Marshall L. Stoller, Maxwell V. Meng-Urinary Stone Disease

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144 Chin

a decreased ability to acidify urine and to excrete acid in the setting of a chronic nongap

metabolic acidosis. This clinical entity is found both as primary defects (usually in

children) and as secondary to multisystem disease processes (more often in adults).

AUSES OF DISTAL RENAL TUBULAR ACIDOSIS

The primary forms and secondary causes of dRTA are listed in Table 4. When first

described, the pathophysiology of dRTA was felt to be the inability of the luminal

membrane to maintain a proton gradient. Microbiological and laboratory information

from the past three decades has demonstrated that the underlying cause of dRTA often

involves a H

secretion problem, either through a direct H

-ATPase defect or a second-

ary defect resulting in decreased proton secretion. The pathophysiology of dRTA can be

better understood by recollecting that acidification of the urine requires: (1) appropriate

distal tubular proton secreting mechanism; (2) functional intracellular carbonic anhy-

drase; (3) adequate luminal electronegativity to allow H

secretion; and 4) intact luminal

membrane to prevent back diffusion of H

. Although some genetic mutations have been

discovered for a subset of the primary, inherited forms of dRTA, the mechanisms of

secondary dRTA are not finalized. Figure 10 points out a few of the proposed mecha-

nisms of dRTA and where in the collecting ducts the defects reside.

Proton Secretion Defect

An inability to move H

from the intracellular space of the intercalated cell out into

the luminal space would impair NAE and urinary acidification. An autosomal recessive

Table 4

Classification and Causes of Distal Renal Tubular Acidosis

Secretory defect Voltage/rate dependent defect

• Primary • Decreased distal sodium delivery

Autosomal dominant • Drugs

Autosomal recessive

Amiloride

Carbonic anhydrase deficiency

Triamterene

• Secondary

Obstructive uropathy Permeability defect

Renal transplant rejection • Drugs

Autoimmune disorder

Amphotericin B

 Sjogren’s syndrome • Spontaneous

 SLE

 Rheumatoid arthritis Combined ammonia ± distal secretion defect

 Primary biliary cirrhosis • Incomplete RTA

• Genetic diseases

Increase ammonium production

Ehler-Danlos syndrome

Partial secretory defect

Wilson’s disease • Chronic interstitial disease

Fabry’s disease • Obstructive uropathy

• Toxin/drug • Hyperkalemia

Toluene

Vanadate

Lithium

Chapter 8 / Renal Acid–Base Balance 145

mutation in the gene coding for a subunit (B1) of the H

-ATPase apical pump is found

in many patients with a form of inherited dRTA, which is also associated with neurosen-

sory deafness (56,57). A mutation in a different gene also coding for a subunit of the H

ATPase is implicated in other cases of sporadic and autosomal recessive dRTA (58).

One form of autosomal dominant dRTA is now believed to be caused by a mutation

in the gene coding for the basolateral HCO

–

/Cl

–

exchanger (AE1 or band 3 protein)

(59,60). The dysfunction of this transporter would lead to an inability to remove bicar-

bonate from the intracellular space of the collecting duct, decrease the H

O + CO

→ H

+ HCO

–

reaction, and would secondarily limit the ability to generate protons for apical

secretion. The same mutation in this AE1 exchanger can also lead to red blood cell

abnormalities, including hereditary spherocytosis and ovalocytosis (61,62). However,

there must be more to this condition because only a small number of patients with

autosomal dominant dRTA have a red cell abnormality and only a small number of

patients with the red cell defect have dRTA (46).

Other nongenetic causes of dRTA related to proton secretory defects include medul-

lary sponge kidney disease and chronic renal transplant rejection (63). In addition,

autoimmune diseases such as Sjogren syndrome are associated with dRTA. Obstructive

nephropathy related dRTA is also mentioned as a secretory defect in some classifications

(63) and borne out by some studies showing altered distribution of vacuoles containing

-ATPase (64). However, the etiology of the tubular defect in obstruction is probably

more complicated than this because hyperkalemia is a frequent finding. Experimentally,

defective salt handling (leading to a voltage defect) secondary to impaired basolateral

-ATPase is also touted as a cause of dRTA in obstructive nephropathy.

Carbonic Anhydrase Defect

Carbonic anhydrase is intricately involved in the proper function of the intercalated

cell by providing the substrate for the apical H

-ATPase. Defects or deficiencies in this

Fig. 10. Mechanisms of distal renal tubular acidosis and the associated membrane structural/

functional defect.

146 Chin

enzyme lead to findings consistent with a dRTA. Some mutations in the gene for this

enzyme, located on chromosome 8q22 (65) will also cause significant bone, central

nervous system and mental development problems (66). The majority of the cases (72%)

are found in individuals of Arabic descent (67). Defects in CA2 can lead to findings of

pRTA or dRTA or both (68–70). This is not surprising because CA2 is just as important

for normal proximal tubular bicarbonate reabsorption as it is for distal proton secretion.

The use of the carbonic anhydrase inhibitor acetazolamide provides a similar finding of

proximal and distal acidification problems.

A combined proximal and distal defect in acid handing was originally termed type 3

RTA. The term has fallen out of favor, and the initial use of this term probably referred

to pediatric cases where immature channels or a high salt intake were the etiology of the

combined defect (38).

Gradient Defect

A proton gradient or membrane permeability defect is well documented for ampho-

tericin B induced dRTA. This polyene antibiotic is arguably one of the most powerful

antifungal agents available and has been in clinical use for over 35 yrs. The antifungal

effects of this medication are due to its high affinity to ergosterol found in fungal cell

membranes. The binding of Amphotericin B to the fungal membrane forms pores and

increases permeability to ions, which leads to cell destruction (71,72). A similar process

occurs in the collecting tubular cells (73), with ion “holes” being punched into the cells.

The back leak of H

prevents adequate proton gradient formation. Urine acidification

and net acid excretion is then impaired. Interestingly, there has been one report of a

sporadic, pediatric case of dRTA where a gradient defect is demonstrated to be the

probable etiology (74).

Voltage Dependent Defect

A voltage dependent defect resulting in decreased luminal electronegativity in the

collecting ducts would decrease transmembrane potential for secretion of positively

charged particles. Sodium absorption in the principal cells leaves a relatively negative-

charged environment consisting of Cl

–

molecules. Although chloride moves passively

out of the urine through cellular and paracellular channels, its movement is slower than

that of sodium. In effect, the lag in Cl

–

uptake provides a negative luminal environment.

The prototypical defect of this process is observed with the use of amiloride and

trimethoprin, which block the Na

channels in the principal cells (Fig. 6). This decrease

in sodium absorption makes for a relatively more positive lumen than usual, which

impedes the secretion of both H

and K

. The result is a nongap metabolic acidosis often

with elevated serum K

, hence the term hyperkalemic dRTA.

Hyperkalemic dRTA from obstructive nephropathy is felt, at least in part, to be caused

by such a voltage defect by some investigators. The impaired sodium handling may be

secondary to an underlying problem with decreased function of the basolateral Na

ATPase from the obstruction (75,76). Na

-ATPase dysfunction would certainly also

disrupt K

excretion leading to hyperkalemia. However, abnormal proton secretion may

also be part of the pathophysiology of obstructive nephropathy as mentioned previously

(63,64). Chronic tubulointerstitial diseases and autoimmune diseases (systemic lupus

erythematosus in particular), often with mild renal insufficiency, may manifest a

hyperkalemic dRTA possibly caused by a voltage defect with variable degrees of cellular

resistance to the mineralocorticoids (77). Hyperkalemic dRTA may involve a combina-

Chapter 8 / Renal Acid–Base Balance 147

tion of voltage defect and H

-ATPase defect, as investigators have found mixed findings

with testing of patients with this form of RTA (78,79).

Aldosterone deficiency can lead to a salt wasting state with a similar pathophysiology

of acidosis and hyperkalemic dRTA. Mineralocorticoid deficiencies, especially with

underlying mild renal insufficiency, are often associated with other proximal tubular

abnormalities such as impaired ammoniagenesis with clinical findings consistent with

the definition of a type 4 RTA. Therefore, the line between hyperkalemic dRTA and type

4 RTA is not always clear. Indeed, some classification schemes do not make the distinc-

tion between hyperkalemic dRTA and type 4 RTA, and essentially group both disorders

under type 4 RTA. Nonetheless, subtle differences such as in baseline urine pH values

may substantiate the delineation of these two entities.

Other Disease States

The cause of dRTA in various autoimmune diseases has been investigated and

deserves mention. Systemic lupus erythematosus (SLE) and Sjogren syndrome are

two of many autoimmune diseases clearly associated with dRTA (80–82). Immu-

nochemical staining has demonstrated a decrease or absence of H

-ATPase in many

but not all of these patients (83,84). One theory proposes that autoantibodies from

these diseases destroy or impair the apical proton pumps in the intercalated cells.

Autoantibodies to the intracellular carbonic anhydrase (CA2) have also been demon-

strated in SLE (85,86). A recent case report of IgE-related vasculitis and dRTA (87)

found antibodies binding to CA2 and other membrane proteins on the intercalated cell,

giving this antibody-mediated mechanism of tubular dysfunction some additional

support.

LINICAL PRESENTATION

Children with underlying dRTA present for evaluation of growth retardation (88).

Unlike pRTA, dRTA is associated with hypocitraturia, hypercalciuria and nephrocal-

cinosis. Combined with a mildly alkaline urine pH, nephrolithiasis can be the present-

ing issue in many cases. An additional presenting symptom may include deafness (for

many autosomal recessive forms). Bone abnormalities are seen in dRTA, especially

with CA2 mutations. This defect, however, probably involves the proximal tubule as

well (69,70).

Secondary forms of dRTA usually involve a fairly obvious systemic disease. The

symptoms related to the tubular abnormalities may include weakness if hypokalemia is

a prominent finding. Because dRTA is not a self-limiting condition (as is the case in

pRTA), the metabolic acidosis can progress to dangerous levels.

ABORATORY FINDINGS AND TESTING IN DRTA

The primary initial laboratory findings in dRTA include a hyperchloremic metabolic

acidosis and an inappropriately elevated (>5.5) urinary pH in light of the acidemia. Net

acid excretion is impaired and should be reflected by a positive urine anion gap or urine

osmolar gap. Despite acid loading in dRTA, urine pH remains >5.5. Serum potassium

is also useful in further defining the probable defective mechanism. Hypocitraturia and

hypercalciuria are two additional findings, at least for the classic type of dRTA.

Provocative testing is sometimes used to prove a distal acidification defect. These

tests have already been discussed; the bicarbonate load test and furosemide test are

particularly useful in examining distal nephron acidification. Bicarbonate loading in

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dRTA would reveal a fractional excretion of bicarbonate of <15% and U-P pCO

gra-

dient of <20 mmHg.

Measurement of renin and aldosterone levels may prove useful in differentiating the

hyperkalemic dRTA from type 4 RTA. However, the aldosterone level in hyperkalemic

dRTA from tubulointerstitial diseases can be quite variable (79). Typically, the urine pH

in hyperkalemic dRTA is >5.5, implying a distal acidification problem. The urine pH

in type 4 RTA, however, is usually <5.5 despite impaired NAE, suggesting that the

decreased capability to distally acidify the urine is matched by a decrease in supplied

ammonia (Fig. 11). Table 3 provides some basic laboratory differences among the

RTAs.

REATMENT OF DISTAL RTA

Provision of alkali and citrate represents the primary treatment of dRTA. The alkali

required is usually substantially less than that required to treat pRTA. Because endo-

genous acid production is about 1 meq/kg body weight, a similar replacement of alkali

should provide the amount of buffer needed to maintain acid–base homeostasis in adults.

Children and infants require substantially higher doses (4–10 meq/kg) as a result of

ongoing bone growth and, especially in infants, a decreased bicarbonate reabsorptive

capacity (89). If there is significantly decreased serum bicarbonate to begin with, not

uncommon with dRTA, the initial replacement dose may need to be larger to replace this

deficit. Sodium bicarbonate can be used, in two or three divided doses per day. Children

treated with alkali for dRTA can resume normal growth, minimize nephrolithiasis and

nephrocalcinosis, and possibly preserve kidney function (8).

Fig. 11. Balance of ammonia availability and distal proton availability determines net acid

excretion (NAE) and the urine pH. Type 4 RTA and distal RTA both have decreased NAE but,

typically, have differing urine pH because of this mismatch of buffer to proton.

Chapter 8 / Renal Acid–Base Balance 149

Hypokalemia is often seen with classic dRTA, and the use of potassium containing

salts may be necessary or preferable. The combination sodium and potassium citrate

salts are commonly used to not only replace alkali and potassium, but also to supply

citrate to treat the hypocitraturia.

In secondary forms of dRTA, treatment of the underlying disorder, such as SLE, may

improve the RTA (90). Individuals with hyperkalemic forms of dRTA may require the

discontinuation of medications that suppress the renin–aldosterone axis. This includes

many of the medications that can cause a type 4 RTA. Mineralocorticoid replacement

can sometimes help this form of dRTA if other measures fail. Although loop diuretics

may help with the hyperkalemia, the increased calciuria may be counterproductive if

nephrolithiasis is an issue.

With treatment of the acidosis, hypercalciuria in dRTA can lessen. The hypocitraturia,

on the other hand, may persist (38,91). Caution must be taken to avoid overly aggressive

sodium bicarbonate replacement, because excess sodium excretion will cause hypercal-

ciuria as well.

Rate-Dependent RTA

The term “rate dependent” RTA is a vague term in the classification of RTA. In

general, the term applies to those situations where there is a mild defect in urine acidi-

fication with perhaps a milder degree of metabolic acidosis; this may imply a non-H

pump related defect of dRTA. This would encompass all causes of dRTA owing to

voltage dependent defects as well as aldosterone deficiency or resistance. More specifi-

cally, the term has also been used to designate individuals who have impaired distal H

capacity based on measurement of U-B pCO

(<20mmHg), but appropriate urine acidi-

fication (<5.5) when an acid load is given (92).

Although the pathophysiology is probably varied and overlaps the various mecha-

nisms outlined previously, a partial distal tubular defect in the availability of protons,

from any cause, can give this constellation of findings. At baseline mild acidosis, the H

defect would theoretically lead to an elevated urine pH. The tests of the distal tubule

would be abnormal (U-P pCO

<20 mmHg after bicarbonate load, and urine pH >5.5

with furosemide challenge). When an acid load is provided, and thus a greater acidemic

stimulus, distal acidification takes place with urine pH of <5.5. Whether there is further

progression of these rate-dependent RTAs to a complete dRTA is unclear. Rate-depen-

dent RTA is sometimes categorized as a subset of incomplete RTA. Mechanistically,

though, the above definition of rate-dependent RTA differs from at least one theory of

incomplete RTA.

Incomplete RTA

Incomplete RTA is usually discovered in the metabolic evaluation of nephrolithiasis

or osteoporosis. Osteopenia and osteoporosis may also be associated with an underlying

incomplete RTA (93). This entity is characterized by normal serum electrolytes and

normal serum bicarbonate levels (41,93) implying appropriate net acid excretion under

normal acid loads. Hence, abnormalities of acid regulation are often initially overlooked.

More thorough investigation, however, usually reveals a mildly elevated urine pH,

decreased urine citrate excretion and elevated urine calcium excretion (91,94). The

“gold standard” for evaluation of incomplete RTA remains the acid load test. The lack

of a renal acid excretory reserve characterizes this problem. At this point, two different

150 Chin

mechanisms for incomplete RTA have been described. These two theories have substan-

tially different findings with careful, formal testing of tubular function.

The first theory of the mechanism of incomplete RTA speculates that there is a mild

secretion defect. This, in effect, describes a milder form of the classic type I RTA,

characterized by distal tubular secretion defects not severe enough to give an obvious

metabolic acidosis. As would be expected, the findings on U-P pCO

gradient measure

and furosemide challenge would be abnormal. This condition is sometimes included in

the “rate-dependent” form of dRTA—the acidification defect is mild and brought out

only with acid loading or testing of the distal segments.

The second theory of incomplete RTA demonstrates a vastly different mechanism.

The elevated urine pH in this form of incomplete RTA is felt to be caused by a greatly

exaggerated increase in ammonia production and distal delivery, not caused by impaired

distal H

secretion. The increased ammonia delivery to the distal nephron is felt to be so

large, that the majority of the H

is bound, leaving relatively fewer free protons; a high

urine pH is the result. Evidence of an exaggerated ammonia production rate despite

normal serum pH and bicarbonate levels hint that a proximal tubular cell abnormality

may be the basis of incomplete RTA (41). This theory contrasts with the mechanism

described earlier, where urine pH remains elevated because of a distal tubular secretory

defect despite normal ammoniagenesis. Net acid excretion is theoretically different

between the two entities; incomplete RTA caused by a mild secretory defect would have

slightly decreased NAE, whereas incomplete dRTA caused by ammonia overproduction

would have normal or even elevated NAE.

Overall, the etiology of incomplete RTA is not well described, and the diagnosis

may encompass various defects, ranging from AE1 (basolateral HCO

–

/Cl

–

exchanger

on intercalated cells) mutations (95) to decreased intracellular pH in the proximal

tubular cells. The findings of provocative tests are summarized in Table 3. In addition,

whereas incomplete RTA is usually discussed in the context of distal RTAs because of

the elevated urine pH, a proximal tubular abnormality may be the primary defect based

on some evidence. One proposed mechanism of incomplete RTA mentioned previ-

ously suggests that the proximal tubule may have a chronically decreased intracellular

pH as a reason for the increased ammonia production (41). This would also prompt

hypocitraturia despite the absence of overt systemic acidosis, typical for incomplete

RTA. The chronic increased ammonia production and cycling may stimulate inflam-

mation, eventually leading to chronic interstitial disease and possibly complete dRTA

with a distal acidification problem (96–98). The development of complete dRTA from

incomplete RTA is speculative but noted in some case reports.

There are numerous diseases associated with incomplete RTA, including vitamin D

or lithium use, sickle cell, medullary sponge kidney, and glycogen storage diseases.

Autoimmune disorders, more commonly associated with complete dRTA or hyper-

kalemic RTA, can be associated with incomplete RTA (99,100). Treatment of incom-

plete RTA is directed predominantly at the nephrolithiasis and osteoporosis. This entails

correction of hypocitraturia and maneuvers to decrease calcium excretion. Because

metabolic acidosis is not a finding in this form of RTA, the use of alkali has questionable

benefit.

Type 4 Renal Tubular Acidosis

Type 4 RTA is the most common form of RTA in adults (63). The disorder is char-

acterized by distal tubular findings consistent with a combination of a “rate-limited” H

Chapter 8 / Renal Acid–Base Balance 151

secretory defect and a voltage dependent defect. The hyperkalemia that is usually asso-

ciated with type 4 RTA contributes to impairment in proximal tubular ammoniagenesis.

In addition, a level of aldosterone deficiency characterizes this type of RTA and probably

also leads to decreased ammoniagenesis (101). The combination of these defects results

in a hyperchloremic metabolic acidosis with hyperkalemia, a positive urine anion gap

(impaired NAE), and an acidified urine (<5.5) at baseline. Many patients also have some

mild renal insufficiency.

AUSES OF TYPE 4 RTA

Aldosterone deficiency or resistance is the underlying issue in many of the causes of

type 4 RTA. As aldosterone is important in the sodium absorption in the principal cells

of the collecting tubule, a low aldosterone state would decrease the voltage gradient for

secretion (voltage defect). In addition, aldosterone deficiency would impair distal

tubular proton secretory capability (secretory defect). The hyperkalemia seen in type 4

RTA can also be attributed to low aldosterone, to some degree. Ammoniagenesis is

decreased, perhaps as a result of the hyperkalemia (101). Table 5 lists disease states and

medications associated with these conditions.

Many commonly used medications can cause aldosterone resistance and induce a type

4 RTA. Oftentimes this is clinically evident in patients who are predisposed to develop-

ing this form of RTA. Individuals with diabetes mellitus or mild chronic interstitial renal

disease are especially prone to this condition when ACE inhibitors, nonsteroidal anti-

inflammatory medications or spironolactone is used.

Table 5

Causes of Type 4 RTA

Mineralocorticoid deficiency

• Normal renal function

Addison’s Disease

Congenital adrenal hyperplasia

Hereditary

• Chronic renal disease

Diabetic nephropathy

HIV associated nephropathy

Mineralocorticoid resistance

• Genetic

Pseudohypoaldosteronism type I

Pseudohypoaldosteronism type II (Gordon’s syndrome)

• Chronic renal disease

Obstructive uropathy

Renal transplant rejection

Medullary cystic kidney disease

Medications

• Spironolactone/eplerenone

• Angiotensin converting enzyme receptor blocker

• Long-term heparin

• Cyclosporine

152 Chin

CLINICAL FINDINGS AND LABORATORY FINDINGS

The clinical findings in type 4 RTA are usually not very remarkable. The hyperkale-

mia is usually silent unless there is severe dietary indiscretion or the use of antagonizing

medications. Renal stones are usually not associated with this form of RTA. Although

urine citrate excretion may be decreased, there is commonly a mild degree of renal

insufficiency, which decreases calcium excretion and may protect from nephrolithiasis

(102).

The baseline urine pH is usually acidic in type 4 RTA despite an underlying mild distal

acidification defect, which can be detected by U-P pCO

measurement after bicarbonate

loading. The decreased ammoniagenesis may account for the low urine pH, because

buffer delivery is low, and the matched decrease in urine proton availability is enough

to provide a urine pH of <5.5. Overall, NAE is decreased (Fig. 11).

REATMENT

Treatment for type 4 RTA includes mineralocorticoids to correct the underlying low

aldosterone state, loop diuretics to manage the hyperkalemia, and dietary restrictions to

limit potassium intake. Mineralocorticoids such as fludrocortisone may increase distal

nephron tubular sodium absorption and provide a more favorable electronegative lumen

for both H

and K

secretion (103). The increased sodium absorption, however, may lead

to edema and hypertension, especially in those with some renal insufficiency to begin

with. Loop diuretics are especially useful for type 4 RTA (104). The K

wasting effect

not only treats the hyperkalemia, but in doing so may also stimulate ammoniagenesis in

the proximal tubules to aid in NAE. The increase in distal sodium delivery also favors

distal proton secretion. If the acidosis remains severe despite these measures, alkali is

often provided at about 1–2 meq/kg (104). Dietary restriction of potassium by itself has

been found to ameliorate the acidosis of type 4 RTA by the mechanisms mentioned

previously (105).

REFERENCES

1. Lemann J, Jr., Litzow JR, Lennon EJ. The effects of chronic acid loads in normal man: further

evidence for the participation of bone mineral in the defense against chronic metabolic acidosis.

J Clin Invest 1966; 45(10): 1608–1614.

2. Bushinsky DA. Net proton influx into bone during metabolic, but not respiratory, acidosis. Am J

Physiol 1988; 254(3 Pt 2): F306–310.

3. Bushinsky DA. Stimulated osteoclastic and suppressed osteoblastic activity in metabolic but not

respiratory acidosis. Am J Physiol 1995; 268(1 Pt 1): C80–88.

4. Kamel KS, Briceno LF, Sanchez MI, et al. A new classification for renal defects in net acid

excretion. Am J Kidney Dis 1997; 29(1): 136–146.

5. Reddi AS. Essentials of renal physiology. College Book Publishers. East Hanover, NJ 1999: 337.

6. Nissim I, Cattano C, Lin Z. Acid-base regulation of hepatic glutamine metabolism and ureagenesis:

study with 15N. J Am Soc Nephrol 1993; 3(7): 1416–1427.

7. Boon L, Blommaart PJ, Meijer AJ, et al. Acute acidosis inhibits liver amino acid transport: no

primary role for the urea cycle in acid-base balance. Am J Physiol 1994; 267(6 Pt 2): F1015–

1020.

8. Caldas A, Broyer M, Dechaux M, et al. Primary distal tubular acidosis in childhood: clinical study

and long-term follow-up of 28 patients. J Pediatr 1992; 121(2): 233–241.

9. Tashian RE. The carbonic anhydrases: widening perspectives on their evolution, expression and

function. Bioessays 1989; 10(6): 186–192.

10. Breton S. The cellular physiology of carbonic anhydrases. JOP 2001; 2(4 Suppl): 159–164.

11. Dobyan DC, Bulger RE. Renal carbonic anhydrase. Am J Physiol 1982; 243(4): F311–324.

Chapter 8 / Renal Acid–Base Balance 153

12. Wakabayashi S, Shigekawa M, Pouyssegur J. Molecular physiology of vertebrate Na+/H+ exchang-

ers. Physiol Rev 1997; 77(1): 51–74.

13. Putney LK, Denker SP, Barber DL. The changing face of the Na+/H+ exchanger, NHE1: structure,

regulation, and cellular actions. Annu Rev Pharmacol Toxicol 2002; 42:527–552.

14. Ghishan FK, Knobel SM, Summar M. Molecular cloning, sequencing, chromosomal localization,

and tissue distribution of the human Na+/H+ exchanger (SLC9A2). Genomics 1995; 30(1): 25–

30.

15. Abuladze N, Lee I, Newman D, et al. Molecular cloning, chromosomal localization, tissue distri-

bution, and functional expression of the human pancreatic sodium bicarbonate cotransporter. J

Biol Chem 1998; 273(28): 17,689–17,695.

16. DuBose TD, Jr., Good DW. Role of the thick ascending limb and inner medullary collecting duct

in the regulation of urinary acidification. Semin Nephrol 1991; 11(2): 120–128.

17. Igarashi T, Sekine T, Inatomi J, et al. Unraveling the molecular pathogenesis of isolated proximal

renal tubular acidosis. J Am Soc Nephrol 2002; 13(8): 2171–2177.

18. Smulders YM, Frissen PH, Slaats EH, et al. Renal tubular acidosis. Pathophysiology and diagno-

sis. Arch Intern Med 1996; 156(15): 1629–1636.

19. DuBose TD, Jr., Good DW, Hamm LL, et al. Ammonium transport in the kidney: new physiologi-

cal concepts and their clinical implications. J Am Soc Nephrol 1991; 1(11): 1193–1203.

20. Wall SM. Ammonium transport and the role of the Na,K-ATPase. Miner Electrolyte Metab 1996;

22(5–6): 311–317.

21. Hamm LL, Simon EE. Ammonia transport in the proximal tubule. Miner Electrolyte Metab 1990;

16(5): 283–290.

22. Tanner MJ. Band 3 anion exchanger and its involvement in erythrocyte and kidney disorders. Curr

Opin Hematol 2002; 9(2): 133–139.

23. Karet FE, Finberg KE, Nelson RD, et al. Mutations in the gene encoding B1 subunit of H+-ATPase

cause renal tubular acidosis with sensorineural deafness. Nat Genet 1999; 21(1): 84–90.

24. Halperin ML, Kamel KS, Ethier JH, et al. What is the underlying defect in patients with isolated,

proximal renal tubular acidosis? Am J Nephrol 1989; 9(4): 265–268.

25. Kurtz I. Role of ammonia in the induction of renal hypertrophy. Am J Kidney Dis 1991; 17(6):

650–653.

26. Sastrasinh S, Tannen RL. Effect of potassium on renal NH3 production. Am J Physiol 1983;

244(4): F383–391.

27. Halperin ML, Ethier JH, Kamel KS. Ammonium excretion in chronic metabolic acidosis: benefits

and risks. Am J Kidney Dis 1989; 14(4): 267–271.

28. Remer T. Influence of nutrition on acid-base balance–metabolic aspects. Eur J Nutr 2001; 40(5):

214–220.

29. Krapf R, Pearce D, Lynch C, et al. Expression of rat renal Na/H antiporter mRNA levels in response

to respiratory and metabolic acidosis. J Clin Invest 1991; 87(2): 747–751.

30. Kuwahara M, Sasaki S, Marumo F. Mineralocorticoids and acidosis regulate H+/HCO3– transport

of intercalated cells. J Clin Invest 1992; 89(5): 1388–1394.

31. Hays SR. Mineralocorticoid modulation of apical and basolateral membrane H+/OH–/HCO3–

transport processes in the rabbit inner stripe of outer medullary collecting duct. J Clin Invest 1992;

90(1): 180–187.

32. Schwartz GJ, Al-Awqati Q. Regulation of transepithelial H+ transport by exocytosis and endocy-

tosis. Annu Rev Physiol 1986; 48:153–161.

33. Da Silva Junior JC, Perrone RD, Johns CA, et al. Rat kidney band 3 mRNA modulation in chronic

respiratory acidosis. Am J Physiol 1991; 260(2 Pt 2): F204–209.

34. Hamm LL, Hering-Smith KS. Acid-base transport in the collecting duct. Semin Nephrol 1993;

13(2): 246–255.

35. Ortiz PA, Garvin JL. Role of nitric oxide in the regulation of nephron transport. Am J Physiol Renal

Physiol 2002; 282(5): F777–784.

36. Simpson DP. Citrate excretion: a window on renal metabolism. Am J Physiol 1983; 244(3): F223–

234.

37. Dyck RF, Asthana S, Kalra J, et al. A modification of the urine osmolal gap: an improved method

for estimating urine ammonium. Am J Nephrol 1990; 10(5): 359–362.