Metabolic Acidosis due to Gluesniffing

Patients who sniff glue for its intoxicating properties absorb a significant quantity of toluene (methylbenzene). Toluene is metabolized via a series of reactions in the liver to hippuric acid that provides the load of H+

(Figure 23). Deipite the production of the hippurate anion, the plasma anion gap is generally not significantly elevated because the kidney, both via filtration and more impori tantly by tubular secretion, very efficiently excretes hippurate. As a result, there is the development of a hyperchloremic type ofmeta-bolic acidosis. Together with the anion excretion, variable amounts of urinary excretion of Na+ and K+ may be seen, leading to a degree of ECF volume contraction and hypokalemia, both of which aggravate the degree of intra-cellular acidosis (Figure 7). Even though there is an enhanced rate of exiretion of NH4+, this does not result in a negative urine net charge (i.e., UNa+K > uci, Figure 11) because of the very high rate of excretion of the hippurate anion. The presence of NH4+ and hippurate in the urine could be detected by the presence of a significant urine osmolal gap (Figure 11). Thus the clinical features of toluene intoxication include metabolic acidosis, near-normal plasma anion gap, normal plasma osmolal gap, ECF volume contraction, hypokalemia, lower than expected BUN and a high urine osmolal gap. It had formerly been thought that glue-sniffing was a cause of distal RTA [144], but the high rate of excretion of NH4+ in response to the metabolic acidosis in many of these patients means that they do not have distal RTA. Some patients may have another reason for a low rate of excretion of NH4+ (e.g., a low GFR) so they have two reasons for the metabolic acidosis, excessive overproduction of hippuric acid and a low rate of NH4+ excretion. If the GFR is low enough, there may now be a high anion gap in plasma [21].

Treatment of Metabolic Acidosis due to Glue-sniffing

The treatment of toluene inhalation requires that each of these clinical features be addressed. When the inhalation of toluene stops, ultimately the production of hippuric acid will be diminished, but there can be a lag of 1 - 3 days before there is little hippuric acid generation because of the large volume of distribution of toluene [21]. Hypokalemia and ECF volume contraction need to be corrected with the administration of KCl and saline, according to their severity. If metabolic acidosis is particularly severe, consideration should be given to the use of NaHCO3 because there is no anion present in the body that can be me-tab olized to HCO3-. The major caveat to the use of NaHCO3 in this setting is that coexisting K+ depletion could be severe. Given the risk of a cardiac arrhythmia, the PK must be raised first to the low 3 range before NaHCO3 is admini st ered because of the concern that NaHCO3 may exacerbate hypokalemia.

Organic Acid Load from the GI Tract (D-lactic Acidosis)

Certain bacteria in the gastrointestinal (GI) tract may convert carbohydrate (cellulose and fructose) into organic acids. The three factors that make this possible are slow GI transit (blind loops, obstruction), change of the normal flora (usually with antibiotic therapy), and the supply of carbohydrate substrate to these bacteria (foods containing fructose or sorbitol [145] (Figure 24, [70]). The most preval ent organic acid is D-lactic acid [71]. Humans metabolize this D-isomer somewhat more slowly than L-lactate, but acidosis per se rarely is life-threatening. Although humans lack the enzyme D-lactate dehydro-genase, metabolism of D-lactate occurs via the enzyme D-2-hydroxy acid dehydrogenase.

There are three additional points that should be noted with re ipect to D-lactic acidoiis. First, the usual clinical laboratory test for lac-tate is specific for the L-lactate isomer. Hence the usual laboratory measurement for lactate will not be elevated. Second, GI bacteria produce amines, mercaptans, and other comi pounds that may cause the clinical symptoms related to CNS dysfunction (personality changes, gait changes, confusion, etc.). Third, some of the D-lactate will be lost in the GI tract or in the urine (if the GFR is not too low) [146, 147]. Hence the degree of rise in the plasma anion gap may not be as high as expected for the fall in the Phco3.

Treatment should be directed at the GI problem. The oral intake of fructose and complex carbohydrates should be decreased. Antacids should be avoided to decrease the rate of fermentation. Insul in may be helpful by lowering the rate of oxidation of fatty acids and hence permit a higher rate of oxidation of organic acids (Figure 25). Antibiotics could be considered to change the bacterial flora.

Hyperchloremic Metabolic Acidosis Tube

Figure 24. Organic acid production in the GI tract. Bacteria are normally segregated from dietary sugar by GI "geography". For overproduction of D-lactic acid, bacteria in the lower GI tract must mix with sugars. The supply of sugar is crit i cal for organic acid production. Bacteria migrate up to and pro i iferate in the small intestine. When provided with sugar in this "friendly environment", fermentation produces a variety of organic acids and noxious alcohols, aldehydes and amines; more are produced if more alkali is supplied. There must also be enough mucosal surface area to transport these acids into the body and cause the high plasma anion gap; otherwise the H+ produced might simply destroy luminal HCO3- from the secreted NaHCO3 and lead to the loss of Na+ plus D-lactate in the stool (a normal anion gap type of metabolic acidosis). The degree of the acidosis also depends on the rate that these organic acids can be oxidized and/or converted to glucose or fat (primari ly in the liver).

Figure 24. Organic acid production in the GI tract. Bacteria are normally segregated from dietary sugar by GI "geography". For overproduction of D-lactic acid, bacteria in the lower GI tract must mix with sugars. The supply of sugar is crit i cal for organic acid production. Bacteria migrate up to and pro i iferate in the small intestine. When provided with sugar in this "friendly environment", fermentation produces a variety of organic acids and noxious alcohols, aldehydes and amines; more are produced if more alkali is supplied. There must also be enough mucosal surface area to transport these acids into the body and cause the high plasma anion gap; otherwise the H+ produced might simply destroy luminal HCO3- from the secreted NaHCO3 and lead to the loss of Na+ plus D-lactate in the stool (a normal anion gap type of metabolic acidosis). The degree of the acidosis also depends on the rate that these organic acids can be oxidized and/or converted to glucose or fat (primari ly in the liver).

Pyroglutamic Acidosis

The list of causes of metibolic acido sis with a high anion gap in plasma does not usually include pyroglutamic acidosis (PGA) because it was thought to repr esent primari ly rare inborn errors of metabolism in the glutathione synthesis pathway (defects in 5-oxo-prolinase or in glutathione synthetase, Figure 26) [148, 149]. Notwithstanding, there have been an increasing number of case reports where PGA accumul ated and caused meta -bolic acidosis with an increase in the anion gap in plasma [131, 150 - 152]. When plasma levels of PGA rose to the 5 - 10 mM range, the

24-h urine contained 50 - 150 mmol of PGA [131, 150, 151]. The question raised by these observat ions is, what is responsible for the accumulation of PGA?

Key to the understanding of the accumulation of PGA is the fact that the reduced form of glutathione (GSH) feeds back to inhibit the enzyme (y-glutamylcysteine synthetase) that catalyzes the first step in the cycle that leads to the synthesis of glutathione, the conversion of glutamate to y-glutamylcysteine (Figure 26) [153].

A major function of reduced glutathione is to detoxify reactive oxygen species (ROS). In this process, the reduced form of GSH is converted to its oxidized form (GS-SG) (Equa-

Figure 25. Strategies for therapy in D-lactic acidosis. There are two fami lies of organic acids depending on whether they yield pyruvate or acetyl-CoA, bypassing pyruvate as a metabolic product. Organic anions that cannot be converted to pyruvate can only be oxi dized, converted to storage fat, or be converted to ketoacids, but are not substrates for the synthesis of glucose. Fatty acid synthesis only oc curs at ap pre cia ble rates when insulin levels are high (with meals). If insulin acts and depresses the rate of oxidation of fatty acids, more organic acids may be oxidized [70].

Pyroglutamic Acid Glutamic AcidPyroglutamic Acid Glutamic Acid

Figure 26. Production of pyroglutamic acid. The pathway begins with glutamate, a key intermediate in transamination reactions. When there are low levels of reduced glutathione (e.g., due to combination with a metabolite of acetaminophen), the production of y-glutamylcysteine is stimulated. If the y-glutamylcysteine so-formed accumulates, pyroglutamic acid will be formed. In addition, if 5-oxyprolinase is inhibited, pyroglutamic acid will also accumulate. As described in the text, a diminished ability to detoxify ROS is likely to be more important than the acidosis in this setting. Reproduced with permission [187].

Figure 26. Production of pyroglutamic acid. The pathway begins with glutamate, a key intermediate in transamination reactions. When there are low levels of reduced glutathione (e.g., due to combination with a metabolite of acetaminophen), the production of y-glutamylcysteine is stimulated. If the y-glutamylcysteine so-formed accumulates, pyroglutamic acid will be formed. In addition, if 5-oxyprolinase is inhibited, pyroglutamic acid will also accumulate. As described in the text, a diminished ability to detoxify ROS is likely to be more important than the acidosis in this setting. Reproduced with permission [187].

tion 13). Hence when ROS accumui ate, the concentration of GSH declines and this leads to an accelerated formation of y-glutamyl-cysteine (y-GC). This y-GC will be converted to PGA by the enzyme y-glutamylcysteine cyclotransferase when its concentration rises (Figure 26). Components of the glutathione cycle reside in different compartments of the cell [1]. This adds to the complexity of understanding the regulation of this feedback system.

PGA can be synthetized from glutamate when an internal peptide bond forms between its y-carboxyl group and the free a-amino group (i.e., if glutamate is free or the N-termi-nal amino acid is a peptide or protein) as long as the latter's y-carboxyl group is in an activated state. A number of drugs have been identified as potential causes of PGA acidosis. Some like acetaminophen, after conversion to a metabolite N-acetyl-p-benzoquinonimide (NAPBQI), decrease the concentration of GSH, thereby driving the synthesis of y-glutamylcysteine, and thereby PGA (Figure 26). Other drugs (e.g., the antibiotic flucloxacillin [150] and the anticonvulsant, vigabatrin [154]) may inhibit 5-oxoprolinase. A third mode of action could be with drugs or inborn errors of metabolism (e.g., G6PDH deficiency) that result in a diminished concentration of NADPH, the co factor that reduces GS-SG to GSH [1] (Equation 13).

Acid-base aspects: Applymg concept 1 to this pathway, H will only accumulate when the pre cur sor of pyroglutamic acid is gluta-mine providmg that the NH4+ so-formed is metabolized to urea in the liver (Equation 14).

Glutamine ^ Glutamate- + NH4+ ^ Pyroglutamate"+NH4+ ^ Urea + H+ (14)

Renal Acidosis

As des cribed in Table 6, renal disorders may cause metabolic acidosis with either a normal or an increased anion gap in plasma. Most causes have in common a reduced rate of NH4+ excretion [56]; in contrast, with a recent onset of proximal RTA, the excretion of HCO3- may also contribute to the degree of metabolic acidosis. Whether the plasma anion gap will be elevated or not depends primarily on the GFR. For example, if the GFR is very low, anions such as phosphate and SO4 " need to have higher concentrations in plasma to be excreted at their usual rate. This in turn leads to a rise in the plasma anion gap (Figure 6), but it does not usually exceed 22 mEq/l or about 10 mEq/l above normal. In this semiquantitative interpretation, it is important to examine the concentration of albumin in plasma because this is the most important constituent of the normal plasma ani on gap and hypoalbuminemia is not an uncommon finding in this group of patients. The possible molecular basis for a low rate of excretion of NH4+ (Figure 5)

or a high rate of excretion of HCO3" is shown in Figure 27.

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 components of net acid (Table 18). Our approach to patients with HCMA starts with an assessment of the rate of excretion ofNH4+ (Figure 28). 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 and an alkaHmzed PCT ICF pH. In the latter group, the low rate of excretion of NH4+ is usually due to a dimim shed rate of production of NH4+ because of excessive distal delivery of HCO3- from the PCT. If an assay of urine NH4+ is not available, the

Blood Molecular Components

Figure 27. Molecular components for H and HCO3" transport in the nephron. The events in the PCT are shown in the left portion of the figure and the events in the collecting duct (CD) are shown in the right portion of the figure. Carbonic anhydrase (CA) is depicted by the small solid circles. Abbreviations: NHE = Na+/H+ exchanger in the PCT; NBC = Na(HCO3)32- exit step in the PCT; AE = Cl"/HCO3" ani on exchanger.

Figure 27. Molecular components for H and HCO3" transport in the nephron. The events in the PCT are shown in the left portion of the figure and the events in the collecting duct (CD) are shown in the right portion of the figure. Carbonic anhydrase (CA) is depicted by the small solid circles. Abbreviations: NHE = Na+/H+ exchanger in the PCT; NBC = Na(HCO3)32- exit step in the PCT; AE = Cl"/HCO3" ani on exchanger.

urine osmolal gap should be used to reflect this excretion rate (Figure 11).

If the rate of excretion of NH4+ is high in a patient with HCMA (e.g., overproduction of P-hydroxybutyric acid) (Figure 28), a renal component to the acidosis could be present if there is a large loss of the metabolizable P-hydroxybutyrate anions in the urine [155]. 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+ + K+ + NH4+ in the urine greatly exceeds that of Cl- (Figure 11).

In a patient with HCMA and a low rate of excretion ofNH4+, the basis for lowNH4+ excretion can be deduced from the urine pH. If the urine pH is greater than 7, one should examine the secretion of H+ in the PCT (reabsorption of HCO3-) and in the distal nephron (Figure 28). We recommend examining the PCO2 in alkaline urine to detect whether there

Figure 28. Approach to patients with HCMA. If there is a low rate of excre-ion of NH4+, the urine pH is helpful to determine whether a low distal and/or proximal H+ secretion or a low NH3 availabil i ty was the cause for the low rate of NH4+ ex cre tion.

Figure 28. Approach to patients with HCMA. If there is a low rate of excre-ion of NH4+, the urine pH is helpful to determine whether a low distal and/or proximal H+ secretion or a low NH3 availabil i ty was the cause for the low rate of NH4+ ex cre tion.

Nh3 Nh4 Secretion

is a de tect in distal H+ secretion. If urine PCO2 is < 70 mm Hg, a primary H+ATPase pump defect or an alkaline a-intercalated collecting duct cell pH (e.g., CA11 deficiency) should be suspected. This latter lesion also involves the PCT, caustng proximal RTA. If urine PCO2 > 70 mm Hg, suspect a back leak of H+ from the collecting duct or a detect causing distal HCO3" secretion (e.g., a mis-targeted ClTHCO3" anion exchange.

HCMA with a low rate of excretion of NH4+ and a low value for the urine pH (the actual value is difficult to define precisely, but we consider a low value to be less than 5.3) suggests that there is a reduced availabiltty of NH4+/NH3 in the renal medullary interstitial compartment (Figure 12). The usual causes for the low NH4/NH3 subgroup are a low GFR or hyperkalemia (Table 18). In their absence, we would look for low levels of glutamine [158], the substrate in plasma for renal ammoniagenesis, and/or a high level of fat-derived fuels (e.g., patients on TPN), because these fuels may compete with glutamine as the source for regeneration of ATP in cells of the PCT [159], and hence lead to a lower rate of production ofNH4+. Patients with proximal RTA also have a low rate ofex-cretion of NH4+. This could be due to an alkaline PCT cell or it could be part of a generalized PCT cell dysfunction (the Panconi syndrome [156, 157]). Both of these groups of patients will have hypercitraturia despite the presence of metabolic acidosis. In the former group, the hypercitraturia is due to an alkaline PCT cell and may disappear if an acid load were admintstered. In the latter group, the hypercitraturia is part of the generalized PCT cell transport defects.

Loss of NaHCO3 in the Urine

The initial mechanism for the acidosis in patients with proximal RTA is the loss of HCO3" in the urine. In contrast, once a steady state supervenes, chronic metabolic acidosis is sustained because the rate of NH4+ excretion is much lower than expected in this setting [30, 31]. As mentioned above, these patients will have hypercitraturia despite having metabolic acidosis. The defect in proximal HCO3- re ab sorp tion can be demon strated by finding a FEhco3 that exceeds 10 - 15% during NaHCO3 loadtng. This, however, need not be performed because the diagno tis is usually evident when large doses of NaHCO3 fail to the PHCO3 the normal range. Proximal RTA can occur as an isolated defect [160] or as part of a generalized proximal tubular cell dysfunction (Fanconi's syndrome with a glucosuria, phos phaturia, aminoacidosis, uricosuria and citraturia among others) [156]. The major causes of proximal RTA in adults include increased blood levels of monoclonal immunoglobulins found in patients with multiple myeloma and patients who use the carbonic anhydrase inhibitor, acetazolamide. In contrast, cystinosis [161] and the use of ifosfamide [ 162] are the most common causes of proximal RTA in children. The hereditary isolated proximal RTA is a rare autosomal recessive disease that can present with ocul ar abnormalities such as band keratopathy, cataracts and glaucoma [163]. Mutations in the gene encoding for the Na(HCO3)3 co-transporter (NBC1) has been identified in these families. The autosomal dominant form may be caused by mutations in the gene for NHE [164].

Recently, the use of Chinese herbs was described as a cause of the Fanconi's syndrome [165]. Typ ical Chinese herb nephropathy is associated with acellular interstitial fibrosis and tubut ar atrophy. Some of these patients have a profound degree of hypokalemia with muscle paralysis as the presenting feature

[166]. Hypokalemia in other causes of the Fanconi's syndrome is usually absent or mild in degree.

The pathological mechanisms of Fanconi's syndrome due to Chinese herb remain unclear. Aristolochic acid found in the Chinese herb has an inhibitory effect on calcium-dependent phospholipase A2. This may in turn lead to a defect in energy-produc-ng or energy-linked transporting mechanisms and/or have a direct toxic effect on the brush-border membrane of the tubul ar cells that may cause renal tubule inj ury with the resultant Fanconi's syndrome.

From a therapeutic standpoint, the acidosis in these patients is usually mild and complications due to the ac-do -is are minor. These facts alone argue against alkali therapy in adults. In addition, if exogenous NaHCO3 is given, as the Phco3 rises temporarily, but its excretion will also rise markedly. A large increase in de-ivery of Na+ and HCO3- to the CCD may augment the secretion of K+ [84], resulting in hypokalemia and possibly nephro-calcinosis. In contrast, alkali therapy is useful in children to prevent growth retardation

Cause of a Low Rate of Excretion of NH4+

Renal failure: As the GFR falls, the synthesis of NH4+ declines in the PCT due to ATP turnover constraints [33]. Metabolic acidosis is therefore a common finding with advanced renal insufficiency, although the degree of acidosis is variable. It is rarely severe enough to require urgent therapy with NaHCO3. On the other hand, chronic met abolic ac ido sis may con-ribute to fa-igue and anorexia, and also skeletal muscle wasting [168] and bone disease [169]. Therefore it is reasonable to give oral NaHCO3 to these patients to maintain the

PHCO3 close to 20 - 25 mM mak-ng certain that the Na+ load does not lead to hypertension or congestive heart failure. With the onset of dialysis therapy, acid-base balance is maintained by the addition of NaHCO3 or a metabolic precursor of HCO3" (e.g., acetate, L-lactate) added to the dialysis fluid.

Distal RTA (classical RTA): The hallmark of dis-al RTA is a low rate of excre-ion of NH4+ in a patient with chronic metabolic acidosis, a normal value for the an-on gap in plasma, and a GFR that is not markedly reduced [56]. Hav-ng de fined these compo -nents, the next step is to find out why the rate of excretion of NH4+ is lower than expected in this set-ing. We rely on the urine pH at this point to separate the patients into 3 categories, those with a primary problem with NH3 availability (urine pH less than 5.3), those where there is a structural lesion in the renal medulla that compromises both medullary NH3 availability and distal H+ secretion (urine pH close to 6), and those with a defect in net distal H+ secre-ion (urine pH close to 7). In this latter group, the low rate of excretion of NH4+ is due primarily to reduced dis-al H+ secretion per se and/or to an excessive amount of HCO3" de-ivered to or secreted in the dis-al nephron (Figure 29). Generalized medullary damage with a urine pH that is close to 6 is the most common clinical subgroup [53]. Autoimmune disorders (such as Sjogren's syndrome and rheumatoid arthritis, hyper-gammaglobul-nemia) are the most common causes of distal RTA with a very high urine pH in adults [56]. RTA in patients with Sjogren's syndrome seems to be due to a defect in H+ secretion in the distal nephron. In some of these patients, there was an absence of the H -ATPase pump in intercalated cells of the collecting tubule as revealed by an immunocytochemical analysis of tissue obtained by renal biopsy [170]. It is not known how the immune inj ury leads to the loss of

Low Urine Due Glucagon

Figure 29. Basis for a high urine pH. There are two subgroups to consider. First, those where the net addition of HCO3" by failing to reabsorb NaHCO3 in upstream nephron segments (site 1) or via secretion in the MCD via AE (site 2), exceeds the usual H+ secretion by the H+-ATPase in the CCD and MCD (site 2). Second, as shown to the right of the dashed line, those where there is a high medullary NH3 concentration (due to enhanced PCT production of NH4+, site 5) exceeds the secretion of H+ by

H-ATPase activity. It has also been suggested that the defect may be due to autoantibodies against carbonic anhydrase II, as high levels of these antibodi es were de -tected in some patients. If these antibodies could enter cells, one would also expect to find a de fect in H secretion in the PCT. Ifosfamide, an analog of cyclophosphamide, is also a cause of proximal and distal RTA in both children and adults [162].

Hereditary RTA is most common cause in children [171]. Familial distal RTA is inherited in both dominant and recessive patterns. The autosomal dommant form is associated with mutations in the gene encodmg for the AE [172]. Red blood cells of these individuals display normal AE polypeptide abundance. These mutant forms show only a modest reduction in function and do not have a dominant negative effect when expressed in heterologous systems. It is not clear how these mutations lead to the phenotype of distal RTA. In vivo defects in stability, trafficking or sorting of these mutant anion exchangers are possible mechanisms. In Caucasians, AE1 has not been associated with the recessive form of distal RTA; however, AE1 mutations are the maj or cause of recessive distal RTA in Thailand, Malaysia and Papua New Guinea [173]. In those Southeast Asian patients in whom distal RTA is associated with ovalocytosis, compound heterozygotes of AE1 plus distal RTA mutations with the in-frame deletion ovalocytosis mutation were found [174]. Altered targeting of the mutant AE1 was suggested in one patient with distal RTA and Southeast Asian ovalocytosis be t cause of a high U-B PCO2 in alkaline urine [175].

Mutations in the gene encoding for the Vi subunit B1 of the apical membrane vascular H -ATPase have been described to cause autosomal recessive distal RTA and bilateral sensorineural hearing loss [176]. Recessive distal RTA without deafness due to mutations in the a Vo subunit of the H-ATPase have also been reported [177]. Mutations in the cytoplasmic carbonic anhydrase II are inherited in autosomal recessive fashion [178]. Patients with this disorder exhibit osteopetrosis, cerebral calcification and defect in H+ secretion in both the PCT and the distal nephron.

While nephrocalcinosis may be a conte t quence of distal RTA, hypercalciuria and nephrocalcinosis seem to be the primary events leading to distal RTA in patients with

Dent's disease [179]. Dent's disease is characterized by low molecular weight proteinuria, hyperphosphatemia, hypercalciuria. The ClC-5 chloride channel has been identified as the mutated gene in patients with Dent's disease [180].

RTA with hypokalemia: Distal RTA is often complicated by hypokalemia [181] (the high luminal concentration of HCO3" stimulates net secretion of K+ in the CCD [84], see Chapter on K+ for more discussion). If distal RTA is present with a severe degree of hypokalemia (PK < 2 mM), symptoms of muscle weakness or even paralysis might be present [182]. Of greater importance, there is a danger of a cardiac arrhythmia, especially if the EKG is significantly abnormal. Even if the degree ofmetabolic acidosis is severe, the administration of alkali alone could cause movement of K+ into cells, worsening the degree ofhypokalemia with resultant cardiac effects and/or acute respiratory acidosis. In this circumttance, there is a better strategy for therapy. KCl should be given first; larger amounts can be given safely by the oral or by a nasogastric tube than intravenously providing that the patient can absorb this K+ load -i.e., that bowel sounds are present. Glucose-containing solutions should be avoided, since they may stimulate insulin release, which may cause an acute shift of K+ into the cells. Although the addition of K-sparing diuretics such as amiloride will reduce the ongoing urine K+ loss, their quantitative effect is very small and they may provoke hyper-kalemia later on; hence we do not recommend their use in this setting. Admintstration or larger amounts ofNaHCO3 should be delayed until the PK is above 3.0 mM. In the absence of serious hypokalemia, one then asks, how much alkali is required? The answer is not easy to deduce. One must ultimately give enough NaHCO3 to bring the Phco3 to the normal range. Thereafter, the dose of NaHCO3

needed can be deduced. Since the daily normal acid load from the diet is usually about 70 mmol/day [7]. Since urine net acid excretion is usually reduced but not absent, considerably less NaHCO3 is usually required. Supplemental K is often needed as well.

Dis tal RTA with hyperkalemia: In some classifications, this is called type IV RTA. We do not think that this nomenclature is particularly helpful and prefer a classification that is based on pathophysiology (see reference Kamel et al. 1997 [56] for more discussion). Reduced excretion of NH4+ is commonly associated with hyperkalemia [32]. Hyperkalemia leads to reduced excretion of NH4+ primarily because it inhibits ammoniag-enesis. This subtype of low excretion ofNH4+ is recognized by finding a low urine pH (usually < 5.3) (Figure 30). A more detailed discus sion of hyperkalemia can be found in the Chapter on Potassium in this book.

Therapy depends on the pathogenesis of the hyperkalemia and on the patients' ECF volume status. In patients with hypoaldosteron-ism due to adrenal disease, ECF volume and blood pressure are usually reduced and al-

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