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Metabolic Acidosis
Aciditiy Increased due to Metabolic Disorder

Metabolic acidosis is a metabolic state in the body where there is an increase of acid in the body fluids. Metabolic acidosis is also physiologically defined as the primary reduction in HCO3 ion concentration in the blood with a compensatory reduction in PCO2 ion levels while pH remains subnormal.

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Presentation

Most cases of metabolic acidosis present with non-specific signs and symptoms. These symptomatology and signs are most commonly seen among patients with established metabolic acidosis:

  • Hyperventilation: The respiratory centers are stimulated to cause hyperventilation to help eliminate carbon dioxide from the blood during acidotic states. 
  • Dyspnea: Breathing will be too fast and shallow impairing adequate oxygen exchange in the lungs.
  • Chest pain: The acidic plasma triggers the release of some cytokines that may cause angina and temporary coronary vasospasm.
  • Palpitation: The compensatory tachycardia will be felt as palpitation.
  • Neurologic signs: Headache and confusion are common findings when the cerebrospinal fluid becomes acidic.
  • Fatigue and weakness: Sodium channels are impaired during metabolic acidosis causing an essential hyponatremia in the extracellular space lowering the action potential in muscles.
  • Nausea and vomiting: The toxic state of metabolic acidosis is exemplified as nausea and vomiting among children.
  • Bone pains: The acidotic state causes vasospasm of the smaller arterioles that supply the bones presenting as sharp bone pains. Chronic calcium depletion with the acidemic state can also cause untimely osteoporosis among patients. 

Respiratoric

  • Kussmaul Respiration

    Kussmaul’s respirations B. Glucose 110 C. Hypoventilation D. Neuro-excitability The answer is A: Kussmaul’s respirations 10. A patient has the following arterial blood gases: PaCO2 33, HCO3 15, pH 7.23. Which condition below is presenting? A. [registerednursern.com]

    Infants will try to correct metabolic acidosis by a reflex respiratory alkalosis using hyperventilation and Kussmaul respirations. [mhmedical.com]

    EFFECTS Respiratory Effects hyperventilation (Kussmaul respirations) – this is the compensatory response shift of oxyhaemoglobin dissociation curve (ODC) to the right – due to the acidosis occurs rapidly decreased 2,3 DPG levels in red cells (shifting [litfl.com]

    Kussmaul's respiration may be noted where there is deep, slowly rhythmic breathing that increases the minute tidal volume. Children with chronic metabolic acidosis may have growth restriction and show signs of rickets. [patient.info]

  • Tachypnea

    During the initial examination by the physician at our hospital, the patient presented with tachypnea, a precordinal burning sensation, nausea and metabolic acidosis. [ncbi.nlm.nih.gov]

    The resulting tachypnea and hyperpnea reduces the PaCO 2 in an attempt to increase the pH back toward normal. [emedicine.com]

    Hyperventilation (tachypnea) B. Hypoventilation (bradypnea) C. Increased potassium level (hyperkalemia) D. Constipation 5. What of the following is NOT a cause of metabolic alkalosis? * A. Hyperaldosteronism B. Usage of Diamox C. [registerednursern.com]

    Tachycardia, tachypnea (with severe lactic acidosis), hypotension with symptoms similar to septic shock. Specific laboratory tests are to help identify the severity and presence of multiorgan involvement. [clinicaladvisor.com]

    Tachypnea and hyperventilation worsened during the ensuing 12 h. Blood gas analysis showed severe metabolic acidosis resulting in hypocapnia and a normal pH ( table 1 ). [anesthesiology.pubs.asahq.org]

  • Hyperpnea

    The most characteristic sign is hyperpnea (long, deep breaths at a normal rate), reflecting a compensatory increase in alveolar ventilation; this hyperpnea is not accompanied by a feeling of dyspnea. [merckmanuals.com]

    The resulting tachypnea and hyperpnea reduces the PaCO 2 in an attempt to increase the pH back toward normal. [emedicine.com]

  • Abnormal Breathing

    Other symptoms for lactic acidosis include: Nausea Vomiting Abdominal pain Lethargy Abnormal breathing Low blood pressure Irregular heart rhythm Causes of Lactic Acidosis Lactic Acidosis is caused if a person reaches the anaerobic threshold or lactate [acidalkalinediet.net]

Gastrointestinal

  • Vomiting

    Laboratory examinations reveal the presence of significant metabolic alkalosis despite the severe vomiting of the patient. Hypochloremic alkalosis would be expected to be present in this patient. [ncbi.nlm.nih.gov]

    Nausea and vomiting: The toxic state of metabolic acidosis is exemplified as nausea and vomiting among children. Bone pains: The acidotic state causes vasospasm of the smaller arterioles that supply the bones presenting as sharp bone pains. [symptoma.com]

    2 ↓ in HCO 3 Sepsis Salicylate toxicity Renal failure with CHF or pneumonia Advanced liver disease Metabolic acidosis with metabolic alkalosis pH in normal range HCO 3 - normal Uremia or ketoacidosis with vomiting, NG suction, diuretics, etc. [thoracic.org]

    […] acidosis, hyperglycaemia, other sign of BSI such as apathy mt Rapport dwar it-Trattat ta' Liżbona [#/#(INI)]- Kumitat għall-Affarijiet Kostituzzjonali en Typical adverse reactions of non-steroidal anti-inflammatory drugs (NSAIDs) such as loss of appetite, vomiting [mt.glosbe.com]

  • Nausea

    Approximately 60 mL (20 mL/day) was used and after the third application he developed agitation, nausea, vomiting, respiratory distress, tachycardia, and metabolic acidosis. His clinical symptoms and metabolic acidosis normalized within 20 hours. [ncbi.nlm.nih.gov]

    Nausea and vomiting: The toxic state of metabolic acidosis is exemplified as nausea and vomiting among children. Bone pains: The acidotic state causes vasospasm of the smaller arterioles that supply the bones presenting as sharp bone pains. [symptoma.com]

  • Abdominal Pain

    Also, nonspecific GI complaints, such as abdominal pain, nausea, or vomiting, may be present. [emedicine.com]

    It causes nausea, vomiting, and abdominal pain and can progress to cerebral edema, coma, and death. DKA is diagnosed by detection of hyperketonemia and anion gap metabolic acidosis in the presence of hyperglycemia. [merckmanuals.com]

    pain Hyperventilation (respiratory alkalosis) Villous adenoma This can cause hypokalaemia. [anaesthesiamcq.com]

    Other symptoms for lactic acidosis include: Nausea Vomiting Abdominal pain Lethargy Abnormal breathing Low blood pressure Irregular heart rhythm Causes of Lactic Acidosis Lactic Acidosis is caused if a person reaches the anaerobic threshold or lactate [acidalkalinediet.net]

    Symptoms may include palpitations, headache, altered mental status such as severe anxiety due to hypoxia, decreased visual acuity, nausea, vomiting, abdominal pain, altered appetite and weight gain, muscle weakness, bone pain, and joint pain. [en.wikipedia.org]

  • Polydipsia

    Symptoms of undiagnosed diabetes - eg, polyuria, polydipsia or weight loss. Symptoms of renal failure such as nocturia, polyuria, oliguria, pruritus and anorexia. Recent history of urinary problems such as nephrolithiasis may indicate RTA. [patient.info]

Cardiovascular

  • Hypotension

    However, a change in consciousness and hypotension subsequently developed 6h later, combined with severe metabolic acidosis (pH7.16), high anion gap (25.5), and high osmolal gap (83). A presumed diagnosis of methanol intoxication was suspected. [ncbi.nlm.nih.gov]

    Metabolic acidosis due to paraldehyde overdose is exceedingly rare Iron and isoniazid are just two of many drugs and toxins that cause hypotension and lactic acidosis (isoniazid can also generate a component of ketoacidosis). [emergencymedicinecases.com]

    More severe uncompensated acidosis can decrease peripheral vascular resistance and cardiac ventricular function, leading to hypotension, pulmonary edema, and tissue hypoxia, which will further complicate the picture by increasing lactate production because [mhmedical.com]

  • Tachycardia

    Commonest signs were tachycardia (100%) and moaning (73%). At presentation 52% were in cardiogenic shock. Response to thiamine was dramatic with moaning and irritability subsiding in two hours and tachycardia in four hours. [ncbi.nlm.nih.gov]

    Initial evaluation revealed tachycardia (111/min,) mild hypothermia (95.5 o F,) and a depressed level of consciousness with non-focal neurological examination. Blood glucose was 362 mg/dL. [thepoisonreview.com]

    Tachycardia is the most common cardiovascular effect seen with a mild metabolic acidosis. As the serum pH continues to fall below 7.2, myocardial depression occurs because hydrogen ions act as a negative inotrope and peripheral vasodilation occurs. [emedicine.com]

    # Ħin li fih tkompliet is-seduta en at least two of: temperature > 38 °C or < 36,5 °C or temperature instability, tachycardia or bradycardia, apnoea, extended capillary refilling time (CRT), metabolic acidosis, hyperglycaemia, other sign of BSI [mt.glosbe.com]

Eyes

  • Photophobia

    Visual disturbances such as dimming, photophobia, scotomata or blindness may indicate methanol poisoning. Blurred vision may occur with salicylate poisoning. Tinnitus or vertigo may occur with salicylate poisoning. [patient.info]

Ears

  • Tinnitus

    Tinnitus or vertigo may occur with salicylate poisoning. Ask about any chest pain, palpitations, dyspnoea or oedema indicating possible cardiovascular causes for lactic acidosis. [patient.info]

    Clinical presentation varies and ranges from nausea, vomiting, tinnitus, lethargy, ataxia to more severe presentations such as pulmonary edema, seizures, coma and cerebral edema. [clinicaladvisor.com]

Musculoskeletal

  • Fracture

    Age, race, gender, ISS, American Society of Anesthesiologists score (ASA), body mass index (BMI), outside hospital transfer status, number of fractures, and the specific fractures were also reviewed. [ncbi.nlm.nih.gov]

    The lady I had been asked to see was in her 80s and had fractured her hip. On admission she had normal renal function and acid base status. [renalfellow.blogspot.com]

    Two months prior she had a fractured tibia, complicated by osteomyelitis. Physical examination showed dehydration and malnourishment. [pure.au.dk]

    Here are some health problems that can happen if metabolic acidosis is not treated: Your kidney disease can get worse Bone loss (osteoporosis), which can lead to a higher chance of fractures in important bones like your hips or backbone. [kidneyfund.org]

  • Arthritis

    An 82-year-old white woman was admitted to our intensive care unit because of septic shock caused by right knee methicillin-sensitive Staphylococcus aureus-induced arthritis. [ncbi.nlm.nih.gov]

    This may occur due to impairment in H + secretion, as seen with a variety of autoimmune (Sjögren syndrome, lupus, rheumatoid arthritis) or renal disorders. Hypercalciuria is another main cause of distal RTA in adults. [unboundmedicine.com]

    Also, acidosis creates fertile ground for inflammation, which could lead to many health problems, such as osteoporosis Rheumatism, gout Sciatica, herniated disc Arthritis, Osteoarthritis dental caries Gum inflammation Mouth ulcers, herpes Cracks at the [medinat.ca]

    D-dimer concentrations may rise in the elderly, cardura 4 mg علاج and false positives may be seen with high levels of rheumatoid factor, a protein seen in people with rheumatoid arthritis. [motioncraftcreative.com]

  • Osteopenia

    Chronic acidemia causes bone demineralization disorders (eg, rickets, osteomalacia, osteopenia). [merckmanuals.com]

    This bone buffering can lead to significant loss of bone calcium with resulting osteopenia and osteomalacia. [emedicine.com]

  • Bone Pain

    Bone pains: The acidotic state causes vasospasm of the smaller arterioles that supply the bones presenting as sharp bone pains. Chronic calcium depletion with the acidemic state can also cause untimely osteoporosis among patients. [symptoma.com]

    Patients with metabolic acidosis often present with nonspecific symptoms, including headache, chest pain, palpitation, shortness of breath, nausea, vomiting, muscle weakness, and bone pain. [renalandurologynews.com]

    Symptoms may include palpitations, headache, altered mental status such as severe anxiety due to hypoxia, decreased visual acuity, nausea, vomiting, abdominal pain, altered appetite and weight gain, muscle weakness, bone pain, and joint pain. [en.wikipedia.org]

Urogenital

  • Flank Pain

    Patients present with CNS symptoms, including slurred speech, confusion, stupor or coma, myocardial depression, and renal failure with flank pain. [emedicine.com]

  • Polyuria

    CASE REPORT An otherwise-healthy 24-year-old female presented for elective spine surgery and was found to have metabolic acidosis, hypotension, and polyuria intraoperatively. [ncbi.nlm.nih.gov]

    Symptoms of undiagnosed diabetes - eg, polyuria, polydipsia or weight loss. Symptoms of renal failure such as nocturia, polyuria, oliguria, pruritus and anorexia. Recent history of urinary problems such as nephrolithiasis may indicate RTA. [patient.info]

Neurologic

  • Confusion

    The first paper focuses on two similar case histories including that of a 63-year-old woman with mild chronic kidney disease admitted to intensive care following a 9-day history of unexplained lethargy, breathlessness and confusion. [acutecaretesting.org]

    You become weak or confused. You cannot be woken easily. Care Agreement You have the right to help plan your care. Learn about your health condition and how it may be treated. [drugs.com]

    People with respiratory acidosis often have headache and confusion, and breathing may appear shallow, slow, or both. Tests on blood samples typically show pH below the normal range. Doctors treat the cause of the acidosis. [msdmanuals.com]

  • Lethargy

    The first paper focuses on two similar case histories including that of a 63-year-old woman with mild chronic kidney disease admitted to intensive care following a 9-day history of unexplained lethargy, breathlessness and confusion. [acutecaretesting.org]

    Clinical presentation is heterogeneous, usually characterised by repetitive vomiting and diarrhoea, lethargy, failure to thrive until to dehydration with hypotension and shock. [ncbi.nlm.nih.gov]

    Symptoms and signs in severe cases include nausea and vomiting, lethargy, and hyperpnea. Diagnosis is clinical and with ABG and serum electrolyte measurement. The cause is treated; IV sodium bicarbonate may be indicated when pH is very low. [msdmanuals.com]

    Central nervous system (CNS) manifestations can include headache, lethargy, confusion, or any change in mental status secondary to a decrease in intracerebral pH. [emedicine.com]

  • Stupor

    We report a 33 year-old woman addicted to chronic unspecified solvents abuse with stupor, respiratory disorders, tetraplegia and severe metabolic acidosis. [ncbi.nlm.nih.gov]

    Stupor and coma can develop within moments if breathing stops or is severely impaired, or over hours if breathing is less dramatically impaired. [msdmanuals.com]

    Examination Lethargy, stupor and progression to a state of coma may occur, particularly in cases of poisoning. An intoxicated-appearing patient who has no smell of alcoholic drink on their breath may have ingested ethylene glycol. [patient.info]

  • Somnolence

    Lethargy and somnolence are symptoms of more severe decompensation. Patients may be hypotensive and tachycardic due to dehydration and acidosis; they may breathe rapidly and deeply to compensate for acidemia (Kussmaul respirations). [merckmanuals.com]

    Plasma VPA levels above 180 mg/mL usually have some degree of lethargy or somnolence. VPA levels have little correlation with severity of intoxication and prognosis. [clinicaladvisor.com]

  • Apathy

    […] or apathy or ignorance. mt Ir-rifużjoni għandha titħallas sa mhux aktar tard minn ħames xhur wara d-data li fiha jkun intemm il-kontroll ipprovdut fl-Artikolu en Political apathy and polarisation in elections has also risen, reflecting citizens' faltering [mt.glosbe.com]

Workup

The following laboratory examinations and tests are utilized for the work up of patients with metabolic acidosis:

  • Serum electrolytes: The bicarbonate (HCO3) ion is usually inadequate during metabolic acidosis. 
  • Arterial blood gases (ABG): Blood gases analysis will reveal a pH level less than 7.4 during acidotic states. Concentration of HCO3 can also be determined in the ABG [4].
  • Urinalysis: Urine pH may be determined from the urinalysis. Electrolytes such as sodium, chloride, and potassium can also be measured in the urine [5]. The determination of ketones in the urine is associated with diabetic, starvation, and alcoholic ketoacidosis.
  • Anion gap: An increasing anion gap (AG) is indicative of an acidemic state where there is an increased number of undetected ions in the serum [6]. 
  • Complete blood count: An elevated white blood cell (WBC) count may connote septicemia which could cause lactic acidosis.
  • Blood urea nitrogen (BUN): This renal function test is sensitive in assessing the degree of metabolic acidosis during renal failure [7].
  • Serum lactate level: An elevation of up to 3 times the normal serum lactate level is indicative of lactic ketoacidosis. 
  • Salicylate level in serum: An elevated serum level of salicylate from oral medications can induce metabolic acidosis.
  • Iron serum level: Iron levels exceeding 300 mg/dl is already considered toxic and could consequently lead to metabolic acidosis. 
  • Electrocardiography (ECG): This test will detect rhythm abnormalities in the heart during eg. hyperkalemia.

Urine

  • Ketonuria

    Ketoacidosis • In patients with IDDM, alcoholics and pts undergoing fasting or starvation • due to the overproduction of ketone bodies (Ketosis) leading to accumulation of ketones in plasma (Ketonemia) and urine (Ketonuria). • In starvation states where [slideshare.net]

    Caution if ketonuria or drug anions are in the urine as it would invalidate the calculation. Diarrhea : UAG is a negative value. Renal tubular acidosis : UAG is positive value. As an aid, UAG is neGUTive when associated with bowel causes. [pulmonologyadvisor.com]

Serum

  • Hypercapnia

    Post-hypocapnia In prolonged hypercapnia renal tubular cells compensate for a prolonged respiratory alkalosis by decreasing reclaimation and generation of HCO 3 (which takes 12-24 hrs for full affect). [nimbot.com]

    Hypercapnia is usually the result of hypoventilation rather than of increased CO2 production. [accessmedicine.mhmedical.com]

    The development of normocapnia or hypercapnia when a severe metabolic acidosis is present often signals respiratory muscle fatigue, impending respiratory failure, and the possible need for initiating mechanical ventilation. [emedicine.com]

    In any condition, sodium bicarbonate may also cause sodium and volume overload, hypokalemia, and, by inhibiting respiratory drive, hypercapnia. [merckmanuals.com]

    […] mechanical ventilation settings Table 4 : Selected causes of metabolic alkalosis Hypovolemia with Cl- depletion GI loss of H+ Vomiting, gastric suction, villous adenoma, diarrhea with chloride-rich fluid Renal loss H+ Loop and thiazide diuretics, post-hypercapnia [thoracic.org]

  • Hypocapnia

    Post-hypocapnia In prolonged hypercapnia renal tubular cells compensate for a prolonged respiratory alkalosis by decreasing reclaimation and generation of HCO 3 (which takes 12-24 hrs for full affect). [nimbot.com]

    Blood gas analysis showed severe metabolic acidosis resulting in hypocapnia and a normal pH ( table 1 ). [anesthesiology.pubs.asahq.org]

    Underexcretion of CO2 produces hypercapnia, and overexcretion causes hypocapnia. Nevertheless, production and excretion are again matched at a new steady-state Paco2. [accessmedicine.mhmedical.com]

    Mineralocorticoid Deficiency Angiotensin Deficiency: Liver Failure ACE Inhibitor Renin Deficiency Aging Extracellular fluid volume expansion Lead Beta Blocker s Prostaglandin Inhibitor Methyldopa Carbonic anhydrase inhibitor Acetazolamide Mefenamic acid Post-hypocapnia [fpnotebook.com]

  • Lactate Decreased

    Likewise, no lactate decrease or a decrease of less than 20% in the first 2- to 4-h is associated with a worse prognosis in trauma patients [77]. Initial hyperlactatemia is also associated with a greater treatment burden. [annalsofintensivecare.springeropen.com]

Treatment

The goal in the treatment of metabolic acidosis is to raise the serum pH to more than 7.2 to prevent life-threatening complications like cardiac arrhythmia. The most common drug used to balance metabolic acidosis is sodium bicarbonate [8]. Bicarbonate deficit is generally computed as desired HCO3 is equal to HCO3 deficit per Liter multiplied by 0.5 times body weight.

This computation will give a crude estimate of the HCO3 deficit in serum where sodium bicarbonate is administered intravenously to correct the imbalance. In the same way potassium citrate can also be given to correct metabolic acidosis with hypokalemia. Oral sodium bicarbonate is indicated for metabolic acidosis states that requires exogenous bases or alkalis to correct [9]. Researches have determined that potassium citrate may be superior to sodium bicarbonate because it requires lesser volume and does propagate the unnecessary excretion of calcium ion in the urine [10].

Prognosis

In general, the prognosis of metabolic acidosis is related to the underlying condition that gave rise to it. Cohort studies have shown that mortality with metabolic acidosis is usually caused by unabated acidotic states from hyperchloremia [3]. Significant morbidity is also observable among patients with uncorrected and late correction of acid-base imbalances from the time of admission. Severe uncorrected metabolic acidosis can lead to shock or death.

Etiology

Medical conditions that lead to the buildup of acid in the body can potentially cause metabolic acidosis. These medical conditions include:

  • Diabetic ketoacidosis
  • Hyperchloremic acidosis
  • Alcoholism
  • Malignancy
  • Liver failure
  • Intense exercise
  • Sepsis
  • Heart failure
  • Acidic medications
  • Renal tubular acidosis
  • Renal failure [1]
  • Poisoning
  • Severe dehydration

Epidemiology

There are no exact epidemiologic data that give the incidence and prevalence of metabolic acidosis. The relative prevalence of this metabolic state is reflected in each primary disease etiology that result in this acidemic state. Moreover, metabolic acidosis is oftentimes underdiagnosed and underdocumented because metabolic acidosis is just a mere sign of a primary disease process.

Pathophysiology

In general, the basic pathophysiology of metabolic acidosis is two folds. There could be an increased acid production within any organ system or there is an inadequate production of bicarbonates from the buffering systems of the body [2]. The body regulates plasma acidity by means of these buffering systems: the bicarbonate buffering system, renal compensatory system, respiratory compensatory system, and the intracellular absorption of hydrogen atoms. The bicarbonate system receives the hydrogen from the acidic compounds and neutralizes them into carbon dioxide and water. Any imbalance in the buffering system moves the pH lower than 7.4 making the serum acidic.

Prevention

Prevention of metabolic acidosis is grossly dependent on the primary prevention of its underlying causes. Diabetic control is essential to prevent diabetic ketoacidosis from ensuing. Alcohol should be taken in moderation to avoid alcoholic ketoacidosis from taking place. Athletic sports and exercises should be done in moderation to prevent lactic acidosis from developing. The injudicious use of salicylate-base pain relievers and iron supplements must be checked to prevent it’s toxicity that may lead to metabolic acidosis.

Summary

Metabolic acidosis is defined as a medical condition where there is an imbalance of the acid-base ions causing plasma acidity. The metabolic acidosis state is usually a sign of underlying disease process. Correction of the primary cause of the metabolic imbalance will normalize or reverse the metabolic state. An indepth understanding of the nature of the acid-base regulation mechanism is required to understand the complex processes that give rise to metabolic acidosis.

Patient Information

  • Definition: Metabolic acidosis is defines as a clinical condition where there is an imbalance of the acid-base ions causing too much acid in plasma.
  • Cause: Ketoacidosis is the leading cause of metabolic acidosis which could be brought about by diabetes, alcoholism, starvation, and cancer. Hyperchloremic states with diarrhea and vomiting may also induce acidemic states in the serum.
  • Symptoms: Acidotic patients will present with varying degrees of dyspnea, hyperventilation, chest pains, palpitation, and bone pain. 
  • Diagnosis: The ideal workup for metabolic acidosis include ABG, CBC, serum lactate levels, and ECG readings. 
  • Treatment and follow-up: The prompt correction of the acidemic state is imperative to prevent life-threatening arrhythmia. Patients may be given sodium bicarbonate intravenously, oral sodium bicarbonate, and potassium citrate to correct the metabolic acidosis.

References

  1. Morimatsu H, Toda Y, Egi M, et al. Acid-base variables in patients with acute kidney injury requiring peritoneal dialysis in the pediatric cardiac care unit. J Anesth. 2009; 23(3):334-40.
  2. Mitch WE. Metabolic and clinical consequences of metabolic acidosis. J Nephrol. 2006; 19 Suppl 9:S70-5 (ISSN: 1121-8428)
  3. Maciel AT, Park M. Differences in acid-base behavior between intensive care unit survivors and nonsurvivors using both a physicochemical and a standard base excess approach: a prospective, observational study. J Crit Care. Dec 2009; 24(4):477-83.
  4. Schauer KL, Freund DM, Prenni JE, Curthoys NP. Proteomic profiling and pathway analysis of the response of rat renal proximal convoluted tubules to metabolic acidosis. Am J Physiol Renal Physiol. 2013; 305(5):F628-40 
  5. Pereira PC, Miranda DM, Oliveira EA, Silva AC. Molecular pathophysiology of renal tubular acidosis. Curr Genomics. Mar 2009; 10(1):51-9.
  6. Reddy P, Mooradian AD. Clinical utility of anion gap in deciphering acid-base disorders. Int J Clin Pract. Oct 2009; 63(10):1516-25.
  7. Mathur RP, Dash SC, Gupta N, Prakash S. Effects of correction of metabolic acidosis on blood urea and bone metabolism in patients with mild to moderate chronic kidney disease: a prospective randomized single blind controlled trial. Ren Fail. 2006; 28(1):1-5.
  8. Goraya N, Simoni J, Jo CH, Wesson DE. A comparison of treating metabolic acidosis in CKD stage 4 hypertensive kidney disease with fruits and vegetables or sodium bicarbonate. Clin J Am Soc Nephrol. Mar 2013; 8(3):371-81.
  9. Abramowitz MK, Melamed ML, Bauer C, Raff AC, Hostetter TH. Effects of oral sodium bicarbonate in patients with CKD. Clin J Am Soc Nephrol. May 2013; 8(5):714-20.
  10. Starke A, Corsenca A, Kohler T, Knubben J, Kraenzlin M, Uebelhart D, et al. Correction of metabolic acidosis with potassium citrate in renal transplant patients and its effect on bone quality. Clin J Am Soc Nephrol. Sep 2012; 7(9):1461-72.
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