Metabolic Acidosis-Normal Anion Gap (Non-Anion Gap Metabolic Acidosis, NAGMA)

Etiology

Type 1 Distal RTA (see Type 1 Distal Renal Tubular Acidosis)

Genetic Disease

Tubulointerstitial Renal Disease

  • Chronic Pyelonephritis
  • Leprosy (see Leprosy)
  • Obstructive Uropathy
  • Renal Transplant Rejection (see Renal Transplant)

Nephrocalcinosis Syndromes

Autoimmune Disease

Hypergammaglobulinemic States

Drugs/Toxins

Other

Type 2 Proximal RTA (see Type 2 Proximal Renal Tubular Acidosis)

Genetic Disease

  • Carbonic Anhydrase II Deficiency
  • Cystinosis
  • Galactosemia
  • Hereditary Fructose Intolerance
  • Glycogen Storage Disease Type I
  • Lowe Syndrome
  • Metachromatic Leukodystrophy
  • Methylmalonic Acidemia
  • Proximal Tubule Cell Sodium Bicarbonate Co-Transporter (NBCe1) Defect
  • Pyruvate Carboxylase Deficiency
  • Tyrosinemia
  • Wilson Disease (see Wilson Disease, [[Wilson Disease]]): produces both distal and proximal RTA

Renal Interstitial Disease

  • Balkan Nephropathy
  • Medullary Cystic Disease: produces both distal and proximal RTA
  • Renal Transplant Rejection (see Renal Transplant)
  • Sjogren’s Syndrome (see Sjogren’s Syndrome)

Carbonic Anhydrase-Related Conditions

  • Acetazolamide (Diamox) (see Acetazolamide, [[Acetazolamide]])
    • Physiology: carbonic anhydrase inhibition -> bicarbonate loss in urine
  • Carbonic Anhydrase II Deficiency/Osteopetrosis
  • Dichlorphenamide (Keveyis) (see Dichlorphenamide, [[Dichlorphenamide]])
    • Physiology: carbonic anhydrase inhibition -> bicarbonate loss in urine
  • Mafenide Acetate (Sulfamylon) (see Mafenide Acetate, [[Mafenide Acetate]])
    • Mechanism: topical sulfonamide antibiotic (which is rapidly absorbed systemically in burn patients) with carbonic anhydrase inhibitor properties -> bicarbonate loss in urine
  • Sulfanilamide
  • Topiramate (Topamax) (see Topiramate, [[Topiramate]])
    • Mechanism: carbonic anhydrase inhibitor properties -> bicarbonate loss in urine

Dysproteinemias

Drugs/Toxins

  • Cadmium (see Cadmium, [[Cadmium]])
  • Copper (see Copper, [[Copper]])
  • Gentamicin (see Gentamicin, [[Gentamicin]])
  • Ifosfamide (Ifex) (see Ifosfamide, [[Ifosfamide]]): produces both distal and proximal RTA
  • L-Arginine
  • Lead (see Lead, [[Lead]])
  • Mercury (see Mercury, [[Mercury]])
  • Outdated Tetracycline (see Tetracycline, [[Tetracycline]])
  • Streptozotocin (see Streptozotocin, [[Streptozotocin]])
  • Tenofovir (Viread) (see Tenofovir, [[Tenofovir]])
  • Uranium (see Uranium, [[Uranium]])
  • Valproic Acid (see Valproic Acid, [[Valproic Acid]])

Other

Type 4 Renal Tubular Acidosis (RTA)/Hypoaldosteronism (see Type 4 Renal Tubular Acidosis, [[Type 4 Renal Tubular Acidosis]] and Hypoaldosteronism, [[Hypoaldosteronism]])

Decreased Aldosterone Synthesis

  • Inherited Disorders
    • 21 Hydroxylase Deficiency
    • Pseudohypoaldosteronism Type 2 (Gordon’s Syndrome)
  • Hyporeninemic Hypoaldosteronism
  • Drugs
    • Angiotensin Converting Enzyme (ACE) Inhibitors
      • Captopril (Capoten) (see Captopril, [[Captopril]])
      • Enalapril (Vasotec, Enalaprilat) (see Enalapril, [[Enalapril]])
      • Fosinopril (Monopril) (see Fosinopril, [[Fosinopril]])
      • Lisinopril (Zestril) (see Lisinopril, [[Lisinopril]])
      • Moexipril (Univasc) (see Moexipril, [[Moexipril]])
      • Perindopril (Coversyl, Coversum, Preterax, Aceon) (see Perindopril, [[Perindopril]])
      • Quinapril (Accupril) (see Quinapril, [[Quinapril]])
      • Ramipril (Altace) (see Ramipril, [[Ramipril]])
      • Trandolapril (Mavik) (see Trandolapril, [[Trandolapril]])
    • Angiogensin II Receptor Blockers (ARB’s)
      • Candesartan (Atacand) (see Candesartan, [[Candesartan]])
      • Fimasartan (Kanarb) (see Fimasartan, [[Fimasartan]])
      • Irbesartan (Avapro, Aprovel, Karvea) (see Irbesartan, [[Irbesartan]])
      • Losartan (Cozaar) (see Losartan, [[Losartan]])
      • Olmesartan (Benicar, Olmecip) (see Olmesartan, [[Olmesartan]])
      • Telmisartan (Micardis) (see Telmisartan, [[Telmisartan]])
      • Valsartan (Diovan) (see Valsartan, [[Valsartan]])
    • Heparins
      • Enoxaparin (Lovenox) (see Enoxaparin, [[Enoxaparin]])
      • Heparin (see Heparin, [[Heparin]])
    • Renin Inhibitors
      • Aliskiren (Tekturna, Rasilez) (see Aliskiren, [[Aliskiren]]): renin inhibitor (may cause hyperkalemia when used in combination with ACE inhibitors or ARB’s)
  • Other

Aldosterone Resistance

  • Inherited Disorders
    • Pseudohypoaldosteronism Type 1
  • Drugs
    • Aldosterone Antagonists
      • Drospirenone (Yasmin, Yasminelle, Yaz, Beyaz, Ocella, Zarah, Angeliq) (see Drospirenone, [[Drospirenone]])
      • Eplerenone (Inspra) (see Eplerenone, [[Eplerenone]])
      • Spironolactone (Aldactone) (see Spironolactone, [[Spironolactone]])
    • Epithelial Sodium Channel (ENaC) Antagonists (see Epithelial Sodium Channel Antagonists): these agents act to close sodium channels on the luminal membrane of cells in the collecting tubule (collecting tubule is the site of action of aldosterone)
  • Other

Gastrointestinal (GI) Bicarbonate Loss

  • Biliary Drainage (Biliary Drain or T-Tube)
    • Mechanism: external loss of biliary fluid (biliary fluid contains 35 mmol bicarbonate per L)
  • Cholestyramine (see Cholestyramine, [[Cholestyramine]])
    • Mechanism: cationic resin which that is administrated as a chloride salt -> formation of calcium carbonate or the bicarbonate salt of cholestyramine within the gastrointestinal lumen -> increased gastrointestinal bicarbonate loss
  • Diarrhea (see Diarrhea, [[Diarrhea]])
    • Mechanism: gastrointestinal loss of bicarbonate in stool
  • Enterovesical Fistula/Colovesical Fistula
    • Mechanisms: both require retrograde movement of urine into the intestine
      • Urinary Chloride is Exchanged for Bicarbonate by Chloride/Bicarbonate Transporter, Resulting in Bicarbonate Loss in the Stool
      • Urinary Urea is Metabolized by Colonic Bacterial Ureases into Ammonium Ions with Ammonium Ion Reabsorption Via Colonic Sodium-Hydrogen Antiporter (as Ammonium Takes the Place of Sodium): result in a net gain of ammonium and chloride ions and a loss of bicarbonate
  • Ileal Conduit (Neobladder) (see Ileal Conduit, [[Ileal Conduit]])
    • Epidemiology: since metabolic acidosis is a common complication of ureteroenterostomy, ileal conduits have largely replaced this procedure (however, metabolic acidosis still occurs in 10% of ileal conduit cases, especially in the presence of obstruction)
    • Mechanisms
      • Intestinal Mucosal Exchange of Urinary Chloride for Bicarbonate: results in urinary bicarbonate loss and hyperchloremia
      • Intestinal Mucosal Absorption of Urinary NH4: results in hepatic conversion to NH3 and hydrogen ion
        • Increased risk of this occurring when large loop of bowel used to make the neo-bladder, stoma is obstructed, or when sigmoid colonic section is used instead of ileal section
  • Laxative Abuse (see Laxative Abuse, [[Laxative Abuse]])
    • Mechanism: gastrointestinal loss of bicarbonate in stool
  • Oral Calcium Chloride (see Calcium Chloride, [[Calcium Chloride]])
    • Epidemiology: with oral administration only
    • Mechanism: calcium chloride administered orally is excreted as calcium bicarbonate (due to exchange of the chloride for bicarbonate) -> results in gastrointestinal bicarbonate loss and metabolic acidosis
  • Oral Magnesium Sulfate (see Magnesium Sulfate, [[Magnesium Sulfate]])
    • Mechanism: increases gastrointestinal bicarbonate loss
  • Pancreaticocutaneous Fistula
    • Mechanism: results in external loss of pancreatic fluid (pancreatic fluid contains 115 mmol bicarbonate per L)
  • Pancreaticopleural Fistula
    • Mechanism: loss of pancreatic fluid into pleural space (pancreatic fluid contains 115 mmol bicarbonate per L)
  • Small Intestinal Enterocutaneous Fistula
    • Mechanism: external loss of small intestinal fluid (duodenal secretions contain 10 mmol bicarbonate per L, ileal secretions contain 30 mmol bicarbonate per L)
  • Ureteroenterostomy/Ureterosigmoidostomy
    • Epidemiology: metabolic acidosis is a common complication of ureteroenterostomy
    • Mechanism: urinary diversion into the colon -> urinary ammonium is absorbed by the colonic mucosa, resulting in bicarbonate loss in the stool
  • Villous Adenoma
    • Mechanism: secretion of bicarbonate-rich fluid into the gastrointestinal lumen

Dilutional Metabolic Acidosis

  • Rapid Infusion of Bicarbonate-Free (and Lactate-Free) Normal Saline (see Normal Saline, [[Normal Saline]])
    • Physiology: dilutional metabolic acidosis results predominantly from an expansion in the extracellular fluid volume by fluids that are bicarbonate-free or contain no organic acid salts that could potentially be metabolized to bicarbonate (such as lactate or acetate)
      • Mechanisms Favoring the Development of Dilutional Metabolic Acidosis
        • Narrowing of strong ion difference between sodium and chloride
        • Volume expansion -> decreased renal bicarbonate absorption
      • Mechanisms Countering the Development of Dilutional Metabolic Acidosis
        • Movement of bicarbonate from bone and intracellular stores into the extracellular space
        • Binding of hydrogen ions by proteins (albumin, hemoglobin)
    • Clinical Significance: however, in a dog model with a 28% expansion of the extracellular volume with isotonic saline, the serum bicarbonate only decreased 10% [MEDLINE] -> this suggests that dilutional acidosis is unlikely to occur unless extremely large amounts of bicarbonate-free intravenous fluids are administered

Other

  • Acidic Salt Infusion
    • Ammonium Chloride (see Ammonium Chloride, [[Ammonium Chloride]]): intravenous ammonium chloride is a systemic and urinary acidifying agent, which is converted to ammonia and hydrochloric acid through hepatic oxidation
    • Calcium Chloride (see Calcium Chloride, [[Calcium Chloride]]): generates hydrogen chloride
    • Arginine Hydrochloride: generates hydrogen chloride
  • D-Lactic Acidosis with Normal Renal Function (see Lactic Acidosis, [[Lactic Acidosis]])
    • Mechanism: the proximal tubule sodium/L-lactate co-transporter is stereospecific and does not transport D-lactate
      • Therefore, filtered D-lactate is rapidly excreted in the urine (assuming normal renal function)
    • Diagnosis: delta anion gap/delta bicarbonate ratio is 1 or <1 (obviously, as the delta anion gap/delta bicarbonate ratio approaches zero, this would be observed as a non-anion gap metabolic acidosis)
      • This is in contrast with L-lactic acidosis, where the delta anion gap/delta bicarbonate ratio is typically between 1.1-1.6
  • Hydrochloric Acid (HCl) Infusion (see Hydrochloric Acid, [[Hydrochloric Acid]]): hydrogen chloride added to the extracellular space results in replacement of bicarbonate by chloride in an equimolar basis
  • Late Phase of Diabetic Ketoacidosis (DKA) (see Diabetic Ketoacidosis and Hyperosmolar Hyperglycemic State, [[Diabetic Ketoacidosis and Hyperosmolar Hyperglycemic State]])
    • Mechanism: urinary loss of ketoanions with sodium and potassium -> this is equivalent to a loss of potential bicarbonate, since each ketoanion (if retained) would have consumed a proton and been converted to a new bicarbonate molecule
  • Methionine Intoxication (see Methionine, [[Methionine]])
  • Moderate Renal Failure
    • Acute Kidney Injury (AKI) (see Acute Kidney Injury, [[Acute Kidney Injury]])
    • Chronic Kidney Disease (CKD) (see Chronic Kidney Disease, [[Chronic Kidney Disease]])
      • Mechanisms
        • Early Kidney Disease: greater dysfunction in acid excretion than acid anion excretion -> typically have non-anion gap metabolic acidosis or anion gap metabolic acidosis with delta anion gap/delta bicarbonate ratio <1
        • Later Kidney Disease: typically have anion gap metabolic acidosis with delta anion gap/delta bicarbonate ratio >1
  • Total Parenteral Nutrition (TPN) (see Total Parenteral Nutrition, [[Total Parenteral Nutrition]])
  • Post-Hypocapnic Metabolic Acidosis
    • Mechanism: chronic hypocapnia results in renal loss of bicarbonate -> when hypocapnia is remedied (often by placing the pt on mechanical ventilation, etc), metabolic acidosis is observed until the kidney is able to compensate by rebabsorbing bicarbonate
  • Toluene Intoxication (see Toluene, [[Toluene]])
    • May Present as Anion Gap Metabolic Acidosis (see Metabolic Acidosis-Elevated Anion Gap, [[Metabolic Acidosis-Elevated Anion Gap]])
      • Early in the Course
      • With Impaired Renal Function
    • May Present as Non-Anion Gap Metabolic Acidosis:
      • Late in the Course
      • With Intact Renal Function: due to renal excretion of sodium and potassium hippurate

Physiology

  • Biliary/Duodenal/Pancreatic Secretions are Normally Alkaline: they serve to neutralize the acidity of gastric secretions
    • Jejunal Mucosal (Luminal) Na/Hydrogen Ion Exchanger: normally functions in jejunum to reabsorb sodium bicarbonate, resulting in normal stool having small amounts of bicarbonate
      • However, increased stool volume (diarrhea) results in increased bicarbonate excretion, resulting in metabolic acidosis

Diagnosis

Serum Chemistry

  • Serum Bicarbonate: decreased
  • Serum Chloride: hyperchloremia
  • Anion Gap: normal
    • Calculation of Anion Gap = Na – (Cl + HCO3)
      • Anion gap reflects the difference between unmeasured cations and anions (i.e. the anions in the blood that are not routinely measured)

Serum Lactate (see Serum Lactate, [[Serum Lactate]])

  • Normal

Arterial Blood Gas (ABG) (see Arterial Blood Gas, [[Arterial Blood Gas]])

  • Decreased Serum Bicarbonate with Respiratory Compensation

Urine Anion Gap (see Urine Anion Gap, [[Urine Anion Gap]])

  • Rationale: renal ammonia excretion is the predominant component of renal net acid excretion
    • Proximal Tubule: apical Na+/H+ exchanger, NHE-3, is a major mechanism of preferential NH4+ secretion
    • Thick Ascending Loop of Henle: apical Na+-K+-2Cl- cotransporter, NKCC2, is a major contributor to ammonia reabsorption and the basolateral Na+/H+ exchanger, NHE-4, appears to be important for basolateral NH4+ exit
    • Collecting Duct: major site for renal ammonia secretion, involving parallel H+ secretion and NH3 secretion
  • Calculation of Urine Anion Gap = (Urine Na + Urine K) – (Urine Cl)
    • Normal Urine Anion Gap: 20 to 90 mEq/L
      • On a Typical Western Diet, the Quantity of Sodium and Potassium Absorbed from the Gastrointestinal Tract Exceeds the Quantity of Absorbed Chloride: therefore, renally excreted urine Na and K is greater than the amount of renally excreted urine Cl, making the urine AG positive
    • Urine AG >-20 mEq/L (Indicating Increased Renal NH4 Ion Excretion): urine AG becoming more negative indicates gastrointestinal bicarbonate loss
      • Diarrhea Results in Gastrointestinal Loss of Na, K, and Non-Chloride Anions (Including Bicarbonate, Butyrate, Citrate, and Lactate)
        • Gastrointestinal Loss of Bicarbonate Results in Increased Renal Excretion of Hydrogen Ion (H+) in the Form of Ammonium (NH4+) Chloride: urine chloride serves as a surrogate for NH4 ion excretion
      • Hypovolemia occurs with decreased sodium delivery to distal nephron
      • Bicarbonate is replaced by chloride in serum (producing hyperchloremia)
    • Urine AG Positive (Indicating Normal-Low Renal NH4 Ion Excretion): indicates altered urinary acidification, suggestive of distal renal tubular acidosis
  • Clinical Situations Where the Urine Anion Gap is Unreliable
    • Urine Anion Gap is Not Reliable in Neonates: neonates excrete other unmeasured anions at relatively high rates
    • Diabetic Ketoacidosis: due to increased urinary excretion of unmeasured non-chloride anions, beta-hydroxybutyrate and acetoacetate -> this alters the relationship between the urine NH4 and urine anion gap
    • Toluene Intoxication: due to increased urinary excretion of unmeasured non-chloride anion, hippurate
    • Proximal RTA Treated with Alkali Therapy: due to increased urinary excretion of unmeasured non-chloride anion, bicarbonate
    • D-Lactic Acidosis: due to increased urinary excretion of unmeasured non-chloride anion, D-lactate
    • Pyroglutamic Acidosis: due to increased urinary excretion of unmeasured non-chloride anion, 5-oxoproline

Urine Osmolal Gap

  • Rationale: urine osmolal gap performs better as a surrogate of the urine NH4 concentration when urinary ammonium (NH4) ion is excreted with an anion other than chloride (such as beta-hydroxybutyrate, acetoacetate, bicarbonate, or hippurate)

Clinical Manifestations

Renal Manifestations

  • Non-Anion Gap Metabolic Acidosis

Treatment


References

  • Effect of isotonic volume expansion on extracellular bicarbonate stores in normal dogs. Am J Physiol. 1973 Sep;225(3):628-36 [MEDLINE]
  • Dilution acidosis and contraction alkalosis: review of a concept [MEDLINE]
  • Total parenteral nutrition-associated metabolic acidosis. JPEN J Parenter Enteral Nutr. 1986 May-Jun;10(3):306-10 [MEDLINE]
  • Enterovesical fistula presenting as life-threatening normal anion gap metabolic acidosis. Am J Kidney Dis. 1997 Jul;30(1):131-3 [MEDLINE]
  • Rapid saline infusion produces hyperchloremic acidosis in patients undergoing gynecologic surgery. Anesthesiology. 1999 May;90(5):1265-70 [MEDLINE]
  • Toxicity of methionine in humans. J Nutr. 2006 Jun;136(6 Suppl):1722S-1725S [MEDLINE]
  • Severe metabolic acidosis and hypokalemia in a patient with enterovesical fistula. Clin Exp Nephrol. 2007 Sep;11(3):225-9. Epub 2007 Sep 28 [MEDLINE]
  • Non–Anion Gap Metabolic Acidosis in a Patient With a Pancreaticopleural Fistula. JAOA • Vol 111, No 5, May 2011, 344-345 [MEDLINE]
  • An unrecognised case of metabolic acidosis following neobladder augmentation cystoplasty. Int J Surg Case Rep. 2015;11:129-31. doi: 10.1016/j.ijscr.2015.03.039. Epub 2015 Mar 25 [MEDLINE]