A New Perspective on Metabolic acidosis

Taipei Veterans General Hospital, Hsin-Chu branch

Director of Nephrology

Steve Chen

H+

Analysis of Acid-Base Disorders

NORMAL ACID-BASE BALANCE

23-27 mEq/L 22-26 mEq/LStandard HCO3

42-50 mmHg 35-45 mmHgPaCO2

42-48 nEq/L35-45 nEq/LH+

7.32-7.387.35-7.45pH

VenousArterialParameter

Basic Regulation of Acid-Base Balance

CO2 + H2O ↔ H2CO3 ↔ H+ + HCO3

The lungs help control acid-base balance by blowing off or retaining CO2. The kidneys help regulate acid-base balance by

excreting or retaining HCO3

Na+

NHE-3

H+ HCO3-

Na+

NBC

H2O CO2+

CA-2

Na+

K+

Na/K ATPase

PCT: Re-absorption of HCO3-

H+HCO3-

H+ATPase

H+

H2O

OH- CO2

HCO3-

+Cl-

CA

CCD: H+ secretion

AE-1

CCD: HCO3- secretion generation

Pendrin

Types of Acids in the body

Volatile acids:– Can leave solution and enter the atmosphere.– H2C03 (Carbonic acid).– Pco2 is most important factor in pH of body

tissues.

• Pco2 is a measurement of tension or partial pressure of carbon dioxide in the blood.

Types of Acids in the body

Fixed Acids:– Acids that do not leave solution.– Sulfuric and phosphoric acids.

( H2SO4& H3PO4)– Catabolism of amino acids, nucleic acids, and

phospholipids.

Types of Acids in the body

Organic Acids:– Byproducts of aerobic metabolism, during

anaerobic metabolism and during starvation, diabetes.

– Lactic acid , Ketones

Types of Acids in the body

Toxic Acids:– Hippuratic acid

Immediate response (Hb)

1~2 X all chemical ECF buffers

1 x

3x

Chemical buffer system

– Bicarbonate/carbonic acid • major plasma buffer

– Phosphate: H2PO4- / HPO42- • major urine buffer

– Ammonium: NH3 / NH4+ • also used to buffer the urine

– Proteins: important in ICF– Hb: is the main buffer against CO2 change

~ 25%

~75%

Bicarbonate Buffer System

Carbonic acid (H2CO3)– Weak acid

Bicarbonate ion (HCO3-)

– Weak base CO2 + H20 H2CO3 H+ + HCO3

-

Works along with lung and kidney– These systems remove CO2 or HCO3

-

• Bicarbonate/Carbonic acid = 20:1 normally • Alterations in the ratio changes pH

irrespective of absolute concentrations

Phosphate Buffer System

• Dihydrogen phosphate ion (H2PO4-)

– Weak acid• Monohydrogen phosphate ion (HPO4

2-)– Weak base

• H2PO4- H+ + HPO4

2-

• More important in buffering kidney filtrate than in tissue• The amount of phosphate filtered is limited and relatively

fixed, and only a fraction of the secreted H+ can be buffered by HPO4

2-

Degree of phosphate buffering if 50 mmol/L of phosphate excreted

Segment pH HPO4 H2PO4 Amount buffered by HPO4

Filtrate 7.4 40 10 0

Proximal tubule

6.8 25 25 15

Final urine 4.8 0.5 49.5 39.5

Titratable acid excretion

15 ~40

Ammonia Buffer System

• NH4+– Weak acid

• NH3– Weak base

• NH4+ H+ + NH3-

• Ammonia is produced in the proximal tubule from the amino acid glutamine, and this reaction is enhanced by an acid load and by hypokalemia

• Under basal conditions, ~50% of the ammonia that is produced is excreted in urine and 50% is added to the systemic circulation via renal veins

NH4+ excretion

Arterial pH and urine pH on NH4 excretion

Diet acid load on NH4 excretion

Renal Control of Acid-Base Balance

• Acidosis →↑ urinary HCO3- re-absorption ↑ new HCO3- production

HCO3 reabsorption ↑ HCO3 generation↑

AE-1

H+

K+

TYPES OF ACID-BASE DISTURBANCES

Depression of the central nervous system, as evidenced by disorientation followed by coma

Excitability of the nervous system; muscles may go into a state of tetany and

convulsions

Regulatory mechanisms of metabolic acidosis in the bone microenvironment

Acid-sensing ion channels (ASIC), Transient receptor potential vanilloid channels (TRP), G-protein-associated receptors such as OGR1,  Receptor activator of the nuclear factor κB ligand (RANKL) V-ATPase ion pump, an enzyme that promotes acidification of the bone surface where the resorption process will take place

In persons with chronic uremic acidosis, bone salts contribute to buffering, and the serum HCO3

- level usually remains > 12 mEq/L.

Ulcerative colitisHigh intestinal fistula Prolonged intestinal aspiration

H

Unmeasured anions: 10~16 meq/L

Anion Gap

– This is a calculated estimation of the undetermined or unmeasured anions in the blood Anion gap(AG) = (Na) - (HCO3+Cl)

– Normal anion gap ~ 10-16 meq / L

Unmeasured cations = K/Ca/Mg

Unmeasured anions ↑:↑Pi ; ↑Albumin

Unmeasured cations ↓ : ↓K ; ↓Ca ; ↓Mg

AG ↑

Anion Gap

– This is a calculated estimation of the undetermined or unmeasured anions in the blood Anion gap(AG) = (Na) - (HCO3+Cl)

– Normal anion gap ~ 10-16 meq / L– Albumin(↓1G/dl) = AG (↓2.3-2.5 meq/L) – If K included(↑), normal AG drops 4 meq/L(↓)

AG metabolic acidosis• Ketoacidosis: DKA/SKA/AKA

(Beta-hydroxybutyrate, acetoacetate)

• Lactic acidosis• Salicylate poisoning• Ethelene glycol intoxication (glycolate, oxalate)

• Methanol poisoning: Formaldehyde ( Formate); Formic acid

• Renal failure (Sulfate, phosphate, urate, and hippurate)

• Massive rhabdomyolysis (release of H + and organic anions from damaged muscle)

Non AG metabolic acidosis: ↑Cl/↓HCO3

• Acid load / Total parenteral nutrition (TPN)

• Chronic renal failure• Carbonic anhydrase inhibitors: acetazolamide

• Renal tubular acidosis(RTA)• Ureterosigmoidostomy/Intestinal fisula or

drainage• Expansion• Diarrhea

Plasma osmolar gap (POG)Posm = [2 X Na+]+ [glucose in mg/dL] /18+

[BUN in mg/dL]/2.8POG = the difference between the measured

value and the calculated one: no more than 10-15 mOsm/kg

↑ POG: Mannitol, radioactive contrast agents High-AG acidosis: Methanol, ethylene glycol, and acetone …

Urine anion gap (UAG) = Na + K – Cl: ~ NH4+ (near zero in normal)

Cl-

Na+ K+

HCO3-~ 0 meq/L

NH4 +~ 0 meq/L

Urine anion gap (UAG): negative in metabolic acidosis

Cl-

Na+ K+

NH3 + H+ = NH4 +

Acid load

Positive UAG in non AG metabolic acidosis RTA

Cl-

Na+ K+

NH3 + H+ = NH4 +

HCO3-

Simple or mixed ?Conditions Primary event Secondary response

Metabolic acidosis(30 minutes onset, 12-24H completion)

HCO3 ↓ 1 meq/L pCO2 ↓ 1.2 mmHg

Metabolic alkalosis (30 minutes onset, 12-24H completion)

HCO3 ↑ 1 meq/L pCO2 ↑ 0.7 mmHg

Respiratory acidosis Acute Chronic > 3-5days

pCO2 ↑ 10 mmHg HCO3 ↑ 1 meq/L ↑ 3.5-4 meq/L

Respiratory alkalosis Acute Chronic >3-5 days

pCO2 ↓ 10 mmHg HCO3 ↓ 2 meq/L ↓ 4-5 meq/L

General Principles of TreatmentExogenous alkali may not be required if the

acidemia is not severe (arterial pH >7.20), the patient is asymptomatic, and the underlying process, such as diarrhea, can be controlled

Bicarbonate therapy is generally not given unless the arterial pH is < 7.00 in Ketoacidosis or < 7.10 in Lactic acidosis

Potential Acids in the body

Organic Acids Potential bicarbonate – Byproducts of aerobic metabolism, during

anaerobic metabolism and during starvation, diabetes.

– Ketones – Lactate – Conservative supply of HCO3-

Bicarbonate deficit Assuming that respiratory function is normal,

attainment of a pH of 7.20 usually requires raising the serum Bicarbonate to 10 ~ 12 meq/L

HCO3 deficit = HCO3 space x HCO3 deficit per liter

HCO3 space = [0.4 + (2.6 ÷ [HCO3])] x lean body weight (LBW, Kg) = 0.55~0.7 x LBW

Approximately 250 meq of alkali (usually as intravenous sodium bicarbonate) can be given over the first 4 to 8 hours

Positive UAG in non AG metabolic acidosis RTA

Cl-

Na+ K+

NH3 + H+ = NH4 +

HCO3-

Renal Tubular Acidosis:RTA-1 Any patient with non-AG metabolic acidosis and a

urine pH > 5.0 Re-absorb HCO3

- normally FE of HCO3

- < 3% Serum HCO3

- : variable; in some cases ( < 10 mEq/L )

Serum K+ level typically is low in patients with distal RTA; can be high if the distal RTA is secondary to voltage-dependent Hyper-kalemic RTA-1

H+ATPase

H+

H2O

OH- CO2

HCO3-

+Cl-

CA

CCD: H+ secretion ↓ in RTA-1

H+

K+

AE-1

The causes of RTA-1 Primary: Genetic or sporadic Drug-related: Amphotericin B, lithium, analgesics,

ifosfamide, topiramate, toluene Autoimmune disease: SLE, chronic active

hepatitis, Sjögren syndrome, RA, primary biliary cirrhosis

Other systemic diseases: Sickle cell disease, hyperparathyroidism, light chain disease, cryoglobulinemia, Wilson disease, Fabry disease

Tubulointerstitial disease - Obstructive uropathy, transplant rejection, medullary cystic kidney disease, hypercalciuria

Hypokalemia in RTA-1 Decreased net H + secretion results in more

Na + re-absorption in exchange for K The drop in serum HCO 3 - and, therefore, filtered

HCO 3 -, reduces the amount of Na + reabsorbed by the Na +/H + exchanger in the proximal tubule, leading to mild volume depletion. The associated activation of the RAA system increases K + secretion in the collecting duct. + secretion.

A possible defect in K +/H + –ATPase results in decreased H + secretion and decreased K + re-absorption.

Nephrocalcinosis and Nephrolithiasis in RTA-1

A constant release of calcium phosphate from bones to buffer the extracellular H +

↓ Re-absorption of calcium and phosphate hypercalciuria and hyperphosphaturia

Relatively alkaline urine promotes calcium phosphate precipitation

Metabolic acidosis and hypokalemia lead to hypocitraturia, a risk factor for stones

Renal Tubular Acidosis:RTA-2 Any non-AG metabolic acidosis with a serum

HCO3- > 15 mEq/L (usually) + acidic urine (pH <

5.0) the strong ability of the collecting duct to reabsorb some HCO3

FEHCO3- less than 3% when their serum HCO3

- is low. However, raising serum HCO3

- above their lower threshold and closer to normal levels results in significant HCO3

- wasting and an FEHCO3exceeding 15% HCO3

- loading test

Patients with type 2 RTA typically have hypokalemia and increased urinary K+wasting Bicarbonaturia

Na+

NHE3

H+ HCO3-

Na+

NBC

H2O CO2+

CA-2

Na+

K+

Na/K ATPase

PCT: Re-absorption of HCO3- in RTA-2

H+HCO3-

The causes of RTA-2 Primary: Genetic or sporadic Inherited systemic disease - Wilson disease,

glycogen storage disease, tyrosinemia, Lowe syndrome, cystinosis, fructose intolerance

Related to other systemic disease - Multiple myeloma, amyloidosis, hyperparathyroidism, Sjögren syndrome

Drug- and toxin-related - Carbonic anhydrase inhibitors, ifosfamide, gentamicin, valproic acid, lead, mercury, streptozotocin

Osteomalacia in RTA-2Any chronic acidemic stateProximal tubular conversion of 25(OH)-

cholecalciferol to the active 1,25(OH)2-cholecalciferol is impaired

Patients with more generalized defects in proximal tubular function (as in Fanconi syndrome) may have phosphaturia and hypophosphatemia, which also predispose to osteomalacia.

Renal Tubular Acidosis:RTA-4 Any patient with a mild non-AG metabolic

acidosis : Diminished ammoniagenesis CKD stages 2-3 in most patients; Diabetes mellitus (in

approximately 50% of patients) Serum HCO3

-  > 15 mEq/L (usually), and the urine pH is < 5.0 

A TTKG less than 5 in the presence of hyperkalemia indicates aldosterone deficiency or resistance

Hyperkalemia also reduces proximal tubular NH4

+ production and decreases NH4+absorption by the

thick ascending limb: ↓ the ability of the kidneys to excrete an acid load

The causes of RTA-4 Hyporeninemic hypoaldosteronism (diabetes mellitus/mild

renal impairment, chronic interstitial nephritis, nonsteroidal anti-inflammatory drugs, beta-blockers)

Hypoaldosteronism (high renin) - Primary adrenal defect (isolated: congenital hypoaldosteronism; generalized: Addison disease, adrenalectomy, AIDS), inhibition of aldosterone secretion (heparin, ACE inhibitors, AT1 receptor blockers)

Aldosterone resistance (drugs) - Diuretics (amiloride, triamterene, spironolactone), calcineurin inhibitors (cyclosporine, tacrolimus), antibiotics (trimethoprim, pentamidine)

Aldosterone resistance (genetic) - Pseudohypoaldosteronism (PHA) types I and II

L-Lactic acidosis Daily L-lactate production in a healthy person is

substantial (approximately 20 mEq/kg/d), and this is usually metabolized to pyruvate in the liver, the kidneys, and, to a lesser degree, in the heart.

Serum lactate > 5 mEq/L Type A lactic acidosis occurs in hypoxic states,

while type B occurs without associated tissue hypoxia

D-lactic acidosis is a form of lactic acidosis that occurs from overproduction of D-lactate by intestinal bacteria. It is observed in association with intestinal bacterial overgrowth syndromes

L-Lactic acidosis Definition of acute lactic acidosis: blood lactate level ≥ 5

mEq/L, blood pH ≤ 7.35, and serum bicarbonate concentration ≤ 20 mEq/L

Sustained hyperlactatemia in sepsis or low-flow states carries mortality ≥ 60%

Sodium bicarbonate does not improve cardiac function or reduce mortality

In individuals predisposed to develop intracellular acidification with bicarbonate, other buffers (such as THAM [tris-hydroxymethyl aminomethane] or buffers containing disodium carbonate) should be considered

Hyperventilation to reduce carbon dioxide accumulation and infusion of calcium to stabilize calcium concentration improve myocardial function

Lactate-guided therapy with the goal of normalizing blood lactate levels (to <2 mEq/L) has shown some benefit

Renal failure CKD (GFR 20 ~ 50 mL/min): normal AG metabolic acidosis

Ammoniagenesis ↓ NH3 reabsorption and recycling↓ ; medullary interstitial NH3 concentration ↓ Serum HCO3

-  > 12 mEq/L GFR < 20: high AG metabolic acidosis

Accumulation of sulfates, urates and phosphates Serum HCO3

-  > 12 mEq/L, but significant loss of bone calcium with resulting osteopenia and osteomalacia

Methanol poisoningMethanol is metabolized by alcohol

dehydrogenase to formaldehyde and then to formic acid

High AG: formic acid, lactic acid, and ketoacid

Formaldehyde: optic nerve and CNS toxicity

Retinal edema, CNS depression, and unexplained metabolic acidosis with high anion and osmolar gaps

Ethylene glycol poisoning Ethylene glycol is converted by alcohol

dehydrogenase first to glycoaldehyde and then to glycolic and glyoxylic acids. Glyoxylic acid then is degraded to several compounds, including oxalic acid, which is toxic, and glycine, which is relatively innocuous

High AG: accumulation of these acids + mild lactic acidosis

CNS symptoms ( slurred speech, confusion, stupor or coma) , myocardial depression, and renal failure with flank pain

Oxalate crystals in the urine; elevated osmolar gap

Toluene Toxicity –Renal Renal tubular acidosis (RTA)HypokalemiaHypophosphatemiaHyperchloremiaAzotemiaSterile pyuriaHematuriaProteinuria

Toluene Toxicity -CNS Acute intoxication from inhalation is characterized

by rapid onset of CNS symptoms: euphoria, hallucinations, delusions, tinnitus, dizziness, confusion, headache, vertigo, seizures, ataxia, stupor, and coma.

Chronic CNS sequelae: neuropsychosis, cerebral and cerebellar degeneration with ataxia, seizures, choreoathetosis, optic and peripheral neuropathies, decreased cognitive ability, anosmia, optic atrophy, blindness, tinnitus, and hearing loss

Toluene Toxicity -CP Toluene has direct negative effects on

cardiac automaticity and conduction and can sensitize the myocardium to circulating catecholamines.

"Sudden sniffing death" secondary to cardiac arrhythmias has been reported.

Pulmonary effects include bronchospasm, asphyxia, acute lung injury (ALI), and aspiration pneumonitis.

Toluene Toxicity -GI GI symptoms from inhalation and ingestion:

abdominal pain, nausea, vomiting, and hematemesis.

Hepatotoxicity: ascites, jaundice, hepatomegaly, and liver failure.

A rare form of hepatitis: hepatic reticuloendothelial failure (HREF)

Hepatitis secondary to toluene toxicity, not just infectious causes, should be considered in the differential diagnosis in the younger population

Mechanisms AG↑ Normal AG

Acid production ↑ Lactic acidosisKetoacidosisMethanol intoxicationEthylene glycol Diethylene glycolPropylene glycol Aspirin Pyroglutamic acid(5 oxo proline)Toluene

Toluene ( if preserved renal function/excretion of Na and K hippurate in urine later)

Loss of HCO3 or its precursors

Diarrhea (tube drainage)Other intestinal lossesT2RTACA inhibitorsUreteral diversion(ileal loop) Post-treatment of ketoacidosis

Renal acid secretion↓ CKD-5 (GFR <20) CKD (GFR 20~50)

T1RTAT4RTA(hypoaldosteronism)

RhCG in urinary ammonium excretion

RhCG

RhCG

NH3

H-ATPaseAE1

H/K ATPase

CO2+H2OHCO3HCl

K

H

NH3

CA

C (cortical) CD

Lithium

Model of collecting duct ammonia secretion 

NH4+ excretion

Glutamine synthase (GS)

HCO- transporter: NBC e1

GS: NH4 + + glutamate + ATP -> glutamine + H+ + ADP + Pi.

PDG: glutamate dehydrogenasePEPCK

RhCG in urinary ammonium excretion

RhCG

RhCG

NH3

H-ATPaseAE1

H/K ATPase

CO2+H2OHCO3HCl

K

H

NH3

NaK ATPaseK(NH4)

CA

Inner medullay

CD

Lithium

NaKCCK(NH4)

Metabolic acidosisIssues Traditional views New aspectsDefinition PHCO3↓ HCO3 content if ECFV↓

Look for new Anions by P anion gap Adjusted when P albumin (adjusted by P albumin is low) is high if ECFV is low = Na-Cl-HCO3 in plasma Detect new anions in urine (UAG=Na+K+NH4-Cl) Detect NH4(urine) UAG = Na+K-Cl Uosm gap(UOG): best indirect Urine pH indicator for NH4Compare fall in PHCO3 Expect 1:1 Calculate HCO3 content in with rise in P anion gap ECFV to estimate deficit

Examine effectiveness of Rely only on PaCO2 Use capillary PCO2 in HCO3 buffer system skeletal muscle (reflected by brachial venous PCO2)