Treatment of metabolic acidosis in renal failure

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Original ArticlesChronic Kidney Disease

Open Access

A Systematic Review and Meta-Analysis

CJASN July 2019, 14 [7] 1011-1020; DOI: //doi.org/10.2215/CJN.13091118

Abstract

Background and objectives Metabolic acidosis is associated with progression of CKD and has significant adverse effects on muscle and bone. A systematic review and meta-analysis was conducted to evaluate the benefits and risks of metabolic acidosis treatment with oral alkali supplementation or a reduction of dietary acid intake in those with CKD.

Design, setting, participants, & measurements MEDLINE, Embase, and Cochrane CENTRAL were searched for relevant trials in patients with stage 3–5 CKD and metabolic acidosis [1 year follow-up [Figure 3]. Sensitivity analysis conducted by excluding studies with low-normal serum bicarbonate levels are presented in Supplemental Figures 1 and 2. There was a significant reduction in urinary ACR [two trials, 167 patients; mean difference −51.55 mg/g; 95% CI, −75.73 to −27.38; I2=0%; 95% CI, 0% to 73%; Table 2] with treatment [very low certainty]. In addition, on the basis of low certainty, oral alkali supplementation or dietary intervention significantly reduced the risk of progression to ESKD [four trials, 434 patients; RR, 0.32; 95% CI, 0.18 to 0.56; I2=17%; 95% CI, 0% to 73%; Figure 4] with no heterogeneity between these two types of interventions.

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Figure 4.

Forest plot shows potentially reduced risk of end stage kidney disease with oral alkali supplementation or reduction of dietary acid intake. I2 for the combined effect estimate: [95% CI, 0% to 73%]. df, degrees of freedom; M-H, Mantel-Haenszel.

Biochemical Measurements

Oral alkali supplementation or dietary intervention significantly increased the serum bicarbonate level compared with the control groups [Table 3]. There were no significant differences in serum potassium, calcium, phosphate, albumin, and parathyroid hormone levels, and midarm muscle circumference between the groups [Table 3].

Adverse Effects

Oral Alkali Supplementation.

One trial reported that oral alkali supplementation significantly increased 24-hour urinary sodium excretion [n=134] [7], and urinary sodium-to-creatinine ratio [n=59] [15]. Pooled analyses also showed worsening edema requiring increased diuretic therapy and worsening hypertension or the requirement for increased antihypertensive therapy in the treatment [sodium bicarbonate or sodium citrate] group [Table 4, very-low certainty]. Table 4 outlines other adverse events.

Table 4.

Adverse effects of oral alkali supplementation or reduction of dietary acid intake in patients with CKD with metabolic acidosis

Dietary Intervention.

In contrast to oral alkali supplementation, treatment of metabolic acidosis with dietary intervention significantly reduced systolic BP. There was also a trend toward decreased body weight and diastolic BP, although these were not statistically significant [Table 4].

Study Quality and Publication Bias.

Supplemental Figure 3 outlines the risk of bias of the included studies. Publication bias was not tested for outcomes other than eGFR decline and serum bicarbonate because of the smaller number of studies [fewer than ten studies] [Supplemental Figures 4 and 5]. There was no evidence of publication bias for these outcome measures.

Discussion

This meta-analysis of clinical trials using oral alkali supplementation or reduction in dietary acid intake, compared with no treatment, usual care, or placebo, for the treatment of metabolic acidosis in patients with stage 3–5 CKD found that these treatments significantly increased serum bicarbonate and resulted in a slower decline in eGFR and a reduction in ACR, along with a reduction in the risk of progression to ESKD. Oral alkali supplementation, however, was associated with worsening edema requiring increased diuretic therapy and worsening hypertension or the requirement for increased antihypertensive therapy. Dietary intervention was associated with a significant reduction in systolic BP. In general, the strength of evidence for reported outcomes varied from very low to moderate certainty evidence using the Grading of Recommendations, Assessment, Development and Evaluations criteria [22].

Retrospective studies in humans have found that serum bicarbonate levels below the normal range were associated with more rapid decline in kidney function [3–6]. Experimental studies in animals with reduced nephron mass also have shown that acid-inducing diets cause a progressive decline in GFR that is mediated by metabolic acidosis [30,31]. Proposed mechanisms through which acidosis accelerates the progression of CKD include increased production of hormones [e.g., endothelin, angiotensin II, and aldosterone] and proinflammatory cytokines, and activation of complement induced by increased ammonia production per nephron, each of which promotes acute acid excretion but chronically results in kidney inflammation and fibrosis through enhanced complement and renin-angiotensin system activation [32]. Studies using oral alkali therapy in animals and humans with reduced kidney function have demonstrated a slower decline in eGFR [7,33,34]. A previous meta-analysis included six studies [two short-term, 2 months] on the effects of alkali therapy. In aggregate, they demonstrated improvement in kidney function but differences in study protocol and small sample size precluded the authors from reaching definitive conclusions [9]. Dietary interventions were not included in this earlier review.

Our analyses of pooled data from the existing clinical trials note that treatment of metabolic acidosis, using either oral alkali or dietary interventions, significantly increased serum bicarbonate levels, and offered kidney benefits in patients with stage 3–5 CKD and metabolic acidosis. These data also indicate that there may be a potentially higher effect eGFR decline at the end of study period with oral alkali [mean difference −4.00 [95% CI, −5.07 to −2.93] ml/min slower decline] than dietary interventions [mean difference −2.70 [95% CI, −4.71 to −0.70] ml/min slower decline], but the test of subgroup difference was not significant [P=0.26] [Figure 2]. As expected, interventions testing oral alkali or dietary interventions had several differences in their characteristics [study population, interventions, follow-up, etc.]. Effects of oral alkali on albuminuria were assessed only in two trials, limiting the reliability of ascertaining the benefits of treatment of metabolic acidosis on this parameter. Although it is encouraging to see potential benefits, it is important to note that data for kidney disease progression to ESKD were derived from only four trials, two each for oral alkali supplementation and dietary intervention, with significant reduction for ESKD using dietary intervention but not with oral alkali supplementation [Figure 4]. Given the lack of trials comparing oral alkali and dietary interventions head to head, superiority of one over the other is unclear. Additional adequately powered trials are needed to derive definitive conclusions regarding the effect of treatment of metabolic acidosis on the risk of kidney disease progression to ESKD with these different types of interventions.

Higher consumption of acid-producing animal protein contributes to metabolic acidosis in patients with CKD. Dietary interventions have been shown to provide an effective means of raising serum bicarbonate in patients with CKD who have metabolic acidosis or low-normal bicarbonate levels. Our summary data from the dietary intervention studies showed smaller but significantly slower reduction in kidney function, although with significant heterogeneity between the included studies that could be attributed to the differences among the dietary intervention protocols. These data should be interpreted with caution since these studies were not primarily designed to address the metabolic effect of these diets and included different levels of protein restriction. Base-providing diets tend to have a high potassium content and hence participants in these studies were carefully selected to be at very low risk to develop hyperkalemia [11,13,14]. Further, willingness to adhere to a restrictive diet is a challenging factor in dietary intervention studies in patients with CKD. In one study, only 14% of screened patients who met all eligibility criteria agreed to adhere to the dietary requirements and were randomized [16]. Other dietary interventions that could alter acid-base status in patients with CKD were not included in this analysis because of a lack of bicarbonate data. Further, some patients with normal serum bicarbonate levels could have been included these studies; future individual patient-level [rather than study-level] meta-analysis could provide additional insights. Further, it is possible that the observed benefits with dietary interventions could be ascribed to effects apart from the noted improvement in metabolic acidosis. Despite these limitations, the potential benefits of dietary intervention merit carefully designed larger studies.

Potential benefits of oral alkali supplementation on nutritional assessments such as serum albumin and potassium, midarm muscle circumference, and handgrip strength were suggested in a few single-center studies with a limited number of patients [7,35], but no significant differences were noted in our analysis. Ongoing trials could provide additional details about the effects of bicarbonate supplementation on physical function and quality of life [36]. We also did not find outcome data for several prespecified outcomes [outlined in the Materials and Methods], and thus, a meta-analysis could not be conducted for these outcomes. In this analysis, there was a significant increase in worsening edema requiring increased diuretic therapy and worsening hypertension or the requirement for increased antihypertensive therapy associated with oral alkali supplementation in patients with CKD. Further, two trials reported a significantly increased urinary sodium excretion associated with oral alkali supplementation in those with CKD. Observational data associate higher urinary sodium excretion with kidney disease progression and cardiovascular events [37,38]. It is important to note that the prospective studies included in this analysis were designed to exclude patients with CKD and comorbidities including uncontrolled hypertension, decompensated congestive heart failure, morbid obesity, volume overload, or hyperkalemia [39]. Hence, the generalizability of these data to patients with CKD and multiple comorbidities is unclear.

This review has several strengths and limitations. Strengths include a systematic search of all major medical databases, data extraction and analysis, and trial quality assessment according to a prespecified protocol [17]. Most included studies enrolled patients with stage 3–5 CKD and metabolic acidosis [serum bicarbonate