ACKD

Adverse Effects of the Metabolic Acidosis of

Chronic Kidney Disease
Jeffrey A. Kraut and Nicolaos E. Madias

The kidney has the principal role in the maintenance of acid-base balance, and therefore, a fall in renal net acid excretion and
positive H1 balance often leading to reduced serum [HCO32] are observed in the course of CKD. This metabolic acidosis can
be associated with muscle wasting, development or exacerbation of bone disease, hypoalbuminemia, increased inflammation,
progression of CKD, protein malnutrition, alterations in insulin, leptin, and growth hormone, and increased mortality. Impor-
tantly, some of the adverse effects can be observed even in the absence of overt hypobicarbonatemia. Administration of
base decreases muscle wasting, improves bone disease, restores responsiveness to insulin, slows progression of CKD, and
possibly reduces mortality. Base is recommended when serum [HCO32] is ,22 mEq/L, but the target serum [HCO32] remains
unclear. Evidence that increments of serum [HCO32] .26 mEq/L might be associated with worsening of cardiovascular disease
adds complexity to treatment decisions. Further study of the mechanisms through which positive H1 balance in CKD contrib-
utes to its various adverse effects and the pathways involved in mediating the benefits and complications of base therapy is
warranted.
Q 2017 by the National Kidney Foundation, Inc. All rights reserved.
Keywords: Metabolic acidosis, CKD, Bicarbonate, Bone disease, Progression of chronic kidney disease, Muscle wasting

INTRODUCTION Sarcopenia is found at all stages of CKD, but its prevalence

The most common cause of chronic metabolic acidosis is
CKD.1 This form of metabolic acidosis develops as net
acid excretion falls below net endogenous acid production
causing acid retention. The retained acid appears to accu-
mulate in interstitial and intracellular compartments of
various tissues increasing their acidity; when sufficiently
large, it also causes a detectable fall in serum [HCO32]
and systemic pH.2 The phase when acid retention is pre-
sent in the absence of a detectable fall in serum [HCO32]
has been termed subclinical or eubicarbonatemic meta-
bolic acidosis. Importantly, even subclinical metabolic
acidosis can impair the function of several organ systems.1
In the present review, we describe the nature of the
cellular dysfunction engendered by the metabolic acidosis
of CKD, its pathogenesis, and the impact of base treatment.
CELLULAR DYSFUNCTION
Although the cellular dysfunction caused by the metabolic
acidosis of CKD is similar to that found with other chronic
acidoses, CKD itself can potentially modify the cellular
response to acidosis. For example, CKD is associated
with abnormalities of parathyroid hormone (PTH) and in-
sulin secretion, which will impact changes in these hor-
mones driven by metabolic acidosis.1
The adverse effects of cellular function can take time to
appear even if factors responsible for initiating damage
are present soon after induction of metabolic acidosis. For
example, processes promoting bone dissolution are acti-
vated promptly although overt bone disease might not be
detectable for months or years.3 Also, factors that can injure
the kidney, such as increments of pro-inflammatory cyto-
kines, are present early,4 but fibrosis and a permanent
reduction in glomerular filtration rate take time to occur.
The metabolic acidosis of CKD is associated with
dysfunction of several organ systems as described subse-
quently.
Muscle Wasting
A loss of muscle mass or sarcopenia in CKD contributes to
adoption of a sedentary lifestyle and increased mortality.5
increases as GFR falls.6,7 Thus, in the third National Health
and Nutrition Examination Survey (NHANES III), the
percentage of individuals with a normal skeletal mass
index fell from 61% at a GFR of 60 to 89 mL/min/1.73 m2
to 39.9% at a GFR ,60 mL/min/1.73 m2.7 Metabolic
acidosis has been implicated as an important factor
contributing to the reduced muscle mass.8,9 The
NHANES III data revealed that individuals with a serum
[HCO32] ,23 mEq/L had slower gait speed and
decreased quadriceps strength10 and young adults with
lower serum [HCO32] had lower cardiorespiratory
fitness.11
Furthermore, administration of base to pre-dialysis pa-
tients with CKD or those with ESRD treated with chronic
hemodialysis or peritoneal dialysis increased lean body
mass, improved muscle strength, improved dietary pro-
tein intake, reduced protein catabolic rate, and increased
serum albumin levels.12-15
Muscle wasting is characterized by increased muscle
turnover rate and atrophy of type II muscle fibers. It is
associated with increased muscle protein degradation
without a change in muscle protein synthesis.16-18 The
mechanisms underlying muscle wasting are summarized
in Figure 1. The degradation of muscle protein appears
to be mediated by upregulation of the ubiquitin-
proteasome pathway19 and the caspase-3 protease.20
From Medical and Research Services VHAGLA Healthcare System, UCLA
Membrane Biology Laboratory and Division of Nephrology VHAGLA Health-
care System and David Geffen School of Medicine, Los Angeles, CA; and Divi-
sion of Nephrology, Department of Medicine, St. Elizabeth’s Medical Center and
Department of Medicine, Tufts University School of Medicine, Boston, MA.
Financial Disclosure: See Acknowledgment(s) on page 295.
Address correspondence to Nicolaos E. Madias, MD, Division of
Nephrology, St. Elizabeth’s Medical Center, 736 Cambridge Street, Boston,
MA 02135. E-mail: nicolaos.madias@steward.org
Ó 2017 by the National Kidney Foundation, Inc. All rights reserved.
1548-5595/$36.00
http://dx.doi.org/10.1053/j.ackd.2017.06.005

Adv Chronic Kidney Dis. 2017;24(5):289-297 289

290 Kraut and Madias

Impaired insulin-like growth factor 1 (IGF-1) signaling,20 develop osteomalacia.35 A retrospective examination of
increased levels of glucocorticoids,21,22 and increased acid-base parameters in patients with CKD revealed that
inflammation are considered important in activation of those with a normal bone biopsy had a serum [HCO32]
the ubiquitin-proteasome pathway.23 close to normal (24-26 mEq/L), whereas those with bone
A reduction in systemic or intracellular pH contributes to disease had mild-to-moderate acidosis.36 Chronic hemodi-
increased glucocorticoid secretion, but a reduction in inter- alysis patients with a pre-dialysis serum [HCO32] ,21
stitial pH seems to be integral to muscle wasting.20,24 mEq/L had a higher incidence of bone fractures,37 suggest-
Indeed, H1 retention in paraspinal muscles has been ing that the metabolic acidosis contributes to brittleness of
observed via microdialysis in rats with CKD and a bone. Correction of metabolic acidosis results in healing of
presumed reduction in interstitial pH even in the bone lesions in patients with distal RTA35 and prevention
absence of a detectable fall in serum [HCO32].25,26 Also, of progression of kidney osteodystrophy in hemodialysis
administration of base to postmenopausal women with a patients.38
normal serum [HCO32] reduces urinary nitrogen Subclinical metabolic acidosis might also have injurious
excretion consistent with less muscle protein effects on bone. Feeding of an acid-producing diet to
breakdown.27 These findings suggest that accumulation two-third nephrectomized rats is associated with bone
of acid in interstitial compartments before a fall in serum injury (as shown by an increase in urine deoxypyridinoline
[HCO32] can induce muscle damage. excretion) in the absence of a reduction in serum
[HCO32].39 Also, administration of base to postmeno-
Hypoalbuminemia pausal women with a normal serum [HCO32] was associ-
Decreased albumin synthe- ated with biochemical
sis has been found with evidence of bone accretion.40
metabolic acidosis induced CLINICAL SUMMARY The mechanisms underly-
by 7, but not 2, days of ing the adverse effect of
NH4Cl feeding.28,29 The  The metabolic acidosis of chronic kidney disease can metabolic acidosis on bone
explanation for the produce or worsen bone disease, contribute to are summarized in Figure 2.
divergent results is not progression of chronic kidney disease, produce muscle In vitro studies showed that
clear, but since the wasting, induce inflammation, contribute to protein an acidic milieu causes disso-
metabolic acidosis of CKD malnutrition and development of hypoalbuminemia, and lution of bone mineral
is months to years in increase mortality.
directly, activates osteo-
duration, the findings in  Some of these adverse effects, particularly progression of clasts, and inhibits osteoblast
patients with more chronic kidney disease, muscle wasting, and exacerbation function.3,41,42 These effects
prolonged acidosis seem of bone disease, can be observed even in the absence of have been linked to
more relevant. hypobicarbonatemia. activation of the ovarian
Analysis of the NHANES cancer G-protein-coupled
 Retention of acid in the interstitial tissues leading to an
III data in patients with increase in the acidity of this compartment is a major receptor 1 (OGR-1)43 and
CKD revealed that a serum factor in the progression of chronic kidney disease and the transient receptor poten-
[HCO32] ,22 mEq/L was perhaps other adverse effects. tial cation channel subfamily
associated with hypoalbu- V member 1 (TRPV1),44 2
minemia (adjusted odds  Administration of base decreases muscle wasting,
improves bone disease and augments growth in children, proton-sensing receptors or
ratio of 1.54).30 Also, admin- channels.
and slows progression of chronic kidney disease.
istration of base to individ- In animal studies, meta-
uals with CKD (creatinine bolic acidosis is associated
clearance 15-30 mL/min/ with increased PTH secre-
1.73 m2) and metabolic acidosis (serum [HCO32] 16-20 tion but blunting of the cAMP response to PTH.45 A
mEq/L) led to an increase in serum albumin and lean reduced concentration of 1,25-dihydroxyvitamin D caused
body mass.12 Thus, although proteinuria and inflamma- by acidosis is an attractive inciting event, but serum con-
tion (which enhances proteolysis and increases anorexia) centrations of 1,25-dihydroxyvitamin D measured in hu-
are major contributors to hypoalbuminemia in CKD, mans with acidosis have not been consistently
improvement in acid-base balance will aid in optimizing decreased.35,46
albumin synthesis. Fibroblast growth factor 23 (FGF23) induces phospha-
turia, reduces systemic 1,25-dihydroxyvitamin D produc-
Bone Disease tion, and inhibits PTH secretion.47 In vitro studies
Bone disease in patients with CKD is primarily attributed showed metabolic acidosis increases the FGF23 concentra-
to abnormalities of vitamin D metabolism and excess PTH tion and RNA expression in mouse bone,48 yet correction
secretion,31 but metabolic acidosis can also induce or exac- of metabolic acidosis in humans with CKD increases
erbate bone disease.3,31,32 serum FG23 concentration.47 Thus, a possible role of
Animal studies showed a correlation between metabolic FG23 in the development of bone disease associated with
acidosis induced by NH4Cl and development of osteopo- metabolic acidosis remains to be clarified.
rosis and osteomalacia.33,34 In humans, approximately Children with distal RTA had a lower mean height and
20% of patients with distal renal tubular acidosis (RTA) greater incidence of short stature than normal controls49

Adv Chronic Kidney Dis. 2017;24(5):289-297

 Adverse Effects of the Metabolic Acidosis of CKD 291

Glomerular FiltraƟon Rate

H+ RetenƟon

Muscle
le pH
H Systemic pH GlucocorƟcoids

Pro- AcƟvaƟon of UbiquiƟn- Caspace-3 Insulin/IGF-1

inflammatory Proteasome Pathway Proteolysis Signaling
Cytokines

Muscle Protein
DegradaƟon

Muscle
l WasƟng

Figure 1. Putative mechanisms whereby metabolic acidosis contributes to muscle wasting in CKD. Acid retention leads to
increase in the acidity of the interstitial compartment of muscle (muscle pH). In addition, the acid retention can lead to an in-
crease in systemic pH, which increases glucocorticoid secretion. The combination of both factors results in impaired insulin
signaling, activation of the ubiquitin-proteasome pathway, and activation of caspace-3 proteolysis. An increase in systemic
pH might also stimulate secretion of pro-inflammatory cytokines by macrophages, which can contribute to muscle wasting.
The increased muscle protein degradation resulting from these processes adds to muscle wasting caused by other factors
associated with CKD.

and correction of the acidosis strikingly enhances vertical
growth.50 In children with CKD, correction of metabolic
acidosis has less impact on growth because additional fac-
tors play an important role.51
Acceleration of Progression of CKD
Experimental studies in animals indicated that metabolic
acidosis promotes progression of CKD25,52,53 and limited
interventional data in humans support that conclusion.12,54
Large observational studies in humans are in accord with
the acceleration of progression of CKD by metabolic
acidosis. In a study of .5000 individuals followed for a
median of 3.4 years, a serum [HCO32] ,22 mEq/L was
associated with acceleration of progression of CKD.55 In
the 3500 patients of the Chronic Renal Insufficiency
Cohort, those who maintained a serum [HCO32] ,22
mEq/L had almost a 2-fold increased risk of CKD progres-
sion.56 In 2 studies involving .1000 CKD patients each,
subjects with a higher serum [HCO32], even though within
the normal range, had a higher GFR and a lower incidence
of ESRD.57,58 In the Multi-Ethnic Study of Atherosclerosis,
a lower serum [HCO32] was associated with a more rapid
decline in GFR.59 Furthermore, in a study of individuals 70
to 79 years of age, those with a serum [HCO32] ,23 mEq/L
had a nearly 2-fold greater odds of a decrease in GFR to
,60 mL/min/1.73 m2 independent of the baseline
eGFR.60 In the NephroTest Cohort study, a lower serum to-
tal CO2 was associated with a more rapid decline in GFR61
and in the Atherosclerosis Risk in Communities Study, in-
dividuals with a higher estimated dietary acid load had a
higher incident CKD after 21 years of follow-up.62
Most important, base administration to animals and hu-
mans with evidence of acid retention, both in the presence
and absence of hypobicarbonatemia, slowed the progres-
sion of CKD.2,12,24,63-66 Thus, metabolic acidosis is
associated with kidney fibrosis and acceleration of the
progression of CKD, which can be slowed by
administration of base.
The potential mechanisms through which acid retention
promotes acceleration of the progression of CKD are sum-
marized in Figure 3. An increase in kidney tissue levels of
aldosterone,24 endothelin,24,67 and angiotensin II68 has
been reported in both animals and humans with acid
retention associated with CKD. Each of these hormones
not only stimulates renal acidification tending to lessen
acid retention but also promotes fibrosis, a final common
pathway for renal destruction. Also, correction of the
acidosis causes a decrease in the levels of these hormones
and slowing of the decline in GFR in both animals and hu-
mans.54,64,66,68,69 Although not proved, attachment of
protons to an extracellular receptor in the kidney,
possibly GPR4,70 is postulated to be a possible link be-
tween acid retention and stimulation of hormone release.
An increment in ammonia production leading to an in-
crease in net acid excretion is an important adaptive mech-
anism of the kidney in response to acid retention. In CKD,
ammonia production per residual nephron increases
markedly even if urinary ammonia excretion decreases

Adv Chronic Kidney Dis. 2017;24(5):289-297

292 Kraut and Madias

Glomerular filtraƟon
fil rate

H+ retenƟon
t

pH of IntersƟƟal Systemic pH IIntracellular

t ll pH of
Fluid of Bone Osteoclasts and Osteoblasts

PTH AcƟvaƟon of OGR-1 and TRPV1 1,25-Vitamin D ?

DissoluƟon
uƟo of Bone Bone FormaƟon Cell-Mediated
di Bone
Mineral ResorpƟon

Osteomalacia
O OsteiƟs Fibrosa CysƟca
O

Figure 2. Putative mechanisms whereby metabolic acidosis contributes to bone disease in CKD. Retention of H1 in CKD
leads to reduction in systemic pH and the pH of the interstitial fluid of bone, and possibly a fall in the intracellular pH of os-
teoclasts and osteoblasts. The increased acidity of the bone matrix causes dissolution of bone mineral (physicochemical buff-
ering). Cell-mediated bone resorption is also increased, although the precise signal is unclear. Activation of the ovarian cancer
G-protein-coupled receptor 1 (OGR-1) and possibly the transient receptor potential cation channel subfamily V member 1
(TRPV1) has been suggested as mediator of both increased bone resorption by osteoclasts and decreased bone formation
by osteoblasts. Increases in PTH secretion and decreases in 1, 25-dihydroxyvitamin D production have been found in
some studies but not others. Changes in these hormones produced by increased acidity are less prominent than those found
in CKD. The destruction of bone by these processes contributes to the development of osteomalacia and osteitis fibrosa cyst-
ica. The bone disease will be modified by factors altered by a reduction in GFR independent of changes in acidity.

progressively. The increased ammonia production in
the injured kidney is associated with activation of comple-
ment and an inflammatory cascade resulting in kidney
fibrosis.52 Based on this thesis, one might speculate that
progression of CKD would be more rapid in patients
who have the highest level of ammonia production per re-
sidual nephron, such as those with a higher dietary acid
load; these patients would be expected to have increased
acid retention and eventually decreased serum [HCO32]
levels. A lower urinary ammonia excretion and, thus,
increased acid retention is associated with a higher risk
of ESRD; further, a lower urinary ammonia excretion
and a lower plasma total CO2 are associated with a faster
rate of GFR decline.61 Finally, cell culture studies demon-
strate that exposure of kidney tubular cells to an acidic
milieu for 24 hours stimulates renal production of certain
pro-inflammatory cytokines and chemokines,4 an addi-
tional mechanism whereby metabolic acidosis can cause
kidney injury.
Glucose Tolerance
Experimentally produced metabolic acidosis is associated
with glucose intolerance.71 Potential mechanisms underly-
ing this effect include decreased binding of insulin to its
cognate receptor by the acidic environment72 and interfer-
ence with insulin-induced intracellular signaling by sup-
pression of PI3K activity in muscle.20
Despite reduced renal metabolism of insulin and, there-
fore, potentially higher serum concentrations of this hor-
mone in patients with CKD, metabolic acidosis can
impair glucose tolerance.73-75 In a small number of
patients with advanced CKD (mean GFR 17 6 1 mL/
min/1.73 m2) and metabolic acidosis, insulin sensitivity
was blunted compared with controls with a normal
GFR and serum [HCO32].73 Furthermore, in subjects
with type II diabetes and CKD (GFR of 32-35 mL/min)
and metabolic acidosis (mean serum [HCO32] of
21.4 mEq/L), normalization of serum [HCO32] lowered in-
sulin levels and reduced the need for oral antidiabetic
medications.76 Also, in nondiabetic patients with various
stages of CKD, insulin resistance was present that was
correlated with the severity of metabolic acidosis.74
Dialysis patients with metabolic acidosis manifested
greater insulin resistance during a constant insulin infu-
sion and had lower insulin secretion during constant hy-
perglycemia compared with controls without CKD or
metabolic acidosis.77 Correction of the acidosis by
administration of bicarbonate improved insulin resis-
tance and glucose tolerance.77 Thus, metabolic acidosis
increases insulin resistance in both diabetic and

Adv Chronic Kidney Dis. 2017;24(5):289-297

 Adverse Effects of the Metabolic Acidosis of CKD 293

Glomerular FiltraƟon Rate

H+ RetenƟon
t

pH of IntersƟƟal IIntracellular
t ll pH of
Fluid of Kidney Renal Tubular Cells

Angiotensin
t II Pro-inflammatory
fl NH3 with
Endothelin
th Cytokines AcƟvaƟon of
Aldosterone and Chemokines Complement

IIntersƟƟal
t ƟƟ Ɵ l Fibrosis
Fib i

Progression
i of CKD

Figure 3. Putative factors induced by H1 retention that produce renal injury and accelerate progression of CKD. Acidosis in-
creases the production of aldosterone, angiotensin II, and endothelin, factors involved in promoting renal injury and fibrosis.
Metabolic acidosis is also associated with increased renal ammonia production. This process activates complement leading
to injury and fibrosis. Finally, exposure to an acidic environment stimulates various pro-inflammatory cytokines, which also
could lead to renal injury and fibrosis. Reprinted with permission from Kraut and Madias,1 Am J Kidney Dis. 2016; 67(2):311,
Figure 1.

nondiabetic patients and affects glucose regulation in
patients with CKD.
b2-Microglobulin Accumulation
In individuals with normal kidney function, metabolic
acidosis causes an increase in b2-microglobulin mRNA
expression in isolated lymphocytes.78 In studies of non-
dialysis-dependent individuals with CKD78 and in
some,78 but not all studies of dialysis patients,79 there
was an inverse correlation between b2-microglobulin
levels and serum [HCO32]. Also, raising plasma
[HCO32] in dialysis patients produced a fall in b2-micro-
globulin levels.78 In a human myeloid cell line (U 937)
exposed to an acidic pH, the cell surface expression of
b2-microglobulin was decreased and its release to the me-
dia was enhanced.
The results suggest that metabolic acidosis enhances
both cellular b2-microglobulin generation and release
from cells into surrounding tissues,78 thereby making
CKD patients more susceptible to deposition of amyloid
in various tissues.
acid load in both children and adults with normal kidney
function has been associated with increased risk of hyper-
tension in some studies,80 but not others.81 Presumably,
patients with CKD ingesting a higher dietary acid load
might have acid retention even without overt metabolic
acidosis, and this could activate mechanisms contributing
to development of hypertension.82 Also, individuals with
a higher serum [HCO32], albeit in the normal range, had
lower systolic blood pressures57 and a lower prevalence
of hypertension in nonobese adult women.83 These obser-
vations are consistent with the thesis that increased tissue
acidity contributes to the development of hypertension.
One intriguing mechanism by which acidity could affect
blood pressure regulation is through stimulation of the
proton receptor GPR4 in blood vessels. Knockout of
GPR4 in mice was associated with lower systolic blood
pressure and lower binding of angiotensin II to its receptor
in the subfornical organ; thus, this acid sensor might be
involved in blood pressure regulation by affecting activa-
tion of the renin-angiotensin system in the central nervous
system.84

Hypertension Growth Hormone, IGF-1, Leptin, and Thyroid

Hypertension in patients with CKD is primarily attributed
to sodium retention, activation of the renin-angiotensin
system, and stimulation of the sympathetic nervous sys-
tem. It has been suggested that metabolic acidosis might
contribute to the genesis of hypertension although only in-
direct data support this association. An increased dietary
Hormone
Alterations in the concentration or responsiveness to
several critical hormones that affect the basal metabolic
rate, energy consumption, lean body mass, and nutritional
status, such as growth hormone, IGF-1, leptin, and thyroid
hormone, have been described in metabolic acidosis. In

Adv Chronic Kidney Dis. 2017;24(5):289-297

294 Kraut and Madias
animals with metabolic acidosis, growth hormone secre-
tion was blunted in men but not women.85 In humans,
metabolic acidosis was associated with decreased free
serum IGF-1 concentrations, a blunted IGF-l response to
administration of pharmacologic doses of growth hor-
mone, and an exaggerated increase in serum growth hor-
mone concentration in response to growth hormone-
releasing factor administration. The latter finding indi-
cates the loss of normal feedback inhibition of pituitary
growth hormone secretion with acidosis is presumed to
be due in part to the reduced levels of IGF-1.86 In dialysis
patients, correction of metabolic acidosis improved the
IGF-1 responsiveness to growth hormone administration,
similar to the findings in humans with normal kidney
function and experimentally produced metabolic
acidosis.86,87 These findings suggest that metabolic
acidosis contributes to some of the nutritional
abnormalities observed with CKD through its impact on
the growth hormone-IGF-1 axis.
The adipocyte hormone leptin communicates the body’s
nutritional status to regulatory centers in the brain to
inhibit appetite, increase energy expenditure, and reduce
fat stores. Increased leptin levels observed with CKD are
associated with increased energy expenditure, a decrease
in appetite, and increased cardiovascular risk.88 The levels
of leptin are affected by metabolic acidosis.89 Leptin secre-
tion from cultured adipocytes was reduced by exposure to
an acidic pH and serum levels of the hormone were
reduced in acidotic rats with CKD compared with those
in whom the acidosis was corrected.90 In patients with
CKD, correction of metabolic acidosis caused an increase
in serum leptin levels.91 In contrast, correction of metabolic
acidosis in dialysis patients led to a decrease in serum lep-
tin levels.88 Given the inconsistency of the data, larger in-
terventional studies will be necessary to elucidate the
interaction between metabolic acidosis and leptin and
the impact of these changes on the nutritional status of pa-
tients with CKD, before and after initiation of chronic he-
modialysis.92
Induction of metabolic acidosis in normal humans causes
reduced T3 and T4 levels and elevated thyroid-stimulating
hormone levels, findings consistent with hypothyroid-
ism.93 In patients with CKD or ESRD maintained on
chronic hemodialysis, there is low plasma T3 and T4 levels
with normal thyroid-stimulating hormone and blunted
response to TRH.94 Correction of the metabolic acidosis
alone raised the free T3, free T4, and total T3 levels.87,95
Stimulation of Inflammation
An acidic milieu causes increased release of pro-
inflammatory cytokines from macrophages96 and from
kidney tubular cells in culture.4 Lower extracellular pH
also appeared to increase neutrophil production and
delay neutrophil apoptosis.97 These in vitro findings sug-
gest that metabolic acidosis might be associated with
enhancement of inflammation. Additional studies have
shown that lower extracellular pH activates other compo-
nents of the immune system, including dendritic cells98
and the complement system.99 Indeed, in the NHANES
III study, a serum [HCO32] ,22.9 6 0.2 mEq/L was asso-
ciated with increased C-reactive protein and leukocyte
count, two biomarkers of inflammation.97 In the Chronic
Renal Insufficiency Cohort study, biomarkers of inflam-
mation, such as IL-1b, IL-1 receptor antagonist (IL-1ra),
IL-6, tumor necrosis factor-a (TNFa), C-reactive protein,
and fibrinogen, were higher at lower GFR, although a
specific link with acidosis was not examined.100 Partial
correction of metabolic acidosis in patients with CKD
stages 4 and 5 led to a fall in the monocyte secretion of
the anti-inflammatory cytokine IL-10 but no significant
change in the secretion of other pro-inflammatory and
anti-inflammatory cytokines, including IL-1b, IL-2, IL-6,
TNFa, IFNg, and IL-1ra.23 In hemodialysis patients
with metabolic acidosis, there was lower secretion from
peripheral monocytes of the anti-inflammatory cytokine
IL-10 but not of the pro-inflammatory cytokine IL-6 or
other cytokines.101
Taken together, studies of CKD patients confirm meta-
bolic acidosis is associated with an inflammatory state
and that correction of the acidosis can lessen the degree
of inflammation. The chronic state of inflammation is an
important contributor to protein energy malnutrition
and the increased rate of atherosclerotic cardiovascular
disease in the CKD population.102 Some investigators
believe that the malnutrition-inflammation complex is
the strongest predictor of mortality and poor outcome in
maintenance dialysis patients.92
Increased Mortality
Given the potential effects of metabolic acidosis to induce
inflammation and to negatively impact the nutritional sta-
tus of the patient, it might be expected that it would affect
the mortality of patients with CKD.103 Indeed, examina-
tion of a CKD registry at the Cleveland Clinic including
more than 41,000 patients showed that patients with stage
3 CKD experienced increased mortality when serum
[HCO32] was ,23 mEq/L.104 Furthermore, analysis of
both the MDRD database and the NHANES III database
revealed that a serum [HCO32] ,22 mEq/L in patients
with CKD (GFR , 60 mL/min/1.73 m2) was also associated
with increased mortality. Strikingly, the hazard of death
was increased by 2.6-fold in the NHANES study.103
In a cohort of healthy older individuals, mortality was
increased with lower serum [HCO32] independent of the
presence of CKD.105 Similar findings were described in a
large group of veterans with moderate and advanced
non-dialysis-dependent CKD.57 Higher mortality was
observed with baseline serum [HCO32] ,22 mEq/L. Inter-
estingly, lowest mortality was observed with baseline
serum [HCO32] between 26 and 29 mEq/L. In both hemo-
dialysis106 and peritoneal dialysis patients,107 a low serum
[HCO32] is predictive of increased mortality. A serum
[HCO32] ,19 mEq/L was associated with increased mor-
tality and a value .22 mEq/L was considered optimal.
Although there is a strong relationship between a low-
serum [HCO32] and poor clinical outcome, only limited
data on the impact of alkali therapy on mortality are avail-
able. In a prospective observational study of 591 patients
who started dialysis (491 hemodialysis and 100 peritoneal
dialysis) previously monitored in the CKD clinic,
Adv Chronic Kidney Dis. 2017;24(5):289-297
 Adverse Effects of the Metabolic Acidosis of CKD
correction of metabolic acidosis before initiation of dialysis
was one of the major factors associated with a reduction in
mortality within the first 15 to 50 months of dialysis treat-
ment.108 Given the limitations of this study, randomized
controlled studies to examine this issue are warranted.
A possible mechanism for the beneficial effects of base
therapy on mortality was suggested by evidence that
correction of acidosis in patients with CKD reduced the
QTc interval measured on surface electrocardiogram,
thereby potentially reducing the risk of cardiac arrhyth-
mias, a major cause of death in this population.109 Also,
base administration improves protein-energy malnutri-
tion theoretically lessening the impact of this factor on
mortality.110 Finally given that inflammation is postulated
to contribute to development of ischemic heart disease,
lessening of inflammation by correction of acidosis could
also lower the burden of ischemic heart disease.
CONCLUSIONS AND FUTURE DIRECTIONS
In patients with CKD, metabolic acidosis leads to dysfunc-
tion of several organ systems and increased mortality.
Although several mechanisms underlying abnormalities
of the various organ systems have been uncovered, further
investigation might reveal additional factors that could be
involved. Such development could be important as pre-
sent treatment options are restricted to reducing acid gen-
eration or administering base. Delineation of pathways or
proteins that could be selectively targeted might provide
other treatment options, as has been suggested for treat-
ment of acute metabolic acidosis.111
ACKNOWLEDGMENTS
This work was supported in part by funds from the Veterans
administration (J.A.K.) and the UCLA Academic Senate (J.A.K.).
Financial Disclosure: The authors declare that they have no
relevant financial interests.
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