Acid Base Balance and Progression of Kidney Disease

doi:10.1016/j.semnephrol.2019.04.009

Seminars in Nephrology

Volume 39, Issue 4, July 2019, Pages 406-417

https://doi.org/10.1016/j.semnephrol.2019.04.009 Get rights and content

Summary: A large body of work in animals and human beings supports the hypothesis that metabolic acidosis has a deleterious effect on the progression of kidney disease. Alkali therapy, whether pharmacologically or through dietary intervention, appears to slow CKD progression, but an appropriately powered randomized controlled trial with a low risk of bias is required to reach a more definitive conclusion. Recent work on urinary ammonium excretion has shown that the development of prognostic tools related to acidosis is not straightforward, and that application of urine markers such as ammonium may require more nuance than would be predicted based on our understanding of the pathophysiology.

Section snippets

Mechanism of Maintaining Acid-Base Balance

Tight regulation of acid-base balance plays a pivotal role in normal human physiology. Substantial changes in intracellular and extracellular pH are not compatible with life. Human beings have multiple mechanisms in place to protect against extracellular acidemia and alkalemia. The three major regulators of acid-base balance are as follows: excretion of carbon dioxide via the lungs, intracellular and extracellular buffering systems, and renal elimination of nonvolatile acid and generation of

CLINICAL ACID-BASE PARAMETERS IN CKD

The National Kidney Foundation Kidney Disease Outcomes Quality Initiative Guidelines suggest treating metabolic acidosis and maintaining bicarbonate level at 22 mEq/L or greater.³⁶ Use of serum bicarbonate as a treatment target oversimplifies the disease process and treatment of metabolic acidosis in patients with CKD. Besides bicarbonate concentration, dietary acid load, renal acid excretion, and net acid balance also are significant parameters involved in metabolic acidosis (Table 1).

Dietary

Low Bicarbonate Concentration and CKD Progression

Low bicarbonate concentrations were shown to be associated with faster CKD progression in multiple epidemiologic studies (Table 2). Overall, with every 1 mEq/L increase in bicarbonate concentration, the risk of CKD progression (defined as either end-stage renal disease [ESRD] or a 50% reduction in GFR) decreased by 3% to 8% in approximately 4 years.47, 48, 49 In the Chronic Renal Insufficient cohort (CRIC), which includes non-institutionalized partipants with CKD, participants with CKD stages 2

INTERVENTIONAL STUDIES ON THE EFFECT OF ALKALI THERAPY ON CKD PROGRESSION

Several interventional studies investigated the effect of alkali therapy on CKD progression. We have identified seven main studies and summarized the findings in Table 4.21, 5759, 60, 61, 62, 63 The findings from these studies suggest that alkali therapy using either sodium bicarbonate/citrate or fruits and vegetables has promising effects on preserving renal function. However, most of these studies were conducted in hypertensive patients with either normal to mildly low bicarbonate levels.

Ongoing Clinical Trials on Alkali Therapy and CKD Progression

There are several ongoing clinical trials examining the effect of sodium bicarbonate supplementation in CKD, and they have been described previously.5, 31 Two of these trials examine CKD progression as the primary outcome. One clinical trial is based in Italy (ClinicalTrials.gov; NCT01640119) and is a multicenter, randomized controlled, open-label study.⁶⁶ The investigators plan to randomize 728 patients with CKD stages 3b to 4 to either bicarbonate groups (with administration of sodium

SUMMARY

A large body of work in animals and human beings supports the hypothesis that metabolic acidosis has a deleterious effect on the progression of kidney disease. Alkali therapy, whether pharmacologically or through dietary intervention, appears to slow CKD progression, but a larger randomized controlled trial with a low risk of bias is required to reach a more definitive conclusion. Recent work on urinary ammonium excretion has shown that the development of prognostic tools related to acidosis is

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Cited by (20)

Sodium bicarbonate for kidney transplant recipients with metabolic acidosis in Switzerland: a multicentre, randomised, single-blind, placebo-controlled, phase 3 trial
2023, The Lancet
Metabolic acidosis is common in kidney transplant recipients and is associated with declining graft function. Sodium bicarbonate treatment effectively corrects metabolic acidosis, but no prospective studies have examined its effect on graft function. Therefore, we aimed to test whether sodium bicarbonate treatment would preserve graft function and slow the progression of estimated glomerular filtration rate (GFR) decline in kidney transplant recipients.
The Preserve-Transplant Study was a multicentre, randomised, single-blind, placebo-controlled, phase 3 trial at three University Hospitals in Switzerland (Zurich, Bern, and Geneva), which recruited adult (aged ≥18 years) male and female long-term kidney transplant recipients if they had undergone transplantation more than 1 year ago. Key inclusion criteria were an estimated GFR between 15 mL/min per 1·73 m² and 89 mL/min per 1·73 m², stable allograft function in the last 6 months before study inclusion (<15% change in serum creatinine), and a serum bicarbonate of 22 mmol/L or less. We randomly assigned patients (1:1) to either oral sodium bicarbonate 1·5–4·5 g per day or matching placebo using web-based data management software. Randomisation was stratified by study centre and gender using a permuted block design to guarantee balanced allocation. We did multi-block randomisation with variable block sizes of two and four. Treatment duration was 2 years. Acid-resistant soft gelatine capsules of 500 mg sodium bicarbonate or matching 500 mg placebo capsules were given at an initial dose of 500 mg (if bodyweight was <70 kg) or 1000 mg (if bodyweight was ≥70 kg) three times daily. The primary endpoint was the estimated GFR slope over the 24-month treatment phase. The primary efficacy analyses were applied to a modified intention-to-treat population that comprised all randomly assigned participants who had a baseline visit. The safety population comprised all participants who received at least one dose of study drug. The trial is registered with ClinicalTrials.gov, NCT03102996.
Between June 12, 2017, and July 10, 2019, 1114 kidney transplant recipients with metabolic acidosis were assessed for trial eligibility. 872 patients were excluded and 242 were randomly assigned to the study groups (122 [50%] to the placebo group and 120 [50%] to the sodium bicarbonate group). After secondary exclusion of two patients, 240 patients were included in the intention-to-treat analysis. The calculated yearly estimated GFR slopes over the 2-year treatment period were a median –0·722 mL/min per 1·73 m² (IQR –4·081 to 1·440) and mean –1·862 mL/min per 1·73 m² (SD 6·344) per year in the placebo group versus median –1·413 mL/min per 1·73 m² (IQR –4·503 to 1·139) and mean –1·830 mL/min per 1·73 m² (SD 6·233) per year in the sodium bicarbonate group (Wilcoxon rank sum test p=0·51; Welch t-test p=0·97). The mean difference was 0·032 mL/min per 1·73 m² per year (95% CI –1·644 to 1·707). There were no significant differences in estimated GFR slopes in a subgroup analysis and a sensitivity analysis confirmed the primary analysis. Although the estimated GFR slope did not show a significant difference between the treatment groups, treatment with sodium bicarbonate effectively corrected metabolic acidosis by increasing serum bicarbonate from 21·3 mmol/L (SD 2·6) to 23·0 mmol/L (2·7) and blood pH from 7·37 (SD 0·06) to 7·39 (0·04) over the 2-year treatment period. Adverse events and serious adverse events were similar in both groups. Three study participants died. In the placebo group, one (1%) patient died from acute respiratory distress syndrome due to SARS-CoV-2 and one (1%) from cardiac arrest after severe dehydration following diarrhoea with hypotension, acute kidney injury, and metabolic acidosis. In the sodium bicarbonate group, one (1%) patient had sudden cardiac death.
In adult kidney transplant recipients, correction of metabolic acidosis by treatment with sodium bicarbonate over 2 years did not affect the decline in estimated GFR. Thus, treatment with sodium bicarbonate should not be generally recommended to preserve estimated GFR (a surrogate marker for graft function) in kidney transplant recipients with chronic kidney disease who have metabolic acidosis.
Swiss National Science Foundation.
Eubicarbonatemic Hydrogen Ion Retention and CKD Progression
2021, Kidney Medicine
Citation Excerpt :
Age, largely through the associated kidney function decline, and dietary H+ load codetermine the small but significant decreases in serum [HCO3ˉ] and blood pH that characterize this life stage evidencing H+ retention.59 Trials on the role of H+ retention in CKD progression have largely examined hypobicarbonatemic metabolic acidosis in patients with CKD 3-5.23-29 Only a single small study has tested the impact of alkali (0.5 mEq/kg of lean body weight) in patients with CKD 2 with subclinical metabolic acidosis yielding a positive outcome at 5 and 10 years of follow-up (Table 1).8,42
Small-scale trials in patients with chronic kidney disease (CKD) 3-5 have shown that hypobicarbonatemic metabolic acidosis promotes progression of CKD. Accordingly, the 2012 KDIGO (Kidney Disease: Improving Global Outcomes) guideline suggests base administration to patients with CKD when serum bicarbonate concentration ([HCO₃ˉ]) is <22 mEq/L (~15% of non–dialysis-dependent patients with CKD). However, individuals with milder CKD largely maintain serum [HCO₃ˉ] within the normal range (eubicarbonatemia) and yet can manifest hydrogen ion (H⁺) retention. Limited data in eubicarbonatemic patients with CKD 2 suggest that base administration ameliorates CKD progression. Furthermore, most patients with moderate and advanced CKD maintain a normal serum [HCO₃ˉ], and of those, the vast majority most likely harbor masked H⁺ retention. The present review probes this expanded concept of metabolic acidosis of CKD: the eubicarbonatemic H⁺ retention or subclinical metabolic acidosis of CKD. It focuses on the high prevalence of the entity, its pathophysiologic features, its clinical course, and recent work on potential biomarkers of the condition. Further, it puts forward the urgent task of investigating definitively whether treatment with alkali of eubicarbonatemic H⁺ retention delays CKD progression. If proven true, such knowledge would trigger a paradigm shift in the indication for alkali therapy in CKD.
Nephrolithiasis and Elevated Urinary Ammonium: A Matched Comparative Study
2020, Urology
Citation Excerpt :
Due to our study design, we were not able to further investigate this link, though further research may be useful in identifying potential sex-specific cutoffs. Chronic kidney disease has also been found to decrease ammonia excretion thus leading to metabolic acidosis16-18 however we did not detect any differences between the 2 groups in comparing their creatinine or estimated glomerular filtration rate. Other factors associated with elevated urinary ammonium included recent positive urine culture with urease producing organisms and recurrent UTIs.
To describe the associations between elevated urinary ammonium and clinical characteristics of kidney stone formers. A 24-hour urine test is recommended in high-risk patients to identify urinary abnormalities and select interventions to reduce the recurrence risk. While elevations in urine ammonium may be seen in acidosis, diarrhea, high protein diets or due to pathogenic bacteria, the clinical characteristics of these patients have not been previously described.
We retrospectively identified adult patients with kidney stone disease who completed a 24-hour urine at our institution between 2006 and 2017. Patients with elevated urinary ammonium were identified (n = 121) and matched 1:1 by age and sex to controls for an overall cohort of n = 242. Differences in medical and surgical history, 24-hour urine analytes and stone composition were compared.
Among 3625 24-hour urine studies screened, 7.1% of patients showed high urinary ammonium. In our study cohort, patients with elevated urinary ammonium also showed higher urine volume, oxalate, calcium, uric acid, sodium, chloride, and sulfate. Clinically, these patients had higher body mass index, and more often had a history of recurrent urinary tract infections, diabetes, gout, bowel resection, and urinary reconstruction history. Struvite stones tended to be more common in the elevated ammonium group vs control (n = 7 vs 1, P = .07).
Elevated urinary ammonium among kidney stone patients is relatively uncommon. However, these patients have higher rates of comorbid metabolic conditions, urinary tract infections, and bowel surgery. This finding should prompt further review of the patient's history and may help direct prevention strategies.
Metabolic acidosis in chronic kidney disease: mere consequence or also culprit?
2024, Pflugers Archiv European Journal of Physiology
Metabolic acidosis in pediatric kidney transplant recipients
2023, Pediatric Nephrology
Older patients are less prone to fast decline of renal function: a propensity-matched study
2023, International Urology and Nephrology

View all citing articles on Scopus

: Financial disclosure: supported by K23 DK114476 from the National Institutes of Health and an American Society of Nephrology Carl W. Gottschalk Research Scholar Grant (W.C.); and by K23 DK099438 and R03 DK116023 from the National Institutes of Health (M.K.A.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

: Conflict of interest statement: Matthew Abramowitz has consulted for Tricida, Inc.

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Acid Base Balance and Progression of Kidney Disease

Section snippets

Mechanism of Maintaining Acid-Base Balance

CLINICAL ACID-BASE PARAMETERS IN CKD

Low Bicarbonate Concentration and CKD Progression

INTERVENTIONAL STUDIES ON THE EFFECT OF ALKALI THERAPY ON CKD PROGRESSION

Ongoing Clinical Trials on Alkali Therapy and CKD Progression

SUMMARY

Adv Chronic Kidney Dis

BMC Nephrol

Adv Chronic Kidney Dis

Am J Kidney Dis

Am J Kidney Dis

Adv Chronic Kidney Dis

Adv Chronic Kidney Dis

Am J Kidney Dis

Kidney Int

Kidney Int

Kidney Int

Kidney Int

Kidney Int

J Pharmacol Sci

Am J Kidney Dis

Am J Clin Nutr

Kidney Int

Am J Med Sci

Kidney Int

J Biol Chem

Kidney Int

Kidney Int

Am J Kidney Dis

Am J Kidney Dis

Am J Kidney Dis

Am J Kidney Dis

Am J Kidney Dis

Semin Nephrol

Kidney Int

Kidney Int

Kidney Int

Kidney Int

Kidney Int

Kidney Int