Pyruvate in the Correction of Intracellular Acidosis: A Metabolic Basis as a Novel Superior Buffer

Abstract

The review focuses on biochemical metabolisms of conventional buffers and emphasizes advantages of sodium pyruvate (Pyr) in the correction of intracellular acidosis. Exogenous lactate (Lac) as an alternative of natural buffer, bicarbonate, consumes intracellular protons on an equimolar basis, regenerating bicarbonate anions in plasma while the completion of gluconeogenesis and/or oxidation occurs via tricarboxylic-acid cycle in mitochondria mainly in liver and kidney, or heart. The general assumption that Lac is 'metabolized to bicarbonate' in liver to serve as a buffer has been questioned. Pyr as a novel buffer would be superior to conventional ones in the correction of metabolic acidosis. Several likely biochemical mechanisms of Pyr action are discussed. Experimental evidence, in vivo, strongly suggested that Pyr would be particularly efficient in the correction of severe acidemia: type A lactic acidosis, hypercapnia with cardiac arrest, and diabetic and alcoholic ketoacidosis in animal experiments and clinic settings. Because of its multi-cytoprotection, Pyrs not only correct acidosis, but also benefit theunderlying dysfunction of vital organs. In addition, Pyr is also a potential buffer component of dialysis solutions. However, the instability of Pyr in aqueous solutions restricts its clinical applications as a therapeutic agent. Attempts to create a stable Pyr preparation are needed.

Full text

Fax +41 61 306 12 34
E-Mail karger@karger.ch
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In-Depth Topic Review
Am J Nephrol 2005;25:55–63
DOI: 10.1159/000084141
Pyruvate in the Correction of
Intracellular Acidosis: A Metabolic Basis
as a Novel Superior Buffer
Fang Qiang Zhou
Fresenius Dialysis Centers, Chicago, Ill. , USA
tion, Pyrs not only correct acidosis, but also benefi t the
underlying dysfunction of vital organs. In addition, Pyr is
also a potential buffer component of dialysis solutions.
However, the instability of Pyr in aqueous solutions re-
stricts its clinical applications as a therapeutic agent. At-
tempts to create a stable Pyr preparation are needed.
Copyright © 2005 S. Karger AG, Basel
Since 1970s, pyruvate (Pyr) has become increasingly
attractive in the protection of dysfunctional vital organs,
particularly in myocardial ischemia and reperfusion in-
jury, pointing to a potential therapeutic value for the dys-
functional myocardium [1–3] . Also, fi ndings strongly in-
dicated that Pyr would be a novel buffer in many clinic
settings [4–6] . This review discusses its distinctive effects
on intracellular pH (pHi), proposing that Pyr may be su-
perior to lactate (Lac) and bicarbonate in the correction
of severe intracellular acidosis.
Lactate Metabolism and Effects on pHi and
Lactic Acidosis
Lac has been traditionally accepted as the best replace-
ment for bicarbonate in the treatment of metabolic aci-
dosis since early 1930s [7]
; it has since become part of
solutions for dialysis and continuous renal replacement
therapy for several decades.
Key Words
Pyruvate  Lactate  Bicarbonate  Glucose  Ischemia 
Intracellular pH  Acidosis
Abstract
The review focuses on biochemical metabolisms of con-
ventional buffers and emphasizes advantages of sodium
pyruvate (Pyr) in the correction of intracellular acidosis.
Exogenous lactate (Lac) as an alternative of natural buf-
fer, bicarbonate, consumes intracellular protons on an
equimolar basis, regenerating bicarbonate anions in
plasma while the completion of gluconeogenesis and/or
oxidation occurs via tricarboxylic-acid cycle in mitochon-
dria mainly in liver and kidney, or heart. The general as-
sumption that Lac is ‘metabolized to bicarbonate’ in liver
to serve as a buffer has been questioned. Pyr as a novel
buffer would be superior to conventional ones in the cor-
rection of metabolic acidosis. Several likely biochemical
mechanisms of Pyr action are discussed. Experimental
evidence, in vivo, strongly suggested that Pyr would be
particularly effi cient in the correction of severe acidemia:
type A lactic acidosis, hypercapnia with cardiac arrest,
and diabetic and alcoholic ketoacidosis in animal experi-
ments and clinic settings. Because of its multi-cytoprotec-
Received: June 24, 2004
Accepted: January 6, 2005
Published online: February 23, 2005
Nephrolo
gy
American Journal of
Dr. Fang Q. Zhou
Fresenius Dialysis Centers at Chicago
4180 Winnetka Avenue
Rolling Meadows, IL 60008 (USA)
Tel. +1 847 394 6250, Fax +1 847 394 4621, E-Mail fqz@hotmail.com
© 2005 S. Karger AG, Basel
0250–8095/05/0251–0055$22.00/0
Accessible online at:
www.karger.com/ajn
The opinions or assertions contained herein are the author’s pri-
vate view and are not to be construed as refl ecting the view of Fre-
senius Dialysis Centers at Chicago, USA .
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Am J Nephrol 2005;25:55–63
56
However, the widely propagated theory that Lac is
‘metabolized to bicarbonate’ on an equimolar basis in
liver represents a simplifi cation. In fact, Lac is an end
product of anaerobic glycolysis with Pyr as its only outlet.
As an alkalizer, it must be converted to Pyr by lactic de-
hydrogenase (LDH) in most mammalian tissues, which
in turn can either be completely oxidized to CO
2
and H
2
O
in the mitochondria mainly in liver, kidney, heart and
brain for the titration of a proton or enter gluconeogen-
esis from two Lac anions in the mitochondria and cytosol
of liver and kidney for the titration of two protons. Both
Lac oxidation and Lac-based gluconeogenesis are a mito-
chondrial tricarboxylic-acid cycle (TCA cycle)-dependent
pathway. The overall reactions can be described as shown
in equations 1 and 2; whichever route of Lac disposal is
followed, one proton (H
+
) is consumed per Lac anion me-
tabolized (Lac
–
:
H
+
= 1: 1):
oxidation) ATP, 17.5 ( OH 3 CO 3 O 3 H
lactate
CHOHCOOCH 22
cycle TCA
23
_ 
enesis)(gluconeog OHC
H 2
lactate
CHOHCOOCH 2 61263
_
o

o
1)
(2)
(
The consumption of a proton in cytosol effectively
means the regeneration of a bicarbonate anion, thus rais-
ing pHi and preserving the blood bicarbonate level stoi-
chiometrically [8, 9] .
The uptake of Lac or Pyr by cells and the entry of Pyr
into mitochondria depend on the Lac
–
/H
+
cotransport
system, monocarboxylate transporters (MCT, fi g. 1 ) with
H
+
([H
+
] in fi g. 1 ) fl ux in symport. The system is located
in the cytoplasma membrane and inner membrane of mi-
tochondria. The oxidation of exogenous Lac to Pyr by
LDH is NAD
+
-dependent in cytosol, which releases two
hydrogen ions with one (H
+
in fi g.1 ) left in the hydrogen
pool of cytosol as shown in equation 3. Both MCT-trans-
ported and Lac-released protons initially decrease pHi
[10, 11] , while the other hydrogen ion (negative hydrogen
or hydride ion) released from Lac reduces cytosolic NAD
+
([NAD
+
]c) to NADH ([NADH]c). Such a decrease of re-
ducing equivalents has been called cellular ‘pseudohy-
poxia’. In aerobic conditions, [NADH
2
]c ([NADH +
H
+
]c) may be transferred into mitochondria and oxidized
with the generation of 1 H
2
O and 2.5 ATP. Thus, the
proton released from Lac is eventually consumed. The
administration of Lac raises the Lac/Pyr ratio and de-
creases the [NAD
+
/NADH]c ratio in cytosol, which may
critically inhibit glycolysis at the level of glyceraldehyde-
3-phosphate dehydrogenase (G-3-PD) [12] . It also reduc-
es the glycolytically derived ATP production that is vital
for sustaining cellular functions in anaerobic conditions.
Pyr oxidative decarboxylation, then, is catalyzed by the
Pyr dehydrogenase complex (PDC) in mitochondria,
coupled with the reduction of mitochondrial NAD
+
([NAD
+
]m) to [NADH]m, yielding acetyl-CoA. It de-
pends on oxygen as an electron acceptor in mitochondria
that one pair of [NADH
2
]m ([NADH + H
+
]m) as well as
transferred [NADH
2
]c is oxidized through the electron
transfer chain, consuming the two hydrogen ions of
[NADH
2
]m with 1 H
2
O and 3 ATP generations.
Catalyzed by PDC, one hydrogen (hydride) ion of
[NADH + H
+
]m is transferred via [FADH
2
] from the
reactive thiol group (-SH) of coenzyme A, HS-CoA,
which does not affect pHi; the other hydrogen ion (pro-
ton) is picked up in the hydrogen pool in the mitochon-
dria matrix [13] . The overall reaction is the oxidation of
imported proton via MCT and raises pHi as reported in
cardiomyocytes of ischemic reperfused rabbit hearts and
failing human myocardium [10, 11] . Thus, for every ex-
ogenous Lac anion metabolized in aerobic conditions
either by oxidative phosphorylation or with glyconeo-
genesis, one endogenous proton is consumed, leading to
the preservation of blood bicarbonate levels on a 1: 1 mo-
lar basis.
In the mitochondria of many cell lines, mainly hepa-
tocytes, carbonic anhydrase isoenzyme (CA V) exists,
which catalyzes hydration (-HCO
3
or H
2
CO
3
) of CO
2
and
H
2
O.
The bicarbonate so generated in the mitochondria
is vital for the activity of bicarbonate-requiring Pyr car-
boxylase (PC) that is essential for the TCA cycle and glu-
coneogenesis [14, 15] . Also, acetazolamide, an inhibitor
of most CA isoenzymes including CA V, may decrease
Lac-induced blood alkalinization and induce lactic aci-
dosis [15] . Although these facts support that CA V plays
an important role in the pHi modulation, they do not
prove the general assumption that ‘the irreversible oxida-
tion of Lac generates alkali from the conversion of CO
2
to bicarbonate by CA’, which then corrects metabolic ac-
idosis [16, 17] . The traditional concept that Lac as a buf-
fer is ‘metabolized to bicarbonate’ in liver mitochondria
catalyzed by CA V to correct acidosis lacks direct evi-
dence. It is well known that the Lac oxidation induces
cytotoxic effects in tissue ischemia or hypoxia, such as the
depletion of reducing equivalents, inhibition of glycolysis
and release of protons in cytosol. Hence, in hypoxic con-
ditions, the administration of sodium Lac may aggravate,
rather than attenuate, intracellular acidifi cation if the
ability of Pyr oxidation is limited and gluconeogenesis is
suppressed in cells such as hepatocytes, cardiomyocytes
and macrophages, which have abundant mitochondria.
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Pyruvate and Metabolic Acidosis
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Am J Nephrol 2005;25:55–63 57
NAD
+
NADH + H
+
NADH + H
+
NAD
+
lactate/pyruvate + [H
+
]
Lactate
acetyl-CoA
oxaloacetate
citrate
malate
CO
2
cytoplasm
mitochondrial
matrix pyruvate
MCT
oxaloacetate
LDH
2-ketoglutarate
glycolysis
oxidative
phosphorylation
extracellular
space
PDC
pyruvate
phosphoenolpyruvate
MCT
PC
ME
Fructose-1,6-bisphosphate
anaplerosis
1,3 bisphosphoglycerate
glyceraldehyde 3-phosphate
glucose
NADH + [H
+
]
NADH + H
+
respiratory chain
NADH + [H
+
]
[H
+
]
[H
+
]
G-3-PD
glucose
O
2
NAD
+
+
lactate/pyruvate + [H
+
]
TCA cycle
alanine
oxidation of ketone bodies
and fatty acids
CoA-SH
CO
2
PFK-1
(2)
(1)
H
2
O + CO
2
+ ATP
pKa
Km
Fig. 1. Pyruvate metabolic pathways and their relationship with the
consumption of protons in intracellular compartments. Pyr and/or
Lac enter cytosol via the MCT system with an extracellular [H
+
]
fl ex in symport. The oxidation of Lac to Pyr with LDH releases an
H
+
coupled with NAD
+
reduction to NADH in cytosol, inhibiting
glycolysis at the G-3-DP step. Both MCT-imported [H
+
] and Lac-
released H
+
initially decrease pHi, whereas the Pyr reduction to Lac
consumes the [H
+
], restoring pHi and glycolysis in anaerobic con-
ditions. In aerobic conditions, the Pyr entry into mitochondria with
[H
+
] yields NADH + [H
+
] by PDC. Oxidative phosphorylation of
both NADH + [H
+
] ([NADH + H
+
]m) and transferred NADH +
H
+
([NADH + H
+
]c) generates ATP and H
2
O, eventually consum-
ing [H
+
] and H
+
, respectively. The overall oxidation of exogenous
Pyr and/or Lac consumes endogenous [H
+
] on an equimolar basis,
raising pHi and pHe. Excess Pyr simultaneously activates the PDC
activity and enhances anaplerotic pathways via PC, accelerating
the TCA cycle fl ux and the [H
+
] consumption. Pyr-based gluconeo-
genesis consumes an additional pair of [NADH + H
+
]c at the step
of G-3-DP in cytosol, compared with Lac-based gluconeogenesis.
The preservation of a near physiologic pHi and the acceleration of
TCA cycle by excess Pyr enhance the Lac oxidation in lactic acido-
sis and the oxidation of ketone bodies and fatty acids in ketoacido-
sis. The shuttle of [NADH + H
+
]c transference from cytosol to
mitochondria is not shown. See the text for details. (1) = Gluconeo-
genesis-coupled reactions in mitochondria; (2) = gluconeogenesis-
coupled reactions in cytosol; G-3-PD = glyceraldehyde-3-phos-
phate dehydrogenase; K m = Michaelis constant; LDH = lactic de-
hydrogenase; MCT = monocarboxylate transporters; ME = malic
enzyme; NAD
+
= oxidized nicotinamide adenine dinucleotide;
NADH = reduced nicotinamide adenine dinucleotide; PC = pyru-
vate carboxylase; PDC = pyruvate dehydrogenase complex;
PFK-1 = phosphofructokinase-1; pK a = dissociation constant;
TCA cycle = tricarboxylic-acid cycle.
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Am J Nephrol 2005;25:55–63
58
In cells with no or a few mitochondria (e.g., erythrocytes
or neutrophils, etc.), exogenous Lac would just deterio-
rate the acidosis and depress cell function [18] even in
normoxymia.
Hyperlactatemia and lactic acidosis could be corrected
with dichloroacetate (DCA) or THAM [16, 19] , but their
values in clinic settings are not clear due to the negative
survival rate and/or potential toxicity [19, 20] . The effi -
cacy of Lac therapy in patients with lactic acidosis has
not been systemically evaluated. In principle, severe aci-
demia: Type A lactic acidosis, hypercapnia with cardiac
arrest and diabetic ketoacidosis, which account for over
90% of severe acidosis in clinic settings with excess mor-
tality [19] , are contraindications of the Lac administra-
tion. The Lac infusion should be avoided in cases of el-
evated serum Lac. Although sodium Lac itself is almost
obsolete in the treatment of clinical acidosis, several re-
cent studies have demonstrated that lactated Ringer’s so-
lution (28 m M ) was benefi cial in the resuscitation of mas-
sive hemorrhagic shock accompanied with lactic acidosis.
It signifi cantly improved acidosis and survival rates [17,
21–23] . In rat working hearts after hemorrhagic shock ac-
companied with lactic acidosis and impaired PDC ac-
tivities, Lac at 8.0 m M in the presence of palmitate in
perfusates saturated with 95% oxygen improved cardiac
effi ciency [21] . Most likely the intracellular acidosis was
attenuated although pHi data were not determined. The
paradoxical effect of exogenous Lac on experimental lac-
tic acidosis above has not been fully interpreted, but may
be associated with several reasons: different species of
models, early stage of shock, over 40 mm Hg of mean ar-
terial pressure of shock and anesthesia conditions [17,
21–23] . The above fi ndings indicated that the TCA cycle
function in vital organs remained, at least partially, intact
for Lac oxidation [24] . Notably, Lac-based gluconeogen-
esis in liver and kidney may still be preserved in the ear-
ly stage of shock [25, 26] . In particular, kidney is as im-
portant a gluconeogenic organ as liver for Lac disposal. It
is estimated that one-half of glucose production within
the Lac Cori cycle takes place in the kidney cortex and
Lac accounts for approximately 50% of renal gluconeo-
genesis. The Lac uptake remains relatively stable in hem-
orrhagic shock dogs until blood loss reaches 40% of total
blood volume [26, 27] . While acidosis signifi cantly de-
presses hepatic uptake of Lac, renal gluconeogenesis is
markedly enhanced by ischemic injury or acidosis [26,
28] due to the rapid stimulation of phosphoenolpyruvate
carboxykinase [29] . Further, a recent clinical investiga-
tion found that in patients with early postoperative car-
diogenic shock accompanied with lactic acidosis, the
clearance of exogenous Lac was not signifi cantly altered,
compared with controls [30] . In contrast, if shock despite
causes in origin are severe [31] or combined with alco-
holic intoxication [23] , preexisting liver diseases, diabetes
or multiple organ injuries, the Lac infusion most likely
exacerbates lactic acidosis. Therefore, it should be taken
into account in the deduction of Lac effects on acidosis
in above-mentioned experimental results if the oxidative
phosphorylation of TCA cycle or gluconeogenesis in vital
organs was, at least in part, sustained during early shock
(hypoxia) or recovered after shock (reoxygenation). On
the other hand, because the anoxia (hypoxia) of tissues
and the dysfunction of TCA cycle commonly coexist in
lactic acidosis, exogenous Lac should be avoided in such
clinical settings even in the early stage of shock if the pa-
tient is critically ill, preferably in consideration of a new
buffer, Pyr, instead.
Pyruvate Improvement of Intracellular
Acidosis
Pyr was initially used in mid-1970 to buffer intracel-
lular hydrogen ions and improve redox status in cardio-
myocytes. The administration of exogenous Pyr promis-
ingly improved glycolysis that was depressed from isch-
emia-reperfusion injury, preserved cardiac contractile
function and prolonged the survival time of ischemic
swine hearts [32] . Also, Pyr (10 m M ), as a sole exogenous
substrate, signifi cantly attenuated the pHi decrease in the
perfused rat ischemic myocardium. It was fi rst discovered
in 1994 that animals treated with the Pyr infusion did not
develop an anesthetic agent-induced mild metabolic aci-
dosis presented in controls [33] . The fi nding confi rmed
that the intravenous Pyr would induce ‘systemic alkaliza-
tion’ that was not emphasized in its conception until 1999
[34] . The comparison of Pyr with Lac on pHi in human
cells was fi rst conducted with neutrophils in 1995 [4] . In
an acidic milieu, following a slight pHi decrease, Pyr
(40 m M ) maintained neutrophilic pHi close to a physio-
logical value, whereas an identical Lac level brought about
a prompt and substantial pHi decline. The extracellular
pH [pHe] of mixture solutions with Pyr was signifi cantly
higher than that with Lac counterparts as well. A subse-
quent report confi rmed the phenomenon [Perit Dial Int
Abstracts, 1997; 17(suppl 1):S33]. The impact of Pyr on
systemic acidosis, however, at present has not been well
appreciated [31] , and potential mechanisms whereby Pyr
preferably corrected severe acidosis have not been fully
elucidated either [6, 34] . There are several likely bio-
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Am J Nephrol 2005;25:55–63 59
chemical sites on which the metabolism of exogenous Pyr
consumes intracellular protons, indicating that Pyr is of
particular signifi cance in the pHi modulation [32, 35–37]
( fi g. 1 ):
(1) By reducing to Lac with LDH, one exogenous Pyr
anion consumes one proton from the cytosolic hydrogen
pool, raising [NAD
+
/NADH]c and pHi, as described in
equation 3:
NAD
lactate
CHOHCOOCH H NADH
pyruvate
COCOOCH __
3
LDH
3
 om (3
)
The [NADH/NAD
+
]c ratio by the law of mass action
is the major determinant of reactive direction. For any
given cellular level of Pyr, the ratio determines what
fraction of Pyr is converted to Lac. When mitochondri-
al oxidative reactions are impaired, the ratio rises, and
the conversion of Pyr to Lac increases. Pyr inhibits gly-
colysis in aerobic conditions, however, it is of pivot im-
portance that Pyr favors anaerobic glycolysis due to the
increase of [NAD
+
/NADH]c ratio and restoration of
pH-sensitive phosphofructokinase (PFK-1) activity [5,
32, 37] . This would preserve glycolytic ATP production
that is essential for maintaining sarcoplasmic mem-
brane function, modulating intracellular protons [38,
39] , and prolonging cell survival of vital organs during
hypoxia [2, 40] . In the swine model of hemorrhagic
shock manifested lactic acidosis, the intravenous infu-
sion of Pyr further raised blood Lac levels, indicating
that the Pyr reduction occurred in cytosol, but lowered
the blood Lac/Pyr ratio and effi ciently avoided or cor-
rected lactic acidosis [6, 34, 41, 42] .
Accordingly, Pyr ‘systemic alkalization’ proposed
originally referred to this cytoplasmic reduction and the
mitochondrial oxidation of exogenous Pyr [34] . In this
respect, Pyr may also consume a proton in neutrophilic
cytosol with the reduction to Lac in addition to its weak-
er buffering capacity, both raising neutrophilic pHi [4] .
(2) By oxidizing into CO
2
and H
2
O via the TCA cycle
in mitochondria, Pyr anions also consume protons on an
equimolar basis (Pyr
–
:H
+
= 1: 1) as equation 4 shows:
oxidation) ATP, 15 ( OH 2 CO 3 O ½ 2 H
pyruvate
COCOOCH 22
cycle TCA
23
_

o
  ( 4)
As mentioned above, the exogenous Pyr consumes en-
dogenous protons stoichiometrically in both anaerobic
glycolysis and aerobic oxidation, raising pHi, and Pyr
does not release a proton as Lac does, but merely con-
sumes it in the oxidation. In addition, Pyr oxidizes with
a less oxygen consumption rate, compared with Lac.
(3) Supraphysiologic doses of exogenous Pyr would
greatly stimulate the activity of PDC although there has
been no data from human beings yet. It has been demon-
strated with various animal tissues in rat, rabbit, bovine
and swine that Pyr at several millimolars simultaneously
stimulated the PDC activity by inhibiting Pyr dehydro-
genase kinase in association with the improvement of car-
diac performance and cerebral and hepatic functions [6,
41–43] .
(4) Although Lac may replenish the TCA cycle by the
malate-aspartate shuttle, an anaplerotic pathway that
transfers Lac-reduced [NADH
2
]c to mitochondria [21] ,
it is with Pyr, other than Lac or other keto acids, that
anaplerosis via carboxylation can be carried out by PC to
oxaloacetate or by malic enzyme to malate. In a near
physiological condition, Pyr cardoxylation may account
for, in vivo, only 5% of the citrate formation in swine
hearts [44] . However, it may increase as many as 7 times
in perfused rat hearts [24] . The increased availability of
Pyr as a substrate and the PDC stimulation together with
enhanced anaplerotic pathways would greatly increase
the TCA cycle fl ux and accelerate the consumption of
protons and the ATP generation. In addition, anaplerosis
pathways, per se, fi x CO
2
in mitochondria. Importantly,
during acute acidosis Pyr may increase the CO
2
fi xation
in the mitochondria of liver and kidney [45] , which may
be of signifi cance in improving local hypercapnia in isch-
emic tissues.
(5) Gluconeogenesis is an energy-requiring process. It
consumes equivalently 3 high-energy phosphate bonds (2
ATP and 1 GTP) for 1 mol of glucose synthesized from
1 mol of Lac. However, the experimental evidence in pHi
within the rat hepatic lobule revealed that gluconeogen-
esis from Lac is a proton-consuming process [46] . Com-
pared with one proton consumed by every Lac anion in
Lac-based gluconeogenesis (equation 1), every Pyr anion
uses two protons in Pyr-based gluconeogenesis (Pyr
–
:H
+
= 1: 2). In the cytosolic process of gluconeogenesis, a pair
of [NADH + H
+
]c is required at the step of G-3-PD. It is
supplied by the Lac oxidation to Pyr in Lac-based gluco-
neogenesis, but is additionally consumed in Pyr-based
gluconeogenesis. Hence, Pyr-based gluconeogenesis in
liver and kidney would be of particular signifi cance in the
preservation of a near physiologic arterial pH (pHa) in
shock. In this regard, it was affi rmed with rat hepatic in-
tralobular mapping results that protons are consumed
stoichiometrically when weak acids are converted into
neutral products (glucose, CO
2
and H
2
O) [46] . The state-
ment may be the case of Lac, other than the case of Pyr
in terms of gluconeogenesis.
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As mentioned earlier, the entry of Lac or Pyr into cells
is carried by a proton-linked MCT family, which includes
seven isoforms in a range of mammalian cells. They ex-
hibit distinct cellular localization and have slightly differ-
ent properties. Isoforms act as Lac
–
/H
+
symport with a
1: 1 stoichiometry. In contrast to the MCT in human neu-
trophils, which has a similar affi nity for both Lac and Pyr
[5] , the isoforms of hepatocytes and cardiomyocytes in
rats have much higher Michaelis constant ( K m) values for
L-Lac than those for Pyr (4.7 and 2.74 m M vs. 1.3 and
0.2 m M ), respectively [47, 48] . Thus, Lac may more read-
ily induce a pHi decline than Pyr when high extracellular
concentrations of both are comparable in human vital
organs. On the other hand, Pyr has a weaker buffering
capacity due to the dissociation constant ( pK a) of 2.49,
compared with Lac pK a of 3.9 [4] . The weaker buffering
capacity usually results in a higher pH value. Owing to
these properties, equimolar doses of external Pyr and Lac
are not expected to result in equivalent pHi reductions in
human cells as shown in neutrophils [4] . In rat cardio-
myocytes, the property of MCT K m was also considered
in the Pyr effect on pHi [49] .
Based on its biochemical and biophysical characteris-
tics, Pyr may be valuable in the treatment of severe met-
abolic acidosis such as type A lactic acidosis, hypercapnia
with cardiac arrest, diabetic ketoacidosis and alcoholic
intoxication although no clinic data have been reported
yet. In theory, Pyr with insulin might be a more effi cient
regime in the correction of diabetic ketoacidosis mainly
due to their potential synergetic effects on the oxidation
of ketone bodies. Pyr in the regime might be also valuable
to restore the sensitivity of insulin receptors inhibited by
severe acidosis and reduce the insulin dosage to avoid
hypoglycemia. Moreover, because of its better consump-
tion of intracellular protons in the absence of the direct
production of CO
2
in hypoxia, Pyr might be also benefi -
cial in respiratory acidosis. However, these deductions
require experimental and clinical validations.
Pyruvate Superiority in the Correction of
Acidosis
Pyr and Lac in the Correction of Metabolic Acidosis
The effect of intravenous Pyr on acid-base balance was
compared with equimolar Lac in anesthetized dogs in late
1970s. Lac infusion was associated with a signifi cantly
slower rate of bicarbonate level rising in comparison with
Pyr, indicating that the additional metabolic steps are
required [50] . The oxidation of Lac-reduced [NADH
2
]c
may take place either in cytoplasm-coupled reactions as-
sociated with gluconeogenesis, or a mitochondrial route
in the presence of oxygen. In addition to the difference of
the proton consumption in gluconeogenesis processes be-
tween Pyr and Lac, the mitochondrial route is an indirect
pathway, which depends on the reducing equivalent of
carrier systems. The malate-aspartate shuttle is the major
step involved in transporting [NADH + H
+
]c into the mi-
tochondria in cells of heart, liver and kidney. The shuttle
operation is driven by the electrical potential across mi-
tochondrial membrane. Thus, the oxidation of Lac to Pyr
is an energy-dependent step and operates slowly (in min-
utes) in physiological conditions [51] . In perfused rabbit
cardiomyocytes, the pHi recovery was delayed by 12 min.
with Lac-added perfusates compared with Pyr-added
counterparts in the presence of DCA [10] . This rate-lim-
ited step, which would display while the [NADH
2
]c load
is increased, may be another interpretation of the retarda-
tion of pHi recovery in addition to the elevated proton
load, per se, from the Lac oxidation and the [NADH]c
increment [10] . Although the ratio of [NAD
+
/NADH]c
determines the balance between Pyr and Lac (equation
3), the reaction is in favor of the direction from Pyr to
Lac as the lesser rise in blood Pyr concentration with Lac
infusion than in blood Lac level with equal Pyr infusion
[50] . Several recent fi ndings evidently supported that Pyr
would be superior to Lac in the treatment of clinic meta-
bolic acidemia including lactic acidosis. In the rat perito-
neal dialysis model, preliminary results revealed that ure-
mic acidosis was better corrected and the functions of
peritoneal cells were more preserved with Pyr-buffered
dialysates than with Lac counterparts [J Am Soc Nephrol
Abstracts, 1998; 9: 236A; also Chin J Nephrol 2001; 17:
365–368]. Also, in the rat model of severe hemorrhagic
shock manifested lactic acidosis, commonly seen in a
clinical setting, the intravenous infusion of Pyr improved,
whereas Lac exacerbated, metabolic acidosis. Pyr Ring-
er’s solution resulted in a higher blood base excess level
and a lower blood Lac level, compared with Lac Ringer’s
counterparts [31] . The study also substantiated that Pyr,
in vivo, signifi cantly decreased the expression of apopto-
sis markers, whereas Lac increased the markers after re-
suscitation in rat lungs [31] as observed, in vitro, in hu-
man neutrophils and endothelial cells [5, 52] . Although
mechanisms of Pyr attenuation of apoptosis in shock re-
suscitation are not fully understood, it is well recognized
that acidosis may be a triggering factor [5, 53] . Studies in
hemorrhagic shock repeatedly confi rmed that Pyr effec-
tively prevented or corrected severe lactic acidosis in
swine [6, 34, 41, 42] . A human trial demonstrated that
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Pyruvate and Metabolic Acidosis
Correction
Am J Nephrol 2005;25:55–63 61
Pyr-fortifi ed cardioplegia solutions provided cardiopro-
tection superior to Lac-based counterparts during surgi-
cal cardiac arrest although pHi data were absent [54] .
These fi ndings strongly suggested that Pyr was preferable
in the correction of intracellular acidosis in both anaero-
bic and aerobic conditions.
In brief, because of the prevalence of LDH in mam-
malian cells, Pyr as an oxidant improves pHi and cellular
functions, which is opposite to the deleterious effects on
pHi and cytotoxic characteristics of Lac as a reductant in
molecular and cellular levels particularly in anaerobic
conditions. Meanwhile, due to the Lac oxidation to Pyr
with LDH, both of them also exhibit somewhat similar
metabolic and biological effects including the modulation
of pHi in aerobic conditions.
Pyr and Bicarbonate in the Treatment of Metabolic
Acidosis in Cardiogenic Shock and Dialysis
Bicarbonate as a natural buffer was not questioned in
the treatment of metabolic acidosis until two decades ago.
The bicarbonate corrects acidosis through chemical neu-
tralization, which depends on a fair respiratory function,
whereas Pyr exerts a metabolic titration of intracellular
acidosis without directly producing CO
2
. Bicarbonate of-
ten benefi ts patients with metabolic acidosis in the ab-
sence of tissue hypoxia (e.g., uremic, diarrheic, and renal
tubular acidosis). However, patients with cardiac arrest
or cardiogenic shock (or septic shock, hepatic failure and
diabetic ketoacidosis, etc.) usually have impaired tissue
oxygen delivery. In these circumstances, the primary
causes of acidosis result from the accumulation of lactic
acid, the proton release from ATP hydrolysis and the re-
tardation of local tissue CO
2
(‘metabolic’ hypercapnia).
And limited glycolytic ATP production may lead to a
progressive pHi decline to !
6.0 in cardiomyocytes [19,
53] . Bicarbonate administration in hypoxic states does
not correct the underlying tissue hypoxia and is generally
not successful in improving the acidosis or patients’ gen-
eral conditions. It usually results in severe adverse effects,
leading to the exacerbation of hypercapnia and lactic ac-
idosis and further decrease of tissue pHi in liver, brain,
skeletal muscle and red cells [19, 55] . In the presence of
high P
CO2
and high non-bicarbonate buffers in plasma,
bicarbonate, per se, would considerably decrease pHi al-
though pHa may increase due to the readily entrance of
CO
2
(but not -HCO
3
) into intracellular spaces [56] . Nev-
ertheless, severe acidosis (pHa ! 7.1) must be timely cor-
rected at any clinical circumstances although mild acido-
sis may be benefi cial. Without an ideal base in the clinic
setting, it is strongly recommended that the bicarbonate
infusion should be cautious in the management of cardio-
pulmonary arrest in order to maintain pHa in 7.10–7.20
after the airway is established [57] . Clinical evidence also
revealed that bicarbonate therapy provided little im-
provement of diabetic ketoacidosis and suggested that it
should not be used unless pHa is !
7.0 [19, 58] . On the
other hand, DCA, which stimulates the PDC activity by
directly inhibiting PDC kinase as one of Pyr actions and
corrects lactic acidosis as a specifi c agent, also can sig-
nifi cantly improve myocardial performance and acidosis
in hypoxia [14, 20] . In comparison, Pyr may be superior
to bicarbonate or DCA in the treatment of hypoxic aci-
dosis. Its unique metabolic and chemical characteristics
may be ideal for the correction of severe acidosis in car-
diogenic shock or hypercapnia with cardiac arrest as it
consumes protons and benefi ts in myocardium perfor-
mance without risking pHi deterioration in anaerobic
conditions. Further, Pyr protects cellular functions of
multiple cell lines and vital organs as a strong antioxidant.
It also inhibits infl ammation mediators (e.g., TNF-

, NF-

B and NO), improves Ca
2+
homeostasis, attenuates
apoptosis and preserves carbohydrates metabolic path-
ways in hyperglycemia and promotes lipid metabolism
[2, 3, 5, 6, 52] . Pyr as an intermediary metabolite of glu-
cose is also an energy-yielding substrate without any
known cytotoxicity. An intravenous Pyr loading test dem-
onstrated its safety in human subjects [59] .
In addition, Pyr might be also a promising buffer to
correct uremic acidosis in patients undergoing peritoneal
dialysis (PD), which markedly improves the biocompat-
ibility of PD solutions [5, 36] . It may effi ciently correct
chronic acidotic status in hemodialysis patients as well,
which is not satisfactorily treated at present [60] . Pyr as
one of the buffer components may decrease bicarbonate
or Lac concentrations in dialysis solutions, reduce oxida-
tive stress induced by high bicarbonate levels [61] and
Lac toxicity. It can also improve glucose and lipid me-
tabolism in dialysis patients particularly with cardiovas-
cular complications and diabetes. However, the instabil-
ity of sodium Pyr in aqueous solutions restricts its clinical
applications at the present time. It is well known that Pyr
in aqueous solutions rapidly undergoes an aldol-like con-
densation, forming parapyruvate to inhibit mitochondri-
al functions [62] . Efforts to overcome Pyr instability in
solutions creating Pyr therapeutic preparations suitable
for intravenous infusion and dialysis are urgently war-
ranted. Several clues point to a possibility.
In conclusion, Pyr as a novel generation of buffers
would be superior to conventional ones both in animal
experiments and in clinic settings, particularly in the
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Zhou
Am J Nephrol 2005;25:55–63
62
treatment of severe acidemia, which still lacks effective
agents to deal with at present. Intravenous administra-
tion of Pyr would not only correct both pHa and pHi and
acidotic symptoms, but also improve underlying cell dys-
functions to a large extent in critically ill patients with
heart, liver, kidney or brain disorders. Further evaluation
of Pyr effects on acid-base balance disorders and their
underlying mechanisms in both animals and clinical tri-
als is required. Attempts to create stable therapeutic prep-
arations of Pyr solutions are warranted.
Acknowledgements
The author is indebted to Dr. Z.D. Zhou at St. Joseph Medical
Center, Syracuse, N.Y. for his help in the improvement of the man-
uscript. The author also thanks the reviewers for their critical com-
ments.
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