFR. This is why in low-volume states, Ang II maintains GFR by constricting the efferent.
- ↓ Efferent resistance (ACEi/ARB): Blood drains freely → hydrostatic pressure ↓ → ↓ GFR → creatinine rises. Expected minor bump (~20%) is acceptable.
- In bilateral RAS: The afferent is obstructed — the only thing keeping GFR alive is the efferent constriction from Ang II. Block Ang II with ACEi/ARB → efferent dilates → both sides of the capillary fail → GFR crashes. AKI.
Tumor Lysis Syndrome — Electrolyte Panel
| Electrolyte | Direction | Mechanism | Consequence |
|---|---|---|---|
| Potassium | ↑↑ (hyperkalemia) | Released from lysed cancer cells | Arrhythmia, cardiac arrest |
| Phosphate | ↑↑ (hyperphosphatemia) | Released from lysed cells (ATP → phosphate) | Binds calcium → ↓ Ca2+ |
| Calcium | ↓↓ (hypocalcemia) | Precipitates with phosphate | Tetany, seizures, QT prolongation |
| Uric acid | ↑↑ (hyperuricemia) | Purine breakdown from DNA of lysed cells | Gout flare + uric acid AKI (crystals in tubules) |
1. Bilateral renal artery stenosis: Will crash GFR acutely — AKI.
2. Pregnancy: Ang II is essential for fetal renal development. ACEi/ARB in 2nd/3rd trimester → oligohydramnios, renal agenesis (Potter sequence), fetal death. Category D → X in 2nd/3rd trimester.
3. History of angioedema with ACEi: Do NOT rechallenge. Switch to ARB (but note ~30% cross-reactivity for angioedema).
4. Hyperkalemia (K+ >5.5 mEq/L): ACEi further impairs K+ excretion.
Unilateral RAS: Contralateral kidney compensates fully. ACEi safe (minor creatinine bump only). Affected kidney releases massive renin → renovascular hypertension that responds to ACEi (treating the angiotensin II driving the HTN).
Bilateral RAS: ACEi causes acute kidney injury — no compensatory kidney. Clinically suspected when creatinine rises dramatically (by >30–50%) on ACEi initiation. Diagnostic: renal Doppler ultrasound (high-resistance waveforms), MR angiography, CT angiography.