Diagnosis and Treatment of Metabolic Acidosis in Patients with Chronic Kidney Disease – Position Statement of the Working Group of the Polish Society of Nephrology
Adamczak M.a · Masajtis-Zagajewska A.b · Mazanowska O.c · Madziarska K.d · Stompór T.e · Więcek A.a
Kidney Blood Press Res 2018;43:959–969
The goal of treatment of metabolic acidosis in patients with chronic kidney disease is to achieve a venous plasma or venous blood bicarbonate concentration equal to or greater than 22 mmol/l (recommendation based on results of interventional studies).
Commentary on recommendations 4 and 5
The first reports of beneficial effects of the combination of a low-protein diet with oral administration of sodium bicarbonate in patients with CKD were published as early as in the 1930s .
In recent years, the results of three clinical trials on the impact of alkali therapy on CKD progression have been published. De Brito-Ashurst et al.  conducted a randomised trial which included 134 patients with CKD stage 4 and a serum bicarbonate concentration between 16 mmol/l and 20 mmol/l, who were treated with standard therapy or additionally received sodium bicarbonate at the average dose of 1.82 g/day. The authors of the study demonstrated that administration of sodium bicarbonate in CKD patients slows CKD progression measured by GFR reduction, reduces the number of patients requiring renal replacement therapy, and improves nutritional status . Mahajan et al.  observed a much slower GFR decrease in patients with hypertensive nephropathy in the course of five-year treatment with sodium bicarbonate compared to patients receiving a similar amount of sodium as sodium chloride.
Based on results of available clinical trials we suggest an initial daily dose of 1-2 g of sodium bicarbonate. Subsequently, while monitoring the venous plasma and venous blood bicarbonate concentration, the dose of sodium bicarbonate should be increased until the target bicarbonate concentration, i.e. equal to or greater than 22 mmol/l, is achieved. Due to the lack of data on the safety of sodium bicarbonate used in high doses, in the opinion of the authors a maximal daily dose of 6 g of sodium bicarbonate should not be exceeded.
It is believed that metabolic acidosis treatment using sodium bicarbonate in patients with CKD is well tolerated and safe.
Treatment of metabolic acidosis with sodium bicarbonate at the most commonly used doses, i.e. 2-3 g/day, may sometimes lead to the development of metabolic alkalosis. Therefore, in the course of alkali therapy, the plasma or venous blood bicarbonate concentration should be checked periodically to prevent the process of excessive alkalisation. Results of observational studies suggest that excessive alkalisation may be potentially dangerous. In the CRIC study, in patients with CKD stages 2 – 4 with a serum bicarbonate concentration above 26 mmol/l, an increase in mortality and in the incidence of heart failure were observed compared to patients with a serum bicarbonate concentration between 22 and 26 mmol/l . Navaneethan et al. found increased mortality in patients with CKD stages 3 – 4 and a serum bicarbonate concentration above 32 mmol/l in comparison to patients with a serum bicarbonate concentration between 23 and 32 mmol/l. In this study, a two-fold prevalence of heart failure and chronic obstructive pulmonary disease was observed in patients with the serum bicarbonate concentration above 32 mmol/l compared to patients with a serum bicarbonate concentration between 23 and 32 mmol/l . Taking this into account, it can be assumed that the increased mortality in patients with a serum bicarbonate concentration higher than 26 or 32 mmol/l in the quoted observational studies, respectively, may result from the co-occurrence of heart failure (administration of diuretics can cause hypokalemia, and subsequently lead to an increase in the concentration of bicarbonate in the serum), or the co-occurrence of chronic obstructive pulmonary disease (in the course of which elevated pCO2 is accompanied by a compensatory increase in the concentration of bicarbonate in the serum). However, given the above mentioned results of observational studies, the temporary cessation of sodium bicarbonate administration can be considered in clinical situations which can foster the development of metabolic alkalosis (e.g.: vomiting, hypokalemia).
Taking into consideration the fact that sodium bicarbonate contains sodium, it could be assumed that administration of sodium bicarbonate would lead to an increase in blood pressure. However, this was not the case in experimental studies, as well as, in the clinical trials in humans. Namely, experimental studies done in salt-dependent deoxycorticosterone hypertensive rats (DOCA – salt-sensitive rats) and spontaneously hypertensive stroke prone rats suggested that sodium bicarbonate, in contrast, to sodium chloride – does not lead to the blood pressure elevation [42–44]. No blood pressure increase was observed in the study of De Bristo – Ashurst et al. . The dose of sodium bicarbonate (1.82 g, containing 499 mg sodium) used in this study provided an amount of sodium corresponding to only 10-14% of daily consumption. In addition, the meta-analysis of intervention studies carried out by Susantitaphong et al.  has shown that sodium bicarbonate supplementation in patients with CKD is not associated with the need to initiate antihypertensive treatment or with an increase in the number antihypertensive drugs used. In the 1970s, Husted et al. showed that oral sodium bicarbonate treatment in patients with CKD, as opposed to administration of NaCl, did not lead to an increase in systolic blood pressure . They stated that the administration of sodium in the form of sodium bicarbonate increased natriuresis, which allowed the maintenance of a normal body content of sodium. On the other hand, the increase in natriuresis as a result of exposure to sodium in the form of NaCl is smaller and insufficient for the compensation of increased sodium supply . Sodium bicarbonate, in contrast to NaCl, does not increase blood pressure either in healthy subjects or in patients with arterial hypertension .
The use of sodium bicarbonate in large doses may (extremely rarely) lead to an increase in the volume of the stomach (through the release of CO2) and even to rupture of the stomach wall. To prevent this complication, it is recommended that sodium bicarbonate is taken between meals .
Interventional study results indicate that oral administration of sodium citrate may be an alternative method of alkali therapy to treatment with sodium bicarbonate. During a two-year observation of 59 patients with hypertensive nephropathy (eGFR ranging 20-60 ml/ min) treated with sodium citrate for metabolic acidosis, Phisitkul et al. showed a reduction in the rate of decrease of eGFR from 3.8 ml/min/year to 1.9 ml/min/year . However, sodium citrate increases absorption of aluminium from the gastrointestinal tract. Therefore, it should not be used in patients with significantly impaired renal function (especially while taking aluminium-containing phosphate binders, although these medications are almost never used nowadays). In addition, the use of sodium citrate does not lead to an increase of bicarbonate concentration in patients with liver damage, as the conversion of citrates into bicarbonates occurs mainly in the liver. The authors of the current recommendations do not have personal experience of the use of sodium citrate in alkali therapy.
In addition to pharmacological treatment, a diet rich in vegetables and fruits (the so-called “alkaline diet”) may have a beneficial effect on metabolic acidosis in CKD patients [50–52]. Renoprotective effects of this diet has been found in patients with hypertensive nephropathy and CKD stage 1 . Goraya et al. , in a study involving 71 patients with hypertensive nephropathy (eGFR > 90 ml/min) and albuminuria, found that proteinuria did not worsen in patients following a diet with an increased content of fruits and vegetables, in contrast to patients not undergoing alkali therapy. In patients with CKD stage 3 and a concentration of tCO2 in the serum between 22 mmol/l and 24 mmol/l treated with sodium bicarbonate or following a diet with an increased content of fruits and vegetables, the decrease in eGFR (calculated based on creatinine and cystatin C plasma concentrations) over a three-year period, was lower than in those not receiving sodium bicarbonate or the above-mentioned diet . In an observational study of 76 non-diabetic patients with hypertensive nephropathy and GFR ranging between 15 ml/min and 29 ml/min taking angiotensin converting enzyme inhibitors, with serum potassium concentrations below 4.6 mmol/l and metabolic acidosis, Goraya et al. showed a similar degree of improvement of metabolic acidosis, reduction of albuminuria and reduction of GFR in patients treated with sodium bicarbonate and those receiving a diet enriched with fruits and vegetables . Careful selection of patients participating in the study (i.e. without a tendency to hyperkalemia) and close monitoring of serum potassium concentrations reduced the risk of hyperkalemia in patients with impaired renal function even though a potassium-rich diet was ingested . Scialla et al. showed that in patients at different CKD stages, a diet rich in vegetable protein increased the concentration of bicarbonate in the blood .
It should be kept in mind that the use of the so-called “alkaline diet”, i.e. a diet rich in fruits and vegetables, in patients with CKD can potentially lead to hyperkalemia. It should also be noted that no studies have been conducted on the safety of a diet with an increased content of fruits and vegetables under the conditions of routine clinical practice (i.e. not under the conditions of a clinical trial). In clinical practice, a diet with an increased content of fruits and vegetables should be considered in CKD patients only in stages 1 – 2.