A new classification for renal defects in net acid excretion

OCCASIONAL HYPOTHESES

A New Classification for Renal Defects in Net Acid Excretion

Kamel S. Kamel, MD, Luis F. Briceno, MD, Marta I. Sanchez, MD, Luis Brenes, MD, Peter Yorgin, MD, Sang Whay Kooh, MD, J. Williamson Balfe, MD, and Mitchell L. Halperin, MD

• The traditional classification of the group of disorders called renal tubular acidosis (RTA) into proximal and distal subclasses is based on which nephron segment is thought to have an abnormal function. Nevertheless, such a distinction may not be correct and also does not characterize the pathophysiology of the renal acidosis in each patient. In this article, we propose an alternative classification, one that is based on the component of net acid excretion that is abnormal. We also suggest expanding the definition of net acid excretion to include a term that describes the renal handling of metabolizable organic anions because their loss in the urine represents the loss of "potential bicarbonate." Because a low rate of excretion of ammonium (NH4 ÷) is present in patients with both distal and isolated proximal RTA, our initial clinical step in patients with hyperchloremic metabolic acidosis (HCMA) is to evaluate the rate of excretion of NH4 ÷. The basis for a low rate of excretion of NH4 ÷ is shown by examining the urine pH. If the urine pH is low, further studies are performed to determine why the availability of NH3 is low; if the urine pH is high, further investigations are initiated to examine if the defect in H ÷ secretion involves the proximal or the distal nephron. Conversely, if the rate of excretion of NH4 ÷ is high in a patient with HCMA, a component of the degree of acidosis could be attributable to a high rate of excretion of metabolizable organic anions. Case examples are provided to illustrate the approach and its implications for future molecular studies. © 1997 by the National Kidney Foundation, Inc.

INDEX WORDS: Ammonium; bicarbonate; carbonic anhydrase; citrate; organic anions; renal tubular acidosis; urine Pc02; urine pH.

I N THE traditional classification of patients with metabolic acidosis of renal origin, the

designation is via nephron segment. Disorders are called proximal (type II) or distal (type I) renal tubular acidosis (RTA). Into this classification, one adds elements such as type IV RTA and incomplete RTA, while forgetting about type III RTA. This classification, apart from being quite cumbersome, does not characterize the pathophysiological characteristics of the acidosis. For example, it is not obvious from the word- ing that distal RTA actually defines a disorder with a low rate of excretion of NH4 +. In addition, a low rate of excretion of NH4 + also may be caused by a defect in the proximal convoluted tubule (PCT)? "2 Adding to the confusion is that in some patients labeled as proximal RTA, bicar-

From the Division of Nephrology, St Michael's Hospital, University of Toronto, Toronto; the Department of Medicine, Hospital Juan de Dios, Costa Rica; the Department of Pediat- rics, University of Arizona; and the Divisions of Endocrinol- ogy and Nephrology, Hospital for Sick Children, Toronto, Canada.

Received February 13, 1996; accepted for publication Au- gust 6, 1996.

Address reprint requests to Mitchell L. Halperin, MD, FRCP(C), Division of Nephrology, St Michael's Hospital, 38 Shuter St, Toronto, Ontario, Canada M5B 1A6.

© 1997 by the National Kidney Foundation, Inc. 0272-6386/97/2901-001953.00/0

bonaturia may also be attributable to a defect in distal H + secretion. Taking into account the re- cent advances in molecular biology and the char- acterization and cloning of several of the trans- port proteins in the kidney, the potential for using these powerful tools to elucidate the physiology of acid-base homeostasis and the pathophysiology of its disorders at the cellular level is enor- mous. Clinicians, however, have the important task of better characterizing the pathophysiological characteristics of the disease processes in their patients to ensure that the genetic and molecular studies are performed in patients who share a common pathophysiological state for their disease.

Bearing this in mind, we propose that patients with a renal cause for metabolic acidosis be clas- sified initially on the basis of the components of net acid excretion that are abnormal. The next step is to deduce the nature of the lesion that could have led to the low rate of net acid excretion. Not only might this provide new insights into the pathophysiology of these disorders, but it should permit more precise molecular identifi- cation of suspected underlying lesions. The discussion is divided into four sections. We shall first provide a brief synopsis of the relevant physiology. The tools that can be used at the bedside to characterize the pathophysiological state in patients with renal acidosis are examined. Our clini-

136 American Journal of Kidney Diseases, Vol 29, No 1 (January), 1997: pp 136-146

RENAL TUBULAR ACIDOSIS 137

cal approach to patients with hyperchloremic metabolic acidosis (HCMA) follows. Finally, four patients with a different basis for a diminished rate of net acid excretion are presented to illustrate how this approach could be used at the bedside.

SYNOPSIS OF RELEVANT PHYSIOLOGY

Metabolism of a typical Western diet yields a net of close to 1 mmol of H+/kg body weight per day. 3 These H + ions are removed for the most part by combining with bicarbonate ions (HCO3-), forming H20 plus CO2-- the CO2 is exhaled and, as a result, the body is left with an overall deficit of HCO3 . To maintain acid-base balance, the kidney must not only reclaim all the filtered HCO3 , but also generate new HCO3-. This latter task is achieved by excreting HaPO4 and NH4 +.4 It is obvious that the rate of excretion of H2PO4- and NH4 + must exceed that of HCO3- to have a positive renal balance for HCO3- - - th i s is the traditional definition of net acid excretion. 4 Because the rate of excretion of H2PO4- varies over only a small range, two major causes of renal acidosis emerge: those in which too much HCO3- is excreted and those in which not enough NH4 + is excreted.

Kamel et al 5 emphasized another role of the kidney in acid-base balance: control of the rate of excretion of metabolizable organic anions. For example, when subjects with chronic ketoacidosis of fasting are faced with an additional acid load (NHeC1 ingestion), their kidneys eliminated this acid load without varying the rate of net acid excre t ion-- that is, the rate of excretion of NH4-- did not rise. Acid-base balance was achieved because NH4 + was excreted with chloride (C1) in- stead of /3-hydroxybutyrate (/3-HB) anions. Three conclusions were drawn from that study: First, there is an additional way that the kidney contributes to acid-base balance, lowering the rate of excretion of metabolizable organic anions when faced with an acid load. This effect is not unique to ketoacids because citrate (and other organic anions) excretion is also markedly diminished by metabolic acidosis. 6'7 Second, although the decrease in/3-HB anion excretion was partly attributable to a lower filtered load, a renal mechanism was operating because the fractional reabsorption o f /3 -HB anions in these patients was markedly enhanced. 5 Third, this defense of acid- base balance requires that the organic anions that

were not excreted be retained and subsequently metabolized to neutral end-products, yielding HCO3- in the process. 8 Therefore, these investi- gators suggested that the definition of net acid excretion should include a term that describes the renal handling of metabolizable organic anions because their loss in the urine represents the loss of potential HCO3-. Hence our revised classification of renal acidosis includes three categories, excessive excretion of HCO3 , low excretion of NH4 +, and excessive excretion of metabolizable organic anions (potential HCO3 ) (equation 1, Table 1).

Net acid excretion = NH4 + + H2PO4-

- HCO3- - Potential HCO 3 (1)

TOOLS THAT CAN BE USED AT THE BEDSIDE

Excessive Excretion of HC03

In a patient with metabolic acidosis, any excretion of HCO3- is excessive. The bulk of filtered HCO3- is reclaimed in the PCT, but an appreciable portion (close to 15%) is normally reclaimed by distal H + secretion. If less than 22 mmol HCO3- is reabsorbed per liter of glomemlar filtrate (GFR), 9'1° the lesion may be caused by a reduced rate of secretion of H + in the proximal or the proximal plus distal nephron. Notwithstanding,

Table 1. Proposed Classification of Patients With Metabolic Acidosis and a Low Rate of

Net Acid Excretion

Type of disorder 1. Low rate of NH4 + excretion

(i) Low NH3 availability Low production of NH3

Usually low GFR, hyperkalemia, alkaline proximal ICF pH, high delivery of fat-derived fuels to the kidney (eg, TPN)

Low NH3 delivery to the medullary interstitium Usually medullary interstitial diseases

(ii) High distal nephron luminal pH Low distal nephron H + secretion

H + ATPase or K+/H + ATPase pump failure, voltage defect, H + backleak

Excessive delivery of aGO 3 to the distal nephron (low proximal H + secretion)

2. Excessive excretion of HCOa- Defect in proximal or distal H + secretion

3. Excessive excretion of potential HCO3 (metabolizable organic anions)

Excessive ketonuria, for example

138 KAMEL ET AL

clinical studies of HCO 3- reabsorption must be interpreted with caution. Two factors affect the interpretation of the handling of HCO3- ions by the PCT; the first relates to extracellular fluid (ECF) volume status and the second to potassium (K) balance. Renal reabsorption of HCO 3- in the PCT is much lower if the ECF volume is increased (eg, by infusing NaHCO3). 10-13 Reabsorption of HCO3-, however, is not "threshold-limited" if the ECF volume is not expanded. 11-16 To avoid an un- wanted expansion of the ECF volume, we believe that the best way to study the renal reabsorption of HCO3- may be to add HCO3- to the body in conjunction with an equimolar loss of C1 ions - - this represents the physiological way HCO3- are added to the body when HC1 is retained in the stomach. 17 When this procedure was performed in rats, there was trivial bicarbonaturia despite a very large increase in the concentration of HCO3- in plasma. 11'18 To perform this study, we would give a loop diuretic (eg, 20 to 40 mg furosemide) to induce a loss of NaC1. All of the K excreted is replaced (usually 10 mmol), and all of the Na excreted is replaced intravenously as NaHCO3. In general, each liter of urine excreted results in the loss of approximately 125 mmol C1, which is then replaced by a similar quantity of HCO3- intravenously. We know of no studies performed in this manner in patients who were being investigated to establish the diagnosis of or the molecular basis for proximal RTA.

With regard to K balance, hypokalemia may enhance proximal reabsorption of HCO3-; alternatively, hyperkalemia appears to have the oppo- site effect. 19 Therefore, studies should be interpreted with caution in a patient who has hypokalemia or hyperkalemia.

Fractional Excretion of Bicarbonate

When the plasma [HCO3-] is 25 mmol/L, a fractional excretion of HCO3- (FEHco3) that exceeds 15% is used to document that proximal RTA is present because distal delivery of HCO3- is normally close to 15% of its filtered load. There are two obvious problems with this definition. First, a less severe disorder of proximal H ÷ secretion could not be diagnosed using such stringent criteria. To put this in a quantitative perspective, consider how much HCO3- would be excreted in the urine if one wished to maintain a normal plasma [HCO3-] (25 mmol/L) in a patient with proximal RTA. Because an adult with

a normal glomerular filtration rate (GFR) (180 L/day) filters 4,500 mmol HCO3- when their plasma [HCO3-] is 25 mmol/L (180 L/day × 25 mmol/L), the daily excretion of HCO3- would be 675 mmol when its FEHco3 is 15%. This value of 675 mmol is equivalent to almost twice the total content of HCO3- in the ECF (15 L × 25 mmol/L = 375 mmol) and is almost 10-fold higher than the daily rate of net acid excretion (70 mEq/day3). Furthermore, a patient would need to ingest close to 10 mmol NaHCO3 per kilogram body weight to keep up with these losses. By demanding such a high value for the FEr~co3 for the diagnosis of proximal RTA, one must expand the ECF volume by close to 10% (raise the plasma HCO3 from 18 to 25 mmol/L in a volume of distribution of half the body weight) and, thereby, possibly obscure the usual physiological process of control of H + secretion in the PCT. 19 The second problem with the current interpretation of the FEr~co3 is that a defect in reclamation of bicarbonate that is attributable to a diminished rate of distal H + secretion is not recognized. The nonspecificity of the FEr~co3 is obvious when the physiological process of proximal H + secretion was explored in rats treated acutely with an inhibitor of the enzyme carbonic anhydrase (CA). 2° When luminal but not intracellular CA was inhib- ited, reabsorption of HCO3 in the PCT of superficial nephrons was decreased to a major degree, yet there was relatively little bicarbonaturia. Hence the capacity of more distal segments to reabsorb HCO3- can indeed be high in the rat. If these data reflect quantitative possibilities in humans, one would have to conclude that the FEHco3 is not a sensitive way to confirm a milder defect in proximal H + secretion.

To summarize, a high FEHco3 could be expected in three major settings: first, a very large defect in H + secretion in the proximal tubule; second, a smaller defect in proximal tubule H + secretion plus a reduced distal capacity for H + secretion; third, normal proximal but a near com- plete defect in distal H + secretion.

Carbon Dioxide Partial Pressure in Alkaline Urine

If the carbon dioxide partial pressure (Pco2) in alkaline urine is 70 mm Hg or higher, one has indirect evidence for a normal rate of distal H + secretion. 21 Nevertheless, there are other factors such as a defect in the renal concentrating ability


that may cause this urine PCO2 to be lower. 22 Furthermore, in some patients with metabolic acidosis attributable to glue sniffing, the urine Pc02 was low despite a high rate of NH4 + excretion (which implies a high rate of distal H + secre- t ion)Y Perhaps this discrepancy could reflect low distal H + secretion in these patients while alka- lemic, but appropriate distal H + secretion when metabolic acidosis was present. Thus, it seems that a high P c Q in alkaline urine suggests that distal H + secretion is present, but a low Pc02 in alkaline urine does not always imply a low rate of distal H + secretion.

Urine pH

A high value for the urine pH almost always reflects bicarbonaturia (with the exception of the presence of an organism that released urease into the urine). Despite the widely used definitions of distal RTA that focus on the value of the urine pH, this parameter is not a reliable index of the rate of excretion of NH4+. 24 A very low value for the urine pH does not imply that NH4 + excretion is high, but rather that the increase in H + secretion by the distal nephron is not matched by an increase in the availability of NH3 in the renal medullary interstitium. Moreover, urines with the highest NH4 + concentration often have a pH in the low 6 range, z5-27

The urine pH is useful, however, once when one knows that a patient with metabolic acidosis has a low rate of excretion of NH4 +. A low urine pH now suggests a decreased NH3 availability, whereas a high value suggests a defect in distal or proximal H + secretion (equation 2, Table 1).

H + + NH3 ~ NH4 + (2)

NH4 + in the Urine

We use an assessment of the rate of excretion of NH4 + to separate patients with hyperchloremic metabolic acidosis (HCMA) into two large groups: those with a high rate of excretion of NH4 + (if a renal component to their acidosis is present, it will be caused by a loss of potential HCO3- in the urine), and those with a low rate of excretion of NH4 +. A low rate of excretion of NH4 + reflects either a failure to produce NH4 + in proximal tubular cells at a sufficiently rapid rate, 2s an inability to achieve a high concentration of NH3 in the renal medullary interstititium, or a defect in the transfer of NH3 to the lumen of

the collecting duct z9 (Table 1). The transfer of NH3 to the lumen of the collecting duct requires the presence of a concentration difference for NH3 between the interstitium and the lumen of the collecting duct. The concentration of NH3 in the lumen of the collecting duct is lowered when H + combines with NH3 to make NH4 + (equation 2). Therefore, a low rate of transfer of NH3 could result from a defect in distal H + secretion or if H + are titrated by an excessive delivery of HCO3- to the distal nephron as a result of a low rate of H + secretion in the PCT. Although low NH4 + excretion is the key finding in patients with distal RTA, 3° it is also present in patients with isolated proximal RTA. 1'2

To make an assessment of the rate of excretion of NH4 +, one must know first what is the "expected rate" for its excretion. Obviously, values should not be compared with those from a population who do not have metabolic ac idos is - - rather one should make comparisons with nor- reals who have received a "chronic" acid load. We emphasize "chronic" here because there is a lag period of a few days before augmented rates of excretion of NH4 + can be achieved. 28'29'37

The expected values are 3 mmol/kg/day in adults 26'2vm and children. 32'33

I f a direct assay for urinary NH4 + is not available, an indirect test must be used to estimate the rate of excretion of NH4 +. Of these indirect tests, two are unreliable. First, and as already mentioned, the urine pH does not reflect the rate of excretion of NH4+. 24 Second, the urine anion gap or net charge 34'35 reflects the rate of excretion

of NH4 + only if the accompanying anion is C1 (Fig 1). Excretion of NH4 + plus C1 occurs in patients who have lost NaHCO3 through the GI tract or previously in the urine (eg, after a carbonic anhydrase inhibitor), or in those given an NH4C1 load. In contrast to the urine anion gap, the urine osmolal gap provides a more reliable index of the rate of NH4 + excretion because it detects all NH4 + salts in the urine (equation 3). 36'37 This index can be improved by including in the calculation the measured values for the cations calcium and magnesium, and the anions sulfate and phosphate in the urine. Nevertheless, and considering that the purpose of the test is to provide a semiquantitative rather than precise information, these latter measurements are not needed in most cases.

140

ANIONS

A"

CI ° = 215

CATIONS

NNg = 136

K+= 57

la+= 24

ANIONS

A"

CI--60

CATIONS

NH~ = 107

K*= 3~

~la + 6~

Fig 1. Urine net charge to detect NH4 + or Anions in the Urine. The urine net charge detects NH4 + in the urine only if excreted with CI- (concentrations shown in left-hand figure, data from a patient late in the course of diabetic ketoacidosis [DKA]). The urine net charge is an unreliable index of the rate of NH4 ÷ excretion, if NH4 ÷ is being excreted with anions (A-) other than CI- (concentrations shown in right-hand figure, data early in that same patient with DKA when NH4 + is being excreted along with ketoacid anions).

Urine NH4 + = 0.5 (urine osmolality

- (2(Na + K) + urea + glucose)),

all in mmol/L terms (3)

Citrate Excretion

The rate of excretion of citrate seems to reflect the pH in PCT cells (high if more alkaline). 7 The rate of excretion of citrate is increased after a NaHCO3 load, but decreases to very low levels during most forms of metabolic acidosis. 6'38 A notable exception to this rule is seen in patients with the isolated form of proximal RTA; an appreciable degree of citraturia is present despite metabolic acidosis. 1'2'39'4° Halperin et al 2 specu- lated that an alkaline PCT cell was the underlying lesion causing low HCO3 reabsorption, low NH4 + production, and citraturia in patients with isolated proximal RTA. If an alkaline proximal cell was also present in patients with carbonic anhydrase II (CAH) deficiency, one would expect to find citraturia during acidemia (true in one reported patient, 41 plus in case 2 summarized in this article).

To ensure that citraturia reflects an alkaline PCT cell rather than a component of a more generalized proximal tubular dysfunction (Fanconi syndrome), citraturia should disappear after an NH4C1 load. These data are only available in the patients described in this report (Tables 2, 3) and in one preliminary report. 39

The rate of excretion of citrate in 21 adults

KAMEL ET AL

consuming their usual diet in our population is 429 + 43 mg/g creatinine, values similar to those of the control population reported in Table 2. In children, eating their usual diet, the rate of citrate excretion is similar to that in adults (440 _+ 49 mg/g creatinine42). As shown in Table 2, citrate excretion decreases markedly in normal subjects given an acid load, in keeping with results of earlier studies by Dedmond and Wrong 6 and Nor- man et al. 43

Anions in the Urine

The excessive loss of metabolizable organic anions in the urine represents the loss of "potential HCO3" and hence a " rena l" defect in net acid excretion. 5'44 To detect excessive anion excretion, one adds the concentrations of the major urine cations Na, K, and NH4 + (the latter either measured or estimated as in equation 3) and sub- tracts the concentration of the major urine anion, C1.

CLINICAL APPROACH TO A PATIENT WITH HCMA

Patients who have HCMA can be divided into three broad categories based on the rate of excretion of the components of net acid (Table 1). Our approach to patients with HCMA starts with an assessment of the rate of excretion of NH4 + (Fig 2). A low rate of excretion of NH4 + is the key finding in patients with distal RTA; it is also expected in patients with proximal RTA (caused by a diminished rate of production of NH4 + or a failure to lower the concentration of NH3 in the lumen of the collecting duct because of excessive distal delivery of HCO3- from the PCT). If an assay of urine NH4 + is not available, the urine osmolal gap should be used to reflect this excretion rate.

If the rate of excretion of NH4 ÷ is high in a patient with HCMA (Fig 2, right side), a renal component to the acidosis could be present if there is a loss of metabolizable organic anions in the urine. It should be clear that the main cause of the metabolic acidosis in this patient is overproduction of organic acids; nevertheless, the severity of the acidosis may be aggravated by the presence of a renal lesion that leads to the loss of organic anions (potential HCO3-) in the urine. An excessive rate of excretion of organic anions in the urine is suspected if the sum of Na


Table 2. Studies With an Additional Acid Load

Controls Case 1

Days of NH4CI Load 0 Day 3 0 Day 3

Plasma pH 7.42 _+ 0.01 7.34 _+ 0.02* 7.30 7.19 H C Q - (mmol/L) 25 -- 1 18 _+ 2 16 9 Pco2 (mm Hg) 38 _+ 2 35 _+ 2 33 24

Urine pH 5.8 _+ 0.2 4.9 +_ 0.2* 5.1 4.7 NH4 + (mmol/day) 24 +_ 4 72 _+ 3* 18 34 Citrate (mg/g creatinine) 307 _+ 38 15 _+ 6* 595 77

NOTE. Control subjects (n = 6) and case 1 were fed 2 mmol NH4CI/kg body weight for 3 days. Blood was taken before and on the third day; urine was collected for the 24-hour period of day 3. Results are presented as the mean _+ SEM for the control subjects.

*P < 0.01 for paired differences.

+ K + NH4 + in the urine greatly exceeds that of C1 (Fig 1).

In a patient with HCMA and a low rate of excretion of NH4 + (Fig 2, left side), the basis for low NH4 + excretion can be deduced from the urine pH. If the urine pH is greater than 6, one should look at the renal handling of HCO3- (Fig 3). We recommend examining the Pc02 in alkaline urine to detect whether there is a defect in distal H-- secretion and the FENco3 to determine if proximal H ÷ secretion is overtly subnormal. One may or may not find other features of im-

paired proximal tubular function, such as glucos- uria, phosphaturia, aminoaciduria, and so fo r t h - - ie, a Fanconi's syndrome. A high rate of excretion of citrate in a patient with metabolic acidosis suggests that an alkaline PCT cell could be the cause of diminished proximal H ÷ secretion. This suspicion is further strengthened if citraturia dis- appears with the administration of an additional acid load (Table 2).

HCMA with a low rate of excretion of NI-I4 + and a low value for the urine pH (the actual value is hard to define, but we would consider a low

Table 3. Illustrative Cases With HCMA

Persistent Isolated pRTA CA, Defect Bicarbonaturia Ketonuria

Plasma pH HCO3 (mEq/L) Anion gap (mEq/L) K (mEq/L) Creatinine (mg/dL)

Urine pH Net charge (mEq/L) Osmolal gap (mOsm/kg H20) NH4 + (#mol/min/kg) Citrate (mg/g creatinine)

Special tests FEHc% (%) Urine Pc% (mm Hg) Fanconi lesion

7.30 7.32 7.30 7.35 16 18 17 19 11 10 10 14

3.9 3.8 3.7 2.9 0.6 0.4 0.3 0.9

5.1 7.0 6.5 5.3 30 30 81 0 70 64 31 404

0.4 0,5 0.3 3.0 595 582 489 <50

18 14 22 <1 89 40 92 90 No No Yes No

NOTE. For details, see text. Urine net charge = [Na + K] - [CI]; the FEHc% was calculated when the plasma H C Q - was close to 25 mmol/L.

142 KAMEL ET AL

What is the urine p H ? ~

• Low NH 3 in

renal medulla • Examine for

proximal defect

in H + secretion

• See F gure 4

+ • D e c r e a s e d distal H + secretion

• Excessive

distal delivery of HCO 3

• See F gure 3

Is urine osmolal gap low (< 100 mosm/I)? (Is NH~ excretion low?)

~ A I u ~en t::nm:~° ricY °f

• Interstitial diseases J

~ GI loss NaHCO 3 NH4CI or HCI oad

• Hippuric acid • Ketoacidosis plus

excessive ketonuria • D-Lactic acidosis

(chronic)

Fig 2. Flow chart: Approach to patients with HCMA. An occult increase in the anion gap in plasma must be ruled out (hypoalbuminemia, unusual cations [myeloma protein], or an overestimation of CI [halides, hyperlipid- emia]). The next step is to assess the rate of excretion of NH4 ÷. If a direct measurement of NH4 ÷ is not available, use the urine osmolal gap. If NH4 ÷ excretion is high, determine whether CI or organic anions are excreted with NH4 ÷. Alternatively, if there is a low rate of excretion of NH4 ÷, the urine pH is helpful to determine whether a low distal or proximal H ÷ secretion or a low NH3 availability was the cause for the low rate of NH4 ÷ excretion. Depending on the results, one should then proceed to Figs 3 or 4. Although the excessive loss of ketoacid anions in the urine represents the loss of potential HCO3 and a form of renal acidosis, this is not the case with the excretion of hippurate because the anion hippurate is not potential HCO3 .

value to be in the 4 to the low 5 range) suggests a defect in NH3 availability in the renal medullary interstitium (Fig 4). The usual causes for the low NH3 are a low GFR or hyperkalemia. In their

absence, we would look for low levels of glutamine, 45 the substrate for ammoniagenesis, in blood or a high level of fat-derived fuels (eg, patients on total parental nutrition), because these

Enter via Figure 2: HCMA + Bicarbonaturia

I I '0mm"gl

What is the FEHc03 ?

• Severe distal

H + secretory

defect

• Combined proximal

and distal defect

in H +secretion

What is the PCO 2 in alkaline urine?

I

Is FEHc03> 15% at 25 mM HCO3?

~ l s citrate

~snea!!iiia!iHdefect I ~ J exc re t~w?

• Alkaline NHE defect

proximal cell Back-leak HCO 3 • ATP deficit in PCT

Fig 3. Flow chart: Exces- sive excretion of HCO3-. Any excretion of HCOs- during metabolic acidosis is excessive (urine pH >6.5). To detect the basis for renal loss of HCO3 , the Pco2 in alkaline urine and the FEHco3 a t 25 mmol/L HCO3- are examined. Based on the results, defects are suggested. NHE = Na+/H ÷ exchanger in the PCT.


Fig 4. Flow chart: Low NH3 availability. The first step to determine the basis for a low urine pH and NH4 + excretion rate is to rule out a low GFR and hyperkalemia (the common causes). In their absence, one could rule out a nutritional problem by measuring the plasma glutamine level and fatty acid metabolites. An alkaline proximal cell is suspected if there is citraturia in the patient with HCMA.

1 Enter via Figure 2: I Low NH 3 causing low NH; ]

Is hyperkalemia p r e s e n t ? ~

• Long list of causes

• Acute or chronic renal failure

Is the GFR very low and/or hyperkalemia present?

~ 1 di~rede~ nutriti°nal

• Alkaline proximal cell

• Inborn errors of ammoniagenesis

• Low glutamine~ • High fat fuels I

(e.g., TPN) J

fue l s m a y c o m p e t e w i t h g l u t a m i n e as t he s o u r c e

fo r r e g e n e r a t i o n o f a d e n o s i n e t r i p h o s p h a t a s e

( A T P ) in t he ce l l s o f t he P C T , a n d h e n c e l e a d to

a l o w e r r a t e o f p r o d u c t i o n o f NH4--. I f n o n e o f

t h e s e are p r e s e n t , w e w o u l d s u s p e c t an a l k a l i n e

p r o x i m a l ce l l pH. T h i s e n t i t y o f a n a l k a l i n e p rox i -

m a l i n t r a c e l l u l a r f lu id ( I C F ) p H r e m a i n s specu l a -

t i ve b e c a u s e t h e r e a re n o h a r d da t a in h u m a n s ,

a n d s u i t a b l e e x p e r i m e n t a l m o d e l s in a n i m a l s are

l ack ing . 46 N e v e r t h e l e s s , i n d i r e c t e v i d e n c e for i ts

e x i s t e n c e m a y b e t he f i nd i ng o f c i t r a t e in t he

u r i n e w h i l e t he p a t i e n t is a c i d e m i c . F u r t h e r m o r e ,

w i t h an a d d i t i o n a l ac id load , a m a r k e d d e c r e a s e

in c i t r a tu r i a a n d a n i n c r e a s e in t he r a t e o f exc re -

t i on o f NH4 + p r o v i d e i n d i r e c t e v i d e n c e to s u g g e s t

t ha t t he p H o f P C T ce l l s w a s h i g h ( see da t a o n

c a s e 1 in T a b l e s 2 a n d 3). A n o t h e r t e s t t ha t m i g h t

b e h e l p f u l n o w is to a s sess the r a t e o f p r o d u c t i o n

o f NH4 + in v i v o b y m e a s u r i n g t he r a t e o f exc re -

t i on o f NH4 + a f t e r t he a d m i n i s t r a t i o n o f a l oop

d iu r e t i c a n d a n a d d i t i o n a l a c id load . 47 A t p e a k

d iu res i s , a h i g h ra t e o f NH4 + e x c r e t i o n ( c lo se to

60 # m o l / m i n ) re f lec t s t h e c a p a c i t y to a u g m e n t

r e n a l a m m o n i a g e n e s i s . F a i l u r e to f ind s u c h a h i g h

ra t e o f NH4 + e x c r e t i o n w o u l d i m p l y a l o w ra te

o f p r o d u c t i o n o f NH4 + in p r o x i m a l cel ls .

CASE EXAMPLES Four patients with HCMA are used to illustrate our ap-

proach; a summary of the relevant laboratory data for each case is provided in Table 3.

Case 1. Isolated Proximal RTA (pRTA)

This patient with HCMA was previously reported by Brenes et al.48 The rate of excretion of NH4 + was low during

acidemia (18 v 72 ± 3 mmol/day in normals with 3 days of NH4C1 loading). A urine pH of 5.1 indicated a low NH3 availability in the medullary interstitinm (Table 3, Fig 2). Moving to Fig 4, because both a low GFR (plasma creatinine 50 #mol/1 [0.6 mg/dL]) and hyperkalemia (plasma [K] 3.9 mmol/L) were not present, and a nutritional problem was ruled out, an alkaline PCT celt was suspected (Table 1). This latter diagnostic impression was supported by finding a high rate of citrate excretion (595 mg/g creatinine) while the patient was in his usual state of HCMA (Table 2). After a 3- day acid load, the rate of excretion of NH4 + increased almost twofold, but not to the same extent as in normals (Table 2), confirming previous observations in similar patientsJ Addi- tionally, with this acid load, the rate of excretion of citrate was only 77 mg/g creatinine (Table 2), again suggesting a high intracellular pH in PCT cells rather than an intrinsic proximal H + secretory defect. Furthermore, the decrease in citrate excretion with the additional acid load suggested that the citraturia was more likely to be attributable to an alkaline proximal cell rather than a feature of a more generalized disorder in proximal tubular function, such as Fanconi syndrome. 39 There was no detectable defect in distal H + secretion (the urine pH was very low and the Pco2 in alkaline urine was above 70 mm Hg, Table 3). A defect in proximal H + secretion was confirmed by finding a FEHco3 that was greater than 15% when the plasma HCO3- was raised to 25 retool/ L. There was no evidence of a Fanconi syndrome type of lesion.

Case 2. Carbonic Anhydrase II Deficiency

A young boy was investigated because of persistent HCMA. As shown in Table 3, the rate of excretion of NH4 + was low. Following the steps outlined in Fig 2, the high urine pH indicated an inappropriately high rate of excretion of HCO3-. To define whether the defect in H ÷ secretion was in the proximal or the distal nephron, the steps outlined in Fig 3 were followed. Because the Pco2 in alkaline urine was only 40 mm Hg, a defect in distal H + secretion was probably present. Because the FEHco3 was 14% when the plasma H C O 3 - was raised to 25 mmol/L, a defect in H + secretion

144 KAMEL ET AL

in the proximal nephron was also likely. A generalized Fan- coni syndrome, however, was not present. The finding of a high rate of excretion of citrate while the patient was acidemic (582 mg/g creatinine) and that citraturia decreased markedly (<20 mg/g creatinine) after an acute load of NH4CI (2 mmol/ kg, plasma pH = 7.22, [HCO3-] = 15 mmol/L) suggested that an alkaline proximal cell was the cause of the defect in proximal H + secretion. A similar defect also may be present in the distal nephron. A low CAn activity was confirmed by direct assay in his erythrocytes. 49 Because the induction of a more severe degree of metabolic acidosis led to a decrease in the urine pH to 5.8, some H + secretion in the distal nephron was present under this acid-base stimulus.

Case 3, Persistent Bicarbonaturia

As shown in Table 3, the patient had HCMA. Given the low rate of NI-I4 + excretion and the urine pH of 6.5, further investigations to explore the basis for the excessive excretion of HCO3- were performed as illustrated in Fig 3. The high Pco2 in alkaline urine (92 mm Hg) suggested that distal H + secretion was intact. The FEHco3 of 22% at a plasma HCO3- of 33 mmol/L suggested that there was a defect in proximal H + secretion. This suspicion was supported by finding of other features of impaired proximal tubular function in keeping with a Fanconi-type lesion. Therefore, the high urine citrate excretion in the face of metabolic acidosis in this case could be part of the Fanconi syndrome.

The defect in proximal H + secretion in this patient merits an additional comment. When the filtered load of HCO3 was increased, the FEHco3 increased, but more HCO3 (mmol per liter GFR) was reabsorbed (data not shown). Therefore, the defect in proximal H ÷ secretion did not seem to be simply one of a rate limit. We speculate that its basis might be a backleak of HCO3 into the lumen of the PCT. This will ensure a large distal delivery of HCO3- at any given plasma HCO3- concentration. A more detailed discussion of the ki- netics of reabsorption of HCO3- is provided by Halperin et aL so

Case 4. Excessive Excretion of Potential HC03 -

A 21-year-old woman with poorly controlled diabetes mellitus presented with persistent HCMA (note that the plasma anion gap was slightly elevated at 14 mEq/L, whereas her albumin concentration in plasma was normal; Table 3). 44 Fol- lowing the approach outlined in Fig 2, the rate of excretion of NH4 + was high during chronic metabolic acidosis (3 #mol/ min/kg). The anions accompanying NH4 + were not C1 (urine net charge = 0); therefore, other anions such as hippurate, fl-HB , or D-lactate were abundant in her urine. Subsequent testing showed that the excretion of 13-HB was very high (3 #mol/min/kg body weight). Hence this patient appeared to have metabolic acidosis attributable to overproduction of ketoacids (insulin-dependent diabetes mellitus); nevertheless its degree was more severe because of a renal defect in their reabsorption (the FE of p-HB was 78% v the expected value of close to 20% to 25%44). FEHco3 was <1% at a plasma HCO3- of 25 mmol/L. Therefore, other components of net acid excretion (HCO3- reabsorption and NH4 + excretion) were normal. The renal component of the acidosis in this

patient was attributable to a defect in reabsorption of potential HCO3- (Table 1).

DISCUSSION

R T A is a t e rm used to desc r ibe a pa t ien t w h o

has ch ron ic m e t a b o l i c ac idos is , no inc rease in the

p l a s m a an ion gap, and the absence o f rena l fail-

ure. T h e t rad i t iona l c lass i f ica t ion into p rox ima l ,

distal, i n c o m p l e t e , and type IV R T A does no t

e m p h a s i z e the p a t h o p h y s i o l o g i c a l charac ter i s t ics

o f the d i so rde r in each pat ient . Fu r the rmore , it

does no t p r o v i d e the hard and fast separat ions ,

as pa t ien ts wi th dis tal R T A m a y h a v e thei r m a j o r

p a t h o p h y s i o l o g i c a l cond i t ions in p r o x i m a l or dis-

tal tubules . 51 T o unders tand the p a t h o p h y s i o l o g i -

cal state in an ind iv idua l case, a m o d i f i e d c lass i -

f ica t ion o f R T A was p roposed , one that is based

on a f o r m u l a o f ne t ac id exc re t i on that conta ins

all o f the ident i f ied c o m p o n e n t s o f renal acid-

base hand l ing . T h r e e m a j o r g roups o f renal aci-

dos is are r ecogn ized : e x c e s s i v e exc re t i on o f

H C O 3 - , l o w exc re t i on o f NH4 +, and e x c e s s i v e

exc re t ion o f po ten t ia l H C O 3 - .

Th is a p p r o a c h should p r o v i d e the c l in ic ian

wi th a s c h e m e for the c l in ica l d i agnos i s in pa-

t ients w i th H C M A that is based on r e c o g n i z i n g

d i sorders by thei r p a t h o p h y s i o l o g i c a l charac ter i s -

t ics and no t by desc r ip t ive labels . Pat ients w i th

H C M A are c lass i f ied ba sed on thei r rate o f excre -

t ion o f NH4 +. In those pat ients w i th a h i g h rate

o f exc re t i on o f NH4 +, a rena l c o m p o n e n t o f thei r

ac idos is cou ld be a t t r ibutable to the loss o f me-

t abo l i zab le o rgan ic an ions in the i r ur ine. In those

wi th a l o w rate o f exc re t i on o f NH4 ÷, the de fec t

in ne t ac id exc re t i on is fur ther cha rac t e r i zed

based on the u r ine pH. T h o s e wi th a l o w ur ine

p H are i nves t iga t ed for causes o f l o w ava i lab i l i ty

o f NH3, w h e r e a s those wi th a h i g h u r ine p H are

e x a m i n e d to in fe r whe the r the de fec t in H ÷ secre-

t ion i n v o l v e s the p r o x i m a l or the dis ta l nephron .

A n o t h e r a d v a n t a g e o f this app roach is that by

s teer ing a w a y f r o m us ing desc r ip t ive t e rms to a

g rea te r e m p h a s i s on p a t h o p h y s i o l o g y , the c l in i -

c ian cou ld m o r e re l i ab ly p red ic t w h i c h e n z y m e

or t ranspor te r m i g h t be d e f e c t i v e in each case so

that the m o l e c u l a r b io log i s t s cou ld d i rec t the i r

s tudies to the ' ' t a rge t g e n e " and con f i rm or re fu te

the c l in ica l i m p r e s s i o n in a h o m o g e n e o u s g roup

o f pat ients w h o h a v e a c o m m o n p a t h o p h y s i o l o g i -

cal condi t ion . Seve ra l e x a m p l e s w e r e used to il-

lus t ra te the po ten t ia l va lue o f our approach. T h e i l lus t ra t ive cases 1 th rough 3 had a m a j o r de fec t


in the reabsorpt ion of fil tered HCO3 and were

all cal led p rox imal RTA, but the basis of their lesion(s) could be bet ter defined.

In case 1, the patient seemed to have a defect in p rox imal and not distal H + secretion. One pos- sible lesion would be in the Na, H + ion exchanger (NHE3) on the luminal membrane of the PCT. If this were the sole lesion, the ICF p H in the PCT would be more acidic, and one would expect

the absence of citraturia. Nevertheless , there was abundant ci t raturia while the patient was acidemic, which led to the suggest ion that an alka- l ine intracel lular pH of the PCT was a poss ib le lesion that should be explored (supported by the finding of low NH4 + excret ion despi te a very low urine pH, in keeping with a low rate of ammoniagenesis) . A poss ib le defect for the molecular b io logis t to cons ider would be in the general t ransport systems that defend ICF pH. 52 These

general lesions might be less l ike ly because the p rob lem seemed to be restr icted to only the PCT. Accord ing ly , a molecu la r defect in the Na(HCO3)32 exit step on the basolateral membrane of PCT cells could expla in these findings, and we suspect a p rob lem result ing in a lower affinity for this ion complex or another that might decrease the act ivi ty of this transporter.

In case 2, there was a suspected defect in both p rox imal and distal H ÷ secretion; the proximal

lesion was suspected because the FEHco3 was 15%, and a defect in distal nephron H + secret ion was suspected because there was a low value for the urine Pc02 in alkal ine urine together with a higher than expected urine pH with acid loading. Our next step was to see i f one could expla in all of these findings by a single lesion. Because the major luminal H + pumps differ in the PCT (Na, H + ion exchanger , NHE3) and distal nephron (vacuolar H ÷ ATPase) , one would be reluctant to suggest two separate lesions. Similar ly , because the major HCO3 exit steps in the PCT (Na[HCO3]32- cotransporter) and o!-intercalated cells in the distal tubule (HCO3, C1 anion exchanger) also differ, a HCO3- exit t ransport step defect is an unl ike ly explanat ion. Our diagnost ic impress ion was a lesion that could diminish the s t imulat ion for net H + secret ion in both nephron segments such as a more alkal ine ICF pH. In this context, CAH deficiency was conf i rmed by direct enzyme assay.

Overal l the combina t ion of an opt imal c l inical classif icat ion and more specific molecular studies

could improve the specifici ty of diagnosis and

provide for a better unders tanding of the renal disorders that lead to metabol ic acidosis.

REFERENCES

1. Brenes LG, Sanchez MI: Impaired urinary ammonium excretion in patients with isolated proximal renal tubular acidosis. J Am Soc Nephrol 4:1073-1078, 1993

2. Halperin ML, Kamel KS, Ethier JH, Magner PO: What is the underlying defect in patients with isolated, proximal renal tubular acidosis? Am J Nephrol 9:265-268, 1989

3. Halperin ML, Jungas RL: Metabolic production and renal disposal of hydrogen ions. Kidney Int 24:709-713, 1983

4. Pitts RF, Lotspeich WD, Schiess WA, Ayer JL: The renal regulation of acid-base balance in man. 1. The nature of the mechanism for acidifying the urine. J Clin Invest 26:48- 56, 1947

5. Kamel K, Ethier J, Stinebaugh B, Schloeder F, Halperin M: The removal of an inorganic acid load in subjects with ketoacidosis of chronic fasting: The role of the kidney. Kid- ney Int 38:507-511, 1990

6. Dedmond RE, Wrong O: The excretion of organic anion in renal tubular acidosis with particular reference to citrate. Clin Sci 22:19-32, 1962

7. Simpson D: Citrate excretion: A window on renal metabolism. Am J Physiol 244:F223-F234, 1983

8. Halperin ML, Rolleston FS: Clinical Detective Stories: A Problem-Based Approach to Clinical Cases in Energy and Acid-Base Metabolism. London, England, Portland Press, 1993

9. Edelman C Jr, Soriano J, Boichis H, Gruskin A, Acosta M: Renal bicarbonate reabsorption and hydrogen ion excretion in normal infants. J Clin Invest 46:1309-1317, 1967

10. Morris RC Jr: Renal tubular acidosis: Mechanisms, classification and implications. N Engl J Med 281:1405-1413, 1969

11. Rubin SI, Sonnenberg B, Zettte R, Halperin ML: Met- abolic alkalosis mimicking the acute sequestration of HC1 in rats: Bucking the alkaline tide. Clin Invest Med 17:515-521, 1994

12. Maddox D, Gennari F: Proximal tubular bicarbonate reabsorption and PcQ in chronic metabolic alkalosis in the rat. J Clin Invest 72:1385-1395, 1983

13. Maddox D, Gennari F: Load dependence of proximal tubular bicarbonate reabsorption in chronic metabolic alkalosis in the rat. J Clin Invest 77:709-716, 1986

14. Purkerson M, Lubowitz H, White R, Bricker N: On the influence of extracellular fluid volume expansion on bicarbonate reabsorption in the rat. J Clin Invest 48:1754-1760, 1969

15. Kurtzman N: Regulation of renal bicarbonate reabsorption by extracellular volume. J Clin Invest 49:586-595, 1970

16. Kurtzman NA, White MG, Rogers PW: The effect of potassium and extracellular volume on renal bicarbonate reabsorption. Metabolism 22:483-492, 1973

17. Halperin ML, Goldstein MB: Fluid, Electrolyte and Acid-Base Physiology: A Problem-Based Approach. Phila- delphia, PA, Saunders, 1994

18. Scheich A, Donnelly S, Cheema-Dhadli S, Schweigert M, Vasuvattakul S, Halperin ML: Does saline 'correct' the

146 KAMEL ET AL

abnormal mass balance in metabolic alkalosis associated with chloride-depletion in the rat. Clin Invest Med 17:448-460, 1994

19. Alpern R: Cell mechanisms of proximal tubule acidi- fication. Physiol Rev 70:79-114, 1990

20. DuBose TD Jr, Lucci MS: Effect of carbonic anhydrase inhibition on superficial and deep nephron bicarbonate reabsorption in the rat. J Clin Invest 71:55-65, 1983

21. Halperin M, Goldstein M, Haig A, Johnson M, Stine- bangh B: Studies on the pathogenesis of type I (distal) renal tubular acidosis as revealed by the urinary PCO2 tensions. J Clin Invest 53:669-677, 1974

22. Berliner RW, DuBose TDJ: Carbon dioxide tension of alkaline urine, in Seldin DW, Giebisch G (eds): The Kidney: Physiology and Pathophysiology (ed 2). New York, NY, Ra- ven Press, 1992, pp 2681-2694

23. Vasuvattakul S, Nimmannit S, Shayakul C, Vareesangthip K, Halperin ML: Should the urine Pco2 or the rate of excretion of NH4 + be the gold standard to diagnose distal renal tubular acidosis? Am J Kidney Dis 19:72-75, 1992

24. Richardson RMA, Halperin ML: The urine pH: A po- tentially misleading diagnostic test in patients with hyperchloremic metabolic acidosis. Am J Kidney Dis 10:140-143, 1987

25. Schloeder FX, Stinebaugh B J: Defect of urinary acidi- fication during fasting. Metabolism 15:17-25, 1966

26. Simpson D: Control of hydrogen ion homeostasis and renal acidosis. Medicine 50:503-541, 1971

27. Madison LL, Seldin DW: Ammonia excretion and renal enzymatic adaptation in human subjects, as disclosed by administration of precursor amino acids. J Clin Invest 37:1615-1627, 1958

28. Halperin ML, Kamel K, Ethier J, Stinebaugh B, Jungas R: Biochemistry and physiology of ammonium excretion, in Seldin D, Giebisch G (eds): The Kidney, Physiology and Pathophysiology, Chap 76. New York, NY, Raven Press, 1992

29. Knepper MA, Packer R, Good DW: Ammonium trans- port in the kidney. Am Physiol Soc 69:179-249, 1989

30. Carlisle EJF, Donnelly SM, Halperin ML: Renal tubular acidosis (RTA): Recognize The Ammonium defect and pHorget the urine pH. Pediatr Nephrol 5:242-248, 1991

31. Pitts RF: Renal production and excretion of ammonia. Am J Med 36:720-742, 1964

32. Rubin MI, Calcagno PL, Ruben BL: Renal excretion of hydrogen ions: A defense against acidosis in premature infants. J Pediatr 59:848-860, 1961

33. Peonides A, Levin B, Young WF: The renal excretion of hydrogen ions in infants and children. Arch Dis Child 40:33-39, 1965

34. Goldstein M, Bear R, Richardson R, Marsden P, Hal- perin M: The urine anion gap: A clinically useful index of ammonium excretion. Am J Med Sci 292:198-202, 1986

35. Baffle D, Hizon M, Cohen E, Gutterman C, Gupta R: The use of the urinary anion gap in the diagnosis of

hyperchloremic metabolic acidosis. N Engl J Med 318:594- 599, 1988

36. Halperin ML, Margolis BL, Robinson LA, Halperin RM, West ML, Bear RA: The urine osmolal gap: A clue to estimate urine ammonium in 'hybrid' types of metabolic acidosis. Clin Invest Med 11:198-202, 1988

37. Dyck R, Asthana S, Kalra J, West M, Massey L: A modification of the urine osmolal gap: An improved method for estimating urine ammonium. Am J Nephrol 10:359-362, 1990

38. Wrong O, Davies HEF: The excretion of acid in renal disease. Q J Med 28:259-313, 1959

39. Donnelly S, Brenes L, Halperin M: Isolated proximal renal tubular acidosis: Dissociation of cellular and systemic pH. Clin Invest Med 14:A134, 1991

40. Halperin ML: How much "new" bicarbonate is formed in the distal nephron in the process of net acid excretion? Kidney Int 35:1277-1281, 1989

41. Ohlsson A, Cumming WA, Paul A, Sly WS: Carbonic anhydrase II deficiency syndrome: Recessive osteopetrosis with renal tubular acidosis and cerebral calcification. Pediat- rics 77:371-381, 1986

42. Miller LA, Stapleton FB: Urinary citrate excretion in children with hypercalciuria. J Pediatr 107:263-266, 1985

43. Norman ME, Feldman NI, Cohn RM, Roth KS, McCurdy DK: Urinary citrate excretion in the diagnosis of distal renal tubular acidosis. J Pediatr 92:394-400, 1978

44. Hammeke M, Bear R, Lee R, Goldstein M, Halperin M: Hyperchloremic metabolic acidosis in diabetes mellitus: A case report and discussion of the pathophysiologic mechanisms. Diabetes 27:16-20, 1978

45. Halperin ML, Chen CB: Plasma glutamine and renal ammoniagenesis in dogs with chronic metabolic acidosis. Am J Physiol 252:F474-F479, 1987

46. Breitschwerdt EB, Ochoa R, Waltman C: Multiple en- docrine abnormalities in Basenji dogs with renal tubular dysfunction. JAVMA 182:1348-1353, 1983

47. Vasuvattakul S, Gougoux A, Halperin ML: A method to evaluate renal ammoniagenesis in vivo. Clin Invest Med 16:265-273, 1993

48. Brenes L, Brenes J, Hernandez M: Familial proximal renal tubular acidosis: A distinct clinical entity. Am J Med 63:244-252, 1977

49. Sly WS, Hewett-Emmett D, Whyte MP: Carbonic anhydrase II deficiency identified as the primary defect in the autosomal recessive syndrome of osteopetrosis with renal tubular acidosis and cerebral calcification. Proc Natl Acad Sci USA 80:2752-2756, 1983

50. Halperin ML, Carlisle EJ, Donnelly S, Kamel KS, Vasuvattakul S: Renal tubular acidosis, in Narins RG (ed): Clinical Disorders of Fluid and Electrolyte Metabolism (ed 5). New York, NY, McGraw Hill, 1994, pp 875-910

51. Donnelly SM, Kamel KS, Vasuvattakul S, Narins RG, Halperin ML: Might distal renal tubular acidosis be a proximal disorder? Am J Kidney Dis 19:272-281, 1992

52. Boron WF: Cellular buffering and intracellular pH, in Seldin DW, Giebisch G (eds): The Regulation of Acid-Base Balance. New York, NY, Raven Press, 1992, pp 33-56

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