A Review on Comprehensive Management of Renal Tubular Acidosis

Renal regulation of acid-base balance

The biochemical processes involved in human metabolism result in an acid excess on a daily basis, due to dietary contribution to acid formation and intestinal loss of bases.¹Both T, Zietse R, Hoorn EJ, et al. Everything you need to know about distal renal tubular acidosis in autoimmune disease. Rheumatol Int. 2014 Aug;34(8):1037-45. However, the kidneys maintain the acid base homeostasis by reabsorbing filtered HCO₃ – and excreting H+ through the titration of urinary buffers and the excretion of ammonium.²Rodriguez Soriano J. Renal tubular acidosis: the clinical entity. J Am SocNephrol. 2002 Aug;13(8):2160-70

HCO₃ – reabsorption

Approximately 80% of the filtered HCO₃ – is reabsorbed by the proximal tubule, while the thick ascending limb and distal convoluted tubule reabsorbs 16%, and the cortical duct reabsorbs the remaining HCO3 – (4%).³Koeppen BM. The kidney and acid-base regulation. AdvPhysiol Educ. 2009 Dec;33(4):275-81

Absorption of HCO₃ – by cells of the proximal convulated tubule (PCT)

Within the cells of PCT, hydration of CO₂ causes formation of H₂CO₃²Rodriguez Soriano J. Renal tubular acidosis: the clinical entity. J Am SocNephrol. 2002 Aug;13(8):2160-70
The H2CO₃ ionizes into H⁺ and HCO₃ -. This is catalyzed by carbonic anhydrase II (CA II). The generated H⁺ is secreted across the apical membrane into the lumen of PCT by a Na⁺/H⁺antiporter , while the HCO₃ – leaves the cell to enter the blood by passive Na⁺– HCO₃ -cotransport²Rodriguez Soriano J. Renal tubular acidosis: the clinical entity. J Am SocNephrol. 2002 Aug;13(8):2160-70
In the tubular lumen, the secreted H⁺ combines with the filtered HCO₃ – in the lumen to form H2CO3 which dissociates into H₂O and CO₂ under the influence of CA IV. The CO₂ enters cell while the H₂O is discarded.²Rodriguez Soriano J. Renal tubular acidosis: the clinical entity. J Am SocNephrol. 2002 Aug;13(8):2160-70

HCO₃ reabsorption in the thick ascending limb of the loop of Henle and the distal convulated tubule

Cellular mechanisms of reabsorption of HCO₃ – is comparable to the mechanisms in the proximal tubule. However, the isforms of the transporters are different.²Rodriguez Soriano J. Renal tubular acidosis: the clinical entity. J Am SocNephrol. 2002 Aug;13(8):2160-70

H+ secretion from the cortical duct

Intercalated cells are responsible for H⁺ and HCO₃ – transport²Rodriguez Soriano J. Renal tubular acidosis: the clinical entity. J Am SocNephrol. 2002 Aug;13(8):2160-70
HCO₃ – exits the cells across the basolateral membrane in exchange for Cl^-2
In addition, the secreted H⁺ can combine with other luminal constituents (termed urinary buffers), such as phosphate²Rodriguez Soriano J. Renal tubular acidosis: the clinical entity. J Am SocNephrol. 2002 Aug;13(8):2160-70
The secreted H⁺ also combines with NH₃ to form NH₄⁺.²Rodriguez Soriano J. Renal tubular acidosis: the clinical entity. J Am SocNephrol. 2002 Aug;13(8):2160-70

Production and excretion of NH₄⁺

Glutamine is metabolized within the cells of the proximal tubule into two molecules each of NH₄⁺ and HCO₃^-3. The NH₃⁺ is excreted into the lumen of the tubule, and the HCO₃ – is returned to the blood³Koeppen BM. The kidney and acid-base regulation. AdvPhysiol Educ. 2009 Dec;33(4):275-81
NH₃⁺ is reabsorbed by the thick ascending loop of Henle and accumulates in the renal medullary interstitial space and is resecreted into the lumen by the collecting duct.³Koeppen BM. The kidney and acid-base regulation. AdvPhysiol Educ. 2009 Dec;33(4):275-81

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Renal response to acidosis

The renal response to acidosis can be summarized as:

Stimulation of H⁺ and HCO₃ – transport by stimulating transporter activity, kinetics and availability,increasing ammoniagenesis, and increasing availability of urinary buffers (i.e., phosphate) by stimulating parathyroid hormone (PTH) secretion
During acidosis, endothelin-1 and glucocorticoids also influence the transporters
Acidosis results in an increases in the quantity of Rhglycoprotein in the collecting duct. Rh glycoproteins are NH4+ transporters and therefore the secretion and excretion of NH₄ ⁺ is increased.

Analysis of acid-base balance

The Henderson-Hasselbalch equation provides the status of a patient’s acid–base status but does not differentiate between the different mechanisms which can lead to acid-base disorder. An improved model to distinguish between the metabolic and the respiratory contributions was developed by Siggaard-Anderson, also known as the standard (base excess) model of acid-base balance.However, two large series have documented a normal BE in one-sixth of critically ill patients with acid–base disorders.Also, the BE model does not suggest an etiology for the acid–base disorder. To address these shortcomings, the anion gap (AG) method and the Stewart method were developed.⁴Fidkowski C, HelstromJ.Diagnosing metabolic acidosis in the critically ill: bridging the anion gap, Stewart, and base excess methods. Can J Anaesth. 2009 Mar;56(3):247-56

The anion gap (AG) method of acid base analysis

The AG is an indicator of acid accumulation and it quantifies changes in the plasma ion composition. The dissociation of strong acids causes a decrease in buffer and an increase in conjugate base, however, electroneutrality is maintained.⁴Fidkowski C, HelstromJ.Diagnosing metabolic acidosis in the critically ill: bridging the anion gap, Stewart, and base excess methods. Can J Anaesth. 2009 Mar;56(3):247-56

The AG is defined as the difference between the unmeasured plasma anions and the unmeasured plasma cations and it is derived from the principle of electroneutrality, such that:

Na⁺ + K⁺ + Mg²⁺ + Ca²⁺ + H⁺ = Cl- + HCO₃– + protein- +PO₄^2- + OH^– + SO₄^2- + CO₃^2- + XA^–

The plasma concentration of OH^–, SO₄^2-, CO₃^2-, and H⁺ isnegligible and therefore they can be ignored . The plasma concentrations of Na+, K+, Cl^–, and HCO₃^– can be determined by standard laboratory reports. The remaining anion species, protein-, PO₄^2-, and XA^–, constitute the unmeasured anions (UA), whereas Mg²⁺ and Ca²⁺, are the unmeasured cations (UC).

Simple algebraic rearrangement of the electroneutrality equation results in the following equation:

AG = UA – UC = (Na⁺ + K⁺) – (Cl^– + HCO₃ ^–)A normal AG is 12 ± 4 mEq/l.

The anion gap (AG), which corresponds to the presence of unmeasured anions, allows for the differentiation of two groups of metabolic acidosis. Metabolic acidosis with a high AG is associated with acid accumulation from increased acid production or acid ingestion. Metabolic acidosis with a normal AG is associated with the loss of HCO₃ – , or the failure to excrete H+. When metabolic acidosis occurs without an increase in the anion gap, the chlorideconcentration is typically increased.⁵Laing CM, Unwin RJ. Renal tubular acidosis. J Nephrol. 2006;19(Suppl.9):S46-52.

Stewart method of acid-base balance

Canadian physiologist, Peter Stewart explained acid-base physiology by a quantitative physiochemical model, which analyses a physiologic system on a mathematical basis.⁶Story DA .Stewart Acid-Base: A Simplifid Bedside Approach. Anesth Analg.2016 Aug;123(2):511-5

The Stewart system can be conceptualized as a solution containing :

Strong ions that are completely dissociated at physiologic pH. The strong cations are Na⁺, K⁺, Ca²⁺,and Mg²⁺, and the strong anion is Cl ^–. The difference between the aggregate cations and anions is known as the apparent strong ion difference (SID), i.e.,SIDApp = (Na⁺ + K⁺ + Ca²⁺ + Mg²⁺) – (Cl^–)⁴
Weak acids that are partially dissociated at physiologic pH. The total concentration of weak acids is symbolized as A_TOT ⁴Fidkowski C, HelstromJ.Diagnosing metabolic acidosis in the critically ill: bridging the anion gap, Stewart, and base excess methods. Can J Anaesth. 2009 Mar;56(3):247-56
Partial pressure of carbon dioxide (pCO₂) that is in equilibrium with an external partial pressure of carbon dioxide.⁴Fidkowski C, HelstromJ.Diagnosing metabolic acidosis in the critically ill: bridging the anion gap, Stewart, and base excess methods. Can J Anaesth. 2009 Mar;56(3):247-56

The basic principles of Stewart’s analysis are:

Only three independent variables are considered,specifically, the SID, the ATOT, and the pCO₂
Acid base balance can only be disrupted by changes in these independent variables (SID, A_TOT, and pCO₂)and the changes in the dependent variables, H⁺ and HCO3 ^–, are secondary⁴Fidkowski C, HelstromJ.Diagnosing metabolic acidosis in the critically ill: bridging the anion gap, Stewart, and base excess methods. Can J Anaesth. 2009 Mar;56(3):247-56
Metabolic acid- base disorders result from changes in either ATOT or SID. Changes in pCO₂ result in respiratory acid-base disorders as pCO₂ is regulated by respiration⁴Fidkowski C, HelstromJ.Diagnosing metabolic acidosis in the critically ill: bridging the anion gap, Stewart, and base excess methods. Can J Anaesth. 2009 Mar;56(3):247-56
Under pathologic conditions, additional strong anions (XA^–) such as lactate, sulfate, ketoacids, salicylate, and formate may be present. As a result,the SID will change such that the effective SID (SIDEff) becomes:

SID_Eff = [Na⁺ + K⁺ + Ca²⁺ + Mg²⁺] – [Cl^– + XA^–]

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The strong anions are conjugate bases, which indicate the presence of acids and the strong cations are the conjugate acids, which indicate the presence of bases.A net increase in cations results in an increased SID and indicates a metabolic alkalosis. A net increase in anions cause a decrease in SID, which indicates metabolic acidosis.At physiologic pH of 7.44, the SID is positive.⁴Fidkowski C, HelstromJ.Diagnosing metabolic acidosis in the critically ill: bridging the anion gap, Stewart, and base excess methods. Can J Anaesth. 2009 Mar;56(3):247-56

A net increase in anions in pathologic conditions due to additional unmeasured anions indicate organic acidosis.These unmeasured anions can be quantified by the strong ion gap (SIG), which is defined as:

SIG = SID_App – SID_Eff = XA^–

SIDApp is calculated from the following equation :
SIDApp = (Na⁺ + K⁺ + Ca²⁺ + Mg²⁺) – (Cl^–).
SIDEff is calculated from the electroneutrality equation:
Na⁺ + K⁺ + Mg²⁺ + Ca²⁺+ H⁺ = Cl^– + HCO3^– + protein^–+ PO₄^2- +OH^– + SO₄^2- + CO3^2- +XA^–

Now, OH^–, SO₄^2-, CO₃^2- , and H⁺ are negligible and can be ignored. The electroneutrality equation can be re-arranged as:

SIDEff = (Na⁺ + K⁺ + Ca²⁺ + Mg²⁺) – ( Cl^– +XA^–) =HCO₃^– + protein^– + PO₄^2-

The values for protein and PO₄^2- can be calculated based on the laboratory reports of plasma concentrations for albumin and phosphate .

SIDEff = (Na⁺ + K⁺ + Ca²⁺ + Mg²⁺) – ( Cl^– +XA^–) = HCO₃^– + (0.28 x albumin g/l ) + (1.8 x phosphate mmol/l)

Now, all components of SIDApp and SIDEff can be determined by routine evaluation in the laboratory. As previously stated, XA^– = SID_App – SID_Eff = SIG, therefore XA^– can be approximated based on the SIG. The above discussion provides clarity on the mechanism by which changes in the independent variable SID result in alterations in acid-base balance.⁴Fidkowski C, HelstromJ.Diagnosing metabolic acidosis in the critically ill: bridging the anion gap, Stewart, and base excess methods. Can J Anaesth. 2009 Mar;56(3):247-56

The Stewart theory considers A_TOT to be the second independent variable that affects metabolic acid-base balance. A_TOT is defined as the aggregate total amount of both dissociated and non-dissociated weak acid species.In physiologic systems, the predominant weak acids are albumin and phosphate. An increase in the weak acid concentration results in a metabolic acidosis.⁴Fidkowski C, HelstromJ.Diagnosing metabolic acidosis in the critically ill: bridging the anion gap, Stewart, and base excess methods. Can J Anaesth. 2009 Mar;56(3):247-56

Renal tubular acidosis: Classification

Diagnosis of RTA

Clinical features in proximal RTA (Type II)

Stunted growth8
Rickets and/or osteomalacia may be associated⁸Bagga A, Sinha A. Evaluation of Renal Tubular Acidosis. Indian J Pediatr.2007 Jul;74(7):679-86.
Nephrocalcinosis and urolithiasis are not seen⁸Bagga A, Sinha A. Evaluation of Renal Tubular Acidosis. Indian J Pediatr.2007 Jul;74(7):679-86.
Symptoms due to hypokalemia are uncommon.⁸Bagga A, Sinha A. Evaluation of Renal Tubular Acidosis. Indian J Pediatr.2007 Jul;74(7):679-86.

Clinical features in distal RTA (Type I)

The Na⁺ – H⁺ ion exchange in the distal tubule is inadequate, resulting in wasting of sodium and bicarbonate by the renal system. Consequently,the extracellular volume contracts which stimulates secretion of aldosterone and this results in hypokalemia. Muscle weakness (including constipation) and lack of renal concentrating ability (polyuria) are the clinical features of hypokalemia⁹Chan JC, Scheinman JI, Roth KS. Consultation with the specialist: renal tubular acidosis. Pediatr Rev. 2001 Aug;22(8):277-87.
In chronic metabolic acidosis, skeletal buffering of excess H+ is necessitated and acidosis may also stimulate PTH secretion. In addition, the renal excretion of citrate, a calcium chelator , is reduced in acidosis due to acidosis induced increased mitochondrial citrate oxidation. Thus, the risk of nephrocalcinosis is increased due to hypercalciuria coupled with hypocitraturia. Osteomalacia in the adult and rickets in the child may be seen.⁹Chan JC, Scheinman JI, Roth KS. Consultation with the specialist: renal tubular acidosis. Pediatr Rev. 2001 Aug;22(8):277-87.

Clinical features in Type IV RTA

Usually asymptomatic¹⁰Rangel EB, Gomes SA, Machado PG, et al. Severe hyperkalemic type 4 renal tubular acidosis after kidney transplantation: a case report. Transplant Proc. 2006 Nov;38(9):3112-5.
Associated with hypoaldosteronism or resistance to the action of aldosterone⁸Bagga A, Sinha A. Evaluation of Renal Tubular Acidosis. Indian J Pediatr.2007 Jul;74(7):679-86.
Associated with hyperkalemia which may lead to paralysis or cardiac arrhythmias⁸Bagga A, Sinha A. Evaluation of Renal Tubular Acidosis. Indian J Pediatr.2007 Jul;74(7):679-86.
Nephrocalcinosis and urolithiasis are absent⁸Bagga A, Sinha A. Evaluation of Renal Tubular Acidosis. Indian J Pediatr.2007 Jul;74(7):679-86.
Bone lesions are rare .⁸Bagga A, Sinha A. Evaluation of Renal Tubular Acidosis. Indian J Pediatr.2007 Jul;74(7):679-86.

Evaluation of RTA

All types of RTA are associated with normal anion gap,therefore the initial step in the evaluation of metabolic acidosis is to determine the plasma anion gap. ⁸Bagga A, Sinha A. Evaluation of Renal Tubular Acidosis. Indian J Pediatr.2007 Jul;74(7):679-86.

Step 1. Calculation of the plasma anion gap

Anion gap = (Na⁺) – [ (Cl^– ) + (HCO₃^– )]
The normal plasma anion gap is 8-16 mEq/L.⁸Bagga A, Sinha A. Evaluation of Renal Tubular Acidosis. Indian J Pediatr.2007 Jul;74(7):679-86.

Step 2. Calculate urine anion gap (UAG)

Urine anion gap (net charge) (urine Na⁺ + K⁺ – Cl^–) provides an estimate of urinary ammonium (NH4 +) excretion. Normally, urine anion gap is positive due to the presence of dissolved anions e.g., sulfates, phosphates. A negative UAG is seen in metabolic acidosis due to a compensatory rise in NH₄⁺ production. However, UAG is positive in patients with RTA due to impaired renal NH₄⁺ excretion.

Step 3. Assessment of urine pH

In the presence of systemic acidosis, the urine pH is normally 5.5 during metabolic acidosis suggests defective distal secretion of H⁺.⁸Bagga A, Sinha A. Evaluation of Renal Tubular Acidosis. Indian J Pediatr.2007 Jul;74(7):679-86.

Step 4: Determination of urine to blood CO₂ gradient

Urinary CO₂ excretion is an indicator of H+ secretion,therefore, urine to blood CO₂ difference is considered an index of distal renal acidification. In the presence of normal blood bicarbonate, low urine to blood CO₂ difference (< 10 mm Hg) suggests distal RTA while normal levels indicate proximal RTA (> 20 mm Hg). It is necessary that the difference be determined after adequate alkalinization with oral sodium bicarbonate.

Step 5: Fractional excretion of bicarbonate (FEHCO₃)

The proximal tubule normally reabsorbs almost all filtered bicarbonate (fractional excretion below 5%). A value greater than 15% indicates proximal RTA while levels are in the normal range in distal RTA. Adequate alkalization should be done before the calculation of the fractional excretion of bicarbonate.

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Step 6: Additional investigations

Tests for phosphate handling⁸Bagga A, Sinha A. Evaluation of Renal Tubular Acidosis. Indian J Pediatr.2007 Jul;74(7):679-86.
Transtubular potassium gradient ⁸Bagga A, Sinha A. Evaluation of Renal Tubular Acidosis. Indian J Pediatr.2007 Jul;74(7):679-86.
Furosemide test.⁸Bagga A, Sinha A. Evaluation of Renal Tubular Acidosis. Indian J Pediatr.2007 Jul;74(7):679-86.

Management of RTA

The objective of treatment is to correct the acidosis and the accompanying electrolyte and biochemical abnormalities such as hypokalemia, hypocitraturia, hypercalciuria,hypophosphatemia. However, administration of bicarbonate can worsen the hypokalemia by causing potassium to enter inside the cells. Therefore, hypokalemia should be corrected before the correction of acidosis by bicarbonate administration.¹¹Munoz-Arizpe R, Escobar L, Medeiros M. Renal tubular acidosis in children: State of the art, diagnosis and treatment. Bol Med Hosp Infant Mex. 2013; 70 :178-194.

Acidosis in distal RTA (type I)

Alkalinizing treatment is achieved with the administration of sodium bicarbonate or a solution of sodium citrate and citric acid (Shohl’s solution) or potassium citrate solution.Use of sodium citrate can lead to hypercalciuria, therefore,potassium citrate is preferred in the management of acidosis in distal RTA. Citrate is converted to bicarbonate in the liver.¹¹Munoz-Arizpe R, Escobar L, Medeiros M. Renal tubular acidosis in children: State of the art, diagnosis and treatment. Bol Med Hosp Infant Mex. 2013; 70 :178-194.

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Advantages of potassium citrate

Potassium citrate causes a significant increase in urinary pH and urinary citrate, and a decrease in urinary calcium¹²Preminger GM, Sakhaee K, Skurla C, et al. Prevention of recurrent calcium stone formation with potassium citrate therapy in patients with distal renal tubular acidosis. J Urol. 1985 Jul;134(1):20-3.
Apart from correcting acidosis, it simultaneously prevents or corrects hypokalemia¹¹Munoz-Arizpe R, Escobar L, Medeiros M. Renal tubular acidosis in children: State of the art, diagnosis and treatment. Bol Med Hosp Infant Mex. 2013; 70 :178-194.
Elevates urine pH preventing uric acid and cystine stone formers¹¹Munoz-Arizpe R, Escobar L, Medeiros M. Renal tubular acidosis in children: State of the art, diagnosis and treatment. Bol Med Hosp Infant Mex. 2013; 70 :178-194.
Potassium citrate has also been demonstrated to prevent stone formation in patients with infectionrelated stones.¹³Zuckerman JM, Assimos DG. Hypocitraturia: Pathophysiology and Medical Management. Reviews in Urology. 2009;11(3):134-144.
Prevents recurrent calcium nephrolithiasis in patients with distal renal tubular acidosis¹²Preminger GM, Sakhaee K, Skurla C, et al. Prevention of recurrent calcium stone formation with potassium citrate therapy in patients with distal renal tubular acidosis. J Urol. 1985 Jul;134(1):20-3.
Potassium citrate treatment in distal RTA patients seems to have positive effects on bone mineral density and bone cell function.¹⁴Domrongkitchaiporn S, Pongskul C, Sirikulchayanonta V, et al . Bone histology and bone mineral density after correction of acidosis in distal renal tubular acidosis. Kidney Int. 2002;62(6):2160-2166

Proximal RTA (Type II)

Alkali therapy by bicarbonate supplements or solution of sodium citrate and citric acid¹⁵Bagga A, Bajpai A, Menon S. Approach to renal tubular disorders. Indian J Pediatr. 2005 Sep;72(9):771-6.
Supplements of phosphate and vitamin D¹⁵Bagga A, Bajpai A, Menon S. Approach to renal tubular disorders. Indian J Pediatr. 2005 Sep;72(9):771-6.
Specific therapy for an underlying disorder (cysteamine for cystinosis, D-penicillamine for Wilson disease and lactose free diet in galactosemia) is possible in few patients.¹⁵Bagga A, Bajpai A, Menon S. Approach to renal tubular disorders. Indian J Pediatr. 2005 Sep;72(9):771-6.

Hyperkalaemic distal RTA (Type IV)

Deficiency of aldosterone causes the distal tubule and collecting duct to decrease reabsorption of Na into the blood and decreased secretion of K+ into the urine, thereby resulting in hyperkalemic RTA. Hyperkalemia contributes to the production of acidosis by suppressing ammonia metabolism and consequently limiting ammonium excretion. Acidosis may be significantly corrected by management of hyperkalemia as it restores ammonium excretion to normal.¹⁶Karet FE. Mechanisms in hyperkalemic renal tubular acidosis. J Am SocNephrol. 2009 Feb;20(2):251-4.

Patients with hyperkalaemic distal RTA may be given solution of sodium citrate and citric acid (Shohl’s solution).Use of K-Shohl’s solution and other forms of citric acid preparations that include the potassium salt should be avoided. A mineralocorticoid such as fludrocortisone may be given as replacement. Appropriate dietary modification to restrict potassium should be advised.Patients with aldosterone resistance do not respond to fludrocortisone and are prescribed a loop diuretic such as furosemide. A liberal salt diet should be maintained.¹⁵Bagga A, Bajpai A, Menon S. Approach to renal tubular disorders. Indian J Pediatr. 2005 Sep;72(9):771-6.

Supplemental therapy in RTA

Patients with Fanconi’s syndrome secondary to cystinosis should receive phosphocysteamine,phosphates and vitamin D¹⁵Bagga A, Bajpai A, Menon S. Approach to renal tubular disorders. Indian J Pediatr. 2005 Sep;72(9):771-6.
Children with rickets and hypophosphatemia should receive supplemental calcium, vitamin D and phosphates.¹⁵Bagga A, Bajpai A, Menon S. Approach to renal tubular disorders. Indian J Pediatr. 2005 Sep;72(9):771-6.

Conclusion

Renal tubular acidosis (RTA) is a group of disorders characterized by a normal anion gap and hyperchlroremic metabolic acidosis. However, the laboratory investigations and their interpretation is complex and demands clear understanding of the renal acid-base homeostasis.Early diagnosis and appropriate management prevents complications such as growth retardation, osteomalacia,muscle wasting, nephrocalcinosis and renal failure.

References

Both T, Zietse R, Hoorn EJ, et al. Everything you need to know about distal renal tubular acidosis in autoimmune disease. Rheumatol Int. 2014 Aug;34(8):1037-45.
Rodriguez Soriano J. Renal tubular acidosis: the clinical entity. J Am SocNephrol. 2002 Aug;13(8):2160-70
Koeppen BM. The kidney and acid-base regulation. AdvPhysiol Educ. 2009 Dec;33(4):275-81
Fidkowski C, HelstromJ.Diagnosing metabolic acidosis in the critically ill: bridging the anion gap, Stewart, and base excess methods. Can J Anaesth. 2009 Mar;56(3):247-56
Laing CM, Unwin RJ. Renal tubular acidosis. J Nephrol. 2006;19(Suppl.9):S46-52.
Story DA .Stewart Acid-Base: A Simplifid Bedside Approach. Anesth Analg.2016 Aug;123(2):511-5
Goswami R P, Mondal S, Karmakar P S et al. Type 3 renal tubular acidosis.Indian J Nephrol 2012;22:466-8
Bagga A, Sinha A. Evaluation of Renal Tubular Acidosis. Indian J Pediatr.2007 Jul;74(7):679-86.
Chan JC, Scheinman JI, Roth KS. Consultation with the specialist: renal tubular acidosis. Pediatr Rev. 2001 Aug;22(8):277-87.
Rangel EB, Gomes SA, Machado PG, et al. Severe hyperkalemic type 4 renal tubular acidosis after kidney transplantation: a case report. Transplant Proc. 2006 Nov;38(9):3112-5.
Munoz-Arizpe R, Escobar L, Medeiros M. Renal tubular acidosis in children: State of the art, diagnosis and treatment. Bol Med Hosp Infant Mex. 2013; 70 :178-194.
Preminger GM, Sakhaee K, Skurla C, et al. Prevention of recurrent calcium stone formation with potassium citrate therapy in patients with distal renal tubular acidosis. J Urol. 1985 Jul;134(1):20-3.
Zuckerman JM, Assimos DG. Hypocitraturia: Pathophysiology and Medical Management. Reviews in Urology. 2009;11(3):134-144.
Domrongkitchaiporn S, Pongskul C, Sirikulchayanonta V, et al . Bone histology and bone mineral density after correction of acidosis in distal renal tubular acidosis. Kidney Int. 2002;62(6):2160-2166
Bagga A, Bajpai A, Menon S. Approach to renal tubular disorders. Indian J Pediatr. 2005 Sep;72(9):771-6.
Karet FE. Mechanisms in hyperkalemic renal tubular acidosis. J Am SocNephrol. 2009 Feb;20(2):251-4.