Renal Tubular Acidosis

Renal tubular acidosis (RTA) is an imbalance in physiologic pH caused by the kidney’s inability to acidify urine to maintain blood pH at physiologic levels. Renal tubular acidos3s exist in multiple types, including distal RTA (type 1), proximal RTA (type 2), and hyperkalemic RTA (type 4). Depending on the type of RTA, various mechanisms cause dysfunction of renal acid–base handling, resulting in a non–anion-gap metabolic acidosis Metabolic acidosis The renal system is responsible for eliminating the daily load of non-volatile acids, which is approximately 70 millimoles per day. Metabolic acidosis occurs when there is an increase in the levels of new non-volatile acids (e.g., lactic acid), renal loss of HCO3-, or ingestion of toxic alcohols. Metabolic Acidosis. All RTAs present clinically with some degree of metabolic acidosis Metabolic acidosis The renal system is responsible for eliminating the daily load of non-volatile acids, which is approximately 70 millimoles per day. Metabolic acidosis occurs when there is an increase in the levels of new non-volatile acids (e.g., lactic acid), renal loss of HCO3-, or ingestion of toxic alcohols. Metabolic Acidosis; however, distal RTA and proximal RTA also have hypokalemia Hypokalemia Hypokalemia is defined as plasma potassium (K+) concentration < 3.5 mEq/L. Homeostatic mechanisms maintain plasma concentration between 3.5-5.2 mEq/L despite marked variation in dietary intake. Hypokalemia can be due to renal losses, GI losses, transcellular shifts, or poor dietary intake. Hypokalemia, while hyperkalemic RTA does not. Diagnosis is primarily through the history and laboratory analysis, including measurement of serum and urine anion gaps. Treatment involves the correction of chronic metabolic acidosis Metabolic acidosis The renal system is responsible for eliminating the daily load of non-volatile acids, which is approximately 70 millimoles per day. Metabolic acidosis occurs when there is an increase in the levels of new non-volatile acids (e.g., lactic acid), renal loss of HCO3-, or ingestion of toxic alcohols. Metabolic Acidosis with alkali to prevent its long-term catabolic effects on bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Structure of Bones and muscles, as well as addressing any underlying causes leading to the RTA.

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Overview

Definition

Renal tubular acidosis (RTA) is an imbalance in physiologic pH caused by the kidney’s inability to acidify urine to maintain blood pH at physiologic levels.

Classification

RTA can be classified based on the clinical characteristics and physiologic defect:

  • Type 1: distal RTA 
  • Type 2: proximal RTA
  • Type 4: hyperkalemic RTA

Comparison of the types of RTA, including the clinical characteristics, physiologic defects, and potential etiologies:

Table: Type 1 RTA (distal)—impaired acid secretion
Characteristics Impaired H+ secretion by the distal segments
  • Urine > pH 5.3
  • Plasma HCO3 variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables
Renal defect
  • ↑ H+–K+–ATPase
  • ↑ Tubule permeability, allowing H+ backflow
  • ↓ Na+ reabsorption
Etiology
  • Familial autoimmune disorders (Sjögren syndrome, rheumatoid arthritis Rheumatoid arthritis Rheumatoid arthritis (RA) is a symmetric, inflammatory polyarthritis and chronic, progressive, autoimmune disorder. Presentation occurs most commonly in middle-aged women with joint swelling, pain, and morning stiffness (often in the hands). Rheumatoid Arthritis)
  • Drugs, toxins
Table: Type 2 RTA (proximal)—impaired bicarbonate secretion
Characteristics Impaired proximal HCO3 reabsorption
  • Urine pH variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables
  • Plasma HCO3 12–20 mM/L
Renal defect Nonspecific tubule dysfunction or mutations in genes involved in HCO3 reabsorption
Etiology
  • Familial
  • Fanconi syndrome
  • Drugs, toxins
  • Carbonic anhydrase inhibitors Carbonic anhydrase inhibitors Carbonic anhydrase inhibitors (CAIs) block the carbonic anhydrase enzymes in the proximal convoluted tubule, inhibiting the reabsorption of sodium bicarbonate (NaHCO3), which results in diuresis and metabolic acidosis. Carbonic Anhydrase Inhibitors
Table: Type 4 RTA ( hypoaldosteronism Hypoaldosteronism Hypoaldosteronism is a hormonal disorder characterized by low levels of aldosterone. These low levels can be caused by decreased aldosterone production or a peripheral resistance to aldosterone. When hypoaldosteronism occurs as a result of an acquired decrease in renin production, the condition is more commonly referred to as renal tubular acidosis (RTA) type 4. Hypoaldosteronism)—impaired acid secretion
Characteristics Impaired aldosterone release or response
  • Urine pH < 5.3
  • Plasma HCO3 > 17 mM/L
  • Hyperkalemia Hyperkalemia Hyperkalemia is defined as a serum potassium (K+) concentration >5.2 mEq/L. Homeostatic mechanisms maintain the serum K+ concentration between 3.5 and 5.2 mEq/L, despite marked variation in dietary intake. Hyperkalemia can be due to a variety of causes, which include transcellular shifts, tissue breakdown, inadequate renal excretion, and drugs. Hyperkalemia
Renal defect Impaired Na+ reabsorption via epithelial Na+ channel
Etiology Congenital hypoaldosteronism Hypoaldosteronism Hypoaldosteronism is a hormonal disorder characterized by low levels of aldosterone. These low levels can be caused by decreased aldosterone production or a peripheral resistance to aldosterone. When hypoaldosteronism occurs as a result of an acquired decrease in renin production, the condition is more commonly referred to as renal tubular acidosis (RTA) type 4. Hypoaldosteronism (Addison disease)
  • Aldosterone resistance
  • Diabetic nephropathy
  • Drugs
  • Diuretics

Epidemiology

  • Hyperkalemic RTA (type 4) is the most common in the United States.
    • Most commonly caused by diabetic nephropathy leading to hyporeninemic hypoaldosteronism Hypoaldosteronism Hypoaldosteronism is a hormonal disorder characterized by low levels of aldosterone. These low levels can be caused by decreased aldosterone production or a peripheral resistance to aldosterone. When hypoaldosteronism occurs as a result of an acquired decrease in renin production, the condition is more commonly referred to as renal tubular acidosis (RTA) type 4. Hypoaldosteronism and urinary tract obstruction Urinary tract obstruction Urinary tract obstruction (UTO) refers to the blockage of the urinary tract, which can occur anywhere in the urinary tract. Urinary tract obstruction can be acute or chronic, partial or complete, and unilateral or bilateral. Urinary tract obstruction can cause acute or chronic kidney disease. Urinary Tract Obstruction
  • Proximal (type 2) and distal (type 1) RTA are rare.
  • RTA associated with medication usage is increasing in incidence: 
    • Antiviral medication
    • Transplant medications (20% incidence of hyperkalemic RTA in renal transplants)

Etiology

Distal renal tubular acidosis (type 1)

In adults, the most common causes are:

  • Autoimmune disease:
    • Sjögren syndrome 
    • Rheumatoid arthritis
    • Systemic lupus erythematosus Systemic lupus erythematosus Systemic lupus erythematosus (SLE) is a chronic autoimmune, inflammatory condition that causes immune-complex deposition in organs, resulting in systemic manifestations. Women, particularly those of African American descent, are more commonly affected. Systemic Lupus Erythematosus 
  • Hypercalciuria:
    • Vitamin D intoxication
    • Hyperparathyroidism Hyperparathyroidism Hyperparathyroidism is a condition associated with elevated blood levels of parathyroid hormone (PTH). Depending on the pathogenesis of this condition, hyperparathyroidism can be defined as primary, secondary or tertiary. Hyperparathyroidism
    • Sarcoidosis Sarcoidosis Sarcoidosis is a multisystem inflammatory disease that causes noncaseating granulomas. The exact etiology is unknown. Sarcoidosis usually affects the lungs and thoracic lymph nodes, but it can also affect almost every system in the body, including the skin, heart, and eyes, most commonly. Sarcoidosis
    • Idiopathic (familial) hypercalciuria 

In children, the most common cause is genetic:

  • Autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance or autosomal recessive: 
    • Mutations of the Cl–HCO3 exchanger
    • Mutations of the H+–ATPase pump
  • Other genetic associations:
    • Marfan syndrome Marfan syndrome Marfan syndrome is a genetic condition with autosomal dominant inheritance. Marfan syndrome affects the elasticity of connective tissues throughout the body, most notably in the cardiovascular, ocular, and musculoskeletal systems. Marfan Syndrome
    • Ehlers-Danlos syndrome Ehlers-Danlos syndrome Ehlers-Danlos syndrome (EDS) is a heterogeneous group of inherited connective tissue disorders that are characterized by hyperextensible skin, hypermobile joints, and fragility of the skin and connective tissue. Ehlers-Danlos Syndrome
    • Sickle cell disease Sickle cell disease Sickle cell disease (SCD) is a group of genetic disorders in which an abnormal Hb molecule (HbS) transforms RBCs into sickle-shaped cells, resulting in chronic anemia, vasoocclusive episodes, pain, and organ damage. Sickle Cell Disease
    • Congenital obstruction of the urinary tract

Other causes: 

  • Drugs:
    • Lithium
    • Amphotericin B
    • NSAIDs 
    • Ifosfamide (more common in type 3 RTA)
  • Obstructive uropathy
  • Kidney transplant rejection
  • Medullary sponge kidney
  • Wilson disease
Nephrocalcinosis

Nephrocalcinosis:
Calcium deposits are visible in the kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys in cases of hypercalciuria. This condition can arise from multiple causes, including hyperparathyroidism, vitamin D intoxication, and sarcoidosis and can result in type 1 renal tubular acidosis.

Image: “Nephrocalcinosis” by FastilyClone. License: Public Domain

Proximal renal tubular acidosis (type 2)

In adults, the most common cause is monoclonal gammopathy:

  • Multiple myeloma Multiple myeloma Multiple myeloma (MM) is a malignant condition of plasma cells (activated B lymphocytes) primarily seen in the elderly. Monoclonal proliferation of plasma cells results in cytokine-driven osteoclastic activity and excessive secretion of IgG antibodies. Multiple Myeloma 
  • Amyloidosis Amyloidosis Amyloidosis is a disease caused by abnormal extracellular tissue deposition of fibrils composed of various misfolded low-molecular-weight protein subunits. These proteins are frequently byproducts of other pathological processes (e.g., multiple myeloma). Amyloidosis

In children, the most common causes are: 

  • Idiopathic
  • Ifosfamide
  • Cystinosis

Other causes:

  • Autoimmune causes (especially Sjögren syndrome)
  • Genetic:
    • Autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance or autosomal recessive 
    • Apical Na+–H+ antiporter of the proximal tubular cells
    • Basolateral Na+–HCO3 cotransporter of proximal tubular cells 
    • Carbonic anhydrase type 2 deficiency
  • Drugs:
    • Heavy metals (lead, mercury)
    • Carbonic anhydrase inhibitors Carbonic anhydrase inhibitors Carbonic anhydrase inhibitors (CAIs) block the carbonic anhydrase enzymes in the proximal convoluted tubule, inhibiting the reabsorption of sodium bicarbonate (NaHCO3), which results in diuresis and metabolic acidosis. Carbonic Anhydrase Inhibitors (such as acetazolamide, topiramate)
    • Aminoglycosides Aminoglycosides Aminoglycosides are a class of antibiotics including gentamicin, tobramycin, amikacin, neomycin, plazomicin, and streptomycin. The class binds the 30S ribosomal subunit to inhibit bacterial protein synthesis. Unlike other medications with a similar mechanism of action, aminoglycosides are bactericidal. Aminoglycosides
    • Antiretrovirals (specifically, tenofovir)
    • Ifosfamide 
    • Cisplatin, oxaliplatin
    • Valproic acid
  • Miscellaneous: 
    • Interstitial nephritis
    • Vitamin D deficiency
    • Secondary hyperparathyroidism
    • Kidney transplant
    • Other diseases associated with Fanconi syndrome:
      • Tyrosinemia
      • Cystinosis
      • Galactosemia Galactosemia Galactosemia is a disorder caused by defects in galactose metabolism. Galactosemia is an inherited, autosomal-recessive condition, which results in inadequate galactose processing and high blood levels of monosaccharide. The rare disorder often presents in infants with symptoms of lethargy, nausea, vomiting, diarrhea, and jaundice. Galactosemia
      • Hereditary fructose intolerance
      • von Gierke disease (glycogen storage disease type I)
      • Wilson disease
      • Lowe disease
      • Paroxysmal nocturnal hemoglobinuria Paroxysmal Nocturnal Hemoglobinuria Paroxysmal nocturnal hemoglobinuria (PNH) is a rare but serious acquired hemolytic anemia with periodic exacerbations. This anemia is caused by nonmalignant clonal expansion of ≥ 1 hematopoietic stem cells that have acquired a somatic mutation of the phosphatidylinositol N-acetylglucosaminyltransferase subunit A (PIG-A) gene. Paroxysmal Nocturnal Hemoglobinuria

Hyperkalemic renal tubular acidosis (type 4)

In adults, the most common causes are:

  • Diabetic nephropathy
  • Interstitial nephritis
  • Mild-to-moderate CKD CKD Chronic kidney disease (CKD) is kidney impairment that lasts for ≥ 3 months, implying that it is irreversible. Hypertension and diabetes are the most common causes; however, there are a multitude of other etiologies. In the early to moderate stages, CKD is usually asymptomatic and is primarily diagnosed by laboratory abnormalities. Chronic Kidney Disease

Other causes:

  • Genetic:
    • Sickle cell disease Sickle cell disease Sickle cell disease (SCD) is a group of genetic disorders in which an abnormal Hb molecule (HbS) transforms RBCs into sickle-shaped cells, resulting in chronic anemia, vasoocclusive episodes, pain, and organ damage. Sickle Cell Disease
    • 21-hydroxylase deficiency
    • Pseudohypoaldosteronism
  • Autoimmune (particularly lupus)
  • Drugs:
    • Potassium-sparing diuretics Potassium-sparing diuretics Potassium-sparing diuretics are medications that act in the principal cells in the collecting ducts to induce diuresis that does not result in excretion of potassium. These diuretics include 2 subclasses: sodium channel blockers and aldosterone antagonists. Potassium-sparing Diuretics
    • NSAIDs
    • Calcineurin inhibitors (cyclosporine, tacrolimus)
    • Angiotensin-converting–enzyme inhibitors (ACEis)
    • Angiotensin-receptor blockers (ARBs)
    • Renin inhibitors
    • Heparin
    • Trimethoprim Trimethoprim The sulfonamides are a class of antimicrobial drugs inhibiting folic acid synthesize in pathogens. The prototypical drug in the class is sulfamethoxazole. Although not technically sulfonamides, trimethoprim, dapsone, and pyrimethamine are also important antimicrobial agents inhibiting folic acid synthesis. The agents are often combined with sulfonamides, resulting in a synergistic effect. Sulfonamides and Trimethoprim
    • Pentamidine
  • Miscellaneous:
    • Chronic obstruction of the urinary tract
    • Primary adrenal insufficiency Adrenal Insufficiency Adrenal insufficiency (AI) is the inadequate production of adrenocortical hormones: glucocorticoids, mineralocorticoids, and adrenal androgens. Primary AI, also called Addison’s disease, is caused by autoimmune disease, infections, and malignancy, among others. Adrenal insufficiency can also occur because of decreased production of adrenocorticotropic hormone (ACTH) from disease in the pituitary gland (secondary) or hypothalamic disorders and prolonged glucocorticoid therapy (tertiary). Adrenal Insufficiency and Addison’s Disease
    • Critical illness

Pathophysiology

Distal renal tubular acidosis (type 1)

The pathophysiology of distal RTA (type 1) is impaired acid secretion at the collecting duct of the distal tubule.

Normal process of urinary acidification:

  • Intercalated cells participate in acid excretion:
    • Located at the collecting duct of the distal tubule
    • ?-intercalated cell:
      • Apical H+/K+–ATPase (1 H+ out of cell, 1 K+ into cell)
      • Apical H+–ATPase (1 H+ out of cell)
      • Basolateral Na+/K+–ATPase
      • Basolateral Cl/HCO3 exchanger 
    • ?-intercalated cell:
      • Apical Cl/HCO3 exchanger (1 HCO3out of cell, 1 Cl into cell)
      • Apical H+/K+–ATPase (1 H+ out of cell, 1 K+ into cell)
      • Basolateral Na+/K+–ATPase
      • Basolateral H+–ATPase
  • Net effect
    • Intercalated cells secrete H+ into the tubular lumen
    • H+ combine with NH3+ (ammonia) and other compounds (titratable acids)
    • NH4+ (ammonium) and titratable acids are excreted.
    • Acid–base homeostasis is maintained

Abnormal processes leading to distal RTA:

  • ↓ Activity of apical H+/K+–ATPase (↓ H+ secretion into tubular lumen)
  • ↑ Permeability of the collecting duct to H+:
    • Collecting duct is normally impermeable to H+:
      • Prevents backflow of recently secreted H+
      • Allows for excretion of urine that is more acidic than plasma
    • Example: amphotericin toxicity
  • ↓ Na+ reabsorption
  • Altered activity of the Cl/HCO3 exchanger:
    • ↑ Activity of apical Cl/HCO3 exchanger 
      • ↑ HCO3 secretion → net HCO3 loss → metabolic acidosis Metabolic acidosis The renal system is responsible for eliminating the daily load of non-volatile acids, which is approximately 70 millimoles per day. Metabolic acidosis occurs when there is an increase in the levels of new non-volatile acids (e.g., lactic acid), renal loss of HCO3-, or ingestion of toxic alcohols. Metabolic Acidosis
      • Occurs at ?-intercalated cells
    • ↓ Activity of basolateral Cl/HCO3 exchanger: 
      • ↓ HCO3 secretion → buildup of intracellular HCO3 → ↑ intracellular pH
      • ↓ H+ secretion via apical ATPases occurs to correct intracellular pH.
      • Occurs at ?-intercalated cells

Complications:

  • Severe metabolic acidosis Metabolic acidosis The renal system is responsible for eliminating the daily load of non-volatile acids, which is approximately 70 millimoles per day. Metabolic acidosis occurs when there is an increase in the levels of new non-volatile acids (e.g., lactic acid), renal loss of HCO3-, or ingestion of toxic alcohols. Metabolic Acidosis may occur in distal RTA (type 1):
    • Serum HCO3 < 10 mEq/L if untreated
    • Occurs in the distal nephron → no downstream processes to compensate
  • Hypokalemia
  • Hypocitraturia (predisposes to nephrolithiasis Nephrolithiasis Nephrolithiasis is the formation of a stone, or calculus, anywhere along the urinary tract caused by precipitations of solutes in the urine. The most common type of kidney stone is the calcium oxalate stone, but other types include calcium phosphate, struvite (ammonium magnesium phosphate), uric acid, and cystine stones. Nephrolithiasis)
Intercalated cells in distal rta (type 1)

Intercalated cells in distal RTA (type I)

Image by Lecturio.

Proximal renal tubular acidosis (type 2)

The pathophysiology of proximal RTA (type II) is impaired bicarbonate reabsorption at the proximal tubule.

Normal process of proximal tubule HCO3 reabsorption:

  • Under normal circumstances, 80% of filtered HCO3 is reabsorbed in the proximal tubule.
  • Requires a complex mechanism because HCO3 is not freely permeable (due to charge):
    • Sodium–hydrogen ion exchanger 3 (NHE3) absorbs Na+ and secretes H+.
    • Secreted H+ combines with the filtered HCO3 to form H2CO3 in the tubular lumen.
    • H2CO3 is converted into H2O and CO2 by apical carbonic anhydrase IV. 
    • CO2 diffuses freely across the apical membrane back into the cell.
    • Intracellular carbonic anhydrase II converts CO2 + H2O back into H2CO3.
    • H2CO3 then can dissociate into H+ and HCO3:
      • H+ is recycled through the process through NHE3
      • HCO3 is absorbed through the basolateral membrane via Na+–HCO3 cotransporter and HCO3–Cl exchanger. 
  • Net effects of the entire process:
    • Excretion of H+
    • Absorption of HCO3– 

Abnormal processes leading to proximal renal tubular acidosis (type 2):

  • Multiple myeloma Multiple myeloma Multiple myeloma (MM) is a malignant condition of plasma cells (activated B lymphocytes) primarily seen in the elderly. Monoclonal proliferation of plasma cells results in cytokine-driven osteoclastic activity and excessive secretion of IgG antibodies. Multiple Myeloma: light chains are directly toxic to the proximal tubule cells  
  • Drugs causing toxicity to the proximal tubule cells via multiple mechanisms
  • Mutations in:
    • Apical NHE3
    • Basolateral Na+–HCO3 cotransporter 
    • Carbonic anhydrase II enzyme

Complications:

  • Moderate metabolic acidosis Metabolic acidosis The renal system is responsible for eliminating the daily load of non-volatile acids, which is approximately 70 millimoles per day. Metabolic acidosis occurs when there is an increase in the levels of new non-volatile acids (e.g., lactic acid), renal loss of HCO3-, or ingestion of toxic alcohols. Metabolic Acidosis
    • Serum HCO3 14–20 mEq/L, even if untreated
    • Majority of proximal tubule HCO3 reabsorption capacity is maintained:
      • Threshold for proximal tubule HCO3 reabsorption lowered
      • Serum HCO3↓ until it matches the new threshold (steady state)
      • Distal acidification is maintained → daily acid load is managed without worsening acidosis
  • Hypokalemia
  • Fanconi syndrome
Bicarbonate reabsorption in proximal tubule

Bicarbonate reabsorption in the proximal tubule

CA-IV: carbonic anhydrase IV
CA-II: carbonic anhydrase II

Image by Lecturio. License: CC BY-NC-SA 4.0

Hyperkalemic renal tubular acidosis (type 4)

The classic mechanism for most individuals with hyperkalemic RTA (i.e., diabetic nephropathy and mild-to-moderate CKD CKD Chronic kidney disease (CKD) is kidney impairment that lasts for ≥ 3 months, implying that it is irreversible. Hypertension and diabetes are the most common causes; however, there are a multitude of other etiologies. In the early to moderate stages, CKD is usually asymptomatic and is primarily diagnosed by laboratory abnormalities. Chronic Kidney Disease) is hyporeninemic hypoaldosteronism Hypoaldosteronism Hypoaldosteronism is a hormonal disorder characterized by low levels of aldosterone. These low levels can be caused by decreased aldosterone production or a peripheral resistance to aldosterone. When hypoaldosteronism occurs as a result of an acquired decrease in renin production, the condition is more commonly referred to as renal tubular acidosis (RTA) type 4. Hypoaldosteronism

  • Normal actions of aldosterone:
    • Net effect is to: 
      • Reabsorb Na+
      • Secrete K+
      • Secrete H+
    • Stimulates epithelial Na channel (ENaC) at the principal cell
      • ↑ Na+ reabsorption → ↑ electrical gradient for K+ secretion
      • K+ secretion occurs via the renal outer medullary potassium channel (ROMK) at the principal cell.
  • Hyperkalemia Hyperkalemia Hyperkalemia is defined as a serum potassium (K+) concentration >5.2 mEq/L. Homeostatic mechanisms maintain the serum K+ concentration between 3.5 and 5.2 mEq/L, despite marked variation in dietary intake. Hyperkalemia can be due to a variety of causes, which include transcellular shifts, tissue breakdown, inadequate renal excretion, and drugs. Hyperkalemia contributes to metabolic acidosis Metabolic acidosis The renal system is responsible for eliminating the daily load of non-volatile acids, which is approximately 70 millimoles per day. Metabolic acidosis occurs when there is an increase in the levels of new non-volatile acids (e.g., lactic acid), renal loss of HCO3-, or ingestion of toxic alcohols. Metabolic Acidosis:
    • ↑ K+ inhibits ammoniagenesis in the proximal tubule
    • ↓ Urinary ammonium → ↓ acid excretion
  • All other etiologies also involve some disturbance in the RAAS → ↓ aldosterone state, which could be absolute or relative (i.e., aldosterone resistance).

Clinical Presentation

Renal tubular acidoses often do not have a specific clinical presentation and are only considered once metabolic acidosis Metabolic acidosis The renal system is responsible for eliminating the daily load of non-volatile acids, which is approximately 70 millimoles per day. Metabolic acidosis occurs when there is an increase in the levels of new non-volatile acids (e.g., lactic acid), renal loss of HCO3-, or ingestion of toxic alcohols. Metabolic Acidosis is discovered. Although some individuals are asymptomatic, many have significant symptoms caused by the underlying etiology of the RTA, rather than symptoms from the acidosis itself.

Distal renal tubular acidosis (type 1)

  • Adults:
    • Unexplained nephrolithiasis Nephrolithiasis Nephrolithiasis is the formation of a stone, or calculus, anywhere along the urinary tract caused by precipitations of solutes in the urine. The most common type of kidney stone is the calcium oxalate stone, but other types include calcium phosphate, struvite (ammonium magnesium phosphate), uric acid, and cystine stones. Nephrolithiasis 
    • Sjögren syndrome with unexplained metabolic acidosis Metabolic acidosis The renal system is responsible for eliminating the daily load of non-volatile acids, which is approximately 70 millimoles per day. Metabolic acidosis occurs when there is an increase in the levels of new non-volatile acids (e.g., lactic acid), renal loss of HCO3-, or ingestion of toxic alcohols. Metabolic Acidosis
  • Children: 
    • Growth failure
    • Osteomalacia Osteomalacia Rickets and osteomalacia are disorders of decreased bone mineralization. Osteomalacia affects the sites of bone turnover in children and adults. Although most cases are due to vitamin D deficiency, other genetic and nutritional disorders as well as medications can cause these disorders. Osteomalacia can present with bone pain, difficulty with ambulation and pathologic fractures. Osteomalacia and Rickets
    • Rickets Rickets Rickets and osteomalacia are disorders of decreased bone mineralization. Rickets affects the cartilage of the epiphyseal growth plates in children. Although most cases of rickets are due to vitamin D deficiency, other genetic and nutritional disorders as well as medications can cause these disorders. Rickets commonly presents with skeletal deformities and growth abnormalities. Osteomalacia and Rickets
Open bite in rta

Dental presentation of rickets seen in distal renal tubular acidosis:
Rickets Rickets Rickets and osteomalacia are disorders of decreased bone mineralization. Rickets affects the cartilage of the epiphyseal growth plates in children. Although most cases of rickets are due to vitamin D deficiency, other genetic and nutritional disorders as well as medications can cause these disorders. Rickets commonly presents with skeletal deformities and growth abnormalities. Osteomalacia and Rickets can be seen in individuals with distal renal tubular acidosis, as it involves calcium wasting in the urine.

Image: “Showing open bite” by Department of Pedodontics and Preventive Dentistry, Sharad Pawar Dental College, Sawangi (M), Mahartashtra State, Wardha 442102, India. License: CC BY 3.0

Proximal renal tubular acidosis (type 2)

  • Usually occurs as a part of Fanconi syndrome, rather than isolated RTA:
    • Fanconi syndrome refers to broad proximal tubule dysfunction
    • Abnormal reabsorption of phosphorus, uric acid, amino acids, and glucose 
    • Urinary wasting of all these substances occurs
  • Adults: 
    • Individuals with multiple myeloma and Fanconi syndrome
    • Fanconi syndrome due to medication 
  • Children: 
    • Genetic disease causing Fanconi syndrome (cystinosis, tyrosinemia)
    • Fanconi syndrome due to medication

Hyperkalemic renal tubular acidosis (type 4)

  • In adults, this is usually an incidental lab finding related to:
    • Diabetes
    • Mild-to-moderate CKD CKD Chronic kidney disease (CKD) is kidney impairment that lasts for ≥ 3 months, implying that it is irreversible. Hypertension and diabetes are the most common causes; however, there are a multitude of other etiologies. In the early to moderate stages, CKD is usually asymptomatic and is primarily diagnosed by laboratory abnormalities. Chronic Kidney Disease
    • Medications (NSAIDs, K-sparing diuretics, ACEis, ARBs, heparin, trimethoprim)
  • In children, this is usually due to a rare genetic disease: 
    • Pseudohypoaldosteronism type 2 (Gordon syndrome)
    • Congenital isolated hypoaldosteronism Hypoaldosteronism Hypoaldosteronism is a hormonal disorder characterized by low levels of aldosterone. These low levels can be caused by decreased aldosterone production or a peripheral resistance to aldosterone. When hypoaldosteronism occurs as a result of an acquired decrease in renin production, the condition is more commonly referred to as renal tubular acidosis (RTA) type 4. Hypoaldosteronism

Diagnosis

Renal tubular acidosis should be considered in the differential diagnosis of non–anion-gap metabolic acidosis Metabolic acidosis The renal system is responsible for eliminating the daily load of non-volatile acids, which is approximately 70 millimoles per day. Metabolic acidosis occurs when there is an increase in the levels of new non-volatile acids (e.g., lactic acid), renal loss of HCO3-, or ingestion of toxic alcohols. Metabolic Acidosis (NAGMA).

Step 1

Once NAGMA is identified, consider the differential diagnosis:

  • RTA
  • Diarrhea
  • Dilutional acidosis (i.e., excessive IV normal saline)
  • CKD CKD Chronic kidney disease (CKD) is kidney impairment that lasts for ≥ 3 months, implying that it is irreversible. Hypertension and diabetes are the most common causes; however, there are a multitude of other etiologies. In the early to moderate stages, CKD is usually asymptomatic and is primarily diagnosed by laboratory abnormalities. Chronic Kidney Disease (early-to-moderate severity)
  • Urinary diversion to the GI tract (i.e., ureterosigmoid fistula)
  • Toluene toxicity (glue “huffing”)

Step 2

Check the urine osmolal gap (UOG) and/or urine anion gap (UAG).

  • Differentiates RTA from other cause of NAGMA, since the formulas approximate urine ammonium excretion:
    • Renal tubular acidoses generally do not have increased ammonium excretion.
    • Other causes of NAGMA up-regulate ammonium excretion. 
  • Urine osmolal gap is more useful than urine anion gap:
    • Urine anion gap is inaccurate in many common clinical situations:
      • Hypovolemia
      • Unmeasured urinary anions (i.e., ketoacidosis)
      • Renal dysfunction
    • Urine osmolal gap accounts for those conditions, but is inaccurate if:
      • Urease positive urinary tract infection is present
      • Toxic alcohol poisoning (e.g., methanol, ethylene glycol)
  • Urine osmolal gap = measured urine osmolality – calculated urine osmolality
    • Urine osmolality = 2(Na+ + K+) + (BUN/2.8) + (glucose/18)
    • Urine osmolal gap ranges:
      • 10 to 100 = normal
      • < 150 = RTA
      • > 400 = NAGMA not due to RTA
  • Urine anion gap = urine (Na+ + K+ – Cl)
    • 0–20: normal or RTA
    • –20 to –50: NAGMA not due to RTA (i.e., diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea)

Step 3

To differentiate between the types of RTA, evaluate:

Serum bicarbonate level:

  • Distal (type 1): < 10 mEq/L
  • Proximal (type 2): 14–20 mEq/L
  • Hyperkalemic (type 4): >15 mEq/L

Urine pH:

  • Distal (type 1): ≥ 5.5
  • Proximal (type 2): variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables
    • ≥ 5.5 if serum HCO3 is > proximal tubule reabsorption threshold
      • Early in disease course → not yet in steady state
      • During treatment with bicarbonate 
    • < 5.5 if serum HCO3 is ≤ proximal tubule reabsorption threshold
      • Untreated and at steady state 
      • No urinary HCO3 wasting is occurring 
  • Hyperkalemic (type 4): < 5.5

Serum potassium:

  • Distal (type 1): low
  • Proximal (type 2): low
  • Hyperkalemic (type 4): high

Step 4

If the diagnosis is still unclear, a bicarbonate infusion test can be done:

  • Helps differentiate distal (type 1) from proximal (type 2) RTA 
  • Rarely done in practice
  • IV bicarbonate is given until the serum HCO3 = 18–20 mEq/L.
  • Distal RTA (type 1)
    • Urine pH does not change, despite ↑ serum HCO3
    • Fractional excretion of  HCO3 is < 3% (normal level)
  • Proximal RTA (type 2) 
    • Urine pH increases as the serum HCO3 increases.
    • Fractional excretion of  HCO3 is > 15% (↑ due to HCO3 wasting).

Management

General principles for distal and proximal renal tubular acidosis

  • Goal of therapy is to normalize the serum bicarbonate.
  • Mainstay of therapy is alkali (i.e., bicarbonate) replacement.
  • Oral bicarbonate or citrate can be used:
    • Citrate is converted into bicarbonate in the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver.
    • 1:1 ratio: 1 mEq of citrate becomes 1 mEq of bicarbonate.
    • Citrate is beneficial for the treatment of nephrolithiasis Nephrolithiasis Nephrolithiasis is the formation of a stone, or calculus, anywhere along the urinary tract caused by precipitations of solutes in the urine. The most common type of kidney stone is the calcium oxalate stone, but other types include calcium phosphate, struvite (ammonium magnesium phosphate), uric acid, and cystine stones. Nephrolithiasis.
  • Serum potassium must be considered:
    • Potassium-containing preparations may be preferred if hypokalemia Hypokalemia Hypokalemia is defined as plasma potassium (K+) concentration < 3.5 mEq/L. Homeostatic mechanisms maintain plasma concentration between 3.5-5.2 mEq/L despite marked variation in dietary intake. Hypokalemia can be due to renal losses, GI losses, transcellular shifts, or poor dietary intake. Hypokalemia is present.
    • Sodium-containing preparations are used otherwise.
    • Separate oral potassium replacement is often needed.
  • Pill burden is a large problem:
    • Most bicarbonate and citrate tablets have relatively low doses of bicarbonate
    • Dosing is often multiple tablets per dose given multiple times per day.
    • Predisposes to noncompliance and poor quality of life
  • Medication options:
    • Over-the-counter baking soda
      • 1 teaspoon = 54 mEq sodium bicarbonate
      • Most cost-effective option 
      • Useful when high doses are needed to help reduce pill burden
    • Sodium bicarbonate tablets 
    • Potassium bicarbonate tablets 
    • Sodium citrate liquid
    • Potassium citrate tablets or liquid

Distal renal tubular acidosis (type 1)

  • Oral bicarbonate (or equivalent): 1–2 mEq/kg/day in divided doses
  • Relatively easy to correct, because proximal tubule HCO3reabsorption is normal
  • May also require potassium supplementation

Proximal renal tubular acidosis (type 2)

Treatment for proximal RTA is more complicated than simply replacing bicarbonate:

Rationale:

  • Some supplemental bicarbonate will always be wasted in the urine:
    • Much higher doses of bicarbonate are needed.
    • Often unable to normalize the serum bicarbonate regardless of treatment
  • Bicarbonate wasting results in worsening hypokalemia Hypokalemia Hypokalemia is defined as plasma potassium (K+) concentration < 3.5 mEq/L. Homeostatic mechanisms maintain plasma concentration between 3.5-5.2 mEq/L despite marked variation in dietary intake. Hypokalemia can be due to renal losses, GI losses, transcellular shifts, or poor dietary intake. Hypokalemia:
    • HCO3 travels through the nephron bound to Na+ (NaHCO3).
    • ↑ NaHCO3 → ↑ distal delivery of Na+ to principal cells of collecting duct
    • ↑ Na+ reabsorption by ENaC channel→ ↑ K+ secretion via ROMK channel

Treatment involves a combination approach:

  • Stop any offending drug/medication, if possible.
  • Treat underlying condition, if possible.
  • Bicarbonate supplementation: 
    • Oral bicarbonate
    • Hydrochlorothiazide can be used to improve the pill burden: 
      • Diuretic → mild volume contraction → stimulates proximal tubule reabsorption of Na+ and HCO3 
      • Side effect is worsening hypokalemia Hypokalemia Hypokalemia is defined as plasma potassium (K+) concentration < 3.5 mEq/L. Homeostatic mechanisms maintain plasma concentration between 3.5-5.2 mEq/L despite marked variation in dietary intake. Hypokalemia can be due to renal losses, GI losses, transcellular shifts, or poor dietary intake. Hypokalemia
  • Potassium supplementation:
    • Much more of an issue than with distal RTA (type 1)
      • Exacerbated by bicarbonaturia
      • Exacerbated by thiazide use
    • Usually requires more K+ than is included in bicarbonate supplements
    • K+-sparing diuretics can be used to ↓ K+ supplementation need
  • Additional supplementation may be needed for Fanconi syndrome:
    • Phosphorus
    • Vitamin D
  • Frequent labs to monitor serum HCO3, K+, and phosphate

Hyperkalemic renal tubular acidosis (type 4)

Treatment for hyperkalemic RTA differs significantly from that for the other forms of RTA, primarily in that oral bicarbonate therapy is not the 1st-line treatment.

  • Fludrocortisone: 
    • Oral aldosterone analog
    • Side effect of Na+ retention can limit utility
      • Worsens hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension
      • Can lead to volume overload (peripheral and pulmonary edema Pulmonary edema Pulmonary edema is a condition caused by excess fluid within the lung parenchyma and alveoli as a consequence of a disease process. Based on etiology, pulmonary edema is classified as cardiogenic or noncardiogenic. Patients may present with progressive dyspnea, orthopnea, cough, or respiratory failure. Pulmonary Edema)
  • Low-K+ diet
  • Loop or thiazide diuretics Thiazide diuretics Thiazide and thiazide-like diuretics make up a group of highly important antihypertensive agents, with some drugs being 1st-line agents. The class includes hydrochlorothiazide, chlorothiazide, chlorthalidone, indapamide, and metolazone. Thiazide Diuretics (particularly if unable to use fludrocortisone)
  • Oral bicarbonate therapy is not usually used.

Differential Diagnosis

  • Multiple myeloma Multiple myeloma Multiple myeloma (MM) is a malignant condition of plasma cells (activated B lymphocytes) primarily seen in the elderly. Monoclonal proliferation of plasma cells results in cytokine-driven osteoclastic activity and excessive secretion of IgG antibodies. Multiple Myeloma: malignant plasma cell dyscrasia that leads to toxic levels of serum paraprotein. Presentation is with the CRAB syndrome, which includes hyperCalcemia, Renal failure, Anemia, and Bone lesions/ pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain. Proximal RTA (type 2) may also be present. Diagnosis is made with serum protein electrophoresis (SPEP) with immunofixation (IFE), which identifies the abnormal paraprotein (known as the M-spike on the SPEP). Additional testing includes urine protein electrophoresis (UPEP) and the serum free light chain ratio. Treatment involves chemotherapy and hematopoietic stem cell transplantation.
  • Pseudohypoaldosteronism type 1: rare disorder that presents in the neonatal period as hyponatremia Hyponatremia Hyponatremia is defined as a decreased serum sodium (sNa+) concentration less than 135 mmol/L. Serum sodium is the greatest contributor to plasma osmolality, which is very tightly controlled via antidiuretic hormone (ADH) release from the hypothalamus and by the thirst mechanism. Hyponatremia, hyperkalemia, and metabolic acidosis Metabolic acidosis The renal system is responsible for eliminating the daily load of non-volatile acids, which is approximately 70 millimoles per day. Metabolic acidosis occurs when there is an increase in the levels of new non-volatile acids (e.g., lactic acid), renal loss of HCO3-, or ingestion of toxic alcohols. Metabolic Acidosis (type 4 hyperkalemic RTA). Pseudohypoaldosteronism type 1 can be diagnosed by an elevated plasma renin activity and an elevated aldosterone level. Management includes sodium supplementation and aggressive fluid and electrolyte management.
  • Cystinosis: Autosomal recessive lysosomal storage disease Lysosomal storage disease Lysosomal storage diseases are a group of metabolic disorders caused by genetic mutations in the enzymes responsible for normal lysosomal function. The dysfunction of enzymatic processes causes an accumulation of undigested metabolites, resulting in cellular death. The main groups include sphingolipidoses, oligosaccharidoses, and mucolipidoses. Overview of Lysosomal Storage Diseases is the most common hereditary cause of Fanconi syndrome in children and is caused by a mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in a gene encoding for the carrier protein cystinosin. Intralysosomal cystine accumulates throughout the body, including in the proximal tubule cells, during the 1st year of life (resulting in type 2 proximal RTA and Fanconi syndrome). Progressive kidney damage (including to the glomerulus) occurs, and end-stage renal disease occurs during childhood. Treatment includes the cystine-depleting agent cysteamine and renal replacement therapy (including renal transplantation).
  • Sjögren syndrome: autoimmune disease in which glandular tissues, such as the salivary and lacrimal glands, are infiltrated by lymphocytes Lymphocytes Lymphocytes are heterogeneous WBCs involved in immune response. Lymphocytes develop from the bone marrow, starting from hematopoietic stem cells (HSCs) and progressing to common lymphoid progenitors (CLPs). B and T lymphocytes and natural killer (NK) cells arise from the lineage. Lymphocytes, causing symptoms such as dry eyes and dry mouth. There are a wide range of extraglandular manifestations of Sjögren syndrome, including distal RTA (type 1), Raynaud phenomenon, neuropathy, and cutaneous vasculitis. Diagnosis is validated by the clinical examination, serologic studies, and salivary gland biopsy.  A multidisciplinary approach is needed to treat affected individuals and to target symptom relief.
  • Systemic lupus erythematosus Systemic lupus erythematosus Systemic lupus erythematosus (SLE) is a chronic autoimmune, inflammatory condition that causes immune-complex deposition in organs, resulting in systemic manifestations. Women, particularly those of African American descent, are more commonly affected. Systemic Lupus Erythematosus ( SLE SLE Systemic lupus erythematosus (SLE) is a chronic autoimmune, inflammatory condition that causes immune-complex deposition in organs, resulting in systemic manifestations. Women, particularly those of African American descent, are more commonly affected. Systemic Lupus Erythematosus): chronic autoimmune disease that causes immune complex deposition in organs, resulting in a wide range of possible systemic manifestations. Notable possible clinical features include malar rash, nondestructive arthritis, lupus nephritis, serositis, cytopenias, thromboembolic disease, seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures, and/or psychosis. Hyperkalemic RTA (type 4), may also be present. The diagnosis is made by meeting clinical criteria, which includes antinuclear antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins, SLE SLE Systemic lupus erythematosus (SLE) is a chronic autoimmune, inflammatory condition that causes immune-complex deposition in organs, resulting in systemic manifestations. Women, particularly those of African American descent, are more commonly affected. Systemic Lupus Erythematosus-specific antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins, and specific clinical findings. Treatment options include hydroxychloroquine and immunosuppressive medications (e.g., prednisone, methotrexate, mycophenolate mofetil).  
  • Tyrosinemia: autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritancegenetic disorder caused by a defect in the breakdown of the amino acid Amino acid Amino acids (AAs) are composed of a central carbon atom attached to a carboxyl group, an amino group, a hydrogen atom, and a side chain (R group). Basics of Amino Acids tyrosine, resulting in failure to thrive Failure to Thrive Failure to thrive (FTT), or faltering growth, describes suboptimal weight gain and growth in children. The majority of cases are due to inadequate caloric intake; however, genetic, infectious, and oncological etiologies are also common. Failure to Thrive during the 1st month of life. Other clinical manifestations include proximal RTA (type 2), Fanconi syndrome,  bloody stools, a cabbage-like odor, jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice, hepatomegaly, and vomiting. Without treatment, cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic parenchymal necrosis and scarring (fibrosis) most commonly due to hepatitis C infection and alcoholic liver disease. Patients may present with jaundice, ascites, and hepatosplenomegaly. Cirrhosis can also cause complications such as hepatic encephalopathy, portal hypertension, portal vein thrombosis, and hepatorenal syndrome. Cirrhosis and hepatocellular carcinoma Hepatocellular carcinoma Hepatocellular carcinoma (HCC) typically arises in a chronically diseased or cirrhotic liver and is the most common primary liver cancer. Diagnosis may include ultrasound, CT, MRI, biopsy (if inconclusive imaging), and/or biomarkers. Hepatocellular Carcinoma (HCC) and Liver Metastases will develop. Treatment includes nitisinone and a low-tyrosine (i.e., low-protein) diet.
  • Wilson disease: also known as hepatolenticular degeneration. Wilson disease is an autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritancedisorder associated with mutations in the ATP7B gene, which result in copper accumulation in the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver, brain, and cornea. Presentation is with hepatic, neurologic, and psychiatric symptoms. Distal RTA (type 1), may also be present. Diagnosis is established by detection of corneal deposits of copper (Kayser-Fleischer rings), low plasma ceruloplasmin, and/or elevated levels of copper in the urine. Management is with the use of copper-chelating agents such as penicillamine.

References

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