Download HCO3/NH3

Renal Pathophysiology: Acid Base Regulation (Rossi)
INTRODUCTION TO ACID BASE REGULATION:

Hydrogen Ion in the Body:
Extracellular[H+]= 40nM (very low compared to other ions)
pH= -log[H+]= 7.40
o Many body functions are pH dependent (therefore, it is tightly regulated)
o pH range of 6.8-7.8 is generally compatible with life

Systems Involved in Acid Base Balance:
Intracellular/Extracellular Chemical Buffers:
o Virtually IMMEDIATE (rapid)*
o Tie up or release H+ as needed
Respiratory System (Compensation):
o Rapid
o Carbonic acid system (H2C03CO2 + HCO3)
o Rapidly retains or excretes CO2 (volatile acid)

Hypoventilation (retain CO2)

Hyperventilation (excrete CO2)
Renal System (Compensation):
o Slow
o Reclaims filtered HCO3
o Excretes nonvolatile acid

Hemoglobin as a Buffer:
Blood: Hgb is a very important buffer in the blood (ICF of RBCs)
o pK of Hgb close to physiological pH (imidazole of histidine pK=7.0)

Carbonic Acid Buffer System:
Basics: most important buffer system in the ECF
Dual Control: under the control of both the lungs and the kidneys
Reaction: CO2 + H2O CA H2CO3  H + HCO3
o First reaction is rate-limited (tremendously accelerated by carbonic anhydrase)
o Secondary reaction is basically instantaneous
Henderson Hasselbach Equation: pH= 6.1 + log [HCO3]/0.03 x pCO2
o Therefore, extracellular pH will change when either [HCO3] or pCO2 changes*

Metabolic Acid-Base Disorders: primary change is in [HCO3]

Respiratory Acid-Base Disorders: primary change is in pCO2
METABOLIC PRODUCTION OF ACIDS AND BASES:

Volatile Acids (Class I):
Chemical Form: CO2
Quantity: 13-20 moles/day
Source: fats and carbohydrates (in the presence of insulin with adequate tissue perfusion)
Excretion: by the LUNGS

Non-Volatile Acids (Class II):
Chemical Form: HCl, H2SO4, H3PO4, NH4Cl (ie. acids other than CO2)
Quantity: 70-150 mmoles/day (much less)*
Source:
o Amino Acids:

Sulfur containing (cysteine, methionine)  H2SO4

Cationic (lysine, arginine, histidine)  HCl

Anionic (aspartate, glutatamate)  BICARBONATE
 Subtracted from total amount of non-volatile acid produced (acts as buffer)
o Net production of non-volatile acid= ~70mmol/day (1mmol/day/kg bw)
 Through buffering of non-volatile acids, forms CO2 (volatile acid)
o Phosphates: H3PO4
Excretion: by the KIDNEYS
Titration of Non-Volatile Acids: do NOT circulate as free acids; need to be buffered by proteins or HCO3
o Imidazole in Hgb (or other proteins): HCl + Hgb-IM  Hg-HIM + Cl
o Carbonic Acid System: HCl + NaHCO3  NaCl +CO2 + H2O

Question: if HCO3 is used in buffering, how does the body replace it to maintain balance?

Maintenance of Acid Base Balance by the Kidney:
Produce New HCO3: excrete an amount of acid that is EXACTLY equal to nonvolatile acid produced
(~70mmol/day), which replenishes the consumed HCO3 (used to buffer non-volatile acid)
o Recall: kidney reabsorbs HCO3 by secreting H+
Reclaim (Reabsorb) Filtered HCO3: prevent the loss of filtered HCO3 in the urine (~4500mmol/day)
o Filtered Load= GFR x plasma concentration of substance

4500 mmol/day= 125ml/min x 25mmol/L x 1440min/day
MECHANISMS OF BICARBONATE REABSORPTION:

Basics: reabsorption of bicarbonate in the kidney is achieved by secretion of H+*
Total H+ that needs to be secreted/day= 4570 mmol
o 4500 mmol (H+ secreted to reclaim filtered HCO3-), PLUS
o 70 mmol (H+ secreted to titrate non-volatile acid)
Total H+ Secretion= HHCO3 + HNH4 + HTA
o Titratable Acid: phosphates and sulfates
o Note: H+ that is secreted to reabsorb bicarbonate does not enter the urine as acid, but as WATER*
Total H+ Excreted in Urine= [(UNH4V) + (UTAV)] – (UHCO3V)
o Therefore, the total acid excreted in the urine is equal to the H+ excreted to titrate non-volatile acid (in
the form of NH4 or titratable acid) MINUS the amount of bicarbonate in the urine (usually very small)

Note: in some diseases (ie. renal tubular acidosis) HCO3 in the urine may be higher
o Note that this is because H+ secreted to reabsorb bicarbonate appears in the urine as WATER*
Important Point:
o To maintain acid base balance,

NET ACID EXCRETION MUST EQUAL NONVOLATILE ACID PRODUCTION

Summary of Reabsorption of Filtered HCO3 by the Tubules:
Proximal Tubule: 85%
TALH: 10%
Distal Tubule and Collecting Duct: 5%

Proximal Tubule Bicarbonate Reabsorption:
Apical Membrane: SECRETION OF H+
o Na/H Exchanger: Na into cell, H+ into tubule lumen
o H-ATPase: H+ into tubule lumen
Intracellular: PRODUCTION OF H+ AND HCO3
o CO2 + H2O CA type II H2CO3  H + HCO3
Basolateral Membrane: REABSORPTION OF HCO3
o Na/HCO3 Co-Transport: 1Na:3HCO3
o Note: HCO3 itself NEVER crosses the apical membrane*
Tubule Lumen: FORMATION OF CO2 AND WATER
o H+ (secreted) combines with filtered HCO3  H2CO3
o H2CO3 CA type IV CO2 and H2O (rapid conversion due to CAIV on apical membrane)
o CO2 and H2O rapidly reabsorbed
Net Effect:
o 1 HCO3 is removed from tubular fluid
o 1 HCO3 appears in peritubular blood (reabsorbed)

Thick Ascending Limb of Henle Bicarbonate Reabsorption:
Apical Membrane: SECRETION OF H+
o Na/H Exchanger: Na into cell, H+ into tubule lumen
Intracellular: PRODUCTION OF H+ AND HCO3
o Same as proximal tubule (CAII)
Basolateral Membrane: REABSORPTION OF HCO3
o Anion Exchanger 2 (HCO3/Cl): Cl into cell, HCO3 reabsorbed into interstitium
Tubule Lumen: FORMATION OF CO2 AND WATER
o Same as proximal tubule, EXCEPT there is less carbonic anhydrase in apical membrane
o Reaction still proceeds due to slower tubular flow rate

Distal Tubules and Collecting Duct Bicarbonate Reabsorption:
Alpha Intercalated Cells (Type A Cell): HCO3 REABSORPTION (normally predominates)*
o Apical Membrane: SECRETION OF H+ (independent of Na)

H-ATPase: H+ into lumen


H/K-ATPase: K+ into cell, H+ into lumen
 Note: this H+ secretion requires energy because pumping H+ against a gradient (ie.
pH inside the cell is greater than tubular fluid pH)
o Intracellular: PRODUCTION OF H+ AND HCO3

Same as in proximal tubule (CAII)
o Basolateral Membrane: REABSORPTION OF HCO3

Anion Exchanger 1 (HCO3/Cl): Cl into cell, HCO3 reabsorbed into interstitium

Cl Channel: permits Cl to exit cells into interstitium (drives above exchange by creating
gradient to pump Cl back into cell)
o Tubule Lumen: FORMATION OF WATER AND CO2

Same as proximal tubule (CA type IV in the apical membrane)
Beta Intercalated Cells: HCO3 SECRETION (increase activity during metabolic alkalosis)*
o Apical Membrane: HCO3 SECRETION (independent of Na)

Pendrin Exchanger (HCO3/Cl): HCO3 into lumen, Cl into cell
o Intracellular: FORMATION OF HCO3 AND H+

Same as in other tubules
o Basolateral Membrane: REABSORPTION OF H+

H-ATPase: H+ to interstitium for reabsorption

Cl Channel: Cl to interstitium (allows for Cl- to be pumped in by pendrin exchanger)
Regulation of Filtered HCO3 Reabsorption:
Na+ Balance:
o ECV Expansion:

Decreases proximal tubule Na reabsorption

Decreases proximal tubule HCO3 reabsorption
o ECV Contraction:

Increases proximal tubule Na reabsorption
 Catecholamine stimulation
 Angiotensin II proximal tubular effects (increases transcription of the Na/H
exchanger mRNA increased # of transporters on apical membrane)

Increases proximal tubule HCO3 reabsorption
Filtered HCO3:
o Increase filtered HCO3  increased H+ secretion  increased HCO3 reabsorption

Note: this can be detrimental!
o Decrease filtered HCO3  decreased H+ secretion  decreased HCO3 reabsorption
pCO2:
o Increased pCO2 increased H+ secretion  increased HCO3 reabsorption

Also increases Na/H exchanger mRNA increased # of transporters in apical membrane
o Decreased pCO2 decreased H+ secretion decreased HCO3 reabsorption
Changes in pH:
o Acidosis (decrease plasma HCO3/increase plasma pCO2)  stimulate HCO3 reabsorption

Mechanism: lower intracellular pH results in a more favorable cell-to-lumen H+ gradient,
leading to increased H+ secretion (and increased HCO3 absorption)
o Alkalosis (increase plasma HCO3/decrease plasma pCO2) inhibits HCO3 reabsorption
Aldosterone:
o Proximal Tubule: no effects
o Distal Tubule/Collecting Duct:

DIRECTLY stimulates H+ secretion by alpha intercalated cells

INDIRECTLY stimulates H secretion by increasing Na reabsorption by principal cells
 Makes lumen more NEGATIVE*
Summary of Factors Influencing HCO3 Reabsorption:
Factors Stimulating Reabsorption
Factors Inhibiting Reabsorption
Decreased ECV
Increased ECV
Decreased plasma pH (acidosis)
Increased plasma pH (alkalosis)
Increased filtered load HCO3
Decreased filtered HCO3
Increased blood pCO2 (acidosis)
Decreased blood pCO2 (alkalosis)
Increased aldosterone
Decreased aldosterone
Increased angiotensin II
FORMATION OF NEW BICARBONATE:

Basics: required to replenish the HCO3 lost in buffering/titrating of non-volatile acids produced by metabolism
While reabsorption of filtered bicarbonate is necessary for maintaining balance, it cannot replenish bicarbonate
Formation of new HCO3 (NET ACID EXCRETION) requires the presence of NON-BICARBONATE BUFFERS*

Process of New Bicarbonate Formation:
H+ is secreted into the tubular lumen
H+ combines with a NON-BICARBONATE BUFFER (ie. ammonium, phosphates)
H+ excreted into urine while HCO3- is produced intracellularly and reabsorbed in the blood
o Therefore, H+ is lost without loss of HCO3 gain 1 net HCO3*

Two Major Urinary Non-Bicarbonate Buffer Systems:
Titratable Acid (HPO4/H2PO4/HSO4):
o Derived from the diet (relatively constant amount from day to day)
o Filtered at the glomerulus
Ammonium (NH3/NH4):
o Produced by the kidneys
o Regulated by acid base status (varies from day to day)

Renal Excretion of Ammonium (NH4+):
Proximal Tubule: SECRETION OF NH4
o Glutamine 2NH4 + 2HCO3 + αketoglutarate (catalyzed by glutaminase, which can be regulated,
and then glutamine dehydrogenase)

HCO3 exits basolateral membrane  peritubular capillaries

NH4 secreted into tubular lumen via Na/H exchanger (substitutes for H)
TALH: REABSORPTION OF NH4
o NH4 substitutes for K on NaK2Cl transporter (primary method of entry)

May also use K+ channel to enter the cell
o NH4 leaves cell via the Na/K-ATPase to enter the medullary interstitium

Note that there is also some suspicion that an Rhcg-like channel exists here for exit
Medullary Interstitium:
o NH4 accumulates (in equilibrium with NH3)
Collecting Duct:
o Basolateral Membrane:

NH4 enters collecting duct cells via K+ channel, OR

NH3 enters alpha intercalated cells via Rhcg (glycoprotein channel)
o Apical Membrane:

NH3 secreted into lumen using Rhcg on apical membrane
o Tubule:

NH3 is protonated by H+ secreted by H-ATPase of alpha intercalated cell, forming NH4+

NH4+ becomes trapped in tubular lumen (excreted)
Important Point: H+ secretion by the collecting duct is CRUCIAL for the excretion of NH4+ (if it does not occur,
NH4+ reabsorbed in the TALH will enter systemic circulation and be metabolized in the liver)
o Overall Result: HCO3 used to titrate the non-volatile acids would not be replenished*

Regulation of NH3/NH4+ System:
Systemic Acidosis (pH Low):
o Stimulates proximal tubule glutamine conversion to NH4

Low pH stimulates glutaminase enzyme (also called glutamine deamidase in notes)*

High pH inhibits glutaminase enzyme
o Leads to INCREASED NH4+ production:

Increases H+ secretion and excretion

Increases NEW HCO3 production and reabsorption
Plasma [K+]:
o High Plasma [K+] inhibits glutaminase less NH4+  decreased H+ excretion metabolic ACIDOSIS
o Low Plasma [K+]stimulates glutaminasemore NH4+more H+ excretionmetabolic ALKALOSIS
ACID BASE DISORDERS:

Definitions:
Acidemia: plasma pH <7.40 (+/- 0.02)
Alkalemia: plasma pH >7.40 (+/- 0.02)
Acidosis: a process, which left unopposed, leads to acidemia
Alkalosis: a process, which left unopposed, leads to alkalemia
Metabolic: primary change in HCO3 (non-volatile)
Respiratory: primary change in pCO2 (volatile)

Types of Acid Base Disorders:
Metabolic Acidosis:↓pH, ↓pCO2, ↓[HCO3]
o Low plasma pH
o Low plasma [HCO3]
o pCO2 formed removed by ventilation (compensation decreased pCO2)
Metabolic Alkalosis: ↑pH, ↑pCO2, ↑[HCO3]
o High plasma pH
o High plasma [HCO3]
o Ventilation decreases to allow pCO2 to rise (compensation)
Respiratory Acidosis: ↓pH, ↑pCO2, ↑[HCO3]
o Low plasma pH due to primary increase in pCO2

CO2 moves into cell and combines with H2O H2CO3 (dissociates)

H+ is buffered by cellular proteins (Hgb and others)

HCO3- exits the cell and raises plasma [HCO3-]
Respiratory Alkalosis: ↑pH, ↓pCO2, ↓[HCO3]
o High plasma pH due to primary decrease in pCO2

HCO3 is used up to form H2CO3 CO2 + H2O (increase CO2)

Defense of Acid Base Status:
Buffering: RAPID (instantaneous-minutes)
o Extracellular:

HCO3/CO2

Phosphates

Plasma proteins
o Intracellular:

Movement of H+ into cells (buffers nonvolatile acids)

Movement of H+ out of cells (buffers nonvolatile alkalki)

H+ titrated inside cells by proteins (ie. Hgb) and phosphates
Compensation:
o Respiratory: changes in alveolar ventilation (FAST; minutes-hours)

Metabolic acidosis increased ventilation and removal of CO2

Metabolic alkalosis decreased ventilation and build-up of CO2
o Renal: changes in acid excretion (SLOW; hours-days)

Acidosis (Metabolic or Respiratory):
 Net EFFECT: increase pH and HCO3 towards normal (UNLESS kidney is the culprit)
o ↑ tubular H+ secretion
o ↑ HCO3 reabsorption
o ↑ production and excretion of NH4+
o ↑ net acid excretion

Alkalosis (Metabolic or Respiratory):
 Net EFFECT: decrease pH and HCO3 towards normal (UNLESS kidney is the culprit)
o ↓ tubular H+ secretion
o ↓ HCO3 reabsorption
o ↓ production and excretion of NH4+
o ↓ net acid excretion

Diagnosis of Acid Base Disorders:
1. Type of Disorder: acidemia OR alkalemia
2. Cause of Disorder: metabolic OR respiratory
3. Compensation: is it appropriate AND sufficient?
4. Differential Diagnosis
METABOLIC ACIDOSIS:

Basic Defects: ↓pH (normal 7.4), ↓pCO2 (normal 40), ↓[HCO3] (normal 25)

Potential Causes:
Major:
o Addition of readily dissociated acid
o Loss of [HCO3] (associated with GAIN OF Cl)
Minor:
o Dilutional (rapid dilution of ECV reduction [HCO3])

Defense:
Extracellular/intracellular buffering (bone buffering in chronic forms)

Compensation:
Renal: INCREASE net acid excretion
Respiratory: alveolar HYPERVENTILATION
o Fall in pCO2 should be 1-1.3 x fall in [HCO3]

Example: patient with [HCO3] of 15 (fall of 10) should have fall of 10-13mmHg (pCO2 27-30)
 If yes appropriately compensated
 If no not appropriately compensated

Differential Diagnosis:
Based on Anion Gap (X):
o Positive Charges=Negative Charges in the plasma
o Therefore, Na = Cl + HCO3 + proteins (not measured) + phosphates (not measured) etc.
o Na = [Cl + HCO3] + X (unmeasured anions)
o X (Anion Gap)= Na – [Cl + HCO3]

Normal Value: 10 +/- 2 [140-(105+25)]
Increased Anion Gap Acidosis:
o Cause: production/addition of [H+][unmeasured anion]
o Potential Etiologies:

Addition of Ketoacids: increased production of beta-hydrpxybutyric and acetoacetic acid
 Diabetic ketoacidosis
 Starvation
 Alcoholic ketosis
 Isopropyl alcohol ingestion

Lactic Acidosis: increased lactic acid production
 Ischemia/infarction of tissue (anaerobic metabolism)

Renal Failure: decreased net acid excretion

Ingestions:
 Salicylate overdose: salicylic acid + increased organic acid production
o Important: tends to give a MIXED acid base problem, depending on
severity and time after overdose

Metabolic acidosis with respiratory alkalosis (early on, due to
stimulation of respiratory center)

Metabolic acidosis with respiratory acidosis (later, due to
depressed consciousness)
 Methanol ingestion: formic acid + organic acid production
 Ethylene glycol ingestion: glycolic acid
 Metformin: increased lactic acid production
o Important: do not give to patients with renal failure
 Paraldehyde overdose: unknown organic acid metabolite
 Acetaminophen (some patients): mutation in metabolism leads to build up of
pyroglutamic acid (rare)
Normal Anion Gap Acidosis:
o Cause: addition of HCl or primary loss of HCO3 (with gain of Cl)
o Potential Etiologies:

Non-Renal Loss of HCO3: loss of HCO3 rich fluid from GI tract with gain of HCl
 Diarrhea
 Small bowel or pancreatic drainage
 Ureterosigmoidostomy/malfunctioning ileal loop
 Anion-exchange resins (ie. cholestyramine)

o
o
Renal Loss of HCO3: decreased reclamation of filtered HCO3
 Renal Tubular Acidosis: presence determined using urinary anion gap (below)*
o Proximal (decreased ability to reabsorb filtered HCO3)
o Distal (decreased H+ excretion-αIC; increased HCO3 secretion-βIC)
 Carbonic Anhydrase Inhibitors: inhibits renal HCO3 reabsorption

Other:
 Dilutional (rare)
 Parenteral nutrition (contains arginine-HCl, lysine-HCl)
 HCl, NH4Cl ingestion (equivalent to adding HCl)
Urinary Anion Gap:

Basics: used in NORMAL ANION GAP acidosis to determine if the excess H+ is due to impaired
urinary acidification (distal renal tubular acidosis- type I)

Ions in the Urine:
 Major Cations in the Urine: Na, K, NH4 (not usually measured; 20-40mM usually)
 Major Anion in the Urine: Cl (note that HCO3 is not normally in the urine)

Urinary Anion Gap:
 UNa + UK + UNH4 = UCl + Uother anions
o But, since UNH4 is not usually measured, needs to be rearranged
 UNa + UK - UCl = Uother anions (-UNH4)
o Since there really aren’t any other anions and since UNH4 isn’t measured
 UNa + UK - UCl should equal ZERO or SLIGHTLY POSITIVE

Use of Urinary Anion Gap in Metabolic Acidosis:
 NEGATIVE Urinary Anion Gap: due to MORE NH4+ (appropriate response to
normal plasma gap metabolic acidosis)*
o GI losses of base
o Addition of Cl- containing acid
 POSITIVE Urinary Anion Gap: not the appropriate response to acidosis (not
increasing NH4+ production/excretion)
o Inappropriate urine acidification DISTAL renal tubular acidosis
o Note that this is NOT seen with proximal renal tubular acidosis
Renal Tubular Acidosis:

RTA Type II (Proximal Tubule H+ Secretion Defect):
 Decreased reclamation of filtered HCO3
 Urinary pH <5.5 when plasma [HCO3] <15mM
 Normal urinary anion gap (no problem in NH4+ production/excretion)
 Potential causes include:
o Cystinosis
o Fanconi syndrome
o Carbonic anhydrase inhibitors
o HIV drugs

RTA Type I (Distal Tubule H+ Secretion Defect):
 Impaired H+ secretion by alpha intercalated cells
 Decreased TA and NH4+ trapping decreased net acid excretion
 Urinary pH >5.5 even with very low plasma [HCO3]
 Urinary anion gap should be negative, but is ZERO or POSITIVE (inadequate NH4+
excretion in the face of acidosis)
o Important: urinary anion gap used to diagnose RTA type I
 Potential causes include:
o Medullary sponge kidney
o Drugs (amphotericin B, tenofovir)
o Obstruction
o Hereditary mutation in H+-ATPase

Inadequate NH4+ Production (Advanced Chronic Kidney Disease):
 Proximal and distal tubule H+ secretion is normal
 Lack of sufficient NH4+ decreased net acid excretion
 Urinary pH can still be maximally acidic (pH 4.5)
METABOLIC ALKALOSIS:

Basic Defects: ↑pH, ↑pCO2, ↑[HCO3]

Causes:
Generation Phase:
o Excess loss of H+ from the body, OR
o Loss of fluid containing Cl- in a concentration greater than Cl in ECF
o Gain of HCO3
Maintenance Phase:
o Volume depletion increased Na reabsorption increased H+ secretion

Angiotensin II and Catecholamines: increase Na/H exchange in proximal tubule
 Increase Na reabsorption
 Increase H+ secretion

Aldosterone: increases Na reabsorption in distal tubule (lumen more negative)
 Increased K+ secretion
 Increase H+ secretion

Important Point: kidney will do anything to preserve ECF volume (including mess up acidbase balance)
o Lack of Cl- (emesis)  reabsorption of HCO3 in its place
o Hypokalemia stimulation of NH4+ production  increased net acid excretion

Low [K+] stimulates deamidation of glutamine to form NH4+

Defense:
ICF/ECF buffers (release H+ from weak acids)

Compensation:
Renal: increase HCO3 excretion
o Reduce H+ secretion and try to reduce HCO3 reabsorption (may require correction of decreased ECV)
o Secretion of HCO3 by beta intercalated cells
Respiratory: alveolar HYPOVENTILATION
o Rise in pCO2 should be equal to 0.5-1 x rise in [HCO3]

Note: this compensation is less than in acidosis (hypoventilation limited by need for O2)

Example: patient with [HCO3] of 35 (increase of 10) should have pCO2 increase of 5-10

Differential Diagnosis:
Based on Urine [Cl]:
o Saline Responsive: ECV low; urine [Cl] <20mM
o Saline Unresponsive: ECV normal/high; urine [Cl] >20mM
o Unclassified
Saline Responsive Metabolic Alkalosis (Urine [Cl] <20mM):
o Diuretics:

Generated: renal Cl loss > HCO3 loss

Maintained: decreased ECF, aldosterone, decreased [K+]
o Vomiting:

Generated: HCl loss

Maintained: same as diuretics
o Villous Adenoma and Congenital Chloride Losing Diarrhea:

Generated: secretion of Cl-rich, HCO3 poor, K+ rich bowel fluid

Maintained: same as diuretics
o Cystic Fibrosis:

Generation: loss of NaCl from skin (rarely lose enough to cause metabolic alkalosis)

Maintained: decreased ECV, increased aldosterone, lack of Cl
o Post-Hypercapnia:

Generation: high [HCO3] due to renal compensation for hyerpcapnia

Maintained: lack of available Cl to replace HCO3 (HCO3 remains high)
Saline Unresponsive Metabolic Alkalosis (Urine [Cl] >20mM):
o Excess Mineralcorticoids:

Generation: K+ and H+ secretion in DT and CD

Maintenance: increased aldosterone, decreased K+

Causes: primary hyperalosteronism, Cushing’s, licorice ingestion
 Licorice Ingestion: glycyrrhizic acid inhibits 11-beta hydroxysteroid dehydrogenase
so cortisol can act like aldosterone on the mineralcorticoid receptor
o
-
Bartter’s Syndrome:

Cause: mutation in TALH (different types- NaKCl2 transporter is an example)

Generation: renal Cl- loss > HCO3- loss

Maintenance: decreased ECV, increased aldosterone, decreased K+

Why isn’t it saline responsive if it behaves like a diuretic?
 Defect cannot be fixed since the transporters are mutated
 Saline will not fix the problem (hypokalemia and metabolic alkalosis will persist
even if volume status improves)
o Severe K+ Depletion: increased NH4 production/excretion net acid excretion (HCO3 reabsorption)
Unclassified Metabolic Alkalosis:
o Excess alkali intake: intake > excretory rate
o Milk-alkali syndrome: intake > excretory rate
o Non-hyperparathyroid hypercalcemi: release of bone alkali with suppression of PTH

PTH normally decreases proximal tubule HCO3 reabsorption

Decrease in PTH leads to increase in HCO3 reabsorption
COMPENSATION FOR RESPIRATORY ACID BASE DISORDERS:

Respiratory Acidosis:
Acute: rise in [HCO3]= 1mM per 10mmHg rise in pCO2
Chronic: rise in [HCO3]= 3.5mM per 10mmHg rise in pCO2 ([HCO3] ≥ 35mM)

Respiratory Alkalosis:
Acute: fall in [HCO3]= 2mM per 10mmHg fall in pCO2
Chronic: fall in [HCO3]= 5mM per 10mmHg fall in pCO2 ([HCO3)≤14mM)
SUMMARY OF APPROACH TO ACID BASE DISORDERS:
1. Type of Disorder: acidemia OR alkalemia
2. Cause of Disorder: metabolic OR respiratory
3. Compensation:
o Simple appropriate
o Mixed compensation not appropriate
4. Differential Diagnosis
o Serum anion gap (ALWAYS calculate to check for hidden acidosis)
o Urinary anion gap (if metabolic acidosis with NORMAL serum anion gap)
o Urinary [Cl] (if metabolic alkalosis)