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A chapter by chapter recap of Burton Rose’s classic, The Clinical Physiology of Acid Base and Electrolyte Disorders, a kidney physiology book for nephrologists, fellows, residents and medical students.</p>
References
JC mentioned that the diagnostic accuracy of 24 hour urine collection increases with more collections! Metabolic evaluation of patients with recurrent idiopathic calcium nephrolithiasis
We didn't refer to a particular study on sodium intake and the 24 hour urine but this meta-analysis Comparison of 24‐hour urine and 24‐hour diet recall for estimating dietary sodium intake in populations: A systematic review and meta‐analysis - PMC 24‐hour diet recall underestimated population mean sodium intake.
Anna looking up ace i and urinary sodium Effects of ACE inhibition on proximal tubule sodium transport | American Journal of Physiology-Renal Physiology
The original FENa paper by Espinel: The FeNa Test: Use in the Differential Diagnosis of Acute Renal Failure | JAMA | JAMA Network
Schreir’s replication and expansion of Espinel’s data: Urinary diagnostic indices in acute renal failure: a prospective study
Here’s a report from our own JC on the Diagnostic Utility of Serial Microscopic Examination of the Urinary Sediment in Acute Kidney Injury | American Society of Nephrology
JC shared his journey regarding FENa and refers to his recent paper Concomitant Identification of Muddy Brown Granular Casts and Low Fractional Excretion of Urinary Sodium in AKI
And Melanie’s accompanying editorial Mind the Cast: FENa versus Microscopy in AKI : Kidney360 (with a great image from Samir Parikh)
JC referenced this study from Schrier on FENa with a larger series: Urinary diagnostic indices in acute renal failure: a prospective study
A classic favorite: Acute renal success. The unexpected logic of oliguria in acute renal failure
Marathon runners had granular casts in their urine without renal failure. Kidney Injury and Repair Biomarkers in Marathon Runners
Cute piece from Rick Sterns on urine electrolytes! Managing electrolyte disorders: order a basic urine metabolic panel
The Urine Anion Gap: Common Misconceptions | American Society of Nephrology
The urine anion gap in context CJASN
Excellent review from Halperin on urine chemistries (including some consideration of the TTKG): Use of Urine Electrolytes and Urine Osmolality in the Clinical Diagnosis of Fluid, Electrolytes, and Acid-Base Disorders - Kidney International Reports
Renal tubular acidosis (RTA): Recognize The Ammonium defect and pHorget the urine pH | SpringerLink
Outline
Chapter 13
- New part: Part 3, Physiologic approach to acid-base and electrolyte disorders
- Do you remember the previous two parts?
- Renal physiology
- Regulation of water and electrolyte balance
- Chapter 13: Meaning and application of urine chemistries
- Measurement of urinary electrolyte concentrations, osmolality and pH helps diagnose some conditions
- There are no fixed normal values
- Kidney varies rate of excretion to match intake and endogenous production
- Example: urine Na of 125/day can be normal if patient euvolemic on a normal diet, and wildly inappropriate in a patient who is volume depleted.
- Urine chemistries are:
- Useful
- Simple
- Widely available
- Usually a random sample is adequate
- 24-hour samples give additional context
- Gives example of urinary potassium, with extra renal loss of K, urine K should be < 25, but if the patient has concurrent volume deficiency and urine output is only 500 mL, then urine K concentration can appropriately be as high as 40 mEq/L
- Table 13-1
- Seems incomplete, see my notes on page 406
- What is Gravity ARF?
- Sodium Excretion
- Kidney varies Na to maintain effective circulating volume (I’d say volume homeostasis)
- Urine Na affected by RAAS and ANP
- Na concentration can be used to determine volume status
- Urine Na < 20 is hypovolemia
- Says it is especially helpful in determining the etiology of hyponatremia
- Calls out SIADH and volume depletion
- Used 40 mEq/L for SIADH
- Also useful in AKI
- Where differential is pre-renal vs ATN
- In addition to urine Na (and FENa) look at urine osmolality
- Again uses 40 mEq/l
- Mentions FENa and urine osmolality
- Urine Na can estimate dietary sodium intake
- Suggests doing this during treatment of hypertension to assure dietary compliance
- 24 hour urine Na is accurate with diuretics as long as the dose is stable and the drugs are chronic
- Diuretics increase Na resorption in other segments of the tubule that are not affected by the diuretic
- Points to increased AT2 induced proximal Na resorption and aldosterone induced DCT resoprtion
- In HTN shoot for less than 100 mEq/Day
- Urine Na useful in stones
- Urine uric acid and urine Ca can cause stones and their handling is dependent on sodium
- Low sodium diet can mask elevated excretion of these stone forming metabolites
- 24-hour Na > 75 and should be enough sodium to avoid this pitfall
- Pitfalls
- Low urine sodium in bilateral renal artery stenosis or acute GN
- High urine sodium with diuretics, aldo deficiency, advanced CKD
- Altered water handling can also disrupt this
- DI with 10 liters of urine and urine sodium excretion of 100 mEq is 10 mEq/L but in this case there is no volume deficiency
- Opposite also important, a lot of water resorption can mask volume deficiency by jacking up the urine sodium
- Advises you to use the FENa
- THE FENA
- < 1% dry
- >2-3% ATN
- It will fail with chronic effective volume depletion
- Heart failure, cirrhosis, and burns
- Suggests that tubular function will be preserved in those situations
- Also with contrast, rhabdo, pigment nephropathy
- Limitations
- Dependent on the amount of Na filtered
- Goes through the math of a normal person with GFR of 125/min and Na of 150 has filtered sodium of 27,000/day so if they eat 125-250 mEq their FENa will be <1%
- Talks about diuretics
- Can use FE lithium
- Mainly reabsorbed in the proximal tubule
- Not affected by loop diuretics
- 20% in healthy controls
- <15% in pre-renal disease
- Can use FE Uric acid
- Also not affected by loop diuretics
- Below 12% is pre-renal
- No FEUrea
- Chloride excretion
- Urine Cl and Na usually move in parallel
- However as many as 30% of hypovolemic patients have more than a 15 mEq/L difference between urine Na and Cl
- Due to Na excretion with another anion, HCO3 or carbenicillin or Cl with another cation, NH4+
- Discusses the metabolic alkalosis issue
- Says the urine Na can be over 100 in volume depleted patients with metabolic alkalosis!
- In metabolic acidosis (normal anion gap)
- Urine Cl should rise to balance out the NH4
- RTA should also have urine pH > 5.3
- Potassium excretion
- Can go as low at 5-25/day
- Low in extra renal losses
- Or after the diuretics have worn off
- More than 25/day indicates renal losses
- Not so helpful in hyperkalemia since chronic hyperkalemia is always due to a defect renal potassium excretion
- Expect always to have inappropriately low K with hyperkalemia due to
- Renal failure
- Hypoaldo
- Urine osmolality
- In hyponatremia it should < 100
- Hyponatremia here should be due to excessive water intake
- In hypernatremia it should be > 600-800
- Urine osm < plasma osm in face of hypernatremia indicates renal water loss due to lack of or resistance to ADH
- In ATN urine OSM < 400
- In pre-renal disease it could be over 500
- Specific but not sensitive due to people with CKD who are unable to concentrate urine
- Specific gravity
- Plasma is 8-10% igher than plasma so specific gravity is 1.008 to 1.010
- Every 30-35 mOsm/L raises urine Osm of 0.001
- so 1.010 is 300-350 mOsm/L H2O
- Glucose raises urine specific gravity more than osmolality
- Same with contrast
- Carbenicillin
- pH
- Normally varies with systemic acid-base status
- PH should fall before 5.3 (usually below 5.0) with systemic metabolic acidosis
- Above 5.3 in adults and 5.6 in children indicate RTA
- PH goal 6.0-6.5
- Separate individual RTAs through FR of HCO3 at various serum HCO3 levels
- Also can monitor urine pH to look for success in treating metabolic alkalosis
- Look for pH > 7
- In treatment of uric acid stone disease
- Want to shift eq: H + urate – <=> uric acid to the left because urate is more soluble
- PH goal 6.0-6.5
References
We considered the complexity of the machinery to excrete ammonium in the context of research on dietary protein and how high protein intake may increase glomerular pressure and contribute to progressive renal disease (many refer to this as the “Brenner hypothesis”). Dietary protein intake and the progressive nature of kidney disease: the role of hemodynamically mediated glomerular injury in the pathogenesis of progressive glomerular sclerosis in aging, renal ablation, and intrinsic renal disease
A trial that studied low protein and progression of CKD The Effects of Dietary Protein Restriction and Blood-Pressure Control on the Progression of Chronic Renal Disease
(and famously provided data for the MDRD eGFR equation A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group
We wondered about dietary recommendations in CKD. of note, this is best done in the DKD guidelines from KDIGO Executive summary of the 2020 KDIGO Diabetes Management in CKD Guideline: evidence-based advances in monitoring and treatment.
Joel mentioned this study on red meat and risk of ESKD. Red Meat Intake and Risk of ESRD
We referenced the notion of a plant-based diet. This is an excellent review by Deborah Clegg and Kathleen Hill Gallant. Plant-Based Diets in CKD : Clinical Journal of the American Society of Nephrology
Here’s the review that Josh mentioned on how the kidney appears to sense pH Molecular mechanisms of acid-base sensing by the kidney
Remarkably, Dr. Dale Dubin put a prize in his ECG book Free Car Prize Hidden in Textbook Read the fine print: Student wins T-bird
A review of the role of the kidney in DKA: Diabetic ketoacidosis: Role of the kidney in the acid-base homeostasis re-evaluated
Josh mentioned the effects of infusing large amounts of bicarbonate The effect of prolonged administration of large doses of sodium bicarbonate in man and this study on the respiratory response to a bicarbonate infusion: The Acute Effects In Man Of A Rapid Intravenous Infusion Of Hypertonic Sodium Bicarbonate Solution. Ii. Changes In Respiration And Output Of Carbon Dioxide
This is the study of acute respiratory alkalosis in dogs: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC293311/?page=1
And this is the study of medical students who went to the High Alpine Research Station on the Jungfraujoch in the Swiss Alps https://www.nejm.org/doi/full/10.1056/nejm199105163242003
Self explanatory! A group favorite! It Is Chloride Depletion Alkalosis, Not Contraction Alkalosis
A review of pendrin’s role in volume homeostasis: The role of pendrin in blood pressure regulation | American Journal of Physiology-Renal Physiology
Infusion of bicarbonate may lead to a decrease in respiratory stimulation but the shift of bicarbonate to the CSF may lag. Check out this review Neural Control of Breathing and CO2 Homeostasis and this classic paper Spinal-Fluid pH and Neurologic Symptoms in Systemic Acidosis.
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
The Channelers went where no nephrology podcasters have gone before, recording in front of a live audience at the National Kidney Foundation Clinical Meeting in Austin. We had all eight Channelers doing a live podcast.
We did a Freely Filtered-inspired draft of the best diuretics.
The draft order:
Leticia Rolon
Anna Gaddy
Joel Topf
Roger Rodby
Josh Waitzman
Amy Yau
JC Velez
And Melanie Hoenig
References
JC
Tolvaptan in Later-Stage Autosomal Dominant Polycystic Kidney Disease
Tolvaptan, a Selective Oral Vasopressin V2-Receptor Antagonist, for Hyponatremia
Josh
Review on amiloride development https://pubmed.ncbi.nlm.nih.gov/7039345/
Toad bladder: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1351665/
Amiloride derivatives that inhibit flagella: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8544414/
Amiloride as taste sensor: https://www.science.org/doi/10.1126/science.6691151
Amiloride + ddavp for DI https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2518801/
Amy
Acetazolamide reversibly inhibits water conduction by aquaporin-4
Inhibition of Human Aquaporin-1 Water Channel Activity by Carbonic Anhydrase Inhibitors
Acetazolamide Attenuates Lithium-Induced Nephrogenic Diabetes Insipidus
Acetazolamide in Lithium-Induced Nephrogenic Diabetes Insipidus
In Vivo Antibacterial Activity of Acetazolamide
Roger
50th anniversary of aldosterone
Joel
Sotagliflozin in Patients with Diabetes and Recent Worsening Heart Failure
Empagliflozin and Heart failure: Diuretic and Cardiorenal Effects
Anna
Clinical Results of Treatment of Diabetes Insipidus with Drugs of the Chlorothiazide Series
Treatment of nephrogenic diabetes insipidus with hydrochlorothiazide and amiloride
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
References for Chapter 10
We did not mention many references in our discussion today but our listeners may enjoy some of the references below.
Effects of pH on Potassium: New Explanations for Old Observations - PMC although the focus of this article is on potassium, this elegant review by Aronson and Giebisch reviews intracellular shifts as it relates to pH and K+.
Josh swooned for Figure 10-1 is this right? Which figure was it? which shows the relationship between [H+] and pH. You can find this figure in the original reference from Halperin ML and others, Figure 1 here. Factors That Control the Effect of pH on Glycolysis in Leukocytes
Here’s Leticia Rolon’s favorite Henderson-Hasselbalch calculator website: Henderson-Hasselbalch Calculator | Buffer Solutions [hint! for this site, use the bicarbonate (or “total CO2”) for A- and PCO2 for the HA] There’s also a cooking tab for converting units!
Fundamentals of Arterial Blood Gas Interpretation - PMC this review published posthumously from the late but beloved Jerry Yee and his group at Henry Ford Hospital, explores the details and underpinnings of our understandings of arterial blood gas interpretation (and this also addresses how our colleagues in clinical chemistry measure total CO2 - which JC referenced- but JC said “machine” and our colleagues prefer the word “instrument.”)
Amy went deep on bicarbonate in respiratory acidosis. Here are her refs:
Sodium bicarbonate therapy for acute respiratory acidosis
Sodium Bicarbonate in Respiratory Acidosis
Bicarbonate therapy in severe metabolic acidosis
Bicarbonate Therapy in Severe Metabolic Acidosis | American Society of Nephrology this review article from Sabatini and Kurtzman addresses the issues regarding bicarbonate therapy including theoretical intracellular acidosis.
Bicarbonate in DKA? Don’t do it: Bicarbonate in diabetic ketoacidosis - a systematic review
Here’s a review from Bushinsky and Krieger on the effect acidosis on bone
https://www.sciencedirect.com/science/article/abs/pii/S0085253822002174
Here is the primary resource that Anna used in here investigation of meat replacements Nutritional Composition of Novel Plant-Based Meat Alternatives and Traditional Animal-Based Meats
We enjoyed this paper that Dr. Rose references from the Journal of Clinical Investigation 1955 in which investigators infused HCl into nephrectomized dogs and observed changes in extracellular ions. https://www.jci.org/articles/view/103073/pd
We wondered about the amino acids/protein in some available meat alternatives they are explored in this article in the journal Amino Acids: Protein content and amino acid composition of commercially available plant-based protein isolates - PMC and you may enjoy this exploration of the nutritional value of these foods: Full article: Examination of the nutritional composition of alternative beef burgers available in the United States
Outline
Chapter 10: Acid-Base Physiology
- H concentration regulated tightly
- Normal H+ is 40 nm/L
- This one millionth the concentration of Na and K
- It needs to be this dilute because H+ fucks shit up
- Especially proteins
- Cool foot note H+ actually exists as H3O+
- Under normal conditions the H+ concentration varies little from normal due to three steps
- Chemical buffering by extracellular and intracellular bufffers
- Control of partial pressure of CO2 by alterations of alveolar ventilation
- Control of plasma bicarbonate by changes in renal H+ excretion
- Acid and bases
- Use definition by Bronsted
- Acid can donate protons
- Base can accept protons
- There are two classes of acids**
- Carbonic acid H2CO3
- Each day 15000 mmol of CO2 are generated
- CO2 not acid but combines with water to form carbonic acid H2CO3
- CO2 cleared by the lungs
- Noncarbonic acid
- Formed from metabolism of protein. Sulfur containing AA generate H2SO4. Only 50-100 mEq of acid produced from these sources.
- Cleared by the kidneys
- Law of Mass Action
- Velocity of reaction proportional to the product of the concentrations of the reactants
- Goes through mass action formula for water
- Concludes that water has H of 155 nanoM/L, more than the 40 in plasma
- Says you can do the same mass experiment for every acid in the body
- Can do it also for bases but he is not going to.
- Acids and Bases can be strong or weak
- Strong acids completely dissociate
- Weak acids not so much
- H2PO4 is only 80% dissociated
- Weak acids are the principle buffers in the body
- Then he goes through how H is measured in the blood and it becomes clear why pH is a logical way to measure.
- Then there is a lot of math
- HH equation
- Derives it
- Then uses it to look at phos. Very interesting application
- Buffers
- Goes tot he phosphate well again. Amazing math describing how powerful buffers can be
- Big picture the closer the pKa is to the starting pH the better buffer, i.e. it can absorb lots of OH or H without appreciably changing pH
- HCO3 CO2 system
- H2CO3 to H + HCO3 has a PKA of 2.72 but then lots of Math and the bicarb buffer system has a pKa of 6.1
- But the real power of the bicarb buffer is that it is not a sealed system. The ability to ventilate and keep CO2 constant increases the buffering efficiency by 11 fold and the ability to lower the CO2 below normal increases 18 fold.
- Isohydric principle
- There is only one hydrogen ion concentration and since that is a critical part of the buffer equation, all buffer eq are linked and you can understand all of them by understanding one of them. So we just can look at bicarb and understand the totality of acid base.
- Bicarb is the most important buffer because
- High concentration in plasma
- Ability for CO2 to ventilate
- Other buffers include
- Bone
- Bone is more than just inorganic reaction
- Live bone releases more calcium in response to an acid load than dead bone
- More effect with metabolic acidosis than respiratory acidosis
- Hgb
- Phosphate
- Protein
References for Chapter 9
One of the few papers that Rose wrote as a single author explores electrolyte free water clearance. This seminal paper explores the issue in greater detail than the book. A New approach to disturbances in the plasma sodium concentration
Wondering about the volume of sweat? Josh taught us that the volume of “transepidermal volume loss” is not affected by humidity https://www.jidonline.org/article/S0022-202X(15)48145-X/pdf but is greatly affected by temperature: Skin temperature and transepidermal water loss
Regarding normal sweat physiology, there is a nice review (with figures!) titled Physiological mechanisms determining sweat composition which describes all the important cells and channels which make up sweat glands. And an important follow on paper titled Higher Bioelectric Potentials due to Decreased Chloride Absorption in the Sweat Glands of Patients with Cystic Fibrosis describing specifically the sweat characteristics of patients with cystic fibrosis.
Melanie was enchanted by work from RA McCance who did early experiments to induce sodium deficiency using very low sodium diets and a homemade sauna-like tent. His musings are fascinating. Lancet 1936 Experimental human salt deficiency MEDICAL PROBLEMS IN MINERAL METABOLISM
Age-related decline in urine concentration may not be universal: Comparative study from the US and two small-scale societies from Jeff Sands (of urea transport fame!)
In this initial report, after continually water loading 21 volunteers, the younger group (mean age 31) had a urine osmolality of 52 mOsm/kg compared to in the older group (mean age 84). Influence of age, renal disease, hypertension, diuretics, and calcium on the antidiuretic responses to suboptimal infusions of vasopressin. In a later report older subjects (mean age 72) vs younger controls (mean age 26) drank 20 ml/kg over 40 minutes. The younger group excreted more of the water in the first 2 hours and had a lower mean urine osmolality 86 vs 112 mOsm/kg compared to the older participants. Age-associated Alterations in Thirst and Arginine Vasopressin in Response to a Water or Sodium Load
Howard Furst suggests the urine to plasma electrolyte ratio as a simpler strategy to consider the free water clearance: https://nephrology.edublogs.org/files/2014/03/Water-Restriction-in-Hyponatremia1-1eb8n40.pdf or via pubmed: The urine/plasma electrolyte ratio: a predictive guide to water restriction
References for chapter 8
Robert Schrier proposed a unifying hypothesis to explain the sodium retention seen in edematous states like cirrhosis and heart failure, coining the term effective arterial blood volume (EABV). An open access review in JASN 2007 can be found here: https://jasn.asnjournals.org/content/18/7/2028#ref-3
John P Peters
ASN Annual Award: https://www.asn-online.org/about/awards/award.aspx?awh_key=0ea83199-f86d-4506-9507-d7e4ce688cb4
Short article discussing contributions of Dr. Peters by mentees Dr. Franklin Epstein and Dr. Donald Seldin: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2588700/ and https://pubmed.ncbi.nlm.nih.gov/12097739/
Epstein FH et al. Studies of the antidiuresis of quiet standing: the importance of changes in plasma volume and glomerular filtration. JCI 1950. In this classic report, investigators studied their own sodium excretion supine, standing and with a variety of maneuvers (saline or albumin infusion) and showed that urinary sodium excretion is limited in the upright position compared to supine position. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC436228/pdf/jcinvest00414-0077.pdf
An interesting review of early concepts on hypertension feature notes on John J Hay and Paul Dudley White. The former was known to say, “The greatest danger to a man with high blood pressure lies in its discovery because then some fool is certain to try and reduce it!” and the latter has been quoted as saying that hypertension might be compensatory but apparently, these quotes are out of context. To find out what they really said, check out: Elias MF and Goodell AL. Setting the record straight for two heroes in hypertension John J Hay and Paul Dudley White. J Clin Hypertens 2019 https://onlinelibrary.wiley.com/doi/epdf/10.1111/jch.13650
VA Cooperative Trial was an important study to establish the hypertension should, in fact, be treated The VA Cooperative Study and the Beginning of Routine Hypertension Screening, 1964-1980
This study was stopped after only 18 months because of an excess of deaths in the untreated group who had a mean diastolic BP of 115 mmHg.
For a long time, only the diastolic BP was felt to be important until the Systolic Hypertension in Elderly Patients (“SHEP study”) clarified that treatment of isolated systolic hypertension is also important
Prevention of Stroke by Antihypertensive Drug Treatment in Older Persons With Isolated Systolic Hypertension
We continued to try to grapple with the work of Jens Titze on sodium which turns many of our assumptions about sodium upside down. His team studied astronauts on a long term high sodium diet and found an unexpected weekly (circaseptan) rhythm seemingly related inversely to aldosterone and directly with cortisol. His work also probes our notion of body sodium content. For a great first hand read, check out Dr TItze’s review in Kidney International 2014 which he aptly dubs, “Spooky Sodium Balence.” https://www.sciencedirect.com/science/article/pii/S0085253815562807
Epstein M. The cardiovascular and renal effects of head-out of water Immersion in Man. Circulation Research 1976 Cardiovascular and renal effects of head-out water immersion in man: application of the model in the assessment of volume homeos
Space flight is an exaggeration of the water immersion experiments. Astronauts on either a low or normal sodium diet had a reset of natriuetic peptides. A Salty Tale: Study Examines Sodium Regulation in Space and Natriuretic Peptide Resetting in Astronauts | Circulation
Baroreceptors feature mechanically activated ion channels called PIEZO1 and PIEZO2. Zeng W, Marshall KL, Min S, Daou I, Chapleau MW, Abboud FM. PIEZOs mediate neuronal sensing of blood pressure and the baroreceptor reflex. Science 2018 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5102061/
We also relearned an unfortunate truth: lots of folks pee in pools. De Laat et al. Water Res. 2011. Concentration levels of urea in swimming pool water and reactivity of chlorine with urea
At the American College of Cardiology meeting in April, investigators shared the news that the combination of an ARB with new class of drugs called angiotensin receptor neprilysin inhibitor (ARNI) was not superior to ACE inhibitors at reduction of heart failure following acute MI. Here’s the press release for the PARADISE-MI trial. Prospective ARNI vs. ACE inhibitor trial to DetermIne Superiority in reducing heart failure Events after Myocardial Infarction
A series of elegant experiments by Alicia McDonald’s team to characterize pressure natriuresis. In these studies, they induce hypertension by constriction of the superior mesenteric artery, the celiac artery and the infrarenal aorta (essentially increasing afterload without directly altering the blood flow to the kidney). With this maneuver, the blood pressure of the experimental animal rises, urinary sodium excretion increases and then they demonstrate a shift in the Na-H ATPase from the apical membrane to intracellular vesicles in the proximal tubule and a shift in NCC from the luminal membrane to the intracellular vesicles in the distal tubules.
Yang L et. al Acute hypertension provokes internalization of proximal tubule NHE3 without inhibition of transport activity. Am J Physiol Renal 2002 https://journals.physiology.org/doi/full/10.1152/ajprenal.00298.2001?rfr_dat=cr_pub++0pubmed&url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org
Lee DH Riquier ADM, Yang LE, Leong PK, Maunsbach and McDonough AA. Acute hypertension provokes acute trafficking of distal tubule NaCl (NCC) to subapical cytoplasmic vesicles. Am J Physiol Renal Physiol. 2009 Acute hypertension provokes acute trafficking of distal tubule Na-Cl cotransporter (NCC) to subapical cytoplasmic vesicles This review in KI reports is also worth a read McDonough AA. Maintaining Balance under pressure-hypertension and the proximal tubule. 2015 ISN Forefronts Symposium 2015: Maintaining Balance Under Pressure—Hypertension and the Proximal Tubule
Chapter 7
References
Sands JM, Blount MA and Klein JD. Regulation of Renal Urea Transport by Vasopressin. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3116377/
In this invited piece, Sands and colleagues explain that although urea is permeable across membranes, this is slow, thus urea transporters in the kidney, under control of vasopressin, are needed to facilitate transport and create the medullary gradient.
Text book using 20% of extracellular compartment being in the intravascular compartment. https://courses.lumenlearning.com/ap2/chapter/body-fluids-and-fluid-compartments-no-content/
The chapter I wrote where I went through the math in figure 7-3. It was a major revelation to me: https://docs.google.com/document/d/17BM1xihvlztuQlU8GVNhEDoPLzr6GounHYZAtVUkLvw/edit?usp=sharing
Association Between ICU-Acquired Hypernatremia and In-Hospital Mortality https://journals.lww.com/ccejournal/fulltext/2020/12000/association_between_icu_acquired_hypernatremia_and.26.aspx
Rate of Correction of Hypernatremia and Health Outcomes in Critically Ill Patients https://pubmed.ncbi.nlm.nih.gov/30948456/
Edelman IS, Leibman J, O’Meara MP and Birkenfeld LW. Interrelations between serum sodium concentration, serum osmolarity and total exchangeable sodium, total exchangeable potassium and total body water. JCI 1958. This classic paper calculates the total body exchangeable sodium and potassium and establishes the relationship between these. Understanding this painstacking work helps understand the effect of supplementing potassium in the setting of hyponatremia.
https://dm5migu4zj3pb.cloudfront.net/manuscripts/103000/103712/cache/103712.1-20201218131357-covered-e0fd13ba177f913fd3156f593ead4cfd.pdf
Edelman is the Root of Almost All Good in Nephrology https://www.renalfellow.org/2014/11/20/edelman-is-root-of-almost-all-good-in/
Jens Titze and his team published a pair of articles that shocked those interested in salt and water in JCI in 2017.
High Salt intake reprioritizes osmolyte and energy metabolism for body fluid conservation https://www.jci.org/articles/view/88532
Increased salt consumption induces body water conservation and decreases fluid intake https://www.jci.org/articles/view/88530
in this exciting exploration of the basic assumptions that we hold true regarding salt and water (and staring Russian cosmonauts and an incredible controlled simulation of salt and water intake), Titze shows that high sodium intake does not simply drive water consumption (as we usually teach) but instead leads to a complex hormonal and metabolic response (even with diurnal variation!) and results in body water conservation and decreased water consumption.
And accompanying editorial from Mark Zeidel: salt and water, not so simple. https://www.jci.org/articles/view/94004
In addition, Titze and others have done interesting work on sodium deposition in tissues where it may also be a source for systemic inflammation.https://pubmed.ncbi.nlm.nih.gov/28154199/
Jens Titze talking about salt, water, thirsting a TEDx talk. https://www.youtube.com/watch?v=jQQPBmnIuCY
A discussion/debate of the overfill vs. underfill theory of edema in the nephrotic syndrome (hint- overfill theory triumphs) would be incomplete without a reference to congenital analbuminemia. This reference from Frontiers in Genetics explores the diagnosis, phenotype and molecular genetics and reveal that patients tend to have only mild edema but severe hyperlipidemia. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6478806/
The finding that proteinuria can directly lead to sodium retention based on a study when puromycin aminoglycoside induced proteinuria of one kidney lead to sodium retention by that kidney which was localized to the distal nephron. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC436841/?page=9
Plasmin may be the culprit at the level of the epithelial sodium channel based on Tom Kleyman’s work: https://jasn.asnjournals.org/content/20/2/233
Amiloride may help! (stay tuned for amiloride in a future episode) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6016639/
An old favorite of JC’s from the Kidney International feature which debates the cause of edema in the nephrotic syndrome.
https://www.sciencedirect.com/science/article/pii/S0085253815583075
Under protest, we hobbled through a discussion of the Gibbs Donnan affect even encouraged by one of Amy’s fellows based on this article from QJM: https://academic.oup.com/qjmed/article/101/10/827/1520972 suggesting that our understanding of the role of hyponatremia in fractures might be all wrong- it could be related to hypoalbuminemia.
Chapter 6 part 2.
References
Josh touts the PARADIGM-HF Trial Angiotensin–Neprilysin Inhibition versus Enalapril in Heart Failure | NEJM which found this combination was superior to an ARB alone
Joel mentions an early atrial natriuretic peptide trial by Julie Lewis et al. Atrial natriuretic factor in oliguric acute renal failure - American Journal of Kidney Diseases and here’s a metanalysis that put this option to bed: Atrial Natriuretic Peptide for Management of Acute Kidney Injury: A Systematic Review and Meta-analysis
Snack attack? Check out “Snack induced ANP” Snack-Induced Release of Atrial Natriuretic Factor | NEJM
Want more natriuretic peptides than we discussed? Check out this review! Cardiac natriuretic peptides | Nature Reviews Cardiology or this fantastic review: Here’s an excellent review of ANP effect on the kidney: ANP-induced signaling cascade and its implications in renal pathophysiology
Joel mentions the study which probed CRIC cohort regarding NSAIDs. Association of Opioids and Nonsteroidal Anti-inflammatory Drugs With Outcomes in CKD: Findings From the CRIC (Chronic Renal Insufficiency Cohort) Study - American Journal of Kidney Diseases and you may like the discussion on NephJC: No Pain for the Kidneys from NSAIDs — NephJC
The KDIGO guidelines can be found here CKD-Mineral and Bone Disorder (CKD-MBD) – KDIGO
Regulation and Effects of FGF23 in Chronic Kidney Disease
Elegant work on the calcium sensing receptor by Martin Pollak https://doi.org/10.1016/0092-8674(93)90617-Ye
Claudin 14, PTH, and calcium absorption in the loop of Henle: Parathyroid hormone controls paracellular Ca 2+transport in the thick ascending limb by regulating the tight-junction protein Claudin14
Carboxymaltose induced hypophosphatemia by increasing FGF-23. Randomized trial of intravenous iron-induced hypophosphatemia
Current "corrected" calcium concept challenged. | The BMJ
The Dialysis Encephalopathy Syndrome — Possible Aluminum Intoxication | NEJM
NephMadness covered Aluminum binders in 2016.
Roger mentioned the use of ferric citrate as a phosphate binder Ferric Citrate Controls Phosphorus and Delivers Iron in Patients on Dialysis | American Society of Nephrology
Joel reminded us of the misadventures in efforts to normalize hemoglobin, first in hemodialysis patients The Effects of Normal as Compared with Low Hematocrit Values in Patients with Cardiac Disease Who Are Receiving Hemodialysis and Epoetin | NEJM
Later, in patients with CKD, normalization was also not shown to be better: Correction of Anemia with Epoetin Alfa in Chronic Kidney Disease | NEJM , Normalization of Hemoglobin Level in Patients with Chronic Kidney Disease and Anemia | NEJM
A quick shout out for roxadustat and the Nephmadness Anemia region! Roxadustat Treatment for Anemia in Patients Undergoing Long-Term Dialysis | NEJM, #NephMadness 2021: Anemia Region – AJKD Blog
In this review of vasopressin, you can find an excellent discussion of basic stimuli and vasopressin receptors: Vasopressin V1a and V1b Receptors: From Molecules to Physiological Systems | Physiological Reviews
X-Linked Nephrogenic diabetes insipidus is very rare and there was theory that all patients originated from the same family and traveled to the US on the Hopewell ship JCI - X-linked nephrogenic diabetes insipidus mutations in North America and the Hopewell hypothesis. This report describes another family from the Netherlands with nephrogenic DI including the finding that the urine osmolarity never exceeds 200 mOsm/kg. Hereditary Nephrogenic Diabetes Insipidus - GeneReviews® (and here’s a family with central diabetes insipidus https://academic.oup.com/jcem/article/81/1/192/2649423?login=true )
Although we have all learned that thiazides should be used with diabetes insipidus, to induce mild volume depletion, several case reports and animal data have found that acetazolamide might be the best diuretic for the job. Clinicians from Boston Medical Center tried it out in this report: Acetazolamide in Lithium-Induced Nephrogenic Diabetes Insipidus | NEJM based on exciting data in mice! https://jasn.asnjournals.org/content/27/7/2082.short
ADH appears to have an effect on potassium excretion. This was investigated by Giebesch who found, with clearance and micropuncture studies in rats plus isolated perfused tubules, ADH increased potassium secretion Influence of ADH on renal potassium handling: A micropuncture and microperfusion study A corollary should be that inhibition of ADH would increase the risk of hyperkalemia but this was not observed in the SALT-1 and SALT-2 trials. 5% of patients developed hyperkalemia in both the tolvaptan group and the placebo group Tolvaptan, a Selective Oral Vasopressin V2-Receptor Antagonist, for Hyponatremia | NEJM
V1 vasopressin as a pressor Exogenous Vasopressin-Induced Hyponatremia in Patients With Vasodilatory Shock: Two Case Reports and Literature Review
We wondered/debated on our observation that hyponatremia is not reliably seen in patients receiving vasopressin in the ICU. In the VASST trial, Vasopressin versus Norepinephrine Infusion in Patients with Septic Shock, 1 patient in each study arm of nearly 400 patients developed hyponatremia. Note that patients with hyponatremia (<130 mEq/L) were excluded from the study.
Excellent review! Vasopressin and the Regulation of Aquaporin-2
This report looks at the PET scan in individuals who are thirsty. Neuroimaging of genesis and satiation of thirst and an interoceptor-driven theory of origins of primary consciousness
Here’s a little discussion of Dr. Grant Liddle. In addition to his eponymous syndrome, he coined the term “ectopic” and developed the dexamethasone suppression test. Grant Liddle (1921–1989) : The Endocrinologist
This is the sad case of licorice gluttony in NEJM which led to hypokalemia and a cardiac arrest. Case 30-2020: A 54-Year-Old Man with Sudden Cardiac Arrest
In this review of the principal and intercalated cells, check out Figure 8 which has an excellent figure of the aldosterone paradox. https://cjasn.asnjournals.org/content/clinjasn/early/2015/01/30/CJN.08880914.full.pdf?with-ds=yes%3Fversioned%3Dtrue
Remarkably, licorice has been used in dialysis patients to lower potassium in patients in this short term trial. Glycyr-rhetinic acid food supplementation lowers serum potassium concentration in chronic hemodialysis patients
Animal studies on pregnant rats demonstrating the reset osmostat as predicted by Roger. Osmoregulation during Pregnancy in the Rat: EVIDENCE FOR RESETTING OF THE THRESHOLD FOR VASOPRESSIN SECRETION DURING GESTATION
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