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

Genetic Disease

• Carbonic Anhydrase I (CA-I) Deficiency/Alteration
• Ehlers-Danlos Syndrome (see Ehlers-Danlos Syndrome)
• Familial Type 1 Distal Renal Tubular Acidosis
  • Autosomal Dominant
  • Autosomal Recessive
• Hereditary Elliptocytosis (see Hereditary Elliptocytosis)
• Marfan Syndrome (see Marfan Syndrome)
• Medullary Cystic Disease: produces both distal RTA and proximal RTA
• Neuroaxonal Dystrophy
• Osteopetrosis
• Sickle Cell Disease (see Sickle Cell Disease)
• Wilson Disease (see Wilson Disease)

Tubulointerstitial Renal Disease

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

Nephrocalcinosis Syndromes

• Fabry Disease (see Fabry Disease)
• Hereditary Fructose Intolerance
• Hypercalcemia (see Hypercalcemia
• Hyperthyroidism (see Hyperthyroidism)
• Milk Alkali Syndrome (see Milk Alkali Syndrome)
• Medullary Sponge Kidney
• Primary Hypercalciuria
• Primary Hyperoxaluria (see Primary Primary Hyperoxaluria)
• Primary/Familial Hyperparathyroidism (see Hyperparathyroidism)
• Sarcoidosis (see Sarcoidosis)
• Vitamin D Intoxication (see Vitamin D)

Autoimmune Disease

• Chronic Active Hepatitis
• Hashimoto’s Thyroiditis (see Hashimoto’s Thyroiditis,)
• Primary Biliary Cirrhosis (PBC) (see Primary Biliary Cirrhosis)
• Idiopathic Pulmonary Fibrosis (IPF) (see Idiopathic Pulmonary Fibrosis)
• Rheumatoid Arthritis (RA) (see Rheumatoid Arthritis)
• Sjogren’s Syndrome (see Sjogren’s Syndrome): produces both distal RTA and proximal RTA
• Systemic Lupus Erythematosus (SLE) (see Systemic Lupus Erythematosus)
• Vasculitis (see Vasculitis)

Hypergammaglobulinemic States

• Amyloidosis (see Amyloidosis): produces both distal RTA and proximal RTA
• Cryoglobulinemia (see Cryoglobulinemia)
• Multiple Myeloma (see Multiple Myeloma): produces both distal RTA and proximal RTA

Drugs/Toxins

• Amphotericin B (see Amphotericin)
• Cyclamate
• Non-Steroidal Anti-Inflammatory Drugs (NSAID) (see Non-Steroidal Anti-Inflammatory Drug)
• Ifosfamide (see Ifosfamide): produces both distal RTA and proximal RTA
• Lithium Carbonate (see Lithium)
• Toluene Intoxication (see Toluene)

Other

• Cirrhosis (see End-Stage Liver Disease)
• Human Immunodeficiency Virus (HIV)/AIDS (see Human Immunodeficiency Virus): possible etiology
• Idiopathic (Sporadic) Type 1 Distal Renal Tubular Acidosis

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

• Amyloidosis (see Amyloidosis, [[Amyloidosis]])
• Cryoglobulinemia (see Cryoglobulinemia, [[Cryoglobulinemia]])
• Light Chain Disease
• Monoclonal Gammopathy of Unclear Significance (MGUS) (see Monoclonal Gammopathy of Unclear Significance, [[Monoclonal Gammopathy of Unclear Significance]])
• Multiple Myeloma (see Multiple Myeloma, [[Multiple Myeloma]]): produces both distal and proximal RTA

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

• Chronic Renal Vein Thrombosis (see Renal Vein Thrombosis, [[Renal Vein Thrombosis]])
• Idiopathic (Sporadic) Type 2 Proximal Renal Tubular Acidosis
• Malignancies
  • Burkitt’s Lymphoma (see Lymphoma, [[Lymphoma]])
• Nephrotic Syndrome (see Nephrotic Syndrome, [[Nephrotic Syndrome]])
• Paroxysmal Nocturnal Hemoglobinuria (PNH) (see Paroxysmal Nocturnal Hemoglobinuria, [[Paroxysmal Nocturnal Hemoglobinuria]])
• Tetralogy of Fallot (see Tetralogy of Fallot, [[Tetralogy of Fallot]])
• Vitamin D Deficiency (see Vitamin D, [[Vitamin D]])
• Vitamin D Resistance see Vitamin D, [[Vitamin D]])

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
  • Advanced Age
  • Drug-Induced Hyporeninemic Hypoaldosteronism
    • Beta Blockers (see β-Adrenergic Receptor Antagonists, [[β-Adrenergic Receptor Antagonists]])
    • Calcineurin Inhibitors (see Calcineurin Inhibitors, [[Calcineurin Inhibitors]])
    • Non-Steroidal Anti-Inflammatory Drug (NSAID) (see Non-Steroidal Anti-Inflammatory Drug, [[Non-Steroidal Anti-Inflammatory Drug]])
  • Intrinsic Renal Disease
    • Acute Glomerulonephritis with Volume Expansion (see Acute Glomerulonephritis, [[Acute Glomerulonephritis]])
    • Chronic Kidney Disease (CKD) (see Chronic Kidney Disease, [[Chronic Kidney Disease]]): with chronic interstitial nephritis
    • Diabetic Nephropathy (see Diabetes Mellitus, [[Diabetes Mellitus]])
• 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
  • Severe illness
  • Primary Adrenal Insufficiency (see Adrenal Insufficiency, [[Adrenal Insufficiency]])

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)
    • Amiloride (see Amiloride, [[Amiloride]])
    • Cimetidine (Tagamet) (see Cimetidine, [[Cimetidine]])
    • Nafamostat: synthetic serine protease inhibitor, used as an anticoagulant
    • Pentamidine (see Pentamidine, [[Pentamidine]])
    • Triamterene (see Triamterene, [[Triamterene]])
    • Trimethoprim (see Sulfamethoxazole-Trimethoprim, [[Sulfamethoxazole-Trimethoprim]])
• Other
  • Tubulointerstitial Renal Disease
    • Amyloidosis (see Amyloidosis, [[Amyloidosis]])
    • Obstructive Uropathy
    • Post-Acute Tubular Necrosis (ATN) (see Acute Kidney Injury, [[Acute Kidney Injury]])
    • Sickle Cell Disease (see Sickle Cell Disease, [[Sickle Cell Disease]])
    • Systemic Lupus Erythematosus (SLE) (see Systemic Lupus Erythematosus, [[Systemic Lupus Erythematosus]])

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

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)