6.16 Disorders of Water, Electrolytes, and Acid-Base Renal tubular acidosis

FIGURE 6-25 FEATURES OF THE RENAL TUBULAR ACIDOSIS (RTA) SYNDROMES Renal tubular acidosis (RTA) defines a group of disorders in which tubular hydro- gen ion secretion is impaired out of propor- Feature Proximal RTA Classic Distal RTA Hyperkalemic Distal RTA tion to any reduction in the glomerular fil- tration rate. These disorders are character- Plasma bicarbonate 14–18 mEq/L Variable, may be 15–20 mEq/L ized by normal anion gap (hyperchloremic) ion concentration < 10 mEq/L metabolic acidosis. The defects responsible Plasma chloride Increased Increased Increased for impaired acidification give rise to three ion concentration distinct syndromes known as proximal RTA Plasma potassium Mildly decreased Mildly to Mildly to severely increased (type 2), classic distal RTA (type 1), and ion concentration severely decreased hyperkalemic distal RTA (type 4). Plasma anion gap Normal Normal Normal Glomerular filtration rate Normal or Normal or Normal to slightly decreased slightly decreased moderately decreased pH during acidosis ≤5.5 >6.0 ≤5.5 Urine pH after acid loading ≤5.5 >6.0 ≤5.5

U-B PCO2 in alkaline urine Normal Decreased Decreased Fractional excretion of >15% <5% <5% - - HCO3 at normal [HCO3]p - Tm HCO3 Decreased Normal Normal Nephrolithiasis Absent Present Absent Nephrocalcinosis Absent Present Absent Osteomalacia Present Present Absent Fanconi’s syndrome* Usually present Absent Absent Alkali therapy High dose Low dose Low dose

- Tm HCO3—maximum reabsorption of bicarbonate; U-B PCO2—difference between partial pressure of carbon dioxide values in urine and arterial blood. *This syndrome signifies generalized proximal tubule dysfunction and is characterized by impaired reabsorption of , amino acids, phosphate, and urate. Disorders of Acid-Base Balance 6.17

LumenProximal tubule cell Blood B. CAUSES OF PROXIMAL RENAL TUBULAR ACIDOSIS

CA CO2 CO + OH– HCO– 3HCO– Selective defect (isolated bicarbonate wasting) Dysproteinemic states CA 2 3 3 H CO + Primary (no obvious associated disease) Multiple myeloma 2 3 H O 1Na 2 Genetically transmitted Monoclonal gammopathy – + + Transient (infants) HCO3+ H H Drug- or toxin-induced + + Due to altered carbonic anhydrase activity Outdated tetracycline Na Na 3Na+ Acetazolamide 3-Methylchromone Na+ Sulfanilamide 2K+ Streptozotocin Glucose Mafenide acetate Lead Amino acids Genetically transmitted Mercury Phosphate Idiopathic Arginine Osteopetrosis with carbonic Valproic acid Indicates possible cellular mechanisms responsible anhydrase II deficiency Gentamicin A for Type 2 proximal RTA York-Yendt syndrome Ifosfamide Generalized defect (associated with multiple dysfunctions of the proximal tubule) Tubulointerstitial diseases FIGURE 6-26 Renal transplantation A and B, Potential defects and causes of proximal renal tubular Primary (no obvious associated disease) Sporadic Sjögren’s syndrome acidosis (RTA) (type 2). Excluding the case of carbonic anhydrase Medullary cystic disease inhibitors, the nature of the acidification defect responsible for Genetically transmitted Genetically transmitted systemic disease Other renal diseases bicarbonate (HCO3) wastage remains unknown. It might represent defects in the luminal sodium ion– hydrogen ion (Na+-H+) Tyrosinemia Nephrotic syndrome + - Wilson’s disease Amyloidosis exchanger, basolateral Na -3HCO3 cotransporter, or carbonic anhydrase activity. Most patients with proximal RTA have addi- Lowe syndrome Miscellaneous tional defects in proximal tubule function (Fanconi’s syndrome); Hereditary fructose intolerance (during Paroxysmal this generalized proximal tubule dysfunction might reflect a defect administration of fructose) nocturnal hemoglobinuria in the basolateral Na+-K+ adenosine triphosphatase. K+—potassium Cystinosis Hyperparathyroidism ion; CA—carbonic anhydrase. Causes of proximal renal tubular Pyruvate carboxylate deficiency acidosis (RTA) (type 2). An idiopathic form and cystinosis are the Metachromatic leukodystrophy most common causes of proximal RTA in children. In adults, mul- Methylmalonic acidemia tiple myeloma and carbonic anhydrase inhibitors (eg, acetazo- Conditions associated with chronic hypocalcemia lamide) are the major causes. Ifosfamide is an increasingly and secondary hyperparathyroidism common cause of the disorder in both age groups. Vitamin D deficiency or resistance Vitamin D dependence 6.18 Disorders of Water, Electrolytes, and Acid-Base

B. CAUSES OF CLASSIC DISTAL RENAL TUBULAR ACIDOSIS

LumenαIntercalated cell (CCT & MCT) Blood Primary (no obvious associated disease) Disorders associated Sporadic with nephrocalcinosis Primary or familial hyperparathyroidism CO HCO– Genetically transmitted 2 3 Vitamin D intoxication + CA Autoimmune disorders H – Milk-alkali syndrome Cl Hypergammaglobulinemia OH– Hyperthyroidism Hyperglobulinemic purpura Idiopathic hypercalciuria + H O Cryoglobulinemia H 2 Genetically transmitted – Familial K+ Cl Sporadic Sjögren’s syndrome Hereditary fructose intolerance Thyroiditis (after chronic fructose ingestion) – Pulmonary fibrosis Cl Medullary sponge Chronic active hepatitis Fabry’s disease Primary biliary cirrhosis Wilson’s disease Indicates possible cellular mechanisms responsible Systemic lupus erythematosus A for Type 1 distal RTA Vasculitis Drug- or toxin-induced Amphotericin B Genetically transmitted systemic disease Toluene Ehlers-Danlos syndrome FIGURE 6-27 Analgesics Hereditary elliptocytosis A and B, Potential defects and causes of classic distal renal tubular Lithium Sickle cell anemia acidosis (RTA) (type 1). Potential cellular defects underlying classic Cyclamate Marfan syndrome distal RTA include a faulty luminal hydrogen ion–adenosine triphos- Balkan nephropathy phatase (H+ pump failure or secretory defect), an abnormality in the Carbonic anhydrase I deficiency basolateral bicarbonate ion–chloride ion exchanger, inadequacy of or alteration Tubulointerstitial diseases carbonic anhydrase activity, or an increase in the luminal membrane Osteopetrosis with carbonic Chronic permeability for hydrogen ions (backleak of protons or permeability anhydrase II deficiency Obstructive uropathy defect). Most of the causes of classic distal RTA likely reflect a secre- Medullary cystic disease Renal transplantation tory defect, whereas amphotericin B is the only established cause of a Neuroaxonal dystrophy Leprosy permeability defect. The hereditary form is the most common cause of this disorder in children. Major causes in adults include autoim- mune disorders (eg, Sjögren’s syndrome) and hypercalciuria [19]. CA—carbonic anhydrase.