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Acid-Base and Electrolyte Teaching Case

Approach to the Treatment of Chronic Metabolic Acidosis in CKD


Kalani L. Raphael, MD, MS

Chronic metabolic acidosis is not uncommon in patients with chronic kidney disease (CKD). Clinical practice
guidelines suggest that clinicians administer alkali to maintain serum bicarbonate level at a minimum of 22
mEq/L to prevent the effects of acidosis on bone demineralization and protein catabolism. Small interventional
studies support the notion that correcting acidosis slows CKD progression as well. Furthermore, alkaline
therapy in persons with CKD and normal bicarbonate levels may also preserve kidney function. Observational
studies suggest that targeting a serum bicarbonate level near 28 mEq/L may improve clinical outcomes above
and beyond targeting a value $ 22 mEq/L, yet values . 26 mEq/L have been reported to be associated with
incident heart failure and mortality in the CRIC (Chronic Renal Insufficiency Cohort) Study. Furthermore,
correcting acidosis may provoke vascular calcification. This teaching case discusses several uncertainties
regarding the management of acidosis in CKD, such as when to initiate alkali treatment, potential side effects
of alkali, and the optimum serum bicarbonate level based on current evidence in CKD. Suggestions regarding
the maximum sodium bicarbonate dose to administer to patients with CKD to achieve the target serum bi-
carbonate concentration are offered.
Am J Kidney Dis. 67(4):696-702. 2016 by the National Kidney Foundation, Inc.

INDEX WORDS: Chronic metabolic acidosis; chronic kidney disease (CKD); sodium bicarbonate; oral alkali;
alkaline therapy; alkalinizing agent; serum bicarbonate; renal function.

Note from Feature Editor Jeffrey A. Kraut, MD: This article is


NKF-KDOQI (National Kidney FoundationKidney
part of a series of invited case discussions highlighting either Disease Outcomes Quality Initiative) to recommend
the diagnosis or treatment of acid-base and electrolyte maintaining serum bicarbonate concentration at $22
disorders. mEq/L using oral alkali in CKD.5,6 Since then, 2 small
open-labeled interventional studies found that cor-
recting metabolic acidosis with alkali improved kidney
INTRODUCTION measures7,8 and nutritional status7 in CKD. de Brito-
Chronic metabolic acidosis is not uncommon in Ashurst et al7 randomly assigned 134 participants
chronic kidney disease (CKD). Although renal tubular with CKD stage 4 or 5 and serum bicarbonate con-
acidosis and gastrointestinal bicarbonate loss cause centrations of 17 to 19 mEq/L to either sodium bicar-
metabolic acidosis, CKD is the most common culprit in bonate or usual care. The sodium bicarbonate group
the outpatient setting. In CKD, metabolic acidosis is had a slower creatinine clearance decline and remark-
usually diagnosed when serum bicarbonate concen- ably lower risk for end-stage renal disease after 2 years
tration is ,22 mEq/L over weeks to months. The of follow-up (Table 1).7 Phisitkul et al8 compared in-
prevalence of metabolic acidosis in nondialysis- dividuals with an estimated glomerular ltration rate
requiring CKD is w15%, and the prevalence increases (eGFR) of 20 to ,60 mL/min/1.73 m2 and bicarbonate
as CKD advances.1,2 For example, in the CRIC level , 22 mEq/L who were prescribed oral sodium
(Chronic Renal Insufciency Cohort) Study, 7%, 13%, citrate with similar patients who received no alkali.
and 37% of participants with CKD stages 2, 3, and 4, After 2 years of follow-up, the sodium-citrate group
respectively, had metabolic acidosis at baseline.2 The had higher eGFRs by cystatin C level and lower
adverse consequences of metabolic acidosis on bone albuminuria compared to the control group despite
demineralization3 and protein catabolism4 prompted having similar values of each at baseline (Table 1).8
These ndings add weight to the KDOQI recom-
mendation, although it is important to conrm them in
From the Salt Lake City Veterans Affairs Healthcare System large clinical trials. Table 1 presents completed and
and Department of Internal Medicine, University of Utah, Salt
Lake City, UT. ongoing interventional alkali trials in patients with
Received August 21, 2015. Accepted in revised form December CKD. In the meantime, it is reasonable to treat
14, 2015. Originally published online January 6, 2016. metabolic acidosis with oral alkali to increase serum
Address correspondence to Kalani L. Raphael, MD, MS, 85 N bicarbonate concentrations to $22 mEq/L. However,
Medical Dr E, Salt Lake City, UT 84112. E-mail: kalani.raphael@ observational data suggest that a higher bicarbonate
hsc.utah.edu
 2016 by the National Kidney Foundation, Inc. concentration target might be better in CKD. Whether
0272-6386 increasing bicarbonate concentration to a higher level
http://dx.doi.org/10.1053/j.ajkd.2015.12.016 is safe and effective is unknown. A representative

696 Am J Kidney Dis. 2016;67(4):696-702


Chronic Metabolic Acidosis

Table 1. Completed and Ongoing Trials of Alkaline Therapy in CKD

HCO32
at Entry, Duration of
Study Key Entry Criteria mEq/L N Intervention & Dose Follow-up Outcomes

Completed
deBrito-Ashurst CKD stage 4/5 17-19 134 NaHCO3 titrated to achieve 2y Lesser eGFR decline (21.88 vs
et al7 HCO32 $23 mEq/L vs 25.93 mL/min/1.73 m2);
usual care lower relative risk for ESRD
(0.13; 95% CI, 0.04-0.40)
Phisitkul et al8 eGFR, 20-60 mL/min/ ,22 59 NaCitrate, 1 mEq/kg/d, vs 2y Lesser eGFR decline (23.6 vs
1.73 m2, HTN usual care 28.7 mL/min/1.73 m2)
Mahajan et al18 CKD stage 2, HTN, NA 120 NaHCO3, 0.5 mEq/kg/d, vs 5y Lesser eGFR decline (26.8 vs
urinary ACR equimolar NaCl vs 210.8 vs 212.7 mL/min/
$300 mg/mg placebo 1.73 m2)
Ongoing
SoBic24 CKD stage 3/4 ,21 200 Enteric-coated NaHCO3 2y eGFR, bone turnover markers,
titrated to achieve death, RRT
HCO32 of 24 6 1 vs
20 6 1 mEq/L (anticipated
max dose 5,040 mg/d)
BiCARB25 CKD stage 4/5, age ,22 380 NaHCO3 titrated to achieve 2y Short Physical Performance
$60 y HCO32 $22 mEq/L vs Battery, muscle strength,
placebo (max dose, quality of life, kidney function,
3,000 mg/d) bone turnover markers
UBI26 CKD stage 3b/4 $18 600 NaHCO3 titrated to achieve 3y eGFR, mortality, RRT, bone
HCO32 24-28 mEq/L vs metabolism
usual care (max dose,
4,000 mg/d)
Alkali therapy eGFR, 15-45 mL/min/ 20-26 150 NaHCO3, 0.4 mEq/kg/d, vs 2y Insulin resistance, sit-to-stand
in CKD27 1.73 m2 placebo speed, renal injury markers
BASE Pilot28 eGFR 20-,45 or 45- 20-28 192 NaHCO3, 0.5 vs 0.8 mEq/ 28 wk Pharmacodynamics, safety,
,60 mL/min/1.73 m2 kg/d vs placebo tolerability, treatment
1 ACR $ 100 mg/mg adherence
NaHCO3 in CKD stages 2-4, 20-28 74 NaHCO3, 0.5 mEq/kg/d, vs 6 mo Urinary injury markers, physical
diabetic CKD29 DM, urinary placebo function, mineral metabolism
ACR $30 mg/mg
Abbreviations: ACR, albumin-creatinine ratio; BASE, Bicarbonate Administration to Stabilize; CI, confidence interval; CKD, chronic
kidney disease; DM, diabetes mellitus; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; HCO32, bicar-
bonate; HTN, hypertension; NA, not applicable; NaCitrate, sodium citrate; NaCl, sodium chloride; NaHCO3, sodium bicarbonate; RRT,
renal replacement therapy.

case is presented to illustrate an approach to the low blood pressure, the lisinopril dose was reduced to 10 mg
management of metabolic acidosis in CKD. The daily and diltiazem treatment was discontinued. Figure 1 presents
the course of key clinical features.
target serum bicarbonate concentration and potential
side effects of treatment are considered. Diagnosis
Chronic metabolic acidosis secondary to CKD stage 4.
CASE REPORT
Clinical Follow-up
Clinical History and Initial Laboratory Data Sodium bicarbonate dosage was increased from 650 mg thrice
A 58-year-old woman was seen for routine follow-up of CKD daily to 1,300 mg thrice daily. Serum bicarbonate concentrations 3
stage 4 from hypertensive nephrosclerosis. Sodium bicarbonate, and 9 months later were 24 and 22 mEq/L, respectively (Fig 1).
650 mg, thrice daily was prescribed 36 months prior because Although serum potassium level decreased, potassium replace-
serum bicarbonate concentration was consistently 21 mEq/L ment was not required and systolic blood pressure did not increase
(Fig 1). She had a history of excellent blood pressure control on to a clinically concerning level with the higher sodium bicarbonate
stable daily doses of lisinopril, 20 mg, and extended-release dil- dose. Eventually, antihypertensive medications were discontinued;
tiazem, 240 mg. She had intentionally lost 17 kg over the past 4 the improved blood pressure control was attributed to weight loss,
years. On the day of the visit, she reported feeling well. Pertinent not the increase in serum bicarbonate concentration. Weight gain
clinical and laboratory data included systolic blood pressure of was not observed 3 months later, but was apparent at 9 months.
92 mm Hg, weight of 78 kg, absence of peripheral edema, eGFR Because there was no peripheral edema or other signs of uid
of 21 mL/min/1.73 m2 (as calculated by the isotope-dilution mass excess, this was not ascribed to uid retention. Because her bi-
spectrometrytraceable 4-variable MDRD [Modication of Diet carbonate concentration was 22 mEq/L and there were no overt
in Renal Disease] Study equation), bicarbonate concentration of side effects, sodium bicarbonate dose was continued at 1,300 mg
19 mEq/L, and serum potassium level of 4.3 mEq/L. Because of thrice daily.

Am J Kidney Dis. 2016;67(4):696-702 697


Kalani L. Raphael

26
Start NaHCO3 Increase NaHCO3
650 mg thrice daily to 1,300 mg thrice daily

Serum HCO3- (mEq/L)


24

22

20

18

16
-48 -36 -24 -12 0 3 9
Month
SBP (mm Hg) 125 123 133 122 92 110 122
eGFR (mL/ 27 27 23 24 21 22 23
min/1.73 m2)
Serum K+ 4.6 4.3 4.3 3.5 4.3 4.0 3.9
(mEq/L)
Weight (kg) 95 92 88 83 78 78 82
BMI (kg/m2) 31.0 30.0 28.7 27.1 25.5 25.5 26.8
HTN Lisinopril None
medications Lisinopril 20 mg + diltiazem 240 mg daily 10 mg/d

Figure 1. Clinical information in this patient. Potassium supplements and diuretics were never prescribed. Peripheral edema was
not observed at any visit. Abbreviations: BMI, body mass index; eGFR, estimated glomerular filtration rate; HCO32, bicarbonate; K1,
potassium; HTN, hypertension; NaHCO3, sodium bicarbonate; SBP, systolic blood pressure.

DISCUSSION mortality and CKD progression were lowest at bi-


In this patient with CKD stage 4, sodium bicar- carbonate concentrations of w28 mEq/L in veterans
bonate was prescribed to ameliorate the negative ef- with CKD9 and participants in AASK (African
fects of metabolic acidosis on bone, protein, and American Study of Kidney Disease and Hyperten-
kidney function. Initially, sodium bicarbonate of sion).10 Navaneethan et al11 also showed that the risk
650 mg thrice daily (1,950 mg daily) was prescribed; for death was lowest at w28 mEq/L in more than
however, this dose failed to increase the bicarbonate 40,000 patients with CKD. Thus, results from these
concentration to .21 mEq/L. In her case, 1,300 mg observational studies suggest that targeting bicar-
thrice daily increased the bicarbonate concentration bonate concentrations of w28 mEq/L may be better
to $22 mEq/L without apparent side effects. Al- for patients with CKD. However, results from the
though she had initially achieved a bicarbonate con- CRIC Study suggest that values .26 mEq/L associate
centration of 24 mEq/L with 3,900 mg of sodium with higher mortality and incident heart failure risk,12
bicarbonate daily, the bicarbonate concentration sub- which may be related to vascular calcication.13
sequently decreased to 22 mEq/L. Because she had Furthermore, bicarbonate concentrations .32 mEq/L
none of the common side effects, increasing the also associated with mortality in the study of
dosage of sodium bicarbonate to achieve a higher Navaneethan et al.11
bicarbonate concentration was considered although Based on these data, it is reasonable to titrate the
the KDOQI threshold of 22 mEq/L had been alkali dose to increase the bicarbonate concentration
achieved. into the range of 24 to 26 mEq/L provided that the
Why consider increasing the dose of sodium bi- dose is not excessive such that it impairs adherence
carbonate to target a bicarbonate concentration .22 and there are no side effects of treatment. That being
mEq/L? First, the mean achieved bicarbonate con- said, alkali is generally safe in CKD. Perhaps the most
centration was w24 mEq/L in the de Brito-Ashurst commonly discussed side effect is elevation of blood
et al7 and Phisitkul et al8 studies, in which im- pressure related to sodium-mediated uid retention.
proved kidney function was observed after 2 years. Weight loss and dietary changes during the 3 years
Second, several observational studies have found an this patient was treated with 1,950 mg of sodium bi-
association between improved kidney measures and carbonate daily may have protected her from elevated
survival for patients with CKD with higher bicar- blood pressure and edema. However, there was no
bonate concentrations. For example, the risks for increase in weight or other signs of uid excess after 3

698 Am J Kidney Dis. 2016;67(4):696-702


Chronic Metabolic Acidosis

months of 3,900 mg of sodium bicarbonate daily observed before prescribing alkali? It is reasonable to
(which increased sodium intake by w1,000 mg). withhold alkaline therapy until a low bicarbonate
These observations should not be surprising because concentration is conrmed after a period of weeks to
sodium-related uid retention is more likely when months. However, it is also reasonable to initiate
sodium is accompanied by the chloride anion.14,15 alkaline therapy without conrmation depending on
Another potential side effect of sodium bicarbonate the severity of the low bicarbonate concentration
is hypokalemia; however, this was not observed in her (eg, #18 mEq/L) provided there is not a reversible
case. The safety of sodium bicarbonate with respect to cause of low bicarbonate concentration such as acute
uid, blood pressure, and potassium level in her case diarrhea or acute kidney injury (Fig 2). Second,
is backed by an absence of signicant differences the current paradigm is to withhold alkaline therapy
between participants who received alkali and control until the bicarbonate concentration decreases to ,22
participants in the studies of de Brito-Ashurst et al7 mEq/L. However, results from a single-center study
and Phisitkul et al.8 The available data suggest that challenge this practice. Mahajan et al18 randomly
these side effects are not a major concern, can be seen assigned patients with CKD stage 2 with hypertensive
for a variety of other reasons in CKD, and can usually nephropathy to receive either sodium bicarbonate of
be medically managed. Other complications include 0.5 mEq per kilogram of lean body weight daily,
ionized hypocalcemia if alkalemia develops. Some equimolar sodium chloride, or placebo (n 5 40 per
patients have gastrointestinal side effects with sodium group). Notably, mean bicarbonate concentration at
bicarbonate. Often, this is due to bloating or burping the beginning of the study was w24 mEq/L in all 3
related to the conversion of bicarbonate to carbon groups. After 5 years of follow-up, those who
dioxide in the stomach. These symptoms can usually received sodium bicarbonate had more preserved
be alleviated with a proton pump inhibitor. Enteric- kidney function than the other 2 groups (Table 1).18
coated sodium bicarbonate preparations are avail- This suggests that alkaline therapy preserves GFR in
able in some countries, and delivery of bicarbonate to CKD even if the bicarbonate concentration is normal.
the intestine for absorption may circumvent these Mechanistically, compensatory responses, such as
symptoms. enhanced renal ammonia production19 and endothelin
Despite the apparent safety of alkali, possible side 1mediated acid secretion,20 maintain serum bicar-
effects that have not been well explored are the effect bonate concentration in the normal range but
of correcting metabolic acidosis on vascular13 and secondarily promote renal brosis in CKD. Hence,
renal calcication in CKD.16,17 de Solis et al13 found alkaline therapy would neutralize excess acid and
substantially greater vascular calcication in uremic attenuate these compensatory responses irrespective
animals treated with intraperitoneal sodium bicar- of bicarbonate concentration. Nonetheless, it is pre-
bonate. This did not appear to be due to excessive mature to recommend starting alkali treatment for
correction of metabolic acidosis and subsequent patients with CKD who have not developed metabolic
alkalemia because bicarbonate concentration was acidosis, and other interventional studies investigating
w18 mEq/L in these animals. By comparison, the the pleiotropic benets of alkaline therapy in patients
bicarbonate concentration in healthy animals was
w19 mEq/L. Furthermore, uremic animals with un-
Average [HCO3-] = 19-21 mEq/L
treated metabolic acidosis had bicarbonate concen- [HCO3-] 18 mEq/L
on 2 consecutive measurements
trations of w13 mEq/L and similar levels of vascular
calcication compared with healthy animals.13 These Start NaHCO3 Start NaHCO3
ndings raise the possibility that metabolic acidosis 650 mg twice daily 1,300 mg twice daily
prevents vascular calcication in CKD and correcting
metabolic acidosis promotes vascular calcication in
CKD. Metabolic acidosis seems to also protect Titrate NaHCO3 up to 3,900 mg/d
against renal calcication and GFR loss in uremic (Target [HCO3-] is 24-26 mEq/L)
animals on a high-phosphate diet.16,17 Hence, it might
be worthwhile withholding alkaline therapy in pa- If [HCO3-] < 2
22 mEq/L
tients with hyperphosphatemia. These potentially se-
vere complications in humans underscore the need for
Titrate NaHCO3 up to 5850 mg/d
large-scale clinical trials with long-term follow-up to (Target [HCO3-] 22 mEq/L)
determine whether alkaline therapy is safe and
efcacious. Figure 2. Approach to the management of chronic metabolic
Two practical questions regarding alkaline therapy acidosis in chronic kidney disease. Sodium bicarbonate dose
should be reduced if bicarbonate level is .26 mEq/L.
relate to when it should be initiated in CKD. First, for Abbreviations: NaHCO3, sodium bicarbonate; [HCO32], bicar-
how long should a low bicarbonate concentration be bonate concentration.

Am J Kidney Dis. 2016;67(4):696-702 699


Kalani L. Raphael

with CKD with normal bicarbonate concentrations are bicarbonate concentration remains at ,22 mEq/L. The
ongoing (Table 1). rationale for these dose restrictions is that the average
Figure 2 presents an approach to the management bicarbonate dose prescribed by de Brito-Ashurst et al7
of metabolic acidosis in CKD. For patients with bi- was 1.82 g daily, and there is less condence that
carbonate concentrations of 19 to 21 mEq/L, a low higher doses are safe over the long term. Because this
bicarbonate concentration is conrmed (ie, within 3 patients bicarbonate concentration reached the
months) before starting alkali treatment. For those KDOQI target of 22 mEq/L while taking 3,900 mg of
with bicarbonate concentrations # 18 mEq/L, it is sodium bicarbonate daily, the bicarbonate dosage was
reasonable to start alkali treatment without conrming not increased to target a higher bicarbonate concen-
a low value provided there is not an acute reason for tration. If her bicarbonate concentration were to
the low bicarbonate concentration. Table 2 presents decrease to ,22 mEq/L in the future, the sodium bi-
characteristics of commonly prescribed alkalinizing carbonate dosage would be increased until the bicar-
agents. In general, potassium-based agents are avoi- bonate concentration reaches 22 mEq/L, while
ded unless hypokalemia is also present. Although limiting the total daily dose to 5,850 mg.
citrate-based agents enhance aluminum absorption,21 Adherence and intolerance should be considered if
they are probably safe as long as aluminum-based the bicarbonate concentration remains at ,22 mEq/L
binders are avoided. Sodium bicarbonate is attrac- after several months of treatment with 5,850 mg daily.
tive because it avoids these concerns and is less If the number of pills impairs adherence, 1/2 teaspoon
expensive than citrate-based therapies. The initial of sodium bicarbonate powder dissolved in water
sodium bicarbonate dose should consider the potential provides equimolar bicarbonate to 3.7 tablets of
for gastrointestinal intolerance as well as the bicar- 650 mg. If gastrointestinal intolerance occurs, citrate-
bonate concentration. Gastrointestinal concerns aside, based agents should be tried. Other strategies to in-
650 mg twice daily is started if bicarbonate concen- crease bicarbonate concentration include increasing
tration is 19 to 21 mEq/L, or 1,300 mg twice daily if dietary alkali intake with fruits and vegetables pro-
bicarbonate concentration is #18 mEq/L. vided serum potassium level is ,5.0 mEq/L22 and
The ideal target bicarbonate concentration seems to reducing dietary, particularly animal, protein intake.23
be 24 to 26 mEq/L based on the achieved mean bi- In refractory cases, a detailed dietary history may be
carbonate concentration in small interventional helpful and an arterial blood gas should be considered
studies and the observational data. Therefore, sodium to rule out respiratory alkalosis, although unlikely.
bicarbonate dose is titrated every few months or so Some medications commonly prescribed in CKD
to achieve bicarbonate concentrations of 24 to 26 promote low bicarbonate concentrations. For
mEq/L. However, the daily dose of sodium bicar- example, bicarbonate concentrations are lower in pa-
bonate is limited to 3,900 mg unless bicarbonate tients receiving renin-angiotensin system blockers2;
concentration remains at ,22 mEq/L. Daily doses up however, these should not be discontinued in
to 5,850 mg of sodium bicarbonate are prescribed if CKD for obvious reasons. By contrast, bicarbonate

Table 2. Commonly Prescribed Alkalinizing Agents, Doses, and Considerations

Agent/Dose [HCO32] Considerations

NaHCO3
325-mg tablet 3.9 mEq Inexpensive; nonpotassium based; conversion of
650-mg tablet 7.7 mEq HCO32 to CO2 causes upper GI symptoms
600-mg (1/8 tsp) powdera 7.1 mEq
Sodium citrate/citric acid solution
500 mg/334 mg per 5 mL 1 mEq/mL Fewer GI symptoms than NaHCO3; nonpotassium
490 mg/640 mg per 5 mL 1 mEq/mL based; enhances aluminum absorption; conversion
of citrate to HCO32 may be impaired in liver disease
Potassium citrate 6 citric acid
540-mg potassium citrate tablet 5 mEq 10- & 15-mEq tablets have more mEq of HCO32 than
1,080-mg potassium citrate tablet 10 mEq NaHCO3 tablets; solution delivers more mEq/mL of
1,620-mg potassium citrate tablet 15 mEq HCO32 than sodium citrate solution; rare cause of GI
1,100 mg potassium citrate/334 mg 2 mEq/mL ulceration; enhances aluminum absorption; may
citric acid per 5-mL solution cause hyperkalemia; conversion of citrate to HCO32
3,300 mg potassium citrate/1,002 mg 30 mEq per packet may be impaired in liver disease
citric acid packeta
Abbreviations: CO2, carbon dioxide; GI, gastrointestinal; HCO32, bicarbonate; NaHCO3, sodium bicarbonate.
a
Should be dissolved in water.

700 Am J Kidney Dis. 2016;67(4):696-702


Chronic Metabolic Acidosis

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Support: Dr Raphael receives support from Career Develop-
ment Award IK2 CX000537 from the US Department of Veterans Effect of ammonium chloride and dietary phosphorus in the azo-
Affairs Clinical Sciences Research and Development Service, taemic rat. Part IIkidney hypertrophy and calcium deposition.
Robert Wood Johnson Foundation (Harold Amos Medical Faculty Nephrol Dial Transplant. 2004;19(8):1993-1998.
Development Award), and National Institutes of Diabetes, 17. Jara A, Felsenfeld AJ, Bover J, Kleeman CR. Chronic
Digestive, and Kidney Disease (1U01DK099933). metabolic acidosis in azotemic rats on a high-phosphate diet
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