Renal Failure

ISSN: 0886-022X (Print) 1525-6049 (Online) Journal homepage: https://www.tandfonline.com/loi/irnf20

Effects of Correction of Metabolic Acidosis on

Blood Urea and Bone Metabolism in Patients
with Mild to Moderate Chronic Kidney Disease: A
Prospective Randomized Single Blind Controlled
Trial

Rajendra P. Mathur, Suresh C. Dash, Nandita Gupta, Sunil Prakash, Sanjeev

Saxena & Dipankar Bhowmik

To cite this article: Rajendra P. Mathur, Suresh C. Dash, Nandita Gupta, Sunil Prakash,
Sanjeev Saxena & Dipankar Bhowmik (2006) Effects of Correction of Metabolic Acidosis on
Blood Urea and Bone Metabolism in Patients with Mild to Moderate Chronic Kidney Disease:
A Prospective Randomized Single Blind Controlled Trial, Renal Failure, 28:1, 1-5, DOI:
10.1080/08860220500461187

To link to this article: https://doi.org/10.1080/08860220500461187

Published online: 07 Jul 2009.

Submit your article to this journal

Article views: 924

View related articles

Citing articles: 36 View citing articles

Full Terms & Conditions of access and use can be found at

https://www.tandfonline.com/action/journalInformation?journalCode=irnf20
Renal Failure, 28:1–5, 2006
Copyright © Taylor & Francis Group, LLC
ISSN: 0886-022X print / 1525-6049 online
DOI: 10.1080/08860220500461187

CLINICAL STUDY
LRNF

Effects of Correction of Metabolic Acidosis on Blood Urea and Bone Metabolism

in Patients with Mild to Moderate Chronic Kidney Disease: A Prospective
Randomized Single Blind Controlled Trial

Rajendra P. Mathur, M.D. and Suresh C. Dash, M.D.

Correction of Metabolic Acidosis

Department of Nephrology, All India Institute of Medical Sciences, New Delhi, India

Nandita Gupta, M.D.

Department of Endocrinology, All India Institute of Medical Sciences, New Delhi, India

Sunil Prakash, M.D., Sanjeev Saxena, M.D., and Dipankar Bhowmik, M.D.
Department of Nephrology, All India Institute of Medical Sciences, New Delhi, India

Background. There are no controlled trials on the efficacy of
oral bicarbonate therapy in patients with mild to moderate chronic
kidney disease (CKD). This prospective randomized controlled
study was done to evaluate the effects of correction of metabolic
acidosis on renal functions and bone metabolism in this group
of patients. Patients and Methods. Forty patients were randomized
to treatment with oral bicarbonate or placebo for a period of 3 months.
Investigations at baseline included venous pH, bicarbonate, renal
functions, serum iPTH, and bone radiology. The treatment group
(Group B) received daily oral sodium bicarbonate therapy at a dose of
1.2 mEq/kg of body weight. Their venous blood pH and bicarbonate
levels were estimated weekly to keep blood pH near 7.36 and bicar-
bonate at 22–26 mEq/L by adjusting the dose of sodium bicarbonate.
At the end of 3 months, all the tests were repeated in both
groups. Results. After oral bicarbonate therapy (OBT), there was a
significant decline in the rise of blood urea level in Group B associated
with a sense of well-being in 50% patients. The rise in parathormone
(PTH) was six times the baseline value in Group A and only 1.5 times
baseline value in Group B, although not statistically significant. There
was no significant change in total calcium, phosphorus, alkaline
phosphatase, creatinine, total protein, or albumin levels. Conclusion.
Correction of metabolic acidosis in patients with moderate CKD atten-
uates the rise in blood urea and PTH, which might prevent the delete-
rious long-term consequences of secondary hyperparathyroidism.
Keywords chronic kidney disease, metabolic acidosis, oral
bicarbonate therapy
INTRODUCTION
Uremic metabolic acidosis is the consequence of
decreased ammonia generation associated with a decreased
functioning renal mass, besides renal bicarbonate wasting,
defect in hydrogen ion secretion, and retention of organic
acids.[1] This leads to several clinical complications. Meta-
bolic acidosis (MA) has been shown to be one of the trig-
gers of chronic inflammation resulting in catabolic and anti-
anabolic effects.[2] Correction of acidosis decreases protein
degradation and amino acid metabolism with increases in
serum albumin and prealbumin levels.[3–6] The other impor-
tant consequence of MA is its role in divalent ion metabo-
lism and pathogenesis of renal osteodystrophy.[7] However,
there are few intervention studies in this regard. Lefebvre
showed that optimal correction of acidosis changes progres-
sion of dialysis osteodystrophy.[8] The recent NFK/DOQI
clinical practice guidelines recommend that in CKD stages
3, 4, and 5, the serum levels of total CO2 should be main-
tained at >22 mmol/L with the use of supplemental alkali
salts if necessary;[9] there are no controlled trials on this
issue. Hence, we performed a prospective randomized sin-
gle blind controlled trial of the effect of correction of MA in
patients with moderate CKD.
PATIENTS AND METHODS

Address correspondence to Dr. S.C. Dash, Department of The present study was comprised of 40 patients with
Nephrology, All India Institute of Medical Sciences, New Delhi - stable mild to moderate CKD with serum creatinine <5
110029, India; E-mail: scdash@hotmail.com mg/dL. Clinical examination, baseline hematological and

1
2 R. P. Mathur et al.

biochemical work-up (blood urea, creatinine, electrolytes,
calcium, phosphorus, alkaline phosphatase, serum pro-
teins), skeletal survey, and abdominal ultrasonography
were done for each patient. Venous blood pH and bicar-
bonate levels were measured by the blood gas analyzer.
Estimation of intact PTH in serum was done for all the
patients and 10 age- and sex-matched normal healthy vol-
unteers by Coat-A-Count Intact PTH IRMA-kit (Diagnos-
tic Products Corporation, Los Angeles, CA, USA). The
dietary intake of protein and calories for all the subjects in
both groups remained unchanged during the study period.
Drugs that could alter PTH activity (e.g., aluminium
hydroxide, calcium supplements, vitamin D analogues,
Dilantin, H2 blockers, beta blockers) were stopped 2 weeks
prior to inclusion in the study. Also, none had any other
intercurrent illness or had undergone parathyroidectomy.
Written informed consent was obtained from each patient.
The study was a prospective randomized single blind
controlled trial. The patients were randomly allocated to
two groups: Group A (control group) included 20 patients
who received only placebo (containing glucose) for a
period of 3 months, however, the medications for associ-
ated conditions (e.g., hypertension, diabetes mellitus, etc.)
were continued. Group B (test group) included 20 patients
who, after initial work-up, received oral base therapy
(OBT) in the form of sodium bicarbonate powder 1.2
mEq/kg body weight in three divided doses. Their venous
blood pH and bicarbonate levels were estimated every
week to guide dose adjustment to achieve a serum bicar-
bonate concentration of 22–26 mEq/L. Subsequently, the
same dose was continued for a period of 3 months, when
the venous blood pH, bicarbonate level, biochemical
profile including serum total proteins and albumin, serum
intact PTH level, and skeletal survey were repeated. The
results were subjected to statistical analysis by paired t test.
RESULTS
The present study was conducted on 40 patients with
mild to moderate stable chronic renal failure (CRF), divided
into two equal groups. Group A (control group) had 20
patients, 13 males and 7 females, mean age 43.5 ± 10.5 yr
(range 25–68). Group B (test group) was comprised of 20
patients, 12 males and 8 females, mean age 37.5 ± 17 yr
(range 15–76). The results are summarized in Tables 1 and 2.
Three months of OBT was associated with significant cor-
rection of metabolic acidosis with increase in blood pH
and serum bicarbonate levels in Group B. The dose of
sodium bicarbonate required to achieve the desired blood

Table 1
Clinical parameters

Control group Test group

Parameter Baseline After 3 months Baseline After 3 months p value

Weight (kg) 58.2 ± 1.5 59.4 ± 0.9 57.6 ± 0.8 58.4 ± 1.2 NS
SBP 132 ± 6 134 ± 4 136 ± 7 140 ± 4 NS
DBP 88 ± 4 86 ± 3 86 ± 5 88 ± 3 NS

SBP: systolic blood pressure; DBP: diastolic blood pressure.

Table 2
Biochemical parameters

Control group Test group

Parameter Baseline After 3 months Baseline After 3 months p value

pH 7.29 ± 0.05 7.27 ± 0.06 7.26 ± 0.05 7.37 ± 0.04 <0.001

HCO3 (mEq/L) 19.35 ± 3.74 17.89 ± 4.67 19.49 ± 5.51 22.93 ± 7.12 <0.05
PTH (pg/mL) 48.0 ± 61.6 147.3 ± 133 83.1 ± 76.9 121.5 ± 79.9 0.07
Ca (mg/dL) 8.83 ± 1.39 8.69 ± 1.06 9.05 ± 1.09 8.69 ± 1.22 NS
P (mg/mL) 4.43 ± 0.69 4.75 ± 0.89 4.49 ± 1.08 4.42 ± 0.87 NS
Alk Phos (IU) 177.9 ± 130.7 206 ± 149.2 210.6 ± 118.4 278.7 ± 374.9 NS
Blood urea (mg/dL) 71.5 ± 28.3 90.3 ± 26.1 64.1 ± 23.4 67.3 ± 23.5 <0.05
Serum creatinine (mg/dL) 3.09 ± 1.11 3.62 ± 1.18 2.71 ± 0.94 2.86 ± 1.21 NS
Total protein (g/dL) 6.63 ± 1.03 6.82 ± 1.08 7.60 ± 0.77 7.42 ± 0.74 NS
Serum albumin (g/dL) 3.64 ± 0.82 3.37 ± 0.92 4.29 ± 0.82 3.74 ± 0.74 NS
 Correction of Metabolic Acidosis 3

pH and bicarbonate levels was 90–180 mEq/day. The
average time to achieve desired levels was 4 weeks. The
correction of metabolic acidosis was associated with atten-
uation of rise in blood urea in Group B as compared to
Group A. The mean blood urea value at the end of the
study period was 90.25 ± 26.09 mg/dL in Group A and
67.32 ± 23.51 mg/dL in Group B (p value <0.05; Figure
1). There was no significant difference in serum creatinine
values in two groups. There was no significant change in
serum total proteins and albumin levels in the two groups.
The correction of metabolic acidosis did not significantly
affect the levels of divalent ions (total calcium, inorganic
phosphorus) and Ca × P product. Serum alkaline phos-
phatase levels remained within the normal range in Group
A and were mildly elevated in Group B, the difference was
not statistically significant (p value >0.05)
The mean intact serum PTH level in 10 healthy volun-
teers was 49.20 ± 19.16 pg/mL (range 10–74.0 pg/mL).
The intact serum PTH level was 48.00 ± 61.63 pg/mL in
Group A at the beginning of the study and 147.33 ± 133.00
pg/mL at the end of the study (Figure 2). However, in
Group B, the mean intact serum PTH level was higher
than normal (83.06 ± 76.88 pg/mL) to begin with and was
121.46 ± 79.90 pg/mL at the end of the study period (Fig-
ure 2). Thus, there was a significant rise (p value <0.05) in
PTH from the baseline value in both the groups at the end
of the study period. Although comparison of PTH values
at the end of the study period in the two groups did not
show any significant difference; the rise of the PTH level
in Group A was about sixfold, while in group B, it was
only increased one and half times.
Out of 40 cases of CRF in this study, 12 cases (30%)
had radiological changes suggestive of ROD. There were
four cases of renal osteodystrophy (ROD) in Group A, out
of which two patients had symptoms of bone and muscle
pain but no evidence of proximal muscle weakness. The
symptoms and radiological changes were the same after
the study period of 3 months. In Group B, there were eight
cases with radiological evidence of ROD, of which three
had symptoms of bone and muscle pain; one patient also
had proximal myopathy. There was symptomatic improve-
ment in all the cases after OBT, but no significant radio-
logical change was observed.
There were important clinical effects of correction of
metabolic acidosis in Group B. A sense of well-being was
felt in half of the cases, with significant relief in bone and
muscle ache in the three patients with ROD. One patient
with proximal myopathy had partial improvement in his
clinical condition. In three cases, there was difficulty in
controlling blood pressures, and the dose of antihyperten-
sive had to be increased. Two cases of diabetic nephropa-
thy had weight gain and edema requiring an increase in the
dose of diuretic.

DISCUSSION
100
90
80
CRF is a catabolic illness, and the waste products
70 from endogenous protein catabolism can contribute to the
60 uremic syndrome. Our data showed that the rise in mean
mg/dL

Baseline
50
After 3 months blood urea level at the end of the study period was signifi-
40
30 cantly lower in Group B, although there was no significant
20 difference in the rise of serum creatinine levels in the two
10 groups. As there was no change in dietary intake in the
0
Control Test
two groups, this difference in the rise of BUN was proba-
bly the result of correction of metabolic acidosis leading to
Figure 1. Mean blood urea levels. decreased rate of catabolism of proteins or increased pro-
tein synthesis. It is possible that a lack of a significant
increase of blood urea or the correction of metabolic aci-
160
dosis might have contributed to the sense of well-being
140
observed in 50% of cases in Group B. A similar observa-
120
tion was made by Papadoyannakis[10] in a small group of
PTH (ng/mL)

100
Baseline six nondialyzed patients showing significant decrease of
80
After 3 months BUN of 36% during sodium bicarbonate supplementation
60
(9.3 ± 0.6 days) as compared to the period of sodium chlo-
40
ride supplementation (9.8 ± 0.8 days). However, as the
20
duration of the study was short and the number of patients
0
Control Test very small, the results may have been skewed. In our
study, although the intake of sodium was higher in the
Figure 2. Mean intact PTH levels. study population (the placebo contained only glucose), we
4 R. P. Mathur et al.
do not think that this made any difference in the outcome
of the study. Blood pressures in both groups remained
steady throughout the study period.
Renal osteodystrophy is the consequence of an
interplay of several factors, including hypocalcemia,
hyperphosphatasemia, secondary hyperparathyroidism,
and exposure to toxins including aluminium and amyloid.
MA associated with CKD has been implicated as an addi-
tional factor contributing to the pathogenesis of ROD.[11]
Krieger et al. showed a direct suppressive effect of MA on
osteoblast-induced collagen synthesis.[12] Studies have
shown that MA stimulates osteoclastic function leading to
enhanced bone resorption.[12–13] MA also increases PTH
secretion and enhances its biologic action, thereby indi-
rectly stimulating osteoclastic activity.[14] In fact, PTH
levels have been shown to increase in response to MA
even in patients with normal renal function.[15] The present
study revealed normal total serum calcium and phosphorus
levels in mild to moderate CRF. Pitts et al.[16] also demon-
strated normal blood levels of ionized calcium and phos-
phorus levels in patients with mild to moderate CRF.
Evidence of metabolic acidosis was observed in both
groups of patients at the beginning of study, which
improved significantly with oral bicarbonate therapy.
There was no significant difference in the levels of total
Ca, P, Ca X P product, serum alkaline phosphatase, total
protein, and albumin levels at the onset of the study, and it
was not observed after 3 months of oral base therapy.
Caruana[17] and Van Stone et al.[18] had similar observa-
tions in patients of CRF on maintenance hemodialysis.
The correction of metabolic acidosis in Group B prevented
the steep rise in serum PTH levels, as the rise was about
six times in the control group and only one and a half
times in the test group. Uncontrolled studies in patients
with MA and normal, mild, or moderate CRF have shown
benefits of bicarbonate therapy.[19–20] There is only one
controlled study on the effect of correction of metabolic
acidosis in hemodialysis patients.[8] Lefebvre et al.[8]
enrolled 21 long-term hemodialysis patients and randomly
assigned them to receive dialysis with or without oral
bicarbonate supplementation to maintain serum HCO3 >
20 mEq/L. In patients with high bone turnover and ele-
vated iPTH, bone resorption surface and iPTH levels rose
in the control compared to the bicarbonate-treated group.
But, the correction of metabolic acidosis in the
present study retarded the rise of the PTH level but did not
prevent it completely. This observation of an increase in
serum PTH levels in spite of correction of acidosis is in
agreement with the findings of Caruana et al.[17] who
found that OBT in dialysis patients resulted in a decrease
in serum ionized calcium levels and a significant increase
in the already elevated PTH levels. He proposed that the
sustained reduction of serum ionized calcium levels after
OBT might promote further increases in PTH secretion
and worsening of parathyroid bone disease.
Out of 40 cases of CRF in the present study, 12 had
radiological changes suggestive of ROD. Malluche et
al.[21] demonstrated by bone biopsies evidence of parathy-
roid activity even at a very early stage of chronic renal
failure. In all three symptomatic cases in Group B, correc-
tion of metabolic acidosis was associated with symptom-
atic improvement of muscle and bone pain. However, no
significant radiological improvement was noticed in the
eight cases with ROD at the end of the short study period
of 3 months. A mild rise in the serum alkaline phosphatase
level in Group B was not significantly different from the
normal level observed in Group A.
The current guidelines recommend the correction of
metabolic acidosis in patients with CKD,[9,22] although no
study has been conducted in mild to moderate CRF to
examine the effects of correction of metabolic acidosis.
Hence, the results of the present study are important. How-
ever, the long-term consequences of correction of metabolic
acidosis in CRF are not known. On one hand, correction of
metabolic acidosis might prevent the deleterious long-term
consequences like ROD associated with the body’s com-
pensatory mechanism to combat acidosis; while, on the
other hand, the alkali therapy, by reducing ionized calcium
levels, might aggravate the preexisting hyperparathyroid
state associated with CRF. The present study seems to
refute this later fact, as the serum calcium level showed no
change, and the rise of PTH was attenuated.
REFERENCES
1. Warnock DG. Uremic acidosis. Kidney Int. 1988;34:278–287.
2. Mehrotra R, Kopple JD, Wolfson M. Metabolic acidosis in
maintenance dialysis patients: clinical considerations. Kidney
Int. 2003;88:S13–25.
3. Reaich D, Channon SM, Scrimgeour CM, Daley SE, Williamson
R, Goodstrip TH. Correction of acidosis in humans with
chronic renal failure decreases protein degradation and amino
acid oxidation. Am J Physiol. 1993;265:E230–235.
4. Pickering WP, Price SR, Bischer G, Marinovic AC, Mitch
WE, Walls J. Nutrition in chronic ambulatory peritoneal dial-
ysis; serum bicarbonate and the ubiquitin-protease system in
muscle. Kidney Int. 2002;61:1286–1292.
5. Brady JP, Hasbargen JA. A review of the effects of correction
of acidosis on nutrition in dialysis patients. Sem Dial.
2000;13:252–255.
6. Verove C, Maisonneuve N, El Azouzi A, Boldron A, Azar R.
Effect of the correction of metabolic acidosis on nutritional
status in elderly patients with chronic renal failure. J Ren
Nutr. 2004;14:127–133.
7. Buschinsky DA. Internal changes of hydrogen ions: Bone. In:
Selding DW, Giebish G, eds. The Regulation of Acid Base
Balance. New York: Raven Press; 1989:69–88.
 Correction of Metabolic Acidosis
8. Lefebvre A, de Verneloul MC, Gueris J, Goldfarb B,
Graulet AM, Morieux C. Optimal correction of acidosis
changes progression of dialysis osteodystrophy. Kidney
Int. 1989;36:1112–1118.
9. K/DOQI clinical practice guidelines for bone metabolism
and diseases in chronic kidney disease. Am J Kidney Dis.
2003;42(Suppl 3):S29–S44.
10. Papadoyannakis NJ, Stefanides CJ, Mc Geown M. The effect
of correction of metabolic acidosis on nitrogen and protein
balance of patients with chronic renal failure. Am J Clin
Nutr. 1984;40:623–627.
11. Kraut JA. Disturbances of acid–base balance and bone dis-
ease in end-stage renal disease. Sem Dial. 2000;13:261–266.
12. Krieger NS, Sessler NE, Bushinsky DA. Acidosis inhibits
osteoblastic and stimulates osteoclastic activity in vitro. Am
J Physiol. 1992;262:F442–F448.
13. Kraut JA, Mishler DR, Singer FR, Goodman WG. The
effects of metabolic acidosis on bone formation and bone
resorption in the rat. Kidney Int. 1986;30:694–700.
14. Kraut JA. The role of metabolic acidosis in the pathogenesis
of renal osteodystrophy. Adv Renal Replace Ther.
1995;2:40–51.
15. Coe FL, Fipro JJ Jr, Hollandswoth DL, Segil L, Canterbury
JM, Reiss E. Effect of acute and chronic metabolic acidosis
5
on serum immunoreactive parathyroid hormone in man.
Kidney Int. 1975;8:262–273.
16. Pitts TO, Piraino BH. Hyperparathyroidism and 1,25 dihy-
droxyvitamin D deficiency in mild, moderate and severe
renal failure. J Clin Endocrinol Metab. 1988;67:876–881.
17. Caruana RJ, Weinstein RS, Campbell HT, Chaudhary BA, Smith
KL, Kurunsaari KM. Effects of oral base therapy on serum ion-
ized calcium, phosphorus and parathyroid hormone in chronic
hemodialysis patients. J Int Artif Organs. 1989;12:778–781.
18. Van Stone JC. Oral base replacement in patients on hemodi-
alysis. Ann Intern Med. 1984;101:199–201.
19. Richards P, Chamberland MJ, Wrong OM. Treatment of
osteomalacia of renal tubular acidosis by sodium bicarbonate
alone. Lancet. 1972;2:994–997.
20. Cochran M, Wikinson R. Effect of correction of metabolic
acidosis on bone mineralization rates in patients with renal
osteomalacia. Nephron. 1975;15:98–110.
21. Malluche HH, Ritz E, Lange HP, et al. Bone histology in
incipient and advanced renal failure. Kidney Int.
1976;9:355–362.
22. St Peter, Schoolwerth AC, McGowan T, McClellan WM.
Chronic kidney disease: issues and establishing programs
and clinics for improved patient outcomes. Am J Kidney Dis.
2003;41:903–925.