CME INDIA Presentation by Admin.

Chronic metabolic acidosis refers to a condition in which there is a prolonged imbalance in the acid-base balance of the body, leading to excess acid accumulation.

This condition is commonly observed in patients with chronic kidney disease (CKD) and has been associated with increased morbidity and mortality in this population. However, there is evidence to suggest that interventions aimed at increasing serum bicarbonate levels can help mitigate the negative effects of chronic metabolic acidosis and improve outcomes in CKD patients.

Several approaches have been proposed to address chronic metabolic acidosis in CKD. Alkali supplementation, which involves providing the body with substances that can increase serum bicarbonate levels, has been shown to be effective in correcting metabolic acidosis. This can be achieved through the administration of medications such as sodium bicarbonate or potassium citrate.

But..

Question in Discussion (CME INDIA Discussion, June 2023)

Dr. Awadhesh Kumar Singh, DM (Endo), Kolkata:

• Our nephrologist colleagues nearly always prescribe 2 additional Rx in CKD –
• Tab Sodium Bicarbonate.
• Tab Acetyl cysteine + Pyridoxamine.
• Each company earns several billions in selling these two products.
• Does any evidence exist? If no why overprescribing?
• Sodium bicarbonate: being alkaliser – may correct features of metabolic acidosis and gastric acidity. No effect on kidney function. Sodium salt may compromise BP and can-do damage.
• Acetyl cysteine hasn’t been studied in CKD. Pyridoxamine was studied in only trial in 2012 (Lewis et al) – failed to show any benefit.
• The biggest irony is when you say to the patient that it doesn’t work – patients get annoyed and disappointed. As a result, many doctors let them continue – and company building up stacks of companies.
• We need to fix ourselves!

Dr. Pragya Pant (DM Nephrologist), Ranchi:

• Treatment of metabolic acidosis might lead to decrease in rate of progression of CKD, this is endorsed by KIDGO also.
• But yes, I agree, it should be given only after checking serum bicarbonate levels done.
• Not all CKD patients are acidotic.
• Drugs like Tab Acetyl cysteine + Pyridoxamine – No evidence.

Dr. Partha Karamkar, Nephrologist, Kolkata:

• SODIUM BICARBONATE: Definitely has evidence
• NAC +_others: do not have strong evidence, except a few showing reductions in proteinuria and one biased Indian study showing effectiveness.
• Mostly NAC is used non-medical reasons

Dr. Awadhesh K. Singh DM endo. Kolkata:

• Please post those evidence of Sodium Bicarbonate.

Dr. Basab Ghosh, Diabetologist, Agartala:

(I quote as per my nephrologist colleague says about Na Bicarb.)

• The study by Cheng F, Li Q, Wang J, Wang Z et (Ref-9) in 2021did concluded that treatment of metabolic acidosis with sodium bicarbonate may slow the decline rate of kidney function and potentially significantly improve vascular endothelial function in patients with CKD. But the Study subjects were low-normal HCO3(22–24 mEq/L)) here. Most of the included studies in meta-analysis were single-center, open-label trials that enrolled only a small number of patients, preventing the analysis of patient-centered endpoints.

Dr. Awadhesh Kumar Singh, DM (Endo), Kolkata:

Final nail in CKD and acidosis coffin

See the data

What Metabolic Acidosis in CKD leads to?

KIDGO 2022, Crystal Clear Points

Dr. Manisha Singh, MD, FASN, Nephrologist, Arkansas, USA:

• Yes, benefits are there- the important part is to check blood gas and know that there really is metabolic acidosis … just looking at bicarb can lead it errors.
• My personal opinion is that unless the pH is below 7.35, we may not have any benefit of adding sodium bicarb. Lots of happening on Na Bicarbonate front.
• In our study, we found that lowering bicarbonate targets in other clinical scenarios like liver failure, pregnancy, and cardiac failure may be prudent and will lead to a lower sodium load.

Courtesy: http://www.nephjc.com/news/tag/kidney+transplant

Dr. Avinash Kumar Dubey, DM, Nephrology, Ranchi:

• Our research at JIPMER showed that alkali supplementation to increase venous bicarbonate levels to 24–26 mEq/L is associated with preservation of Lean body mass and kidney function in patients with CKD stages 3 and 4.
• One article based on RCT done in CKD stage 3 and 4 shows that some set of patients definitely is being benefitted by soda bicarbonate supplementation.
• Probably diabetic kidney disease patients may not be benefitted much because of increased side effects.

Dr. Basab Ghosh Agartala:

• Tab Sod. Bicarb is over prescribed drug and detrimental.
• Tab Acetyl cysteine + Pyridoxin is just a placebo, unnecessarily increasing economic burden to the terminal cases as 6th or 8th drug.

Dr. Navin Burnwal, Nephrologist Ranchi:

• CKD related metabolic acidosis worsens CKD related mineral bone disease. As metabolic acidosis is almost universal in all patients with CKD stage 4 and beyond, standard practice is to prescribe sodabicarb to keep serum bicarb level above 22.
• Role of Tab Acetyl cysteine + Pyridoxin (Alfa ketone analogue) is very controversial, only few trials with a smaller number of patients have shown their benefits in prevention of progression of CKD, however the dose they used in those trials were very high (around 30 tablets/day- each tablet cost around 50-100 Rs/tablet depending upon brand).

Courtesy: Michal L. Melamed et al A Review of Recent Findings, Kidney Medicine, Volume 3, Issue 2,2021, Pages 267-277, ISSN 2590-0595, https://doi.org/10.1016/j.xkme.2020.12.006

Summary of major associations between serum bicarbonate levels and adverse outcomes in chronic kidney disease (CKD).(Ref-2)

Some other comments:

• Tab Acetyl cysteine + Pyridoxin – how much it saves once patient reached creatinine, means prongs dialysis?
• The mechanism of acetyl cysteine effect is unknown but possible stimulation of tubular secretion of creatinine has been hypothesized based upon a lack of effect on Cystatin C levels.
• It has no specific role in retardation of progress to overt nephropathy, it is just like vitamins we prescribe in illness.
• But pill burden also loosing compliance due to lot of medication they are taking for resistant hypertension.
• Now when patient goes to nephrologist, he has to give some medication for patient satisfaction.

Dr. Nizamuddin, MD, Physician, Thalassery, Kerala:

• Tab Acetyl cysteine + Pyridoxin is an anti-oxidant Value not proven yet but does no harm
• But Soda bicarbonates has a definite role in stage 3 and 4 when there is metabolic acidosis
• Acidosis not only depresses cellular functions, but also Activates complement and causes tubule-interstitial fibrosis It improves albumin excretion and also Endothelin and angiotensinogen…

CME INDIA Learning Points

Dr. Awadhesh K. Singh DM endo. Kolkata:

Not all CKD having acidosis. Global data suggest 15%

CME INDIA Learning Edge

Dr. Manisha Singh, MD, FASN, Nephrologist, Little Rock Arkansas, USA:

The take-home points:

CME INDIA Tail Piece

A

Dosing considerations.

• Before initiating alkali supplementation, it is advisable to obtain a second measurement of serum bicarbonate due to its variation. It is also recommended, particularly when suspecting respiratory alkalosis, to confirm the acid-base disorder through venous blood gas measurement.
• According to clinical guidelines, sodium bicarbonate is commonly used as an alkali supplement, starting at a dose of 650 mg twice daily (equivalent to 15.5 mEq/day of bicarbonate), with the option to increase the dose based on the individual’s response. The recommended dosage ranges from 0.5-1.0 mEq bicarbonate or its equivalent per kilogram of body weight per day.
• Sodium bicarbonate is a cost-effective and readily available option, generally well tolerated, although the most common side effects are bloating and burping. For individuals who experience less bloating, sodium citrate may be used as an alternative. However, it’s important to note that citrate promotes the absorption of intestinal aluminum, which increases the risk of aluminum toxicity for those taking aluminium-containing antacids.
• The use of sodium salts carries potential risks, including exacerbation of hypertension, volume overload, and congestive heart failure. Concerns have been raised regarding higher doses in individuals with chronic kidney disease (CKD) potentially leading to volume retention and worsening hypertension. However, studies using sodium bicarbonate at doses much higher than those recommended by KDIGO and KDOQI did not show an increase in blood pressure or oedema. Although these findings are reassuring, it’s important to consider that the patients in these studies were pre-selected, and individuals with congestive heart failure and uncontrolled hypertension were often excluded.
• It should be noted that alkali therapy can result in metabolic alkalosis, in which case sodium bicarbonate should be temporarily discontinued. Regular monitoring of serum bicarbonate levels is crucial for dose adjustment and to address potential over-treatment. The goal of oral alkali treatment should be to achieve a normal serum bicarbonate level.

B

Any Diabetes related Study? (Ref-3)

• To investigate the potential benefits of alkali therapy in patients with chronic kidney disease (CKD) and diabetes who had normal bicarbonate levels, a randomized, double-blinded, placebo-controlled trial was conducted.
• The study included 74 US veterans with stages 2-4 CKD and diabetes. Key entry criteria consisted of a urinary albumin-creatinine ratio of ≥30 mg/g, a serum bicarbonate level ranging from 22 to 28 mEq/L, and a blood pressure below 140/90 mm Hg. The trial aimed to examine the kidney effects of sodium bicarbonate in this specific population.
• During the trial, participants were administered a dose of sodium bicarbonate equivalent to 0.5 mEq per kilogram of lean body weight per day. After a 6-month treatment period, the primary outcome, which was the urinary transforming growth factor β1 level, did not show a significant difference between the experimental group receiving sodium bicarbonate and the control group receiving a placebo.
• Additionally, there were no notable differences observed between the groups in terms of the urinary kidney injury molecule 1 to creatinine ratio, fibronectin to creatinine ratio, or neutrophil gelatinase-associated lipocalin to creatinine ratio. Furthermore, there were no significant differences in terms of side effects between the two groups.
• In summary, the study did not find any significant improvements in the measured outcomes or notable differences in side effects when comparing sodium bicarbonate therapy to a placebo in individuals with diabetes and CKD who had normal bicarbonate levels.

C

Diagnosis of Metabolic Acidosis in CKD(Ref-5)

• The diagnosis of metabolic acidosis in patients with chronic kidney disease (CKD) is typically based on a consistent serum total carbon dioxide (tCO2) concentration of less than 22 mEq/L, which serves as an indirect measure of bicarbonate concentration.
• However, it’s important to note that low serum tCO2 concentration can also be indicative of respiratory alkalosis. To differentiate between these acid-base disorders, it is preferable to measure systemic pH and Pco2, preferably from an arterial sample.
• However, performing blood gas tests is uncommon in CKD patients with low tCO2 concentrations, as they are not readily available in outpatient settings and are generally unnecessary in most cases.
• Considering the significance of kidney non-volatile acid excretion, a presumptive diagnosis of metabolic acidosis can be made in CKD patients with low tCO2 concentrations without relying on a blood gas analysis.
• However, a blood gas test may be useful in patients with risk factors for chronic respiratory alkalosis, such as liver or cardiopulmonary disease, residing at high altitudes, or if the serum tCO2 concentration does not normalize with alkali therapy. Urine pH is often not helpful in determining the acid-base disorder due to its susceptibility to the influence of urinary buffers.
• In most cases, patients with CKD and metabolic acidosis exhibit a normal serum anion gap, and an increased anion gap is typically absent unless the estimated glomerular filtration rate (eGFR) is very low (less than 15 mL/min/1.73 m2), resulting in the accumulation of phosphate, sulfate, and other anions.
• However, it is crucial to consider the impact of hypoalbuminemia on the anion gap to avoid overlooking subtle increases in the anion gap that may be present.

Suggested Readings:

1. https://www.kidney.org/sites/default/files/02-10-8119_cbj_kls_profed_bulletin_metabolicacidosis_slim.pdf
2. Michal L. Melamed, Kalani L. Raphael,Metabolic Acidosis in CKD: A Review of Recent Findings,Kidney Medicine,Volume 3, Issue 2,2021,Pages 267-277,ISSN 2590-0595,https://doi.org/10.1016/j.xkme.2020.12.006
3. K.L. Raphael, T. Greene, G. Wei, et al.Sodium bicarbonate supplementation and urinary TGF-beta1 in nonacidotic diabetic kidney disease: a randomized, controlled trial.Clin J Am Soc Nephrol, 15 (2) (2020), pp. 200-208
4. https://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=&cad=rja&uact=8&ved=2ahUKEwiGpZfm7uT_AhXhbGwGHWILCLkQFnoECBIQAQ&url=https%3A%2F%2Fkdigo.org%2Fwp-content%2Fuploads%2F2022%2F08%2FKDIGO-Metabolic-Acidosis-Infographic-Set-2022.pdf&usg=AOvVaw1k81dNfjY0rb-RkFJDM_Ev&opi=89978449
5. K.L. Raphael.Metabolic acidosis in CKD: core curriculum 2019.Am J Kidney Dis, 74 (2) (2019), pp. 263-275
6. Avinash Kumar Dubey , Jayaprakash Sahoo, Balasubramanian Vairappan , Satish Haridasan , Sreejith Parameswaran and P.S. Priyamvada. Correction of metabolic acidosis improves muscle mass and renal function in chronic kidney disease stages 3 and 4: a randomized controlled trial. Nephrol Dial Transplant (2018) 1–9 doi: 10.1093/ndt/gfy214
7. Samira Chandra, MD, Sreelakshmi Ravula, MD, Praveen Errabelli, MD, Horace Spencer, MS, and Manisha Singh, MD, FASN .  Good Deed: Acidosis in Chronic Kidney and Liver DiseaseJournal of Renal Nutrition, Vol 33, No 3 (May), 2023: pp 499-502
8. http://www.nephjc.com/news/tag/kidney+transplant
9. Cheng F, Li Q, Wang J, Wang Z, Zeng F, Zhang Y. The Effects of Oral Sodium Bicarbonate on Renal Function and Cardiovascular Risk in Patients with Chronic Kidney Disease: A Systematic Review and Meta-Analysis. Ther Clin Risk Manag. 2021 Dec 7;17:1321-1331. doi: 10.2147/TCRM.S344592. PMID: 34908841; PMCID: PMC8665881.

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