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Renal Tubular Acidosis

Renal tubular acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis (RTA) is an imbalance in physiologic pH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance caused by the kidney’s inability to acidify urine Urine Liquid by-product of excretion produced in the kidneys, temporarily stored in the bladder until discharge through the urethra. Bowen Disease and Erythroplasia of Queyrat to maintain blood pH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance at physiologic levels. Renal tubular acidoses exist in multiple types, including distal RTA ( type 1 Type 1 Spinal Muscular Atrophy), proximal RTA ( type 2 Type 2 Spinal Muscular Atrophy), and hyperkalemic RTA ( type 4 Type 4 Spinal Muscular Atrophy). 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 Urine Liquid by-product of excretion produced in the kidneys, temporarily stored in the bladder until discharge through the urethra. Bowen Disease and Erythroplasia of Queyrat 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. Bones: Structure and Types and muscles, as well as addressing any underlying causes leading to the RTA.

Last updated: 21 Jan, 2022

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Overview

Definition

Renal tubular acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis (RTA) is an imbalance in physiologic pH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance caused by the kidney’s inability to acidify urine Urine Liquid by-product of excretion produced in the kidneys, temporarily stored in the bladder until discharge through the urethra. Bowen Disease and Erythroplasia of Queyrat to maintain blood pH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance at physiologic levels.

Classification

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

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

Table: Type 1 Type 1 Spinal Muscular Atrophy RTA (distal)—impaired acid secretion Secretion Coagulation Studies
Characteristics Impaired H+ secretion Secretion Coagulation Studies by the distal segments
  • Urine > pH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance 5.3
  • Plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products 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
Table: Type 2 Type 2 Spinal Muscular Atrophy RTA (proximal)—impaired bicarbonate Bicarbonate Inorganic salts that contain the -HCO3 radical. They are an important factor in determining the ph of the blood and the concentration of bicarbonate ions is regulated by the kidney. Levels in the blood are an index of the alkali reserve or buffering capacity. Electrolytes secretion Secretion Coagulation Studies
Characteristics Impaired proximal HCO3 reabsorption
  • Urine pH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance 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 Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products HCO3 12–20 mM MM 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/L
Renal defect Nonspecific tubule dysfunction or mutations in genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure involved in HCO3 reabsorption
Etiology
  • Familial
  • Fanconi syndrome
  • Drugs, toxins
  • Carbonic anhydrase Carbonic anhydrase A family of zinc-containing enzymes that catalyze the reversible hydration of carbon dioxide. They play an important role in the transport of carbon dioxide from the tissues to the lung. Carbonic Anhydrase Inhibitors inhibitors
Table: Type 4 Type 4 Spinal Muscular Atrophy 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 Secretion Coagulation Studies
Characteristics Impaired aldosterone Aldosterone A hormone secreted by the adrenal cortex that regulates electrolyte and water balance by increasing the renal retention of sodium and the excretion of potassium. Hyperkalemia release Release Release of a virus from the host cell following virus assembly and maturation. Egress can occur by host cell lysis, exocytosis, or budding through the plasma membrane. Virology or response
  • Urine pH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance < 5.3
  • Plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products HCO3 > 17 mM MM 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/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 Congenital Chorioretinitis 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 Aldosterone resistance A heterogeneous group of disorders characterized by renal electrolyte transport dysfunctions. Congenital forms are rare autosomal disorders characterized by neonatal hypertension, hyperkalemia, increased renin activity and aldosterone concentration. The type I features hyperkalemia with sodium wasting; type II, hyperkalemia without sodium wasting. Pseudohypoaldosteronism can be the result of a defective renal electrolyte transport protein or acquired after kidney transplantation. Hypoaldosteronism
  • Diabetic nephropathy Diabetic nephropathy Kidney injuries associated with diabetes mellitus and affecting kidney glomerulus; arterioles; kidney tubules; and the interstitium. Clinical signs include persistent proteinuria, from microalbuminuria progressing to albuminuria of greater than 300 mg/24 h, leading to reduced glomerular filtration rate and end-stage renal disease. Chronic Diabetic Complications
  • Drugs
  • Diuretics Diuretics Agents that promote the excretion of urine through their effects on kidney function. Heart Failure and Angina Medication

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 Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency
    • Antiviral Antiviral Antivirals for Hepatitis B medication
    • Transplant medications (20% incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency of hyperkalemic RTA in renal transplants)

Etiology

Distal renal tubular acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis (type 1)

In adults, the most common causes are:

  • Autoimmune disease:
  • Hypercalciuria Hypercalciuria Excretion of abnormally high level of calcium in the urine, greater than 4 mg/kg/day. Nephrolithiasis:
    • Vitamin D Vitamin D A vitamin that includes both cholecalciferols and ergocalciferols, which have the common effect of preventing or curing rickets in animals. It can also be viewed as a hormone since it can be formed in skin by action of ultraviolet rays upon the precursors, 7-dehydrocholesterol and ergosterol, and acts on vitamin D receptors to regulate calcium in opposition to parathyroid hormone. Fat-soluble Vitamins and their Deficiencies 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 Idiopathic Dermatomyositis (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 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 Inheritance
  • 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 Congenital Chorioretinitis obstruction of the urinary tract

Other causes: 

Nephrocalcinosis

Nephrocalcinosis Nephrocalcinosis A condition characterized by calcification of the renal tissue itself. It is usually seen in distal renal tubular acidosis with calcium deposition in the distal kidney tubules and the surrounding interstitium. Nephrocalcinosis causes renal insufficiency. X-linked Hypophosphatemic Rickets:
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: Anatomy 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 Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis.

Image: “ Nephrocalcinosis Nephrocalcinosis A condition characterized by calcification of the renal tissue itself. It is usually seen in distal renal tubular acidosis with calcium deposition in the distal kidney tubules and the surrounding interstitium. Nephrocalcinosis causes renal insufficiency. X-linked Hypophosphatemic Rickets” by FastilyClone. License: Public Domain

Proximal renal tubular acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis (type 2)

In adults, the most common cause is monoclonal gammopathy Monoclonal gammopathy Conditions characterized by the presence of m protein (monoclonal protein) in serum or urine without clinical manifestations of plasma cell dyscrasia. MALT Lymphoma:

  • 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: 

Other causes:

  • Autoimmune causes (especially Sjögren syndrome Sjögren Syndrome Rheumatoid Arthritis)
  • 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 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 Inheritance 
    • Apical Na+–H+ antiporter Antiporter Membrane transporters that co-transport two or more dissimilar molecules in the opposite direction across a membrane. Usually the transport of one ion or molecule is against its electrochemical gradient and is ‘powered’ by the movement of another ion or molecule with its electrochemical gradient. The Cell: Cell Membrane of the proximal tubular cells
    • Basolateral Na+–HCO3 cotransporter of proximal tubular cells 
    • Carbonic anhydrase Carbonic anhydrase A family of zinc-containing enzymes that catalyze the reversible hydration of carbon dioxide. They play an important role in the transport of carbon dioxide from the tissues to the lung. Carbonic Anhydrase Inhibitors type 2 deficiency
  • Drugs:
    • Heavy metals (lead, mercury)
    • Carbonic anhydrase Carbonic anhydrase A family of zinc-containing enzymes that catalyze the reversible hydration of carbon dioxide. They play an important role in the transport of carbon dioxide from the tissues to the lung. Carbonic Anhydrase Inhibitors inhibitors (such as acetazolamide Acetazolamide One of the carbonic anhydrase inhibitors that is sometimes effective against absence seizures. It is sometimes useful also as an adjunct in the treatment of tonic-clonic, myoclonic, and atonic seizures, particularly in women whose seizures occur or are exacerbated at specific times in the menstrual cycle. However, its usefulness is transient often because of rapid development of tolerance. Its antiepileptic effect may be due to its inhibitory effect on brain carbonic anhydrase, which leads to an increased transneuronal chloride gradient, increased chloride current, and increased inhibition. Carbonic Anhydrase Inhibitors, topiramate Topiramate A sulfamate-substituted fructose analog that was originally identified as a hypoglycemic agent. It is used for the treatment of epilepsy and migraine disorders, and may also promote weight loss. Second-Generation Anticonvulsant Drugs)
    • 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 Tenofovir An adenine analog reverse transcriptase inhibitor with antiviral activity against HIV-1 and hepatitis b. It is used to treat HIV infections and chronic hepatitis b, in combination with other antiviral agents, due to the emergence of antiviral drug resistance when it is used alone. Anti-HIV Drugs)
    • Ifosfamide Ifosfamide Positional isomer of cyclophosphamide which is active as an alkylating agent and an immunosuppressive agent. Alkylating Agents and Platinum 
    • Cisplatin Cisplatin An inorganic and water-soluble platinum complex. After undergoing hydrolysis, it reacts with DNA to produce both intra and interstrand crosslinks. These cross links appear to impair replication and transcription of DNA. The cytotoxicity of cisplatin correlates with cellular arrest in the g2 phase of the cell cycle. Alkylating Agents and Platinum, oxaliplatin Oxaliplatin An organoplatinum complex in which the platinum atom is complexed with 1, 2-diaminocyclohexane, and with an oxalate ligand which is displaced to yield active oxaliplatin derivatives. These derivatives form inter- and intra-strand DNA crosslinks that inhibit DNA replication and transcription. Oxaliplatin is an antineoplastic agent that is often administered with fluorouracil and folinic acid in the treatment of metastatic colorectal neoplasms. Alkylating Agents and Platinum
    • Valproic acid Valproic acid A fatty acid with anticonvulsant and anti-manic properties that is used in the treatment of epilepsy and bipolar disorder. The mechanisms of its therapeutic actions are not well understood. It may act by increasing gamma-aminobutyric acid levels in the brain or by altering the properties of voltage-gated sodium channels. First-Generation Anticonvulsant Drugs
  • Miscellaneous: 
    • Interstitial nephritis
    • Vitamin D deficiency Vitamin D Deficiency A nutritional condition produced by a deficiency of vitamin D in the diet, insufficient production of vitamin D in the skin, inadequate absorption of vitamin D from the diet, or abnormal conversion of vitamin D to its bioactive metabolites. It is manifested clinically as rickets in children and osteomalacia in adults. Fat-soluble Vitamins and their Deficiencies
    • Secondary hyperparathyroidism Secondary hyperparathyroidism Abnormally elevated parathyroid hormone secretion as a response to hypocalcemia. It is caused by chronic kidney failure or other abnormalities in the controls of bone and mineral metabolism, leading to various bone diseases, such as renal osteodystrophy. 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 Hereditary fructose intolerance An autosomal recessive fructose metabolism disorder due to deficient fructose-1-phosphate aldolase activity, resulting in accumulation of fructose-1-phosphate. The accumulated fructose-1-phosphate inhibits glycogenolysis and gluconeogenesis, causing severe hypoglycemia following ingestion of fructose. Prolonged fructose ingestion in infants leads ultimately to hepatic failure and death. Patients develop a strong distaste for sweet food, and avoid a chronic course of the disease by remaining on a fructose- and sucrose-free diet. Disorders of Fructose Metabolism
      • von Gierke disease ( glycogen storage disease Glycogen storage disease A group of inherited metabolic disorders involving the enzymes responsible for the synthesis and degradation of glycogen. In some patients, prominent liver involvement is presented. In others, more generalized storage of glycogen occurs, sometimes with prominent cardiac involvement. Benign Liver Tumors 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 Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis (type 4)

In adults, the most common causes are:

  • Diabetic nephropathy Diabetic nephropathy Kidney injuries associated with diabetes mellitus and affecting kidney glomerulus; arterioles; kidney tubules; and the interstitium. Clinical signs include persistent proteinuria, from microalbuminuria progressing to albuminuria of greater than 300 mg/24 h, leading to reduced glomerular filtration rate and end-stage renal disease. Chronic Diabetic Complications
  • 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 21-hydroxylase deficiency Congenital Adrenal Hyperplasia
    • Pseudohypoaldosteronism Pseudohypoaldosteronism A heterogeneous group of disorders characterized by renal electrolyte transport dysfunctions. Congenital forms are rare autosomal disorders characterized by neonatal hypertension, hyperkalemia, increased renin activity and aldosterone concentration. The type I features hyperkalemia with sodium wasting; type II, hyperkalemia without sodium wasting. Pseudohypoaldosteronism can be the result of a defective renal electrolyte transport protein or acquired after kidney transplantation. Hypoaldosteronism
  • Autoimmune (particularly lupus)
  • Drugs:
    • Potassium Potassium An element in the alkali group of metals with an atomic symbol k, atomic number 19, and atomic weight 39. 10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte that plays a significant role in the regulation of fluid volume and maintenance of the water-electrolyte balance. Hyperkalemia-sparing diuretics
    • NSAIDs NSAIDS Primary vs Secondary Headaches
    • Calcineurin Calcineurin A calcium and calmodulin-dependent serine/threonine protein phosphatase that is composed of the calcineurin a catalytic subunit and the calcineurin B regulatory subunit. Calcineurin has been shown to dephosphorylate a number of phosphoproteins including histones; myosin light chain; and the regulatory subunits of camp-dependent protein kinases. It is involved in the regulation of signal transduction and is the target of an important class of immunophilin-immunosuppressive drug complexes. Vitiligo inhibitors ( cyclosporine Cyclosporine A cyclic undecapeptide from an extract of soil fungi. It is a powerful immunosupressant with a specific action on T-lymphocytes. It is used for the prophylaxis of graft rejection in organ and tissue transplantation. Immunosuppressants, tacrolimus Tacrolimus A macrolide isolated from the culture broth of a strain of streptomyces tsukubaensis that has strong immunosuppressive activity in vivo and prevents the activation of T-lymphocytes in response to antigenic or mitogenic stimulation in vitro. Immunosuppressants)
    • Angiotensin-converting–enzyme inhibitors ( ACEis ACEIs A class of drugs whose main indications are the treatment of hypertension and heart failure. They exert their hemodynamic effect mainly by inhibiting the renin-angiotensin system. They also modulate sympathetic nervous system activity and increase prostaglandin synthesis. They cause mainly vasodilation and mild natriuresis without affecting heart rate and contractility. Heart Failure and Angina Medication)
    • Angiotensin- receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors blockers ( ARBs ARBs Agents that antagonize angiotensin receptors. Many drugs in this class specifically target the angiotensin type 1 receptor. Heart Failure and Angina Medication)
    • 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 Primary adrenal insufficiency An adrenal disease characterized by the progressive destruction of the adrenal cortex, resulting in insufficient production of aldosterone and hydrocortisone. Clinical symptoms include anorexia; nausea; weight loss; muscle weakness; and hyperpigmentation of the skin due to increase in circulating levels of acth precursor hormone which stimulates melanocytes. Adrenal Insufficiency and Addison’s Disease
    • Critical illness

Pathophysiology

Distal renal tubular acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis (type 1)

The pathophysiology of distal RTA (type 1) is impaired acid secretion Secretion Coagulation Studies at the collecting duct Collecting duct Straight tubes commencing in the radiate part of the kidney cortex where they receive the curved ends of the distal convoluted tubules. In the medulla the collecting tubules of each pyramid converge to join a central tube (duct of bellini) which opens on the summit of the papilla. Renal Cell Carcinoma of the distal tubule.

Normal process of urinary acidification:

  • Intercalated cells Intercalated cells Tubular System participate in acid excretion:
    • Located at the collecting duct Collecting duct Straight tubes commencing in the radiate part of the kidney cortex where they receive the curved ends of the distal convoluted tubules. In the medulla the collecting tubules of each pyramid converge to join a central tube (duct of bellini) which opens on the summit of the papilla. Renal Cell Carcinoma of the distal tubule
    • α-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 
    • β-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

Abnormal processes leading to distal RTA:

  • ↓ Activity of apical H+/K+–ATPase (↓ H+ secretion Secretion Coagulation Studies into tubular lumen)
  • ↑ Permeability of the collecting duct Collecting duct Straight tubes commencing in the radiate part of the kidney cortex where they receive the curved ends of the distal convoluted tubules. In the medulla the collecting tubules of each pyramid converge to join a central tube (duct of bellini) which opens on the summit of the papilla. Renal Cell Carcinoma to H+:
    • Collecting duct is normally impermeable to H+:
      • Prevents backflow of recently secreted H+
      • Allows for excretion of urine Urine Liquid by-product of excretion produced in the kidneys, temporarily stored in the bladder until discharge through the urethra. Bowen Disease and Erythroplasia of Queyrat that is more acidic than plasma
    • Example: amphotericin toxicity Toxicity Dosage Calculation
  • ↓ Na+ reabsorption
  • Altered activity of the Cl/HCO3 exchanger:
    • ↑ Activity of apical Cl/HCO3 exchanger 
      • ↑ HCO3 secretion Secretion Coagulation Studies → 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 β-intercalated cells
    • ↓ Activity of basolateral Cl/HCO3 exchanger: 

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 Nephron The functional units of the kidney, consisting of the glomerulus and the attached tubule. Kidneys: Anatomy → no downstream processes to compensate
  • 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
  • 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 Intercalated cells Tubular System in distal RTA (type I)

Image by Lecturio.

Proximal renal tubular acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis (type 2)

The pathophysiology of proximal RTA (type II) is impaired bicarbonate reabsorption Bicarbonate reabsorption Acid-Base Balance at the proximal tubule Proximal tubule The renal tubule portion that extends from the bowman capsule in the kidney cortex into the kidney medulla. The proximal tubule consists of a convoluted proximal segment in the cortex, and a distal straight segment descending into the medulla where it forms the u-shaped loop of henle. Tubular System.

Normal process of proximal tubule Proximal tubule The renal tubule portion that extends from the bowman capsule in the kidney cortex into the kidney medulla. The proximal tubule consists of a convoluted proximal segment in the cortex, and a distal straight segment descending into the medulla where it forms the u-shaped loop of henle. Tubular System HCO3 reabsorption:

  • Under normal circumstances, 80% of filtered HCO3 is reabsorbed in the proximal tubule Proximal tubule The renal tubule portion that extends from the bowman capsule in the kidney cortex into the kidney medulla. The proximal tubule consists of a convoluted proximal segment in the cortex, and a distal straight segment descending into the medulla where it forms the u-shaped loop of henle. Tubular System.
  • Requires a complex mechanism because HCO3 is not freely permeable (due to charge):
    • Sodium–hydrogen ion exchanger 3 ( NHE3 NHE3 A sodium-hydrogen antiporter expressed primarily by epithelial cells in the kidneys, it localizes to the apical membrane of the proximal kidney tubule, where it functions in sodium and water reabsorption and possibly calcium homeostasis. It also is expressed in heart, brain, and lung tissues and is resistant to amiloride inhibition. Carbonic Anhydrase Inhibitors) 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 NHE3 A sodium-hydrogen antiporter expressed primarily by epithelial cells in the kidneys, it localizes to the apical membrane of the proximal kidney tubule, where it functions in sodium and water reabsorption and possibly calcium homeostasis. It also is expressed in heart, brain, and lung tissues and is resistant to amiloride inhibition. Carbonic Anhydrase Inhibitors
      • 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 Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory 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 Light chains Polypeptide chains, consisting of 211 to 217 amino acid residues and having a molecular weight of approximately 22 kda. There are two major types of light chains, kappa and lambda. Two ig light chains and two ig heavy chains (immunoglobulin heavy chains) make one immunoglobulin molecule. Immunoglobulins: Types and Functions are directly toxic to the proximal tubule Proximal tubule The renal tubule portion that extends from the bowman capsule in the kidney cortex into the kidney medulla. The proximal tubule consists of a convoluted proximal segment in the cortex, and a distal straight segment descending into the medulla where it forms the u-shaped loop of henle. Tubular System cells  
  • Drugs causing toxicity Toxicity Dosage Calculation to the proximal tubule Proximal tubule The renal tubule portion that extends from the bowman capsule in the kidney cortex into the kidney medulla. The proximal tubule consists of a convoluted proximal segment in the cortex, and a distal straight segment descending into the medulla where it forms the u-shaped loop of henle. Tubular System cells via multiple mechanisms
  • Mutations in:
    • Apical NHE3 NHE3 A sodium-hydrogen antiporter expressed primarily by epithelial cells in the kidneys, it localizes to the apical membrane of the proximal kidney tubule, where it functions in sodium and water reabsorption and possibly calcium homeostasis. It also is expressed in heart, brain, and lung tissues and is resistant to amiloride inhibition. Carbonic Anhydrase Inhibitors
    • Basolateral Na+–HCO3 cotransporter 
    • Carbonic anhydrase Carbonic anhydrase A family of zinc-containing enzymes that catalyze the reversible hydration of carbon dioxide. They play an important role in the transport of carbon dioxide from the tissues to the lung. Carbonic Anhydrase Inhibitors 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 Proximal tubule The renal tubule portion that extends from the bowman capsule in the kidney cortex into the kidney medulla. The proximal tubule consists of a convoluted proximal segment in the cortex, and a distal straight segment descending into the medulla where it forms the u-shaped loop of henle. Tubular System HCO3 reabsorption capacity is maintained:
      • Threshold Threshold Minimum voltage necessary to generate an action potential (an all-or-none response) Skeletal Muscle Contraction for proximal tubule Proximal tubule The renal tubule portion that extends from the bowman capsule in the kidney cortex into the kidney medulla. The proximal tubule consists of a convoluted proximal segment in the cortex, and a distal straight segment descending into the medulla where it forms the u-shaped loop of henle. Tubular System HCO3 reabsorption lowered
      • Serum HCO3↓ until it matches the new threshold ( steady state Steady state Enzyme Kinetics)
      • Distal acidification is maintained → daily acid load is managed without worsening acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis
  • 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
  • Fanconi syndrome
Bicarbonate reabsorption in proximal tubule

Bicarbonate reabsorption in the proximal tubule Proximal tubule The renal tubule portion that extends from the bowman capsule in the kidney cortex into the kidney medulla. The proximal tubule consists of a convoluted proximal segment in the cortex, and a distal straight segment descending into the medulla where it forms the u-shaped loop of henle. Tubular System

CA CA Condylomata acuminata are a clinical manifestation of genital HPV infection. Condylomata acuminata are described as raised, pearly, flesh-colored, papular, cauliflower-like lesions seen in the anogenital region that may cause itching, pain, or bleeding. Condylomata Acuminata (Genital Warts)-IV: carbonic anhydrase IV
CA CA Condylomata acuminata are a clinical manifestation of genital HPV infection. Condylomata acuminata are described as raised, pearly, flesh-colored, papular, cauliflower-like lesions seen in the anogenital region that may cause itching, pain, or bleeding. Condylomata Acuminata (Genital Warts)-II: carbonic anhydrase II

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Hyperkalemic renal tubular acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory 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 Aldosterone A hormone secreted by the adrenal cortex that regulates electrolyte and water balance by increasing the renal retention of sodium and the excretion of potassium. Hyperkalemia:
  • 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 Proximal tubule The renal tubule portion that extends from the bowman capsule in the kidney cortex into the kidney medulla. The proximal tubule consists of a convoluted proximal segment in the cortex, and a distal straight segment descending into the medulla where it forms the u-shaped loop of henle. Tubular System
    • ↓ Urinary ammonium → ↓ acid excretion
  • All other etiologies also involve some disturbance in the RAAS RAAS A blood pressure regulating system of interacting components that include renin; angiotensinogen; angiotensin converting enzyme; angiotensin i; angiotensin ii; and angiotensinase. Renin, an enzyme produced in the kidney, acts on angiotensinogen, an alpha-2 globulin produced by the liver, forming angiotensin I. Angiotensin-converting enzyme, contained in the lung, acts on angiotensin I in the plasma converting it to angiotensin II, an extremely powerful vasoconstrictor. Angiotensin II causes contraction of the arteriolar and renal vascular smooth muscle, leading to retention of salt and water in the kidney and increased arterial blood pressure. In addition, angiotensin II stimulates the release of aldosterone from the adrenal cortex, which in turn also increases salt and water retention in the kidney. Angiotensin-converting enzyme also breaks down bradykinin, a powerful vasodilator and component of the kallikrein-kinin system. Adrenal Hormones → ↓ aldosterone Aldosterone A hormone secreted by the adrenal cortex that regulates electrolyte and water balance by increasing the renal retention of sodium and the excretion of potassium. Hyperkalemia state, which could be absolute or relative (i.e., aldosterone Aldosterone A hormone secreted by the adrenal cortex that regulates electrolyte and water balance by increasing the renal retention of sodium and the excretion of potassium. Hyperkalemia resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing).

Clinical Presentation

Renal tubular acidoses often do not have a specific clinical presentation Presentation The position or orientation of the fetus at near term or during obstetric labor, determined by its relation to the spine of the mother and the birth canal. The normal position is a vertical, cephalic presentation with the fetal vertex flexed on the neck. Normal and Abnormal Labor 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 Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis itself.

Distal renal tubular acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory 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 Sjögren Syndrome Rheumatoid Arthritis 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: 
Open bite in rta

Dental presentation Presentation The position or orientation of the fetus at near term or during obstetric labor, determined by its relation to the spine of the mother and the birth canal. The normal position is a vertical, cephalic presentation with the fetal vertex flexed on the neck. Normal and Abnormal Labor of rickets Rickets Disorders caused by interruption of bone mineralization manifesting as osteomalacia in adults and characteristic deformities in infancy and childhood due to disturbances in normal bone formation. The mineralization process may be interrupted by disruption of vitamin d; phosphorus; or calcium homeostasis, resulting from dietary deficiencies, or acquired, or inherited metabolic, or hormonal disturbances. Osteomalacia and Rickets seen in distal renal tubular acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis:
Rickets can be seen in individuals with distal renal tubular acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis, as it involves calcium Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Electrolytes wasting in the urine Urine Liquid by-product of excretion produced in the kidneys, temporarily stored in the bladder until discharge through the urethra. Bowen Disease and Erythroplasia of Queyrat.

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 Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis (type 2)

  • Usually occurs as a part of Fanconi syndrome, rather than isolated RTA:
    • Fanconi syndrome refers to broad proximal tubule Proximal tubule The renal tubule portion that extends from the bowman capsule in the kidney cortex into the kidney medulla. The proximal tubule consists of a convoluted proximal segment in the cortex, and a distal straight segment descending into the medulla where it forms the u-shaped loop of henle. Tubular System dysfunction
    • Abnormal reabsorption of phosphorus, uric acid Uric acid An oxidation product, via xanthine oxidase, of oxypurines such as xanthine and hypoxanthine. It is the final oxidation product of purine catabolism in humans and primates, whereas in most other mammals urate oxidase further oxidizes it to allantoin. Nephrolithiasis, amino acids Amino acids Organic compounds that generally contain an amino (-NH2) and a carboxyl (-COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. Basics of Amino Acids, and glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance 
    • 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 Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis (type 4)

  • In adults, this is usually an incidental lab finding related to:
    • Diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus
    • 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 NSAIDS Primary vs Secondary Headaches, K-sparing diuretics, ACEis ACEIs A class of drugs whose main indications are the treatment of hypertension and heart failure. They exert their hemodynamic effect mainly by inhibiting the renin-angiotensin system. They also modulate sympathetic nervous system activity and increase prostaglandin synthesis. They cause mainly vasodilation and mild natriuresis without affecting heart rate and contractility. Heart Failure and Angina Medication, ARBs ARBs Agents that antagonize angiotensin receptors. Many drugs in this class specifically target the angiotensin type 1 receptor. Heart Failure and Angina Medication, heparin, trimethoprim)
  • In children, this is usually due to a rare genetic disease: 
    • Pseudohypoaldosteronism Pseudohypoaldosteronism A heterogeneous group of disorders characterized by renal electrolyte transport dysfunctions. Congenital forms are rare autosomal disorders characterized by neonatal hypertension, hyperkalemia, increased renin activity and aldosterone concentration. The type I features hyperkalemia with sodium wasting; type II, hyperkalemia without sodium wasting. Pseudohypoaldosteronism can be the result of a defective renal electrolyte transport protein or acquired after kidney transplantation. Hypoaldosteronism type 2 (Gordon syndrome)
    • Congenital Congenital Chorioretinitis 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 Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory 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 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
  • Dilutional acidosis Dilutional acidosis Metabolic Acidosis (i.e., excessive IV normal saline Normal saline A crystalloid solution that contains 9. 0g of sodium chloride per liter of water. It has a variety of uses, including: as a contact lens solution, in ophthalmic solutions and nasal lavage, in wound irrigation, and for fluid therapy. Intravenous Fluids)
  • 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 Fistula Abnormal communication most commonly seen between two internal organs, or between an internal organ and the surface of the body. Anal Fistula)
  • Toluene toxicity Toxicity Dosage Calculation (glue “huffing”)

Step 2

Check the urine Urine Liquid by-product of excretion produced in the kidneys, temporarily stored in the bladder until discharge through the urethra. Bowen Disease and Erythroplasia of Queyrat osmolal gap Osmolal gap Metabolic Acidosis (UOG) and/or urine Urine Liquid by-product of excretion produced in the kidneys, temporarily stored in the bladder until discharge through the urethra. Bowen Disease and Erythroplasia of Queyrat anion gap Anion gap Metabolic Acidosis (UAG).

  • Differentiates RTA from other cause of NAGMA, since the formulas approximate urine Urine Liquid by-product of excretion produced in the kidneys, temporarily stored in the bladder until discharge through the urethra. Bowen Disease and Erythroplasia of Queyrat ammonium excretion:
    • Renal tubular acidoses generally do not have increased ammonium excretion.
    • Other causes of NAGMA up-regulate ammonium excretion. 
  • Urine osmolal gap Osmolal gap Metabolic Acidosis is more useful than urine Urine Liquid by-product of excretion produced in the kidneys, temporarily stored in the bladder until discharge through the urethra. Bowen Disease and Erythroplasia of Queyrat anion gap Anion gap Metabolic Acidosis:
    • Urine anion gap Anion gap Metabolic Acidosis is inaccurate in many common clinical situations:
      • Hypovolemia Hypovolemia Sepsis in Children
      • Unmeasured urinary anions Anions Negatively charged atoms, radicals or groups of atoms which travel to the anode or positive pole during electrolysis. Electrolytes (i.e., ketoacidosis Ketoacidosis A life-threatening complication of diabetes mellitus, primarily of type 1 diabetes mellitus with severe insulin deficiency and extreme hyperglycemia. It is characterized by ketosis; dehydration; and depressed consciousness leading to coma. Metabolic Acidosis)
      • Renal dysfunction
    • Urine osmolal gap Osmolal gap Metabolic Acidosis accounts for those conditions, but is inaccurate if:
      • Urease Urease An enzyme that catalyzes the conversion of urea and water to carbon dioxide and ammonia. Nocardia/Nocardiosis positive urinary tract infection is present
      • Toxic alcohol poisoning (e.g., methanol Methanol A colorless, flammable liquid used in the manufacture of formaldehyde and acetic acid, in chemical synthesis, antifreeze, and as a solvent. Ingestion of methanol is toxic and may cause blindness. Metabolic Acidosis, ethylene glycol Ethylene glycol A colorless, odorless, viscous dihydroxy alcohol. It has a sweet taste, but is poisonous if ingested. Ethylene glycol is the most important glycol commercially available and is manufactured on a large scale in the United States. It is used as an antifreeze and coolant, in hydraulic fluids, and in the manufacture of low-freezing dynamites and resins. Nephrolithiasis)
  • Urine osmolal gap Osmolal gap Metabolic Acidosis = measured urine Urine Liquid by-product of excretion produced in the kidneys, temporarily stored in the bladder until discharge through the urethra. Bowen Disease and Erythroplasia of Queyrat osmolality Osmolality Plasma osmolality refers to the combined concentration of all solutes in the blood. Renal Sodium and Water Regulation – calculated urine Urine Liquid by-product of excretion produced in the kidneys, temporarily stored in the bladder until discharge through the urethra. Bowen Disease and Erythroplasia of Queyrat osmolality Osmolality Plasma osmolality refers to the combined concentration of all solutes in the blood. Renal Sodium and Water Regulation
    • Urine osmolality Osmolality Plasma osmolality refers to the combined concentration of all solutes in the blood. Renal Sodium and Water Regulation = 2(Na+ + K+) + (BUN/2.8) + ( glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance/18)
    • Urine osmolal gap Osmolal gap Metabolic Acidosis ranges:
      • 10 to 100 = normal
      • < 150 = RTA
      • > 400 = NAGMA not due to RTA
  • Urine anion gap Anion gap Metabolic Acidosis = urine Urine Liquid by-product of excretion produced in the kidneys, temporarily stored in the bladder until discharge through the urethra. Bowen Disease and Erythroplasia of Queyrat (Na+ + K+ – Cl)
    • 0–20: normal or RTA
    • –20 to –50: NAGMA not due to RTA (i.e., diarrhea)

Step 3

To differentiate between the types of RTA, evaluate:

Serum bicarbonate Bicarbonate Inorganic salts that contain the -HCO3 radical. They are an important factor in determining the ph of the blood and the concentration of bicarbonate ions is regulated by the kidney. Levels in the blood are an index of the alkali reserve or buffering capacity. Electrolytes level:

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

Urine pH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance:

  • 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 Proximal tubule The renal tubule portion that extends from the bowman capsule in the kidney cortex into the kidney medulla. The proximal tubule consists of a convoluted proximal segment in the cortex, and a distal straight segment descending into the medulla where it forms the u-shaped loop of henle. Tubular System reabsorption threshold
      • Early in disease course → not yet in steady state Steady state Enzyme Kinetics
      • During treatment with bicarbonate Bicarbonate Inorganic salts that contain the -HCO3 radical. They are an important factor in determining the ph of the blood and the concentration of bicarbonate ions is regulated by the kidney. Levels in the blood are an index of the alkali reserve or buffering capacity. Electrolytes 
    • < 5.5 if serum HCO3 is ≤ proximal tubule Proximal tubule The renal tubule portion that extends from the bowman capsule in the kidney cortex into the kidney medulla. The proximal tubule consists of a convoluted proximal segment in the cortex, and a distal straight segment descending into the medulla where it forms the u-shaped loop of henle. Tubular System reabsorption threshold
  • 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 Bicarbonate Inorganic salts that contain the -HCO3 radical. They are an important factor in determining the ph of the blood and the concentration of bicarbonate ions is regulated by the kidney. Levels in the blood are an index of the alkali reserve or buffering capacity. Electrolytes infusion test can be done:

  • Helps differentiate distal (type 1) from proximal (type 2) RTA 
  • Rarely done in practice
  • IV bicarbonate Bicarbonate Inorganic salts that contain the -HCO3 radical. They are an important factor in determining the ph of the blood and the concentration of bicarbonate ions is regulated by the kidney. Levels in the blood are an index of the alkali reserve or buffering capacity. Electrolytes is given until the serum HCO3 = 18–20 mEq/L.
  • Distal RTA (type 1)
    • Urine pH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance does not change, despite ↑ serum HCO3
    • Fractional excretion of  HCO3 is < 3% (normal level)
  • Proximal RTA (type 2) 
    • Urine pH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance 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 Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis

  • Goal of therapy is to normalize the serum bicarbonate Bicarbonate Inorganic salts that contain the -HCO3 radical. They are an important factor in determining the ph of the blood and the concentration of bicarbonate ions is regulated by the kidney. Levels in the blood are an index of the alkali reserve or buffering capacity. Electrolytes.
  • Mainstay of therapy is alkali (i.e., bicarbonate Bicarbonate Inorganic salts that contain the -HCO3 radical. They are an important factor in determining the ph of the blood and the concentration of bicarbonate ions is regulated by the kidney. Levels in the blood are an index of the alkali reserve or buffering capacity. Electrolytes) replacement.
  • Oral bicarbonate Bicarbonate Inorganic salts that contain the -HCO3 radical. They are an important factor in determining the ph of the blood and the concentration of bicarbonate ions is regulated by the kidney. Levels in the blood are an index of the alkali reserve or buffering capacity. Electrolytes or citrate can be used:
    • Citrate is converted into bicarbonate Bicarbonate Inorganic salts that contain the -HCO3 radical. They are an important factor in determining the ph of the blood and the concentration of bicarbonate ions is regulated by the kidney. Levels in the blood are an index of the alkali reserve or buffering capacity. Electrolytes 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: Anatomy.
    • 1:1 ratio: 1 mEq of citrate becomes 1 mEq of bicarbonate Bicarbonate Inorganic salts that contain the -HCO3 radical. They are an important factor in determining the ph of the blood and the concentration of bicarbonate ions is regulated by the kidney. Levels in the blood are an index of the alkali reserve or buffering capacity. Electrolytes.
    • 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 Potassium An element in the alkali group of metals with an atomic symbol k, atomic number 19, and atomic weight 39. 10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte that plays a significant role in the regulation of fluid volume and maintenance of the water-electrolyte balance. Hyperkalemia-containing preparations may be preferred if hypokalemia is present.
    • Sodium-containing preparations are used otherwise.
    • Separate oral potassium replacement is often needed.
  • Pill burden is a large problem:
    • Most bicarbonate Bicarbonate Inorganic salts that contain the -HCO3 radical. They are an important factor in determining the ph of the blood and the concentration of bicarbonate ions is regulated by the kidney. Levels in the blood are an index of the alkali reserve or buffering capacity. Electrolytes and citrate tablets have relatively low doses of bicarbonate Bicarbonate Inorganic salts that contain the -HCO3 radical. They are an important factor in determining the ph of the blood and the concentration of bicarbonate ions is regulated by the kidney. Levels in the blood are an index of the alkali reserve or buffering capacity. Electrolytes
    • Dosing is often multiple tablets per dose given multiple times per day.
    • Predisposes to noncompliance Noncompliance Clinician–Patient Relationship and poor quality Quality Activities and programs intended to assure or improve the quality of care in either a defined medical setting or a program. The concept includes the assessment or evaluation of the quality of care; identification of problems or shortcomings in the delivery of care; designing activities to overcome these deficiencies; and follow-up monitoring to ensure effectiveness of corrective steps. Quality Measurement and Improvement of life
  • Medication options:
    • Over-the-counter baking soda
      • 1 teaspoon = 54 mEq sodium Sodium A member of the alkali group of metals. It has the atomic symbol na, atomic number 11, and atomic weight 23. Hyponatremia bicarbonate Bicarbonate Inorganic salts that contain the -HCO3 radical. They are an important factor in determining the ph of the blood and the concentration of bicarbonate ions is regulated by the kidney. Levels in the blood are an index of the alkali reserve or buffering capacity. Electrolytes
      • Most cost-effective option 
      • Useful when high doses are needed to help reduce pill burden
    • Sodium bicarbonate Bicarbonate Inorganic salts that contain the -HCO3 radical. They are an important factor in determining the ph of the blood and the concentration of bicarbonate ions is regulated by the kidney. Levels in the blood are an index of the alkali reserve or buffering capacity. Electrolytes tablets 
    • Potassium Potassium An element in the alkali group of metals with an atomic symbol k, atomic number 19, and atomic weight 39. 10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte that plays a significant role in the regulation of fluid volume and maintenance of the water-electrolyte balance. Hyperkalemia bicarbonate Bicarbonate Inorganic salts that contain the -HCO3 radical. They are an important factor in determining the ph of the blood and the concentration of bicarbonate ions is regulated by the kidney. Levels in the blood are an index of the alkali reserve or buffering capacity. Electrolytes tablets 
    • Sodium citrate liquid
    • Potassium Potassium An element in the alkali group of metals with an atomic symbol k, atomic number 19, and atomic weight 39. 10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte that plays a significant role in the regulation of fluid volume and maintenance of the water-electrolyte balance. Hyperkalemia citrate tablets or liquid

Distal renal tubular acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis (type 1)

  • Oral bicarbonate Bicarbonate Inorganic salts that contain the -HCO3 radical. They are an important factor in determining the ph of the blood and the concentration of bicarbonate ions is regulated by the kidney. Levels in the blood are an index of the alkali reserve or buffering capacity. Electrolytes (or equivalent): 1–2 mEq/kg/day in divided doses
  • Relatively easy to correct, because proximal tubule Proximal tubule The renal tubule portion that extends from the bowman capsule in the kidney cortex into the kidney medulla. The proximal tubule consists of a convoluted proximal segment in the cortex, and a distal straight segment descending into the medulla where it forms the u-shaped loop of henle. Tubular System HCO3reabsorption is normal
  • May also require potassium supplementation

Proximal renal tubular acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis (type 2)

Treatment for proximal RTA is more complicated than simply replacing bicarbonate Bicarbonate Inorganic salts that contain the -HCO3 radical. They are an important factor in determining the ph of the blood and the concentration of bicarbonate ions is regulated by the kidney. Levels in the blood are an index of the alkali reserve or buffering capacity. Electrolytes:

Rationale:

  • Some supplemental bicarbonate Bicarbonate Inorganic salts that contain the -HCO3 radical. They are an important factor in determining the ph of the blood and the concentration of bicarbonate ions is regulated by the kidney. Levels in the blood are an index of the alkali reserve or buffering capacity. Electrolytes will always be wasted in the urine Urine Liquid by-product of excretion produced in the kidneys, temporarily stored in the bladder until discharge through the urethra. Bowen Disease and Erythroplasia of Queyrat:
    • Much higher doses of bicarbonate Bicarbonate Inorganic salts that contain the -HCO3 radical. They are an important factor in determining the ph of the blood and the concentration of bicarbonate ions is regulated by the kidney. Levels in the blood are an index of the alkali reserve or buffering capacity. Electrolytes are needed.
    • Often unable to normalize the serum bicarbonate Bicarbonate Inorganic salts that contain the -HCO3 radical. They are an important factor in determining the ph of the blood and the concentration of bicarbonate ions is regulated by the kidney. Levels in the blood are an index of the alkali reserve or buffering capacity. Electrolytes regardless of treatment
  • Bicarbonate wasting results in worsening hypokalemia:
    • HCO3 travels through the nephron Nephron The functional units of the kidney, consisting of the glomerulus and the attached tubule. Kidneys: Anatomy bound to Na+ (NaHCO3).
    • ↑ NaHCO3 → ↑ distal delivery of Na+ to principal cells Principal cells Tubular System of collecting duct Collecting duct Straight tubes commencing in the radiate part of the kidney cortex where they receive the curved ends of the distal convoluted tubules. In the medulla the collecting tubules of each pyramid converge to join a central tube (duct of bellini) which opens on the summit of the papilla. Renal Cell Carcinoma
    • ↑ Na+ reabsorption by ENaC ENaC Sodium channels found on salt-reabsorbing epithelial cells that line the distal nephron; the distal colon; salivary ducts; sweat glands; and the lung. They are amiloride-sensitive and play a critical role in the control of sodium balance, blood volume, and blood pressure. Liddle Syndrome channel→ ↑ K+ secretion Secretion Coagulation Studies via ROMK channel ROMK channel Renal Potassium Regulation

Treatment involves a combination approach:

  • Stop any offending drug/medication, if possible.
  • Treat underlying condition, if possible.
  • Bicarbonate supplementation: 
    • Oral bicarbonate Bicarbonate Inorganic salts that contain the -HCO3 radical. They are an important factor in determining the ph of the blood and the concentration of bicarbonate ions is regulated by the kidney. Levels in the blood are an index of the alkali reserve or buffering capacity. Electrolytes
    • Hydrochlorothiazide Hydrochlorothiazide A thiazide diuretic often considered the prototypical member of this class. It reduces the reabsorption of electrolytes from the renal tubules. This results in increased excretion of water and electrolytes, including sodium, potassium, chloride, and magnesium. It is used in the treatment of several disorders including edema, hypertension, diabetes insipidus, and hypoparathyroidism. Thiazide Diuretics can be used to improve the pill burden: 
      • Diuretic → mild volume contraction → stimulates proximal tubule Proximal tubule The renal tubule portion that extends from the bowman capsule in the kidney cortex into the kidney medulla. The proximal tubule consists of a convoluted proximal segment in the cortex, and a distal straight segment descending into the medulla where it forms the u-shaped loop of henle. Tubular System reabsorption of Na+ and HCO3 
      • Side effect is worsening hypokalemia
  • Potassium Potassium An element in the alkali group of metals with an atomic symbol k, atomic number 19, and atomic weight 39. 10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte that plays a significant role in the regulation of fluid volume and maintenance of the water-electrolyte balance. Hyperkalemia supplementation:
    • Much more of an issue than with distal RTA (type 1)
      • Exacerbated by bicarbonaturia
      • Exacerbated by thiazide Thiazide Heterocyclic compounds with sulfur and nitrogen in the ring. This term commonly refers to the benzothiadiazines that inhibit sodium-potassium-chloride symporters and are used as diuretics. Hyponatremia use
    • Usually requires more K+ than is included in bicarbonate Bicarbonate Inorganic salts that contain the -HCO3 radical. They are an important factor in determining the ph of the blood and the concentration of bicarbonate ions is regulated by the kidney. Levels in the blood are an index of the alkali reserve or buffering capacity. Electrolytes supplements
    • K+-sparing diuretics can be used to ↓ K+ supplementation need
  • Additional supplementation may be needed for Fanconi syndrome:
    • Phosphorus
    • Vitamin D Vitamin D A vitamin that includes both cholecalciferols and ergocalciferols, which have the common effect of preventing or curing rickets in animals. It can also be viewed as a hormone since it can be formed in skin by action of ultraviolet rays upon the precursors, 7-dehydrocholesterol and ergosterol, and acts on vitamin D receptors to regulate calcium in opposition to parathyroid hormone. Fat-soluble Vitamins and their Deficiencies
  • Frequent labs to monitor serum HCO3, K+, and phosphate Phosphate Inorganic salts of phosphoric acid. Electrolytes

Hyperkalemic renal tubular acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis (type 4)

Treatment for hyperkalemic RTA differs significantly from that for the other forms of RTA, primarily in that oral bicarbonate Bicarbonate Inorganic salts that contain the -HCO3 radical. They are an important factor in determining the ph of the blood and the concentration of bicarbonate ions is regulated by the kidney. Levels in the blood are an index of the alkali reserve or buffering capacity. Electrolytes therapy is not the 1st-line treatment.

  • Fludrocortisone Fludrocortisone A synthetic mineralocorticoid with anti-inflammatory activity. Mineralocorticoids
    • Oral aldosterone Aldosterone A hormone secreted by the adrenal cortex that regulates electrolyte and water balance by increasing the renal retention of sodium and the excretion of potassium. Hyperkalemia analog
    • Side effect of Na+ retention can limit Limit A value (e.g., pressure or time) that should not be exceeded and which is specified by the operator to protect the lung Invasive Mechanical Ventilation 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 Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema)
  • Low-K+ diet
  • Loop or thiazide Thiazide Heterocyclic compounds with sulfur and nitrogen in the ring. This term commonly refers to the benzothiadiazines that inhibit sodium-potassium-chloride symporters and are used as diuretics. Hyponatremia diuretics (particularly if unable to use fludrocortisone)
  • Oral bicarbonate Bicarbonate Inorganic salts that contain the -HCO3 radical. They are an important factor in determining the ph of the blood and the concentration of bicarbonate ions is regulated by the kidney. Levels in the blood are an index of the alkali reserve or buffering capacity. Electrolytes 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 Plasma cell Specialized forms of antibody-producing B-lymphocytes. They synthesize and secrete immunoglobulin. They are found only in lymphoid organs and at sites of immune responses and normally do not circulate in the blood or lymph. Lymphocytes: Histology 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 An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways. Proximal RTA (type 2) may also be present. Diagnosis is made with serum protein electrophoresis Electrophoresis An electrochemical process in which macromolecules or colloidal particles with a net electric charge migrate in a solution under the influence of an electric current. Blotting Techniques (SPEP) with immunofixation (IFE), which identifies the abnormal paraprotein (known as the M-spike on the SPEP). Additional testing includes urine Urine Liquid by-product of excretion produced in the kidneys, temporarily stored in the bladder until discharge through the urethra. Bowen Disease and Erythroplasia of Queyrat protein electrophoresis Electrophoresis An electrochemical process in which macromolecules or colloidal particles with a net electric charge migrate in a solution under the influence of an electric current. Blotting Techniques (UPEP) and the serum free light chain ratio. Treatment involves chemotherapy Chemotherapy Osteosarcoma and hematopoietic stem cell transplantation Hematopoietic stem cell transplantation Transfer of hematopoietic stem cells from bone marrow or blood between individuals within the same species (homologous transplantation) or transfer within the same individual (autologous transplantation). Hematopoietic stem cell transplantation has been used as an alternative to bone marrow transplantation in the treatment of a variety of neoplasms. Organ Transplantation.
  • Pseudohypoaldosteronism Pseudohypoaldosteronism A heterogeneous group of disorders characterized by renal electrolyte transport dysfunctions. Congenital forms are rare autosomal disorders characterized by neonatal hypertension, hyperkalemia, increased renin activity and aldosterone concentration. The type I features hyperkalemia with sodium wasting; type II, hyperkalemia without sodium wasting. Pseudohypoaldosteronism can be the result of a defective renal electrolyte transport protein or acquired after kidney transplantation. Hypoaldosteronism 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 Pseudohypoaldosteronism A heterogeneous group of disorders characterized by renal electrolyte transport dysfunctions. Congenital forms are rare autosomal disorders characterized by neonatal hypertension, hyperkalemia, increased renin activity and aldosterone concentration. The type I features hyperkalemia with sodium wasting; type II, hyperkalemia without sodium wasting. Pseudohypoaldosteronism can be the result of a defective renal electrolyte transport protein or acquired after kidney transplantation. Hypoaldosteronism type 1 can be diagnosed by an elevated plasma renin activity Plasma renin activity Renal Artery Stenosis and an elevated aldosterone Aldosterone A hormone secreted by the adrenal cortex that regulates electrolyte and water balance by increasing the renal retention of sodium and the excretion of potassium. Hyperkalemia level. Management includes sodium Sodium A member of the alkali group of metals. It has the atomic symbol na, atomic number 11, and atomic weight 23. Hyponatremia 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 Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics encoding for the carrier Carrier Vaccination protein cystinosin. Intralysosomal cystine Cystine A covalently linked dimeric nonessential amino acid formed by the oxidation of cysteine. Two molecules of cysteine are joined together by a disulfide bridge to form cystine. Nephrolithiasis accumulates throughout the body, including in the proximal tubule Proximal tubule The renal tubule portion that extends from the bowman capsule in the kidney cortex into the kidney medulla. The proximal tubule consists of a convoluted proximal segment in the cortex, and a distal straight segment descending into the medulla where it forms the u-shaped loop of henle. Tubular System 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 Cystine A covalently linked dimeric nonessential amino acid formed by the oxidation of cysteine. Two molecules of cysteine are joined together by a disulfide bridge to form cystine. Nephrolithiasis-depleting agent cysteamine and renal replacement therapy (including renal transplantation).
  • Sjögren syndrome Sjögren Syndrome Rheumatoid Arthritis: autoimmune disease in which glandular tissues, such as the salivary and lacrimal glands Lacrimal Glands Dacryocystitis, 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: Histology, causing symptoms such as dry eyes and dry mouth. There are a wide range of extraglandular manifestations of Sjögren syndrome Sjögren Syndrome Rheumatoid Arthritis, including distal RTA (type 1), Raynaud phenomenon, neuropathy Neuropathy Leprosy, and cutaneous vasculitis Vasculitis Inflammation of any one of the blood vessels, including the arteries; veins; and rest of the vasculature system in the body. Systemic Lupus Erythematosus. Diagnosis is validated by the clinical examination, serologic studies, and salivary gland Salivary gland Glands that secrete saliva in the mouth. There are three pairs of salivary glands (parotid gland; sublingual gland; submandibular gland). Diseases of the Salivary Glands biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma.  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 Rash Rocky Mountain Spotted Fever, nondestructive arthritis Arthritis Acute or chronic inflammation of joints. Osteoarthritis, lupus nephritis Lupus nephritis Glomerulonephritis associated with autoimmune disease systemic lupus erythematosus. Lupus nephritis is histologically classified into 6 classes: class I – normal glomeruli, class II – pure mesangial alterations, class III – focal segmental glomerulonephritis, class IV – diffuse glomerulonephritis, class V – diffuse membranous glomerulonephritis, and class VI – advanced sclerosing glomerulonephritis (the world health organization classification 1982). Diffuse Proliferative Glomerulonephritis, serositis Serositis Inflammation of a serous membrane. Systemic Lupus Erythematosus, cytopenias Cytopenias IPEX Syndrome, 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: Types and Functions, SLE-specific antibodies SLE-specific antibodies Systemic Lupus Erythematosus, and specific clinical findings. Treatment options include hydroxychloroquine Hydroxychloroquine A chemotherapeutic agent that acts against erythrocytic forms of malarial parasites. Hydroxychloroquine appears to concentrate in food vacuoles of affected protozoa. It inhibits plasmodial heme polymerase. Immunosuppressants and immunosuppressive medications (e.g., prednisone Prednisone A synthetic anti-inflammatory glucocorticoid derived from cortisone. It is biologically inert and converted to prednisolone in the liver. Immunosuppressants, methotrexate Methotrexate An antineoplastic antimetabolite with immunosuppressant properties. It is an inhibitor of tetrahydrofolate dehydrogenase and prevents the formation of tetrahydrofolate, necessary for synthesis of thymidylate, an essential component of DNA. Antimetabolite Chemotherapy, mycophenolate Mycophenolate Immunosuppressants 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 Inheritance genetic 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 Tyrosine A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine; thyroid hormones; and melanin. Synthesis of Nonessential Amino Acids, 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 Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia. 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 Tyrosine A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine; thyroid hormones; and melanin. Synthesis of Nonessential Amino Acids (i.e., low-protein) diet.
  • Wilson disease: also known as hepatolenticular degeneration Hepatolenticular degeneration Wilson disease (hepatolenticular degeneration) is an autosomal recessive disorder caused by various mutations in the ATP7b gene, which regulates copper transport within hepatocytes. Dysfunction of this transport mechanism leads to abnormal copper accumulations in the liver, brain, eyes, and other organs, with consequent major and variably expressed hepatic, neurologic, and psychiatric disturbances. Wilson’s Disease. 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 Inheritance disorder associated with mutations in the ATP7B gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics, which result in copper Copper A heavy metal trace element with the atomic symbol cu, atomic number 29, and atomic weight 63. 55. Trace Elements 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: Anatomy, brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification, and cornea Cornea The transparent anterior portion of the fibrous coat of the eye consisting of five layers: stratified squamous corneal epithelium; bowman membrane; corneal stroma; descemet membrane; and mesenchymal corneal endothelium. It serves as the first refracting medium of the eye. Eye: Anatomy. 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 Copper A heavy metal trace element with the atomic symbol cu, atomic number 29, and atomic weight 63. 55. Trace Elements ( Kayser-Fleischer rings Kayser-Fleischer rings Copper deposits in Descemet’s membrane of the cornea, manifested as green-brown rings that encircle the iris. Wilson’s Disease), low plasma ceruloplasmin Ceruloplasmin A multi-copper blood ferroxidase involved in iron and copper homeostasis and inflammation. Wilson’s Disease, and/or elevated levels of copper Copper A heavy metal trace element with the atomic symbol cu, atomic number 29, and atomic weight 63. 55. Trace Elements in the urine Urine Liquid by-product of excretion produced in the kidneys, temporarily stored in the bladder until discharge through the urethra. Bowen Disease and Erythroplasia of Queyrat. Management is with the use of copper Copper A heavy metal trace element with the atomic symbol cu, atomic number 29, and atomic weight 63. 55. Trace Elements-chelating agents such as penicillamine Penicillamine 3-mercapto-d-valine. The most characteristic degradation product of the penicillin antibiotics. It is used as an antirheumatic and as a chelating agent in wilson’s disease. Wilson’s Disease.

References

  1. Bello, C., Duarte, J. S., & Vasconcelos, C. (2017). Diabetes mellitus and hyperkalemic renal tubular acidosis: case reports and literature review. J Bras Nefrol 39, pp. 481–485. https://doi.org/10.5935/0101-2800.20170086
  2. Berend, K. (2017). Review of the diagnostic evaluation of normal anion gap metabolic acidosis. Kidney Dis (Basel) 3, pp. 149–159.
  3. Dobbin, S., Petrie, J. R., Lean, M., & McKay, G. A. (2017). Fludrocortisone therapy for persistent hyperkalaemia. Diabetic medicine : a journal of the British Diabetic Association, 34(7), pp. 1005–1008. https://doi.org/10.1111/dme.13359
  4. Emmett M., & Kelepouris E. (2019). Overview and pathophysiology of renal tubular acidosis and the effect on potassium balance. UpToDate. Retrieved May 5, 2021, from https://www.uptodate.com/contents/overview-and-pathophysiology-of-renal-tubular-acidosis-and-the-effect-on-potassium-balance
  5. Emmett M., & Palmer, B. F. (2020). Etiology and diagnosis of distal (type 1) and proximal (type 2) renal tubular acidosis. UpToDate. Retrieved May 3, 2021, from https://www.uptodate.com/contents/etiology-and-diagnosis-of-distal-type-1-and-proximal-type-2-renal-tubular-acidosis
  6. Emmett, M., & Palmer, B. F. (2020). Treatment of distal (type 1) and proximal (type 2) renal tubular acidosis. UpToDate. Retrieved May 3, 2021, from https://www.uptodate.com/contents/treatment-of-distal-type-1-and-proximal-type-2-renal-tubular-acidosis
  7. Emmett M., & Palmer B. F. (2021). Urine anion and osmolal gaps in metabolic acidosis. UpToDate. Retrieved May 5, 2021, from https://www.uptodate.com/contents/urine-anion-and-osmolal-gaps-in-metabolic-acidosis
  8. Grompe, M. (2020). Disorders of tyrosine metabolism. UpToDate. Retrieved May 7, 2021, from https://www.uptodate.com/contents/disorders-of-tyrosine-metabolism
  9. Karet, F. E. (2009). Mechanisms in hyperkalemic renal tubular acidosis. Journal of the American Society of Nephrology (JASN), 20(2), pp. 251–254. https://doi.org/10.1681/ASN.2008020166
  10. Koratala, A., & Ruchi, R. (2017). Hypokalemia: A potentially life-threatening complication of tenofovir therapy. SAGE open medical case reports, 5. https://doi.org/10.1177/2050313X17741010
  11. Marangella, M. (2017). Impiego del citrato nel paziente con Nefrolitiasi [Use of citrate in patients with nephrolithiasis]. Giornale italiano di nefrologia: organo ufficiale della Societa italiana di nefrologia, 34(4), pp. 51–60.
  12. Mattoo, T. K. (2019). Etiology and clinical manifestations of renal tubular acidosis in infants and children. UpToDate. Retrieved May 5, 2021, from https://www.uptodate.com/contents/etiology-and-clinical-manifestations-of-renal-tubular-acidosis-in-infants-and-children
  13. Mohebbi N., & Wagner C. A. (2018). Pathophysiology, diagnosis and treatment of inherited distal renal tubular acidosis. J Nephrol 31, pp. 511–522.
  14. Mustaqeem R, & Arif A. (2021). Renal tubular acidosis. StatPearls. https://www.ncbi.nlm.nih.gov/books/NBK519044/
  15. Sarma, A. (2018). Hypokalemic paralysis due to primary Sjögren syndrome. Indian J Endocrinol Metab 22, pp. 287–289.
  16. Weiner, S. M. (2018). [Renal involvement in connective tissue diseases]. Dtsch Med Wochenschr 143, pp. 89–100.
  17. Yaxley, J., & Pirrone C. (2016). Review of the diagnostic evaluation of renal tubular acidosis. Ochsner J 16, pp. 525–530.
  18. Young, W. F. Jr. (2019). Etiology, diagnosis, and treatment of hypoaldosteronism (type 4 RTA). UpToDate. Retrieved May 4, 2021, from https://www.uptodate.com/contents/etiology-diagnosis-and-treatment-of-hypoaldosteronism-type-4-rta

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Complement your med school studies with Lecturio’s all-in-one study companion, delivered with evidence-based learning strategies.

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