12 - Disorders of Acid-Base Balance

What is an acid?

Acids are substances that release H+ when dissolved in water

What is a base, and what is the main one in the body?

Bases are substances that pick up H+, the main one is bicarbonate(HCO3-)

What does the equation pH = −log[H⁺] mean

It just means that with more H+, pH goes down, so low pH = acidic

A pH change in a whole number means?

It means a ten-fold change, so a pH of 6 would be 10x more acidic than pH 7

Normal pH range

7.35-7.45

Acidemia/alkalemia vs acidosis/alkalosis

-emia is the measured state of the blood: pH below 7.35 (acidemia) or above 7.45 (alkalemia). -osis is the process pushing pH in one direction. You can have an -osis with a normal pH, because of compensation or because two opposite processes cancel out.

Types of acids our body has to deal with, what they are, their differences, and how they’re removed

1. Volatile: CO2, which acts like an acid because it reacts with water to become H2CO3 and then splits into H+(the acid) and HCO3-. CO2 is removed by breathing out

2. Fixed acid: Mostly from dietary proteins, like sulfuric acid, phosphoric acid, but also in disease like lactic acids and ketoacids. Fixed acids are WAY less than CO2, however, they can’t be removed by breathing, only by the kidneys

What controls pH levels in the body?

The balance between bicarbonate and CO2, because if bicarbonate is increased, then the bicarbonate buffer system will shift the reaction to bind it with H+, form H2CO3, form H2O and CO2, which reduces free H+ and increases pH, and if CO2 increases, it will react with water to form H2CO3, then H+ and HCO3-, which makes pH lower.

Bicarbonate buffer system

• Equation

• What does it do?

• Key note/limitation

CO2 + H2O ⇌H2CO3 ⇌ H+ + HCO3-

• Bicarbonate neutralizes the H⁺ from fixed acids (like sulfuric acid), forming water and CO₂. The H⁺ is now in water and no longer affects pH. The CO₂ is breathed out, which stops it from building up and pushing the reaction backward to release the H⁺ again. So if the CO₂ isn't breathed out (a breathing problem), it builds up and drives the reaction backward, producing H⁺. Each H⁺ neutralized uses up one bicarbonate, which the kidneys must replace.

• Most CO₂ comes from cellular respiration. If it builds up (a breathing problem), it reacts with water to make H⁺ and HCO₃⁻. Bicarbonate can't buffer this H⁺: combining them would just make CO₂ again, and nothing would change. Instead, hemoglobin and other proteins buffer the H⁺, the kidneys raise bicarbonate over days to compensate, and only fixing the breathing actually clears the CO₂.

Normal PaCO2 and HCO3- values

• PaCO2: 35-45 mmHg

• HCO3-: 22-26 mmol/L

Why does acidemia raise blood potassium?

• Cells help buffer acid by taking H⁺ in, and K⁺ moves out in exchange to keep charges balanced, so blood potassium rises. Alkalemia does the reverse and lowers potassium. It matters because potassium changes can cause dangerous heart rhythms.

Which buffer is used in chronic acidosis, and how does it work?

Bone. Its mineral (hydroxyapatite) stores carbonate and phosphate, which are bases. Over weeks to months of acidosis, bone is broken down to release them and neutralize H⁺. The cost: calcium is released too, leading to weaker bones and kidney stones. Seen in CKD and distal RTA.

How does CO2 go from tissues to lungs, and how is this relevant to acid base clearing? (LONG VERSION)

Firstly, the tissue produces CO2, and it diffuses into the bloodstream.

1. Dissolved CO2: Only 10% since CO2 doesn’t dissolve well in blood

2. Carbamino-hemoglobin(HbCO2): 10% enter RBCs and just bind hemoglobin

3. Bicarbonate: 80%, CO2 enters RBCs where carbonic anhydrase converts it to H2CO3 then becomes H+ and HCO3-, then the HCO3- leaves the cell(With a Cl- entering the cell to keep charges balanced, called a chloride shift done by Anion Exchanger 1) while the H+ binds hemoglobin(which has just delivered O2 to the tissue, so it’s free).

At the lung,

1. The dissolved CO2 diffuses into the alveolus

2. O2 from the alveolus binds Hb and that makes the HbCO2 release from each other and that CO2 diffuses into alveolus

3. The main 80% also has it’s Hb release the H+, which binds the HCO3- that’s currently in the plasma. For that to happen, HCO3- needs to come back in, Cl- needs to go out, and now they combine to form H2CO3, then CO2 and water via carbonic anhydrase, and the CO2 can now diffuse out into plasma, then into alveolus

It’s relevant because this removes volatile acids from the body and prevents acidosis

How does CO2 go from tissues to lungs, and how is this relevant to acid base clearing? (SHORT VERSION)

At the tissues:
1. CO₂ enters red blood cells and is turned into H⁺ and HCO₃⁻.
2. HCO₃⁻ moves out into the plasma and travels there.
3. H⁺ stays inside the red blood cell, held by hemoglobin.

At the lungs:
1. Hemoglobin picks up O₂ and lets go of its H⁺.
2. HCO₃⁻ comes back into the red blood cell and joins the H⁺.
3. They turn back into CO₂, which is breathed out.

(About 80% of CO₂ travels this way. The rest is dissolved in plasma or bound directly to hemoglobin.)

Connection: the bicarbonate reaction isn't only for buffering fixed acids. The same reaction is how most CO₂ (volatile acid) is carried to the lungs. What it can't do is buffer a buildup of CO₂, which is why hemoglobin and other proteins handle that.

Job #1 for the kidney in acid/base regulation

• Process

• Result

• What powers it

• Threshold

• Reclaiming filtered bicarbonate(Bicarbonate reclamation). At theproximal tubule, the bicarbonate in the lumen can't be reabsorbed directly. NHE3 brings Na⁺ into the cell and secretes H⁺ into the lumen. Then, the H⁺ binds HCO₃⁻ and forms H₂CO₃, then carbonic anhydrase IV converts that into CO₂ and water, and the CO₂ diffuses into the cell. Carbonic anhydrase II in the cell turns that back into H₂CO₃, then into H⁺ and HCO₃⁻. The H⁺ is secreted again via NHE3 to repeat the cycle, while the HCO₃⁻ returns to the blood.
  About 80% is reclaimed in the proximal tubule.

• No acid excretion because the H+ is recycled in the lumen, and one base is returned(Not created, so a net of 0, we just prevented a loss)

• Na⁺/K⁺-ATPase keeps sodium low inside the cell, so Na⁺ keeps flowing in through NHE3, and that drives H⁺ out into the lumen.

• Maxes out at 24-26 mmol/L, so if our body is too basic, it can’t do more and the rest of the bicarbonate will spill into urine

What affects Job 1's threshold, and why?

The threshold depends on how much H⁺ the proximal tubule secretes, since each H⁺ reclaims one bicarbonate. The more H+ secreted, the bicarb. keeps coming back despite surpassing HCO3- levels of 26 mmol/L

• Raised by:

  • low volume (saving sodium through NHE3 means secreting H⁺),

  • low chloride (sodium is taken back with bicarbonate instead of chloride, and the collecting duct can't swap bicarbonate out without chloride)

  • low potassium (H⁺ moves into tubule cells, which then act as if the body is acidotic). These keep metabolic alkalosis going.

• Lowered by: proximal RTA (damaged machinery, less H⁺ secretion).

Job #2 for the kidney in acid/base regulation

• Why it’s needed

• Process

• Difference in scale from Job #1

• Result

• When fixed acids enter the blood, bicarbonate buffers them and is converted into CO₂, which is breathed out. That bicarbonate is used up, and reclamation doesn't replace it, so new bicarbonate has to be made.

• The α-intercalated cells in the collecting duct use carbonic anhydrase II to make H⁺ and HCO₃⁻ from CO₂ and water. Then, H⁺-ATPase and H⁺/K⁺-ATPase pump the H⁺ into the lumen, while the HCO₃⁻ goes into the blood (via AE1, in exchange for Cl⁻). After that, the H⁺ has to be carried out on buffers, because urine pH can't go below about 4.5, so very little H⁺ can leave free. There are two buffers: The first is phosphate. HPO₄²⁻ picks up H⁺ to form H₂PO₄⁻, which is excreted (titratable acid). Its amount is fixed by how much phosphate is filtered, so it can't increase much. The second is ammonia. In the proximal tubule, glutamine is broken down into 2 NH₄⁺ and 2 HCO₃⁻. The HCO₃⁻ goes to the blood, and the NH₄⁺ is secreted into the tubule. It's taken back out in the thick ascending limb of the loop of Henle and builds up in the medulla, where some becomes NH₃. The NH₃ diffuses into the collecting duct lumen, picks up H⁺ secreted by the α-intercalated cells, and is trapped as NH₄⁺, which leaves in urine. The NH₄⁺ must be excreted. If it returns to the blood, the liver turns it into urea, which cancels the new bicarbonate.

• Ammonium is the adjustable system: in acidosis, ammonia production increases several-fold over 3–5 days, so there’s not really a limit

• Each H⁺ excreted in urine adds one new HCO₃⁻ to the blood, so aka a gain of one HCO3-

4 primary acid base disorders

1. Respiratory acidosis: CO2 increases

2. Respiratory alkalosis: CO2 decreases

3. Metabolic acidosis: HCO3- decreases

4. Metabolic alkalosis: HCO3- increases

2 main causes of metabolic acidosis

• Gain of acid like DKA or lactic acidosis from shock → wide gap

• Primary loss of bicarbonate like severe diarrhea → normal gap

Compensation in metabolic acidosis

1. Buffering; bicarbonate in blood buffers the incoming acid while cells also take up H+ in exchange for K+ (Seconds)

2. We increase breathing to blow off CO2 to try to bring pH back up (Minutes/hours)

3. Renal compensation by increasing acid excretion and producing new bicarbonate(mostly via ammonium)(3-5 days)

Winter’s formula

• What is it

• Meaning and use case

• PaCO2 = (1.5 x HCO3-) + 8 +- 2

• Used in metabolic acidosis to evaluate respiratory compensation

  • If the value is in that expected range, the lungs are functioning normally

  • If the value is higher, the lungs aren’t doing enough, so there’s respiratory acidosis on top

  • If the value is lower, there is respiratory alkalosis too

Cause of respiratory acidosis

Alveolar hypoventilation

Compensation in respiratory acidosis

1. Buffers: Non-bicarbonate buffers, because if HCO₃⁻ combined with H⁺ from CO₂, it would just make CO₂ again. Hemoglobin and other proteins take up the H⁺, which lets bicarbonate rise slightly (+1 per 10, acute). (Minutes)

2. No respiratory compensation, since the lungs are the problem.

3. Renal compensation: the kidneys increase reclamation and regeneration to raise bicarbonate further (+4 per 10, chronic). (3–5 days)

Hand method

• What is it?

• Used to do what

• Take your hand, put down the 3rd finger.

  • Acidosis, alkalosis, acidosis, alkalosis

  • Acute, acute, chronic, chronic

  • +10 PaCO2, -10 PaCO2, +10 PaCO2, -10 PaCO2

  • Expected HCO3- change: +1, -2, +4, -5 mmol/L

• It is used to tell us what the expected bicarbonate should be in a patient with a respiratory issue(alkalosis or acidosis). If bicarbonate is higher than expected, there's also a metabolic alkalosis. If lower, there's also a metabolic acidosis.

Respiratory alkalosis cause

Hyperventilation → CO2 low

Compensation in respiratory alkalosis

1. Buffers: non-bicarbonate buffers (hemoglobin and proteins inside cells) release H⁺, which combines with bicarbonate and lowers it slightly (−2 per 10, acute). The problem is inside the bicarbonate reaction itself, so bicarbonate can't be the fix.

2. No respiratory compensation, since the lungs are the cause.

3. Renal compensation over 3-5 days: the kidneys reclaim less bicarbonate and make less ammonium, so bicarbonate falls further (−5 per 10, chronic).

Anion gap

• What is it

• When is it used

• What does it tell us

• AG = Na+ - (Cl- + HCO3-)

• Metabolic acidosis

• The body has equal charges. Although it seems like there’s a gap of 8-12, but that’s just because the test doesn’t measure negative charges like albumin. When an acid is added, like a ketoacid, it splits into a H+ and a negative particle(called anion), and the H+ is buffered by a bicarbonate(using up the bicarbonate and becoming H2O and CO2, with the CO2 being exhaled) while the ketoacid anion stays, so the charges remain the same(but anion isn’t measured, so the gap seems wider). However, if bicarbonate is lost, we lose a negative charge, so chloride increases to replace it, and since chloride is measured, the gap doesn’t change. So, a wide gap tells us an acid is added, while a normal gap tells us that bicarbonate has been lost.

Secondary changes never overcome primary changes; what does this mean for pH?

It means that pH is always on the side of the primary disorder

• For example a pt. w severe diarrhea loses bicarbonate → metabolic acidosis

  • The body compensates via breathing harder, so PaCO2 falls and pH becomes 7.31

    • Without the compensation, the pH would be even lower, but the secondary change brings it up a bit, but still not 7.35 and definitely not 7.4

Metabolic alkalosis formula

• What is it

• Meaning and use case

• Expected PaCO2 = (0.8 x HCO3-) + 20 +-2

• The purpose is to see if the lungs are compensating normally. If the PaCO2 is higher than expected, the lungs aren’t compensating well enough(respiratory acidosis). If it’s lower than expected, we’re breathing out too much → respiratory alkalosis

Corrected anion gap equation

• What is it

• Why it’s needed

• Corrected AG = measured AG + 2.5 x (4 - albumin)

• Normally the AG is 8-12 due to unmeasured negative charges like albumin, so in a case of hypoalbuminemia, the patient’s baseline gap is lower, and an 8-12 could be hiding a wide anion gap

What is a delta ratio, and why is it used?

It compares how much acid was added vs how much bicarbonate disappeared

• This is done because in a pure wide anion gap, they should match because the bicarbonate is used up to buffer the added acid, leaving the anion(like lactate) behind. We want to make sure that there isn’t something else raising/lowering bicarbonate

• Delta AG = Measured AG - normal AG(10)

• Delta HCO3- = normal HCO3-(24) - measured HCO3-

• Delta ratio: Delta AG/Delta HCO3-

• If the ratio is within 1-2 then it’s only wide anion gap acidosis. If it’s below 0.8, there’s something else causing bicarbonate to drop(normal gap acidosis) while if it’s above 2, there’s something adding bicarbonate back(metabolic alkalosis)

A patient with DKA and vomiting has AG 32 and HCO3- 14

What’s the diagnosis?

1. We see that his anion gap is wide, so check the delta ratio

2. 32 - 10 = 22

3. 24 - 14 = 10

4. Delta AG/Delta HCO3- = 2.2

5. The value is greater than 2, showing that something is adding bicarbonate back, in this case, the vomiting(Metabolic alkalosis)

Wide anion gap metabolic acidosis (DKA) + metabolic alkalosis (vomiting)

Plasma osmolal gap

• What is it

• Equation

• Used in what?

• It is a test to detect large amounts of small molecules in blood, mainly toxic alcohols

• Osmolal gap = measured osmolality - calculated osmolality

  • Calculated osmolality = 2Na + glucose/18 + BUN/2.8

  • Measured is given

  • The gap should be under about 10, if it’s above 15-20 we suspect that there is toxic alcohol ingestion

• Used in a high anion gap metabolic acidosis patient once we rule out ketones, lactate, and kidney failure

A patient has diarrhea and shock, along with these measurements

• pH = 7.1

• PaCO2 = 30

• Na+= 140

• Cl- = 114

• HCO3- = 8

• AG = 18

Diagnose them

1. Firstly, their pH is 7.1, which is acidemia

2. The HCO3- reflects that with just a value of 8, so we can say it’s primary metabolic acidosis

3. Now we see what PaCO2 should be, which in this case we get (1.5 × 8) + 8 which gives 20, so PaCO2 should be 18-22, which it isn’t. It’s way too high, meaning we aren’t compensating well enough → respiratory acidosis(usually tired breathing muscles)

4. Next we see the anion gap, which here it’s 140 - (114 + 8) = 18, which is wide, meaning an unmeasured acid has been added.

5. However, we do the delta ratio and see that it’s (18 − 10) ÷ (24 − 8) = 8 ÷ 16 = 0.5, which is below 0.8, meaning that something else is causing more acidosis, and here it’s the diarrhea which removes bicarbonate(normal gap acidosis)

Wide anion gap metabolic acidosis with normal anion gap metabolic acidosis and respiratory acidosis

Causes of normal anion gap metabolic acidosis

• HCl gain from outside: parenteral nutrition (TPN), large volumes of normal saline (chloride-rich, no bicarbonate).

• Bicarbonate loss:
  GI: diarrhea (urine NH₄⁺ high, since the kidney is healthy and responding)
  Renal: proximal RTA, carbonic anhydrase inhibitors like acetazolamide (Job 1 fails)

• Can't make new bicarbonate (Job 2 fails, urine NH₄⁺ low): distal RTA(less H+ secreted to bind w ammonia/phosphate), type IV RTA(too much K+, ammonia production down), CKD(ammonia production down).

How does NH4+ help separate GI and renal causes of normal gap anion metabolic acidosis?

• High urine NH4+ means the kidneys are working normally, trying to excrete as much acid as possible → GI cause

• Low urine NH4+ means that the kidneys aren’t responding despite the acidosis, meaning the kidney itself is the cause → Renal cause

If we can’t measure urine ammonium directly, what else can we measure?

Urine pH, urine anion gap

Urine pH

• What is it?

• Limitations

• Urine pH should be below 5.5 in acidosis because the kidney is supposed to be pumping out lots of H+. If it isn’t, it suggests a kidney issue like distal RTA.

• Not good in UTIs because some bacteria will break urea into ammonia and bicarbonate, which are bases. They raise the urine pH, so the urine looks alkaline even though the kidney is acidifying normally.

• Chronic acidosis also leads to a lot of ammonia production(To grab H+ and leave as ammonium), so little free H+ is left, and urine pH can read above 5.5 even when the kidneys are normal

Urine anion gap

• Other name

• Equation

• What is it

• When is it used

• Interpretation

• Urine net charge

• Urine anion gap = urine Na⁺ + urine K⁺ − urine Cl⁻

• A calculation on a urine sample that estimates how much ammonium (NH₄⁺) the kidney is excreting. It works because ammonium is excreted with chloride, so the measured chloride rises when the unmeasured ammonium rises, which will affect the equation

• In a pt. w normal anion gap metabolic acidosis to decide if the cause is outside the kidney or in the kidney

• If the gap is negative it shows that the kidney is responding appropriately and trying to excrete acid(extra-renal issue like diarrhea)

• If the gap is positive it shows that we have low ammonium despite acidosis, so the cause is renal

Renal tubular acidosis types and the pH and potassium values in them

• Proximal RTA(Type II): Prox. tubule can’t take back bicarbonate so it leaks into urine, traveling with Na+. This means that more Na+ is present at the collecting duct, taken up by ENaC and more K+ is exchanged out → low potassium

  • pH can go below 5.5 because collecting duct still can pump out H+

• Distal RTA(Type I): Collecting duct can’t pump out H+ → ENaC takes up sodium → H+ can’t be pushed out, so more K+ is pushed out → low potassium and urine pH of more than 5.5, often found w kidney stones

• Type IV RTA: Aldosterone deficiency/resistance → Less signal for ENaC to take up sodium and push out K+ → high potassium → high K+ reduces renal ammonia production → acidic urine because H+ still pumped out, yet the total urine excreted is small because ammonia can’t bind with H+ and leave with it

A patient presents with muscle weakness, nocturia and a kidney stone
Blood: Na 135, K 3.0, HCO₃⁻ 10, AG 12

Urine pH 6.3
Urine: Na 60, K 30, Cl 70

What do we do here?

1. Notice the very low HCO3- → metabolic acidosis

2. The anion gap is normal → normal gap acidosis

3. Urine pH is 6.3, so it could be a kidney defect or pitfall, so check the urine anion gap

4. 60 + 30 - 70 = 20 → This means that ammonium excretion is low despite acidosis → renal acidification defect

5. What type is it? K+ is low, so rule out type IV. Type 2 would normally allow for urine pH to drop below 5.5, and this pt. has low K+ and urine pH more than 5.5(Type 2 would lose a ton of HCO3- until barely any is released into the tubules, so the damaged prox. tubule can reabsorb all of it again, and no bicarb. can neutralize the acid in urine)

6. Distal RTA(Type 1)

2 mechanisms of metabolic alkalosis

1. Generation: Something raises bicarbonate

2. Maintenance: Something stops the kidney from excreting the extra bicarbonate because the kidney is really good at excreting bicarb.(If bicarb. goes over 26mmol/L, the excess will spill into urine)

Methods of generation

1. Loss of H+: Vomiting, aldosterone

2. Adding bicarbonate(directly or indirectly): Blood transfusion, large amounts of calcium carbonate(Milk-alkali syndrome, where the carbonate(a base) can’t be excreted because the calcium damages the kidneys)

3. Contraction alkalosis: Diuretics → Kidneys excrete NaCl and water, so ENaC pulls back more sodium and kicks out more H+ and K+(Not the only mechanism → Removing NaCl and water also keeps bicarbonate while removing fluid → higher concentration), then aldosterone senses the fluids leaving, so it boosts sodium retention and kicks out even more H+ and K+

4. Primary aldosteronism: The adrenal gland makes too much aldosterone on its own, driving H⁺ and K⁺ loss(Each H+ lost causes a HCO3- to enter the blood)

How can maintenance happen?

1. Low blood volume: Kidney holds onto sodium at the prox. tubule via NHE3, pushing out H+ which then reclaims bicarbonate. Aldosterone also rises, increasing H⁺ secretion.

2. Low chloride: Normally, β-intercalated cells push bicarbonate out into the urine in exchange for chloride, but without chloride reaching them, they can't. Also, sodium has to be taken back with a negative partner. With little chloride available, more sodium is taken back through NHE3 (pushing H⁺ out), which reclaims bicarbonate, so sodium effectively returns with bicarbonate instead of chloride.

3. Low potassium: Low K+ → K+ leaves cells and H+ moves in, which makes the tubule cells act as if the body is acidotic and will secrete H+ and make more ammonia to generate bicarbonate

A 70y pt. has HT treated with HCTZ and amlodipine, and has had fever, nausea and poor appetite for 3 days

• Examination: BP 100/80, HR 100, flat jugular veins

• pH 7.49, HCO3- 36, PaCO2 48, anion gap 10

Diagnose and explain?

1. pH 7.49 is high, so alkalemia.

2. HCO₃⁻ 36 is high, which causes alkalosis, so this is metabolic alkalosis. The high PaCO₂ is compensation.

3. Expected PaCO₂ = 0.8 × 36 + 20 = about 49. Actual is 48, so the lungs are compensating properly and there's no respiratory disorder.

4. AG 10 is normal, so there's no hidden wide gap acidosis.

5. Volume is low: BP is low for someone with hypertension, HR is fast, and jugular veins are flat.
   Diagnosis: simple metabolic alkalosis.
   Generation: HCTZ causes loss of salt and water, so bicarbonate is concentrated in less fluid. It also sends more sodium to the collecting duct, which increases H⁺ and K⁺ secretion. Each H⁺ excreted adds one bicarbonate to the blood. Low volume raises aldosterone, which increases H⁺ and K⁺ loss further.
   Maintenance: low volume (diuretic plus poor intake), so the kidney holds on to sodium and reclaims bicarbonate with it(Remember, Na+ in via NHE3, H+ out, H+ meets HCO3-, becomes CO2 and water, CO2 gets back into cell, becomes bicarb). Low chloride (90), so the collecting duct can't swap bicarbonate out and it uses the NHE3 pathway and sodium is taken back with bicarbonate instead. Low potassium (3.0), so tubule cells act as if the body is acidotic and make more bicarbonate.
   Treatment: stop the diuretic, give IV saline, replace potassium.

Urine chloride test

• What is it

• Interpretation

• Treatment

• A test that shows whether the kidney is holding on to salt, used in a dehydrated patient with metabolic alkalosis(Because low volume and sodium keep metabolic alkalosis going). When the body is low in fluid, the kidney holds on to sodium to save water, and chloride (sodium's main partner) comes back with it, so a healthy kidney makes urine low in chloride. Chloride is used instead of sodium because in alkalosis, bicarbonate spilling into urine takes sodium with it, so urine sodium can look high even when the kidney is saving salt.

• Interpretation

  • Below 20: the kidney is saving salt properly, so the chloride was lost elsewhere or in the past (vomiting, NG suction, a diuretic that has worn off).

  • Above 20: the kidney is still losing chloride despite the shortage, so the kidney is the source

• Treatment

  • Below 20: saline-responsive. IV saline restores volume and chloride, so the kidney no longer needs to hold on to bicarbonate and excretes the excess.

  • Above 20: saline-resistant. Saline alone won't fix it, so treat the cause (stop the diuretic, replace potassium or magnesium, deal with aldosterone excess).