Effect of Bicarbonate Supplementation on Renal Function and Nutritional Indices in Predialysis Advanced Chronic Kidney Disease

Chronic metabolic acidosis is a common complication of advanced chronic kidney disease (CKD), especially among patients with an estimated glomerular filtration rate (eGFR) lower than 25mL/min/1.73m² 1). It can have substantial adverse effects, including exacerbation of bone disease, increase of muscle degradation with muscle wasting, reduction of albumin synthesis, and possible acceleration of the progression of CKD2).

Current practice guidelines recommend correcting the serum bicarbonate to greater than 22mEq/L to prevent potential adverse effects related to chronic metabolic acidosis in CKD3). However, clinicians may be reluctant to prescribe the oral bicarbonate in advanced CKD patients with edema or uncontrolled hypertension. Although alkali therapy in CKD has been examined in some clinical trials4, 5, 6, 7, 8, 9), information for the impact of bicarbonate supplementation in advanced CKD patients who have a high risk of severe malnutrition and edema is very limited.

We investigated the effect of oral bicarbonate supple mentation on renal function and nutritional indices in predialysis advanced CKD patients.We compared the effect of bicarbonate supplementation in patients with stage 4 and predialysis stage 5 CKD.

Forty patients with stage 5 CKD not receiving renal replacement therapy (eGFR <15mL/min per 1.73m²) and 40 patients with stage 4 CKD(eGFR 15 to 30mL/min per 1.73m²) who had total CO₂ less than 22mEq/L were enrolled from outpatient clinics of Chungbuk National University Hospital. Patients were assigned to receive either oral sodium bicarbonate in the treatment group or standard care without alkali in the control group for 12 months. In the 40 patients with alkali treatment group, the dosage of sodium bicarbonate (Tasna®, HCO₃ 5.95 mEq/500mg) were started 1,000mg thrice daily and then were adjusted as necessary to maintain total CO₂ level greater than 22mEq/L. We excluded patients with malignant disease, liver cirrhosis, infection, sepsis, and overt congestive heart failure. This study was approved by the Institutional Review Board of Chungbuk National University Hospital. Blood pressure, body weight, serum electrolyte, total CO₂, creatinine, BUN, eGFR, calcium, phosphorous, intact PTH were assessed at baseline and 12 month of the study. The eGFR was calculated by the Modification of Diet in Renal Disease formula: eGFR (mL/min/1.73m²)=186×(serum creatinine)^-1.154×(Age)^-0.203× 0.742 (female).

Nutritional indices were assessed body mass index (BMI), mid-arm muscle circumference (MAMC), prealbumin, albumin, transferrin, total lymphocyte count (TLC), and Onodera's prognostic nutritional index (OPNI) at baseline and 12 month of study. BMI was derived using weight and height. MAMC was derived from the Bishop10) formula using mid-arm circumference (MAC) and triceps skin-fold thickness (TSF):MAMC(cm)=MAC(cm)-TSF (mm)×0.314. TLC was calculated by multiplying the percentage of lymphocytes with the total white blood cell count. The OPNI was calculated based on the serum albumin and total lymphocyte count, using the following equation: OPNI=10×serum albumin (g/dL)+0.005×total lymphocyte count (/mm³)11).

SigmaPlot 12.0 for windows software was used for all statistical analysis (Systat Software Inc, San Jose, CA, USA). Values are expressed as mean±SD. The comparisons between baseline and 12 month were assessed by paired t-test, and comparisons between groups were assessed by unpaired t-test or Wilcox singed-rank test. A p-value of less than 0.05 was considered statistically significant.

Overt chronic metabolic acidosis in CKD patients develops after a drop in GFR to less than approximately 25mL/min/1.73m² 1). The National Kidney Foundation Kidney Disease Outcomes Quality Initiative guidelines recommend correcting the serum bicarbonate to greater than 22mEq/L to prevent potential adverse effects related to chronic metabolic acidosis, including bone disease, progression of CKD and malnutrition1, 3). Although alkali therapy in CKD has been examined in some clinical trials4, 5, 6, 7, 8, 9), information on the effects of bicarbonate supplementation in advanced CKD patients who have a high risk of severe malnutrition, uncontrolled hypertension and edema is very limited.

In a randomized, prospective study, de Brito-Ashurst et al.5) suggested that sodium bicarbonate slowed the rate of creatinine clearance decline from 5.93 to 1.88mL/min per 1.73m²/year in patients with stage 4 CKD. Phisitkul et al.12) noted sodium citrate slowed the rate of decrease in eGFR in patients with hypertensive nephropathy with eGFR of 20 to 60mL/min/1.73m².

We compared the effects of oral bicarbonate supplementation on the progression of CKD and nutritional indices in predialysis stage 5 and stage 4 CKD. This study demonstrated that oral bicarbonate supplementation slowed the rate of decline of eGFR in stage 4 CKD. However, rate of decline of eGFR was similar between the treatment group and control group in stage 5 CKD. In this study, the annual decline of eGFR in stage 4 CKD is similar to the previously reported study5, 12).

Malnutrition is a potential consequence of chronic metabolic acidosis13). In advanced CKD, treatment of severe acidosis has produced improvements in anthropometric measures of lean body mass in some but not all reports14, 15, 16, 17). Several small, short-term clinical trials, mainly of dialysis patients, suggested that correction of acidosis is associated with increased serum albumin and improved nutritional status18). Uremic acidosis can increase skeletal muscle breakdown and diminish albumin synthesis, leading to muscle wasting and muscle weakness1, 13). The catabolic state appears to be mediated by acidosis, acting in part by the increased release of cortisol and diminished release of insulin-like growth factor-I, leading to the loss of lean body mass and muscle weakness19). These abnormalities in muscle function and/or albumin metabolism can be reversed by alkali therapy to correct the acidosis, including optimal correction of acidosis in patients undergoing chronic dialysis16, 17, 18).

We were unable to demonstrate the beneficial effect of alkali therapy on serum albumin, and mid-arm muscle circumference in contrast to the previous studies5). However, in this study, there were significant differences in the changes of TLC and OPNI during the study period between the treatment group and control group in stage 5 CKD, but not stage 4 CKD. Our study demonstrated that oral sodium bicarbonate supplementation for 12 months might improve the biochemical nutritional indices in stage 5 CKD.

TLC has been proposed as a prognostic factor20). Malnutrition can induce a decrease in TLC and suppression of cellular immunity including delayed hypersensitivity reaction21). Reddan et al.22) showed that the lymphocyte count was associated with the nutritional status and mortality in dialysis patients. Onodera et al.11) first reported the validity of the OPNI to predict the prognosis in gastrointestinal surgical patients.

In advanced CKD, the anticipated adverse effects of sodium bicarbonate supplementation were worsening hypertension and edema as a result of sodium retention. The adverse event of both groups were similar. In this study, after sodium bicarbonate supplementation, there was a tendency of weight gain and increased blood pressure in stage 5 CKD.

In meta-analysis, the sodium bicarbonate administered in the long-term trials had no adverse effect on blood pressure or cardiac function23). Although alkali therapy is well tolerated in advanced CKD, potential complications of sodium bicarbonate, such as volume overload and worsened hypertension, need to be monitored carefully in stage 5 CKD.

This study has several strengths. To the best of our knowledge, the study is the first to examine the effect of bicarbonate supplementation in stage 5 CKD patients not on dialysis. In addition, various biochemical nutritional indices such as prealbumin, transferrin, TLC, and OPNI as well as albumin were used for assessment of nutritional status. Despite the strengths, there are limitations to this study. The small number of subjects in a single center study was not enough to compare the differences between groups. The serum total CO₂ level did not reach greater than 22mEq/L during bicarbonate treatment.

Our results demonstrate that bicarbonate supplementation in advanced CKD with metabolic acidosis slows the rate of decline of renal function only in stage 4 CKD, but not stage 5 CKD. In addition, bicarbonate supplementation may have a beneficial effect on malnutrition in stage 5 CKD, but not stage 4 CKD. Alkali therapy in advanced CKD may have a beneficial effect on renal function and malnutrition, which may differ depending on the stage of CKD.