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Hyperchloremic Acidosis

  • Author: Sai-Ching Jim Yeung, MD, PhD, FACP; Chief Editor: Romesh Khardori, MD, PhD, FACP  more...
 
Updated: Jul 08, 2014
 

Background

This article covers the pathophysiology and causes of hyperchloremic metabolic acidoses, in particular the renal tubular acidoses (RTAs). It also addresses approaches to the diagnosis and management of these disorders.

A low plasma bicarbonate (HCO3-) concentration represents, by definition, metabolic acidosis, which may be primary or secondary to a respiratory alkalosis. Loss of bicarbonate stores through diarrhea or renal tubular wasting leads to a metabolic acidosis state characterized by increased plasma chloride concentration and decreased plasma bicarbonate concentration. Primary metabolic acidoses that occur as a result of a marked increase in endogenous acid production (eg, lactic or keto acids) or progressive accumulation of endogenous acids when excretion is impaired by renal insufficiency are characterized by decreased plasma bicarbonate concentration and increased anion gap without hyperchloremia.

The initial differentiation of metabolic acidosis should involve a determination of the anion gap (AG). This is usually defined as AG = (Na+) - [(HCO3- + Cl-)], in which Na+ is plasma sodium concentration, HCO3- is bicarbonate concentration, and Cl- is chloride concentration; all concentrations in this formula are in mmol/L (mM or mEq/L) (see also the Anion Gap calculator). The AG value represents the difference between unmeasured cations and anions, ie, the presence of anions in the plasma that are not routinely measured.

An increased AG is associated with renal failure, ketoacidosis, lactic acidosis, and ingestion of certain toxins. It can usually be easily identified by evaluating routine plasma chemistry results and from the clinical picture.

A normal AG acidosis is characterized by a lowered bicarbonate concentration, which is counterbalanced by an equivalent increase in plasma chloride concentration. For this reason, it is also known as hyperchloremic metabolic acidosis.

This finding suggests that plasma HCO3- has been effectively replaced by plasma Cl-; hyperchloremic metabolic acidosis arises from one of the following conditions[1, 2] :

  • Bicarbonate loss from body fluids through the GI tract or kidneys, with subsequent chloride retention
  • Defective renal acidification, with failure to excrete normal quantities of metabolically produced acid (whereby the conjugate base is excreted as the sodium salt and sodium chloride is retained)
  • Addition of hydrochloric acid to body fluids
  • Addition or generation of another acid with rapid titration of bicarbonate and rapid renal excretion of the accompanying anion and replacement by chloride
  • Rapid dilution of the plasma bicarbonate by saline

Go to Metabolic Acidosis, Pediatric Metabolic Acidosis, and Emergent Management of Metabolic Acidosis for complete information on these topics.

Associated disorders

Conditions associated with hyperchloremic acidosis include the following:

  • Underlying GI, renal, or autoimmune conditions
  • Hereditary disorders
  • Effects of agents used in treatment (eg, cardiac complications)
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Etiology

The kidneys maintain acid-base balance by bicarbonate reclamation and acid excretion. Most conditions that affect the kidneys cause a proportionate simultaneous loss of glomerular and tubular function. Loss of glomerular function (associated with decreased glomerular filtration rate [GRF]) results in the retention of many end products of metabolism, including the anions of various organic and inorganic acids and urea. Loss of tubular function prevents the kidneys from excreting hydrogen cations (H+) and thereby causes metabolic acidosis. The development of azotemia, anion retention, and acidosis is defined as uremic acidosis, which is not hyperchloremic.

The term hyperchloremic acidosis (ie, RTA) refers to a diverse group of tubular disorders, uncoupled from glomerular damage, characterized by impairment of urinary acidification without urea and anion retention. Consequently, typically RTA is unaccompanied by significant decreases in GFR. These disorders can be divided into 2 general categories, proximal (type II)and distal (types I and IV).

Proximal renal tubular acidosis (type II [bicarbonate-wasting acidosis]; pRTA)

The proximal convoluted tubule (PCT) is the major site for reabsorption of filtered bicarbonate. In proximal RTA (pRTA), bicarbonate reabsorption is defective. Proximal RTA rarely occurs as an isolated defect of bicarbonate transport and is usually associated with multiple PCT transport defects; therefore, urinary loss of glucose, amino acids, phosphate, uric acid, and other organic anions, such as citrate, can also occur (Fanconi syndrome).

A distinctive feature of type II pRTA is that it is nonprogressing, and when the serum bicarbonate is reduced to approximately 15 mEq/L, a new transport maximum for bicarbonate is established and the proximal tubule is able to reabsorb all of the filtered bicarbonate. A fractional excretion of bicarbonate (FE[HCO3-]) greater than 15% when the plasma bicarbonate is normal after bicarbonate loading is diagnostic of pRTA. In contrast, the fractional excretion of bicarbonate in low and normal bicarbonate levels is always less than 5% in distal RTA (dRTA). Another feature of pRTA is that the urine pH can be lowered to less than 5.5 with acid loading.

The pathogenic mechanisms responsible for the tubular defect in persons with pRTA are not completely understood. Defective pump secretion or function, namely aberrations in the function of the proton pump ([H+ adenosine triphosphatase [ATPase]),[3] the Na+/H+ antiporter, and the basolateral membrane Na+/K+ ATPase, impair bicarbonate reabsorption. Deficiency of carbonic anhydrase (CA) in the brush-border membrane or its inhibition also results in bicarbonate wasting. Finally, structural damage to the luminal membrane with increased bicarbonate influx or a failure of generated bicarbonate to exit is a proposed mechanism that does not currently have strong experimental backing.

Distal renal tubular acidosis (dRTA)

The distal nephron, primarily the collecting duct (CD), is the site at which urine pH reaches its lowest values. Inadequate acid secretion and excretion produce a systemic acidosis. A metabolic acidosis occurring secondary to decreased renal acid secretion in the absence of marked decreases in GFR and characterized by a normal AG is due to diseases that are usually grouped under the term dRTA. These are further classified into hypokalemic (type I) and hyperkalemic (type IV) RTA.

Until the 1970s, dRTA was thought to be a single disorder caused by an inability to maintain a steep H+ gradient across the distal nephron, either as a failure to excrete H+ or as a result of increased back-diffusion of H+ through an abnormally permeable distal nephron. Structural damage to the nephron from a variety of sources has been shown to result in different pathogenic mechanisms.

Excretion of urinary ammonium (NH4+) accounts for the largest portion of the kidneys' response to the accumulation of metabolic acids. Patients with dRTA are unable to excrete ammonium in amounts adequate to keep pace with a normal rate of acid production in the body. In some forms of the syndrome, maximally acidic urine can be formed, indicating the ability to establish a maximal H+ gradient. However, despite the maximally acidic urine, the total amount of ammonium excretion is low. In other forms, urine pH cannot reach maximal acidity despite systemic acidemia, indicating low H+ secretion capacity in the collecting duct.

In the presence of systemic acidemia, a low rate of urinary ammonium secretion is related either to decreased production of ammonia by the cells of the PCT or to failure to accumulate ammonium in the distal convoluted tubule (DCT) and excrete it in the urine. Decreased ammonium production is observed in hyperkalemic types of dRTA, also known as type IV RTA, because hyperkalemia causes an intracellular alkalosis with resultant impairment of ammonium generation and excretion by renal tubular cells. Acid secretion is thus reduced because of the deficiency of urinary buffers. This type of acidosis is also observed in early renal failure, due to a reduction in renal mass and decreased ammonium production in the remaining proximal tubular cells.

Hypokalemic (classic) distal renal tubular acidosis (type I)

In hypokalemic dRTA, also known as classic RTA or type I RTA, the deficiency is secondary to 2 main pathophysiological mechanisms: (1) a secretory defect and (2) a permeability defect.

When a secretory defect predominates, the decreased secretion of protons (H+) fails to maximally decrease the urinary pH. A decrease in the formation of titratable acidity (TA) and in ammonium trapping and secretion results in systemic acidosis. The mechanism of the hypokalemia is unclear, but hypotheses include (1) increased leakage of K+ into the lumen, (2) volume contraction due to urinary sodium loss and resulting in aldosterone stimulation that increases potassium losses, and (3) decreased proximal K+ reabsorption due to acidemia and hypocapnia.

When a permeability defect predominates, the CD proton pump functions normally, but the high intratubular concentration of H+ dissipates due to abnormal permeability of the tubular epithelium.

Incomplete distal renal tubular acidosis is another clinically important entity. It is considered a variant/milder form (forme fruste) of type I RTA, in which the plasma bicarbonate concentration is normal, but there is a defect in tubular acid secretion. However, daily net acid excretion is maintained by increased ammoniagenesis. Hypercalciuria and hypocitraturia are present, so there is a propensity to nephrolithiasis and nephrocalcinosis. Most of the cases are those of idiopathic calcium phosphate stone formers, relatives of individuals with RTA or with unexplained osteoporosis. Any idiopathic stone former should be evaluated to exclude incomplete type I RTA (by NH4Cl infusion).

Hyperkalemic distal renal tubular acidosis (type IV)

The pathogenesis of hyperkalemic dRTA, the most common RTA, is ascribed to either of 2 mechanisms: (1) a voltage defect or (2) a K+ and H+ secretion rate defect due to aldosterone deficiency or resistance.

The voltage-related type is rarer and is thought to be caused by inadequate negative intratubular electrochemical potential at the cortical collecting duct. This, in turn, causes inadequate secretion of protons and potassium, with decreased trapping and excretion of ammonium and decreased excretion of potassium.

Inadequate voltage generation may be secondary to several factors, including (1) administration of certain drugs, such as amiloride; (2) structural defects that inhibit active sodium reabsorption, such as sickle cell nephropathy; (3) severe limitation of sodium reabsorption in the distal tubule because of proximal sodium avidity, secondary to diseases such as cirrhosis; and (4) increased epithelial permeability to chloride, causing increased reabsorption and preventing the formation of negative voltage linked to sodium reabsorption.

The more common form of hyperkalemic dRTA is due to aldosterone resistance or deficiency. Postulated mechanisms include the following:

  • Destruction of juxtaglomerular cells
  • Decreased sympathetic denervation of the juxtaglomerular apparatus (JGA)
  • Decreased production of prostacyclin, causing a decrease in renin-aldosterone production
  • Primary hypoaldosteronism
  • Secondary hypoaldosteronism from the long-term use of heparin

Aldosterone increases Na+ absorption and the negative intratubular electrochemical potential. It also increases luminal membrane permeability to potassium and stimulates basolateral Na+/K+/ATPase,[3] causing increased urinary potassium losses. Because aldosterone also directly stimulates the proton pump, aldosterone deficiency or resistance would be expected to cause hyperkalemia and acidosis. Another major factor in decreasing net acid excretion is the inhibition of ammoniagenesis due to hyperkalemia (which causes an intracellular alkalosis).

Diarrhea in alkali loss

Diarrhea is the most common cause of external loss of alkali resulting in metabolic acidosis. Biliary, pancreatic, and duodenal secretions are alkaline and are capable of neutralizing the acidity of gastric secretions. In normal situations, a luminal Na+/H+ exchanger in the jejunal mucosa effectively results in sodium bicarbonate (NaHCO3) reabsorption, and, therefore, normally the 100 mL of stool excreted daily has very small amounts of bicarbonate.

The development of diarrheal states and increased stool volume (potentially several L/d) may cause a daily loss of several hundred millimoles of bicarbonate. Some of this loss may not occur as bicarbonate loss itself; instead, intestinal flora produces organic acids that titrate bicarbonate, resulting in loss of organic anions in the stool stoichiometrically equivalent to the titrated bicarbonate. Because diarrheal stools have a higher bicarbonate concentration than plasma, the net result is a metabolic acidosis with volume depletion. Diarrhea may also be caused by external pancreatic, biliary, or small bowel drainage; an ileus; a ureterosigmoidostomy; a jejunal loop; or an ileal loop, resulting in hyperchloremic metabolic acidosis.

Other causes of alkali loss

Other GI conditions associated with external losses of fluids may also lead to large alkali losses. These include enteric fistulas and drainage of biliary, pancreatic, and enteric secretions; ileus secondary to intestinal obstruction, in which up to several liters of alkaline fluid may accumulate within the blocked intestinal lumen; and villous adenomas that secrete fluid with a high bicarbonate content.

Drugs that increase GI bicarbonate loss include calcium chloride, magnesium sulfate, and cholestyramine.

Causes of proximal renal tubular acidosis

Causes of proximal tubular bicarbonate wasting are numerous. A selective defect (eg, isolated bicarbonate wasting) can occur as a primary disorder (with no obvious associated disease) that can be genetically transmitted or occur in transient form in infants.

Alterations in CA activity through drugs such as acetazolamide, sulfanilamide, and mafenide acetate produce bicarbonate wasting. Osteopetrosis with CA II deficiency and genetically transmitted and idiopathic CA deficiency also fall into the selective defect category.

A generalized PCT defect associated with multiple dysfunctions of the PCT can also occur as a primary disorder in sporadic and genetically transmitted forms. It also occurs in association with genetically transmitted systemic diseases, including Wilson disease, cystinosis and tyrosinemia, Lowe syndrome, hereditary fructose intolerance, pyruvate carboxylase deficiency, metachromatic leukodystrophy, and methylmalonic acidemia.

Proximal RTA is also observed in conditions associated with chronic hypocalcemia and secondary hyperparathyroidism, such as vitamin D deficiency or vitamin D resistance. Dysproteinemic states, such as multiple myeloma and monoclonal gammopathy, are also associated with pRTA.

Drugs or toxins that can induce pRTA include streptozotocin, lead, mercury, L-arginine, valproic acid, gentamicin, ifosfamide, and outdated tetracycline.

Renal tubulointerstitial conditions that are associated with pRTA include renal transplantation, Sjögren syndrome, and medullary cystic disease. Other renal causes include nephrotic syndrome and amyloidosis.

Paroxysmal nocturnal hemoglobinuria (PNH) and hyperparathyroidism can also cause pRTA.

A summary of the causes of pRTA (type II) is as follows:

  • Primary - Familial or sporadic
  • Dysproteinemic states - Multiple myeloma (pRTA and dRTA), amyloidosis (pRTA and dRTA), light chain disease (LCD), cryoglobulinemia, and monoclonal gammopathy
  • CA-related conditions - Osteopetrosis (carbonic anhydrase II deficiency), acetazolamide, and mafenide
  • Drug or toxic nephropathy - Lead, cadmium, mercury, streptozotocin, outdated tetracycline, and ifosfamide (pRTA and dRTA)
  • Hereditary disorders - Cystinosis, galactosemia, Wilson disease, hereditary fructose intolerance, glycogen storage disease (GSD) type I, tyrosinemia, and Lowe syndrome
  • Interstitial renal conditions - Sjögren syndrome, medullary cystic disease (pRTA and dRTA), Balkan nephropathy, and renal transplant rejection (pRTA and dRTA)
  • Miscellaneous - PNH, malignancies, nephrotic syndrome, and chronic renal vein thrombosis (CRVT)

Causes of hypokalemic (classic) distal renal tubular acidosis (type I)

Primary dRTA has been described in sporadic and genetically transmitted forms.

Autoimmune disorders such as hypergammaglobulinemia, cryoglobulinemia, Sjögren syndrome, thyroiditis, idiopathic pulmonary fibrosis, chronic active hepatitis (CAH), primary biliary cirrhosis (PBC), systemic lupus erythematosus (SLE), and systemic vasculitis can be associated with dRTA.

Distal RTA can be secondary to genetically transmitted systemic diseases, including Ehlers-Danlos syndrome, hereditary elliptocytosis, sickle cell disease, Marfan syndrome, CA I deficiency or alteration, medullary cystic disease, and neuroaxonal dystrophy.

Disorders associated with nephrocalcinosis that cause hypokalemic dRTA include primary or familial hyperparathyroidism, vitamin D intoxication, milk-alkali syndrome, hyperthyroidism, idiopathic hypercalciuria, hereditary fructose intolerance, Fabry disease, and Wilson disease.

Drugs or toxins that can cause dRTA include amphotericin B, toluene, nonsteroidal anti-inflammatory drugs (NSAIDs), lithium, and cyclamate.

Renal tubulointerstitial conditions associated with dRTA include chronic pyelonephritis, obstructive uropathy, renal transplantation, leprosy, and hyperoxaluria.

A summary of the causes of dRTA (type I) is as follows:

  • Primary - Idiopathic, isolated, and sporadic
  • Tubulointerstitial conditions - Renal transplantation, chronic pyelonephritis, obstructive uropathy, and leprosy
  • Genetic - Familial, Marfan syndrome, Wilson disease, Ehlers-Danlos syndrome, medullary cystic disease (dRTA and pRTA), and osteopetrosis
  • Conditions associated with nephrocalcinosis - Hyperoxaluria, primary hypercalciuria, hyperthyroidism, primary hyperparathyroidism, vitamin D intoxication, milk-alkali syndrome, and medullary sponge kidney
  • Autoimmune disorders - Chronic active hepatitis, primary biliary cirrhosis, Sjögren syndrome (dRTA and pRTA), systemic lupus erythematosus, autoimmune thyroiditis, pulmonary fibrosis, and vasculitis
  • Drugs and toxicity - Amphotericin B, analgesics, lithium, toluene, ifosfamide (dRTA and pRTA)
  • Hypergammaglobulinemic states - Myeloma (both dRTA and pRTA), amyloidosis (dRTA and pRTA), and cryoglobulinemia
  • Miscellaneous - Hepatic cirrhosis and acquired immunodeficiency syndrome (AIDS) (possibly)

Causes of hyperkalemic distal renal tubular acidosis (type IV)

Deficiency of or resistance to aldosterone is the most common cause of hyperkalemic dRTA. Deficiency of aldosterone with glucocorticoid deficiency is associated with Addison disease, bilateral adrenalectomy, and certain enzymatic defects in the steroidogenetic biochemical pathways (eg, 21-hydroxylase deficiency, 3 beta-hydroxysteroid-dehydrogenase deficiency, desmolase deficiency). Isolated aldosterone deficiency can be secondary to states of deficient renin secretion, including diabetic nephropathy, tubulointerstitial renal disease, nonsteroidal anti-inflammatory drug (NSAID) use, beta-adrenergic blocker use, AIDS/HIV disease, and renal transplantation.

Isolated aldosterone deficiency can also be observed secondary to heparin use; in corticosterone methyl oxidase (CMO) deficiency, a genetically transmitted disorder; and in a transient infantile form.

Angiotensin1-converting enzyme (ACE) inhibition, either endogenously or through ACE inhibitors such as captopril, and the newer angiotensin AT1 receptor blockers can cause hyperkalemic dRTA.

Resistance to aldosterone secretion is observed in pseudohypoaldosteronism, childhood forms of obstructive uropathy, cyclosporine nephrotoxicity, renal transplantation, and the use of spironolactone.

Voltage-mediated defects that cause hyperkalemic dRTA can be observed in obstructive uropathy; sickle cell disease; and the use of lithium, triamterene, amiloride, trimethoprim, or pentamidine.

Miscellaneous

The administration of calcium chloride (CaCl2) or cholestyramine (cationic resin that is given as its chloride salt) may cause acidosis because of the formation of calcium carbonate or the bicarbonate salt of cholestyramine in the lumen of the intestine, which is then eliminated in the stool.

Ureteral-GI connections, such as ureterosigmoidostomy for urinary diversion, also cause a potentially severe acidosis in virtually all patients.[4] This acidosis results from the retention of urinary ammonium across the colonic mucosa and from the stool losses of bicarbonate. Because of this complication, ileal conduits have now largely replaced the procedure. However, hyperchloremic metabolic acidosis still occurs in approximately 10% of patients with ileal conduits, especially if obstruction is present.

The occurrence of metabolic acidosis with a normal AG is common in the late phase of diabetic ketoacidosis (DKA). This results from urinary loss of ketoanions with sodium and potassium. This external loss is equivalent to a loss of potential bicarbonate because each ketoanion, if retained and metabolized, would consume a proton and generate a new molecule of bicarbonate.

Infusion of large volumes of solutions containing sodium chloride and no alkali can cause a hyperchloremic metabolic acidosis. This is due to a dilution of the preexisting bicarbonate and to decreased renal bicarbonate reabsorption as a result of volume expansion.

In patients with a chronic respiratory alkalosis, renal acid secretion is decreased but endogenous acid production and chloride reabsorption are normal, resulting in a decreased plasma bicarbonate concentration and elevated chloride concentration. When the hypocapnia is repaired, the return of the PaCO2 to normal unveils a transient metabolic acidosis, which will self-correct shortly.

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Patient Education

Inform patients about the dietary issues related to the hyperchloremic acidoses.

For patient education information, see the Thyroid & Metabolism Center and Low Potassium (Hypokalemia).

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Contributor Information and Disclosures
Author

Sai-Ching Jim Yeung, MD, PhD, FACP Professor of Medicine, Department of Emergency Medicine, Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center

Sai-Ching Jim Yeung, MD, PhD, FACP is a member of the following medical societies: American Association for Cancer Research, American College of Physicians, American Medical Association, American Thyroid Association, Endocrine Society

Disclosure: Nothing to disclose.

Coauthor(s)

Mahendra Agraharkar, MD, MBBS, FACP FASN, Clinical Associate Professor of Medicine, Baylor College of Medicine; President and CEO, Space City Associates of Nephrology

Mahendra Agraharkar, MD, MBBS, FACP is a member of the following medical societies: American College of Physicians, American Society of Nephrology, National Kidney Foundation

Disclosure: Received ownership interest/medical directorship from South Shore DaVita Dialysis Center for other; Received ownership/medical directorship from Space City Dialysis /American Renal Associates for same; Received ownership interest from US Renal Care for other.

Nicholas J Sarlis, MD, PhD, FACP Vice President, Head of Medical Affairs, Incyte Corporation

Nicholas J Sarlis, MD, PhD, FACP is a member of the following medical societies: American Association for the Advancement of Science, American Association for Cancer Research, American Association of Clinical Endocrinologists, American College of Physicians, American Federation for Medical Research, American Head and Neck Society, American Medical Association, American Society for Radiation Oncology, American Thyroid Association, Endocrine Society, New York Academy of Sciences, Royal Society of Medicine, Association for Psychological Science, American College of Endocrinology, European Society for Medical Oncology, American Society of Clinical Oncology

Disclosure: Received salary from Incyte Corporation for employment; Received ownership interest from Sanofi-Aventis for previous employment; Received ownership interest/ stock & stock option (incl. rsu) holder from Incyte Corporation for employment.

Mark T Fahlen, MD Private Practice, Mark T Fahlen, MD, Inc

Mark T Fahlen, MD is a member of the following medical societies: American College of Physicians, Renal Physicians Association

Disclosure: Nothing to disclose.

Kanwarpreet Baweja, MD Fellow in Nephrology, University of Texas Health Science Center

Kanwarpreet Baweja, MD is a member of the following medical societies: American Medical Association, American Society of Nephrology, National Kidney Foundation, Medical Council of India

Disclosure: Nothing to disclose.

Chief Editor

Romesh Khardori, MD, PhD, FACP Professor of Endocrinology, Director of Training Program, Division of Endocrinology, Diabetes and Metabolism, Strelitz Diabetes and Endocrine Disorders Institute, Department of Internal Medicine, Eastern Virginia Medical School

Romesh Khardori, MD, PhD, FACP is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Physicians, American Diabetes Association, Endocrine Society

Disclosure: Nothing to disclose.

Acknowledgements

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Christie P Thomas, MBBS, FRCP, FASN, FAHA Professor, Department of Internal Medicine, Division of Nephrology, Medical Director, Kidney and Kidney/Pancreas Transplant Program, University of Iowa Hospitals and Clinics

Christie P Thomas, MBBS, FRCP, FASN, FAHA is a member of the following medical societies: American College of Physicians, American Federation for Medical Research, American Heart Association, American Society of Nephrology, American Society of Transplantation, American Thoracic Society, International Society of Nephrology, and Royal College of Physicians

Disclosure: Genzyme Grant/research funds Other

References
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  2. Davenport A. Potential adverse effects of replacing high volume hemofiltration exchanges on electrolyte balance and acid-base status using the current commercially available replacement solutions in patients with acute renal failure. Int J Artif Organs. 2008 Jan. 31(1):3-5. [Medline].

  3. Blake-Palmer KG, Karet FE. Cellular physiology of the renal H+ATPase. Curr Opin Nephrol Hypertens. 2009 Jun 24. [Medline].

  4. Basic DT, Hadzi-Djokic J, Ignjatovic I. The history of urinary diversion. Acta Chir Iugosl. 2007. 54(4):9-17. [Medline].

  5. Grünfeld JP, Rossier BC. Lithium nephrotoxicity revisited. Nat Rev Nephrol. 2009 May. 5(5):270-6. [Medline].

 
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