In this study, the serum bicarbonate levels of the elderly CKD patients were controlled within the normal range. We demonstrated that a high serum bicarbonate level was associated a low risk of CKD progression in elderly CKD patients. Our findings are consistent with previous reports that a low serum bicarbonate level is associated with CKD progression [4–7, 12]. There has been no study of serum bicarbonate level in elderly CKD patients. The participants in our present study were older than those in other studies . This study also showed that, although the average serum bicarbonate level of the low-bicarbonate group was controlled within the normal range in accordance with K/DOQI guidelines 2000, being in the lowest quartile of serum bicarbonate levels was associated with a high risk of CKD progression. In this analysis, a low serum bicarbonate level remained independently related to a high HR of CKD progression. These findings suggest that a high serum bicarbonate level within the normal range may prevent CKD progression in elderly CKD patients.
The optimal management of acidemia or metabolic acidosis in CKD patients, including the monitoring of serum bicarbonate level and sodium bicarbonate administration, has not been established yet. Our study showed that the patients with a serum bicarbonate level lower than 25.5 mEq/l had a high risk of CKD progression. The K/DOQI guidelines 2000 and CARI guidelines recommend that the serum bicarbonate level should be maintained at or above 22 mEq/l [16, 17]. In a trial, the effect of sodium bicarbonate on CKD progression was compared between the bicarbonate-treated group and the control group . The average serum bicarbonate level of the control group at baseline was 19.9 mEq/l, and the average serum bicarbonate level of the bicarbonate-treated group gradually became higher than 22 mEq/l . As the lower limit, 22 mEq/l may be a useful target serum bicarbonate level in clinical practice presently.
This study showed that a high serum bicarbonate level within the normal range decreased the risk of CKD progression in elderly CKD patients. A subanalysis of the African American Study of Kidney Disease and Hypertension showed that a higher baseline serum bicarbonate level within the range from 20 to 30 mEq/l was associated with a lower risk of the composite of death, dialysis, and GFR events . A retrospective cohort study of the Modification of Diet in Renal Disease Study showed that patients with serum bicarbonate levels from 26 to 40 mEq/l had a lower risk of kidney failure or death than patients with serum bicarbonate levels from 11 to 25 mEq/l . However, the target serum bicarbonate level in the upper limit has not been established. A cohort study showed that patients with serum bicarbonate levels higher than 32 mEq/l showed a higher risk of death than patients with serum bicarbonate levels from 23 to 32 mEq/l . The effect of a high serum bicarbonate level on mortality is related to complications such as hypokalemia, hypocalcemia, or hypomagnesemia, with resultant cardiac arrhythmias . These studies suggest that, as long as serum bicarbonate level is controlled within the normal range, a serum bicarbonate level higher than the lower limit may reduce the risk of CKD progression. Thus, the upper limit of the target serum bicarbonate might be equal to the upper limit of the normal range, 32 mEq/l.
It has been reported that the capacity to excrete net endogenous acid decreases significantly with age . Elderly CKD patients have a high risk of metabolic acidosis. It is necessary to regularly monitor their serum bicarbonate level to prevent metabolic acidosis. There has been no report about the mechanisms that definitely explain CKD progression in response to metabolic acidosis in not only elderly CKD patients but also young CKD patients. From studies using animal models, a few mechanisms are suggested. The increase in renal medullary ammonia level resulting from the stimulation of ammonia production by metabolic acidosis activates the alternative complement pathway and causes progressive tubulointerstitial injury . New bicarbonate synthesized by the kidney in response to acidosis alkalinizes the interstitium and promotes precipitation of calcium in the kidney . Increased endothelin production may mediate the tubulointerstitial injury and decrease in GFR associated with metabolic acidosis in CKD [10, 23]. The mechanism underlying the renal protective effect of sodium bicarbonate in humans has not been clarified yet, either. Studies using experimental animal models of CKD suggest that alkali therapy attenuates tubulointerstitial inflammation and may slow the progression to kidney failure [21, 24]. A cohort study of the African American Study of Kidney Disease and Hypertension showed that net endogenous acid production was associated with faster CKD progression in CKD patients, whose serum bicarbonate levels were within the normal range . The present study showed that a low serum bicarbonate level within the normal range was independently related to a high HR of CKD progression. These results suggest that a lower serum bicarbonate level might indicate a higher net production of endogenous or exogenous acids, which might be the main cause of CKD progression. The administration of sodium bicarbonate to attain an upper limit of serum bicarbonate level within the normal range may suppress CKD progression caused by net endogenous acid production, and may prevent the subsequent events such as interstitial fibrosis that lead to CKD progression.
This study has several limitations. First, as with any observational study, we were unable to compare two groups whose characteristics were controlled. The patient distribution in CKD stages was not balanced, which might have affected the results on the CKD progression in the low-bicarbonate group. Nonetheless, this study showed that serum bicarbonate level was independently associated with CKD progression after the adjustment for patient characteristics. Second, in this study, the population included patients treated and untreated with sodium bicarbonate. The proportion of sodium bicarbonate use and the dose of sodium bicarbonate were higher in the low-bicarbonate group than in the control group. The sample size was not large enough to analyze the treated and untreated patients separately. Third, in this study, we examined 113 patients. The statistical power of this study may not be sufficient for detecting the relationship between laboratory variables and CKD progression. Fourth, the number of censored observations was high. The main reason for censoring was the change of hospital. Selection and geographical biases may have been included in this study. Fifth, acidosis-related markers such as arterial blood gas, arterial pH, and endogenous acid production were not measured. We were unable to investigate the determinants of the low serum bicarbonate levels that may contribute to CKD progression. Sixth, CKD-mineral-bone-disease-related markers, such as serum calcium, phosphate, and parathyroid hormone levels, were not measured. Therefore, we were unable to evaluate the relationship between serum bicarbonate level and bone metabolism.