Kidney International, Vol. 64, Supplement 88 (2003), pp.

S13S25

Metabolic acidosis in maintenance dialysis patients: Clinical considerations

RAJNISH MEHROTRA, JOEL D. KOPPLE, and MARSHA WOLFSON
Division of Nephrology and Hypertension and Research and Education Institute at Harbor-UCLA Medical Center; and David Geffen School of Medicine at UCLA and UCLA School of Public Health, Torrance, California; and Renal Division, Baxter HealthCare, McGaw Park, Illinois

Metabolic acidosis in maintenance dialysis patients: Clinical considerations. Metabolic acidosis is a common consequence of advanced chronic renal failure (CRF) and maintenance dialysis (MD) therapies are not infrequently unable to completely correct the base decit. In MD patients, severe metabolic acidosis is associated with an increased relative risk for death. The chronic metabolic acidosis of the severity commonly encountered in patients with advanced CRF has two well-recognized major systemic consequences. First, metabolic acidosis induces net negative nitrogen and total body protein balance, which improves upon bicarbonate supplementation. The data suggest that metabolic acidosis is both catabolic and antianabolic. Emerging data also indicate that metabolic acidosis may be one of the triggers for chronic inammation, which may in turn promote protein catabolism among MD patients. In contrast to these ndings, metabolic acidosis may be associated with a decrease in hyperleptinemia associated with CRF. Several studies have shown that correction of metabolic acidosis among MD patients is associated with modest improvements in the nutritional status. Second, metabolic acidosis has several effects on bone, causing physicochemical dissolution of bone and cell-mediated bone resorption (inhibition of osteoblast and stimulation of osteoclast function). Metabolic acidosis is probably also associated with worsening of secondary hyperparathyroidism. Data on the effect of correction of metabolic acidosis on renal osteodystrophy, however, are limited. Preliminary evidence suggest that metabolic acidosis may play a role in b2microglobulin accumulation, as well as the hypertriglyceridemia seen in renal failure. Given the body of evidence pointing to the several systemic consequences of metabolic acidosis, a more aggressive approach to the correction of metabolic acidosis is proposed.

Metabolic acidosis is a common accompaniment of chronic renal failure (CRF) and it results from an inability to excrete nonvolatile acid in the face of reduced renal bicarbonate synthesis. The severity of metabolic acidosis can vary widely among uremic patients with a similar degree of renal dysfunction [1, 2]; at least two studies

Key words: metabolic acidosis, nutrition, catabolism, bone, osteodystrophy.

C

2003 by the International Society of Nephrology S-13

suggest that for a given level of renal function, diabetic individuals may have a less severe degree of metabolic acidosis [3, 4]. One of the goals of dialysis therapy is to correct the metabolic abnormalities of uremia, including metabolic acidosis. Dialysis therapies, as practiced today, are unable to completely correct metabolic acidosis in a substantial proportion of patients undergoing maintenance hemodialysis (MHD). Moreover, the serum bicarbonate levels in patients undergoing MHD follow a saw-tooth pattern, with the lowest bicarbonate levels in the immediate predialysis period. Treatment with chronic peritoneal dialysis (CPD), on the other hand, appears to maintain stable serum bicarbonate within the normal range in the majority of patients, without the uctuations seen among patients undergoing MHD [5]. Even though CPD therapy is successful in normalizing the serum CO2 levels in almost 90% of patients, the anion gap remains wide in over 95% of patients [5]. The magnitude of anion gap in CPD patients is associated with higher serum urea nitrogen and phosphorus concentration, suggesting an inadequate metabolic control by the dialysis prescription. The relevance of these ndings is addressed below. Increasing evidence points to a role, at least in part, for metabolic acidosis in the genesis, of several uremic manifestations (Table 1). Moreover, in a retrospective analysis of a large cohort of patients, Lowrie et al [6] demonstrate that total serum CO2 was associated with a J-shaped risk for death: increasing risk for death was observed when the total serum level was less than 17.5 mmol/ L or greater than 25 mmol/L. The magnitude of the anion gap has sometimes been used as a surrogate for the severity of metabolic acidosis. The available data suggest that this assumption may be erroneous at least among patients undergoing CPDthe vast majority of patients with a widened anion gap have normal serum bicarbonate concentrations [5]. When the data are adjusted for casemix, a high anion gap is associated with lower odds for death in MHD patients [7]. However, when the data are adjusted for serum albumin and creatinine levels along with case-mix, an increase in anion gap is associated with

S-14

Mehrotra, Kopple, and Wolfson: Metabolic acidosis in maintenance dialysis patients

Table 1. Adverse systemic consequences of metabolic acidosis Nutritional consequences Catabolic effectsIncreased proteolysis Antianabolic effectsDecreased protein synthesis Insulin resistance Systemic inammation Decreased serum leptin levels Bone disease Direct effects Physicochemical dissolution of bone Decreased function of osteoblast Increased function of osteoclast Indirect effects Increased release of parathyroid hormone Increased number of parathyroid hormone receptors Increased binding of parathyroid hormone to its receptor Reduced activity of 1-a hydroxylase Other systemic effects Increased generation and release of b2-microglobulin Hypertriglyceridemia

a progressive increase in the risk for death [7]. The direct association of a widened anion gap with the risk for death is consistent with the thesis that a persistent increase in anion gap may reect inadequate dialysis with respect to metabolic control. It is not clear, however, if an increase in dialysis dose can normalize the anion gap, or what the effect of the normalization of the anion gap would have on morbidity and mortality. In this review, we present a brief overview of some of the systemic consequences of metabolic acidosis in individuals with advanced CRF or undergoing MHD. There are many other consequences of metabolic acidosis, especially if very severe, (e.g., malaise, weakness, hypotension, resistance to catecholamines). However, we shall limit the discussion herein to metabolic acidosis that results from CRF and consequences from the range of severity that usually occurs in nondialyzed CRF and MHD patients. Even though it is assumed that the systemic consequences arise from an increase in the total hydrogen ion concentration in the blood (acidemia), some of the data presented here are based only upon a measurement of plasma bicarbonate or serum total CO2 . GENERAL CONSIDERATIONS There are two major considerations to take into account while assessing the acid-base status of patients undergoing MHD: factors related to the measurement of total serum CO2 levels; and the effect of changing patterns of use of phosphate binders on the acid-base status. Factors related to measurement of serum total CO2 levels Close attention needs to be paid to two variables with respect to measurement of total CO2 levels. First, underlling of sample tubes should be avoided because evanescence of carbon dioxide may result in falsely low

measurements [8]. Second, shipping blood samples by overnight airfreight to laboratories several hundred miles away is a standard practice in a large number of dialysis units in the United States. This practice has been shown to be associated with a frequent occurrence of spurious metabolic acidosis; the mean total CO2 content of blood samples thus shipped is 5 mEq/L lower than samples that undergo more immediate processing [9, 10]. This decrease in total CO2 content cannot be accounted for by an increase in lactate content or by the interval between sample collection and processing. It is likely that changes in atmospheric pressure in the pressurized airliner cabin or in a cargo hold lead to the escape of CO2 from the tube [11]. Indeed, if the sample is stored either at room temperature or refrigerated for 24 hours without air transport, the change in total CO2 is only 1 mEql/L [9, 12]. Thus, in MD patients, caution needs to be exercised in interpreting serum chemistry measurements that indicate metabolic acidosis. The effect of changing patterns of use of phosphate binders on the acid-base status Until recently, almost all MHD patients were treated with calcium-based phosphate binders, calcium acetate and calcium carbonate. Both of these calcium salts are alkalies and these medications have a salutary effect on metabolic acidosis. However, one recent study suggests that a high dose of calcium-based phosphate binders is associated with the presence of coronary artery calcication in MHD patients [13]. In a randomized control trial involving 200 MHD patients, the median percent change in coronary artery (25% vs. 6%) and aortic (28% vs. 5%) calcium scores was signicantly greater with calciumbased phosphate binders, compared with sevalemer hydrochloride [14]. These ndings have engendered an increasing use of sevalemer hydrochloride as a phosphate binder. However, sevalemer hydrochloride acts like an ion-exchange resin in the gastrointestinal tractit releases one mole of chloride for every mole of phosphorus that it binds. Because 17% of sevalemer hydrochloride is chloride by weight, treatment with four 800 mg tablets of sevalemer hydrochloride three times per day with meals provides 46 mEq of chloride load per day. The chloride thus released is buffered by bicarbonate, leading to a nongap metabolic acidosis. These considerations suggest that a change from widespread use of alkalies for phosphate binding to the use of an agent that fosters chloride loading may lead to a greater prevalence of persistent metabolic acidosis among MHD patients [1517].

METABOLIC ACIDOSIS AND NUTRITION In 1931, Lyon et al [18] rst suggested that there may be a link between metabolic acidosis and nutritional status

Mehrotra, Kopple, and Wolfson: Metabolic acidosis in maintenance dialysis patients

S-15

Mechanisms yet to be elucidated Metabolic acidosis

Insulin resistance

Increased activity of Increased activity of branched chain ketoacid ATP-dependent dehydrogenase ubiquitin-proteasome system Reduced serum leptin

Inflammation

Decreased muscle protein synthesis Decreased albumin synthesis

Increased muscle protein breakdown

Protein energy malnutrition

Fig. 1. The mechanisms by which metabolic acidosis may induce protein-energy malnutrition. Of the various pathways, the stimulation of the ATP-dependent ubiquitin-proteasome system by metabolic acidosis is the most well dened. Dotted lines indicate that the data supporting the role of these pathways are less well documented at this time.

of patients with CRF. A large body of literature has subsequently accumulated that suggests that metabolic acidosis may play an important role in the pathogenesis of the nutritional abnormalities associated with uremia. There are ve potential mechanisms by which metabolic acidosis contributes to these nutritional abnormalities. One of these is well-researched and understood (increased protein catabolism); more is being learned about two others (decreased protein synthesis and increased insulin resistance); and research has only begun to explore the role of two others (inammation and reduction in serum leptin levels) (Fig. 1). Increased protein breakdown (catabolic effects of metabolic acidosis) Evidence for proteolysis. Evidence derived from animal and human studies suggests that acidosis, including that associated with CRF, is associated with proteolysis, and correction of this acidosis leads to a decrease in protein breakdown. Acute metabolic acidosis in dogs leads to increased total-body leucine oxidation, which is reduced with metabolic alkalosis [19]. Studies in rats with normal renal function demonstrate that ammonium chlorideinduced metabolic acidosis leads to an increase in skeletal mus-

cle protein degradation and amino acid oxidation [20 23]. Increased muscle protein degradation has also been reported in rats with experimental renal failure; this increased protein breakdown was ameliorated by adding sodium bicarbonate to their diet [24]. In both healthy humans and individuals with CRF, metabolic acidosis may also engender negative N balance [2527]. A large number of investigations in humans with various stages of renal failure have demonstrated that metabolic acidosis promotes proteolysis (Table 2) [2835]. Pathophysiologic mechanisms for the increased proteolysis associated with metabolic acidosis. Two key mechanisms have been identied that mediate the catabolic effects of metabolic acidosis. Increased activity of branched-chain ketoacid dehydrogenase (BCKAD). Studies in intact rats and in isolated muscles demonstrate that acidosis stimulates the breakdown of branched-chain amino acids (BCAA) [36]. This catabolic response in muscle is associated with increased mRNAs and activity of the rate-limiting enzyme branched-chain ketoacid dehydrogenase (BCKAD) [21, 37]. The plasma and muscle levels of BCAA are signicantly lower in animal models of metabolic acidosis, as well as in humans undergoing MD therapy [21, 38, 39]. Moreover, in MHD patients, the free valine

S-16

Mehrotra, Kopple, and Wolfson: Metabolic acidosis in maintenance dialysis patients

Table 2. Summary of controlled metabolic studies in humans that suggest that metabolic acidosis promotes catabolism Author Papadoynnakis [27] Williams [28] No. of subjects 6 6 Stage of renal Baseline failure pH Nondialyzed Nondialyzed
a

Final pH
a

Biologic phenomena studied N and K balance 3-methyl histidine:creatinine ratio

Results of correction of metabolic acidosis Both N and K balance improved In patients on low protein diets, increased urinary excretion in the presence of metabolic acidosis, reduced with NaHCO3 supplementation Reduced protein degradation and synthesis and leucine oxidation Net phenylalanine release inversely related to degree of acidosis Reduced whole body protein degradation and synthesis; no effect on leucine oxidation Reduced whole body protein degradation and synthesis; no effect on leucine oxidation Increased intracellular concentrations of branched-chain amino acids Signicant increase in leucine oxidation, insignicant increase in protein degradation and synthesis Acidotic children had higher rates of protein degradation

7.28

7.35

Reaich [29] Garibotto [30] Graham [31]

9 9 7

Nondialyzed Nondialyzed CPD

7.31
a

7.38
a

L[1-13 C]leucine kinetics

3 H-phenylalanine

kinetics

7.39

7.41

L[1-13 C]leucine kinetics L[1-13 C]leucine kinetics Intracellular branched amino acids L[1-13 C]leucine kinetics L[1-13 C]leucine kinetics

Graham [32] Lofberg [33]

6 9

MHD MHD

7.36
a

7.40
a

Lim [34]

Nondialyzed

7.29
a

7.39
a

Boirie [35]

10

Nondialyzed

CPD, chronic peritoneal dialysis; MHD, maintenance hemodialysis. a Data not available.

concentrations in the muscle correlate with both the pre- and postdialysis plasma bicarbonate levels [38]. Correction of metabolic acidosis in MHD patients is associated with an increase in plasma BCAA (leucine, isoleucine, and valine) levels [40]. Thus, it is likely that in humans, the metabolic acidosis associated with renal failure engenders an increased activity of BCKAD, which in turn leads to increased catabolism of BCAA. Increased activity of the ATP-dependent ubiquitinproteasome pathway. There are several lines of evidence that establish the role of this pathway in mediating the catabolic effects of metabolic acidosis in CRF. First, metabolic acidosis in rats with CRF is associated with an increase in the muscle content of the mRNAs encoding the ATP-dependent ubiquitin, as well as the subunits of the proteasome [41]. Feeding chow mixed with sodium bicarbonate reversed these responses. This increase in mRNA is secondary to increased gene transcription [41, 42]. Second, when isolated rat muscles are either depleted of ATP or exposed to an inhibitor of the proteasome in the presence of metabolic acidosis, the increase in protein degradation is abolished [20, 23, 41]. Third, incubating skeletal muscle from CRF rats with metabolic acidosis with an inhibitor of the proteasome suppresses proteolysis [41]. Finally, in a recent study involving CPD patients, Pickering et al [43] demonstrated that an increase in serum total CO2 was associated with a signicant reduction in the muscle content of ubiquitin mRNA. In contrast, there was no demonstrable increase in the

muscle ubiquitin mRNA levels in eight MHD patients with only mild metabolic acidosis as compared to healthy control patients [44]. These data suggest that the ubiquitin-proteasome pathway plays an important role in protein catabolism associated with metabolic acidosis. Triggers for acidosis-induced enhancement of proteolysis in skeletal muscle. Despite the impressive progress in understanding the molecular mechanisms involved in proteolysis in the setting of metabolic acidosis, the triggers that activate these molecular mechanisms are poorly understood. It appears unlikely to be the pH itself, because metabolic acidosis in CRF does not cause a sustained alteration in the intracellular pH of muscle [45]. Several hormonal triggers have been proposed and studied. Ammonium chlorideinduced metabolic acidosis in adrenalectomized rats does not induce protein degradation, an increase in the gene expression of BCKAD or its activity, or an elevation in any of the mRNAs of the ubiquitin-proteasome system in muscle [20, 42, 46]. Moreover, the urinary excretion of corticosterone in rats with acidotic experimental renal failure is signicantly higher than of pair-fed control rats [21]. These data suggest that glucocorticoids may play a facilitative role in inducing the catabolic pathways in the setting of metabolic acidosis. Indeed, a glucocorticoid responsive element in the promoter region of BCKAD has recently been discovered [47]. Increased urinary cortisol excretion has also been reported in one experimental study of ammonium

Mehrotra, Kopple, and Wolfson: Metabolic acidosis in maintenance dialysis patients

S-17

chlorideinduced metabolic acidosis of eight days duration [48]. The role of glucocorticoids, however, in triggering the catabolic pathways in metabolic acidosis with CRF is less clear. Garibotto et al [30] found that muscle protein degradation correlated directly with plasma levels of cortisol and negatively with serum bicarbonate, suggesting that both acidosis and glucocorticoids may be needed to stimulate muscle protein degradation. Other investigators have been unable to demonstrate elevated cortisol concentrations in the setting of chronic metabolic acidosis [26, 4951]. These observations, however, do not exclude the possibility that corticosteroids may need to be present for acidemia to stimulate skeletal muscle protein degradation. Insulin resistance may play a role in the activation of the ubiquitin-proteasome system. The high rate of protein degradation in rats with acute onset of diabetic mellitus is not reduced by correction of the diabetic ketoacidosis, but administration of insulin for 12 hours eliminated the excess proteolysis and higher ubiquitin mRNAs [52]. Moreover, insulin-stimulated phosphorylation of insulinreceptor substrate-1 phosphatidylinositol 3 kinase activity is signicantly reduced in the muscle of rats with renal failure [53]. It is possible, then, that suppressed phosphatidylinositol 3 kinase activity may lead to activation of the ubiquitin-proteasome pathway and muscle protein degradation [53]. Reduced tissue levels of or increased resistance to other anabolic hormones may also play a role in stimulating the catabolic pathways (see below). Decreased muscle protein synthesis (antianabolic effects of metabolic acidosis) Cell culture studies using BC3H1 myocytes have shown a signicant reduction in protein synthesis in an acidic medium [abstract; Ding et al, J Am Soc Nephrol 9:607A, 1998] [54]. Increases in the pH of the medium (up to 7.70), even above normal physiologic pH, were associated with progressively higher rates of protein synthesis [abstract; Ding et al, J Am Soc Nephrol, 9:607A, 1998]. Similarly, protein synthesis is signicantly reduced in L6 muscle cells cultured in an acidic medium [55]. Finally, acidic culture medium signicantly reduces the albumin and transferrin concentrations in the supernatant of HepG2 cell cultures [56]. Rather analogous results have been observed in some but not all studies of metabolic acidosis in humans. Acute ammonium chlorideinduced metabolic acidosis in normal individuals is associated with a signicant reduction in the fractional synthetic rate of muscle protein; the fractional, as well as the absolute, rate of albumin synthesis remained unchanged [50]. On the other hand, chronic ammonium chlorideinduced metabolic acidosis is reported to signicantly reduce the fractional syn-

thetic rate of albumin [25]. The applicability of these ndings to metabolic acidosis in CRF is uncertain. Some studies in MHD patients, using L-(13 C)-leucine kinetics, demonstrate an increased total body protein synthesis with metabolic acidosis, which decreases upon correction of acidosis [29, 31, 32]. In these studies, however, the presence of metabolic acidosis was also associated with a signicantly greater increase in the rate of protein degradation, resulting in a net negative protein balance [29, 31, 32]. Thus, additional data are needed to determine the effects on protein synthesis of metabolic acidosis associated with CRF in humans. Alterations in one or more of three hormonal systems may be responsible for the antianabolic effects of ammonium chlorideinduced metabolic acidosis. First, metabolic acidosis may reduce the release of growth hormone; experimental data also suggest that metabolic acidosis may lead to peripheral resistance to growth hormone [57, 58]. Second, animal and human studies show that metabolic acidosis is associated with a signicant reduction in the plasma levels of insulin-like growth factor (IGF) and the hepatic content of IGF-I mRNA [25, 5860]. Third, thyroid hormones exert anabolic effects, and decreased thyroid function induced by metabolic acidosis might contribute to reduced synthesis of muscle protein. In acute metabolic acidosis, there is a slight but signicant increase in thyroid-stimulating hormone levels without any change in free triiodothyronine levels [50]. In chronic metabolic acidosis, the same investigators reported a signicant reduction in triiodothyronine levels without any change in thyroid-stimulating hormone levels [25]. Brungger et al [60] have reported similar results in an experimental study of chronic acidosis in humans. The relative contributions of these hormonal systems to the altered anabolic and catabolic pathways induced by metabolic acidosis, however, needs to be dened more precisely. Insulin resistance Insulin resistance is a known complication of CRF [61]. Evidence suggests that this insulin resistance may in part be secondary to metabolic acidosis [62]. In the presence of acidosis, insulin binding in rat adipocytes is reduced by up to 30%. Hyperglycemic and euglycemic clamp studies in the presence of ammonium chlorideinduced metabolic acidosis revealed impaired glucose metabolism due to reduced tissue sensitivity to insulin [62]. Indeed, correction of metabolic acidosis in nondialyzed patients with CRF enhances insulin-stimulated glucose uptake.

Metabolic acidosis and inammation: Is there a link? Incubation of peritoneal macrophages in an acidic cell culture medium results in an increased production of

S-18

Mehrotra, Kopple, and Wolfson: Metabolic acidosis in maintenance dialysis patients

Table 3. Epidemiologic cross-sectional studies evaluating relationship between nutritional status and metabolic acidosis in MHD patients Author [ref.] Kang [73] Uribarri [74] Dumler [75] Ge [76] Movilli [77] Dumler [78] Uribarri [79] Gao [80] Leavey [81] Chauveau [82] Kung [83] Lin [64] No. of subjects 106 23 50 75 81 124 995 50 3891 7123 43 120 Dialysis type CPD MHD CPD MHD MHD Key ndings suggesting that metabolic acidosis may not be associated with impaired nutritional status Patients with serum total CO2 <22, compared to with total CO2 26, had higher relative body weight, SUN, serum albumin, nPNA, and ultraltration volume Patients with serum total CO2 21 vs. total CO2 25 had higher serum creatinine and SUN; signicant inverse relationship between total CO2 and nPNA No difference in body cell mass or fat-free, edema-free mass between acidotic and nonacidotic groups; BMI higher in acidotic group Lower relative body weight, triceps skin-fold thickness, midarm muscle circumference, serum albumin, transferrin, and bronectin levels in patients with severe metabolic acidosis Direct association between serum bicarbonate and albumin levels Higher serum albumin, creatinine, and nPNA2 in acidotic group; no difference in body cell mass, fat-free edema-free mass or mid-arm circumference between acidotic and non-acidotic group Serum total CO2 inversely associated with DPI4 , nPNA2 and predialysis serum potassium, phosphorus, creatinine, SUN1 ; no relationship with BMI3 or skinfold thickness Serum total CO2 inversely related to SUN, serum phosphorus, and uric acid Signicant inverse relationship with serum albumin Plasma HCO3 inversely associated with nPNA2 , serum albumin, prealbumin, BMI, and fat-free, edema-free mass Malnourished subjects determined by subjective global assessment, had higher serum total CO2 than well-nourished subjects Higher BMI, triceps skin-fold thickness, DPI, nPNA, serum creatinine, and potassium in acidemic patients

MHD MHD MHD MHD CPD MHD

Abbreviations are: SUN, serum urea nitrogen; nPNA, normalized protein equivalent of nitrogen appearance; BMI, body mass index; DPI, dietary protein intake; CPD, chronic peritoneal dialysis; MHD, maintenance hemodialysis.

tumor necrosis factor a (TNFa), suggesting a possible link between metabolic acidosis and the inammatory cascade [63]. Two recent studies have investigated the link between metabolic acidosis and inammation. In a crosssectional study of MHD patients, there was no signicant difference in the serum levels of C-reactive protein and interleukin-6 in three groups of patients, divided on the basis of their serum total CO2 levels (mean total CO2 in the three groups, 19.2, 24.4, and 27.5 mmol/L) [64]. On the other hand, the correction of metabolic acidosis in eight CPD patients was associated with a signicant decrease in TNFa levels [43]. Future studies need to dene the relationship between metabolic acidosis associated with CRF and inammation.

Leptin and metabolic acidosis Leptin, a product of the ob gene, has been studied as a potential mediator of protein-energy malnutrition. Serum leptin is elevated in CRF. Even though the precise role of leptin in human renal disease remains to be dened, three longitudinal studies have demonstrated that individuals with high serum leptin levels are more likely to lose weight [6567]. Several recent studies have explored the interaction between metabolic acidosis and hyperleptinemia, two frequent consequences of CRF. Adipocytes exposed to a low pH (pH 7.1) in a culture medium exhibit decreased leptin secretion [68]. In rats with renal failure treated with sodium bicarbonate, the serum leptin is signicantly lower than in those not supplemented with bicarbonate [68]. Furthermore, plasma leptin concentrations are lower in patients with diabetic

ketoacidosis than in healthy subjects, and the leptin levels increase after initiation of insulin therapy [69, 70]. However, diabetic ketoacidosis is associated with insulinopenia, ketonemia, and increased sympathetic nervous activity and these factors may independently affect serum leptin levels. Among nondialyzed individuals with CRF, correction of metabolic acidosis is associated with an increase in serum leptin levels [71]. In a cross-sectional study of 94 MHD patients, Kokot et al [72] were unable to demonstrate any correlation between blood hydrogen ion concentration and serum leptin levels; there was a trend, not statistically signicant, toward a progressively lower median leptin concentration with progressively higher blood hydrogen concentration. Because elevated serum leptin levels lead to weight loss, a decrease in serum levels could adaptively ameliorate the catabolic effects of metabolic acidosis. To the authors knowledge, there are no published data regarding the interaction of metabolic acidosis with serum leptin levels and the relative contribution of each on the nutritional status of MHD patients. Cross-sectional and interventional studies concerning potential adverse effects of metabolic acidosis on the nutritional status of MHD patients Notwithstanding the preponderance of metabolic studies that indicate an adverse catabolic response to metabolic acidosis, the vast majority of cross-sectional studies demonstrate an inverse relationship between metabolic acidosis and the nutritional status of MHD patients (Table 3) [64, 7383]. The explanation for this phenomenon may lie in the likelihood that healthy

Mehrotra, Kopple, and Wolfson: Metabolic acidosis in maintenance dialysis patients

S-19

Table 4. Interventional studies that have evaluated the nutritional response to correction of metabolic acidosis in MHD patients Author [ref.] Seyffart [84] Roberts [85] Kooman [40] No. of subjects Duration of treatment Randomized Baseline vs. nal pH Final pH (control control trial in study group vs. study group) No No No
a a

Key ndings (benecial effects are italicized) Signicant increase in dry body weight in 11 of 21 patients No change in nPNA or DPI No change in body composition, serum proteins or dietary intake; increased plasma branched-chain amino acid levels Increased triceps skin-fold thickness; no change in serum albumin, nPNA, or midarm muscle circumference No change in serum albumin or total lymphocyte count Increase in serum albumin, decrease in nPNA No change in any nutritional parameters Signicant increase in serum albumin and prealbumin levels; decrease in nPNA; no change in DPI Greater gain in body weight and midarm muscle circumference

MHD patients 21 1219 months 8 12 Four weeks Six months

7.32 vs. 7.36

a

Williams [86] Brady [87] Movilli [88] Lin, 02 [64] Verove [89]

46 36 12 17 18 CPD patients 200

Six months Four months Three months Six months Six months

Yes (double crossover) Yes No No No

7.38 vs. 7.43

a

a a a a

7.34 vs. 7.40 7.34 vs. 7.41

a

Stein [90]

One year

Yes

7.40 vs. 7.44

nPNA, normalized protein equivalent of nitrogen appearance; DPI, dietary protein intake. a Data not available or applicable.

people tend to have greater appetite and, hence, ingest more protein. Healthier people are not likely to show manifestations of protein-energy malnutrition. Moreover, a higher protein (and consequently higher energy) diet may reduce the risk of protein-energy malnutrition. Finally, a higher intake of dietary protein is associated with a higher dietary acid load and, thus, a lower serum total CO2 level. This, in turn, appears to confound the association of low serum total CO2 levels with increased protein catabolism. However, cross-sectional studies only demonstrate associations, and care must be exercised before concluding that mild to moderate metabolic acidosis has no deleterious effect on the nutritional status of MD patients. In contrast to these ndings, in a crosssectional evaluation of 81 MHD patients, Movilli et al [77] demonstrated a direct association between serum bicarbonate and serum albumin. Similarly, Ge et al [76] demonstrated that MHD patients with severe metabolic acidosis had signicantly lower relative body weight, triceps skin-fold thickness, midarm muscle circumference, serum albumin, transferrin, and bronectin levels when compared to those with higher serum bicarbonate levels. It is also possible that the protein catabolic effects associated with metabolic acidosis may be rather transient because in most studies, the metabolic acidosis or bicarbonate therapy was maintained for a relatively short period of time. Several investigators have prospectively evaluated the effect of correcting metabolic acidosis on the nutritional status of MD patients [40, 64, 8490]. As is shown in Table 4, the benecial results were inconsistent and usually limited. There are two major limitations of these stud-

ies. First, the sample size in most of these studies was small and, thus, underpowered to detect an improvement in nutritional status. Indeed, the largest study reported to date successfully demonstrated an improvement in body weight and triceps skin-fold thickness upon correction of metabolic acidosis [90]. Second, a signicant number of the individuals studied had either normal or only mildly impaired nutritional status. These considerations suggest that there is a need for a large, controlled trial to evaluate the effects of correction of metabolic acidosis on the nutritional status of MD patients. METABOLIC ACIDOSIS AND BONE DISEASE Early studies in humans with advanced CRF not treated by MHD indicate that a marked reduction in net acid excretion leads to daily net positive proton balance [91, 92]. It has been suggested that the cost of maintaining a stable serum total CO2 in the face of uncorrected metabolic acidosis was a constant dissolution of bone buffers (Fig. 2) [92, 93]. Studies by Uribarri et al [94] have, however, demonstrated that early studies had methodologic errors that may have led to an overestimation of endogenous acid production and/or underestimation of net acid excretion. Thus, the magnitude of daily positive proton balance in the presence of renal failure may have been signicantly overestimated. Direct effects of acidosis on bone In vitro studies have shown that metabolic acidosis is associated with net calcium efux from bone [95]. The

S-20

Mehrotra, Kopple, and Wolfson: Metabolic acidosis in maintenance dialysis patients

Metabolic acidosis

Direct effects

Indirect effects

Parathyroid hormone

Vitamin D

Physicochemical dissolution of bone

Inhibition of osteoblasts

Increased Increased receptor Increased binding Decreased 1 Stimulation of to receptor expression circulating levels hydroxylase osteoclasts

Bone disease
Fig. 2. The various mechanisms by which metabolic acidosis may contribute to bone disease. Dotted lines indicate that the data supporting the role of these pathways are less well documented at this time.

net calcium efux is a result of direct physicochemical dissolution of bone as well as cell-mediated bone resorption (inhibition of osteoblast and stimulation of osteoclast function) [9698]. Metabolic acidosis also stimulates osteoblasts to release prostaglandins, which in turn inhibits osteoblastic activity and stimulates osteoclastic function [99102]. Glucocorticoids inhibit the production of prostaglandins by osteoblasts, and this in turn inhibits the acidosis-induced bone resorption [103]. Furthermore, since acid loading in normal animals and humans is associated with hypercalciuria and phosphaturia, it has been suggested that bone is a major site for the extracellular buffering of the retained acid [92, 97, 104109]. Consistent with this thesis is the observation that metabolic acidosis is associated with a decrease in the content of bone bicarbonate [110, 111]. Finally, bicarbonate supplementation in postmenopausal women with normal renal function is associated with decreases in urinary calcium, phosphorus, and hydroxyproline, and increased osteocalcin levels, suggesting an overall benecial effect [112]. These observations also suggest that uncorrected metabolic acidosis has adverse consequences on bone anatomy and physiology. Since acidosis in CRF is not associated with hypercalciuria, the relevance of these ndings to human renal failure has been questioned [113, 114]. Several lines of evidence support a role for metabolic acidosis in the pathogenesis of bone disease in CRF; most of these studies were published 20 to 35 years ago. First, advanced uremia in

humans is associated with a decrease in the content of calcium carbonate in bone [115117]. Second, metabolic acidosis in CRF is associated with a net negative calcium balance; when metabolic acidosis is corrected, the calcium balance becomes less negative [92, 106]. It is not known if such acute effects of metabolic acidosis on calcium balance will persist chronically. Third, studies in nondialyzed individuals with CRF showed that severe metabolic acidosis is associated with impaired bone mineralization and an increased incidence of osteomalacia [106, 118120]. Indeed, Mora Palma et al [119] reported that over one third of 327 nondialyzed patients with renal failure who had undergone a bone biopsy had evidence for osteomalacia; the individuals with osteomalacia were characterized by a more severe degree of metabolic acidosis. Fourth, Cochran et al [106] demonstrated a signicant increase in bone mineralization rate after the correction of metabolic acidosis in nondialyzed individuals with CRF. Fifth, cross-sectional analyses of individuals with a renal transplant demonstrate a significant direct relationship between bone mineral density and plasma bicarbonate levels, using Cox multivariate proportional hazard analysis [121]. Finally, acute correction of metabolic acidosis in nondialyzed CRF patients is associated with increased plasma levels of osteocalcin and procollagen type 1 carboxyterminal propeptide, suggesting an improvement in osteoblast function [122, 123]. Notwithstanding these ndings, the precise contribution of metabolic acidosis to the bone disease in

Mehrotra, Kopple, and Wolfson: Metabolic acidosis in maintenance dialysis patients

S-21

nondialyzed individuals with CRF and MHD patients remains uncertain. Indirect effects: Acidosis and parathyroid hormone Among individuals with normal renal function, metabolic acidosis is associated with three physiologic changes with varying effects on serum parathyroid hormone (PTH) concentrations: there is an increase in serum ionized calcium, hypercalciuria, and a reduced sensitivity of the PTH secretion in response to ionized calcium [124126]. With decreased sensitivity of the parathyroid gland to calcium, the rise in ionized calcium may not be sufcient to maintain the normal serum PTH levels. Indeed, early investigations among individuals with normal renal function suggest that the hypercalciuria associated with metabolic acidosis leads to an increase in serum PTH levels [125]. In nondialyzed individuals with CRF, there is an inverse relationship between plasma bicarbonate and serum PTH levels that is consistent with these observations [127]. This relationship may have been secondary to the bicarbonaturia that is associated with elevated serum PTH levels. However, the rapid correction of metabolic acidosis in this latter group of patients is associated with a decrease in serum PTH levels, arguing against a role for bicarbonaturia [123]. The available evidence, although not conclusive, suggests that metabolic acidosis is also associated with an increase in serum PTH levels in MHD patients. In a randomized controlled study of 21 patients, Lefebvre et al [128] demonstrated that in MHD patients treated with a higher dialysate bicarbonate, there was no signicant increase in serum PTH levels over time; however, in the group of patients treated with standard dialysate bicarbonate and persistent metabolic acidosis, serum PTH levels increased signicantly. In addition, some (although not all) investigators report a decrease in serum PTH levels after correction of metabolic acidosis in MHD patients [64, 86, 129, 130]. Early studies reported that PTH causes a greater increase in serum calcium in the presence of metabolic acidosis [131]. Moreover, using isolated perfused canine tibia, Martin et al [132] demonstrated that metabolic acidosis enhances the generation of cyclic AMP in response to PTH, an event which may promote bone resorption. Two recent studies have shed greater light on this issue. First, using neonatal mouse calvariae, Bushinsky and Nilsson [133] have demonstrated that in the presence of metabolic acidosis, PTH stimulates greater net efux of calcium, inhibition of osteoblast activity, and enhancement of osteoclast function. Second, using UMR 106-01 osteoblast-like cells, Disthabanchong et al [134] recently demonstrated that acid culture medium increases PTH receptor mRNA, raises the binding of PTH to its receptor, and enhances the PTH-stimulated generation of cyclic

AMP. These ndings suggest that metabolic acidosis may enhance the peripheral actions of PTH on bone. Thus, although the evidence cannot be considered conclusive, the available data suggest that metabolic acidosis may lead to a worsening of secondary hyperparathyroidism. Indirect effects: Acidosis and vitamin D Metabolic acidosis reduces activity of 1a-hydroxylase in the renal tubules of rats [135]. The data regarding the effects of metabolic acidosis on serum levels of 1,25 dihydroxycholecalciferol are difcult to interpret because they are confounded by the effects of acidosis on levels of serum phosphorus and PTH. Thus, studies have indicated that metabolic acidosis may be associated with increased, unchanged, or decreased levels of serum 1,25 dihydroxycholecalciferol levels [108, 129, 136139]. Does correction of metabolic acidosis increase the risk for metastatic calcication? It has been proposed that postdialysis alkalosis may increase the risk for metastatic calcication. However, Harris et al [140] treated nine MHD patients with a higher dialysate bicarbonate concentration of 40 mmol/L for four weeks. They observed that the risk of metastatic calcication between standard and high dialysis bicarbonate, as determined by plasma inorganic phosphate, estimated plasma tribasic inorganic phosphate (the phosphate component of hydroxyapatite), and magnitude of postdialysis phosphate rebound, was not signicantly different between the two groups with different dialysate bicarbonate concentrations. This evidence, however, is indirect and the question needs further evaluation.

OTHER SYSTEMIC CONSEQUENCES OF ACIDOSIS b2-microglobulin levels Several lines of evidence suggest that metabolic acidosis may increase the serum levels of b2-microglobulin. First, cell culture studies suggest that metabolic acidosis may enhance cellular b2-microglobulin generation and release [141143]. Second, ammonium chlorideinduced metabolic acidosis in healthy adults is associated with a 1.5-fold increase in the b2-microglobulin mRNA expression in lymphocytes [143]. Third, in patients with CRF, a strong inverse relationship has been demonstrated between serum total CO2 and b2-microglobulin levels [143]. Finally, using acetate instead of bicarbonate as a buffer in dialysate is associated with a decrease in blood pH and total CO2 and an increase in plasma b2-microglobulin levels [143]. Thus, even though reduced renal excretion of b2-microglobulin is the predominant mechanism for its

S-22

Mehrotra, Kopple, and Wolfson: Metabolic acidosis in maintenance dialysis patients

accumulation in MHD patients, these data suggest that metabolic acidosis may also play a role. Hypertriglyceridemia In a small, uncontrolled study of MHD patients, the correction of metabolic acidosis was associated with signicant decrease in serum triglycerides, suggesting that metabolic acidosis may contribute to hypertriglyceridemia seen in MHD patients [139]. However, given the limitations of study design, these data need to be conrmed before any denitive conclusions are made.

CONCLUSION A large body of evidence suggests that uncorrected metabolic acidosis is detrimental to the overall health and specically the nutritional status and bone disease among MHD patients. Even though the relative contribution of metabolic acidosis to the development of protein-energy malnutrition or renal osteodystrophy remains to be dened, the correction of metabolic acidosis among MHD patients appears to be a desirable goal.

ACKNOWLEDGMENTS
This work was supported in part by the following grants: Satellite Research grant, Harbor-UCLA General Clinical Research Center grant M01-RR00425 from the National Centers for Research Resources, and a grant from the NIDDK (1RO1 DK61389-0141). We are grateful to Jack Coburn, M.D., for a critical review of the manuscript.

REFERENCES
1. WIDMER B, GERHARDT RE, HARRINGTON JT, COHEN JJ: Serum electrolyte and acid base composition. The inuence of graded degrees of chronic renal failure. Arch Intern Med 139:10991102, 1979 2. HAKIM RM, LAZARUS JM: Biochemical parameters in chronic renal failure. Am J Kidney Dis 11:238247, 1988 3. CARAVACA F, ARROBAS M, PIZARRO JL, ESPARRAGO JF: Metabolic acidosis in advanced renal failure: Differences between diabetic and nondiabetic patients. Am J Kidney Dis 33:892898, 1999 4. WALLIA R, GREENBERG A, PIRAINO B, et al: Serum electrolyte patterns in end-stage renal disease. Am J Kidney Dis 8:98104, 1986 5. MUJAIS S: Acid-base prole in patients on PD. Kidney Int 64(Suppl), 2003 (in press) 6. LOWRIE EG, LEW N: Death risk in hemodialysis patients: The predictive value of commonly measured variables and an evaluation of death rate differences between facilities. Am J Kidney Dis 15:458 482, 1990 7. LOWRIE EG, ZHU X, LEW NL: Primary associates of mortality among dialysis patients: Trends and reassessment of Kt/V and urea reduction ratio as outcome-based measures of dialysis dose. Am J Kidney Dis 32:S1631, 1998 8. HERR RD, SWANSON T: Serum bicarbonate declines with sample size in vacutainer tubes. Am J Clin Pathol 97:213216, 1992 9. BRAY SH, TUNG RL, JONES ER: The magnitude of metabolic acidosis is dependent on differences in bicarbonate assays. Am J Kidney Dis 28:700703, 1996 10. KIRSCHBAUM B: Spurious metabolic acidosis in hemodialysis patients. Am J Kidney Dis 35:10681071, 2000 11. LASKI ME: Penny wise and bicarbonate foolish. Am J Kidney Dis 35:12241225, 2000

12. HOWSE ML, LEONARD M, VENNING M, SOLOMAN L: The effect of different methods of storage on the results of serum total CO2 assays. Clin Sci (Lond) 100:609611, 2001 13. GOODMAN WG, GOLDIN J, KUIZON BD, et al: Coronary-artery calcication in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med 342:14781483, 2000 14. CHERTOW GM, BURKE SK, RAGGI P: Sevelamer attenuates the progression of coronary and aortic calcication in hemodialysis patients. Kidney Int 62:245252, 2002 15. GALLIENI M, COZZOLINO M, BRANCACCIO D: Transient decrease of serum bicarbonate levels with Sevelamer hydrochloride as the phosphate binder. Kidney Int 57:17761777, 2000 16. SADEK T, MAZOUZ H, BAHLOUL H, et al: Sevelamer hydrochloride with or without alphacalcidol or higher dialysate calcium vs calcium carbonate in dialysis patients: An open-label, randomized study. Nephrol Dial Transplant 18:582589, 2003 17. MARCO MP, MURAY S, BETRIU A, et al: Treatment with sevelamer decreases bicarbonate levels in hemodialysis patients. Nephron 92:499500, 2002 18. LYON DM, DUNLOP DM, STEWART CP: The alkaline treatment of chronic nephritis. Lancet 2:10091013, 1931 19. RODRIGUEZ NR, MILES JM, SCHWENK WF, HAYMOND MW: Effects of acute metabolic acidosis and alkalosis on leucine metabolism in conscious dogs. Diabetes 38:847853, 1989 20. MAY RC, KELLY RA, MITCH WE: Metabolic acidosis stimulates protein degradation in rat muscle by a glucocorticoid-dependent mechanism. J Clin Invest 77:614621, 1986 21. MAY RC, HARA Y, KELLY RA, et al: Branched-chain amino acid metabolism in rat muscle: abnormal regulation in acidosis. Am J Physiol 252:E712718, 1987 22. MAY RC, MASUD T, LOGUE B, et al: Chronic metabolic acidosis accelerates whole body proteolysis and oxidation in awake rats. Kidney Int 41:15351542, 1992 23. MITCH WE, MEDINA R, GRIEBER S, et al: Metabolic acidosis stimulates muscle protein degradation by activating the adenosine triphosphate-dependent pathway involving ubiquitin and proteasomes. J Clin Invest 93:21272133, 1994 24. MAY RC, KELLY RA, MITCH WE: Mechanisms for defects in muscle protein metabolism in rats with chronic uremia. Inuence of metabolic acidosis. J Clin Invest 79:10991103, 1987 25. BALLMER PE, MCNURLAN MA, HULTER HN, et al: Chronic metabolic acidosis decreases albumin synthesis and induces negative nitrogen balance in humans. J Clin Invest 95:3945, 1995 26. REAICH D, CHANNON SM, SCRIMGEOUR CM, GOODSHIP TH: Ammonium chloride-induced acidosis increases protein breakdown and amino acid oxidation in humans. Am J Physiol 263:E735739, 1992 27. PAPADOYANNAKIS NJ, STEFANIDIS CJ, MCGEOWN M: The effect of the correction of metabolic acidosis on nitrogen and potassium balance of patients with chronic renal failure. Am J Clin Nutr 40:623 627, 1984 28. WILLIAMS B, HATTERSLEY J, LAYWARD E, WALLS J: Metabolic acidosis and skeletal muscle adaptation to low protein diets in chronic uremia. Kidney Int 40:779786, 1991 29. REAICH D, CHANNON SM, SCRIMGEOUR CM, et al: Correction of acidosis in humans with CRF decreases protein degradation and amino acid oxidation. Am J Physiol 265:E230235, 1993 30. GARIBOTTO G, RUSSO R, SOFIA A, et al: Skeletal muscle protein synthesis and degradation in patients with chronic renal failure. Kidney Int 45:14321439, 1994 31. GRAHAM KA, REAICH D, CHANNON SM, et al: Correction of acidosis in CAPD decreases whole body protein degradation. Kidney Int 49:13961400, 1996 32. GRAHAM KA, REAICH D, CHANNON SM, et al: Correction of acidosis in hemodialysis decreases whole-body protein degradation. J Am Soc Nephrol 8:632637, 1997 33. LOFBERG E, WERNERMAN J, ANDERSTAM B, BERGSTROM J: Correction of acidosis in dialysis patients increases branched-chain and total essential amino acid levels in muscle. Clin Nephrol 48:230 237, 1997 34. LIM VS, YARASHESKI KE, FLANIGAN MJ: The effect of uraemia, acidosis, and dialysis treatment on protein metabolism: a longitudinal leucine kinetic study. Nephrol Dial Transplant 13:17231730, 1998

Mehrotra, Kopple, and Wolfson: Metabolic acidosis in maintenance dialysis patients

S-23

35. BOIRIE Y, BROYER M, GAGNADOUX MF, et al: Alterations of protein metabolism by metabolic acidosis in children with chronic renal failure. Kidney Int 58:236241, 2000 36. HARA Y, MAY RC, KELLY RA, MITCH WE: Acidosis, not azotemia, stimulates branched-chain, amino acid catabolism in uremic rats. Kidney Int 32:808814, 1987 37. ENGLAND BK, GREIBER S, MITCH WE, et al: Rat muscle branchedchain ketoacid dehydrogenase activity and mRNAs increase with extracellular acidemia. Am J Physiol 268:C13951400, 1995 38. BERGSTROM J, ALVESTRAND A, FURST P: Plasma and muscle free amino acids in maintenance hemodialysis patients without protein malnutrition. Kidney Int 38:108114, 1990 39. MOCHIZUKI T: The effect of metabolic acidosis on amino acid and keto acid metabolism in chronic renal failure. Nippon Jinzo Gakkai Shi 33:213224, 1991 40. KOOMAN JP, DEUTZ NE, ZIJLMANS P, et al: The inuence of bicarbonate supplementation on plasma levels of branched-chain amino acids in haemodialysis patients with metabolic acidosis. Nephrol Dial Transplant 12:23972401, 1997 41. BAILEY JL, WANG X, ENGLAND BK, et al: The acidosis of chronic renal failure activates muscle proteolysis in rats by augmenting transcription of genes encoding proteins of the ATP-dependent ubiquitin-proteasome pathway. J Clin Invest 97:14471453, 1996 42. PRICE SR, ENGLAND BK, BAILEY JL, et al: Acidosis and glucocorticoids concomitantly increase ubiquitin and proteasome subunit mRNAs in rat muscle. Am J Physiol 267:C955960, 1994 43. PICKERING WP, PRICE SR, BIRCHER G, et al: Nutrition in CAPD: Serum bicarbonate and the ubiquitin-proteasome system in muscle. Kidney Int 61:12861292, 2002 44. BOSSOLA M, MUSCARITOLI M, COSTELLI P, et al: Muscle ubiquitin m-rNA levels in patients with end-stage renal disease on maintenance hemodialysis. J Nephrol 15:552557, 2002 45. BAILEY JL, ENGLAND BK, LONG RC, JR, et al: Experimental acidemia and muscle cell pH in chronic acidosis and renal failure. Am J Physiol 269:C706712, 1995 46. PRICE SR, WANG X, BAILEY JL: Tissue-specic responses of branched-chain alpha-ketoacid dehydrogenase activity in metabolic acidosis. J Am Soc Nephrol 9:18921898, 1998 47. PRICE SR, WANG X: Glucocorticoids and acidication independently increase transcription of branched-chain ketoacid dehydrogenase subunit genes. Miner Electrolyte Metab 25:224227, 1999 48. SICURO A, MAHLBACHER K, HULTER HN, KRAPF R: Effect of growth hormone on renal and systemic acid-base homeostasis in humans. Am J Physiol 274:F650657, 1998 49. SCHAMBELAN M, SEBASTIAN A, KATUNA BA, ARTEAGA E: Adrenocortical hormone secretory response to chronic NH4Cl-induced metabolic acidosis. Am J Physiol 252:E454460, 1987 50. KLEGER GR, TURGAY M, IMOBERDORF R, et al: Acute metabolic acidosis decreases muscle protein synthesis but not albumin synthesis in humans. Am J Kidney Dis 38:11991207, 2001 51. MANIAR S, LAOUARI D, DECHAUX M, et al: In vivo unaltered muscle protein synthesis in experimental chronic metabolic acidosis. Kidney Int 46:17051712, 1994 52. MITCH WE, BAILEY JL, WANG X, et al: Evaluation of signals activating ubiquitin-proteasome proteolysis in a model of muscle wasting. Am J Physiol 276:C11321138, 1999 53. PRICE SR, DU JD, BAILEY JL, MITCH WE: Molecular mechanisms regulating protein turnover in muscle. Am J Kidney Dis 37:S112 114, 2001 54. ENGLAND BK, CHASTAIN JL, MITCH WE: Abnormalities in protein synthesis and degradation induced by extracellular pH in BC3H1 myocytes. Am J Physiol 260:C277282, 1991 55. BEVINGTON A, POULTER C, BROWN J, WALLS J: Inhibition of protein synthesis by acid in L6 skeletal muscle cells: analogies with the acute starvation response. Miner Electrolyte Metab 24:261266, 1998 56. ULRICH C, KRUGER B, KOHLER H, RIEGEL W: Effects of acidosis on acute phase protein metabolism in liver cells. Miner Electrolyte Metab 25:228233, 1999 57. CHALLA A, KRIEG RJ, JR, THABET MA, et al: Metabolic acidosis inhibits growth hormone secretion in rats: mechanism of growth retardation. Am J Physiol 265:E547553, 1993

58. MANIAR S, KLEINKNECHT C, ZHOU X, et al: Growth hormone action is blunted by acidosis in experimental uremia or acid load. Clin Nephrol 46:7276, 1996 59. CHALLA A, CHAN W, KRIEG RJ, JR, et al: Effect of metabolic acidosis on the expression of insulin-like growth factor and growth hormone receptor. Kidney Int 44:12241227, 1993 60. BRUNGGER M, HULTER HN, KRAPF R: Effect of chronic metabolic acidosis on the growth hormone/IGF-1 endocrine axis: New cause of growth hormone insensitivity in humans. Kidney Int 51:216221, 1997 61. MITCH WE, GOLDBERG AL: Mechanisms of muscle wasting. The role of the ubiquitin-proteasome pathway. N Engl J Med 335:1897 1905, 1996 62. DEFRONZO RA, BECKLES AD: Glucose intolerance following chronic metabolic acidosis in man. Am J Physiol 236:E328334, 1979 63. BELLOCQ A, SUBERVILLE S, PHILIPPE C, et al: Low environmental pH is responsible for the induction of nitric-oxide synthase in macrophages. Evidence for involvement of nuclear factor-kappaB activation. J Biol Chem 273:50865092, 1998 64. LIN SH, LIN YF, CHIN HM, WU CC: Must metabolic acidosis be associated with malnutrition in haemodialysed patients? Nephrol Dial Transplant 17:20062010, 2002 65. ODAMAKI M, FURUYA R, YONEYAMA T, et al: Association of the serum leptin concentration with weight loss in chronic hemodialysis patients. Am J Kidney Dis 33:361368, 1999 66. HEIMBURGER O, LONNQVIST F, DANIELSSON A, et al: Serum immunoreactive leptin concentration and its relation to the body fat content in chronic renal failure. J Am Soc Nephrol 8:14231430, 1997 67. STENVINKEL P, LINDHOLM B, LONNQVIST F, et al: Increases in serum leptin levels during peritoneal dialysis are associated with inammation and a decrease in lean body mass. J Am Soc Nephrol 11:13031309, 2000 68. TETA D, BEVINGTON A, BROWN J, et al: Effects of acidosis on leptin secretion from 3T3-L1 adipocytes and on serum leptin in the uraemic rat. Clin Sci (Lond) 97:363368, 1999 69. HATHOUT EH, SHARKEY J, RACINE M, et al: Changes in plasma leptin during the treatment of diabetic ketoacidosis. J Clin Endocrinol Metab 84:45454548, 1999 70. FLUCK CE, KUHLMANN BV, MULLIS PE: Insulin increases serum leptin concentrations in children and adolescents with newly diagnosed type I diabetes mellitus with and without ketoacidosis. Diabetologia 42:10671070, 1999 71. ZHENG F, QIU X, YIN S, LI Y: Changes in serum leptin levels in chronic renal failure patients with metabolic acidosis. J Ren Nutr 11:207211, 2001 72. KOKOT F, CHUDEK J, ADAMCZAK M, WIECEK A: Interrelationship between plasma leptin concentration and severity of metabolic acidosis in haemodialysed patients with chronic renal failure. Exp Clin Endocrinol Diabetes 109:370373, 2001 73. KANG SW, LEE SW, LEE IH, et al: Impact of metabolic acidosis on serum albumin and other nutritional parameters in long-term CAPD patients. Adv Perit Dial 13:249252, 1997 74. URIBARRI J: Moderate metabolic acidosis and its effects on nutritional parameters in hemodialysis patients. Clin Nephrol 48:238 240, 1997 75. DUMLER F, FALLA P, BUTLER R, et al: Impact of peritoneal dialysis modality and acidosis on nutritional status in peritoneal dialysis patients. Adv Perit Dial 14:205208, 1998 76. GE YQ, WU ZL, XU YZ, LIAO LT: Study on nutritional status of maintenance hemodialysis patients. Clin Nephrol 50:309314, 1998 77. MOVILLI E, BOSSINI N, VIOLA BF, et al: Evidence for an independent role of metabolic acidosis on nutritional status in haemodialysis patients. Nephrol Dial Transplant 13:674678, 1998 78. DUMLER F, FALLA P, BUTLER R, et al: Impact of dialysis modality and acidosis on nutritional status. Asaio J 45:413417, 1999 79. URIBARRI J, LEVIN NW, DELMEZ J, et al: Association of acidosis and nutritional parameters in hemodialysis patients. Am J Kidney Dis 34:493499, 1999 80. GAO H, LEW SQ, BOSCH JP: Moderate metabolic acidosis and its effects on serum parameters in hemodialysis patients. Nephron 86:135138, 2000

S-24

Mehrotra, Kopple, and Wolfson: Metabolic acidosis in maintenance dialysis patients

81. LEAVEY SF, STRAWDERMAN RL, YOUNG EW, et al: Cross-sectional and longitudinal predictors of serum albumin in hemodialysis patients. Kidney Int 58:21192128, 2000 82. CHAUVEAU P, FOUQUE D, COMBE C, et al: Acidosis and nutritional status in hemodialyzed patients. French Study Group for Nutrition in Dialysis. Semin Dial 13:241246, 2000 83. KUNG SC, MORSE SA, BLOOM E, RAJA RM: Acid-base balance and nutrition in peritoneal dialysis. Adv Perit Dial 17:235237, 2001 84. SEYFFART G, ENSMINGER A, SCHOLZ R: Increase of body mass during long-term bicarbonate hemodialysis. Kidney Int Suppl 22:S174 177, 1987 85. ROBERTS RG, GILMOUR ER, GOODSHIP TH: The correction of acidosis does not increase dietary protein intake in chronic renal failure patients. Am J Kidney Dis 28:350353, 1996 86. WILLIAMS AJ, DITTMER ID, MCARLEY A, CLARKE J: High bicarbonate dialysate in haemodialysis patients: Effects on acidosis and nutritional status. Nephrol Dial Transplant 12:26332637, 1997 87. BRADY JP, HASBARGEN JA: Correction of metabolic acidosis and its effect on albumin in chronic hemodialysis patients. Am J Kidney Dis 31:3540, 1998 88. MOVILLI E, ZANI R, CARLI O, et al: Correction of metabolic acidosis increases serum albumin concentrations and decreases kinetically evaluated protein intake in haemodialysis patients: A prospective study. Nephrol Dial Transplant 13:17191722, 1998 89. VEROVE C, MAISONNEUVE N, EL AZOUZI A, et al: Effect of the correction of metabolic acidosis on nutritional status in elderly patients with chronic renal failure. J Ren Nutr 12:224228, 2002 90. STEIN A, MOORHOUSE J, ILES-SMITH H, et al: Role of an improvement in acid-base status and nutrition in CAPD patients. Kidney Int 52:10891095, 1997 91. GOODMAN AD, LEMANN JJ, LITZOW JR: Production, excretion and net balance in patients with renal disease. J Clin Invest 44:495506, 1965 92. LITZOW JR, LEMANN J, JR, LENNON EJ: The effect of treatment of acidosis on calcium balance in patients with chronic azotemic renal disease. J Clin Invest 46:280286, 1967 93. ALPERN RJ, SAKHAEE K: The clinical spectrum of chronic metabolic acidosis: Homeostatic mechanisms produce signicant morbidity. Am J Kidney Dis 29:291302, 1997 94. URIBARRI J, DOUYON H, OH MS: A re-evaluation of the urinary parameters of acid production and excretion in patients with chronic renal acidosis. Kidney Int 47:624627, 1995 95. BUSHINSKY DA: Net calcium efux from live bone during chronic metabolic, but not respiratory, acidosis. Am J Physiol 256:F836 842, 1989 96. KRAUT JA, MISHLER DR, KUROKAWA K: Effect of colchicine and calcitonin on calcemic response to metabolic acidosis. Kidney Int 25:608612, 1984 97. KRAUT JA, MISHLER DR, SINGER FR, GOODMAN WG: The effects of metabolic acidosis on bone formation and bone resorption in the rat. Kidney Int 30:694700, 1986 98. FRICK KK, BUSHINSKY DA: Chronic metabolic acidosis reversibly inhibits extracellular matrix gene expression in mouse osteoblasts. Am J Physiol 275:F840847, 1998 99. GOLDHABER P, RABADJIJA L: H+ stimulation of cell-mediated bone resorption in tissue culture. Am J Physiol 253:E9098, 1987 100. RABADJIJA L, BROWN EM, SWARTZ SL, et al: H(+)-stimulated release of prostaglandin E2 and cyclic adenosine 3 ,5 -monophosphoric acid and their relationship to bone resorption in neonatal mouse calvaria cultures. Bone Miner 11:295304, 1990 101. KRIEGER NS, PARKER WR, ALEXANDER KM, BUSHINSKY DA: Prostaglandins regulate acid-induced cell-mediated bone resorption. Am J Physiol Renal Physiol 279:F10771082, 2000 102. BUSHINSKY DA, PARKER WR, ALEXANDER KM, KRIEGER NS: Metabolic, but not respiratory, acidosis increases bone PGE(2) levels and calcium release. Am J Physiol Renal Physiol 281:F1058 1066, 2001 103. KRIEGER NS, FRICK KK, BUSHINSKY DA: Cortisol inhibits acidinduced bone resorption in vitro. J Am Soc Nephrol 13:25342539, 2002 104. LEMANN J, JR, LITZOW JR, LENNON EJ: The effects of chronic acid loads in normal man: further evidence for the participation of bone

105. 106. 107. 108.

109. 110. 111. 112.

113. 114. 115.

116. 117.

118. 119. 120.

121.

122. 123.

124. 125. 126.

mineral in the defense against chronic metabolic acidosis. J Clin Invest 45:16081614, 1966 SUTTON RA, WONG NL, DIRKS JH: Effects of metabolic acidosis and alkalosis on sodium and calcium transport in the dog kidney. Kidney Int 15:520533, 1979 COCHRAN M, WILKINSON R: Effect of correction of metabolic acidosis on bone mineralisation rates in patients with renal osteomalacia. Nephron 15:98110, 1975 LEVINE BS, HO K, KRAUT JA, et al: Effect of metabolic acidosis on phosphate transport by the renal brush-border membrane. Biochim Biophys Acta 727:712, 1983 KRAPF R, VETSCH R, VETSCH W, HULTER HN: Chronic metabolic acidosis increases the serum concentration of 1,25dihydroxyvitamin D in humans by stimulating its production rate. Critical role of acidosis-induced renal hypophosphatemia. J Clin Invest 90:24562463, 1992 AMBUHL PM, ZAJICEK HK, WANG H, et al: Regulation of renal phosphate transport by acute and chronic metabolic acidosis in the rat. Kidney Int 53:12881298, 1998 BUSHINSKY DA, LECHLEIDER RJ: Mechanism of proton-induced bone calcium release: calcium carbonate-dissolution. Am J Physiol 253:F9981005, 1987 BUSHINSKY DA, LAM BC, NESPECA R, et al: Decreased bone carbonate content in response to metabolic, but not respiratory, acidosis. Am J Physiol 265:F530536, 1993 SEBASTIAN A, HARRIS ST, OTTAWAY JH, et al: Improved mineral balance and skeletal metabolism in postmenopausal women treated with potassium bicarbonate. N Engl J Med 330:17761781, 1994 OH MS: Irrelevance of bone buffering to acid-base homeostasis in chronic metabolic acidosis. Nephron 59:710, 1991 OH MS: New perspectives on acid-base balance. Semin Dial 13:212219, 2000 PELLEGRINO ED, BILTZ RM: The composition of human bone in uremia. Observations on the reservoir functions of bone and demonstration of a labile fraction of bone carbonate. Medicine (Baltimore) 44:397418, 1965 KAYE M, FRUEH AJ, SILVERMAN M, et al: A study of vertebral bone powder from patients with chronic renal failure. J Clin Invest 49:442453, 1970 PELLEGRINO ED, BILTZ RM, LETTERI JM: Inter-relationships of carbonate, phosphate, monohydrogen phosphate, calcium, magnesium and sodium in uraemic bone: Comparison of dialysed and non-dialysed patients. Clin Sci Mol Med 53:307316, 1977 INGHAM JP, KLEEREKOPER M, STEWART JH, POSEN S: Symptomatic skeletal disease in non-terminal renal failure. Med J Aust 1:873 876, 1974 MORA PALMA FJ, ELLIS HA, COOK DB, et al: Osteomalacia in patients with chronic renal failure before dialysis or transplantation. Q J Med 52:332348, 1983 COEN G, MANNI M, ADDARI O, et al: Metabolic acidosis and osteodystrophic bone disease in predialysis chronic renal failure: Effect of calcitriol treatment. Miner Electrolyte Metab 21:375382, 1995 HEAF J, TVEDEGAARD E, KANSTRUP IL, FOGH-ANDERSEN N: Bone loss after renal transplantation: Role of hyperparathyroidism, acidosis, cyclosporine and systemic disease. Clin Transplant 14:457 463, 2000 LIN YF, SHIEH SD, DIANG LK, et al: Inuence of rapid correction of metabolic acidosis on serum osteocalcin level in chronic renal failure. Asaio J 40:M440444, 1994 CHU P, LU KC, LIN YF: Acute correction of metabolic acidosis increases serum procollagen type I carboxyterminal propeptide in patients with chronic renal failure. J Formos Med Assoc 100:748 752, 2001 MOORE EW: Ionized calcium in normal serum, ultraltrates, and whole blood determined by ion-exchange electrodes. J Clin Invest 49:318334, 1970 COE FL, FIRPO JJ, JR, HOLLANDSWORTH DL, et al: Effect of acute and chronic metabolic acidosis on serum immunoreactive parathyroid hormone in man. Kidney Int 8:263273, 1975 GRAHAM KA, HOENICH NA, TARBIT M, et al: Correction of acidosis in hemodialysis patients increases the sensitivity of the

Mehrotra, Kopple, and Wolfson: Metabolic acidosis in maintenance dialysis patients

S-25

127. 128. 129. 130.

131. 132.

133. 134.

parathyroid glands to calcium. J Am Soc Nephrol 8:627631, 1997 ST JOHN A, THOMAS MB, DAVIES CP, et al: Determinants of intact parathyroid hormone and free 1,25-dihydroxyvitamin D levels in mild and moderate renal failure. Nephron 61:422427, 1992 LEFEBVRE A, VERNEJOUL MC, GUERIS J, et al: Optimal correction of acidosis changes progression of dialysis osteodystrophy. Kidney Int 36:11121118, 1989 LU KC, SHIEH SD, LI BL, et al: Rapid correction of metabolic acidosis in chronic renal failure: Effect on parathyroid hormone activity. Nephron 67:419424, 1994 MOVILLI E, ZANI R, CARLI O, et al: Direct effect of the correction of acidosis on plasma parathyroid hormone concentrations, calcium and phosphate in hemodialysis patients: A prospective study. Nephron 87:257262, 2001 BECK N, KIM HP, KIM KS: Effect of metabolic acidosis on renal action of parathyroid hormone. Am J Physiol 228:14831488, 1975 MARTIN KJ, FREITAG JJ, BELLORIN-FONT E, et al: The effect of acute acidosis on the uptake of parathyroid hormone and the production of adenosine 3 ,5 -monophosphate by isolated perfused bone. Endocrinology 106:16071611, 1980 BUSHINSKY DA, NILSSON EL: Additive effects of acidosis and parathyroid hormone on mouse osteoblastic and osteoclastic function. Am J Physiol 269:C13641370, 1995 DISTHABANCHONG S, MARTIN KJ, MCCONKEY CL, GONZALEZ EA: Metabolic acidosis up-regulates PTH/PTHrP receptors in UMR 10601 osteoblast-like cells. Kidney Int 62:11711177, 2002

135. KRAUT JA: The role of metabolic acidosis in the pathogenesis of renal osteodystrophy. Adv Ren Replace Ther 2:4051, 1995 136. LANGMAN CB: Calcitriol metabolism during chronic metabolic acidosis. Semin Nephrol 9:6571, 1989 137. GAFTER U, KRAUT JA, LEE DB, et al: Effect of metabolic acidosis in intestinal absorption of calcium and phosphorus. Am J Physiol 239:G480484, 1980 138. LU KC, LIN SH, YU FC, et al: Inuence of metabolic acidosis on serum 1,25(OH)2D3 levels in chronic renal failure. Miner Electrolyte Metab 21:398402, 1995 139. MAK RH: Effect of metabolic acidosis on hyperlipidemia in uremia. Pediatr Nephrol 13:891893, 1999 140. HARRIS DC, YUILL E, CHESHER DW: Correcting acidosis in hemodialysis: Effect on phosphate clearance and calcication risk. J Am Soc Nephrol 6:16071612, 1995 141. HOCHMAN JH, JIANG H, MATYUS L, et al: Endocytosis and dissociation of class I MHC molecules labeled with uorescent beta-2 microglobulin. J Immunol 146:18621867, 1991 142. POLAKOVA K, KARPATOVA M, RUSS G: Dissociation of beta 2microglobulin is responsible for selective reduction of HLA class I antigenicity following acid treatment of cells. Mol Immunol 30:12231230, 1993 143. SONIKIAN M, GOGUSEV J, ZINGRAFF J, et al: Potential effect of metabolic acidosis on beta 2-microglobulin generation: in vivo and in vitro studies. J Am Soc Nephrol 7:350356, 1996