NON-ANION GAP METABOLIC ACIDOSIS (NAGMA)

AG normal (8–12 mEq/L) with pH <7.35 and HCO3 <22 mEq/L — also called hyperchloremic metabolic acidosis; caused by GI or renal HCO3 loss

SYMPTOMS / ASSOCIATED SX

  • Often milder symptoms than AGMA; fatigue, weakness, nausea

  • Kussmaul respirations (compensatory hyperventilation) if severe

  • Hypokalemia (diarrhea, RTA type I/II) or hyperkalemia (RTA type IV, Addison's)

  • Nephrolithiasis (type I distal RTA — calcium phosphate stones)

  • Osteomalacia, rickets (chronic RTA — inability to acidify urine → calcium/phosphate losses)

  • Features of underlying cause: diarrhea (GI loss), urinary symptoms (RTA), hyperkalemia (type IV RTA, Addison's)

DENIES

  • Diarrhea or high-output GI loss (most common cause of NAGMA — type 4 stool losses)

  • Recent large-volume NS infusion (dilutional/hyperchloremic metabolic acidosis)

  • Renal disease or CKD (reduced tubular acid excretion)

  • DM, hypertension, chronic kidney disease (type IV RTA — most common RTA in adults)

  • Symptoms of Addison's disease (hyperkalemia + hyponatremia + hyperpigmentation + hypotension)

SOCIAL HISTORY

  • Diarrhea history, laxative use, ileostomy/colostomy (GI HCO3 loss)

  • Medications: acetazolamide, topiramate (proximal RTA), TPN (excessive Cl administration)

  • Ureteral diversion (ureterosigmoidostomy → bowel reabsorbs urinary Cl, exchanges for HCO3)

MAIN ETIOLOGY

  • GI bicarbonate losses (most common overall):

    • Diarrhea (most common — bicarbonate-rich stool losses; urine AG negative)

    • High-output ileostomy or colostomy (bicarbonate-rich fluid losses)

    • Intestinal or pancreatic fistula

    • Cholestyramine (binds bicarbonate in gut)

    • Ureteral diversion (ureterosigmoidostomy — bowel absorbs Cl, secretes HCO3)

  • Renal tubular acidosis (RTA):

    • Type I (distal): inability to acidify urine (pH >5.5 despite systemic acidosis); hypokalemia; nephrolithiasis (Ca-phosphate); causes: Sjögren's, SLE, amphotericin B, toluene inhalation; urine AG positive

    • Type II (proximal): impaired HCO3 reabsorption in proximal tubule; hypokalemia; Fanconi syndrome (glucosuria, aminoaciduria, phosphaturia without hyperglycemia); causes: multiple myeloma, Wilson's disease, acetazolamide, topiramate, ifosfamide, heavy metal toxicity; urine AG positive

    • Type IV (hyporeninemic hypoaldosteronism): MOST COMMON RTA in adults; HYPERKALEMIA + non-AG metabolic acidosis; causes: diabetic nephropathy (most common), CKD, NSAIDs, ACE inhibitors, heparin, trimethoprim, calcineurin inhibitors; urine AG positive (low, but less so than types I/II)

  • Iatrogenic hyperchloremia: large-volume NS 0.9% infusion (each liter provides 154 mEq Cl → hyperchloremic metabolic acidosis); TPN with excessive chloride salts

  • Early renal failure (reduced tubular NH4+ excretion before AG rises)

  • Adrenal insufficiency (Addison's): hyperkalemia + hyponatremia + metabolic acidosis

MOST COMMON DDX — Use Urine Anion Gap (UAG)

  • UAG = urine Na + urine K − urine Cl

  • Negative UAG (urine Cl high): appropriate renal NH4+ excretion → GI HCO3 loss (diarrhea, fistula, ileostomy); kidneys working correctly

  • Positive UAG (urine Cl low): impaired renal NH4+ excretion → RTA (types I, II, IV) or early CKD; kidneys are the problem

  • Urine pH >5.5 despite systemic acidosis = type I distal RTA (inability to acidify) vs. type II proximal (urine can acidify once HCO3 fully filtered and no longer reaching distal tubule)

  • Type IV RTA (hyperkalemia + non-AG acidosis + diabetic/CKD patient): aldosterone deficiency or resistance → reduced NH4+ excretion

  • Adrenal insufficiency (hyperkalemia + hyponatremia + hypotension + hyperpigmentation + AM cortisol low)

DATA

  • BMP (confirm AG normal 8–12; calculate corrected AG; identify K level — key for RTA type)

  • ABG or VBG (pH, pCO2, HCO3)

  • Urine electrolytes (Na, K, Cl) → calculate urine AG = urine Na + K − Cl

  • Urine pH (type I RTA: pH >5.5 despite systemic acidosis; type II: pH can be <5.5 when below HCO3 threshold)

  • Serum K (hypokalemia = types I/II; hyperkalemia = type IV, Addison's)

  • Serum aldosterone, plasma renin activity (type IV RTA — low renin, low aldosterone)

  • AM cortisol; ACTH stimulation test (Addison's)

  • Urine glucose, urine protein, urine phosphate, urine uric acid (Fanconi syndrome — type II proximal RTA)

  • CBC; LFTs; SPEP (multiple myeloma — type II RTA cause)

  • UA (proximal tubule dysfunction features)

  • Serum phosphate (low in proximal RTA/Fanconi); serum uric acid

  • Fractional excretion of HCO3 (type II proximal RTA: FEHCO3 >15% when HCO3 normal; <5% in distal RTA)

  • Renal ultrasound (nephrocalcinosis — type I distal RTA; medullary sponge kidney)

HOME MEDS

  • NSAIDs — hold (reduce aldosterone effect → worsen type IV RTA; worsen AKI)

  • ACE inhibitors/ARBs — hold if significant hyperkalemia from type IV RTA

  • Acetazolamide, topiramate — hold if contributing to proximal RTA

  • K supplements — increase if hypokalemia from type I/II RTA; hold if hyperkalemia from type IV

PLAN

  • Identify and treat the underlying cause — cornerstone

  • Diarrhea (GI HCO3 loss): treat underlying cause; aggressive oral/IV rehydration; correct K and HCO3 losses (see Diarrhea card for specific management)

  • Large-volume NS iatrogenic acidosis: switch to balanced crystalloids (LR, PlasmaLyte); allow kidneys to correct over 12–24h; rarely requires NaHCO3

  • RTA Type I (distal):

    • Oral NaHCO3 1–2 mEq/kg/day (divided doses) OR sodium citrate/citric acid (Bicitra, Polycitra) — preferred (better tolerated, also prevents nephrolithiasis)

    • Correct hypokalemia: oral KCl; K citrate preferred (alkalinizing + K repletion)

    • Thiazide diuretic if hypercalciuria and stone formation (reduces urinary calcium)

    • Treat underlying cause (Sjögren's — hydroxychloroquine; stop amphotericin B)

  • RTA Type II (proximal):

    • High-dose NaHCO3 10–15 mEq/kg/day (massive bicarbonaturia when HCO3 near normal; difficult to correct)

    • Thiazide diuretic (mild volume contraction → ↑ proximal HCO3 reabsorption) + low-Na diet

    • K supplementation (renal K wasting accompanies bicarbonaturia)

    • Treat underlying cause (myeloma — chemotherapy; Wilson's — penicillamine; stop causative drug)

    • Phosphate supplementation if hypophosphatemia (Fanconi syndrome)

  • RTA Type IV (most common RTA in adults):

    • Fludrocortisone 0.1–0.2 mg PO daily (mineralocorticoid replacement if true aldosterone deficiency)

    • Loop diuretic (furosemide 40–80 mg PO daily) — promotes kaliuresis → corrects hyperkalemia and acidosis

    • Low-K diet; remove offending medications (NSAIDs, TMP-SMX, heparin, ACE inhibitor/ARB if safe to stop)

    • NaHCO3 supplementation if persistent acidosis despite above

  • Adrenal insufficiency: hydrocortisone 20 mg AM + 10 mg PM; fludrocortisone 0.1 mg daily; correct hyponatremia and hyperkalemia (see respective electrolyte cards)

  • Ureterosigmoidostomy: NaHCO3 supplementation; low-chloride diet; urology/nephrology referral

  • NaHCO3 supplementation general targets: HCO3 >18–20 mEq/L for mild-moderate; >22 for children or bone disease risk

  • Nephrology consult for: refractory or unclassified RTA, CKD-associated NAGMA, severe symptomatic acidosis

  • Trend: BMP q12–24h during active correction; monitor K closely (direction changes with treatment)

DISCHARGE:

  • Document RTA type in chart; nephrology outpatient follow-up

  • RTA I/II: oral NaHCO3 or citrate solution prescription; DEXA scan (bone demineralization); urology if nephrolithiasis

  • Type IV RTA: deprescribe offending medications; low-K diet; fludrocortisone or loop diuretic per response; BMP in 1–2 weeks

  • Diarrhea-related NAGMA: treat underlying GI cause; oral electrolyte repletion; follow-up in 1 week

RED FLAGS

  • Severe acidosis (pH <7.1) from any NAGMA cause → ICU; NaHCO3 IV; nephrology urgently

  • Hyperkalemia (K >6.0) + NAGMA → type IV RTA or Addison's; cardiac monitoring; treat K emergently

  • Adrenal crisis presenting as NAGMA + hyperkalemia + hypotension → hydrocortisone 100 mg IV NOW; do not wait for confirmatory testing

  • Fanconi syndrome (glucosuria without hyperglycemia + aminoaciduria + hypophosphatemia + NAGMA) → work up for multiple myeloma, Wilson's disease, heavy metal toxicity

  • Nephrocalcinosis on imaging + NAGMA + hypokalemia → type I distal RTA; nephrology and urology

  • Ureteral diversion + hyperchloremic NAGMA + hyperkalemia → renal tubular dysfunction from urinary diversion; urology + nephrology

SENIOR IM RESIDENT PEARLS

  • The urine anion gap is your single most useful tool in NAGMA: negative = GI cause (kidneys working correctly); positive = renal cause (kidneys failing to excrete acid)

  • Type IV RTA is the most common RTA in clinical practice — think of it in any diabetic or CKD patient with unexplained hyperkalemia + non-AG metabolic acidosis; fludrocortisone or loop diuretics are treatment options

  • Common mistake: large-volume NS for resuscitation causing iatrogenic hyperchloremic NAGMA — recognized by normal AG, hyperchloremia, and timing with IV fluid administration; switch to balanced crystalloids

  • Type I vs. Type II RTA: both cause hypokalemia; distinguish by urine pH (type I: urine always >5.5; type II: can acidify urine below 5.5 once HCO3 below reabsorption threshold) and FEHCO3 (type II markedly elevated when plasma HCO3 normal)

  • NaHCO3 dosing in type II (proximal) RTA is notoriously difficult: as you give bicarb, more is filtered and excreted → you need very high doses; thiazide + low-Na diet helps by contracting volume and increasing proximal reabsorption

  • Common mistake: attributing all hyperchloremic acidosis to diarrhea without checking urine AG — RTA is easily missed and has different management

  • Aldosterone deficiency vs. resistance in type IV RTA: aldosterone deficiency (Addison's, bilateral adrenal destruction) → fludrocortisone works; aldosterone resistance (tubular unresponsiveness in CKD/DM) → fludrocortisone less effective; use loop diuretics instead