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Acid-Base. Basic definitions An acid a substance that can donate hydrogen ions (H + ) A base a substance that can accept H + ions H 2 CO 3 (acid)«H + + HCO 3 - (base) Strong acids completely ionized in body fluids W eak acids incompletely ionized in body fluids. Acid-Base.

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acid base

Acid-Base

Basic definitions

An acid

a substance that can donate hydrogen ions (H+)

A base

a substance that can accept H+ ions

H2 CO3 (acid)«H+ + HCO3- (base)

Strong acids

completely ionized in body fluids

Weak acids

incompletely ionized in body fluids

acid base1

Acid-Base

Basic definitions

HCl«H+ + Cl-

Hydrochloric acid (HCl)

a strong acid - it is present only in a completely ionized form in the body

H2 CO3 (acid)«H+ + HCO3- (base)

a weak acid - it is ionized incompletely

at equilibrium, all 3 reactants are present in body fluids

acid base2

Acid-Base

Basic definitions

H2 CO3 (acid)«H+ + HCO3- (base)

the law of mass action - the velocity of a reaction is proportional to the product of the reactant concentrations …………………………………………….

the addition of H+ or bicarbonate (HCO3-) drives this reaction to the left

acid base3

Acid-Base

Basic definitions

in body fluids

the concentration of hydrogen ions - H+

normal physiologic concentration = 40 nEq/L

is maintained within very narrow limits

the concentration of HCO3-= (24 mEq/L)

is 600,000 times that of [H+]

acid base4

Acid-Base

Basic definitions

the tight regulation of [H+] at this low concentration is crucial for normal cellular activities

H+ at higher concentrations can bind strongly to negatively charged proteins, including enzymes, and impair their function (!!)

under normal conditions, acids and bases are being added constantly to the extracellular fluid compartment

for the body to maintain a physiologic [H+] of 40 mEq/L,3 processes must take place:

Buffering by extracellular and intracellular buffers

Alveolar ventilation, which controls PaCO2

Renal H+ excretion, which controls plasma [HCO3-]

acid base6

Acid-Base

Buffers

weak acids or bases that are able to minimize changes in pH

by taking up H+

by releasing H+

Phosphate - effective buffer

HPO42- + (H+)«H2 PO4-

upon addition of an H+ to extracellular fluids, the monohydrogen phosphate binds H+ to form dihydrogen phosphate, minimizing the change in pH

when [H+] is decreased, the reaction is shifted to the left

Thus, buffers work as

a first-line of defense (!!)

to blunt the changes in pH that would result from the constant daily addition of acids and bases to body fluids

acid base7

Acid-Base

Buffers

HCO3-/H2 CO3 buffering system

H2 O + CO2 «H2 CO3 «H+ + HCO3

the major extracellular buffering system

a very effective system

has the ability to control PaCO2 by changes in ventilation

increased carbon dioxide (CO2) concentration drives the reaction to the right, a decrease in CO2 concentration drives it to the left

H+ added to the body fluids  formation of carbonic acid = consumption of HCO3

carbonic acid (H2 CO3)  water + CO2 ventilation

CO2 concentration is maintained within a narrow range via the respiratory drive, which eliminates accumulating CO2

the kidneys regenerate the HCO3- consumed during this reaction

acid base8

Acid-Base

Buffers

H2 O + CO2 «H2 CO3 «H+ + HCO3

this reaction continues to move to the left

as long as CO2 is constantly eliminated

or until HCO3 - is significantly depleted, making less HCO3 - available to bind H+

HCO3 - and PaCO2 can be managed independently

HCO3 in the kidneys

PaCO2 in the lungs

that makes this a very effective buffering system

acid base9

Acid-Base

Buffers

HCO3-/H2 CO3 buffering system

H2 O + CO2 «H2 CO3 «H+ + HCO3

Henderson-Hasselbalch equation

pH = 6.10 + log ([HCO3 -]/0.03 X PaCO2)

expresses the relationship between the 3 reactants in the reaction at equilibrium

an alternative - [H+] = 24 X PaCO2/[HCO3 -]

Henderson-Hasselbalch equation relates:

dissolved CO2 (ie, H2 CO3)

to the partial pressure of CO2 (0.03 X PaCO2)

acid base10

Acid-Base

Buffers

pH = 6.10 + log ([HCO3 -]/0.03 X PaCO2)

changes in pH or [H+] are a result of relative changes in the ratio of PaCO2 to [HCO3 -] rather than to absolute change in either one

if both PaCO2 and [HCO3 -] change in the same direction, the ratio stays the same and the pH or [H+] remains relatively stable

the alteration in pH occurs when either HCO3 - or PaCO2 changes the other variable in the same direction

acid base11

Acid-Base

Buffers

intracellular buffers - hemoglobin, bone

in chronic metabolic acidosis extracellular HCO3 level is low

intracellular buffers are more important than HCO3

acid base12

Acid-Base

Renal acid handling

Acids are added daily to the body fluids

volatile acids - carbonic acid

the metabolism of dietary carbohydrates and fat produces approximately 15,000 mmol of CO2 per day, which is excreted by the lungs

failure to do so results in respiratory acidosis

nonvolatile - eg, sulfuric, phosphoric acids

the metabolism of proteins (ie, sulfur-containing amino acids) results in the formation of H2 SO4

dietary phosphate results in the formation of H3 PO4

acid base13

Acid-Base

Renal acid handling

these acids first are buffered by the HCO3 -/H2 CO3 system:

H2 SO4 + 2NaHCO3 «Na2 SO4 + 2H2 CO3 «2H2 O + CO2

a strong acid (H2 SO4) is buffering by 2 molecules of HCO3a weak acid (H2 CO3) is produced this minimizes the change in pH

the lungs excrete the CO2 produced

the kidneys replace the consumed HCO3

to prevent progressive HCO3 - loss and metabolic acidosis

kidneys perform these principally by H+ secretion in the collecting duct

acid base14

Acid-Base

Renal acid handling

prevention of metabolic acidosis  prevention of progressive HCO3 loss

amino acids ( glutamate, aspartate)  formation of citrate and lactate   convertion to HCO3

to maintain normal pH, the kidneys must

“reabsorb” all the filtered HCO3 - (any loss of HCO3 - is equal to the addition of an equimolar amount of H+) (in the proximal tubule)

excrete the daily H+ load (loss of H+ is equal to addition of an equimolar amount of HCO3 -) (in the collecting duct)

acid base15

Acid-Base

Renal acid handling / HCO3 - reabsorption

the daily glomerular ultrafiltrate in a healthy subject, contains 4300 mEq of HCO3– for

a serum HCO3 - concentration of 24 mEq/L

a daily glomerular ultrafiltrate of 180 L

all of filtered HCO3 – has to be reabsorbed

90% in the proximal tubule,

the remainder in the thick ascending limb and the medullary collecting duct

the energy for this process  the 3Na+ -2K+ «ATPase

maintains a low intracellular Na+ concentration and a relative negative intracellular potential  indirectly provides energy for the apical Na+/H+ exchanger - NHE3 (gene symbol SLC9A3)  transports H+ into the tubular lumen  H+ in the tubular lumen combines with filtered HCO3 –

HCO3 - + H+ «H2 CO3 «H2 O + CO2

acid base16

Acid-Base

Renal acid handling / HCO3 - reabsorption

HCO3 - + H+ «H2 CO3 «H2 O + CO2

the dissociation of H2 CO3 into H2 O + CO2 is accelerated by Carbonic anhydrase (CA IV isoform)

present in the brush border of the first 2 segments of the proximal tubule

this shifts the reaction shown above to the right and keeps the luminal concentration of H+ low

CO2 diffuses into the proximal tubular cell, via the aquaporin-1 water channel

carbonic anhydrase (CA II isoform) combines CO2 and water to form HCO3 - and H+

the HCO3 - formed intracellularly returns to the pericellular space and then to the circulation via the basolateral Na+/3HCO3 - cotransporter, NBCe1-A (gene symbol SLC4A4)

acid base17

Acid-Base

Renal acid handling / HCO3 - reabsorption

In essence

the filtered HCO3 - is converted to CO2 in the lumen

CO2 diffuses into the proximal tubular cell

in the tubular cell CO2 is converted back to HCO3 –

HCO3 – is returned to the systemic circulation

in this way the filtered HCO3 – is recuperated

acid base18

Acid-Base

Renal acid handling

Acid excretion

the daily acid load = 50-100 mEq of H+is excreted

through H+ secretion

by the apical H+ «ATPase

in A-type intercalated cells of the collecting duct

acid base19

Acid-Base

Renal acid handling / Acid excretion

HCO3 - formed intracellularly is returned to the systemic circulation via the basolateral Cl-/HCO3 -exchanger, AE1 (gene symbol SLC4A1)

H+ enters the tubular lumen via 1 of 2 apical proton pumps, H+ «ATPase or H+ -K+ «ATPase

The secretion of H+ in these segments is influenced by Na+ reabsorption in the adjacent principal cells of the collecting duct

The reabsorbed Na+ creates a relative lumen negativity, which decreases the amount of secreted H+ that back-diffuses from the lumen

acid base20

Acid-Base

Renal acid handling / Acid excretion

Hydrogen ions secreted by the kidneys can be excreted

as free ions

> 99.9% of the H+ load - buffered by the weak bases NH3 or phosphate

The reason for limited excretion of free H+ ions

the lowest achievable urine pH = 5.0

= 10 µEq/L H+

would require excretion of 5,000-10,000 L of urine a day

urine pH cannot be lowered much below 5.0

because the gradient against which H+ «ATPase has to pump protons (intracellular pH 7.5 to luminal pH 5) becomes too steep

acid base21

Acid-Base

Renal acid handling / urine-buffering system

titratable acidity

the amount of secreted H+ that is buffered by filtered weak acids is called titratable acidity

buffers in this system

phosphate as HPO4 2

ammonia (NH3)

uric acid

creatinine

H2 PO4 «H+ + HPO42-

the amount of phosphate filtered is limited and relatively fixed only a fraction of the secreted H+ can be buffered by HPO42-

acid base22

Acid-Base

Renal acid handling / urine-buffering system / ammonia

Ammonia

NH3 + H+ «NH4 +

ammonia is produced in the proximal tubule from the amino acid glutamine

this reaction is enhanced by

an acid load

hypokalemia

acid base23

Acid-Base

Renal acid handling / urine-buffering system / ammonia

Intracellular - proximal tubules

NH3 + H+ «NH4 +

NH4 + is secreted into the proximal tubular lumen by the apical Na+/H+ (NH4 +) antiporter

Intraluminal - thick ascending limb of the loop of Henle

the apical Na+/K+ (NH4 +)/2Cl- cotransporter in the thick ascending limb of the loop of Henle then transports NH4 + into the medullary interstitium

it dissociates back into NH3 and H+

NH3 diffuses into the lumen of the collecting duct - available to buffer H+ ions and becomes NH4 +.

NH4 + is trapped in the lumen and excreted as the Cl salt

.

acid base24

Acid-Base

Renal acid handling / urine-buffering system

NH3 + H+ «NH4 +

the increased secretion of H+ in the collecting duct  shifts the equation to the right  decreases the NH3 concentration  facilitates continued diffusion of NH3 from the interstitium down its concentration gradient  allows more H+ to be buffered

the kidneys and the liver can adjust the amount of NH3 synthesized to meet demand, making this a powerful system to buffer secreted H+ in the urine

acid base25

Acid-Base

Renal acid handling / urine-buffering system

every H+ ion buffered  an HCO3- gained to the systemic circulation

echilibrul acidobazic ap rarea mpotriva schimb rii concetra iei ionilor de h

Lichid extracelular

Celulă tub proximal

Lumen tubular

Transportactiv

Na+

Na+

Na+ HCO3-

Na HCO3

HCO3-

HCO3- + H+

H+ + CO3-

contraschimb

H2 CO3

H2CO3

Anhidraza carbonică

CO2

CO2 + H2O

CO2 + H2O

eliminată

(rezultat din metabolism)

Cantitate redusă, aciditatea urinii

Filtrare glomerulară

NaHCO3-

Echilibrul acidobazic – apărarea împotriva schimbării concetraţiei ionilor de H+

Intervenţia rinichiuluiîn condiţii de normalitate

Relaţia [H+] [NaHCO3-] la ph normal al mediului intern

echilibrul acidobazic ap rarea mpotriva schimb rii concetra iei ionilor de h1

Celulă tub proximal

Na+

HPO42-

NaHCO3-

H2PO4-

HCO3- H+

HCO3-

Na+

eliminare

H2CO3

AC

CO2 + H2O

CO2

Filtrare glomerulară

a Na2HPO4

Lichid extracelular

Lumen tubular

Echilibrul acidobazic – apărarea împotriva schimbării concetraţiei ionilor de H+

Na2HPO4

Na+

Intervenţia rinichiului în acidoză

sistemul tampon fosfaţi

echilibrul acidobazic ap rarea mpotriva schimb rii concetra iei ionilor de h2

Lichid extracelular

Celulă tub proximal

Na+

Na+

Na H CO3

glutamină

NH3

HCO3-

HCO3- H+

H+

H2CO3

eliminare

AC

CO2

CO2 + H2O

Filtrare glomerulară

a NaCl

Lumen tubular

Echilibrul acidobazic – apărarea împotriva schimbării concetraţiei ionilor de H+

Na+ Cl-

NH4Cl

(acid slab)

Intervenţia rinichiului în acidoză

Formarea amoniacului din glutamină

echilibrul acidobazic ap rarea mpotriva schimb rii concetra iei ionilor de h3

Din catobolismul normal

  • al proteinelor în ficat rezultă
    • amoniac
    • bicarbonat
  • Din amoniac se formează uree
  • Funcţie de necesităţi, o parte din amoniac
  • este transformată în glutamină
    • acidoza stimulează
    • alcaloza inhibă
  • Glutamina trece în circulaţie
  • şi ajunge la nivelul celulei tubulare renale
  • Dezaminarea glutaminei la nivelul celulei tubulare
  • determină refacerea de HCO3-
    • acidoza stimulează
    • alcaloza inhibă
  • Acidoza favorizează eliminarea urinară
  • a NH4+ şi se evită transformarea lui în uree
  • care privează de regenerarea HCO3-

Echilibrul acidobazic – apărarea împotriva schimbării concetraţiei ionilor de H+

echilibrul acidobazic ap rarea mpotriva schimb rii concetra iei ionilor de h4

Filtrare glomerulară

a NaCl

Lichid extracelular

Celulă tub proximal

Lumen tubular

Na+

Na+

Na+ Cl-

Na H CO3

glutamină

NH4Cl

(acid slab)

NH3

HCO3-

HCO3- H+

H+

H2CO3

eliminare

AC

CO2

CO2 + H2O

Echilibrul acidobazic – apărarea împotriva schimbării concetraţiei ionilor de H+

Intervenţia rinichiului în acidoză

Formarea amoniacului din glutamină

  • Eliminarea urinară de amoniu
    • normal - 30 mmol/24 ore
    • la nevoie - până la 300 mmol/zi
echilibrul acidobazic ap rarea mpotriva schimb rii concetra iei ionilor de h5

Lichid extracelular

CL-

Filtrare glomerulară

a NaCl

Celulă tub distal

Lumen tubular

Echilibrul acidobazic – apărarea împotriva schimbării concetraţiei ionilor de H+

Cl-

Na+

Cl-

H+HCO3-

HCO3-

Intervenţia rinichiului /factori perturbatori, de reglare funcţiede necesităţi/ Ph-ul mediului intern

H2CO3

Na+

AC

CO2

CO2 + H2O

NaHCO3

Alcaloză hipercloremică

acid base26

Acid-Base

Metabolic acidosis / Pathophysiology

In healthy people

blood pH is maintained at 7.39-7.41

pH is the negative logarithm of [H+] (pH = - log10 [H+])

an increase in pH indicates a decrease in [H+] and vice versa

an increase in [H+] and a fall in pH is termed acidemia

a decrease in [H+] and an increase in pH is termed alkalemia

the underlying disorders that lead to acidemia and alkalemia are acidosis and alkalosis, respectively

metabolic acidosis is a primary decrease in serum HCO3 - concentration and, in its pure form, manifests as acidemia (pH <7.40)

acid base27

Acid-Base

Metabolic acidosis / Pathophysiology

rarely, metabolic acidosis can be part of a mixed or complex acid-base disturbance

2 or more separate metabolic or respiratory derangements occur together

pH may not be reduced

or the HCO3- concentration may not be low

acid base28

Acid-Base

Metabolic acidosis / Pathophysiology

compensatory mechanism = alveolar hyperventilation  a fall in PaCO2

normally, PaCO2 falls by 1-1.3 mm Hg for every 1-mEq/L fall in serum HCO3- compensatory response that can occur fairly quickly

change in PaCO2 not within this range = a mixed acid-base disturbance

ex, if the a less decrease in PaCO2 than the expected change = a primary respiratory acidosis also present

acid base29

Acid-Base

Metabolic acidosis / Pathophysiology

often the first clue to metabolic acidosis is a decreased serum HCO3 - concentration observed when serum electrolytes are measured

remember, however, that a decreased serum [HCO3 -] level can be observed as a compensatory response to respiratory alkalosis

an [HCO3-] level less than 15 mEq/L, however, almost always is due, at least in part, to metabolic acidosis

acid base30

Acid-Base

Metabolic acidosis / Anion gap

plasma, like any other body fluid compartment, is neutral - total anions match total cations

the major plasma cation is Na+

the major plasma anions are Cl- and HCO3–

in lower concentrations

other cations: K+, Mg2+, and Ca2+

other anions: phosphate, sulfate, and some organic anions

acid base31

Acid-Base

Metabolic acidosis / Anion gap

the anion gap (AG) = the difference between

the concentration of the major measured cation Na+ (140 mEq/L) and the major measured anions Cl- (108 mEq/L) and HCO3–(24 mEq/L)

the gap is usually between 6 and 12 mEq/L

acid base32

Acid-Base

Metabolic acidosis / Anion gap

the AG represents the difference between unmeasured anions and unmeasured cations:

AG = [Na+]-([Cl-] + [HCO3 -]) = unmeasured anions - unmeasured cations

an increase in the AG can result from:

a decrease in unmeasured cations: hypokalemia, hypocalcemia, hypomagnesemia

or an increase in unmeasured anions: hyperphosphatemia, high albumin levels

in certain forms of metabolic acidosis, other anions accumulate

by recognizing the increasing AG  a differential diagnosis for the cause of acidosis

acid base33

Acid-Base

Metabolic acidosis / Urinary AG

helpful in evaluating some cases of non-AG metabolic acidosis

the major measured urinary cations: Na+, K+

the major measured urinary anion is Cl-

Urine AG = ([Na+] + [K+]) - [Cl-]

the major unmeasured urinary anions HCO3-

the major unmeasured urinary cations NH4+

HCO3- excretion in healthy subjects - usually negligible

NH4+ daily average excretion - approximately 40 mEq/L

results in a positive or near-zero gap

acid base34

Acid-Base

Metabolic acidosis / Urinary AG

Urine AG = ([Na+] + [K+]) - [Cl-]

in metabolic acidosis

the kidneys increase the amount of NH3 synthesized to buffer the excess H+  NH4 Cl excretion increases

the increased unmeasured NH4+ increases the measured anion Cl- in the urine,  a negative AG == a normal response to systemic acidification

the finding of a positive urine AG in a non-AG metabolic acidosis == a renal acidification defect: renal tubular acidosis [RTA]

acid base35

Acid-Base

Metabolic acidosis / Urinary AG

Caveats

the presence of ketonuria makes this test unreliable

the negatively charged ketones are unmeasured  urine AG will be positive or zero despite the fact that renal acidification and NH4 + levels are increased

severe volume depletion from extrarenal NaHCO3 loss  avid proximal Na+ reabsorption little Na+ reaching the lumen of the collecting duct is reabsorbed in exchange for H+

limited H+ excretion  reduced NH4+ excretion  positive urinary AG

acid base36

Acid-Base

Metabolic acidosis / Effect of potassium balance on acid-base status

transcellular shift of K+

intracellular K+ is exchanged for extracellular H+ or vice versa influence on renal acid secretion

in hypokalemia  intracellular acidosis

in hyperkalemia  intracellular alkalosis

acid base37

Acid-Base

Metabolic acidosis / Effect of potassium balance on acid-base status

Hypokalemia

increased renal production of NH3 increase in renal acid excretion_____ __

relative intracellular acidosis increasedHCO3- reabsorption

relative intracellular acidosis high activity of the apical Na+/H+ exchanger

The increase in NH3 production by the kidneys may be significant enough to precipitate hepatic encephalopathy in patients who have advanced liver disease. Correcting the hypokalemia can reverse this process.

acid base38

Acid-Base

Metabolic acidosis / Effect of potassium balance on acid-base status

increased renal ammoniagenesis relativelyalkaline urine

excessive NH3 then binds more H+ in the lumen of the distal nephron  increased urine pHsuggestion of RTA as an etiology for non-AG acidosis

differential diagnoses  urine AG

negative in patients with normal NH4+ excretion

positive in patients with RTA

acid base39

Acid-Base

Metabolic acidosis / Effect of potassium balance on acid-base status

causes for hypokalemia + metabolic acidosis

most common - GI loss: diarrhea, laxative use

less common - renal loss of potassium secondary to RTA or salt-wasting nephropathy

differential diagnoses

the urine pH

the urine AG

the urinary K+ concentration

acid base40

Acid-Base

Metabolic acidosis / Effect of potassium balance on acid-base status

Hyperkalemia

opposite effect to hypokalemia

reduction of NH3 synthesis in the proximal tubule reduction of NH4+ reabsorption in the thick ascending limb reduced medullary interstitial NH3 concentration decrease in net renal acid secretion

causes for hyperkalemia + metabolic acidosis

primary or secondary hypoaldosteronism

treatment for hyperkalemia + metabolic acidosis

hyperkalemia has the central role in the generation of the acidosis lowering serum the K+ concentration  correction of the associated metabolic acidosis

acid base41

Acid-Base

Metabolic acidosis / History

symptoms - not specific

patients may report varying degrees of dyspnea

hyperventilation

respiratory center stimulation in an effort to compensate for the acidosis

nausea, vomiting, and decreased appetite

clinical history

helpful in establishing the etiology (related to the underlying disorder )

the age of onset and a family history – to point to inherited disorders

acid base42

Acid-Base

Metabolic acidosis / History

important points in the history:

diarrhea - GI losses of HCO3-

history of diabetes mellitus, alcoholism, or prolonged starvation - accumulation of ketoacids

polyuria, increased thirst, epigastric pain, vomiting - diabetic ketoacidosis (DKA)

nocturia, polyuria, pruritus, and anorexia - Renal failure4

ingestion of drugs or toxins - Salicylates, acetazolamide, cyclosporine, ethylene glycol, methanol

visual symptoms - methanol ingestion

renal stones - RTA or chronic diarrhea

tinnitus - salicylate overdose

acid base43

Acid-Base

Metabolic acidosis / Physical

Kussmaul respirations = the best recognized sign

a form of hyperventilation  increase minute ventilatory volume

slow, deep breathing  an increase in tidal volume rather than respiratory rate

stunted growth and rickets  chronic metabolic acidosis in children

coma and hypotension  acute severe metabolic acidosis

other physical signs  the underlying cause

xerosis, scratch marks on skin, pallor, drowsiness, fetor, asterixis, pericardial rub  renal failure

reduced skin turgor, dry mucous membranes, fruity smell  DKA

acid base44

Acid-Base

Metabolic acidosis / Causes

Metabolic acidosis

normal AG (ie, non-AG)

high AG

Non-AG metabolic acidosis

also characterized by hyperchloremia (hyperchloremic acidosis)

causes of non-AG metabolic acidosis (mnemonic ACCRUED )

acid load

chronic renal failure

carbonic anhydrase inhibitors

renal tubular acidosis

ureteroenterostomy

expansion/extra-alimentation

diarrhea 

acid base45

Acid-Base

Metabolic acidosis / Causes

The conditions that may cause a non-AG metabolic acidosis

GI loss of HCO3- - Diarrhea, enterocutaneous fistula (eg, pancreatic), enteric diversion of urine (eg, ileal loop bladder), pancreas transplantation with bladder drainage

Renal loss of HCO3- - Proximal RTA (type 2), carbonic anhydrase inhibitor

Failure of renal H+ secretion - Distal RTA (type 1), type 4 RTA, renal failure

Acid infusion - Ammonium chloride, hyperalimentation

Other - Rapid volume expansion with normal saline, urinary diverting surgical procedures (eg, ureteroenterostomy)

acid base46

Acid-Base

Metabolic acidosis / Causes

RTA

metabolic acidosis occurs from decreased net renal acid secretion

acid base47

Acid-Base

Metabolic acidosis / Causes / RTA

acid base48

Acid-Base

Metabolic acidosis / Causes

The conditions that may cause a high-AG metabolic acidosis

Azotemia

Ketoacidosis

Lactic acidosis

Salicylate overdose

Ethylene glycol poisoning

Methanol poisoning

Paraldehyde poisoning

acid base49

Acid-Base

Metabolic acidosis / Causes / high-AG metabolic acidosis

mnemonic = SLUMPED

salicylate

lactate

uremia

methanol

paraldehyde

ethylene glycol

diabetes

acid base50

Acid-Base

Metabolic acidosis / Causes/ high-AG metabolic acidosis

to narrow the differential diagnosis of high-AG acidosis - osmolar gap

plasma osmolality

can be calculated using the following equation:Posm = [2 X Na+]+[glucose in mg/dL]/18+[BUN in mg/dL]/2.8

can also be measured in the laboratory

other solutes normally contribute minimally to serum osmolality  the difference between the measured and the calculated value (osmolar gap) is no more than 10-15 mOsm/kg

some osmotically active toxins = methanol, ethylene glycol, acetone

cause a high-AG acidosis

increase the osmolar gap

measuring the osmolar gap  narrowing the differential diagnosis of high-AG acidosis

acid base51

Acid-Base

Metabolic acidosis / Causes / non-AG metabolic acidosis

AG = [Na+] - ([Cl-] + [HCO3 -])

for a patient with metabolic acidosis (with a decrease in HCO3 -) to maintain a normal AG, an equal increase in [Cl-] must occur hyperchloremic metabolic acidosis

hyperchloremic metabolic acidosis

HCO3 - lost

GI tract

the kidneys

renal acidification defect

acid base52

Acid-Base

Metabolic acidosis / Causes / non-AG metabolic acidosis

non-AG metabolic acidosis mechanisms

addition of HCl to body fluids: H+ buffers HCO3 - and the added Cl- results in a normal AG

loss of HCO3 - from the kidneys or the GI tract: the kidneys reabsorb sodium chloride to maintain volume

rapid volume expansion with normal saline: this results in an increase in the chloride load that exceeds the renal capacity to generate equal amounts of HCO3 -

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Metabolic acidosis / Causes / non-AG metabolic acidosis

Specific causes of hyperchloremic metabolic acidosis

Loss of HCO3 - via the GI tract

the secretions of the GI tract, with the exception of the stomach, are relatively alkaline -high concentrations of base (50-70 mEq/L)

significant loss of lower GI secretions  metabolic acidosis, especially when the kidneys are unable to adapt to the loss by increasing net renal acid excretion

such losses - diarrheal states, fistula with drainage from the pancreas or the lower GI tract, vomiting if it occurs as a result of intestinal obstruction, laxatives abuse

treatment - replacing the lost HCO3 –

urine

pH < 5.3

a negative urine AG (normal urine acidification)

increased NH4 + excretion

if distal Na+ delivery is limited because of volume depletion, the urine pH cannot be lowered maximally

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Metabolic acidosis / Causes / non-AG metabolic acidosis

Specific causes of hyperchloremic metabolic acidosis

Distal RTA (type 1)

a decrease in net H+ secreted by the A-type intercalated cells of the collecting duct

H+ is secreted by the apical

H+ –ATPase and

K+/H+ –ATPase(more important in K+ regulation than in H+ secretion)

the secreted H+ is excreted

as free ions (urine pH value)

titrated by urinary buffers, phosphate, and NH3

decreased secreted H+ amount

 reduction in its urinary concentration (ie, increase in urine pH)

 reduction in total H+ buffered by urinary phosphate, NH3

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Metabolic acidosis / Causes / non-AG metabolic acidosis

Specific causes of hyperchloremic metabolic acidosis

Type 1 RTA

should be suspected in any patient with non-AG metabolic acidosis and a urine pH greater than 5.0

patients have a reduction in serum HCO3 - to various degrees, in some cases to less than 10 mEq/L

mechanisms implicated in the development of distal RTA

a defect in 1 of the 2 proton pumps, H+ –ATPase or K+ -H+ –ATPase

acquired or congenital

a defect in the basolateral Cl-/HCO3 - exchanger, AE1, or the intracellular carbonic anhydrase that can be

acquired or congenital

back-diffusion of the H+ from the lumen via the paracellular or transcellular space (lost integrity of the tight junctions)

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Metabolic acidosis / Causes / non-AG metabolic acidosis

Specific causes of hyperchloremic metabolic acidosis

Early renal failure

metabolic acidosis is usual in patients with renal failure

in early to moderate stages of chronic kidney disease (glomerular filtration rate of 20-50 mL/min), it is associated with a normal AG (hyperchloremic)

in more advanced renal failure, the acidosis is associated with a high AG

in hyperchloremic acidosis, reduced ammoniagenesis (secondary to loss of functioning renal mass) is the primary defect, leading to an inability of the kidneys to excrete the normal daily acid load

NH3 reabsorption and recycling may be impaired, leading to reduced medullary interstitial NH3 concentration

In general, patients tend to have a serum HCO3 - level greater than 12 mEq/L, and buffering by the skeleton prevents further decline in serum HCO3 -

!!! patients with hypobicarbonatemia from renal failure cannot compensate for additional HCO3 - loss from an extrarenal source (eg, diarrhea) and severe metabolic acidosis can develop rapidly

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Metabolic acidosis / Causes / high-AG metabolic acidosis

Specific causes of metabolic acidosis

Lactic acidosis

L-lactate = a product of pyruvic acid metabolism in a reaction catalyzed by lactate dehydrogenase that also involves the conversion of nicotinamide adenine dinucleotide (NADH) to the oxidized form of nicotinamide adenine dinucleotide (NAD+). This is an equilibrium reaction that is bidirectional, and the amount of lactate produced is related to the reactant concentration in the cytosol (pyruvate, NADH/NAD+)

daily 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. Thus, production and use of lactate (ie, Cori cycle) is constant, keeping plasma lactate low

the major metabolic pathway for pyruvate is to acetyl coenzyme A, which then enters the citric acid cycle

in the presence of mitochondrial dysfunction, pyruvate accumulates in the cytosol and more lactate is produced

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Metabolic acidosis / Causes / high-AG metabolic acidosis

Specific causes of metabolic acidosis

Lactic acidosis

lactic acid accumulates in blood whenever production is increased or use is decreased

a value greater than 4-5 mEq/L is considered diagnostic of lactic acidosis

type A lactic acidosis occurs in hypoxic states

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

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Metabolic acidosis / Causes / high-AG metabolic acidosis

Specific causes of metabolic acidosis

Ketoacidosis

free fatty acids released from adipose tissue have 2 principal fates. In the major pathway, triglycerides are synthesized in the cytosol of the liver

in the less common pathway, fatty acids enter mitochondria and are metabolized to ketoacids (acetoacetic acid and beta-hydroxybutyric acid) by the beta-oxidation pathway

ketoacidosis occurs when delivery of free fatty acids to the liver or preferential conversion of fatty acids to ketoacids is increased

this pathway is favored when insulin is absent (as in the fasting state), in certain forms of diabetes, and when glucagon action is enhanced

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Metabolic acidosis / Causes / high-AG metabolic acidosis

Specific causes of metabolic acidosis

Ketoacidosis

alcoholic ketoacidosis occurs when excess alcohol intake is accompanied by poor nutrition

alcohol inhibits gluconeogenesis, and the fasting state leads to low insulin and high glucagon levels

these patients tend to have a mild degree of lactic acidosis

this diagnosis should be suspected in alcoholic patients who have an unexplained AG acidosis, and detection of beta-hydroxybutyric acid in the serum in the absence of hyperglycemia is highly suggestive

patients may have more than one metabolic disturbance (eg, mild lactic acidosis, metabolic alkalosis secondary to vomiting)

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Metabolic acidosis / Causes / high-AG metabolic acidosis

Specific causes of metabolic acidosis

Ketoacidosis

starvation ketoacidosis can occur after prolonged fasting and may be exacerbated by exercise

type 1 diabetes by stressful conditions (eg, infection, surgery, emotional trauma), but it can also occur in patients with type 2 diabetes.

hyperglycemia, metabolic acidosis, and elevated beta-hydroxybutyrate confirm the diagnosis.

the metabolic acidosis in DKA is commonly a high-AG acidosis secondary to the presence of ketones in the blood

after initiation of treatment with insulin, ketone production ceases, the liver uses ketones, and the acidosis becomes a non-AG type that resolves in a few days (ie, time necessary for kidneys to regenerate HCO3 -, which was consumed during the acidosis

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Metabolic acidosis / Causes / high-AG metabolic acidosis

Specific causes of metabolic acidosis

Advanced renal failure

patients with advanced chronic kidney disease (glomerular filtration rate of less than 20 mL/min)

present with a high-AG acidosis

the acidosis occurs from reduced ammoniagenesis leading to a decrease in the amount of H+ buffered in the urine

the increase in AG is thought to occur because of the accumulation of sulfates, urates and phosphates from a reduction in glomerular filtration and from diminished tubular function

in persons with chronic uremic acidosis, bone salts contribute to buffering, and the serum HCO3 - level usually remains greater than 12 mEq/L

this bone buffering can lead to significant loss of bone calcium with resulting osteopenia and osteomalacia