Clinical approach to renal tubular acidosis in adult patients

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1 REVIEW ARTICLE Clinical approach to renal tubular acidosis in adult patients P. Reddy Department of Medicine, University of Florida College of Medicine, Jacksonville, FL, USA Correspondence to: Pramod Reddy, MD, Department of Medicine, University of Florida, West Eighth Street, Jacksonville, FL 32209, USA Tel.: Fax: pramod.reddy@jax.ufl.edu Disclosures None. SUMMARY Renal tubular acidosis (RTA) is a group of disorders observed in patients with normal anion gap metabolic acidosis. There are three major forms of RTA: A proximal (type II) RTA and two types of distal RTAs (type I and type IV). Proximal (type II) RTA originates from the inability to reabsorb bicarbonate normally in the proximal tubule. Type I RTA is associated with inability to excrete the daily acid load and may present with hyperkalaemia or hypokalaemia. The most prominent abnormality in type IV RTA is hyperkalaemia caused by hypoaldosteronism. This article extensively reviews the mechanism of hydrogen ion generation from metabolism of normal diet and various forms of RTA leading to disruptions of normal acid-base handling by the kidneys. Review Criteria I gathered the information in this review article from various text books and journals as listed in the references. Message for the Clinic Renal tubular acidosis appears extremely complex when briefly heard in the conferences, but once you spend more time understanding the pathophysiology it becomes unforgettable and easy to teach students and residents. Clinicians are encouraged to study this topic in depth rather than just before the examinations. Introduction Normal urinary acidification involves bicarbonate reabsorption in the proximal tubules and hydrogen ion excretion in the distal tubules. Impairment of any of these critical functions leads to renal tubular acidosis (RTA). All forms of RTA are characterised by a normal anion gap (hyperchloraemic) metabolic acidosis (see Table 1). The first step in the evaluation of a patient with suspected RTA is to confirm the presence of a normal anion gap metabolic acidosis (1). The serum anion gap is: is: ½Na þ Šþ½Cl HCO 3 Š: Pseudo normalisation of the elevated anion gap secondary to severe hypoalbuminaemia must be carefully ruled out (in general, each 1 g dl decline in serum albumin from the normal value of 4.5 g dl, decreases the serum anion gap by 2.5 meq l). Once normal anion gap metabolic acidosis is confirmed, the urine anion gap is calculated to indirectly estimate the urine NH 4 + levels (2). The urine anion gap is: ½urine Na þ þ urine K þ Š urine Cl : High urine chloride levels leading to a negative gap are typically accompanied by high amounts of NH 4 +, as seen with gastrointestinal and proximal renal bicarbonate wasting. A positive urine anion gap suggests the possibility of distal RTAs resulting in lower amounts of NH 4 + and chloride in the urine (3). Gastro-intestinal losses of bicarbonate (diarrhoea, urinary diversion procedures and fistulas) should be ruled out by detailed history and physical examination. Although alkaline urine ph is variably seen in all three types of RTAs, only patients with complete type I distal RTA have a urine ph > 5.3 even during periods of severe metabolic acidosis. By contrast, urine ph transiently becomes acidic in both type II and type IV RTAs till the extra acid load is excreted into the urine (see Figure 1 and Table 1). Basic principles of acid base balance The kidneys have a major role in regulating the H + ion concentration or ph of the body fluids. In a healthy individual, the arterial ph of the extra cellular fluid (ECF) has a range of and this corresponds to the H + ion concentration of nmol l ( mmol l). The major threats to the ph of the body fluids are from the acids formed in the metabolism of carbohydrates, fats and proteins consumed in a daily diet (4,5). These metabolic acids can be divided into three categories. 350 doi: /j x

2 Renal tubular acidosis 351 Table 1 Differential diagnosis of RTA Distal renal tubular acidoses Characteristic features Proximal RTA Type II Type I classic All other causes Back diffusion Type IV hyperkalaemic Acidosis of chronic renal insufficiency Basic defect Diminished ) proximal HCO 3 reabsorption Decreased distal acidification Back diffusion of H + ions Aldosterone deficiency or resistance Inability to produce or to excrete NH 4 + ion + UAG = urine NH 4 Negative or positive Positive Positive Positive Positive Minimal urine ph when < 5.3 > 5.3, usually > 6 > 5.3 < 5.3 < 5.3 HCO ) 3 < 13 (after NH + 4 Cl ) load) Urine ph after alkali (NaHCO 3 ) load > 5.3 > 5.3 > 5.3 > 5.3 > 5.3 U B pco 2 gradient after Normal > 20 mmhg Diminished Normal (> 25) Normal Normal HCO ) 3 loading with urine ph > 7.6 (close to zero) FeHCO ) 3 (%) > 15 < 5 < 5 < 5 < 5 Urine ph after furosemide < 5.3 > 5.3 < 5.3 or > 5.3 < 5.3 < 5.3 GFR N N N fl flfl ) Plasma HCO Variable 8 15 Variable 8 15 > 17 > 17 Plasma K + Low Low or high Low High High (SLE, SCD) Plasma Cl ) 24-h urinary citrate Normal Low Low Normal Normal Nephrocalcinosis ) + + ) ) Osteomalacia ) ) Diagnosis Response Response to Plus U-B pco 2 Plasma aldosterone Creatinine clearance to NaHCO 3 NH + 4 Cl ) or NaHCO 3 difference concentration HCO ) 3 replacement doses Large Modest Modest Modest Modest Mineralocaorticoid replacement ) ) ) ++ ) RTA, renal tubular acidosis; GFR, glomerular filterate rate; UAG, urine anion gap; U B, urine blood; SLE, systemic lupus erythematosis; SCD, sickle cell disease; flfl, severely decreased; fl, decrease;, increase; N, normal. Volatile acids When there is adequate tissue perfusion in the presence of insulin, oxidation of carbohydrates and fats yield carbon dioxide (CO 2 ), as the major end product. CO 2 reacts with water to form carbonic acid (H 2 CO 3 ), which in turn, can dissociate to form H + and HCO ) 3 : CO 2 þ H 2 O ¼ H 2 CO 3 ¼ H þ þ HCO 3 : Carbon dioxide is called a volatile acid, as it can be excreted via the lungs. All acids other than H 2 CO 3 are non-volatile acids, hence they are not excreted by the lungs. Organic acids These acids are formed from incomplete metabolism of carbohydrates (e.g. lactate) and fats (e.g. ketones) when there is poor tissue perfusion and insulin deficiency. Organic acids are considered non-volatile acids and they consume bicarbonate for conversion into CO 2. Fixed acids Fixed acids are typically produced from protein metabolism; Sulphuric acid from sulphur containing amino acids methionine and cysteine. Phosphoric acid from the metabolism of phospholipids, nucleic acids, phospholipoproteins and phosphoglycerides. Amino acids glutamate and aspartate have both COO ) and NH3 + groups at physiological ph and oxidation of these groups will result in production of equal amounts of bicarbonate and ammonium. The liver is the major net producer of fixed acids from protein metabolism. It also removes excess NH 4 + by urea synthesis and also transports ammonia to kidneys via glutamine. For each ammonium converted to urea in the liver, a single molecule of bicarbonate is consumed: 2NH þ 4 þ 2HCO 3 ¼ >Urea þ CO 2 þ 3H 2 O:

3 352 Renal tubular acidosis Hyperchloremic Normal Anion Gap Metabolic Acidosis Proximal (type II) RTA with serum HCO3 above threshold Urine AG ve Urine AG +ve Urine ph <5.3 Urine AG +ve Urine ph >5.3 Urine AG +ve Urine ph <5.3 Proximal (type II) RTA with serum HCO3 below threshold Distal RTA s Acidosis of glomerular Insufficiency Fe HCO3 > 15% Urine ph >5.3 IV Sodium Bicarbonate load NH 4 Cl load Proximal (type II) RTA Confirmed Type I RTA Confirmed Urine ph persistently >5.3 Urine ph transiently <5.3 Type IV RTA Confirmed E.g.; Diabetes Voltage defect Confirmed E.g.; Sickle cell disease Check U-B pco 2 & Urine K before and after diuretics Hyperkalemia and unchanged K excretion after diuretics Urine-Blood pco 2 difference > 25 mm Gradient defect Confirmed E.g.; Amphotericin B Hypokalemia and increased K excretion after diuretics H-ATPase pump defect confirmed E.g.; Sjogren s syndrome Figure 1 Algorithm for diagnosing RTA. RTA, renal tubular acidosis; NH 4 + Cl ), ammonium chloride; AG, anion gap A typical protein rich western diet would yield approximately 100 mmol (1 1.5 mmol kg) H + every day. It represents a 25,000-fold increase in basal H + concentration and could be disastrous unless excreted by the kidneys. As the non-volatile acids are buffered for the most part by the bicarbonate buffer system, the body is left with an overall deficit of HCO ) 3. To maintain acidbase balance, the kidneys must not only reclaim all the filtered HCO ) 3, but also generate new HCO ) 3. Most of the filtered HCO ) 3 is reabsorbed in the ) proximal tubules and generation of new HCO 3 occurs in the distal and collecting tubules during the excretion of H +. Normally, 80 85% of the filtered bicarbonate is reabsorbed in the proximal tubule with the help of the enzyme carbonic anhydrase (CA; 6). Epithelial cells of the proximal tubule synthesise H 2 CO 3 via CA. H 2 CO 3 then ionizes into H + and HCO ) 3. The process of Na + -H + exchange recreates H 2 CO 3 in the lumen and NaHCO3 in the cell, which is absorbed into the peritubular venous blood. The net effect is the reabsorption of one molecule of HCO ) 3 and one molecule of Na + from the tubular lumen into the blood stream for each molecule of H + secreted (7). This mechanism does not lead to the net excretion of any H + from the body as the H + is consumed in the reaction with the filtered bicarbonate in the tubular lumen. Proximal tubule is also the major site of ammonia synthesis from amino acid glutamine (8). Most of the proximally secreted ammonia is removed from the tubular fluid by the thick ascending loop of Henle into the medullary interstitium and is later secreted into the collecting tubules. Around 10% of the filtered bicarbonate is reabsorbed in the loop of Henle and the remaining 5 10% is reabsorbed in the collecting tubules. The process of bicarbonate reabsorption in the distal tubule involves an HCO3Cl ) exchanger. Principal cells reabsorb Na + via the epithelial Na + channels causing an electronegative tubular lumen, which favours the secretion of both K + (principal cells) and H + (intercalated cells) into the lumen. Hydrogen ion secretion from the intercalated cells in the distal convoluted tubule involves the H + - ATPase pump. Although this proton secretory pump is under direct influence of aldosterone, acid excretion can occur indirectly by the negative charge created by Na + reabsorption in the cortical collecting tubules. In comparison, the process of hydrogen ion excretion in the medullary collecting tubules is sodium independent (9).

4 Renal tubular acidosis 353 Distal tubules secrete the daily acid load as H + ions generated within the cells from the dissociation of H 2 O (H 2 O=H + and OH ) ions). These OH ) ions combine with CO 2 to form HCO ) 3 ions by intracellular CA. Thus, secretion of each H + ion into the lumen is associated with generation of one HCO ) 3 ion within the tubular cell, which is returned to the plasma. Distal nephrons are capable of actively secreting hydrogen ions against large concentration gradients (Final urine ph may reach 4.4 while blood ph is 7.4) and the distal luminal membrane is normally resistant to passive back diffusion of secreted H + ions (certain drugs can compromise this barrier, resulting in reduced net secretion of acid). The filtered bicarbonate in the distal tubular lumen combines with the secreted H + ions to form H 2 CO 3. As CA is not readily accessible to the collecting tubular lumen, the formed H 2 CO 3 slowly dehydrates to CO 2 and H 2 O, which are passively reabsorbed and converted into HCO ) 3 ions inside the cells. This delayed dehydration of H 2 CO 3 increases urinary pco 2 values (> 65 mm) well in excess of that in the blood samples (40 mm). As this increment in urinary pco 2 is ultimately derived from distally secreted protons, the urine blood (U B) pco 2 difference (> 25 mm) becomes a semi quantitative index of distal nephron acid secretion during bicarbonate loading. It is important to emphasise that the daily acid ) load cannot be excreted till all of the filtered HCO 3 has been reabsorbed. H + ions secreted in excess of those required to reabsorb filtered HCO ) 3 bind with non-bicarbonate buffers in the tubular fluid, most important of which are ammonia and phosphate. A low ph in the collecting tubule caused by active H + secretion and low bicarbonate concentration greatly augments transfer of ammonia from the medullary interstitium into the luminal fluid. Ammonia buffers the luminal H + ions in the collecting duct and becomes NH + 4 in the tubule lumen and is eliminated in the urine. For every molecule of NH 4 + excreted, a molecule of HCO ) 3 is returned to the systemic circulation from the proximal tubule. In the absence of an acidic ph in the collecting tubule, ammonia in the medullary interstitium will be returned to the liver by the systemic circulation where it will be converted to urea, while consuming HCO ) 3 during the process. Thus, the overall process of HCO ) 3 regeneration is not complete unless the NH + 4 is excreted (10). The amount of ammonia produced by the proximal tubules can increase markedly in acidosis. This involves synthesis of new enzymes and requires several days for complete adaptation (11). Plasma K + concentration alters ammonia production, which is inhibited by hyperkalaemia and stimulated by hypokalaemia. Titratable acidity (TA) represents the H + ion, which is buffered by the limited amounts of filtered phosphate in the urine (HPO 4 ) +H + =H 2 PO 4 ) ). In comparison with ammonia, production of phosphate cannot increase significantly in the presence of acidosis. The TA can be measured in the urine from the amount of sodium hydroxide needed to titrate the urine ph back to 7.4, hence the name titratable acidity (12). Ammonium is not measured as part of the TA because the high pk value of ammonium prevents H + from being removed from NH 4 + during titration to a ph of 7.4. The net effect of the excretion of one H + is the return of one HCO 3 ) and one Na + to the blood stream. RTAs result from various forms of congenital and acquired tubular dysfunction resulting in impaired urinary acidification (13). Their differentiating clinical features are described below (see Table 1). Proximal renal tubular acidosis (type II RTA) Type II RTA occurs in two phases (14). The period of transient HCO ) 3 wasting When the reabsorption capacity of the proximal tubule is impaired (rather than complete inhibition), less of the filtered HCO ) 3 is reabsorbed in this segment. The increased distal HCO ) 3 delivery overwhelms the limited capacity of the distal nephron, leading to bicarbonaturia. This period of transient bicarbonate wasting results in ECF volume contraction and secondary hyperaldosteronism with resulting hypokalaemia. Chloride reabsorption is enhanced secondary to ECF volume contraction. The alkaline collecting tubule lumen reduces net acid excretion causing a hyperchloremic metabolic acidosis as an end result. During this period, FeHCO 3 is high with an alkaline urine ph (> 6) and urine anion gap may be negative. The steady state Urinary bicarbonate wasting continues until the plasma HCO 3 ) level reaches a new low level (12 18 meq l), at which point most of the filtered bicarbonate is reabsorbed as a result of enhanced distal tubular reabsorption, resulting in acidic urine ph (< 5.3). Thus, type II RTA is a self-limiting disorder and the systemic acidosis is not progressive despite total absence of proximal HCO 3 ) reabsorption (15). With oral bicarbonate therapy or when challenged with IV sodium bicarbonate infusion, the amount of

5 354 Renal tubular acidosis bicarbonate in the urine increases (FeHCO 3 > 15%) and the urine ph becomes alkaline. Impaired production of NH 3 in the proximal tubule may result from diffuse tubular dysfunction, which may lower the rate of NH + 4 excretion into the urine with a positive urine anion gap. Aetiology and clinical features of proximal (type II) RTA Proximal (type II) RTA in children results from inherited defects in the genes for the transmembrane transporters responsible for proximal acidification (16 18). Inactivating mutations of the Na + HCO 3 ) symporter can cause permanent isolated proximal RTA. As the Na + HCO 3 ) symporter is expressed in multiple ocular tissues and pancreas, patients may present with various ocular abnormalities (glaucoma, cataracts) and pancreatitis (19,20). Inactivating mutations of the CA II gene leading to proximal (type II) RTA is typically accompanied by osteopetrosis and mental retardation (21). In children, proximal (type II) RTA is also commonly associated with cystinosis and with the chemotherapeutic agent Ifosfamide, which is used in the treatment of several solid tumours. The two most common causes of proximal (type II) RTA in adults are multiple myeloma and the use of CA inhibitors (22,23). The light chains are resistant to degradation by proteases in lysosomes in the proximal tubular cells and their accumulation is presumably responsible for the tubular impairment (24). The proximal defect in bicarbonate reabsorption may appear as an isolated defect or as a more generalised impairment of all the substances reabsorbed by the proximal tubule (varying degrees of phosphate, glucose, amino acids, calcium, citrate and uric acid wasting often accompanies the bicarbonate wasting). The latter form is called Fanconi syndrome and the majority of cases of proximal (type II) RTA are manifested by this abnormality (25) (Table 2). Type II RTA causes osteomalacia, rickets in children and osteopenia, pseudofractures in adults in about 20% of the patients (26). Despite high calcium excretion in patients with proximal (type II) RTA, nephrocalcinosis is rare, because the following factors limit the amount of free calcium available to precipitate with phosphate or oxalate: (i) concomitant excretion of citrate, which can form soluble complexes with calcium, and (ii) acidic distal tubular urine ph in steady state increases the solubility of calcium phosphate. Table 2 Common causes of proximal (type II) RTA Isolated defect Autosomal dominant proximal RTA from unknown gene mutation Autosomal recessive sodium-bicarbonate symporter (NBC1) protein mutation in SLC4A4 gene Inherited carbonic anhydrase II deficiency caused by mutations in CA2 gene associated with mental retardation, cerebral calcifications and osteopetrosis (Sly syndrome) Drugs (acetazolamide) Generalised defect (Fanconi syndrome) Primary (genetic) Inborn errors of metabolism (cystinosis, Wilson s disease, galactosemia, hereditary fructose intolerance, methylmalonic academia, glycogen storage diseases) Dysproteinemic states (myeloma, monoclonal gammopathy) Secondary hyperparathyroidism with chronic hypocalcaemia, vitamin D deficiency Tubulointerstitial diseases (Sjogren s syndrome, medullary cystic disease, renal transplantation) Nephrotic syndrome Amyloidosis Paroxysmal nocturnal haemoglobinuria Toxins (lead, mercury, copper, cadmium, glue sniffing) Drugs (outdated tetracycline, ifosfamide, cisplatin, gentamycin, valproic acid) RTA, renal tubular acidosis. Diagnosis and treatment of proximal (type II) RTA The presence of type II RTA should be suspected in any patient with an unexplained normal anion gap metabolic acidosis, even if the urine ph is below 5.3 and urine anion gap may be negative or positive (see Figure 1). When patients in the steady state are treated with alkali therapy (IV sodium bicarbonate meq kg h), the plasma HCO 3 ) increases above the threshold and bicarbonaturia ensues resulting in urine ph > 7.5 and FeHCO 3 > 15 20% (27): FeHCO 3 ¼ Urine HCO 3 Plasma Cr Plasma HCO 100: 3 Urine Cr As distal renal tubules have substantial bicarbonate reabsorptive capacity, the plasma bicarbonate concentration usually does not fall below 12 meq l in patients with proximal (type II) RTA. As the exogenous alkali is rapidly excreted in the urine, high doses (10 30 meq kg day) of citric acid sodium citrate (Bicitra; Ortho-Mcneil-Janssen pharmaceuticals, Inc., Titusville, NJ) are required to restore adequate serum bicarbonate levels. Citrate is rapidly metabolised to HCO 3 ) and is better tolerated than HCO 3 ) solutions.

6 Renal tubular acidosis 355 Correcting the HCO 3 ) to near-normal values (22 24 meq l) is desirable in children to preserve normal growth, but not required in adults. Patients with proximal (type II) RTA tend to become hypokalemic once alkali therapy is initiated. When the plasma HCO 3 ) concentration is normalised, the high distal delivery of bicarbonate induces kaliuresis, requiring large supplements of K + (28). When large doses of alkali are ineffective or poorly tolerated, the addition of a distal diuretic may increase the proximal reabsorption of sodium along with bicarbonate secondary to volume depletion. Amiloride is preferred over thiazides because of the potassium sparing effect (29). Classic distal renal tubule acidosis (type I RTA) The characteristic feature of classic RTAs is an inability to acidify the urine maximally (to less than ph 5.3) in the face of systemic acidosis (13,30). In most patients with classic RTA, the urine ph is around 6.5, reflecting the unabsorbed normal distal load of bicarbonate. The causes of type I RTA can be grouped as hypokalaemic and hyperkalaemic forms (see Table 3): Hypokalaemic type I RTA Impaired net secretion of H + ions. As a result of the defects in the basolateral membrane ATPase. This could be genetic or acquired because of diseases like Sjogren s syndrome. This results in reduced acid excretion despite normal aldosterone effect on H + -ATPase pump. Increased permeability of the luminal membranes to secreted protons. This results in back diffusion of H + ions despite the presence of an effective pump. This gradient defect is classically seen in patients treated with Amphotericin B (31). Before the back diffusion occurs, the secreted H + ions in the tubular lumen bind with HCO 3 ) to form H 2 CO 3. As there is no luminal CA, H 2 CO 3 is slowly dehydrated to CO 2 and water and this results in transient high urine pco 2 levels in the urine. This is the only type of classic RTA with high urine pco 2 levels (> 65 mmhg) and corresponding high urine-blood pco 2 difference (> 25 mmhg). Patients with the above conditions tend to have urinary potassium wasting and hypokalaemia prior to therapy because sodium reabsorption in the collecting tubules occurs more in exchange with potassium, as the net distal hydrogen ion secretion is diminished. Chronic metabolic acidosis results in less bicarbonate reabsorption by the proximal tubule, which in turn results in less proximal sodium reabsorption. Increased sodium wasting in the urine results in secondary hyperaldosteronism leading to hypokalaemia. Concurrent decreased activity of the second proton pump (H + K + ATPase) in the intercalated cells is Table 3 Common causes of type I RTA Hypokalaemic classic renal tubular acidosis Calcium induced Tubular damage Autoimmune Diseases Idiopathic hypercalciuria Sjogen s syndrome Primary hyperparathyroidism Rheumatoid arthritis Hypervitaminosis D SLE Medullary sponge kidney Polyarteritis nodosa Drugs and Toxins Thyroiditis Amphotericin B Primary biliary cirrhosis Ifosfamide Chronic active hepatitis Lithium Cryoglobulinemia Analgesic abuse Idiopathic and Hereditary causes Multiple myeloma Mutations in the SLC4A1 gene encoding the chloride-bicarbonate exchanger AE1 Toluene H + ATPase subunit mutations in ATP6V1B1 and ATP6V0A4 genes Idiopathic causes Marfan s syndrome Wilson s disease Ehlers-Danlos syndrome Hyperkalaemic classic renal tubular acidosis Decreased effective intravascular volume of any cause Sickle cell anaemia Urinary tract obstruction SLE Renal transplant rejection Amyloidosis RTA, renal tubular acidosis; SLE, systemic lupus erythematosis.

7 356 Renal tubular acidosis sometimes seen along with defective primary proton pump activity. As the main function of this pump is to reabsorb potassium in states of depletion, its inhibition may promote urinary K + wasting. Hyperkalaemic type I RTA (voltage-dependent defect) Normal gradient-driven proton secretion requires a higher number of cations in the cell compared with the lumen, creating a transepithelial negative voltage gradient. This negative gradient can be altered by the following conditions: Reduced distal sodium delivery as a result of enhanced proximal tubule reabsorption. Seen in conditions with decreased effective arterial volume (CHF, nephrotic syndrome, cirrhosis) and also any cause of marked volume depletion. Reduced distal sodium reabsorption. Seen when sodium channels are blocked by use of drugs (Amiloride, Triamterene, Lithium, Trimethoprim or Pentamidine) or by urinary tract obstruction. Patients with sickle cell disease and lupus nephritis may present with hyperkalaemic variant of classic RTA (33,34). As a consequence of increased intraluminal sodium, the distal tubular lumen becomes relatively less electronegative compared with the cell (voltagedependent defect) and transepithelial K + secretion is impaired leading to hyperkalaemia (32). The pathogenesis of metabolic acidosis is the result of the unfavourable voltage, which impairs H + secretion by the intercalated cells or the inhibition of ammonium production and transport as a consequence of hyperkalaemia. These patients have normal aldosterone levels and normal amounts of H + -ATPase in the intercalated cells (34). Aetiology and clinical features of type I RTA The most common causes in adults are autoimmune disorders (Sjogren s syndrome, rheumatoid arthritis), hypercalciuria, recreational toluene sniffing and drug-induced (amphotericin B) and -marked volume depletion (see Table 3). In children, type I RTA is most often a hereditary condition. Genetic mutations in the chloride-bicarbonate cotransporter (SLC4A1 gene) and in the apical H + -ATPase (ATP6V1B1 and ATP6V0A4 genes) have been identified (35 38). Patients with Sjögren s syndrome may reveal complete absence of H + -ATPase pumps in the intercalated cells in renal biopsy (39). They also show presence of high titres of autoantibodies directed against CA II enzyme. CA II inhibition further impairs hydrogen ion generation within the cell for secretion into the lumen (40). Type I RTA is associated with abnormalities in potassium balance, depending on the type of defect. Occasionally, patients with severe hypokalaemia may present with quadriplegia or respiratory arrest (41). Nephrolithiasis is very frequently associated with untreated classic RTA. Chronic persistent metabolic acidosis increases calcium phosphate release from the bone during buffering of excess hydrogen ions and also reduces tubular reabsorption of these ions. The resulting hypercalciuria and hyperphosphaturia lead to the precipitation of calcium phosphate stones. This process is also promoted by low urinary citrate levels, as citrate normally binds to calcium and is excreted in the urine as calcium citrate (42). Hypocitraturia results from enhanced proximal tubule reabsorption, which is facilitated by acidosis in the proximal tubular cells (43,44). Diagnosis and treatment of type I RTA The presence of classic RTA should be suspected in any patient with a normal anion gap metabolic acidosis and a urine ph > 5.3. Urinary tract infection with Proteus and other urea-splitting organisms should be excluded, as NH 3 is generated from hydrolysis of urea and can alkalinise the normally formed urine in the urinary bladder. The characteristic feature of type I RTA is persistent urine ph of > 5.3 even in the presence of a metabolic acidosis induced by NH 4 + Cl ) loading (see Table 1). As oral ammonium chloride administration (100 mg kg) often induces nausea and vomiting, an alternative test of urinary acidification, which is actually faster and more reliable is the simultaneous oral administration of Furosemide (40 mg) and Fludrocortisone (1 mg) (47). Urinary acidification response to simultaneous furosemide and fludrocortisone is typically seen within 3 4 h. Response to loop diuretics and mineralocorticoid Loop diuretics increase distal sodium delivery and increased sodium reabsorption in the cortical collecting tubule enhances the luminal electronegativity resulting in more H + and K + ion secretion. Fludrocortisone may be administered along with loop diuretics to further enhance intercalated cell proton secretion (47). In normal subjects with metabolic acidosis, the expected acidic urine ph (< 5.3) is further lowered by loop diuretics. By contrast, patients with diffuse impairment of the H + -ATPase pump will have a persistently

8 Renal tubular acidosis 357 alkaline urine ph, but will show a rise in K + excretion, reflecting the intact principal cell function (48). In contrast to hypokalaemic classic distal RTA, patients with hyperkalaemic classic RTA (voltagedependent defect) do not increase H + or K + excretion in response to furosemide (49). Hyperkalaemic type I RTA may appear similar to type IV RTA. However, in type I RTA aldosterone levels are normal and the acidifying defect is more severe, leading to a urine ph that is above 5.3 and a plasma bicarbonate concentration below 15 meq l. These patients are unable to increase acid or K + excretion in response to furosemide or fludorcortisone (see Table 4). Urine blood pco 2 difference after bicarbonate loading When the distal tubule becomes markedly alkaline after bicarbonate loading, secretion of H + ions leads to the formation of H 2 CO 3, which dehydrates into CO 2 and H 2 O (45,46). In patients with defective H + ion secretion, the U B pco 2 difference is close to that of blood. Higher U B pco 2 difference (higher pco 2 levels in urine than blood) is seen only in patients with intact H + ion secretion and with H + ion back diffusion. Amphotericin B-induced distal RTA is the most common example of such a gradient defect (31). Incomplete type I RTA Some patients may have an incomplete variant of the disease and retain normal serum bicarbonate levels despite alkaline urine ph. Nephrolithiasis may still occur in them because of hypocitraturia (50). As opposed to complete type I RTA, they retain normal rates of ammonium excretion from possible enhanced production of ammonia by the proximal tubules (51). These patients still fail to excrete the acid load when challenged with ammonium chloride and retain urine ph > 5.3. Recognition of incomplete type I RTA is important in these patients, as the administration of potassium citrate can reduce stone formation. Correction of acidosis is required to allow normal growth in children, to prevent osteopenia and to minimise nephrolithiasis. Alkali requirements may be equal to 1 3 meq kg day. Citric acid, potassium citrate, sodium citrate (Polycitra; Ortho-Mcneil-Janssen pharmaceuticals, Inc.) are especially useful in this setting (52). Maintenance of normal serum bicarbonate with alkali therapy also raises urinary citrate, lowers the frequency of nephrolithiasis and tends to restore normal growth in children (53). Hyperkalaemic type IV renal tubule acidosis Aldosterone directly stimulates H + ion secretion by the H + -ATPase pump in the intercalated cells and also K + ion secretion by the principal cells. By increasing sodium reabsorption, aldosterone increases luminal electronegativity and indirectly increases H + ion secretion (54). Aetiology and clinical features of type IV RTA Aldosterone deficiency, resistance or inhibition (Table 5) may result in hyperkalaemic, hyperchlorae- Table 5 Common causes of type IV RTA Aldosterone deficiency Addison s disease 21-hydroxylase deficiency Hyporeninemia Diabetic nephropathy AIDS Tubulointerstitial disease IgM monoclonal gammopathy NSAIDS Aldosterone inhibition Aldosterone resistance Obstructive uropathy Sickle cell nephropathy Amyloidosis Diabetic nephropathy Lupus nephritis Pseudohypoaldosteronism Drugs that interfere with tubular Na + channel function Amiloride Triamterene Trimethoprim Pentamidine Spironolactone Analgesics Cyclooxygenase inhibitors Heparin Lovenox Drugs that interfere with basolateral Na + K + ATPase Cyclosporine and tacrolimus Table 4 Response to diuretics in different types of type I RTA Urine studies before diuretics Urine studies after diuretics Defect Urine ph Urine K Urine ph Urine K Normal response < 5.0 Normal meq l Further decline in ph Increased H + ion excretion defect > 5.3 Increased > 5.3 Further Increased H + Ion back diffusion > 5.3 Increased < 5.3 or > 5.3 (variable) Further Increased Sodium reabsorptive voltage defect > 5.3 Decreased > 5.3 No response

9 358 Renal tubular acidosis mic acidosis (55 60). In addition, the resulting hyperkalaemia impairs renal ammonia synthesis (61). This effect may result from: Decrease in ammonium production by the proximal tubule. Competitive inhibition of binding of NH + 4 to K + site on the Na + -K + -2Cl ) carrier in the loop of Henle. Decreased NH + 4 concentration in the medullary interstitium. Decrease in NH 3 NH + 4 secretion into outer and inner medullary conducting duct. As gradient driven H + ion secretion continues despite the absence of aldosterone, the resulting metabolic acidosis is not as severe as seen in classic RTA. Urine ph becomes acidic during periods of acute metabolic acidosis or NH + 4 Cl ) loading (see Figure 1). Limitation of basolateral Na + K + -ATPase activity by cyclosporine and tacrolimus decreases intracellular K + and the transepithelial potential, which together decrease the driving force for K + secretion (62). Hyporeninemic hypoaldosteronism is the most common cause of type IV RTA. Patients with this disorder are usually older diabetics and exhibit mild renal insufficiency. Diagnosis and treatment of type IV RTA Both the metabolic acidosis and the hyperkalaemia are usually out of proportion to the level of reduction in glomerular filtration rate (GFR). The metabolic acidosis seen with type IV RTA is generally mild and correcting the hyperkalaemia often leads to increased NH 4 + excretion and correction of acidosis. Although mineralocorticoid replacement is effective, as most patients with type IV RTA have underlying renal insufficiency, this can exacerbate oedema or hypertension. Loop diuretics often effectively induce renal potassium and salt excretion (63). the urine ph during acidosis. The U B pco 2 gradient is normal, reflecting the intact distal H + secretory capacity. When the net acid excretion is impaired, alkaline salts from bone buffer the positive acid load and this results in progressive dissolution of bone and muscle wasting. Alkali replacement (1 2 meq kg day) to maintain the plasma bicarbonate concentration above 22 meq l usually restores acid-base equilibrium and prevents acid retention. Conclusions The presence of RTA should be considered in any patient with an otherwise unexplained normal anion gap metabolic acidosis. The diagnosis of proximal (type II) RTA is made by measurement of the urine ph and fractional bicarbonate excretion during a bicarbonate infusion. The hallmark is urine ph above 7.5 and the appearance of more than 15 per cent of the filtered bicarbonate in the urine when the serum bicarbonate concentration is raised to a normal level. Classic type I distal RTA presents with an inappropriately high urine ph (greater than 5.3) in the presence of acidosis and is often associated with nephrolithiasis. Type IV RTA is because of either aldosterone deficiency or resistance and hyperkalaemia is the primary electrolyte abnormality in these patients. Serum electrolytes such as blood urea nitrogen, calcium, phosphorus and creatinine should be obtained. A urinalysis is performed for the evaluation of glycosuria and proteinuria. Renal ultrasonography can be performed to identify obstructive uropathies. When nephrolithiasis is present, a 24 h urinary calcium measurement may identify hypercalciuria. The mainstay of therapy in all forms of RTA is bicarbonate replacement with varying dose requirements in each condition. As the prognosis is dependent on the nature of the underlying disease, a thorough diagnostic work up should be carried out for any new onset RTA. Acidosis of glomerular insufficiency The metabolic acidosis seen from reduction in functional renal mass is initially hyperchloraemic in nature (GFR, ml min), but converts to the normochloraemic, high-ag variety as renal insufficiency progresses and the GFR falls below 15 ml min (64). The principal defect in net acid excretion in these patients is not an inability to secrete H + in the distal nephron, but rather an inability to produce or to excrete NH + 4 ion. There is impaired net acid excretion when the plasma HCO ) 3 concentration is in the normal range, with preserved ability to lower References 1 Winter SD, Pearson JR, Gabow PA. The fall of the serum anion gap. Arch Intern Med 1990; 150: Batlle DC, Hizon M, Cohen E. The use of the urine anion gap in the diagnosis of hyperchloremic metabolic acidosis. N Engl J Med 1988; 318: Kamel KS, Halperin ML. An improved approach to the patient with metabolic acidosis: a need for four amendments. J Nephrol 2006; 19 (Suppl. 9): S Kurtz I, Maher T, Hulter HN. Effect of diet on plasma acid-base composition in normal humans. Kidney Int 1983; 24: Berne RM, Levy MN. Role of kidneys in acid base balance. In: Berne RM, ed. Principles of Physiology, 3rd edn. Philadelphia: Mosby, 2000:

10 Renal tubular acidosis Maddox DA, Gennari JF. The early proximal tubule: a high-capacity delivery-responsive reabsorptive site. Am J Physiol 1987; 252: F Lonnerholm G, Wistrand PJ. Carbonic anhydrase in the human kidney: a histochemical and immunocytochemical study. Kidney Int 1984; 25: Good DW, Burg MB. Ammonia production by individual segments of the rat nephron. J Clin Invest 1984; 73: Garg LC. Respective roles of H-ATPase and H-K-ATPase in ion transport in the kidney. J Am Soc Nephrol 1991; 2: Hamm LL, Simon EE. Roles and mechanisms of urinary buffer excretion. Am J Physiol 1987; 253: F Tizianello A, Deferrari G, Garibotto G. Renal ammoniagenesis in an early stage of metabolic acidosis in man. J Clin Invest 1982; 69: Quamme GA. Effect of ph on Na + -dependent phosphate transport in renal outer cortical and outer medullary BBMV. Am J Physiol 1990; 258: F Wrong O, Davies HEF. The excretion of acid in renal disease. QJM 1959; 28: PubMed. 14 Rodriguez SorianoJ. Renal tubular acidosis: the clinical entity. J Am Soc Nephrol 2002; 13: Manz F, Waldherr R, Fritz HP. Idiopathic de Toni-Debre-Fanconi syndrome with absence of proximal tubular brush border. Clin Nephrol 1984; 22: Igarashi T, Sekine T, Inatomi J, Seki G. Unraveling the molecular pathogenesis of isolated proximal renal tubular acidosis. J Am Soc Nephrol 2002; 13: Toye AM, Parker MD, Daly CM. The human NBCe1-A mutant R881C, associated with proximal renal tubular acidosis, retains function but is mistargeted in polarized renal epithelia. Am J Physiol Cell Physiol 2006; 291: C Laing CM, Toye AM, Capasso G. Renal tubular acidosis: developments in our understanding of the molecular basis. Int J Biochem Cell Biol 2005; 37: Usui T, Hara M, Satoh H. Molecular basis of ocular abnormalities associated with proximal renal tubular acidosis. J Clin Invest 2001; 108: Satoh H, Moriyama N, Hara C. Localization of Na + -HCO3 ) cotransporter (NBC-1) variants in rat and human pancreas. Am J Physiol Cell Physiol 2003; 284: C Shah GN, Bonapace G, Hu PY. 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: Maldonado JE, Velosa JA, Kyle RA. Fanconi syndrome in adults. A manifestation of a latent form of myeloma. Am J Med 1975; 58: Messiaen T, Deret S, Mougenot B. Adult Fanconi syndrome secondary to light chain gammopathy. Clinicopathologic heterogeneity and unusual features in 11 patients. Medicine (Baltimore) 2000; 79: Leboulleux M, Lelongt B, Mougenot B. Protease resistance and binding of Ig light chains in myeloma-associated tubulopathies. Kidney Int 1995; 48: Izzedine H, Launay-Vacher V, Isnard-Bagnis C, Deray G. Druginduced Fanconi s syndrome. Am J Kidney Dis 2003; 41: Brenner RJ, Spring DB, Sebastian A. Incidence of radiographically evident bone disease, nephrocalcinosis, and nephrolithiasis in various types of renal tubular acidosis. N Engl J Med 1982; 307: DuBose TD, Alpern RJ. Renal tubular acidosis. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease, 8th edn. New York: McGraw-Hill, 2001: Sebastian A, McSherry E, Morris RC Jr. Renal potassium wasting in renal tubular acidosis (RTA): its occurrence in types 1 and 2 RTA despite sustained correction of systemic acidosis. J Clin Invest 1971; 50: Nash MA, Torrado AD, Greifer I. Renal tubular acidosis in infants and children. Clinical course, response to treatment, and prognosis. J Pediatr 1972; 80: DuBose TD, McDonald GA. Renal tubular acidosis. In: DuBose TD, Hamm LL, eds. Acid-Base and Electrolyte Disorders: A Companion to Brenner and Rector s The Kidney. Philadelphia: WB Saunders, 2002: Douglas JB, Healy JK. Nephrotoxic effects of amphotericin B, including renal tubular acidosis. Am J Med 1969; 46: Kurtzman NA. Disorders of distal acidification. Kidney Int 1990; 38: Batlle D, Itsarayoungyuen K, Arruda JA, Kurtzman NA. Hyperkalemic hyperchloremic metabolic acidosis in sickle cell hemoglobinopathies. Am J Med 1982; 72: Bastani B, Underhill D, Chu N. Preservation of intercalated cell H + -ATPase in two patients with lupus nephritis and hyperkalemic distal renal tubular acidosis. J Am Soc Nephrol 1997; 8: Wrong O, Bruce LJ, Unwin RJ. Band 3 mutations, distal renal tubular acidosis, and Southeast Asian ovalocytosis. Kidney Int 2002; 62: Karet FE. Inherited distal renal tubular acidosis. J Am Soc Nephrol 2002; 13: Shayakul C, Alper SL. Defects in processing and trafficking of the AE1 Cl ) HCO 3 ) exchanger associated with inherited distal renal tubular acidosis. Clin Exp Nephrol 2004; 8: Wingo CS, Smulka AJ. Function and structure of H-K-ATPase in the kidney. Am J Physiol 1995; 269: F Cohen EP, Bastani B, Cohen MR. Absence of H + -ATPase in cortical collecting tubules of a patient with Sjogren s syndrome and distal renal tubular acidosis. J Am Soc Nephrol 1992; 3: Takemoto F, Hoshino J, Sawa N. Autoantibodies against carbonic anhydrase II are increased in renal tubular acidosis associated with Sjogren syndrome. Am J Med 2005; 118: Poux JM, Peyronnet P, Le Meur Y. Hypokalemic quadriplegia and respiratory arrest revealing primary Sjögren s syndrome. Clin Nephrol 1992; 37: Batlle DC, Arruda JA, Kurtzman NA. Hyperkalemic distal renal tubular acidosis associated with obstructive uropathy. N Engl J Med 1981; 304: Hamm LL. Renal handling of citrate. Kidney Int 1990; 38: Sabatini S, Kurtzman NA. Enzyme activity in obstructive uropathy: basis for salt wastage and the acidification defect. Kidney Int 1990; 37: Kim S, Lee JW, Park J. The urine-blood PCO gradient as a diagnostic index of H( + )-ATPase defect distal renal tubular acidosis. Kidney Int 2004; 66: DuBose TD Jr. Hydrogen ion secretion by the collecting duct as a determinant of the urine to blood Pco 2 gradient in alkaline urine. J Clin Invest 1982; 69: Walsh SB, Shirley DG, Wrong OM, Unwin RJ. Urinary acidification assessed by simultaneous furosemide and fludrocortisone treatment: an alternative to ammonium chloride. Kidney Int 2007; 71: Schlueter W, Keilani T, Hizon M. On the mechanism of impaired distal acidification in hyperkalemic distal renal tubular acidosis: evaluation with amiloride and bumetanide. J Am Soc Nephrol 1992; 3: Kurtzman NA, Gonzalez J, DeFronzo RA, Giebisch G. A patient with hyperkalemia and metabolic acidosis. Am J Kidney Dis 1990; 15: Preminger GM, Sakhaee K, Pak CY. Hypercalciuria and altered intestinal calcium absorption occurring independently of vitamin D in incomplete distal renal tubular acidosis. Metabolism 1987; 36: Donnelly S, Kamel KS, Vasuvattakul S, Narins RG, Halperin ML. Might distal renal tubular acidosis be a proximal tubular cell disorder? Am J Kidney Dis 1992; 19: Morris RC Jr, Sebastian A. Alkali therapy in renal tubular acidosis: who needs it? J Am Soc Nephrol 2002; 13:

11 360 Renal tubular acidosis 53 Wrong O, Henderson JE, Kaye M. Distal renal tubular acidosis: alkali heals osteomalacia and increases net production of 1,25- dihydroxyvitamin D. Nephron Physiol 2005; 101: White PC. Disorders of aldosterone biosynthesis and action. N Engl J Med 1994; 331: White PC. Aldosterone synthase deficiency and related disorders. Mol Cell Endocrinol 2004; 217: Caramelo C, Bello E, Ruiz E. Hyperkalemia in patients infected with the human immunodeficiency virus: involvement of a systemic mechanism. Kidney Int 1999; 56: Glassock RJ, Cohen AH, Danovitch G, Parsa KP. Human immunodeficiency virus (HIV) infection and the kidney. Ann Intern Med 1990; 112: Perazella MA, Mahnensmith RL. Trimethoprim-sulfamethoxazole: hyperkalemia is an important complication regardless of dose. Clin Nephrol 1996; 46: Kleyman TR, Roberts C, Ling BN. A mechanism for pentamidineinduced hyperkalemia: inhibition of distal nephron sodium transport. Ann Intern Med 1995; 122: Oster JR, Singer I, Fishman LM. Heparin-induced aldosterone suppression and hyperkalemia. Am J Med 1995; 98: DuBose TD Jr, Good DW. Chronic hyperkalemia impairs ammonium transport and accumulation in the inner medulla of the rat. J Clin Invest 1992; 90: Kamel KS, Ethier JH, Quaggin S. Studies to determine the basis for hyperkalemia in recipients of a renal transplant who are treated with cyclosporine. J Am Soc Nephrol 1992; 2: Sebastian A, Schambelan M, Sutton JM. Amelioration of hyperchloremic acidosis with furosemide therapy in patients with chronic renal insufficiency and type 4 renal tubular acidosis. Am J Nephrol 1984; 4: Widmer B, Gerhardt RE, Harrington JT, Cohen JJ. Serum electrolyte and acid-base composition: the influence of graded degrees of chronic renal failure. Arch Intern Med 1979; 139: Paper received September 2009, accepted November 2009