Is There a Retinol Co-Transferer in Kidney Disease?

References

We considered the effect of a high protein diet and potential metabolic acidosis on kidney function. This review is of interest by Donald Wesson, a champion for addressing this issue and limiting animal protein: Mechanisms of Metabolic Acidosis-Induced Kidney Injury in Chronic Kidney Disease

Hostetter explored the effect of a high protein diet in the remnant kidney model with 1 ¾ nephrectomy. Rats with reduced dietary acid load (by bicarbonate supplementation) had less tubular damage. Chronic effects of dietary protein in the rat with intact and reduced renal mass

Wesson explored treatment of metabolic acidosis in humans with stage 3 CKD in this study. Treatment of metabolic acidosis in patients with stage 3 chronic kidney disease with fruits and vegetables or oral bicarbonate reduces urine angiotensinogen and preserves glomerular filtration rate

In addition to the effect of metabolic acidosis from a diet high in animal protein, this diet also leads to hyperfiltration. This was demonstrated in normal subjects;  ingesting a protein diet had a significantly higher creatinine clearance than a comparable group of normal subjects ingesting a vegetarian diet.   Renal functional reserve in humans: Effect of protein intake on glomerular filtration rate.This finding has been implicated in Brenner’s theory regarding hyperfiltration: The hyperfiltration theory: a paradigm shift in nephrology

One of multiple publications from Dr. Nimrat Goraya whom Joel mentioned in the voice over: Dietary Protein as Kidney Protection: Quality or Quantity?

We wondered about the time course in buffering a high protein meal (and its subsequent acid load on ventilation) and Amy found this report:Effect of Protein Intake on Ventilatory Drive | Anesthesiology | American Society of Anesthesiologists 

Roger mentioned that the need for acetate to balance the acid from amino acids in parenteral nutrition was identified in pediatrics perhaps because infants may have reduced ability to generate acid. Randomised controlled trial of acetate in preterm neonates receiving parenteral nutrition - PMC

He also recommended an excellent review on the complications of parenteral nutrition by Knochel https://www.kidney-international.org/action/showPdf?pii=S0085-2538%2815%2933384-6 which explained that when the infused amino acids disproportionately include cationic amino acids, metabolism led to H+ production. This is typically mitigated by preparing a solution that is balanced by acetate. 

Amy mentioned this study that explored the effect of protein intake on ventilation: Effect of Protein Intake on Ventilatory Drive | Anesthesiology | American Society of Anesthesiologists

Anna and Amy reminisced about a Skeleton Key Group Case from the renal fellow network Skeleton Key Group: Electrolyte Case #7

JC wondered about isolated defects in the proximal tubule and an example is found here: Mutations in SLC4A4 cause permanent isolated proximal renal tubular acidosis with ocular abnormalities

Anna’s Voiceover re:  Gastric neobladder → metabolic alkalosis and yes, dysuria.  The physiology of gastrocystoplasty: once a stomach, always a stomach  but not as common as you might think Gastrocystoplasty: long-term complications in 22 patients

Sjögren’s syndrome has been associated with acquired distal RTA and in some cases, an absence of the H+ ATPase, presumably from autoantibodies to this transporter. Here’s a case report: Absence of H(+)-ATPase in cortical collecting tubules of a patient with Sjogren's syndrome and distal renal tubular acidosis

Can't get enough disequilibrium pH? Check this out- Spontaneous luminal disequilibrium pH in S3 proximal tubules. Role in ammonia and bicarbonate transport.

Acetazolamide secretion was studied in this report Concentration-dependent tubular secretion of acetazolamide and its inhibition by salicylic acid in the isolated perfused rat kidney. | Drug Metabolism & Disposition

In this excellent review, David Goldfarb tackles the challenging case of a  A Woman with Recurrent Calcium Phosphate Kidney Stones (spoiler alert, many of these patients have incomplete distal RTA and this problem is hard to treat). 

Molecular mechanisms of renal ammonia transport excellent review from David Winer and Lee Hamm. 

Outline

Outline: Chapter 11

- Regulation of Acid-Base Balance

- Introduction

- Bicarb plus a proton in equilibrium with CO2 and water

- Can be rearranged to HH

- Importance of regulating pCO2 and HCO3 outside of this equation

- Metabolism of carbs and fats results in the production of 15,000 mmol of CO2 per day

- Metabolism of protein and other “substances” generates non-carbonic acids and bases

- Mostly from sulfur containing methionine and cysteine

- And cationic arginine and lysine

- Hydrolysis of dietary phosphate that exists and H2PO4–

- Source of base/alkali

- Metabolism of an ionic amino acids

- Glutamate and asparatate

- Organic anions going through gluconeogenesis

- Glutamate, Citrate and lactate

- Net effect on a normal western diet 50-100 mEq of H+ per day

- Homeostatic response to these acid-base loads has three stages:

- Chemical buffering

- Changes in ventilation

- Changes in H+ excretion

- Example of H2SO4 from oxidation of sulfur containing AA

- Drop in bicarb will stimulate renal acid secretion

- Nice table of normal cid-base values, arterial and venous

- Great 6 bullet points of acid-base on page 328

- Kidneys must excrete 50-100 of non-carbonic acid daily

- This occurs by H secretion, but mechanisms change by area of nephron

- Not excreted as free H+ due to minimal urine pH being equivalent to 0.05 mmol/L

- No H+ can be excreted until virtually all of th filtered bicarb is reabsorbed

- Secreted H+ must bind buffers (phosphate, NH3, cr)

- PH is main stimulus for H secretion, though K, aldo and volume can affect this.

- Renal Hydrogen excretion

- Critical to understand that loss of bicarb is like addition of hydrogen to the body

- So all bicarb must be reabsorbed before dietary H load can be secreted

- GFR of 125 and bicarb of 24 results in 4300 mEq of bicarb to be reabsorbed daily

- Reabsorption of bicarb and secretion of H involve H secretion from tubular cells into the lumen.

- Thee initial points need to be emphasized

- Secreted H+ ion are generated from dissociation of H2O

- Also creates OH ion

- Which combine with CO2 to form HCO3 with the help of zinc containing intracellular carbonic anhydrase.

- This is how the secretion of H+ which creates an OH ultimately produces HCO3

- Different mechanisms for proximal and distal acidification

- NET ACID EXCRETION

- Free H+ is negligible

- So net H+ is TA + NH4 – HCO3 loss

- Unusually equal to net H+ load, 50-100 mEq/day

- Can bump up to 300 mEq/day if acid production is increased

- Net acid excretion can go negative following a bicarb or citrate load

- Proximal Acidification

- Na-H antiporter (or exchanger) in luminal membrane

- Basolateral membrane has a 3 HCO3 Na cotransporter

- This is electrogenic with 3 anions going out and only one cation

- The Na-H antiporter also works in the thick ascending limb of LOH

- How about this, there is also a H-ATPase just like found in the intercalated cells in the proximal tubule and is responsible for about a third of H secretion

- And similarly there is also. HCO3 Cl exchanger (pendrin-like) in the proximal tubule

- Footnote says the Na- 3HCO3 cotransporter (which moves sodium against chemical gradient NS uses negative charge inside cell to power it) is important for sensing acid-base changes in the cell.

- Distal acidification

- Occurs in intercalated cells of of cortical and medullary collecting tubule

- Three main characteristics

- H secretion via active secretory pumps in the luminal membrane

- Both H-ATPase and H-K ATPase

- H- K ATPase is an exchange pump, k reabsorption

- H-K exchange may be more important in hypokalemia rather than in acid-base balance

- Whole paragraph on how a Na-H exchanger couldn’t work because the gradient that H has to be pumped up is too big.

- H-ATPase work like vasopressin with premise H-ATPase sitting on endocarditis vesicles a=which are then inserted into the membrane. Alkalosis causes them to be recycled out of the membrane.

- H secretory cells do not transport Na since they have few luminal Na channels, but are assisted by the lumen negative tubule from eNaC.

- Minimizes back diffusion of H+ and promotes bicarb resorption

- Bicarbonate leaves the cell through HCO3-Cl exchanger which uses the low intracellular Cl concentration to power this process.

- Same molecule is found on RBC where it is called band 3 protein

- Figure 11-5 is interesting

- Bicarbonate resorption

- 90% in the first 1-22 mm of the proximal tubule (how long is the proximal tubule?)

- Lots of Na-H exchangers and I handed permeability to HCO3 (permeability where?)

- Last 10% happens distally mostly TAL LOH via Na-H exchange

- And the last little bit int he outer medullary collecting duct.

- Carbonic anhydrase and disequilibrium pH

- CA plays central role in HCO3 reabsorption

- After H is secreted in the proximal tubule it combines with HCO# to form carbonic acid. CA then dehydrates it to CO2 and H2O. (Step 2)

- Constantly moving carbonic acid to CO2 and H2O keeps hydrogen combining with HCO3 since the product is rapidly consumed.

- This can be demonstrated by the minimal fall in luminal pH

- That is important so there is not a luminal gradient for H to overcome in the Na-H exchanger (this is why we need a H-ATPase later)

- CA inhibitors that are limited tot he extracellular compartment can impair HCO3 reabsorption by 80%.

- CA is found in S1, S2 but not S3 segment. See consequence in figure 11-6.

- The disequilibrium comes from areas where there is no CA, the HH formula falls down because one of the assumptions of that formula is that H2CO3 (carbonic acid) is a transient actor, but without CA it is not and can accumulate, so the pKa is not 6.1.

- Bicarbonate secretion

- Type B intercalated cells

- H-ATPase polarity reversed

- HCO3 Cl exchanger faces the apical rather than basolateral membrane

- Titratable acidity

- Weak acids are filtered at the glom and act as buffers in the urine.

- HPO4 has PKA of 6.8 making it ideal

- Creatinine (pKa 4.97) and uric acid (pKa 5.75) also contribute

- Under normal cinditions TA buffers 10-40 mEa of H per day

- Does an example of HPO4(2-):H2PO4 (1-) which exists 4:1 at pH of 7.4 (glomerular filtrate)

- So for 50 mEq of Phos 40 is HPO4 and 10 is H2PO4

- When pH drops to 6.8 then the ratio is 1:1 so for 50

- So the 50 mEq is 25 and 25, so this buffered an additional 15 mEq of H while the free H+ concentration increased from 40 to 160 nanomol/L so over 99.99% of secreted H was buffered

- When pH drops to 4.8 ratio is 1:100 so almost all 50 mEq of phos is H2PO4 and 39.5 mEq of H are buffered.

- Acid loading decreases phosphate reabsorption so more is there to act as TA.

- Decreases activity of Na-phosphate cotransporter

- DKA provides a novel weak acid/buffer beta-hydroxybutyrate (pKa 4.8) which buffers significant amount of acid (50 mEq/d).

- Ammonium Excretion

- Ability to excrete H+ as ammonium ions adds an important amount of flexibility to renal acid-base regulation

- NH3 and NH4 production and excretion can be varied according to physiologic need.

- Starts with NH3 production in tubular cells

- NH3, since it is neutral then diffuses into the tubule where it is acidified by the low pH to NH4+

- NH4+ is ionized and cannot cross back into the tubule cells(it is trapped in the tubular fluid)

- This is important for it acting as an important buffer eve though the pKa is 9.0

- At pH of 6.0 the ratio of NH3 to NH4 is 1:1000

- As the neutral NH3 is converted to NH4 more NH3 from theintracellular compartment flows into the tubular fluid replacing the lost NH3. Rinse wash repeat.

- This is an over simplification and that there are threemajor steps

- NH4 is produced in early proximal tubular cells

- Luminal NH4 is partially reabsorbed in the TAL and theNH3 is then recycled within the renal medulla

- The medullary interstitial NH3 reaches highconcentrations that allow NH3 to diffuse into the tubular lumen in the medullary collecting tubule where it is trapped as NH4 by secreted H+

- NH4 production from Glutamine which converts to NH4 and glutamate

- Glutamate is converted to alpha-ketoglutarate

- Alpha ketoglutarate is converted to 2 HCO3 ions

- HCO3 sent to systemic circulation by Na-3 HCO3 transporter

- NH4 then secreted via Na-H exchanger into the lumen

- NH4 is then reabsorbed by NaK2Cl transporter in TAL

- NH4 substitutes for K

- Once reabsorbed the higher intracellular pH causes NH4 to convert to NH3 and the H that is removed is secreted through Na-H exchanger to scavenge the last of the filtered bicarb.

- NH3 diffuses out of the tubular cells into the interstitium

- NH4 reabsorption in the TAL is suppressed by hyperkalemia and stimulated by chronic metabolic acidosis

- NH4 recycling promotes acid clearance

- The collecting tubule has a very low NH3 concentration

- This promotes diffusion of NH3 into the collecting duct

- NH3 that goes there is rapidly converted to NH4 allowing more NH3 to diffuse in.

- Response to changes in pH

- Increased ammonium excretion with two processes

- Increased proximal NH4 production

- This is delayed 24 hours to 2-3 days depending on which enzyme you look at

- Decreased urine pH increases diffusion of ammonia into the MCD

- Occurs with in hours of an acid load

- Peak ammonium excretion takes 5-6 days! (Fig 11-10)

- Glutamine is picked up from tubular fluid but with acidosis get Na dependent peritublar capillary glutamine scavenging too

- Glutamine metabolism is pH dependent with increase with academia and decrease with alkalemia

- NH4 excretion can go from 30-40 mEq/day to > 300 with severe metabolic acidosis (38 NaBicarb tabs)

- Says each NH4 produces equimolar generation of HCO3 but I thought it was two bicarb for every alpha ketoglutarate?

- The importance of urine pH

- Though the total amount of hydrogren cleared by urine pH is insignificant, an acidic urine pH is essential for driving the reactions of TA and NH4 forward.

- Regulation of renal hydrogen excretion

- Net acid excretion vary inverse with extracellular pH

- Academia triggers proximal and distal acidification

- Proximally this:

- Increased Na-H exchange

- Increased luminal H-ATPase activity

- Increased Na:3HCO3 cotransporter on the basolateral membrane

- Increased NH4 production from glutamine

- In the collecting tubules

- Increased H-ATPase

- Reduction of tubular pH promotes diffusion of NH3 which gets converted to NH4…ION TRAPPING

- Extracellular pH affects net acid excretion through its affect on intracellular pH

- This happens directly with respiratory disorders due to movement of CO2 through the lipid bilayer

- In metabolic disorders a low extracellular bicarb with cause bicarb to diffuse out of the cell passively, this lowers intracellular pH

- If you manipulate both low pCO2 and low Bicarb to keep pH stable there will be no change in the intracellular pH and there is no change in renal handling of acid. It is intracellular pH dependent

- Metabolic acidosis

- Ramps up net acid secretion

- Starts within 24 hours and peaks after 5-6 days

- Increase net secretion comes from NH4

- Phosphate is generally limited by diet

- in DKA titratable acid can be ramped up

- Metabolic alkalosis

- Alkaline extracellular pH

- Increased bicarb excretion

- Decrease reabsorption

- HCO3 secretion (pendrin) in cortical collecting tubule

- Occurs in cortical intercalated cells able to insert H-ATPase in basolateral cells (rather than luminal membrane)

- Normal subjects are able to secrete 1000 mmol/day of bicarb

- Maintenance of metabolic alkalosis requires a defect which forces the renal resorption of bicarb

- This can be chloride/volume deficiency

- Hypokalemia

- Hyperaldosteronism

- Respiratory acidosis and alkalosis

- PCO2 via its effect on intracellular pH is an important determinant of renal acid handling

- Ratios he uses:

- 3.5 per 10 for respiratory acidosis

- 5 per 10 for respiratory alkalosis

- Interesting paragraph contrasting the response to chronic metabolic acidosis vs chronic respiratory acidosis

- Less urinary ammonium in respiratory acidosis

- Major differences in proximal tubule cell pH

- In metabolic acidosis there is decreased bicarb load so less to be reabsorbed proximally

- In respiratory acidosis the increased serum bicarb increases the amount of bicarb that must be reabsorbed proximally

- The increased activity of Na-H antiporter returns tubular cell pH to normal and prevents it from creating increased urinary ammonium

- Mentions that weirdly more mRNA for H-Na antiporter in metabolic acidosis than in respiratory acidosis

- Net hydrogen excretion varies with effective circulating volume

- Starts with bicarb infusions

- Normally Tm at 26

- But if you volume deplete the patient with diuretics first this increases to 35+

- Four factors explain this increased Tm for bicarb with volume deficiency

- Reduced GFR

- Activation of RAAS

- Ang2 stim H-Na antiporter proximally

- Ang2 also stimulates Na-3HCO3 cotransporter on basolateral membrane

- Aldosterone stimulates H-ATPase in distal nephron

- ALdo stimulates Cl HCO3 exchanger on basolateral membrane

- Aldo stimulates eNaC producing tubular lumen negative charge to allow H secretion to occur and prevents back diffusion

- Hypochloremia

- Increases H secretion by both Na-dependent and Na-independent methods

- If Na is 140 and Cl is 115, only 115 of Na can be reabsorbed as NaCl, the remainder must be reabsorbed with HCO3 or associated with secretion of K or H to maintained electro neutrality

- This is enhanced with hypochloridemia

- Concurrent hypokalemia

- Changes in K lead to trans cellular shifts that affect inctracellular pH

- Hypokalemia causes K out, H in and in the tubular cell the cell acts if there is systemic acidosis and increases H secretion (and bicarbonate resorption)

- PTH

- Decreases proximal HCO3 resorption

- Primary HyperCard as cause of type 2 RTA

- Does acidosis stim PTH or does PTH stim net acid excretion