In general RTA is asymptomatic, but it might involve some bone dysfunctions such as bone pain, osteomalacia in adults and rickets in children due to the marked levels of demineralization, which is particularly frequent in Type 1 and Type 2 RTA. In these types bone involvement is frequently combined with nephrolithiasis and nephrocalcinosis.

The signs and symptoms of hypokalemia, such as muscle weakening, hyporeflexia, and paralysis, are evident, especially in the already mentioned Type 1 and Type 2 RTA. These can sometime be combined with severe electrolyte disturbances, although these are very rare. Type 4 RTA too is usually asymptomatic, apart from a mild acidosis, but if hyperkalemia is severe cardiac arrhythmias or paralysis might become clearly pronounced. Type 2 RTA might also present with signs of extracellular fluid volume depletion due to urinary water loss and marked electrolyte excretion.

• Anemia

  These can vary in severity from no symptoms to a condition called hemolytic anemia, in which red blood cells prematurely break down (undergo hemolysis), causing a shortage of red blood cells (anemia). [medicalneed.com]

  Two patients aged 53 and 51 presented following HNV bites with acute kidney injury and microangiopathic hemolytic anemia. Both underwent multiple cycles of hemodialysis until the polyuric phase was reached. [ncbi.nlm.nih.gov]

  A recessive subtype of dRTA associated with anemia has also been described in Southeast Asia. AR forms are frequently diagnosed in infants and young children. AD dRTA is mostly diagnosed in adolescents and young adults. [orpha.net]

• Poor Feeding

  Poor feeding, vomiting, and failure to thrive may be presenting symptoms in the initial years of life. Distal RTA seen in childhood is usually primary or inherited. [lecturio.com]

• Failure to Thrive

  Clinical symptoms vary from mild acidosis, incidental detection of kidney stones or renal tract calcification to severe findings such as failure to thrive, severe metabolic acidosis, and nephrocalcinosis. [ncbi.nlm.nih.gov]

  Evaluation of Failure to Thrive: Diagnostic Yield of Testing for Renal Tubular Acidosis. Pediatrics. 2003;112: e463–e466. Belldina EB, Huang MY, Schneider JA, Brundage RC, Tracy TS. [pedclerk.bsd.uchicago.edu]

  Clinical Manifestations In children the clinical spectrum is nonspecific including anorexia, failure to thrive, vomiting and dehydration, constipation, polyuria, and polydipsia. [renaltube.com]

  Failure to thrive, rickets, stunting of growth (seen in children) and osteomalacia or osteopenia (seen in adults) are a result of urinary calcium wastage and a loss of calcium salts from the bones. [orpha.net]

• Polydipsia

  […] hemoglobinuria Renal transplant rejection Drugs : ifosfamide, tenofovir, outdated tetracyclines, aminoglycosides Heavy metal poisoning (e.g., lead, cadmium, mercury ) Clinical features Vitamin D -resistant rickets / osteomalacia Stunted growth Polyuria → polydipsia [amboss.com]

  Clinical Manifestations In children the clinical spectrum is nonspecific including anorexia, failure to thrive, vomiting and dehydration, constipation, polyuria, and polydipsia. [renaltube.com]

  Presentation: Polyuria, polydipsia, proximal myopathy. Osteomalacia or rickets. Investigations: Hypokalaemia, hyperchloraemic metabolic acidosis. Treatment: High doses of bicarbonate are required but the prognosis is good. [patient.info]

  Patients with dRTA can be asymptomatic or can present with polyuria, polydipsia, weakness and fatigue (symptoms associated with hypokalemia). [orpha.net]

• Loss of Appetite

  […] of water from body tissues), bloody urine, decreased or increased urine output, and loss of appetite resulting in the inability to eat. [medfriendly.com]

• Bone Pain

  […] caused by multiple myeloma, heavy metal poisoning, or certain drugs Inability to reabsorb bicarbonate from the urine, so too much bicarbonate is excreted High blood acidity Fragile bones Bone pain Mild dehydration Low potassium levels in the blood Decreased [msdmanuals.com]

  This bone disorder is characterized by bone pain, bowed legs, and difficulty walking. [medicalneed.com]

• Irritability

  Fecal transplant is used to treat gut infections and is now being studied as a treatment for obesity, urinary tract infections, irritable bowel syndrome and more. [nytimes.com]

  However, although the ammonium chloride test lasts eight hours and does not require blood testing, it can be unpleasant for some patients, because gastric irritation, nausea, and vomiting are common. [casesjournal.biomedcentral.com]

• Polyuria

  Despite polyuria, both patients developed resistant hyperkalemia that needed further hemodialysis. The urinary pH, arterial pH, delta ratio, and transtubular potassium gradient confirmed RTA4. [ncbi.nlm.nih.gov]

  […] nocturnal hemoglobinuria Renal transplant rejection Drugs : ifosfamide, tenofovir, outdated tetracyclines, aminoglycosides Heavy metal poisoning (e.g., lead, cadmium, mercury ) Clinical features Vitamin D -resistant rickets / osteomalacia Stunted growth Polyuria [amboss.com]

  Clinical Manifestations In children the clinical spectrum is nonspecific including anorexia, failure to thrive, vomiting and dehydration, constipation, polyuria, and polydipsia. [renaltube.com]

  Presents with polyuria, hypernatraemia and uraemia. Phosphate-handling disorders [ 11 ] The kidney is largely responsible for controlling extracellular phosphate levels, under the control of parathyroid hormone. [patient.info]

• Kidney Failure

  This alkali therapy also helps decrease the development of kidney stones and stabilizes kidney function so kidney failure does not progress. [niddk.nih.gov]

  Kidney failure is rare if the other kidney is working normally. However, kidney failure will occur if there is only one functioning kidney. UTI and pain may also occur. [mclaren.org]

  In rare cases, these kidney abnormalities lead to life-threatening kidney failure. Affected individuals may also have low levels of potassium in the blood (hypokalemia). [medicalneed.com]

  Complications of RTA include stunting of growth, bone problems (rickets in children and osteomalacia in adults), and kidney damage (kidney stones and kidney failure). [medindia.net]

• Renal Insufficiency

  […] of kidney and ureter, unspecified 2016 2017 2018 2019 Billable/Specific Code Applicable To Nephropathy NOS Renal disease (acute) NOS Renal insufficiency (acute) Type 1 Excludes chronic renal insufficiency ( N18.9 ) unspecified nephritic syndrome ( N05 [icd10data.com]

  Although a metabolic acidosis also occurs in those with renal insufficiency, the term RTA is reserved for individuals with poor urinary acidification in otherwise well-functioning kidneys. [en.wikipedia.org]

  insufficiency in a patient with Waldenström's macroglobulinemia. [casesjournal.biomedcentral.com]

• Renal Function Impairment

  Protein-losing nephropathy Proximal renal tubular acidosis Pseudohypoaldosteronism, type 2 Renal function impairment with growth failure Renal tubular acidosis Renal tubular acidosis type 4 Renal tubular acidosis with progressive nerve deafness Renal [icd9data.com]

  ICD-10-CM Codes › N00-N99 Diseases of the genitourinary system › N25-N29 Other disorders of kidney and ureter › N25- Disorders resulting from impaired renal tubular function › Other disorders resulting from impaired renal tubular function 2016 2017 2018 [icd10data.com]

In adults the diagnosis of RTA is largely based on the observation of unexplained and incidental laboratory findings regarding blood, electrolyte concentrations and acid-base parameters, while in children it is mainly based on growth retardation, rickets, and failure to thrive.

Studying the clinical history might be useful, as many metabolic diseases, such as diabetes mellitus and adrenal insufficiency, can substantially increase the predisposition to RTA. The study of the patient’s clinical history should also include past exposure to certain drugs and toxins, which as previously seen might damage the nephron tubule both in the distal and the proximal region. The harmful drugs include carbonic anhydrase inhibitors, amphotericin-B, and ibuprofen, while RTA-inducing toxins include heavy metals and cis-platinum.

Laboratory evaluation of blood, urine acid-base parameters and electrolyte concentrations can be performed with routine procedures regularly used in clinical settings. Usually, low plasma bicarbonate concentrations is observed in both acidosis and respiratory alkalosis. Therefore, differentiation between these two disorders in paramount. In this regard, observing elevated pH levels might be very useful, as it can cause low plasma bicarbonate levels in the cases of respiratory alkalosis. The plasma anion gap is normal in all type of RTA, therefore increased levels of this parameter should suggest the presence of another type of acidosis [20] [21]. In general, decreased plasma bicarbonate levels, hyperchloremia, acidemia, and a normal serum anion gap should support the diagnosis of RTA.

Urine analysis should show impaired urinary acidification and failed bicarbonate reabsorption, while plasma bicarbonate should be low and coupled with hyperchloremia. Aldosterone deficiency or resistance can be indicated by hyperkalemia in the cases of distal RTA.

Furthermore, radiologic findings can be useful for the diagnosis of RTA. Abdominal X-ray or abdominal CT scan can detect nephrocalcinosis and the presence of stones in the kidneys in the cases of classic distal RTA. Evaluation of urinary tract obstruction, instead, can be performed with ultrasound, nuclear renal scan, or spiral CT scan in the case of hyperkalemic distal RTA.

• Nephrolithiasis

  Nephrolithiasis, which may occur in any of the subsets of type I renal tubular acidosis, accounts for most of the morbidity in adults and adolescents. Major risk factors for nephrolithiasis include alkaline urine, hypercalciuria and hypocitraturia. [ncbi.nlm.nih.gov]

  Hypercalciuria can often lead to nephrocalcinosis or nephrolithiasis. The risk of nephrocalcinosis/nephrolithiasis is further increased by high urine pH and hypocitraturia, which is caused by proximal citrate reabsorption induced by acidosis. [lecturio.com]

• Glycosuria

  The blood salicylate level was undetectable, and a urinalysis showed glycosuria, proteinuria and elevated beta-2 microglobulin and n-acetyl glucosamine levels, with a normal urinary pH despite the acidosis. [ncbi.nlm.nih.gov]

  Patients with this generalized abnormality, the Fanconi syndrome, usually have glycosuria, aminoaciduria, citraturia, and phosphaturia. [ommbid.mhmedical.com]

  Glycosuria (1.83 g/L) was found on urinalysis with normal blood glucose. Urinary potassium excretion was relatively high (51 mEq/day) despite the presence of hypokalemia. [sjkdt.org]

• Hyperchloremia

  Based on clinical findings (delayed growth and O-bein deformity) and laboratory tests (hypokalemia, hyperchloremia, partially compensated metabolic acidosis, alkaline urine and nephrocalsinosis), a diagnosis of distal renal tubular acidosis (dRTA) was [ncbi.nlm.nih.gov]

  Hyperchloremia is usually present, and secondary derangements may involve other electrolytes, such as potassium (frequently) and calcium (rarely—see table Some Features of Different Types of Renal Tubular Acidosis* ). [msdmanuals.com]

  Features Chronic metabolic acidosis with hyperchloremia and normal anion gap. Urinary pH is usually over 5.5 although acidemia with normal glomerular function. [renaltube.com]

  See also: primary renal tubular acidosis, secondary renal tubular acidosis. renal tubular acidosis (RTA) an abnormal condition associated with persistent dehydration, metabolic acidosis, hypokalemia, hyperchloremia, and nephrocalcinosis. [medical-dictionary.thefreedictionary.com]

• Hypophosphatemia

  In each case, defects of tubular function are not limited to bicarbonate or acid transport and may include defects in resorption of glucose, amino acids, and phosphate yielding concomitant glucosuria, Aminoaciduria, and hypophosphatemia. [pathwaymedicine.org]

  Laboratory investigations revealed chronic kidney disease with serum creatinine of 2.3 mg/dL and creatinine clearance of 40 mL/min, hypokalemia (3.2 mmol/L), hypophosphatemia (0.4 mmol/L), hypocalcemia (2.14 mmol/L) and hyperchloremic metabolic acidosis [ncbi.nlm.nih.gov]

  Laboratory testing is significant for hyperchloremic metabolic acidosis, hypophosphatemia, and hypokalemia. Urinalysis is notable for a urine pH < 5.5, aminoaciduria, and glucosuria. (Fanconi syndrome leading to a type II renal tubular acidosis.) [step2.medbullets.com]

  Clinical features otherwise depend on the type of renal tubular acidosis: type 1: hypercalciuria, polyuria, impaired growth, nephrocalcinosis, urolithiasis and hypokalemia 2 type 2: rickets and osteomalacia are not usually seen unless hypophosphatemia [radiopaedia.org]

  […] above 5.3 if they are getting bicarb – as excess bicarb is spilled into urine, but it can be less than 5.3 if they are not getting bicarb and have an acidic diet Look for other proximal tubular defects: glucosuria (with normal serum glu), proteinuria, hypophosphatemia [hospitalmedicine.org]

• Hypophosphatemia

  In each case, defects of tubular function are not limited to bicarbonate or acid transport and may include defects in resorption of glucose, amino acids, and phosphate yielding concomitant glucosuria, Aminoaciduria, and hypophosphatemia. [pathwaymedicine.org]

  Laboratory investigations revealed chronic kidney disease with serum creatinine of 2.3 mg/dL and creatinine clearance of 40 mL/min, hypokalemia (3.2 mmol/L), hypophosphatemia (0.4 mmol/L), hypocalcemia (2.14 mmol/L) and hyperchloremic metabolic acidosis [ncbi.nlm.nih.gov]

  Laboratory testing is significant for hyperchloremic metabolic acidosis, hypophosphatemia, and hypokalemia. Urinalysis is notable for a urine pH < 5.5, aminoaciduria, and glucosuria. (Fanconi syndrome leading to a type II renal tubular acidosis.) [step2.medbullets.com]

  Clinical features otherwise depend on the type of renal tubular acidosis: type 1: hypercalciuria, polyuria, impaired growth, nephrocalcinosis, urolithiasis and hypokalemia 2 type 2: rickets and osteomalacia are not usually seen unless hypophosphatemia [radiopaedia.org]

  […] above 5.3 if they are getting bicarb – as excess bicarb is spilled into urine, but it can be less than 5.3 if they are not getting bicarb and have an acidic diet Look for other proximal tubular defects: glucosuria (with normal serum glu), proteinuria, hypophosphatemia [hospitalmedicine.org]

• Hyponatremia

  It is associated with increased renin activity, hyponatremia, hyperkalemia and volume depletion. [netscut.templaro.com]

  Non-SIG Acidosis (Drip or IV Fluid) SIG Acidosis (As an IV Fluid) Increased ICP (Drip) Hyperkalemia (As an IV Fluid) Hyponatremia (Drip) ICP NaBicarb can be used as a substitute for hypertonic saline in increased ICP (Neurocrit Care 2010;13:24 & Neurocrit [emcrit.org]

  Type I pseudohypoaldosteronism involves a defect at the aldosterone receptor level and is associated with salt wasting, volume depletion, and hyponatremia.1 Plasma renin and aldosterone levels are increased. [healio.com]

• Abnormal Renal Function

  Admission blood tests demonstrated abnormal renal function with a urea of 22 mmol/l (normal: 2.5–7.0 mmol/l) and creatinine of 176 µmol/l (normal: 60–110 µmol/l). Serum potassium was reduced at 2.9 mmol/l (normal: 3.6–5.0 mmol/l). [academic.oup.com]

The first goal of the treatment of RTA is to restore blood pH and bicarbonate levels, which can be done by giving the patient daily doses of sodium-bicarbonate or a solution of sodium citrate and citric acid (Shohl solution).

In Type 1 (distal) RTA alkali replacement therapy is performed to correct metabolic acidosis and maintain plasma potassium levels, so than consumption of skeleton and muscle mass can be prevented. Potassium deficits might be significant, but its administration should be controlled to avoid adverse side effects. If necessary, potassium supplements can be provided.

In Type 2 (proximal) RTA patients usually need higher doses of alkali which can be provided by adjusting the Shohl solution concentration accordingly. Also in this case, potassium supplements might be provided if necessary. It should be noted that as more alkali is given and bicarbonaturia increases, urinary potassium loss is exacerbated. In this case, to generate a mild volume depletion and increase proximal reabsorption, hydrochlorothiazide can be given to patients. However, this drug might worsen potassium loss, thus potassium supplementation is highly advised also in this case.

Replacement of bicarbonate loss is paramount in Fanconi syndrome, which can be done by following the same treatment for Type 2 RTA. Phosphate supplementation and vitamin D are required, while amino acids loss can be addressed by following an appropriate diet. The description of the treatments for the other metabolic disorders usually associated with Fanconi syndrome goes beyond the purposes of this discussion.

The major issues in Type IV RTA are acidosis and hyperkalemia, which in this condition might be severe. Correction of potassium overload might cause acidosis to increase significantly, due to increased ammonia production and excretion. Therefore, the doctor and patient should pay particular attention to avoid drugs associated with hyperkalemia and salt substitutes containing potassium. When Type 4 RTA is caused by aldosterone deficiency, fludrocortisones might be provided as replacement, while dietary potassium restriction is effective when hyperkalemic distal RTA is the result of inappropriate response to aldosterone. In these cases patients do not respond to fludrocortisone, which should be replaced by furosemide or other loop diuretics. Patients can received Shohl solution, while K-Shohl solution and other forms of citric acid preparations should be avoided.

The prognosis is good, especially in terms of prevention of renal stone formation and amelioration of nephrocalcinosis in the cases of distal RTA. If treatment is started early, it can even restore growth in children with severe proximal RTA, serum potassium can be controlled and acidosis ameliorated in the cases of hyperkalemic distal RTA, even though the long-term outcomes of treatment are still unknown.

The prognosis for Fanconi syndrome depends on the clinical case considered. If the disorder is due to inherited metabolic diseases, prognosis might not be good, and patients might fail to recover. The situation is different when it comes to cases of RTA due to drugs or toxin exposure, where the Fanconi syndrome resolves once the kidneys heal from the injury and recovery can occur once the toxin is removed and further exposure is avoided.

By contrast, in the cases of proteinuria-associated diseases the prognosis largely depends on the treatment of the primary disorder, which is really responsible for the kidney dysfunction, and recovery is only possible when this primary disorder is under control.

The etiology of RTA includes a variety of many factors which can be either genetic and acquired in nature. The genetic etiological factors involve mutations in the genes of those proteins with key role in the renal function. For instance, one of the most important of these genetic factors is represented by the mutations that occur in the gene decoding proton pump and anion exchanger, responsible for removing bicarbonates from the tubule [2] [3] [4] [5] [6], or on the gene decoding the sodium bicarbonate cotransporter [7] [8] [9]. The acquired factors include episodes of interstitial inflammation and injury [10] [11], responsible for tubule cell injury and loss of proton pumps [12]  [13], or aldosterone deficiency [14] [15]. RTA might also be triggered by the use of many drugs, such as amphotericin B, toluene, and nonsteroidal anti-inflammatory drugs (NSAIDs).

Particularly frequent as etiological factor is also Fanconi syndrome, a disease of the proximal renal tubules in which glucose, amino acids, uric acid, phosphate and bicarbonate are lost in great quantity into the urine instead of being reabsorbed. The syndrome affects the proximal tubule and might have genetic origins, even though it is frequently associated to the use of certain drugs or the ingestion of heavy metal.

The prevalence and incidence of RTA are not exactly known as the disorder is often not recognized and its frequency underestimated. However, inherited forms of RTA appear to be much rarer then acquired ones [7] [16] such as those due to renal failure. In the US, the most common forms of RTA are hyperkalemic distal RTA in urinary tract obstruction and hyperkalemic distal RTA secondary to aldosterone deficiency in diabetes.

Fanconi syndrome is very rare as primary cause of RTA, while metal exposure varies significantly according to the location, residence, occupation and in general the social status of the people affected. The incidence of RTA induced by drugs has been constantly increasing over the last years, perhaps due to the unclear side effects or the not always well-defined pharmacological interaction among these medications.

The pathophysiology of RTA varies according to the type and its etiological factor. There are four type of RTA: Type 1 (distal) RTA, Type 2 (proximal) RTA, Type 3 RTA, and Type 4 RTA.

• Type 1 (distal) RTA: This is the first described form of RTA. It is caused by the failure of the alpha intercalated cells of the medullary collecting duct in the distal region of the nephron to secret H+ into the lumen of the duct itself. The failed elimination of H+ causes acidemia in the body, which is combined with hypokalemia due to an inadequate re-absorption of K+ [1]. The proton retention and potassium excretion result in urine stone formation, which is a typical characteristic of this type of RTA not seen in the others, as well as bone demineralization due to this mineral loss. There can be several reasons for the failure of alpha intercalated cells.
• Type 2 (proximal) RTA: In this case the failure interests the proximal tubule of the nephron, where the tubular cells fail to reabsorb filtered bicarbonate from the urine. Because of the proximal position of the problem, this type of RTA does not severely limit the level of urine acidification, which can be lower than 5.3, even though bicarbonate wasting and in general acidemia remain substantial. This form is generally associated with the already mentioned Fanconi syndrome, as general pathological condition affecting the proximal tubule of the nephron due to the inability of reabsorbing several compounds of primary physiological importance. This in turn causes phosphaturia, uricosuria, aminoaciduria, and tubular proteinuria that result in a marked bone demineralization.
• Type 3 RTA (combined proximal and distal RTA): This form of RTA is a combination of Type 1 and Type 2, rarely seen in infants and children. It is mainly due to mutations on the gene of carbonic anhydrase II, an enzyme responsible for the rapid interconversion of carbon dioxide and water into bicarbonate and protons, resulting not only in RTA but also in osteoporosis, cerebral calcification, and mental retardation [17] [18] [19].
• Type 4 RTA: Rather than a form of RTA, Type 4 is more a consequence of hypoaldosteroism, a phatological condition characterized by decreased plasma levels of aldosterone, resulting in a physiological reduction of proximal tubular ammonium excretion and decreased urine buffering capacity. Sometime type 4 RTA can be caused by pseudohypoaldosteronism, a condition mimicking hypoaldosteroism as it is caused by the failure to respond aldosterone rather than the decreased plasma levels of this hormone, or by some drugs like non-steroidal anti-inflammatory drugs (NSAIDs), ACE inhibitors or Angiotensin II receptor blockers (ARBs). The main feature of this type is hyperkalemia, while the levels of urine acidification remain normal. 

Patients are recommended to take alkali on a daily basis. Mixed solution of cold water or lemonade with sweeteners might be a very effective prevention measure, together with a strict avoidance of potassium foods and drugs causing hyperkalemia. As RTA is a lifelong issue, prevention measures should always be followed by patients through prevention programs previously planed with the doctor.

The cause of renal tubular acidosis (RTA) lays in a dysfunction of the kidneys. In normal conditions, blood is filtered in the kidneys through the action of their functional unit known as nephron. The filtrate produced by this system passes through a long tubule where it is progressively processed, allowing the exchange of salts and other important biological compounds which then drain into the bladder to be expelled as urine. Such system is pivotal for maintaining the biochemical balance of blood plasma, that has to be continuously kept within the appropriate physiological ranges.

RTA occurs when this system fails to recover a sufficient quantity of bicarbonates from the filtrate and to secrete the appropriate quantity of hydrogen ions into the urine, in other words an insufficient urinary acidification without urea and anion retention. This condition is an example of metabolic acidosis, a term which indicates a decrease of the plasma pH. Episodes of metabolic acidosis might also be triggered by renal insufficiency, but it is only in RTA that can develop in physiologically-functioning kidneys.

Renal tubular acidosis (RTA) is a pathological condition in which a increased quantity of acid can be seen in plasma due to the failure of kidneys to acidify urine in a proper manner. The consequence of this condition is an impaired balance of major plasma physiological parameters, such as pH, bicarbonate levels and amino acids concentration, which result in the main features of RTA, like acidemia, hypokalemia or bone demineralization. There are four types of renal tubular acidosis.

Patients are recommended to take alkali on a daily basis. Mixed solution of cold water or lemonade with sweeteners might be a very effective prevention measure, together with a strict avoidance of potassium foods and drugs causing hyperkalemia. As RTA is a lifelong issue, prevention measures should always be followed.

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3. Karet FE, Finberg KE, Nelson RD, et al: Mutations in the gene encoding the B1 subunit of H+-ATPase cause renal tubular acidosis with sensorineural deafness. Nat Genet. 1999;21:84-90.
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14. DeFronzo, RA. Hyperkalemia and hyporeninemic hypoaldosteronism. Kidney Int. 1980;17:118-134. 
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18. Shah GN, Bonapace G, Hu PY, Strisciuglio P, Sly WS. Carbonic anhydrase II deficiency syndrome (osteopetrosis with renal tubular acidosis and brain calcification): novel mutations in CA2 identified by direct sequencing expand the opportunity for genotype-phenotype correlation. Hum. Mutat. 2004 24 (3): 272.
19. Pushkin A, Abuladze N, Gross E et al. Molecular mechanism of kNBC1-carbonic anhydrase II interaction in proximal tubule cells. J. Physiol. 2004 (Lond.) 559 (Pt 1): 55–65.
20. Emmett M, Narins RG. Clinical use of the anion gap. Medicine (Baltimore). 1977;56:38-54.
21.  Oh MS, Carroll HJ. Value and determinants of urine anion gap. Nephron. 2002;90:252-255.