DRUG THERAPY: SPECIAL CONSIDERATIONS IN DIALYSIS PATIENTS
Bicarbonate Therapy in End-Stage Renal Disease: Current
Practice Trends and Implications
Jagannath H Saikumar* and Csaba P Kovesdy*†
*Division of Nephrology, University of Tennessee Health Science Center, Memphis, Tennessee, and
†Nephrology Section, Memphis VA Medical Center, Memphis, Tennessee
ABSTRACT
Management of metabolic acidosis covers the entire spec-
trum from oral bicarbonate therapy and dietary modifica-
tions in chronic kidney disease to delivery of high doses
of bicarbonate-based dialysate during maintenance hae-
modialysis (MHD). Due to the gradual depletion of the
body’s buffers and rapid repletion during MHD, many
potential problems arise as a result of our current treat-
One of the ubiquitous manifestations of chronic
kidney disease (CKD) and end-stage renal disease
(ESRD) is metabolic acidosis, and correction of aci-
dosis is one of the primary goals of renal replace-
ment therapy. Maintenance haemodialysis (MHD)
is the predominant modality of renal replacement
therapy in the USA (1). Our current practices for
acidosis management by MHD result in rapid
changes in serum bicarbonate concentration and
can lead to several complications. To better under-
stand the processes involved in alkali delivery and
to improve care, we will review the pathophysiology
of metabolic acidosis in CKD and ESRD, discuss
the outcomes associated with abnormal serum bicar-
bonate concentration and highlight areas of contro-
versy that are in need of more research.
Pathophysiology of Acidaemia in CKD and
ESRD
The regulatory processes of the human body
work to maintain the pH of the body in a tightly
controlled range. Acid production in the average
human body amounts to the generation of about
10,000–15,000 mmol of carbon dioxide per day and
another 1 mEq/kg/day of other non-volatile acids
generated from metabolism of sulphur-containing
Address correspondence to: Csaba P Kovesdy, MD,
Nephrology Section, Memphis VA Medical Center, 1030
Jefferson Ave., Memphis, TN 38104, Tel.: (901) 523-8990,
Fax: (901) 577-7539, or e-mail: csaba.kovesdy@va.gov.
Seminars in Dialysis—2015
DOI: 10.1111/sdi.12373
© 2015 Wiley Periodicals, Inc.
1
ment paradigms. Several studies have given rise to con-
flicting data about the adverse effects of our current
practice patterns in MHD. In this review, we will describe
the pathophysiology and consequences of metabolic
acidosis and its therapy in CKD and ESRD, and discuss
current evidence supporting a more individualized
approach for bicarbonate therapy in MHD.
amino acids (2). These are handled by the lung and
the kidney, respectively, to maintain the pH of the
extracellular fluid in a narrow range. The ability of
the kidney to excrete acid becomes inadequate in
CKD as the glomerular filtration rate (GFR) drops
below 40–50 ml/minute (2–4), resulting initially in
hyperchloraemic (normal anion gap) metabolic aci-
dosis, which may convert to a mixed normal anion
gap and high anion gap metabolic with GFR
decreasing below 15 ml/minute (5). Accumulated
acid is buffered by extracellular fluid bicarbonate,
by bone and by tissue buffers (6,7), which prevents
the development of severe acidaemia even in
patients with advanced CKD (8).
There are multiple adverse consequences of acida-
emia and of metabolic acidosis, warranting their
correction in CKD and ESRD. Acidaemia leads to
a catabolic state mediated by increased cortisol and
reduced insulin like growth factor-1 (IGF-1) (9–11)
along with increased protein turnover (12), culmi-
nating in lower lean muscle mass (9) and lower
serum albumin concentration (10). Correcting acida-
emia with bicarbonate supplementation improves
muscle mass in both pre-MHD CKD patients (13)
and in those on dialysis (14–16) as well as increasing
protein consumption (13) and reducing protein deg-
radation (17).
The excess hydrogen ions in acidaemia are buf-
fered by bone, leading to release of calcium and
phosphate (7,18) and eventually worsening hyper-
parathyroidism (19). Correcting acidaemia in
ESRD improves metabolic bone disease in both
CKD (attenuated PTH increase) (20) and in ESRD
(increased sensitivity of the parathyroid glands to
calcium) (19,21). Additional abnormalities caused
2 Saikumar and Kovesdy
by acidaemia include endocrine abnormalities such
as increased insulin resistance (22), thyroid dys-
function (23), reduction in growth hormone-insu-
lin-like growth factor (IGF-1) levels (24) and
gonadal dysfunction and related disturbances in
sexual function in both men and women (25–27).
An additional consequence of metabolic acidosis
is direct nephrotoxicity, which is not only relevant
to patients with earlier stages of CKD, but may also
be important to those with ESRD and residual kid-
ney function. Conservation of bicarbonate and
excretion of accumulated H+ by the kidneys
involves the induction of various cellular processes
such as ammonia production, activation of the
renin-angiotensin-aldosterone system and produc-
tion of endothelin (8). Persistent activation of these
adaptive systems, as it occurs in CKD as a result of
a chronic positive H+ balance, causes chronic inter-
stitial fibrosis and worsening CKD (8). Administra-
tion of alkali to patients with various stages of
CKD has improved renal outcomes in several small
clinical trials (13,28,29). It is unclear to date if cor-
rection of metabolic acidosis in ESRD could help
conserve residual kidney function.
Treatment Recommendations in Non-dialysis
CKD Patients
Correction of acid-base mass-balance in CKD
can be achieved either by lowering the intake of
acid-precursors, or by increasing the intake of base.
A major source of endogenous acid production is
dietary proteins, due to catabolism of sulphur-con-
taining amino acids, and due to the phosphate con-
tent of dietary proteins (30). Protein in the diet and
serum bicarbonate concentrations were inversely
correlated in the Modification of Diet in Renal Dis-
ease (MDRD) study (31). A smaller study that stud-
ied this effect in patients with advanced CKD
(GFR ~10 ml/minute/1.73 m2) also noted that a
low protein diet (0.3 g/kg/day) resulted in a signifi-
cantly higher serum bicarbonate (32).
Even though primary analysis of the MDRD
study showed that dietary protein intake did not
influence the rate of GFR loss (33), post hoc
analyses of the data from this study did indicate a
potential benefit (34). This has been substantiated
in subsequent studies and meta-analyses (35–37)
and the current KDOQI guidelines suggest a low
protein diet with a high caloric intake to reduce
GFR loss and maintain nutritional status (38).
The effects of protein restriction on CKD progres-
sion are complex, with correction of acidaemia
representing only one of the potential mechanisms
of action responsible for its putative benefits. In
patients presenting with metabolic acidosis in
spite of dietary interventions, oral bicarbonate
supplementation is recommended to maintain
serum bicarbonate in normal range (approximately
23–29 mmol/l) (38).
Acid-Base Status in ESRD
In ESRD the delivery of bicarbonate with renal
replacement therapies is meant to assure acid-base
mass balance in the face of ongoing endogenous acid
production and complete (or nearly complete) lack of
kidney function. Metabolic acidosis could still occur
due to reduced bicarbonate delivery by dialysis (for
reasons such as inadequate time on dialysis, missing
dialysis treatments or erroneous prescription entry),
ingestion of a higher dietary protein (38) resulting in
increased H+ production or gastrointestinal losses of
bicarbonate. Current K/DOQI guidelines recom-
mend a target protein intake of 1.2 g/kg/day of body
weight for MHD patients (38), which is a significant
increase compared to the restricted protein diet rec-
ommended in earlier stages of CKD.
While protein restriction in pre-dialysis stages of
CKD can help correct acid-base imbalances, the
higher-protein intake used in ESRD results in
increased endogenous acid production. Maintaining
a normal nutritional status and preventing protein-
energy wasting is of paramount importance in
ESRD, which necessitates both adequate amounts
of dietary protein intake, and (among others) pre-
vention/treatment of acidaemia. Since the dietary
component of this strategy inherently increases
endogenous acid production, delivery of proper
amounts of base with dialysis becomes the corner-
stone of acid-base balance in ESRD.
History of Base Use in MHD
Since MHD became a viable long-term option for
end-stage renal disease, the management of meta-
bolic acidosis has been addressed in different ways.
In the early days, bicarbonate was introduced into
the dialysate by bubbling carbon dioxide through
the dialysate. This was done to prevent calcium and
magnesium precipitation. Subsequently, acetate was
introduced in the 1960s as a source for bicarbonate
and quickly became the standard of care. With the
introduction of the high-efficiency dialysers, the rate
of diffusion of acetate into the patient’s blood
increased significantly and it sometimes exceeded
the rate of removal by metabolism of acetate by the
liver and skeletal muscle. Accumulation of acetate
in the blood leads to vasodilation and reduced
peripheral vascular resistance (augmented by inter-
leukin-1 release) (39) by conversion to adenosine
and venous pooling of blood with resultant
decreased cardiac filling (40). Along with this direct
effect, there is also an actual loss of bicarbonate
from the blood to the dialysate before the delivered
acetate can be metabolized in the body to generate
bicarbonate (41). Diffusive loss of CO2 during ace-
tate dialysis also leads to pulmonary hypoventila-
tion, and increased oxygen consumption during
acetate metabolism can lead to myocardial ischae-
mia (42) though this has been challenged (43–45).
6 Saikumar and Kovesdy
33. Klahr S, Levey AS, Beck GJ, Caggiula AW, Hunsicker L, Kusek JW,
Striker G: The effects of dietary protein restriction and blood-pressure
control on the progression of chronic renal disease. Modification of
Diet in Renal Disease Study Group. N Engl J Med 330:877–884,
1994
34. Levey AS, Adler S, Caggiula AW, England BK, Greene T, Hunsicker
LG, Kusek JW, Rogers NL, Teschan PE: Effects of dietary protein
restriction on the progression of advanced renal disease in the Modifi-
cation of Diet in Renal Disease Study. Am J Kidney Dis 27:652–663,
1996
35. Levey AS, Greene T, Beck GJ, Caggiula AW, Kusek JW, Hunsicker
LG, Klahr S: Dietary protein restriction and the progression of
chronic renal disease: what have all of the results of the MDRD study
shown? Modification of Diet in Renal Disease Study group. J Am Soc
Nephrol 10:2426–2439, 1999
36. Pedrini MT, Levey AS, Lau J, Chalmers TC, Wang PH: The effect of
dietary protein restriction on the progression of diabetic and nondia-
betic renal diseases: a meta-analysis. Ann Intern Med 124:627–632,
1996
37. Fouque D, Laville M, Boissel JP, Chifflet R, Labeeuw M, Zech PY:
Controlled low protein diets in chronic renal insufficiency: meta-analy-
sis. BMJ 304:216–220, 1992
38. K/DOQI NKF: Clinical Practice Guidelines for nutrition in chronic
renal failure. Am J Kidney Dis 35: 1–140, 2000
39. Lonnemann G, Bingel M, Koch KM, Shaldon S, Dinarello CA:
Plasma interleukin-1 activity in humans undergoing hemodialysis with
regenerated cellulosic membranes. Lymphokine Res 6:63–70, 1987
40. Daugirdas JT: Dialysis hypotension: a hemodynamic analysis. Kidney
Int 39:233–246, 1991
41. Gennari FJ: Acid-base balance in dialysis patients. Kidney Int 28:
678–688, 1985
42. Wolff J, Pedersen T, Rossen M, Cleemann-Rasmussen K: Effects of
acetate and bicarbonate dialysis on cardiac performance, transmural
myocardial perfusion and acid-base balance. Int J Artif Organs 9:
105–110, 1986
43. Nixon JV, Mitchell JH, McPhaul JJ Jr., Henrich WL: Effect of he-
modialysis on left ventricular function. Dissociation of changes in fill-
ing volume and in contractile state. J Clin Investig 71:377–384, 1983
44. Mehta BR, Fischer D, Ahmad M, Dubose TD Jr.: Effects of acetate
and bicarbonate hemodialysis on cardiac function in chronic dialysis
patients. Kidney Int 24:782–787, 1983
45. Anderson LE, Nixon JV, Henrich WL: Effects of acetate and bicar-
bonate dialysate on left ventricular performance. Am J Kidney Dis
10:350–355, 1987
46. Hampl H, Klopp HW, Michels N, Mahiout A, Schilling H, Wolfgru-
ber M, Schiller R, Hanefeld F, Kessel M: Electroencephalogram inves-
tigations of the disequilibrium syndrome during bicarbonate and
acetate dialysis. Proc Eur Dial Transplant Assoc 19:351–359, 1983
47. Bland LA, Ridgeway MR, Aguero SM, Carson LA, Favero MS:
Potential bacteriologic and endotoxin hazards associated with liquid
bicarbonate concentrate. ASAIO Trans 33:542–545, 1987
48. Ebben JP, Hirsch DN, Luehmann DA, Collins AJ, Keshaviah PR:
Microbiologic contamination of liquid bicarbonate concentrate for he-
modialysis. ASAIO Trans 33:269–273, 1987
49. Suri R, Kliger A: Frequent hemodialysis: physiological, epidemiologi-
cal and practical aspects. In: Himmelfarb J, Sayegh MH (eds). Chronic
Kidney Disease, Dialysis and Transplantation, 3rd ed. ???: Saunders,
2010: 357
50. Locatelli F, Covic A, Chazot C, Leunissen K, Luno J, Yaqoob M:
Optimal composition of the dialysate, with emphasis on its influence
on blood pressure. Nephrol Dial Transplant 19:785–796, 2004
51. Sam R, Vaseemuddin M, Leong WH, Rogers BE, Kjellstrand CM,
Ing TS: Composition and clinical use of hemodialysates. Hemodial Int
10:15–28, 2006
52. Meyer KB: Dialysate bicarbonate: the case for foot-dragging. Am J
Kidney Dis 62:650–652, 2013
53. Thews O: Model-based decision support system for individual pre-
scription of the dialysate bicarbonate concentration in hemodialysis.
Int J Artif Organs 15:447–455, 1992
54. Thews O, Hutten H: A comprehensive model of the dynamic exchange
processes during hemodialysis. Med Prog Technol 16:145–161, 1990
55. Heineken FG, Brady-Smith M, Haynie J, Van Stone JC: Prescribing
dialysate bicarbonate concentrations for hemodialysis patients. Int J
Artif Organs 11:45–50, 1988
56. Klein E, Autian J, Bower JD, Buffaloe G, Centella LJ, Colton CK,
Darby TD, Farrell PC, Holland FF, Kennedy RS, Lipps B Jr., Mason
R, Nolph KD, Villarroel F, Wathen RL: Evaluation of hemodialyzers
and dialysis membranes. Report of a study group for the Artificial
Kidney-Chronic Uremia Program NIAMDD-1977. Chapter five. Eval-
uation of toxicity potential of hemodialyzers. Artif Organs 2:284–292,
1978
57. Fernandez PC, Cohen RM, Feldman GM: The concept of bicarbonate
distribution space: the crucial role of body buffers. Kidney Int 36:
747–752, 1989
58. Pellet M: Physiologie Humaine I. Paris: SIMEP, 1977
59. Tzanatos H, Dalamangas A, Retsa K, Kapetanaki A, Agroyannis B:
Relation of interdialytic water retention with apparent bicarbonate
space, HCO3 , and pH in hemodialyzed uremic patients. Ren Fail
27:235–238, 2005
60. Agroyannis B, Fourtounas C, Tzanatos H, Dalamangas A, Vlahakos
DV: Relationship between interdialytic weight gain and acid-base sta-
tus in hemodialysis by bicarbonate. Artif Organs 26:385–387, 2002
61. Morel H, Jaffrin MY, Lux C, Renou M, Fessier C, Petit A, Moriniere
P, Legallais C: A comparison of bicarbonate kinetics and acid-base
status in high flux hemodialysis and on-line post-dilution hemodiafil-
tration. Int J Artif Organs 35:288–300, 2012
62. Ledebo I: Acid-base correction and convective dialysis therapies.
Nephrol Dial Transplant 15(Suppl 2):45–48, 2000
63. Heguilen RM, Sciurano C, Bellusci AD, Fried P, Mittelman G, Rosa
Diez G, Bernasconi AR: The faster potassium-lowering effect of high
dialysate bicarbonate concentrations in chronic haemodialysis patients.
Nephrol Dial Transplant 20:591–597, 2005
64. Zhang H, Schaubel DE, Kalbfleisch JD, Bragg-Gresham JL, Robinson
BM, Pisoni RL, Canaud B, Jadoul M, Akiba T, Saito A, Port FK,
Saran R: Dialysis outcomes and analysis of practice patterns suggests
the dialysis schedule affects day-of-week mortality. Kidney Int
81:1108–1115, 2012
65. Foley RN, Gilbertson DT, Murray T, Collins AJ: Long interdialytic
interval and mortality among patients receiving hemodialysis. N Engl
J Med 365:1099–1107, 2011
66. Bleyer AJ, Hartman J, Brannon PC, Reeves-Daniel A, Satko SG,
Russell G: Characteristics of sudden death in hemodialysis patients.
Kidney Int 69:2268–2273, 2006
67. Graziani G, Casati S, Passerini P, Crepaldi M, Campise M, Ambroso
G: Pathophysiology and clinical consequences of metabolic alkalosis
in hemodialyzed patients. Arch Ital Urol Nefrol Androl 59: 105–111,
1987
68. Gabutti L, Ferrari N, Giudici G, Mombelli G, Marone C: Unexpected
haemodynamic instability associated with standard bicarbonate hae-
modialysis. Nephrol Dial Transplant 18:2369–2376, 2003
69. Gabutti L, Ross V, Duchini F, Mombelli G, Marone C: Does bicar-
bonate transfer have relevant hemodynamic consequences in standard
hemodialysis? Blood Purif 23:365–372, 2005
70. Gabutti L, Bianchi G, Soldini D, Marone C, Burnier M: Haemody-
namic consequences of changing bicarbonate and calcium concentra-
tions in haemodialysis fluids. Nephrol Dial Transplant 24:973–981,
2009
71. Kaye M, Somerville PJ, Lowe G, Ketis M, Schneider W: Hypocalce-
mic tetany and metabolic alkalosis in a dialysis patient: an unusual
event. Am J Kidney Dis 30:440–444, 1997
72. Sethi D, Curtis JR, Topham DL, Gower PE: Acute metabolic alkalo-
sis during haemodialysis. Nephron 51:119–120, 1989
73. Noris M, Todeschini M, Casiraghi F, Roccatello D, Martina G, Mi-
netti L, Imberti B, Gaspari F, Atti M, Remuzzi G: Effect of acetate,
bicarbonate dialysis, and acetate-free biofiltration on nitric oxide syn-
thesis: implications for dialysis hypotension. Am J Kidney Dis 32:115–
124, 1998
74. Grandi E, Govoni M, Furini S, Severi S, Giordano E, Santoro A,
Cavalcanti S: Induction of NO synthase 2 in ventricular cardiomyo-
cytes incubated with a conventional bicarbonate dialysis bath. Nephrol
Dial Transplant 23:2192–2197, 2008
75. Noh US, Yi JH, Han SW, Kim HJ: Varying dialysate bicarbonate
concentrations in maintenance hemodialysis patients affect post-dialy-
sis alkalosis but not pre-dialysis acidosis. Electrolyte Blood Press 5:
95–101, 2007
76. Oettinger CW, Oliver JC: Normalization of uremic acidosis in hemodi-
alysis patients with a high bicarbonate dialysate. J Am Soc Nephrol
3:1804–1807, 1993
77. Alfakir M, Moammar MQ, Ali MI, Alhatem E, Curran RD, Saoud
RM, Chandran C, Khan MA, Debari VA: Pulmonary gas exchange
during hemodialysis: a comparison of subjects with and without
COPD on bicarbonate hemodialysis. Ann Clin Lab Sci 41:315–320,
2011
78. De Broe ME, Heyrman RM, De Backer WA, Verpooten GA, Verme-
ire PA: Pathogenesis of dialysis-induced hypoxemia: a short overview.
Kidney Int Suppl 24:S57–S61, 1988
79. Jacob AI, Gavellas G, Zarco R, Perez G, Bourgoignie JJ: Leukopenia,
hypoxia, and complement function with different hemodialysis mem-
branes. Kidney Int 18:505–509, 1980
80. Pitcher WD, Diamond SM, Henrich WL: Pulmonary gas exchange
during dialysis in patients with obstructive lung disease. Chest
96:1136–1141, 1989
81. Wu DY, Shinaberger CS, Regidor DL, McAllister CJ, Kopple JD,
Kalantar-Zadeh K: Association between serum bicarbonate and death
in hemodialysis patients: is it better to be acidotic or alkalotic? Clin J
Am Soc Nephrol 1:70–78, 2006
82. Vashistha T, Kalantar-Zadeh K, Molnar MZ, Torlen K, Mehrotra R:
Dialysis modality and correction of uremic metabolic acidosis: rela-
tionship with all-cause and cause-specific mortality. Clin J Am Soc
Nephrol 8:254–264, 2013
 BICARBONATE THERAPY IN END-STAGE RENAL DISEASE
83. Bommer J, Locatelli F, Satayathum S, Keen ML, Goodkin DA, Saito
A, Akiba T, Port FK, Young EW: Association of predialysis serum
bicarbonate levels with risk of mortality and hospitalization in the
Dialysis Outcomes and Practice Patterns Study (DOPPS). Am J Kid-
ney Dis 44:661–671, 2004
84. Lowrie EG, Lew NL: Death risk in hemodialysis patients: the
predictive value of commonly measured variables and an evaluation of
death rate differences between facilities. Am J Kidney Dis 15:458–482,
1990
85. Chauveau P, Fouque D, Combe C, Laville M, Canaud B, Azar R,
Cano N, Aparicio M, Leverve X: Acidosis and nutritional status in
hemodialyzed patients. French Study Group for Nutrition in Dialysis.
Semin Dial 13:241–246, 2000
86. Messa P, Mioni G, Maio GD, Ferrando C, Lamperi D, Famularo A,
Paoletti E, Cannella G: Derangement of acid-base balance in
uremia and under hemodialysis. J Nephrol 14(Suppl 4):S12–S21,
2001
7
87. Chen JL, Kalantar-Zadeh K: Is an increased serum bicarbonate con-
centration during hemodialysis associated with an increased risk of
death? Semin Dial 27:259–262, 2014
88. Care FM: Internal Memo: Dialysate Bicarbonate, Alkalosis and Patient
Safety. Available at http://graphics8.nytimes.com/packages/pdf/busi-
ness/fresenius-memo.pdf, accessed March 27, 2015
89. Tentori F, Karaboyas A, Robinson BM, Morgenstern H, Zhang J,
Sen A, Ikizler TA, Rayner H, Fissell RB, Vanholder R, Tomo T, Port
FK: Association of dialysate bicarbonate concentration with mortality
in the Dialysis Outcomes and Practice Patterns Study (DOPPS). Am J
Kidney Dis 62:738–746, 2013
90. Kovesdy CP, Kalantar-Zadeh K: Observational studies versus ran-
domized controlled trials: avenues to causal inference in nephrology.
Adv Chronic Kidney Dis 19:11–18, 2012
91. Checherita IA, David C, Ciocalteu A, Lascar I, Budala L: Oral treat-
ment of metabolic acidosis in hemodialyzed patients and the implica-
tions on the hemodynamic status. Rom J Morphol Embryol 54:
539–543, 2013
 BICARBONATE THERAPY IN END-STAGE RENAL DISEASE
remains speculative, and makes it difficult to pro-
vide firm recommendations about best clinical prac-
tices.
Based purely on inferences from known physio-
logical principles one could postulate that it might
be possible to reduce the adverse effects associated
with the non-physiological delivery of bicarbonate
during thrice-weekly dialysis if a portion of this
bicarbonate was provided using oral bicarbonate
supplementation, combined with a lower (physio-
logic) dialysate bicarbonate concentration. In a
small single centre study the administration of oral
bicarbonate resulted in a lower incidence of haemo-
dynamic instability during dialysis, though post-dia-
lytic hypotension and evolution of left ventricular
hypertrophy was not affected (91). Future studies
are needed to confirm these results, and also to bet-
ter describe the effects of frequent dialytic strategies
on acid-base homeostasis.
Conclusions
Both acidaemia and alkalaemia can be associated
with adverse consequences, and hence maintenance
of acid-base balance remains an important aspect of
renal replacement therapies. The maintenance of a
physiological acid-base balance in most ESRD
patients requires exogenously administered bicarbon-
ate, yet our most common treatment paradigm (i.e.,
thrice-weekly haemodialysis) results in frequent and
potentially extreme fluctuations in serum bicarbon-
ate, with potentially significant adverse consequences.
The optimal method of bicarbonate delivery during
MHD needs to be ascertained with more studies.
Potential solutions include a multifaceted approach
of oral and individualized MHD delivery of bicar-
bonate, or frequent dialysis modalities using lower
dialysate concentrations. These strategies could pre-
vent both pre-dialysis metabolic acidosis and severe
post-dialysis metabolic alkalosis in ESRD patients,
and hence could result in improved outcomes.
References
1. United States Renal Data System 2010 Annual Data Report: Atlas of
Chronic Kidney Disease & End-Stage Renal Disease in the United
States. Am J Kidney Dis 57(Suppl 1):e1–e526, 2011
2. Warnock DG: Uremic acidosis. Kidney Int 34:278–287, 1988
3. Bailey JL: Metabolic acidosis: an unrecognized cause of morbidity in
the patient with chronic kidney disease. Kidney Int Suppl S15–23:2005
4. Widmer B, Gerhardt RE, Harrington JT, Cohen JJ: Serum electrolyte
and acid base composition. The influence of graded degrees of chronic
renal failure. Arch Intern Med 139:1099–1102, 1979
5. Gautheir P, Simmons EE, Lemann J: Acidosis of chronic renal failure.
In: DuBose TD, Hamm L (eds). Acid-Base and Electrolyte Disorders:
A Companion to Brenner and Rector’s The Kidney. Philadelphia: Saun-
ders, 2002: 207–216
6. Goodman AD, Lemann J Jr., Lennon EJ, Relman AS: Production,
excretion, and net balance of fixed acid in patients with renal acidosis.
J Clin Investig 44:495–506, 1965
7. Lemann J Jr., Litzow JR, Lennon EJ: The effects of chronic acid
loads in normal man: further evidence for the participation of bone
mineral in the defense against chronic metabolic acidosis. J Clin Inves-
tig 45:1608–1614, 1966
5
8. Kovesdy CP: Metabolic acidosis and kidney disease: does bicarbonate
therapy slow the progression of CKD? Nephrol Dial Transplant
27:3056–3062, 2012
9. Williams B, Hattersley J, Layward E, Walls J: Metabolic acidosis and
skeletal muscle adaptation to low protein diets in chronic uremia. Kid-
ney Int 40:779–786, 1991
10. Ballmer PE, McNurlan MA, Hulter HN, Anderson SE, Garlick PJ,
Krapf R: Chronic metabolic acidosis decreases albumin synthesis and
induces negative nitrogen balance in humans. J Clin Investig 95:39–45,
1995
11. Bailey JL, Wang X, England BK, Price SR, Ding X, Mitch WE: The
acidosis of chronic renal failure activates muscle proteolysis in rats by
augmenting transcription of genes encoding proteins of the ATP-
dependent ubiquitin-proteasome pathway. J Clin Investig 97:1447–
1453, 1996
12. May RC, Bailey JL, Mitch WE, Masud T, England BK: Glucocortic-
oids and acidosis stimulate protein and amino acid catabolism in vivo.
Kidney Int 49:679–683, 1996
13. de Brito-Ashurst I, Varagunam M, Raftery MJ, Yaqoob MM: Bicar-
bonate supplementation slows progression of CKD and improves
nutritional status. J Am Soc Nephrol 20:2075–2084, 2009
14. Graham KA, Reaich D, Channon SM, Downie S, Gilmour E, Pas-
slick-Deetjen J, Goodship TH: Correction of acidosis in CAPD
decreases whole body protein degradation. Kidney Int 49:1396–1400,
1996
15. Movilli E, Zani R, Carli O, Sangalli L, Pola A, Camerini C, Cancarini
GC, Scolari F, Feller P, Maiorca R: Correction of metabolic acidosis
increases serum albumin concentrations and decreases kinetically eval-
uated protein intake in haemodialysis patients: a prospective study.
Nephrol Dial Transplant 13:1719–1722, 1998
16. Movilli E, Bossini N, Viola BF, Camerini C, Cancarini GC, Feller P,
Strada A, Maiorca R: Evidence for an independent role of metabolic
acidosis on nutritional status in haemodialysis patients. Nephrol Dial
Transplant 13:674–678, 1998
17. Graham KA, Reaich D, Channon SM, Downie S, Goodship TH: Cor-
rection of acidosis in hemodialysis decreases whole-body protein deg-
radation. J Am Soc Nephrol 8:632–637, 1997
18. Alpern RJ, Sakhaee K: The clinical spectrum of chronic metabolic aci-
dosis: homeostatic mechanisms produce significant morbidity. Am J
Kidney Dis 29:291–302, 1997
19. Lefebvre A, de Vernejoul MC, Gueris J, Goldfarb B, Graulet AM,
Morieux C: Optimal correction of acidosis changes progression of
dialysis osteodystrophy. Kidney Int 36:1112–1118, 1989
20. Mathur RP, Dash SC, Gupta N, Prakash S, Saxena S, Bhowmik D:
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. Ren Fail 28:
1–5, 2006
21. Graham KA, Hoenich NA, Tarbit M, Ward MK, Goodship TH: Cor-
rection of acidosis in hemodialysis patients increases the sensitivity of
the parathyroid glands to calcium. J Am Soc Nephrol 8:627–631, 1997
22. DeFronzo RA, Smith D, Alvestrand A: Insulin action in uremia. Kid-
ney Int Suppl 16:S102–S114, 1983
23. Kaptein EM: Thyroid hormone metabolism and thyroid diseases in
chronic renal failure. Endocr Rev 17:45–63, 1996
24. Mahesh S, Kaskel F: Growth hormone axis in chronic kidney disease.
Pediatr Nephrol 23:41–48, 2008
25. Anantharaman P, Schmidt RJ: Sexual function in chronic kidney dis-
ease. Adv Chronic Kidney Dis 14:119–125, 2007
26. Yavuz D, Topcu G, Ozener C, Akalin S, Sirikci O: Macroprolactin
does not contribute to elevated levels of prolactin in patients on renal
replacement therapy. Clin Endocrinol 63:520–524, 2005
27. Albaaj F, Sivalingham M, Haynes P, McKinnon G, Foley RN, Wal-
dek S, O’Donoghue DJ, Kalra PA: Prevalence of hypogonadism in
male patients with renal failure. Postgrad Med J 82:693–696, 2006
28. Phisitkul S, Khanna A, Simoni J, Broglio K, Sheather S, Rajab MH,
Wesson DE: Amelioration of metabolic acidosis in patients with low
GFR reduced kidney endothelin production and kidney injury, and
better preserved GFR. Kidney Int 77:617–623, 2010
29. Mahajan A, Simoni J, Sheather SJ, Broglio KR, Rajab MH, Wesson
DE: Daily oral sodium bicarbonate preserves glomerular filtration rate
by slowing its decline in early hypertensive nephropathy. Kidney Int
78:303–309, 2010
30. Kurtz I, Maher T, Hulter HN, Schambelan M, Sebastian A: Effect of
diet on plasma acid-base composition in normal humans. Kidney Int
24:670–680, 1983
31. Gennari FJ, Hood VL, Greene T, Wang X, Levey AS: Effect of die-
tary protein intake on serum total CO2 concentration in chronic kid-
ney disease: modification of diet in renal disease study findings. Clin J
Am Soc Nephrol 1:52–57, 2006
32. Barsotti G, Cupisti A, Ciardella F, Morelli E, Niosi F, Giovannetti S:
Compliance with protein restriction: effects on metabolic acidosis and
progression of renal failure in chronic uremics on supplemented diet.
Contrib Nephrol 81:42–49, 1990
6 Saikumar and Kovesdy
33. Klahr S, Levey AS, Beck GJ, Caggiula AW, Hunsicker L, Kusek JW,
Striker G: The effects of dietary protein restriction and blood-pressure
control on the progression of chronic renal disease. Modification of
Diet in Renal Disease Study Group. N Engl J Med 330:877–884,
1994
34. Levey AS, Adler S, Caggiula AW, England BK, Greene T, Hunsicker
LG, Kusek JW, Rogers NL, Teschan PE: Effects of dietary protein
restriction on the progression of advanced renal disease in the Modifi-
cation of Diet in Renal Disease Study. Am J Kidney Dis 27:652–663,
1996
35. Levey AS, Greene T, Beck GJ, Caggiula AW, Kusek JW, Hunsicker
LG, Klahr S: Dietary protein restriction and the progression of
chronic renal disease: what have all of the results of the MDRD study
shown? Modification of Diet in Renal Disease Study group. J Am Soc
Nephrol 10:2426–2439, 1999
36. Pedrini MT, Levey AS, Lau J, Chalmers TC, Wang PH: The effect of
dietary protein restriction on the progression of diabetic and nondia-
betic renal diseases: a meta-analysis. Ann Intern Med 124:627–632,
1996
37. Fouque D, Laville M, Boissel JP, Chifflet R, Labeeuw M, Zech PY:
Controlled low protein diets in chronic renal insufficiency: meta-analy-
sis. BMJ 304:216–220, 1992
38. K/DOQI NKF: Clinical Practice Guidelines for nutrition in chronic
renal failure. Am J Kidney Dis 35: 1–140, 2000
39. Lonnemann G, Bingel M, Koch KM, Shaldon S, Dinarello CA:
Plasma interleukin-1 activity in humans undergoing hemodialysis with
regenerated cellulosic membranes. Lymphokine Res 6:63–70, 1987
40. Daugirdas JT: Dialysis hypotension: a hemodynamic analysis. Kidney
Int 39:233–246, 1991
41. Gennari FJ: Acid-base balance in dialysis patients. Kidney Int 28:
678–688, 1985
42. Wolff J, Pedersen T, Rossen M, Cleemann-Rasmussen K: Effects of
acetate and bicarbonate dialysis on cardiac performance, transmural
myocardial perfusion and acid-base balance. Int J Artif Organs 9:
105–110, 1986
43. Nixon JV, Mitchell JH, McPhaul JJ Jr., Henrich WL: Effect of he-
modialysis on left ventricular function. Dissociation of changes in fill-
ing volume and in contractile state. J Clin Investig 71:377–384, 1983
44. Mehta BR, Fischer D, Ahmad M, Dubose TD Jr.: Effects of acetate
and bicarbonate hemodialysis on cardiac function in chronic dialysis
patients. Kidney Int 24:782–787, 1983
45. Anderson LE, Nixon JV, Henrich WL: Effects of acetate and bicar-
bonate dialysate on left ventricular performance. Am J Kidney Dis
10:350–355, 1987
46. Hampl H, Klopp HW, Michels N, Mahiout A, Schilling H, Wolfgru-
ber M, Schiller R, Hanefeld F, Kessel M: Electroencephalogram inves-
tigations of the disequilibrium syndrome during bicarbonate and
acetate dialysis. Proc Eur Dial Transplant Assoc 19:351–359, 1983
47. Bland LA, Ridgeway MR, Aguero SM, Carson LA, Favero MS:
Potential bacteriologic and endotoxin hazards associated with liquid
bicarbonate concentrate. ASAIO Trans 33:542–545, 1987
48. Ebben JP, Hirsch DN, Luehmann DA, Collins AJ, Keshaviah PR:
Microbiologic contamination of liquid bicarbonate concentrate for he-
modialysis. ASAIO Trans 33:269–273, 1987
49. Suri R, Kliger A: Frequent hemodialysis: physiological, epidemiologi-
cal and practical aspects. In: Himmelfarb J, Sayegh MH (eds). Chronic
Kidney Disease, Dialysis and Transplantation, 3rd ed. ???: Saunders,
2010: 357
50. Locatelli F, Covic A, Chazot C, Leunissen K, Luno J, Yaqoob M:
Optimal composition of the dialysate, with emphasis on its influence
on blood pressure. Nephrol Dial Transplant 19:785–796, 2004
51. Sam R, Vaseemuddin M, Leong WH, Rogers BE, Kjellstrand CM,
Ing TS: Composition and clinical use of hemodialysates. Hemodial Int
10:15–28, 2006
52. Meyer KB: Dialysate bicarbonate: the case for foot-dragging. Am J
Kidney Dis 62:650–652, 2013
53. Thews O: Model-based decision support system for individual pre-
scription of the dialysate bicarbonate concentration in hemodialysis.
Int J Artif Organs 15:447–455, 1992
54. Thews O, Hutten H: A comprehensive model of the dynamic exchange
processes during hemodialysis. Med Prog Technol 16:145–161, 1990
55. Heineken FG, Brady-Smith M, Haynie J, Van Stone JC: Prescribing
dialysate bicarbonate concentrations for hemodialysis patients. Int J
Artif Organs 11:45–50, 1988
56. Klein E, Autian J, Bower JD, Buffaloe G, Centella LJ, Colton CK,
Darby TD, Farrell PC, Holland FF, Kennedy RS, Lipps B Jr., Mason
R, Nolph KD, Villarroel F, Wathen RL: Evaluation of hemodialyzers
and dialysis membranes. Report of a study group for the Artificial
Kidney-Chronic Uremia Program NIAMDD-1977. Chapter five. Eval-
uation of toxicity potential of hemodialyzers. Artif Organs 2:284–292,
1978
57. Fernandez PC, Cohen RM, Feldman GM: The concept of bicarbonate
distribution space: the crucial role of body buffers. Kidney Int 36:
747–752, 1989
58. Pellet M: Physiologie Humaine I. Paris: SIMEP, 1977
59. Tzanatos H, Dalamangas A, Retsa K, Kapetanaki A, Agroyannis B:
Relation of interdialytic water retention with apparent bicarbonate
space, HCO3 , and pH in hemodialyzed uremic patients. Ren Fail
27:235–238, 2005
60. Agroyannis B, Fourtounas C, Tzanatos H, Dalamangas A, Vlahakos
DV: Relationship between interdialytic weight gain and acid-base sta-
tus in hemodialysis by bicarbonate. Artif Organs 26:385–387, 2002
61. Morel H, Jaffrin MY, Lux C, Renou M, Fessier C, Petit A, Moriniere
P, Legallais C: A comparison of bicarbonate kinetics and acid-base
status in high flux hemodialysis and on-line post-dilution hemodiafil-
tration. Int J Artif Organs 35:288–300, 2012
62. Ledebo I: Acid-base correction and convective dialysis therapies.
Nephrol Dial Transplant 15(Suppl 2):45–48, 2000
63. Heguilen RM, Sciurano C, Bellusci AD, Fried P, Mittelman G, Rosa
Diez G, Bernasconi AR: The faster potassium-lowering effect of high
dialysate bicarbonate concentrations in chronic haemodialysis patients.
Nephrol Dial Transplant 20:591–597, 2005
64. Zhang H, Schaubel DE, Kalbfleisch JD, Bragg-Gresham JL, Robinson
BM, Pisoni RL, Canaud B, Jadoul M, Akiba T, Saito A, Port FK,
Saran R: Dialysis outcomes and analysis of practice patterns suggests
the dialysis schedule affects day-of-week mortality. Kidney Int
81:1108–1115, 2012
65. Foley RN, Gilbertson DT, Murray T, Collins AJ: Long interdialytic
interval and mortality among patients receiving hemodialysis. N Engl
J Med 365:1099–1107, 2011
66. Bleyer AJ, Hartman J, Brannon PC, Reeves-Daniel A, Satko SG,
Russell G: Characteristics of sudden death in hemodialysis patients.
Kidney Int 69:2268–2273, 2006
67. Graziani G, Casati S, Passerini P, Crepaldi M, Campise M, Ambroso
G: Pathophysiology and clinical consequences of metabolic alkalosis
in hemodialyzed patients. Arch Ital Urol Nefrol Androl 59: 105–111,
1987
68. Gabutti L, Ferrari N, Giudici G, Mombelli G, Marone C: Unexpected
haemodynamic instability associated with standard bicarbonate hae-
modialysis. Nephrol Dial Transplant 18:2369–2376, 2003
69. Gabutti L, Ross V, Duchini F, Mombelli G, Marone C: Does bicar-
bonate transfer have relevant hemodynamic consequences in standard
hemodialysis? Blood Purif 23:365–372, 2005
70. Gabutti L, Bianchi G, Soldini D, Marone C, Burnier M: Haemody-
namic consequences of changing bicarbonate and calcium concentra-
tions in haemodialysis fluids. Nephrol Dial Transplant 24:973–981,
2009
71. Kaye M, Somerville PJ, Lowe G, Ketis M, Schneider W: Hypocalce-
mic tetany and metabolic alkalosis in a dialysis patient: an unusual
event. Am J Kidney Dis 30:440–444, 1997
72. Sethi D, Curtis JR, Topham DL, Gower PE: Acute metabolic alkalo-
sis during haemodialysis. Nephron 51:119–120, 1989
73. Noris M, Todeschini M, Casiraghi F, Roccatello D, Martina G, Mi-
netti L, Imberti B, Gaspari F, Atti M, Remuzzi G: Effect of acetate,
bicarbonate dialysis, and acetate-free biofiltration on nitric oxide syn-
thesis: implications for dialysis hypotension. Am J Kidney Dis 32:115–
124, 1998
74. Grandi E, Govoni M, Furini S, Severi S, Giordano E, Santoro A,
Cavalcanti S: Induction of NO synthase 2 in ventricular cardiomyo-
cytes incubated with a conventional bicarbonate dialysis bath. Nephrol
Dial Transplant 23:2192–2197, 2008
75. Noh US, Yi JH, Han SW, Kim HJ: Varying dialysate bicarbonate
concentrations in maintenance hemodialysis patients affect post-dialy-
sis alkalosis but not pre-dialysis acidosis. Electrolyte Blood Press 5:
95–101, 2007
76. Oettinger CW, Oliver JC: Normalization of uremic acidosis in hemodi-
alysis patients with a high bicarbonate dialysate. J Am Soc Nephrol
3:1804–1807, 1993
77. Alfakir M, Moammar MQ, Ali MI, Alhatem E, Curran RD, Saoud
RM, Chandran C, Khan MA, Debari VA: Pulmonary gas exchange
during hemodialysis: a comparison of subjects with and without
COPD on bicarbonate hemodialysis. Ann Clin Lab Sci 41:315–320,
2011
78. De Broe ME, Heyrman RM, De Backer WA, Verpooten GA, Verme-
ire PA: Pathogenesis of dialysis-induced hypoxemia: a short overview.
Kidney Int Suppl 24:S57–S61, 1988
79. Jacob AI, Gavellas G, Zarco R, Perez G, Bourgoignie JJ: Leukopenia,
hypoxia, and complement function with different hemodialysis mem-
branes. Kidney Int 18:505–509, 1980
80. Pitcher WD, Diamond SM, Henrich WL: Pulmonary gas exchange
during dialysis in patients with obstructive lung disease. Chest
96:1136–1141, 1989
81. Wu DY, Shinaberger CS, Regidor DL, McAllister CJ, Kopple JD,
Kalantar-Zadeh K: Association between serum bicarbonate and death
in hemodialysis patients: is it better to be acidotic or alkalotic? Clin J
Am Soc Nephrol 1:70–78, 2006
82. Vashistha T, Kalantar-Zadeh K, Molnar MZ, Torlen K, Mehrotra R:
Dialysis modality and correction of uremic metabolic acidosis: rela-
tionship with all-cause and cause-specific mortality. Clin J Am Soc
Nephrol 8:254–264, 2013
 BICARBONATE THERAPY IN END-STAGE RENAL DISEASE
83. Bommer J, Locatelli F, Satayathum S, Keen ML, Goodkin DA, Saito
A, Akiba T, Port FK, Young EW: Association of predialysis serum
bicarbonate levels with risk of mortality and hospitalization in the
Dialysis Outcomes and Practice Patterns Study (DOPPS). Am J Kid-
ney Dis 44:661–671, 2004
84. Lowrie EG, Lew NL: Death risk in hemodialysis patients: the
predictive value of commonly measured variables and an evaluation of
death rate differences between facilities. Am J Kidney Dis 15:458–482,
1990
85. Chauveau P, Fouque D, Combe C, Laville M, Canaud B, Azar R,
Cano N, Aparicio M, Leverve X: Acidosis and nutritional status in
hemodialyzed patients. French Study Group for Nutrition in Dialysis.
Semin Dial 13:241–246, 2000
86. Messa P, Mioni G, Maio GD, Ferrando C, Lamperi D, Famularo A,
Paoletti E, Cannella G: Derangement of acid-base balance in
uremia and under hemodialysis. J Nephrol 14(Suppl 4):S12–S21,
2001
7
87. Chen JL, Kalantar-Zadeh K: Is an increased serum bicarbonate con-
centration during hemodialysis associated with an increased risk of
death? Semin Dial 27:259–262, 2014
88. Care FM: Internal Memo: Dialysate Bicarbonate, Alkalosis and Patient
Safety. Available at http://graphics8.nytimes.com/packages/pdf/busi-
ness/fresenius-memo.pdf, accessed March 27, 2015
89. Tentori F, Karaboyas A, Robinson BM, Morgenstern H, Zhang J,
Sen A, Ikizler TA, Rayner H, Fissell RB, Vanholder R, Tomo T, Port
FK: Association of dialysate bicarbonate concentration with mortality
in the Dialysis Outcomes and Practice Patterns Study (DOPPS). Am J
Kidney Dis 62:738–746, 2013
90. Kovesdy CP, Kalantar-Zadeh K: Observational studies versus ran-
domized controlled trials: avenues to causal inference in nephrology.
Adv Chronic Kidney Dis 19:11–18, 2012
91. Checherita IA, David C, Ciocalteu A, Lascar I, Budala L: Oral treat-
ment of metabolic acidosis in hemodialyzed patients and the implica-
tions on the hemodynamic status. Rom J Morphol Embryol 54:
539–543, 2013