This is a summary of a presentation I attended at the National Kidney Foundation Spring Clinical Meeting on 10 April 2025.
Presenter: Stewart Lecker MD PhD
Objectives:
- Kidneys role in body PH
- Kidney Acid excretion
- Role of diet and protein in acid base balances
How does the kidney deal with acid production?
It is a 2-step affair, filtered bicarbonate at 24mEq/L, 3500mEq/day of bicarb is filtered per day.
The kidney needs to suck back bicarbonate by harnessing NaKATPase in the filtrate (soon to be urine). Across the length of the proximal tubule about 80% of the bicarbonate is reabsorbed. Filtering bicarbonate, NaKATPase creates a gradient, which results in the product of CO2 and Water.
The kidney also produces ammonia genesis but taking amino acid and forming ammonia. The ammonia can then be recycled and help the body secrete additional hydrogen (acid). It is reabsorbed by NKCC2 channels, which enables ammonia concentration.
Net acid excretion = titratable acidity + NH4 + HCO3
For every proton that secreted, there is bicarbonate that is reabsorbed. You can think of it as protons secretion and bicarb reabsorption. These work together like two sides of one coin.
But why does this all happen?
Why do we need to get ride of acids?
There are two types of acids:
- Votatile acids: produced by oxidative metabolism of carbohydrates, fat and protein, excreted through lungs as CO2
- Fixed acids – the kidney excretes these. Produced by metabolism of certain amino acids, nucleic acids.
Only methionine and cystine to create additional acids. Other amino acids follow different catabolic pathways.
Most digested foods is excreted as CO2 in the lungs. However the renal response is trigged by consumption of these specific amino acids (see slide).
The mount of acid that the kidneys excrete each day is 1mEq/kg/day.
In a study of women comparing three different diets. The omnivore diet increased the acid excretion in the urine, which was higher than the lacto-ovo vegetarian and higher than the vegan diet, which was the lowest. Why? Because animal based proteins contain more methionine compared to plant based foods.
What three adaptations do the kidney makes to deal with this?
- Clearance: In a study when people were given high red meat diets, their eGFR increased. Likely because the kidney was working harder to get rid of the waste products (methionine).
- Acid: Increased ammonia-genesis following an acid load from a high meat meal. We can increase our titratability in our body as this part is fixed but we can create more ammonia.
- Potassium: Increase the renal excretion of potassium because these diets contain high amounts of potassium. Increase protein metabolism increases urea excretion, resulting in increased urea recycling increases flow through the distal nephron resulting in augmented potassium excretion.
What about plant-based diets?
If you produce an alkalosis by infusing bicarbonate or eating a high alkali diet your urine citrate increases.
Citrate is fuel for the citric acid cycle in the mitochondria. So in situations of alkalosis, the pH gradient is smaller, resulting in lower citrate utilization resulting in less citrate in the urine. The opposite is true when the opposite conditions arise.
But why is high citrate in the urine good? The kidney can use the citrate to increase potassium excretion as well. This suggests that at both ends of the spectrum for dietary acid load can increase potassium excretion.
What mal-adaptations are occurring?
We excrete our acid load to maintain balance, but in patients that have increased acid requirements for excretion, this occurs the augments of ammonia genesis which has trade offs including bone loss, muscle loss and low urine citrate. Overtime acid stress can lead to loss of function nephrons, tubule interstitial injury and fibrosis, proinflammatory responses.
Questions from the audience:
Why does eGFR increase with increase protein load?
There are theories that certain amino acids can increase flow and turn on ammonia genesis. But beyond that the mechanism is well elucidated.
Are all meats the same or do different meat types matter?
All meats are likely similar.
How could phosphorus absorption of different food sources (animal vs plant) impact this process?
Serum phosphates are very well regulated so it may not impact acid base physiology, unless serum phosphate levels are changing.
No Acid, No Acidosis: Reconciling Epidemiology and Clinical Trial Data on Metabolic Acidosis
Presenter: Michal Melamed, MD, MHS
Objectives:
- Describe the difference between observation associations of metabolic acidosis with outcomes and what clinical trails have shown
- Understand current guidelines for treatment of acidosis
What is clinically proven that treatment with sodium bicarbonate does?
- Slow CKD Progression
- Decrease Hyperkalemia
- Protect Bones
- Protect Muscles
The correct answer is: It decreases hyperkalemia.
What do we know about sodium bicarbonate treatment?
In a study, stage 3 and 4 CKD were given sodium bicarbonate vs placebo. They were able to show that over 24 months, serum potassium levels were lower and had almost 50% less hyperkalemia (K>5.0), compared to placebo.
As the kidney starts to fail, increased acid generation, bicarb remains normal and pH is normal. As disease progresses CO2 falls and pH remains normal. Current KDIGO guidelines used to recommend treatment at CO2 of 20mmol/L, but it is now at 18mmol/L. But why did this change?
Rat models have shown that dietary acid load, gave sodium bicarbonate and less tubule interstitial disease and less complement activation.
In epidemiology studies low sodium bicarbonate levels have been found to be associated with increased CKD disease progression. But these are just associations.
In 2009, a study looked at sodium bicarb in people with CKD 4 and 5 vs usual care. At 24 months there was reduced risk of starting dialysis. But this study had some methodological concerns.
In the Goraya studies, they provided sodium bicarb, vs fruits and veg vs usual care (which is not a placebo). They found that eGFR was better in sodium bicarb and fruits and veg vs usual care.
Summary of studies looking at bicarb and CKD progression:
- UBI – positive finding
- Bicarb – negative finding
- Alkali in CKD – not powered sufficiently
- Veterans – no change
- Base trial – not powered to look at CKD progression
- Veverimer – not powered to look at CKD progression
Trials that aren’t placebo control can make interpreting the results of the study more challenging.
What is veverimer?
A medication that has been used to reduce metabolic acidosis without sodium. In a placebo controlled trial of this medication there was no effect on CKD progression. Overall the study was considered null.
One potential reason for the null findings was the failure to achieve significant reductions of CO2 levels with veverimer.
In transplant patients, 240 patients got either sodium bicarb or placebo, but there was no change in eGFR, despite getting good separation in the CO2 levels. Sodium bicarb was associated with increased ACR (which isn’t good).
Summary
- Animal data shows that metabolic acidosis can hasten Kidney damage
- Multiple observational studies show low CO2 are associated with faster progression
- One large study did not achieve separation
- So we cannot say that treating metabolic acidosis slows CKD progression
But why?
The potential concern is the diet. The western diet is thought to be acidogenic and this is associated with increase osteoporosis.
Higher serum CO2 is associated with better BMD based on NHANES data.
K-citrate for 24 months (with normal eGFR) – had higher BMD than placebo.
If bone is one of the primary buffers for acid-base. It is possible that low level acidosis associated with the Western Diet may be impacting bone health.
However no effects on BMD were observed with Alkali therapy in a CKD trial.
Does Sodium Bicarb treatment increase systolic blood pressure?
There have been signals in a study that SBP will be higher with higher doses of Sodium Bicarb. There are signals of increased edema and increased need for antihypertensive therapy.
How dose sodium bicarb treatment in CKD impact bone health?
Summary:
Metabolic acidosis may contribute to osteoporosis and bone disease
Treatment is to treat if CO2 is less than 18mmol/L
Treatment of metabolic acidosis can be dietary
Questions from the Audience
What about sodium citrate? Appears to be equivalent to sodium bicarbonate.
Is there a trial comparing veveremir to sodium bicarbonate? Unfortunately, no
