INTERNAL MEDICINE 3B (NEPHROLOGY)

Acid-Base Disorders
Department of Medicine

TOPIC OUTLINE
I. Normal Acid-Base Homeostasis
a. Respiratory Regulation of Acid-Base Balance
b. Renal Control of Acid-Base Balance
II. Stepwise Approach in Acid-Base Diagnosis
III. Mixed Acid-Base Disorders
IV. Metabolic Acidosis
a. High-Anion Gap Acidosis Step 2
b. Non-Anion Gap Acidosis Step 2
V. Metabolic Alkalosis
VI. References
LEGEND
PPT LECTURE BOOK OTHER TRANS REMEMBER
📈 🔊 📖 📃 📌
NORMAL ACID-BASE HOMEOSTASIS
Step 1
 Acid-base homeostasis normally maintains systemic arterial pH
within a narrow range, certainly between 7.35 and 7.45 pH units.
Shown are the cellular mechanisms for the following: (1) active secretion of
 This tight regulation is accomplished through:
H+ into the renal tubule; (2) tubular reabsorption of HCO3 − by combination with H+ to
o Chemical buffering in each of the body fluid compartments form H2CO3, which dissociates to form CO2 and H2O; and (3) Na+ reabsorption in
o Control of PaCO2 by the CNS and respiratory system exchange for H+ secreted. This pattern of H+ secretion occurs in the proximal tubule,
o Control of plasma HCO3 by the kidneys thick ascending segment of the loop of Henle, and early distal tubule.
 These processes efficiently dispose of the physiologic daily load of A. REABSORPTION OF FILTERED HCO3
acid in the forms of CO2 and non-volatile acids, mainly derived
from metabolism and dietary protein intake, and defend against the  STEP 1: HCO3 do not readily permeate the luminal membranes of the
occasional addition of pathologic quantities of acid and alkali. renal tubular cells; therefore, HCO3 that is filtered by the glomerulus
cannot be directly reabsorbed. Instead, HCO3 is reabsorbed by a special
I. PULMONARY REGULATION OF ACID-BASE BALANCE
process in which it first combines with H+ to form H2CO3, which eventually
 Lungs act as the second line of defense against acid-base becomes CO2 and H2O.
disturbances.  STEP 2: CO2 can move easily across the tubular membrane; therefore, it
 CO2 production and excretion are matched  usual steady-state instantly diffuses into the tubular cell, where it recombines with H2O,
PaCO2 is maintained at 40 mmHg. under the influence of carbonic anhydrase, to generate a new H2CO3.
o Underexcretion produces hypercapnia o This H2CO3 dissociates to form HCO3 and H+; the HCO3 then diffuses
- Decreased ventilation increases CO2 and H+ concentrations through the basolateral membrane into the interstitial fluid and is
in the extracellular fluid. taken up into the peritubular capillary blood.
- Usually the result of hypoventilation rather than of increased o The transport of HCO3 across the basolateral membrane is
CO2 production. facilitated by two mechanisms: (encircled in yellow)
o Overexcretion causes hypocapnia - Na+-HCO3 co-transport in the proximal tubules
- Increase in ventilation eliminates CO2 from extracellular - Cl−- HCO3 exchange in the late segments of the proximal tubule,
fluid, which hreduces the H+ concentration. thick ascending loop of Henle, and collecting tubules and ducts.
 PaCO2 is regulated primarily by neural respiratory factors and is 📌 Each time H+ is formed in the tubular epithelial cells, an HCO3 is also
not subject to regulation by the rate of CO2 production. formed and released back into the blood. The net effect of these reactions is
 Increases or decreases in PaCO2 represent derangements of neural “reabsorption” of HCO3 from the tubules, although the HCO3 that actually
respiratory control or are due to compensatory changes in response enters the ECF is not the same as that filtered into the tubules.
to a primary alteration in the plasma HCO3. The reabsorption of filtered HCO3 does not result in net secretion of H+
 Effect of blood pH on the alveolar ventilation rate: because the secreted H+ combines with the filtered HCO3 and is therefore not
o Alveolar ventilation rate increases 4-5x normal as pH decreases excreted.
from the normal value. When there is an excess of HCO3 over H+ in the urine, as occurs in
- Increased H+ concentration stimulates respiration metabolic alkalosis, the excess HCO3 cannot be reabsorbed. Therefore, the
- Negative feedback mechanism: ↑ H+  stimulates excess HCO3 is left in the tubules and eventually excreted into the urine,
which helps correct the metabolic alkalosis.
respiration  increased ventilation  ↓ H+ concentration
In acidosis, there is excess H+ relative to HCO3, causing complete
o A rise in plasma pH >7.4 (decreased H+ concentration) causes reabsorption of the HCO3; the excess H+ passes into the urine in combination
a decrease in the ventilation rate. with urinary buffers, especially phosphate and ammonia, and eventually is
II. RENAL CONTROL OF ACID-BASE BALANCE excreted as salts.
Thus, the basic mechanism whereby the kidneys correct acidosis or
 Kidneys control acid–base balance by excretion of urine. alkalosis is incomplete titration of H+ against HCO3, leaving one or the other
o Excreting acidic urine reduces the amount of acid in ECF. to pass into the urine and be removed from the extracellular fluid.
- In acidosis: kidneys secrete additional H+ and do not
secrete HCO3 into the urine but reabsorb all the filtered B. MECHANISM FOR PRIMARY ACTIVE H+ SECRETION
HCO3 and produce new HCO3  pH goes back to normal.
o Excreting basic urine removes base from the ECF.
- In alkalosis: kidneys secrete less H+ and fail to reabsorb all
the filtered HCO3, thereby increasing urinary excretion of
HCO3  raises ECF H+ concentration back toward normal
 The primary mechanism for removal of non-volatile acids from
the body is renal excretion because they are not H2CO3 and,
therefore, cannot be excreted by the lungs.
 Kidneys regulate extracellular fluid HCO3 (steady state: 24
mEq/L) concentration through:
o Reabsorption of filtered HCO3
- 80-90% of HCO3 is reabsorbed in the proximal tubule
- Distal nephron reabsorbs the remainder and secretes
protons (H+)
o Formation of titratable acids (H3PO4)
o Excretion of NH4+ in the urine

 It occurs at the luminal membrane, where H+ is transported directly by H+-

transporting ATPase and H+-K+-ATPase transporter.
 The energy required for pumping the H+ is derived from the breakdown of
ATP to adenosine diphosphate.
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 Primary active secretion of H+ occurs in type A intercalated cells Ammonia Recycling within Renal Medulla:
of the late distal tubule and in the collecting tubules.
o Dissolved CO2 in this cell combines with H2O to form H2CO3;
o H2CO3 then dissociates into HCO3, which is reabsorbed into the
blood, plus H+, which is secreted into the tubule by means of
the H+-ATPase and the H+-K+-ATPase transporters.
 For each H+ secreted, a HCO3 is reabsorbed, similar to the process
in the proximal tubules.
o The main difference is that H+ moves across the luminal
membrane by an active H+ pump instead of by counter-
transport, as occurs in the early parts of the nephron.

 As mentioned earlier, luminal membrane is less permeable to NH4+. The

Step 1
Step 3
Step 2
Shown are the cellular mechanisms for the following: (1) Production
and secretion of ammonium ion (NH4+) by proximal tubular cells. Glutamine is
metabolized in the cell, yielding NH4+ and HCO3. The NH4+ is secreted into the
lumen by a Na+- NH4+ exchanger. For each glutamine molecule metabolized,
two NH4+ are produced and secreted, and two HCO3 are returned to the blood.
(2) Buffering of H+ secretion by ammonia (NH3) in the collecting tubules. NH3
diffuses into the tubular lumen, where it reacts with secreted H+ to form NH4,
which is then excreted. For each NH4 excreted, a new HCO3 is formed in the
tubular cells and returned to the blood.
C. GENERATION OF NEW HCO3 BY AMMONIA BUFFER
SYSTEM
 STEP 1: Ammonium (NH4+) ion is synthesized from glutamine,
which comes mainly from metabolism of amino acids in the liver.
o The glutamine delivered to the kidneys is transported into
epithelial cells of the proximal tubules, thick ascending limb of
the loop of Henle, and distal tubules.
o Glutamine is first converted to glutamate by glutaminase.
o Glutamate dehydrogenase converts glutamate to α-
ketoglutarate and 2 NH4+ ions.
o Both enzymatic processes yield HCO3.
o The HCO3 is transported across the basolateral membrane,
along with the reabsorbed Na+, into the interstitial fluid and is
taken up by the peritubular capillaries.
o Angiotensin II stimulates the basolateral Na/HCO3
cotransporter, facilitating absorption of the generated HCO3.
📌 For each molecule of glutamine metabolized in the proximal
tubules, two NH4+ are secreted into the urine and two HCO3 are
reabsorbed into the blood. The HCO3 generated by this process
constitutes new HCO3.
 STEP 2: The NH4+ is secreted into the tubular lumen by a counter-
transport mechanism in exchange for Na+, which is reabsorbed.
o In the collecting tubules, H+ is actively secreted by the tubular
membrane into the lumen, where it combines with NH3 to
form NH4+.
o However, the luminal membrane of this part of the tubules is
much less permeable to NH4+.
o Once H+ has reacted with NH3 to form NH4+, the NH4+ is
trapped in the tubular lumen and eliminated in the urine in the
form of ammonium chloride (NH4Cl).
 STEP 3: NH3 diffuses freely across the renal tubular cell and
combines with H+ excreted by the H-ATPase.
o The H+ is generated from CO2 and H2O by carbonic anhydrase.
o HCO3 leaves the cell in exchange for Cl- by the basolateral Cl-
/HCO3 exchanger.
o The H-ATPase pump on the luminal surface and the basolateral
Cl- /HCO3 exchanger.are stimulated by aldosterone.
📌 Chronic acidosis increases NH4+excretion: An increase
in ECF H+ concentration stimulates renal glutamine metabolism
+
and, therefore, increases formation of NH4 and new HCO3 to be
used in H+ buffering; a decrease in H+ concentration has the
opposite effect.
NH4+ ions generated can be:
o Reabsorbed in the thick ascending limb by substitution for K+ on the
Na+-K+-2Cl– (NKCC2) carrier in the luminal membrane (majority).
o The remainder undergoes partial dissociation into NH3 and H+ (occurs
in the less acid tubular cell).
 The NH3 diffuses into the medullary interstitium, where it reaches
relatively high concentrations.
 The ammonia (NH3) accumulates in the medullary interstitium and is
finally secreted into the lumen of the medullary collecting tubule.
o Due to the low lumen pH (4.5–5) the NH3 accepts an H+ and is
trapped in the lumen and excreted in the urine as ammonium
chloride (NH4Cl).
D. TITRATABLE ACID (H2PO4) FORMATION
Buffering of secreted H+ by filtered phosphate (NaHPO4). New HCO3 is
returned to the blood for each NaHPO4 that reacts with a secreted H+.
 The process of H+ secretion into the tubules is the same as described earlier
(see page 1, section B).
 As long as there is excess HCO3 in the tubular fluid, most of the secreted H+
combines with HCO3. However, once all the HCO3 has been reabsorbed and is
no longer available to combine with H+, any excess H+ can combine with HPO4
and other tubular buffers.
 After the H+ combines with HPO4 to form H2PO4, it can be excreted as a sodium
salt (NaH2PO4), carrying with it the excess H+ (not shown in the picture)
 The HCO3 that is generated in the tubular cell and enters the peritubular blood
represents a net gain of HCO3 by the blood, rather than merely a replacement
of filtered HCO3.
📌 Therefore, whenever an H+ secreted into the tubular lumen combines
with a buffer other than HCO3, the net effect is the addition of a new HCO3 to
the blood. This process demonstrates one of the mechanisms whereby the
kidneys can replenish the extracellular fluid stores of HCO3.
NH4: 30-69 mEq of H+ as NH4
Titratable acid: 10-40 mEq of H+ as titratable acid
Titratable acid (TA) is the acid added to tubular fluid along the nephron to
lower fluid pH to that of the final urine.
The final pH of urine will depend on the amount of urinary buffer,
principally phosphate, and the amount of acid added.
Table 1.0: Plasma or Extracellular Fluid Factors That Increase or
Decrease H+ Secretion and HCO3 Reabsorption by the Renal Tubules
Increase H+ Secretion and HCO3 Decrease H+ Secretion and HCO3
Reabsorption Reabsorption
o Increased PCO2, H+, o Decreased PCO2, H+, angiotensin II,
angiotensin II, aldosterone aldosterone
o Decreased HCO3, ECFV, serum o Increased HCO3, ECFV, serum K+
K+ (hypokalemia) (hyperkalemia)

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STEPWISE APPROACH IN ACID-BASE DIAGNOSIS Respiratory Compensation in Metabolic Alkalosis:

1. Get your ABG and electrolytes at the same time.  Primary defect: gain of HCO3 or loss of H+
2. Know the primary disorder (look at the pH, PaCO2, HCO3)  Compensation: alveolar hypoventilation (↑ PCO2)
3. Compute for range of compensation.  Correction of metabolic alkalosis: ↑ excretion of HCO3 because the
4. For Metabolic Acidosis, compute for Anion Gap (AG) filtered load of HCO3 exceeds the ability of the renal tubule to reabsorb it.
5. Check the delta-delta.  Expected findings: high pH, high plasma HCO3 concentration, and an
If high AG: compare ΔAG and ΔHCO3 increase in Pco2 after partial respiratory compensation.
If normal AG: compare ΔCl and ΔHCO3 Table 1.2: Compensatory Responses for Simple Metabolic Disorders
6. Determine clues to diagnosis (history, signs/symptoms, PE) Expected Range of
7. Prescribe the treatment Disorder Limits of Compensation
Compensation
Metabolic o PCO2 = 1.5 [HCO3] + 8 ± 2
Acidosis o PCO2 = last 2 digits of pH x 100 o PCO2 = 15 mm Hg
o PCO2 = 15 + [HCO3]
Metabolic o PCO2 = +0.6 mm Hg for Δ
Alkalosis [HCO3] of 1 mEq/L o PCO2 = 55 mm Hg
o PCO2 = 15 + [HCO3]
Renal Compensation in Primary Respiratory Acidosis:
 Primary defect: alveolar hypoventilation (↑ PCO2)
 Compensation: ↑ HCO3 reabsorption
o ↑ excretion of H+ as titratable acid and NH4+
o ↑ reabsorption of “new” HCO3
 Correction of respiratory acidosis:
o Acute: no renal compensation yet
o Chronic: renal compensation has occurred (arterial pH has increased
toward normal)
Renal Compensation in Primary Respiratory Alkalosis:
 Primary defect: alveolar hyperventilation (↓ PCO2)
 Compensation: ↓ HCO3 reabsorption
o ↓ excretion of H+ as titratable acid and NH4+
o ↓ reabsorption of “new” HCO3
 Correction of respiratory alkalosis:
o Acute: no renal compensation yet
Analysis of simple acid–base disorders. If the compensatory
o Chronic: renal compensation has occurred (arterial pH has decreased
responses are markedly different from those shown at the bottom of the
figure, one should suspect a mixed acid–base disorder. toward normal)
Table 1.1: Normal ABG Values Table 1.2: Compensatory Responses for Simple Respiratory Disorders
Expected Range of
Source pH H+ PCO2 HCO3 Disorder Limits of Compensation
Compensation
(nEq/L) (mmHg) (mEq/L)
Arterial o Acute: Δ HCO3 = +1 mEq/L for o Acute: HCO3 = 38
7.35-7.45 35-45 35-45 22-26
Respiratory each ↑ ΔPCO2 of 10 mm Hg mEq/L
Venous 7.32-7.38 42-48 42-50 23-27
Acidosis o Chronic: ΔHCO3 = +4 mEq/L o Chronic: HCO3= 45
 Blood for electrolytes and ABGs should be drawn simultaneously for each ↑ ΔPCO2 of 10 mm Hg mEq/L
prior to therapy. o Acute: Δ HCO3= -2 mEq/L for o Acute: HCO3 = 18
Respiratory each ↓ ΔPCO2 of 10 mm Hg mEq/L
 In the determination of ABGs by the clinical laboratory, both pH and
Alkalosis o Chronic: Δ HCO3 = -5 mEq/L o Chronic: HCO3 = 15
PaCO2 are measured, and the HCO3 is calculated from the for each ↓ ΔPCO2 of 10 mm Hg mEq/L
Henderson-Hasselbalch equation.
Buffer Systems in Response to Metabolic Acidosis:
A. DETERMINE THE PRIMARY DISORDER 1. Extracellular buffers
 Check the trend of pH, HCO3, pCO2 2. Intracellular and bone buffers
3. Respiratory compensation
 The change that produces the pH is the primary disorder.
4. Renal H+ excretion (slowest)
*The first 3 act to minimize the increase in H+ concentration until the kidneys
restore acid base balance by eliminating the excess H+ in the urine.

 If the trend is the same, check the percent difference (the bigger
% difference is the primary disorder).
B. COMPUTE FOR THE RANGE OF COMPENSATION
(EXPECTED PCO2)
Respiratory Compensation in Metabolic Acidosis:
 Primary defect: decrease in arterial HCO3 or gain of H+.
 Compensation: ↑ alveolar hyperventilation ( ↓ PCO2)
 Correction of metabolic acidosis:
- Increased excretion of the excess fixed H+ as titratable acid
and NH4+
- Increased reabsorption of “new” HCO3, which replenishes the
blood HCO3 concentration.
 Expected findings: low pH, low plasma HCO3 concentration, and a
reduction in Pco2 after partial respiratory compensation.
Buffering by the extracellular and intracellular buffers follow a characteristic
time course that is dependent upon the rapidity with which the administered
H+ ions move into the different fluid compartments.
Buffering by plasma HCO3 occurs almost immediately Whereas
approximately 15 minutes is required for H+ to diffuse into the interstitial
space to be buffered by interstitial HCO3. H+ entry into the cells occurs more
slowly, as buffering by cell buffers is not complete until 2-4 hours
Extracellular buffers:
 HCO3- most important buffer in the ECF
 From the reaction of H+ with primary extracellular buffer (HCO3)
H+ + HCO3 ↔ H2CO3 ↔ CO2 + H2O
 Metabolic Acidosis can be produced in two ways:
o Addition of H+ ions
o Loss of HCO3 ions (increases the extracellular H+ concentration by
driving the buffering reaction to the left).

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Intracellular and Bone Buffers: If the decrease in plasma HCO3 is not accompanied by increased Cl−,
 Intracellular Buffers there must be increased levels of unmeasured anions and therefore an
o H+ ions enter the cells and taken up by cell and bone buffers increase in the calculated anion gap.
o 55-60% of acid load buffered by bone & cells
o Other buffers: proteins, phosphates and carbonate, and
hemoglobin (erythrocytes)
 Bone Buffers
o Uptake of excess ions
o Dissolution of bone mineral (release of NaHCO3 and KHCO3,
CaCO3 and CaHPO4
o 40% of the buffering of an acute acid load
o Chronic acidosis: increased risk osteoporosis (minerals are
mobilized are to buffer the excess H+)
Respiratory Compensation:
 Metabolic acidosis stimulates central and peripheral
chemoreceptors controlling respiration resulting in an increase in
alveolar ventilation
 Ensuing fall in PCO2 will raise the EC pH toward normal.
 Increase in ventilation begins within 1-2 hrs and reaches its
maximum level at 12-24 hrs
 Increase in tidal volume (as much as 30L; normal = 5-6 L) than
 Increased AG when acidosis due to increase in fixed acids (HCO3 acts
by an increase in respiratory rate (Kussmaul respiration). as buffer so it is depleted and the unmeasured anions increase to
 PCO2 will fall 1.2 mmHg for every 1.0 mEq/L reduction in the preserve neutrality)
plasma HCO3 down to a minimum of 10-15 mmHg.  AG is normal if metabolic acidosis due to loss of base (when HCO3 lost,
Cl- anions increased to maintain neutrality).
Renal Acid-Base Regulation:
 Normal adult diet: generates 50-100 mEq of H+/day excreted in E. CHECK THE DELTA-DELTA (ΔAG/ ΔPLASMA HCO3
the urine. CONCENTRATION)
 2 basic steps:
o Reabsorption of filtered HCO3 (90% in PT; 10% in TAL, DN)  Δ/Δ ratio is normally between 1-2 in uncomplicated high AGMA
o Secretion of dietary acid o Value < 1:1 suggest combined high and normal AG acidosis (HAGMA
w/ NAGMA) ex: diarrhea
Prediction of Compensatory Response (ECR): o Value > 2:1 suggest fall in plasma HCO3 is less than expected due to
o pCO2 will ↓ 1.25 mmHg/mmol ↓ in HCO3 concurrent metabolic alkalosis (HAGMA w/ metabolic alkalosis) ex:
Metabolic o Winter’s formula: PCO2 = (1.5 x HCO3) + 8 ± 2 vomiting
acidosis o PCO2 = HCO3 + 15
For High AG Metabolic Acidosis:
Ex: HCO3 = 14, pH = 7.25, pCO2 = 30
pCO2=1.5 x 14 + 8 = 29 (27-31)  Compare the Δ AG and compare it with ΔHCO3
o PCO2 will ↑ 0.75 mmHg/mmol ↑ in HCO3  Interpretation:
o PCO2 = HCO3 + 15 o Δ AG = Δ HCO3: Pure high AG metabolic acidosis (Δ/Δ = 1-2)
Metabolic Ex: HCO3 = 36.8, pH = 7.45, pCO2 = 53 o Δ AG > Δ HCO3: High AGMA with metabolic alkalosis (Δ/Δ = >2)
alkalosis 36.8 – 24 = 12.8 x 0.75 = 9.6 o Δ AG < Δ HCO3: High AGMA with normal AGMA (Δ/Δ = <1)
Expected pCO2= 9.6 + 40 = 49.6
(Average pCO2 40)
 Values beyond the predicted compensatory response indicate a
Mixed Acid-Base Disturbance which means that there are two or
more underlying causes for the acid–base disturbance.
o pH = 7.73, HCO3 = 9.0, pCO2 = 15.6
o Compute for expected pCO2:
(1.5 x 9) + 8 = 21.5 ± 2
9 + 15 = 24
Respiratory o Compare expected pCO2 (21.5) with actual
alkalosis + pCO2 (15.6):
Metabolic In theory, actual PCO2 should be equal to ePCO2.
acidosis Possible explanation: due to compensatory
hyperventilation, the amount of pCO2 in the blood
decreases. In this case, there will be concomitant
respiratory alkalosis on top of metabolic acidosis.
C. COMPUTE FOR THE ANION GAP
 Anion gap (AG)- difference between the plasma concentrations of
the major cation and the major measured anions F. DETERMINE CLUES TO DIAGNOSIS
o Normal: 12 mEq/L Case: A 35 year old female with Type 1 Diabetes Mellitus was admitted for
o Tool to narrow down potential causes of metabolic acidosis abdominal pain and vomiting accompanied by generalized body weakness.
o Low serum albumin lowers anion gap (cirrhosis, nephrotic Patient is poorly compliant to Insulin and has poor glycemic control for the past
syndrome, malnutrition) year. Upon consult at the emergency room, patient’s vital signs were as follows:
o Approximate correction is a reduction in the AG of 2.5 mEq/L for BP 80/50 HR 104 RR 28. Rapid shallow breathing was noted. Patient had dry
every 1 g/dL decline in the plasma albumin concentration. buccal mucosa and dry skin.
Table 1.3: Concept of Anion Gap Labs: pH = 7.2, pCO2 = 16mmHg, HCO3 = 8 mEq/L, Na+ = 145 mEq/L, K+ = 2.8
Unmeasured Anions Unmeasured Cations mEq/L, Cl- = 89 mEq/L, RBS = 500 mg/dL
o Proteins, albumin 15 mEqs/L o Calcium 5 mEqs/L Primary disorder: metabolic acidosis
o Organic acids 5 mEqs/L o Potassium 4.5 mEqs/L Range of compensation: metabolic acidosis with respiratory alkalosis
o Phosphates 2 mEqs/L o Magnesium 1.5 mEqs/L  Winter’s formula = 1.5 x HCO3 + 8 (± 2)
o Sulafates 1 mEqs/L  Expected PaCO2 = 1.5 X 8 + 8 = 20 ± 2
TOTAL: 23 mEqs/L TOTAL: 11 mEqs/L  Actual pCO2 of patient = 16
AG = unmeasured anions – unmeasured cations; AG: 23-11 = 12 Anion gap: High anion gap metabolic acidosis
 The anion gap will increase if unmeasured anions rise or if  AG = Na+ - (Cl- + HCO3)
 AG = 145 – (89 + 8) = 48
unmeasured cations fall.
Any hidden metabolic problem (Δ/Δ): combined high anion gap and metabolic
📌 In metabolic acidosis, plasma HCO3 is reduced. If plasma acidosis (36/16 = 2.25 = Δ AG > ΔHCO3-)
Na+ concentration is unchanged, the concentration of anions (Cl− or Clues to diagnosis: HAGMA with respiratory alkalosis and metabolic alkalosis
an unmeasured anion) increases to maintain electroneutrality. If  HAGMA- DKA, lactic acidosis from hypotension
plasma Cl− increases in proportion to the fall in plasma HCO3, the  Respiratory alkalosis- from tachypea (Kussmaul’s breathing)
anion gap will remain normal. This is often referred to as  Metabolic alkalosis- from vomiting and volume contraction
hyperchloremic metabolic acidosis. Treatment: IV hydration and insulin drip

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MIXED ACID-BASE DISORDERS I. HIGH-ANION GAP ACIDOSES

 Defined as independently coexisting disorders, not merely
compensatory responses.
o A patient with DKA (metabolic acidosis) may develop an
independent respiratory problem (pneumonia) leading to a
superimposed respiratory acidosis or alkalosis.
o Patients with underlying COPD may not respond to metabolic
acidosis with an appropriate ventilatory response because of
insufficient respiratory reserve.
o Patients with metabolic acidosis due to alcoholic ketoacidosis
may develop metabolic alkalosis due to vomiting and
superimposed respiratory alkalosis due to the hyperventilation
of hepatic dysfunction or alcohol withdrawal.
 Diagnosis requires consideration of the AG, and requires the
presence of or correction to a normal serum albumin of 4.5 g/dL.
Acid-Base Normogram:
 This diagram can be used to determine the type of acidosis or
alkalosis, as well as its severity.
 The central open circle shows normal values and the deviations
that can still be considered within the normal range.
 The shaded areas of the diagram show the 95% confidence limits
for the normal compensations to simple metabolic and respiratory
disorders.
 When using this diagram, one must assume that sufficient time has
elapsed for a full compensatory response, which is 6 to 12 hours
for the ventilatory compensations in primary metabolic
disorders and 3 to 5 days for the metabolic compensations in
primary respiratory disorders.
- If a value is within the shaded area, this suggests that there is a
simple acid–base disturbance.
- If the values lie outside the shaded area, this suggests that the
patient may have a mixed acid–base disorder.
METABOLIC ACIDOSIS
 Can occur because of an increase in endogenous acid production
(lactate and ketoacids), loss of bicarbonate (as in diarrhea), or
accumulation of endogenous acids because of inappropriately low
excretion of net acid by the kidney (CKD).
 Organ system effects:
o Increase in ventilation or tidal volume (Kussmaul respiration).
o Intrinsic cardiac contractility may be depressed with normal
inotropic function
o Both peripheral arterial vasodilation and central
venoconstriction can be present
o Pulmonary edema with even minimal volume overload.
o CNS function is depressed, with headache, lethargy, stupor,
and, in some cases, even coma.
o Glucose intolerance
 Two major categories of clinical metabolic acidosis:
o High-AG metabolic acidosis
o Normal or non-AG acidosis (normal AG and hyperchloremia)
 Treatment with alkali should be reserved for severe acidemia
except when the patient has no “potential HCO3” in plasma.
o Patients with a normal AG acidosis or an AG attributable to a
non-metabolizable anion due to advanced kidney failure should
receive alkali therapy, either PO (NaHCO3 or Shohl’s solution)
or IV (NaHCO3).
o Plasma HCO3 to a target value of 22 mmol/L.
 There are four principal causes of a high-AG acidosis:
o Lactic acidosis
o Ketoacidosis (diabetic, alcoholic, starvation)
o Ingested toxins (ethylene glycol, methanol, salicylates, propylene
glycol, polyglutamic acid or 5-oxoproline)
o Acute and chronic renal failure
GOLDMARK:
G- glycols (ethylene, propylene) M- methanol
O- oxoproline A-aspirin
L- lactate R-renal failure
D- lactate K-ketoacidosis
A. LACTIC ACIDOSIS
Table 1.3: Causes of Lactic Acidosis
Type A (Poor Tissue Perfusion) Type B (Aerobic Disorders)
o Circulatory insufficiency (shock o Malignancies
or cardiac failure) o NRTI agents for HIV
o Severe anemia o Diabetes mellitus
o Mitochondrial enzyme defects o Renal or hepatic failure
o ETC inhibitors (carbon o Thiamine deficiency
monoxide or cyanide) o Severe infections (cholera or malaria)
o Seizures
o Drugs or toxins (biguanides, ethanol,
ethylene or propylene glycol)
 Common cause of lactic acidosis in elderly patients:
o Unrecognized bowel ischemia
o Infarction in a patient with severe atherosclerosis or cardiac
decompensation receiving vasopressors
 d-Lactic acid acidosis by gut bacteria: associated with jejunoileal
bypass, short bowel syndrome, or intestinal obstruction.
 Diagnosis:
o Plasma lactate >4-5 mEq/L (NV: 0.5-1.5 mEq/L)
o High anion gap
o Presence of disorders leading to lactic acidosis
o Cool, clammy extremities & hypotension if shock is present
 Treatment and Management:
o Correct underlying disorder
o Reversal of circulatory failure will reduce further lactate production
and allow metabolism of excess lactate to HCO3
o NaHCO3 therapy to maintain arterial pH 7.2
o ↑ pH improves tissue perfusion, reversing acidemia induced
vasodilatation, improves cardiac contractility, ↓ risk of arrhythmia
o Risk of HCO3 therapy: volume overload, hypertension, hypernatremia,
overshoot metabolic alkalosis, hypokalemia
o Organic acidosis (lactic acidosis or ketoacidosis) should be suspected
if effective treatment (fluid repletion) leads to spontaneous elevation
in plasma HCO3 concentration
B. DIABETIC KETOACIDOSIS
 Uncontrolled DM- most common cause of ketoacidosis
 Plasma glucose usually exceeding 400mg/dL
 Pathophysiology:
o Lack of insulin leads to lipolysis – free fatty acids are converted to
triglycerides, CO2, H2O or ketoacids
o Excess glucagon (along with catecholamine, cortisol) increase
fatty acyl CoA entry into hepatic mitochondria where it is
converted to ketones
- Increased fatty acid metabolism and the accumulation of
ketoacids (acetoacetate and β-hydroxybutyrate).
 DKA usually occurs in insulin-dependent DM in association with cessation
of insulin or an intercurrent illness.
 Diagnosis:
o Serum ketone, blood sugar, and ABG
o ΔAG and ΔHCO3 − is usually 1:1 in DKA.
o Urine: Nitroprusside test (Acetest) tablet or reagent strip.
- Acetoacetate initial ketone formed, reduced to either B
hydroxybutyrate or acetone.
- Acetest reacts with acetoacetate and acetone, but not with B
hydroxybutyrate (75% of circulating ketones in diabetic
ketoacidosis, reach 90% with concurrent lactic acidosis or
alcoholic acidosis)
 Treatment and Management:
o Fluid replacement:
- 2-3 L of NSS over first 1-3 hours (10-20 ml/kg/hr).
- Change to D5 containing when blood sugar reaches 250 mg/dL
o Regular Insulin (IV 0.1 u/kg) then, 0.1 u/kg/hr by IV infusion.
o Glucose and saline: augment endogenous insulin secretion, diminish
glucagon release, normalize FA metabolism and correct any fluid deficit
o HCO3 therapy: marked acidemia pH <7.0-7.1

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o Treat precipitating cause: non-compliance, infection, trauma,  Uremic acidosis:

pregnancy, MI o Reduced rate of NH4 production and excretion (GFR 20-50)
o Aside from BS monitoring, include K+. o Retention of organic anions (such as urates, hippurates, and
C. ALCOHOLIC KETOACIDOSIS benzoates) (GFR <20)
 Treatment: alkali treatment to maintain HCO3 20-24mmol/L (sodium
 Seen in chronic alcoholics citrate or NaHCO3).
 Sudden cessation of alcohol consumption with poor nutrition  Chronic acidosis also increases urinary calcium excretion, proportional to
 Usually associated with: cumulative acid retention, and contributes significantly to muscle wasting.
o Binge-drinking
CASE: She was noticed to be depressed a week ago due to personal
o Vomiting problems. PE: BP 100/60, HR 88, RR 18. Patient was obtunded on admission
o Abdominal pain Labs: Na 138, K 4.3, Cl 105, Ca 2.0, BUN 7.2, RBS 4.3. ABG: pH 7.2, pCO2
o Starvation 40, pO2 92, HCO3 15, measured osmolality- 320
o Volume depletion Urinalysis: Calcium oxalate crystals
 Mixed acid-base disturbance:
o Hypoperfusion enhances lactic acid production Questions:
o Chronic respiratory alkalosis may accompany liver disease 1. What is the acid base disturbance? Anion gap? Degree of compensation
o Metabolic alkalosis from vomiting (expected pCO2)? Delta/delta?
 Pathophysiology:  HAGMA
o Ethanol inhibits gluconeogenesis, directly enhances lipolysis  Anion Gap= 138-(105+15)=18
increasing fatty acid supply in the liver  Expected pCO2= 1.5x15+8=30.5
o Ethanol can be metabolized into acetic acid.  Actual pCO2=40
 Delta/delta=AG 18-12=6 (HAGMA W/ NAGMA)
 ECF deficits almost always accompany AKA and should be 2. Compute the plasma osmolality? What is the significance of plasma and
repleted by IV administration of saline and glucose (5% dextrose measured osmolality?
in 0.9% NaCl).  Posm = 2(138)+ 7.2+ 4.3=287.5
D. SALICYLATE-INDUCED ACIDOSIS  320-287.5=32.5
 High osmolal gap
 Salicylate intoxication (plasma level >40-50 mg/dL) → respiratory
Osmolal Gap:
alkalosis (earliest) or a mixture of HAGMA + respiratory alkalosis.
Calculated Posm = 2 x plasma Na⁺ + glucose mg/dl/18 + BUN mg/dl/2.8
 HAGMA – accumulation of lactate & ketoacids Posm = 2(140)+5mmol/l + 5mmol/l= 290
 First Goal of Treatment: reduction of salicylate Methanol (mwt 32) & ethylene glycol ( mwt 62)
o IV NaHCO3 to alkalinize arterial pH 7.45-7.5 Depending on the amount ingested, this will cause an increase in measured
o Isotonic saline gastric lavage osmolality.
o Activated charcoal/NGT (1g/kg up to 50g) • A high osmolality in a patient with an otherwise unexplained HAGMA with
 Second goal: rapid elimination ECF not significantly contracted is suggestive of the presence of either
o Alkalinize to raise urine pH from 6.5-8.1 methanol or ethylene glycol intoxication.
o Hemodialysis if: • If the history is not suggestive of either lactic acidosis or ketoacidosis, then
- plasma salicylate concentration >80 mg/dL a high osmolal gap (>10 mOsmol/kg H20) strongly points toward
- comatose methanol or ethylene glycol intoxication
- renal failure
II. NON-ANION GAP METABOLIC ACIDOSIS
- fluid overload
 Hypokalemia should be anticipated with vigorous HCO3 therapy and  Alkali can be lost from the GI tract as a result of diarrhea or from the
should be treated promptly and aggressively. kidneys due to renal tubular acidosis.
 Glucose-containing fluids should be administered because of the  Reciprocal changes in Cl− and HCO3 result in a normal AG.
danger of hypoglycaemia. o In pure non–AG acidosis, therefore, the increase in Cl− above the
normal value approximates the decrease in HCO3−.
E. ALCOHOL INTOXICATION
o The absence of such a relationship suggests a mixed disturbance.
 Three alcohols may cause fatal intoxications:
o Ethylene glycol ACCRUED:
o Methanol A-acid load U- ureterosigmoidostomy
o Isopropyl alcohol C- carbonic anhydrase inhibitors E- expansion
 All cause an elevated osmolal gap, but only the first two cause a C- CKD D- diarrhea
high-AG acidosis. R- renal tubular acidosis
 Isopropyl alcohol ingestion does not typically elevate the AG unless
extreme overdose causes hypotension and lactic acid acidosis.
Table 1.4: Examples of Fatal Alcohol Intoxications
Alcohol Pathophysiology Clinical Features Management
o 1st 12 hrs neurologic symptoms o IV or Oral Ethanol – alcohol dehydrogenase has
predominate from drunkenness to greater affinity for ethanol compared to methanol &
coma; followed by CP abnormalities ethylene glycol (ethanol preferred substrate of alcohol
o Metabolized to glycolic and such as tachypnea, pulmonary dehydrogenase)
Ethylene Glycol oxalic acid lead to metabolic edema, flank pain, renal failure o Fomepizole – competitively inhibits alcohol
(Antifreeze) acidosis (glycolate-induced damage to dehydrogenase
o Lethal dose: 100 mL tubules, tubular occlusion by oxalate o Correct acidemia with NaHCO3
crystals) o Oral charcoal to decrease absorption
o Dx: oxalate crystals in the urine, ↑ o Hemodialysis removes parent compound and
serum osmolal gap, HAGMA metabolite
o Metabolites (formaldehyde, - Indications:
Methanol formic acid) cause severe o Osmolal gap is usually present  start if plasma level is > 50mg/dl
(Wood alcohol) optic nerve injury leading to  >30 mL ingested
blindness and CNS damage  acidemia
(coma, death)  visual acuity is decreased
o Absorbed rapidly o High AG acidosis is not present
Isopropyl o Plasma level >400 mg/dL is because acetone is rapidly excreted. o Supportive therapy (IV fluids, pressors, ventilatory
Alcohol life-threatening. o Increased osmolar gap, and support if needed)
o Metabolized by alcohol hypoglycemia is common. o Hemodialysis for prolonged coma or >400mg/dl
dehydrogenase to acetone.
F. CHRONIC KIDNEY DISEASE
 Hyperchloremic acidosis of moderate renal insufficiency (GFR 20-
50 mL/min) is converted to the HAGMA (GFR <20 mL/min) of
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Table 1.5: Differential Diagnosis of Non-Anion Gap - CO2 diffuses freely across the apical membrane back into the cell.
(Hyperchloremic) Metabolic Acidosis - Intracellular carbonic anhydrase II converts CO2 + H2O back into H2CO3.
Gastrointestinal HCO3 Losses - H2CO3 then can dissociate into H+ and HCO3:
o Diarrhea  H+ is recycled through the process through NHE3
o External pancreatic or small bowel drainage  HCO3 is absorbed through the basolateral membrane via Na+–
o Ureterosigmoidostomy, jejunal loop HCO3– cotransporter and HCO3––Cl– exchanger.
o Drugs: calcium chloride (acidifying agent), magnesium sulfate (diarrhea), o Net effects of the entire process:
cholestyramine (bile acid diarrhea) - Excretion of H+
Hypokalemia - Absorption of HCO3–
o Proximal RTA (type II)  Abnormal processes leading to pRTA (type 2 ):
o Distal (classical) RTA (type I) o Multiple myeloma : light chains are directly toxic to the proximal tubule cells
o Drug-induced acidosis o Drugs causing toxicity to the proximal tubule cells via multiple mechanisms
- Proximal RTA: acetazolamide and topiramate o Mutations in apical NHE3, basolateral Na+–HCO3– cotransporter, carbonic
- Distal RTA: amphotericin B and ifosfamide anhydrase II enzyme
Renal Acidosis
o Proximal renal tubular acidosis
- Isolated pure HCO3 wasting (unassociated with Fanconi’s syndrome)
 Primary
 Inherited autosomal recessive with ocular abnormalities
(missense mutations of SLC4A4)
 Autosomal dominant with short stature (mutation of
SLC9A3/NHE3)
 Carbonic anhydrase deficiency, inhibition, or alteration
• Drugs: acetazolamide, topiramate, sulfanilamide, mafenide
acetate
• Carbonic anhydrase II deficiency with osteopetrosis (mixed
proximal and distal RTA type III)
o Classical distal renal tubular acidosis
- Inherited:
 Autosomal dominant (defect in AE1 gene encodes for missense
mutation in the HCO3- -Cl- exchanger)
 Autosomal recessive with deafness
 Carbonic anhydrase II
- Endemic (Northeastern Thailand) possible abnormality in H+-K+
ATPase
- Acquired: Sjogren’s syndrome
Table 1.6: Differences between dRTA and pRTA
Features Type 1 (Distal) Type II (Proximal) B. DISTAL RENAL TUBULAR ACIDOSIS (TYPE I)
Primary Defect Impaired distal NH4+ Reduced proximal  The typical findings in acquired or inherited forms of classic distal RTA
secretion HCO3 reabsorption
(type 1 RTA) include hypokalemia, a non-AG metabolic acidosis, low
Plasma K+ Usually low Normal/low
Urine pH >5.5 <5.5
urinary NH4+ excretion (positive UAG, low urine NH4+), and
Urine AG Positive Negative inappropriately high urine pH (pH > 5.5).
Urine Ca2+ Excretion High Normal  Most patients have hypocitraturia and hypercalciuria
Nephrocalcinosis Common Rare  Nephrolithiasis, nephrocalcinosis, and bone disease are common.
Fractional HCO3 <5% >10-15%
Excretion
Fanconi Syndrome1 Absent Present
Other Tubular Defects Absent Often present
1
manifested by glycosuria, generalized aminoaciduria, and phosphaturia
A. PROXIMAL RENAL TUBULAR ACIDOSIS (TYPE II)
 Most often due to generalized proximal tubular dysfunction, multiple
myeloma, ifosfamide, and acetazolamide.
 Loss of function: Na+/H+, Na+-K+-ATPase, carbonic anhydrase
 When the plasma HCO3− is low the urine pH is acid (pH <5.5), but
exceeds 5.5 with alkali therapy.
 Because HCO3− is not reabsorbed normally in the proximal tubule,
therapy with NaHCO3 will enhance delivery of HCO3 to the distal
Pathophysiology of distal RTA:
nephron and enhance renal K+ secretion causing hypokalemia.
 Impaired acid secretion at the collecting duct of the distal tubule.
 Normal process of urinary acidification:
o Intercalated cells participate in acid excretion located at the collecting duct
of the distal tubule
α-intercalated cell β-intercalated cell
o Apical H+/K+–ATPase (1 H+ out of o Apical Cl–/HCO3– exchanger (1
cell, 1 K+ into cell) HCO3 out of cell, 1 Cl– into cell)
o Apical H+–ATPase (1 H+ out of o Apical H+/K+–ATPase (1 H+ out of
cell) cell, 1 K+ into cell)
o Basolateral Na+/K+–ATPase o Basolateral Na+/K+–ATPase
o Basolateral Cl–/HCO3– exchanger o Basolateral H+–ATPase
o Net effect
- Intercalated cells secrete H+ into the tubular lumen
- H+ combine with NH3+ and other compounds (titratable acids)
- NH4+ (ammonium) and titratable acids are excreted.
- Acid–base homeostasis is maintained
Abnormal processes leading to distal RTA:
 ↓ Activity of apical H+/K+–ATPase (↓ H+ secretion into tubular lumen)
Pathophysiology of proximal RTA:  ↑ Permeability of the collecting duct to H+:
• Impaired bicarbonate reabsorption at the proximal tubule. o Collecting duct is normally impermeable to H+:
• Normal process of proximal tubule HCO3– reabsorption: - Prevents backflow of recently secreted H+
o 80% of filtered HCO3– is reabsorbed in the proximal tubule. - Allows for excretion of urine that is more acidic than plasma
o Requires a complex mechanism because HCO3– is not freely o Example: amphotericin toxicity
permeable (due to charge):  ↓ Na+ reabsorption
- Na+–H+ exchanger 3 (NHE3) absorbs Na+ and secretes H+.  Altered activity of the Cl–/HCO3– exchanger:
- Secreted H+ combines with the filtered HCO3 to form H2CO3 in o ↑ Activity of apical Cl–/HCO3– exchanger
the tubular lumen. - ↑ HCO3– secretion → net HCO3 loss → metabolic acidosis
- H2CO3 is converted into H2O and CO2 by apical carbonic - Occurs at β-intercalated cells
anhydrase IV.

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o ↓ Activity of basolateral Cl–/HCO3– exchanger:
- ↓ HCO3 secretion → buildup of intracellular HCO3 → ↑
intracellular pH
- ↓ H+ secretion via apical ATPases occurs to correct
intracellular pH.
- Occurs at α-intercalated cells
C. GENERALIZED DISTAL NEPHRON DYSFUNCTION (TYPE IV)
 Type I Pseudohypoaldosteronism- has both an autosomal
recessive and an autosomal dominant form.
o Autosomal dominant form- due to loss-of-function mutations in
mineralocorticoid receptor (improves in adulthood).
o Autosomal recessive form- caused by various combinations of
mutations in the three subunits of ENaC, resulting in impaired
Na+ channel activity in principal cells and other tissues (lifelong
salt wasting, hypotension, and hyperkalemia).
o Features: hyperkalemic metabolic acidosis, hypotension,
elevated PRA, angiotensin II, aldosterone
 Type II Pseudohyperaldosteronism (Gordon Syndrome)
o Manifest as hypertension associated with hyperkalemia and a
non-gap acidosis with preserved GFR.
o Mutations in the genes encoding WNK1 or WNK4, leading to
the phosphorylation and activation of the sodium chloride co-
transporter NCC.
o Salt absorption in the distal nephron is increased causing
hypervolemia and hypertension while at the same time
suppressing renin and aldosterone secretion despite
hyperkalemia.
o Decreased expression of the apical K+ efflux channels in the
collecting duct is also described, thereby contributing to
reduced potassium excretion and hyperkalemia
Table 1.7: Causes of Hypoaldosteronism
Decreased Activity of RAAS
o Hyporeninemic hypoaldosteronism
o K sparing diuretics
o NSAID, possible exception of sulindac
o Converting enzyme inhibitor
o Cyclosporine, Tacrolimus
o AIDS
o Hypervolemia in chronic dialysis patients
 Most common causes of hypoaldosteronism:
o Hyporeninemic hypoaldosteronism and K+ sparing
diuretics in adults
o Adrenal deficiencies (21-hydroxylase deficiency) in children.
 Hyporeninemic Hypoaldosteronism- most commonly in older
adults with DM, tubulointerstitial disease and renal insufficiency
o GFR, 20–50 mL/min., NAGMA, serum [K+] (5.2–6.0 mmol/L),
concurrent hypertension, & congestive heart failure
o Both the metabolic acidosis and the hyperkalemia are out of
proportion to impairment in GFR
o Typical clinical features:
- Mean age 65 years
- Asymptomatic hyperkalemia (weakness and arrhythmia)
- Hyperchloremic metabolic acidosis
- Renal insuffiency
- Diabetes mellitus
- Cardiac disorders (arrhythmia, hypertension and congestive
heart failure)
o Hyporeninemic Hypoaldosteronism in Diabetes Mellitus:
- Hyperglycemia leads to increased filtered load of glucose
which enhances Na+ reabsorption by the Na+ glucose co-
transport leading to volume expansion.
- Diabetics has defect in converting prorenin to renin.
- Diabetics has atrophy of zona glomerulosa, as a result of
removal of trophic effect of insulin on these cells.
- Tx: Fludrocortisone (synthetic mineralocorticoid)- mainstay
of therapy in hyporeninemic hypoaldosteronism
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METABOLIC ALKALOSIS
A. MILK-ALKALI SYNDROME
 Excessive ingestion of milk and antacids.
 The incidence is increasing because of the use of calcium
supplementation (e.g., calcium carbonate) by women for osteoporosis
treatment or prevention.
 In Asia, betel nut chewing is a cause because the erosive nut is often
wrapped in calcium hydroxide.
 Both hypercalcemia and vitamin D excess have been suggested to
increase renal HCO3 reabsorption.
 Patients with these disorders are prone to developing nephrocalcinosis,
renal insufficiency, and metabolic alkalosis.
 Discontinuation of alkali ingestion is usually sufficient to repair alkalosis.
B. INCREASED GIT LOSSES OR DIURETICS
 Volume depletion of any cause stimulates RAA.
 Angiotensin II- stimulates Na H exchanger of proximal tubule causing
reabsorption of Na+ and secretion of H+.
o Secreted H+ binds to HCO3 that leads to HCO3 reabsorption leading
to metabolic alkalosis.
 Aldosterone- stimulate Na+ reabsorption, K+ and H+ secretion
o Causes: volume depletion, primary hyperaldosteronism, and
Cushing’s syndrome
o H+ & K+ secretion with aldosterone mediated Na+ reabsorption (ENaC)
- H+ secretion leads to HCO3 reabsorption
o Low K+ stimulates H+-K+-ATPase
- K+ secretion lower serum K+ which stimulated H+-K+-ATPase thus
secreting H+ that will bind to HCO3 that will eventually lead to
HCO3 reabsorption.
C. BARTTER’S SYNDROME
 Autosomal recessive disorder
 Types and defect
o BS type I: Na/K/2Cl- cotransporter (SLC12A1 encoding NKCC2)
o BS type II: apical inward-rectifying potassium channel (KCNJ1
encoding ROMK)
o BS type III: mutations in basolateral chloride channel (CLCNKB
encoding ClC-Kb) in TAL and DCT
o BS type IV: BSND, encoding Barttin, a protein that acts as an
essential activator B-subunit of ClC-Ka and ClC-Kb chloride channels
o BS type V: gain of functions in the CaSR
 Primary defect in sodium chloride reabsorption in the medullary thick
ascending limb of the loop of Henle.
 Clinical features:
o Hypokalemia
o Hypochloremic metabolic alkalosis
o Increase urinary calcium and magnesium excretion
o Nephrocalcinosis
o Hypomagnesemia
o Polyuria, polydipsia, volume depletion
o High renal prostaglandin excretion
o Marked elevation of plasma Angiotensin II, aldosterone, and renin
o Failure to thrive, growth retardation
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Table1.8: Variants of Familial Hypokalemic Alkalosis

Features Bartter’s Syndrome Gitelman’s Syndrome
Inheritance o Autosomal recessive o Autosomal recessive
o Mimics loop diuretics o Mimics thiazide diuretics
Pathophysiology o Genetic defect in thick ascending limb of LoH o Genetic defect in distal tubule
o Defects in NKCC2 cotransporter, K+ or Cl- channels o Defect in NaCl co-transporter in the distal tubule
result in lack of concentrating ability
Age of Presentation o Early in life o Late childhood or early adulthood
o No hypertension o No hypertension
Clinical Presentation o Polyuria and polydipsia are common o Polyuria and nocturia in 50-80%
o Neuromuscular symptoms are uncommon or mild o Often present with neuromuscular symptoms
o Nephrolithiasis and nephrocalcinosis are common
o Chloride-resistant metabolic alkalosis o Chloride-resistant metabolic alkalosis
Laboratory o Hypokalemia o Hypokalemia
o Normal serum Mg2+ (but may be low) o Hypomagnesemia
o Increased urinary Ca2+ excretion (hypercalciuria) o Decreased urinary Ca2+ excretion
o Hypocalciuric
Renal PGE2 o Increased o Normal
Production
Presentation Clues:
o Hypokalemic metabolic alkalosis with hypertension: Liddle’s syndrome
o Hypokalemic metabolic alkalosis without hypertension:
- Bartter syndrome (increased urinary Ca2+ excretion)
- Gitelman’s syndrome (decreased urinary Ca2+ excretion)

D. GITELMAN’S SYNDROME
 Autosomal recessive
 Loss of function mutation of the thiazide-sensitive Na+/Cl- co-
transporter (SLC12A2) channel in the distal convoluted tubule.
 Clinical features:
o Hypokalemia
o Hypochloremic metabolic alkalosis
o Hypocalciuria
o Significant hypomagnesemia
o High plasma renin and aldosterone
o Renal PG excretion is not elevated
E. LIDDLE’S SYNDROME
 Severe hypertension presenting in childhood, with hypokalemic
metabolic alkalosis
 Resemble those of primary hyperaldosteronism but the renin and
aldosterone levels are suppressed
 Gain of function of ENaC (autosomal dominant)
 Persistent Na+ absorption eventuates in volume expansion,
hypertension, hypokalemia, and metabolic alkalosis.
F. MANIESTATIONS OF METABOLIC ALKALOSIS
 Changes in CNS and peripheral nervous system function similar
to those of hypocalcemia.
o Mental confusion
o Obtundation
o Seizures
o Paresthesia
o Muscular cramping
o Tetany
o Respiratory depression
o Hypokalemia and hypophosphatemia
 Treatment:
o Treat the primary cause
o Isotonic saline w/ or w/o K+ replacement
- Volume depleted ( gastric and renal loss )
o Renal HCO3 loss can be accelerated by administration of
acetazolamide

Case: A 70-year-old man diagnosed with Lung Ca was admitted

due generalized body weakness. He has not been eating much for
the past week. He is cachectic, dry skin and oral mucosa.
Labs: ABG pH 7.53, pCO2 38, HCO3 31.6; Na 136(135-145), K
2.76(3.5-5.3), Cl 100(98-107), Ca 3.38(2.12-2.52)
Questions:
1. What is the volume status of the patient? volume depleted
2. What is the acid base abnormality? metabolic alkalosis
3. What factors contributed to the volume status? poor intake
4. What electrolyte abnormality contributed to persistent acid
REFERENCES
base abnormality? hypokalemia (non-corrected hypokalemia
causes persistent metabolic alkalosis. 1. Powerpoint 2022 and PARBS
2. Jameson, J. L., & Loscalzo, J. (2018). Harrison's principles of internal medicine (20th
edition.). New York: McGraw Hill Education.
3. In Yu, A. S. L., In Chertow, G. M., In Luyckx, V. A., In Marsden, P. A., In Skorecki, K.,
& In Taal, M. W. (2020). Brenner & Rector's the kidney.

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