JASN Express. Published on July 16, 2009 as doi: 10.1681/ASN.2008111205 CLINICAL RESEARCH www.jasn.org Bicarbonate Supplementation Slows Progression of CKD and Improves Nutritional Status Ione de Brito-Ashurst, Mira Varagunam, Martin J. Raftery, and Muhammad M. Yaqoob Department of Renal Medicine and Transplantation, William Harvey Research Institute and Barts and the London NHS Trust, London, United Kingdom ABSTRACT Bicarbonate supplementation preserves renal function in experimental chronic kidney disease (CKD), but whether the same benefit occurs in humans is unknown. Here, we randomly assigned 134 adult patients with CKD (creatinine clearance [CrCl] 15 to 30 ml/min per 1.73 m2) and serum bicarbonate 16 to 20 mmol/L to either supplementation with oral sodium bicarbonate or standard care for 2 yr. The primary end points were rate of CrCl decline, the proportion of patients with rapid decline of CrCl (Ͼ3 ml/min per 1.73 m2/yr), and ESRD (CrCl Ͻ10 ml/min). Secondary end points were dietary protein intake, normalized protein nitrogen appearance, serum albumin, and mid-arm muscle circumference. Compared with the control group, decline in CrCl was slower with bicarbonate supplementation (5.93 versus 1.88 ml/min 1.73 m2; P Ͻ 0.0001). Patients supplemented with bicarbonate were significantly less likely to experience rapid progression (9 versus 45%; relative risk 0.15; 95% confidence interval 0.06 to 0.40; P Ͻ 0.0001). Similarly, fewer patients supplemented with bicarbonate developed ESRD (6.5 versus 33%; relative risk 0.13; 95% confidence interval 0.04 to 0.40; P Ͻ 0.001). Nutritional parameters improved significantly with bicarbonate supplementation, which was well tolerated. This study demonstrates that bicarbonate supplementation slows the rate of progression of renal failure to ESRD and improves nutritional status among patients with CKD. J Am Soc Nephrol ●●: –, 2009. doi: 10.1681/ASN.2008111205 Metabolic acidosis (MA), generally perceived by albumin, a reduction in normalized protein cata- Ϫ 8–10 clinicians as a low plasma bicarbonate (HCO3 ), is bolic rate, and an increase in the concentrations a common complication in patients with advanced of total essential amino acids.11,12 chronic kidney disease (CKD), particularly when Evidence implicating MA in the progression of GFR falls below 30 ml/min.1 This, in turn, may renal failure in patients with CKD is less convinc- bring about a variety of sequelae, such as stunted ing. Some experimental studies in rats have indi- growth in children, loss of bone and muscle mass, cated that the MA of CKD is associated with the negative nitrogen balance, and possible accelera- development and worsening of proteinuria and tu- tion of progression of CKD.2 There is good experi- mental but limited clinical evidence that MA con- Received November 24, 2008. Accepted May 18, 2009. tributes to protein-energy wasting (PEW) disorder 3 Published online ahead of print. Publication date available at in patients with CKD. Acidosis is associated with www.jasn.org. increased protein catabolism4 as a result of upregu- 5 This study is registered on the International Standard Random- lation of the ubiquitin-proteasome system, exces- ized Controlled Trial Number Registry (ISRCTN-17109689). sive oxidation of branched-chain amino acids,6 and Correspondence: Prof. Muhammad M. Yaqoob, Department of reduced synthesis of visceral proteins including al- Renal Medicine and Transplantation, Royal London Hospital, bumin.7 Several small, short-term clinical trials, Whitechapel, London E1 1BB UK. Phone: ϩ442073777236; Fax: mainly of dialysis patients, suggested that correc- ϩ442073777003; E-mail: [email protected] tion of acidosis is associated with increased serum Copyright ᮊ 2009 by the American Society of Nephrology J Am Soc Nephrol ●●: –, 2009 ISSN : 1046-6673/●●00- 1 CLINICAL RESEARCH www.jasn.org RESULTS During a 1-yr period, 184 incident patients Ϫ with CKD and low plasma HCO3 were seen. Fifty patients were excluded: 20 refused con- sent, and 30 were ineligible because of exclu- sion criteria (steroid therapy, n ϭ 4; congestive heart failure, n ϭ 7; uncontrolled hyperten- sion, n ϭ 11; cognitive impairment, n ϭ 3; on- going sepsis, n ϭ 2; and morbid obesity, n ϭ 3). A total of 134 patients were recruited. After re- cruitment and randomization, five patients from the treatment group withdrew before re- ceiving any study drug because three were transferred to another affiliated renal unit and two were unwilling to perform the 24-h urine collections every 2 mo (Figure 1). Their 6-monthly data were included for an intention- to-treat analysis. Demographic characteristics were similar for both groups (Table 1). There were no significant differences in any baseline clinical or nutritional parameters between the two groups (Table 2). Oral sodium bicarbonate supplementation was given at a dosage of 1.82 Ϯ 0.80 g/d, Figure 1. Participant enrollment and randomization to the study. Arm A (left whereas the control group received standard column) allocated to oral bicarbonate and arm B (right colum) allocated to Ϫ standard therapy. treatment. Serum HCO3 levels increased sig- nificantly in the treatment group compared bulointerstitial fibrosis and acceleration in the rate of decline with the control group and was maintained throughout the in renal function13–16; however, other studies have failed to study period (P Ͻ 0.001; Figure 2A). This was achieved at confirm this effect. Rats with CKD produced by the 5/6 ne- the expense of an increased sodium intake, as shown by phrectomy model failed to demonstrate a beneficial effect of 17 sodium bicarbonate supplementation. In rats that had CKD Table 1. Baseline demographic characteristics of patientsa and were receiving a high-phosphate diet, MA actually pre- Variable Control Bicarbonate vented progression of renal failure, presumably as a result of inhibition of calcium phosphate deposition in the kidney.18,19 Demographic Ϯ Ϯ Ϯ Few studies have examined the effects of amelioration of MA age (yr; mean SE) 54.77 2.34 54.78 2.56 on renal function in humans. In short-term studies, adminis- male (%) 51 52 white (%) 52 52 tration of oral sodium bicarbonate to patients with moderate black/Asian (%) 48 48 renal failure led to reduced protein catabolism, reduced am- Diagnosis (%) monia production, and tubular damage, as assessed by bio- diabetes 36 37 20 chemical parameters. Because of the short-term follow-up, hypertension 26 29 no substantial impact on renal function could be demonstrat- CRF unknown 14 10 ed; however, in one cohort study,21 MA was independently glomerulonephritis 13 10 associated with acceleration of renal failure in patients with obstructive uropathy 4 1 CKD. The lack of long-term studies examining the impact of other 7 12 alleviation of MA on renal function in predialysis patients and Medications (%) on nutritional status was the particular stimulus to perform loop diuretics 67 70 this study. We proposed the hypothesis that oral bicarbonate moxonodine 15 17 Ϫ ␣ blockers 57 59 supplementation in patients with acidosis (plasma HCO3 ␤ Ͼ Ͻ blockers 17 19 levels 16 and 20 mmol/L) would be associated with atten- calcium channel 48 50 uation of the rate of decline of creatinine clearance (CrCl) and blockers a reduction in number of patients with rapid progression of ACEIs/ARBs 48 50 renal failure defined arbitrarily as an annual fall in CrCl Ͼ3 allopurinol 3 0 2 ml/min per 1.73 m . aCRF, chronic renal failure. 2 Journal of the American Society of Nephrology J Am Soc Nephrol ●●: –, 2009 www.jasn.org CLINICAL RESEARCH Table 2. Baseline characteristics of the study populationa increased urinary sodium excretion in the Variable Control Bicarbonate P treatment group compared with control Ͻ Weight (kg) 74.9 Ϯ 11.5 76.6 Ϯ 21.1 0.84 patients (P 0.05; Figure 2B). Systolic BP (mmHg) 123.7 Ϯ 1.2 124.0 Ϯ 1.3 0.84 Despite increased sodium intake, BP Diastolic BP (mmHg) 75.4 Ϯ 1.9 76.1 Ϯ 1.5 0.91 control was similar between the groups MAMC (cm) 24.8 Ϯ 2.4 24.6 Ϯ 2.9 0.81 (Figure 2C). The number of patients with Albumin (g/L) 35.1 Ϯ 0.8 34.7 Ϯ 0.5 0.76 BP of Ͼ130/80 mmHg was 14 and 10 at Bicarbonate (mmol/L) 19.9 Ϯ 1.5 19.8 Ϯ 2.2 0.66 baseline, 15 and 16 at 12 mo, and 16 and 17 CrCl (ml/min per 1.73 m2) 20.70 Ϯ 5.55 20.12 Ϯ 6.47 0.60 at the end of the study in the control and Urinary Na (mmol/L) 140.1 Ϯ 4.4 140.0 Ϯ 7.9 0.96 bicarbonate groups, respectively. Through- Ϯ Ϯ Urinary protein (g/24 h) 1.8 0.2 1.7 0.8 0.84 out the study period, the proportion of pa- a Ϯ Data are means SE. tients in both groups with BP of Ͼ130/80 mmHg was not statistically significant (P ϭ 0.60). There was no difference in the num- Ϫ Figure 2. (A) Plasma HCO3 levels during the study period. Squares and bars denote means and SD. (B) Urinary sodium (Na) excretion per day. Squares and bars denote means and SD. (C) BP control during the study period. Squares and bars denote means and SD. (D) Urinary total protein excretion per day during the study period. Squares and bars denote means and SD. (E) Rate of decline of CrCl. Squares and bars denote means and SD. J Am Soc Nephrol ●●: –, 2009 Bicarbonate and Progression of CKD 3 CLINICAL RESEARCH www.jasn.org Table 3. Adverse events during the study perioda Control (% of Bicarbonate (% of Adverse Events P Patients) Patients) Hospitalization for CHF 0 0 N/A Worsening hypertension requiring increase in therapy 48 61 0.17 Worsening edema requiring increase in loop diuretics 30 39 0.5 Bad taste requiring switch to powder form of sodium bicarbonate N/A 6.5 N/A aCHF, congestive heart failure.