Metabolic alkalosis

Enrico Fiaccadori

Clinica Medica & Nefrologia Universita’ degli Studi di Parma

Metabolic alkalosisMetabolic alkalosis

• An acid-base disorders characterized by increased serum bicarbonate levels (> 26 mEq/L)

• pH values can be increased (alkalosis withpH values can be increased (alkalosis with alkalemia)

Negative effects of metabolic alkalosisNegative effects of metabolic alkalosis

left shift hemoglobin dissociation curvee s e og ob d ssoc a o cu e reduced cardiac stroke volume reduced cerebral perfusion reduced cerebral perfusion cardiac arrhythmias d d i t d i reduced respiratory drive

HCO3 58 mmol/L, pH 7,56, PCO2 65, 2K 1.8 mol/L

Post-hypercapnic alkalosis and respiratory complications in the ICU

% of patients

60

70

• Metabolic alkalosis50

60 • Metabolic alkalosis also associated with longer ICU stay (14.7 vs 9 5 days)

30

40

metab alk

vs 9.5 days)

20

30norm

0

10

Banga A et al COPD 2009; 6:437 440ventilatordependance

Banga A et al., COPD 2009; 6:437-440

The adaptation to metabolic alkalosis (“compensation”) is by the respiratory( compensation ) is by the respiratory

system (ventilatory depression)

Henderson-Hasselbalch Equation

(Renal-Metabolic)Metabolic Alkalosis

H 6 1 l HCO3

(Renal Metabolic)

pH = 6.1 + log CO3

H COH CO pC

H2CO3(Pulmonary)Respiratory CompensationH2CO3 pC

CO

p

pCO2

Respiratory adaptation to metabolic alkalosis

pH = 6.1 + log pCO2

HCO3p g pCO2

6060m

mH

g

4045505560

4045505560pC

O2

m

2025303540

2025303540

0.7 mmHg/mEq HCO3

101520

101520

2 5 10 15 20 25 30 35 40 45 502 5 10 15 20 25 30 35 40 45 50

[HCO3] mEq/l

pCO2 should increase > 45 mmHg and usually is <55pCO2 should increase 45 mmHg and usually is 55

~~~~

M t b li lk l iMetabolic alkalosisThree pathogenetic aspectsThree pathogenetic aspects

1. Generation

2 Maintenance2. Maintenance

3. Recovery

M t b li lk l i1 Generation: by addition (direct or indirect) of alkali to

Metabolic alkalosis1. Generation: by addition (direct or indirect) of alkali to

body fluids: ingestion of new alkali (bicarbonate, citrate etc.) or extrarenal production of new alkali ) p(nasogastric suction, vomiting etc.)

2. Maintenance: by changes in renal function that prevent the normally rapid excretion of the excess alkali:alkali: a) Renal failure; b) Tubule ion transport is altered in a way that limits ) p yor prevents bicarbonate excretion, or that increases new bicarbonate production in the distal nephron

3. Recovery

Vomiting/NG Suctiong

Proximal Tubule HCO3 ReabsorptionThe Apparent TmaxThe Apparent Tmax

35

40

n

Volume K+

pCO2

25

30

35

orpt

ion

FR

NormalVolumeK+

pCO2 PTH

15

20

25

Rea

bso

Eq/l

GF K

pCO2PTH

5

10

15

HC

O3

Rm

E

A bicarbonate load is rapidly excreted because usually is

associated with volume expansion

0

5

0 5 10 15 20 25 30 35 40

H associated with volume expansion

Plasma HCO3 mEq/l

Maintenance of metabolic alkalosis: theMaintenance of metabolic alkalosis: thekey is the kidney

The pathophysiologic question: Why is bicarbonatehandling in the kidney maladaptive in metabolic alkalosis?

The pathophysiological answer: not only the excessThe pathophysiological answer: not only the excessbicarbonate is not excreted, but bicarbonate is increasinglyproduced by the kidney

Three parts of the answer:

- Bicarbonate reabsorption is increased in the proximaltubule (all the filtered bicarbonate is reclamed)

- Bicarbonate is not secreted in the distal nephron asshould be

- Bicarbonate generation is increased in the corticalcollecting duct (new bicarbonate ions are produced by H+g ( p ysecretion)

Renal bicarbonate handling g10%

ReabsorbedFiltered HCOFiltered HCO3~4,000 mEq/d

90% Reabsorbed

Generation1 mEq/Kg/day

Reabsorbed

Proximal reabsorption of HCO3-

(R l i i f filt d bi b t )(Reclaiming of filtered bicarbonate)

LUMEN INTERSTITIUMNa+ 3Na +

2K +NHE-3Na+/K+/2Cl-

H+HCO3- HCO3

-H+ Na+

NHE-3

H2CO3-

H2CO3-

CA II3HCO3

-

NBE

CO2 CO2 H2O

CA IV

H2O AQP1 Stimulated by:- Filtered load of HCO3

-

- Luminal H+

- Intracellular acidosis (K depl)- Sodium avidity (ANG II)**ANG II PKC

phosphoryl and activ NHE-3

Bicarbonate secretionin the distal nephron

A intercalated cells: proton secreting cells

B intercalated cells: bicarbonate secreting cells

Bicarbonate secretion through pendrin is stimulated by alkalosis

Bicarbonate secretion is made possible only if Cl is present in the lumen)only if Cl is present in the lumen)

The Pendred syndrome: an autosomal recessive disorderThe Pendred syndrome: an autosomal recessive disorder linked to mutations on chromosome 7

The affected gene directed the synthesis of the SLC26A4The affected gene directed the synthesis of the SLC26A4 transporter, later named Pendrin

Bicarbonate regeneration by H+ secretion in CCT

Stimulated by:- Intracellular

id i (K d l)acidosis (K depl)- Sodium avidity (aldo)

K+ and H+ secretion in cortical collecting duct are dependent from Na reabsorption by ENaCdependent from Na reabsorption by ENaC

1. In the principal cells od corticalcollecting duct Na-K-ATPasegmaintains a low intracellularconcentration of Na1

2 2. Na enter the cell throughENaC, creating a lumen-positive gradient in the lumen

23

Cl-

positive gradient in the lumen(electrogenic transport)

3 K+ and H+ leave the cells to the3. K+ and H+ leave the cells to thelumen utilizing specificchannels, respectivelypotassium channels ROMK orpotassium channels ROMK orthe H+ATPase, along theelectric gradient

ENaC activity is increased by:ENaC activity is increased by:

• Flow rate (Na+ delivery)• Flow rate (HCO -• Flow rate (HCO3

delivery)Ald t• Aldosterone

• Alkalemia (basolateral or (tubular fluid bicarbonate)

Gennari FJ. Am J Kidney Dis 2011; 58:626-636

Gennari F J Am J Kidney Dis. 2011 58:626-636.

Bases for increased serum bicarbonatelevels in metabolic alkalosis

The central role ofrole of

chloride losses

The effects of Cl and K depletionth i t f t b li lk l ion the maintenance of metabolic alkalosis

Gennari FJ. Am J Kidney Dis 2011; 58:626-636

Central role of chloride depletion:pCl is more important than K

Same K depletion but different Cl intake:

more severemore severe metabolic alkalosis in

low Cl diet

Gennari F. Am J Kidney Dis 2011 58:626-636

Central role of chloride depletion:pCl- is more important than volume

expansion

Cl- repletion in the face of persistent

expansion

Cl- repletion in the face of persistent volume depletion corrects metabolic

alkalosis whereas volume expansionalkalosis, whereas volume expansion without Cl- not

Rosen RA et al., Am J Med 1988; 84:449-458

Wh t i th l f t iWhat is the role of potassium depletion in metabolic alkalosisp

Cellular cationic shifts in K depletionCellular cationic shifts in K depletion

K +

Na+

H+

I t ll l id i d t K d l tiIntracellular acidosis due to K depletion increases glutamine catabolism increased production of NH increased excretion ofproduction of NH3 increased excretion of NH4

+ increased bicarbonate production

Am J Kidney Dis. 2011 58:626-636.

Causes of metabolic alkalosis in theCauses of metabolic alkalosis in thepast were categorized based on the

t t t t ( lresponse to treatment (volumeresponsive/contraction alkalosis etc.)rather than on the specificpathophysiological processpathophysiological process

Gennari F, J Am J Kidney Dis 2011 58:626-636

Differential diagnosis

Gennari FJ, J Am J Kidney Dis 2011 58:626-636

Not always the causes leading to metabolic alkalosis are evident from history physical examination and urine analysisevident from history, physical examination and urine analysis

MetabolicMetabolic alkalosis:

peculiarities for the ER physician

Joo-Hark Yi et al Am J Kidney Dis 2012 in press

Urine anion gap=

[Na] + [K]- [Cl]

If UAG has a positive value presence of unmeasured anion

(if pH > 7 is bicarbonate)( p )

Joo-Hark Yi et al., Am J Kidney Dis 2012 in press

Metabolic alkalosis: treatment

LOW URINE CHLORIDE KIDNEY FAILURE True Volume Depletion

NaCl Expansion “Effective” Intravascular Depletion

KIDNEY FAILURE Dialysis HCl

Effective Intravascular Depletion(CHF, Cirrhosis, Nephrotic Syndrome) Acid - HCl, NH4Cl, Arginine Cl Acidifying Diuretics (Acetazolamide 250-500 mg x2-3 p.o) +KCl

Surgical Hyperaldosteronism/Mineralocorticoid Excess States

Acidifying Diuretics (Acetazolamide 250 500 mg x2 3 p.o) KCl

HIGH URINE CHLORIDESurgical Hyperaldosteronism/Mineralocorticoid Excess States Surgery

Non-Surgical Aldosteronism – Spironolactone/Eplerenone Exogenous M.C. – Stop Drugs/Agentsg p g g Genetic Disorders

Bartter/Gitelman –KCl, Mg, NaCl, Spironolactone, Eplerenone,Amiloride, ACEI, PG Inhibitors (primarily for Bartter) Liddle – Amiloride/Triamterene (Not Spironolactone or Eplerenone) Cl diarrhea - Replace K, PPI, Organic Acid Salts

Joo-Hark Yi et al., Am J Kidney Dis 2012 in press

Joo-Hark Yi et al., Am J Kidney Dis 2012 in press

Diagnostic ApproachLow Urine Chloride < 15 mEq/l

Volume Contracted/HypotensiveVolume Contracted/HypotensiveNaCl Responsive

Gastrointestinal Causes•Vomiting• Nasogastrric Suction• Nasogastrric Suction• Chloride-Wasting Diarrhea Low Urine Chloride < 15 mEq/lDiarrhea

(Chloridorrhea)• Villous Adenoma

“Effective” Intravascular

qNaCl Unresponsive

Post-HypercapniaCystic FibrosisDiuretics* (Late)

Effective Intravascular Volume Deficit

(Total ECF Volume often –CHF Ci h i N h ti S )Diuretics (Late) CHF, Cirrhosis, Nephrotic S.)

Diagnostic ApproachHigh Urine Chloride > 15 mEq/l

NaCl Unresponsive

Volume Contracted/HypotensiveVolume Expanded/Hypertensive

• Diuretics* (Early)• Bartter Syndrome

Git l S d

yp

ADRENAL/HORMONAL DISORDERS

• Hyperaldosteronism • Gitelman Syndrome• Hyperaldosteronism• Cushing Syndrome

• Pituitary or Adrenal• Ectopic ACTHEctopic ACTH

• Exogenous Steroids• Licorice/Carbenoxalone11- Hydroxysteroid Dehydrogenase y y y g

ActivityLiddle SyndromeAlkali Ingestion/Infusion g

with Kidney Fx Milk Alkali Syndrome

Distal reabsorption of HCO3-

LUME INTERSTITIα-intercalated cellLUMEN

INTERSTITIUM

Cl-

α-intercalated cell (collecting tubule)

H+HCO3-

HCO3-

H+

H2CO3-

H2CO3-H+-ATPase

H2CO3

CO2 CO2 H2O

ATP

H2O Stimulated by:- Filtered load of HCO3

-

- Luminal H+

- Intracellular acidosis (K depl)- Sodium avidity (ANG II)*

Glutamine transporters and ammoniagenesis pathway in a proximal tubular cellpathway in a proximal tubular cell.

Shiak A. H.Am J Physiol Renal Physiol 301: F969–

Differential diagnosis

Pendrin activity in maintenance or recovery of

metabolic lk l ialkalosis