nephrology is the art of homeostasis

Nephrology is the art of homeostasis

Its one thing balancing atoms in millimolar quantities

Its another balancing protons at nanomolar quantities

Introduction to acid-base physiology

Joel Topf, M.D.Assistant Professor of Medicine

Oakland University William Beaumont School of Medicine

http://www.pbfluids.com

Getting acid-base

• Acid base physiology is the regulation of hydrogen ion concentration

• A normal hydrogen concentration is 40 nmol/L

• This is .00004 mmol/L So

• It is measured on a negative log scale called pH, normal is 7.4

40 nanomol/L = 0.00004 milimol/L

Every change of 0.3 pH units represents a change in H+ by a factor of 2

pH only measures free hydrogen

Hydrogen regulation is aided by buffers

bicarbonatehemoglobin

bone

Bicarbonate is the primary buffer in the body

Acid base disorders are disturbances to the mantra.

pH ∝HCO3

–

CO2

There are two independent variables, HCO3 and CO2 and one dependent variable

pH ∝HCO3

–

CO2

Each independent variable can go up or down

pH ∝HCO3

–

CO2

That makes 4 possible disturbances

pH ∝HCO3

–

CO2

pH ∝HCO3

–

CO2

pH ∝HCO3

–

CO2

pH ∝HCO3

–

CO2

Each one gets a name

pH ∝HCO3

–

CO2

pH ∝HCO3

–

CO2

pH ∝HCO3

–

CO2

pH ∝HCO3

–

CO2

Metabolic alkalosis

Metabolic acidosis

Respiratory alkalosis

Respiratory acidosis

In respiratory disorders, the kidney modifies the HCO3

Patients with primary acid-base disorders compensate to restore normal pH.

In metabolic disorders, the lungs modify the pCO2

Compensation minimizes changes in the fraction, to minimize changes in the pH

pH ∝HCO3

–

CO2

Compensation is always in the same direction as the primary disorder.

pCO2HCO3Metabolic acidosis

pCO2HCO3Metabolic alkalosis

HCO3pCO2Respiratory acidosis

HCO3pCO2Respiratory alkalosis

Primary Compensation

Compensation is always in the same direction as the primary disorder.

pCO2HCO3Metabolic acidosis

pCO2HCO3Metabolic alkalosis

HCO3pCO2Respiratory acidosis

HCO3pCO2Respiratory alkalosis

Primary Compensation

pH

pH

pH

pH

If they move in discordant directions it is respiratory

If all three variables move in the same direction the disorder is metabolic.

Determine the primary disorder

1. Acidosis or alkalosis– If the pH is less than 7.4 it is acidosis– If the pH is greater than 7.4 it is alkalosis

2. Determine if it is respiratory or metabolic– If the pH, bicarbonate and pCO2 all move in the same

direction (up or down) it is metabolic

– If the pH, bicarbonate and pCO2 move in discordant directions (up and down) it is respiratory

pH / pO2 / pCO2 / HCO3

Determine the primary disorder

1. Acidosis or alkalosis– If the pH is less than 7.4 it is acidosis– If the pH is greater than 7.4 it is alkalosis

2. Determine if it is respiratory or metabolic– If the pH, bicarbonate and pCO2 all move in the same

direction (up or down) it is metabolic

– If the pH, bicarbonate and pCO2 move in discordant directions (up and down) it is respiratory

7.2 / 78 / 25 / 16pH / pO2 / pCO2 / HCO3

1. Acidosis or alkalosis– If the pH is less than 7.4 it is acidosis– If the pH is greater than 7.4 it is alkalosis

7.2 / 78 / 25 / 16pH / pO2 / pCO2 / HCO3

2. Determine if it is respiratory or metabolic– If the pH, bicarbonate and pCO2 all move in the

same direction (up or down) it is metabolic

– If the pH, bicarbonate and pCO2 move in discordant directions (up and down) it is respiratory

Metabolic Acidosis

1. Respiratory acidosis2. Metabolic acidosis3. Respiratory alkalosis4. Respiratory alkalosis

7.5 / 55 / 24 / 22pH / pO2 / pCO2 / HCO3

1. Respiratory acidosis2. Metabolic acidosis3. Respiratory alkalosis4. Metabolic alkalosis

1. Respiratory acidosis2. Metabolic acidosis3. Respiratory alkalosis4. Metabolic alkalosis

Respiratory alkalosisDetermine the primary disorder

The direction of compensation is determined by the direction of the primary disorder

The magnitude of the compensation is determined by

the magnitude of the primary disorder

Empiric data

pH = 7.3HCO3 = 15 CO2 = 30-26pH = 7.37pH = 7.32-7.38

Vary the bicarboinate, and map all of the CO2 responses

Rinse wash repeat for respiratory disorders

Why do we care?

HCO3 = 9 CO2 = 28pH = 7.12

Why do we care?We care in order to uncover multiple diseases

Determine the primary Acid-Base disorder

Metabolic acidosis

Metabolic alkalosis

Respiratory acidosis

Respiratory alkalosis

Winter’s formula

⅓ the Δ HCO3 1:10 acute3:10 chronic

2:10 acute4:10 chronic

Determine if the compensation is appropriate

To look for a second disease calculate what the compensation should be.

If they overlap, one disease, if they don’t 2 diseases

Compare it to the actual compensation

• Metabolic acidosis: Winter’s Formula

• 1.5 × HCO3 + 8 ± 2

• Metabolic alkalosis:

• pCO2 rises 0.7 per mmol rise in HCO3

• Respiratory acidosis:

• 1 or 3 mmol rise in HCO3 for 10 rise in pCO2

• Respiratory alkalosis:

• 2 or 4 mmol fall in HCO3 for 10 fall in pCO2

Predicting pCO2 in metabolic acidosis

• In metabolic acidosis the expected pCO2 can be estimated from the HCO3

Expected pCO2 = (1.5 x HCO3) + 8 ± 2

• If the pCO2 is higher than predicted then there is an addition respiratory acidosis

• If the pCO2 is lower than predicted there is an additional respiratory alkalosis

• Example:

– Expected pCO2 = (1.5 x HCO3) + 8 ±2– Expected pCO2 = 18-22– Actual pCO2 is 19, which is within the predicted range,

indicating a simple metabolic acidosis

Predicting pCO2 in metabolic acidosis

7.23 / 78 / 19 / 8 pH / pO2 / pCO2 / HCO3

• Example:

– Expected pCO2 = (1.5 x HCO3) + 8 ±2– Expected pCO2 = 24-28– Actual pCO2 is 34, which is above the predicted range,

indicating an additional respiratory acidosis

Predicting pCO2 in metabolic acidosis

7.15 / 112 / 34 / 12 pH / pO2 / pCO2 / HCO3

Respiratory disorders

• Metabolic compensation for respiratory acid-base disorders is slow.

• So the predicted bicarbonate needs to be calculated for pre-compensation, called acute, and after compensation, called chronic.

– Chronic compensation is complete so the pH will be closer to normal at the expense of increased alteration of serum bicarbonate.

Why is metabolic compensation slow?

• The lungs ventilate 12 moles of acid per day as carbon dioxide

• The kidneys excrete less than 0.1 mole of acid per day as ammonia, phosphate and free hydrogen ions

• The high excretion capacity of the lungs relative to the kidneys means that metabolic disorders are rapidly compensated by the lungs while respiratory disorders take hours to days for compensation by the kidneys.

Metabolic acidosis

In respiratory acidosis,

increases in CO2 drive the buffer reaction

to the left

In respiratory acidosis, the

acid is known it and it is

always CO2

In metabolic acidosis, the increase in H+ comes with an associated anion and that anion can be just about anything.

Determining what anion is present in metabolic acidosis is a basic skill of hospital medicine.

=

Defining the anion gap

K+, Ca++

Mg++, IgG

Lactate–

Albumin

PO4–

IgA

Cl + HCO3 + Anions = Na + Cations

Cl + HCO3 + Anions – Cations = Na

Anions – Cations = Na – (Cl + HCO3)

Define (Anions – Cations) as the anion gap

Anions Gap = Na – (Cl + HCO3)

K+, Ca++

Mg++, IgG

Lactate–

Albumin

PO4–

IgA

Normalanion

gap

Anions Gap = Na – (Cl + HCO3)

Normal anion gap Increased anion gap

=

What is the anion?

It is either chloride Or it is not chloride

Non-anion gap anion gap

Non-anion gap metabolic

acidosis

NAGMA

GI loss of HCO3

Diarrhea

Surgical drains

Fistulas

Ureterosigmoidostomy

Obstructed ureteroileostomy

Cholestyramine

Renal loss of HCO3

Renal tubular acidosis

Proximal

Distal

Hypoaldosteronism

Chloride intoxicationDilutional acidosis

HCl intoxication

Chloride gas intoxication

Early renal failure

pH = 5.5Cl = 154 mmol/L

Plasma volume3 litersPlasma Cl = 105

Decreases in bicarbonate force the reaction to the left, replacing the bicarbonate and increasing H+

Increases in exogenous acid drive the reaction to the right, bicarbonate is consumed

in both, the end result is an increase

in H+ and a decrease in HCO3

In NAGMA we will use the “loss of HCO3” model

NAGMA

GI loss of HCO3

Diarrhea

Surgical drains

Fistulas

Ureterosigmoidostomy

Obstructed ureteroileostomy

Cholestyramine

Renal loss of HCO3

Renal tubular acidosis

Proximal

Distal

Hypoaldosteronism

Chloride intoxicationDilutional acidosis

HCl intoxication

Chloride gas intoxication

Early renal failure

140 102 4.4 24135 100 5.0 35135 50 5.0 90135 50 5.0 90

Plasma

Bile

Pancreas

Small intestines

Large intestines

110 90 35 40

Ureterosigmoidostomy Ureteroileostomy

Urine pH=5.5 Serum pH=7.4

100 fold difference

NAGMA

GI loss of HCO3

Diarrhea

Surgical drains

Fistulas

Ureterosigmoidostomy

Obstructed ureteroileostomy

Cholestyramine

Renal loss of HCO3

Renal tubular acidosis

Proximal

Distal

Hypoaldosteronism

Chloride intoxicationDilutional acidosis

HCl intoxication

Chloride gas intoxication

Early renal failure

Renal causes of a non-anion gap is calledRenal Tubular Acidosis (RTA)• RTA is a failure of the kidney

to

– reabsorb all of the filtered bicarbonate

– or synthesize new bicarbonate to replace bicarbonate lost to metabolism

Daily acid load

• Protein metabolism consumes bicarbonate

– 1 mmol/kg

– 2 mmol/kg in children

– 4 mmol/kg in infants

• This bicarbonate must be replaced to maintain homeostasis

• The kidney does this

Normal bicarbonate handling

• Normal plasma HCO3

concentration is 24 mmol/L

• Normal GFR is 100 mL/min, or 0.1 L per minute

• 1440 minutes in a day

• 24 × 0.1 × 1440 =

3,456 mmol of bicarbonate are filtered a day (filtered load)

The kidney’s role in HCO3 handling is not excretory, it needs to synthesize new bicarbonate. All of the filtered bicarbonate must be reclaimed before the kidney can synthesize new HCO3 to compensate for the daily acid load

Bicarbonate handling• The proximal tubule needs to

reabsorb 3,456 mmol of bicarbonate that is filtered every day.

• Proximal tubule

• The kidney must synthesize 50-100 mmol per day of new HCO3 to replace HCO3 lost buffering the daily acid load.

• Cortical collecting tubule

3456 mmol/day 50-100 mmol/day

Proximal tubule: reabsorption of filtered bicarbonate

Bicarbonate handling• The proximal tubule needs to

reabsorb 3,456 mmol of bicarbonate that is filtered every day.

• Proximal tubule

• The kidney must synthesize 50-100 mmol per day of new HCO3 to replace HCO3 lost buffering the daily acid load.

• Cortical collecting tubule

3456 mmol/day 50-100 mmol/day

Distal tubule, completion of reabsorption and replacing bicarbonate lost to the daily acid load.

Electrogenic movement

of sodium into thetubular cells (eNaC)

H+ pumped into the tubular lumen ATPase

Maintain the 1000 fold concentration gradient

3 step process:

Fate of excreted hydrogen ion

The minimal urine pH is 4.5. This is a H+ concentration a 1000 times that of plasma.

ButIt still is only 0.04 mmol/L

In order to excrete 50 mmol (to produce enough bicarb-onate to account for the daily acid load) one would need…

1,250 liters of urine.

Fate of excreted hydrogen ion

Ammonium

Titratable acid

• Excretion of the daily acid load as free hydrogen is limited by a minimum urinary pH of 4.5– Only 0.1% of the daily acid load is excreted this way

• Titratable acid is urinary phosphate – Titratable acid carries a significant portion of the

daily acid load

– Limited by dietary phosphate

– Does not respond to changes in the acid load

• Ammonium carries the bulk of the daily acid load– In response to an acid load the kidney will increase

production of ammonia (NH3) in order to accept additional protons to carry the load

3 steps in renal

bicarbonate handling

3456 mmol/day

50-100 mmol/day

Each step can fail which causes RTA

and NAGMA3456 mmol/day

50-100 mmol/day

Proximal RTA (Type 2)

• The Tm is the maximum plasma concentration of any solute at which the proximal tubule is able to completely reabsorb the solute.

• Beyond the Tm the substance will be incompletely reabsorbed and spill in the urine.

• In Proximal RTA the Tm for bicarbonate is reduced from 26 to 15-20 mmol/L.

Na+

H2OHCO3 Glucose

Amino Acids

Damage to the proximal tubule decreases its Tm from 28 to somewhere in the mid-teensTm for HCO3 at 15

Serum HCO3 is > Tm so HCO3 spills into the urine

Proximal RTA (Type 2)

24 mmol/L

15 mmol/L

pH 8

Proximal RTA (Type 2)

15 mmol/L

15 mmol/L

pH 5

Serum HCO3 then falls

When it falls to the Tm (15 mmol/L) the kidney appears to work normally

Homeostasis resumes but at a decreased HCO3

Proximal RTA (Type 2)

12 mmol/L

12 mmol/L

pH 5

If the patient encounters an acid load, they synthesize new bicarbonate to return the serum HCO3 to altered Tm (15)

Proximal RTA: etiologies

• Acquired– Acetylzolamide – Ifosfamide – Chronic hypocalcemia– Multiple myeloma– Cisplatin– Lead toxicity– Mercury poisoning– Streptozocin– Expired tetracycline

• Genetic– Cystinosis– Galactosemia– Hereditary fructose

intolerance– Wilson’s disease

• Hyperparathyroidism• Chronic hypocapnia

– Intracellular alkalosis

Proximal RTA: consequences

• Loss of potassium (hypokalemia)

• Bone disease

– Bone buffering of the acidosis

• Decreased growth

• Not typically complicated by stones

Each step can fail which causes RTA

and NAGMA3456 mmol/day

50-100 mmol/day

Distal RTA, the Murphy’s Law of distal HCO3

handling

Distal RTA, the Murphy’s Law of distal HCO3

handling

Distal RTA (Type 1)

Failure can happen at any one of the three steps in urinary acidification

Distal RTA: Voltage dependent

• Only variety of distal RTA which is hyperkalemic

• Differentiate from type 4 by failure to respond to fludrocortisone.– Obstructive uropathy– Sickle cell anemia– Lupus– Triameterene– Amiloride

Distal RTA: H+ Secretion

• Called classic distal RTA

• Most common cause of distal RTA– Congenital– Lithium– Multiple myeloma– Lupus– Pyelonephritis– Sickle cell anemia– Sjögren’s syndrome– Toluene (Glue sniffing)– Wilson’s disease

Distal RTA: Gradient defect

• Amphotercin B

Distal RTA: consequences

• Bones– Chronic metabolic

acidosis results in bone buffering.

• Bicarbonate• Phosphate • Calcium

• Kidney stones– Calcium phosphate

stones• Due to hypercalciuria• Increased urine pH• Decreased urinary

citrateWell Mr. Osborne, it may not be kidney stones after all.

Each step can fail which causes RTA

and NAGMA3456 mmol/day

50-100 mmol/day

Type 4 RTA: Hypoaldosteronism

• Chronic hyperkalemia of any etiology decreases ammonia- genesis

• Without ammonia to convert to ammonium total acid excretion is modest

• Acidosis stimulates NH3 production

• NH3 is needed to excrete the H+ in the urine

• Alkalosis suppresses NH3 production

Intracellularalkalosis

With increases in serum potassium, potassium shifts inside the cells

To maintain electroneutrality, H+ moves out of the cells

Intracellular alkalosis decreases intrarenal ammonia production

Hypoaldosteronism: Type 4

• Chronic hyperkalemia decreases ammoniagenesis

• Without ammonia acid excretion is modest

• Urinary acidification is intact

• Acidosis is typically mild without significant bone or stone disease

• Primary problem is high potassium

anion gap metabolic acidosis

The anion gap metabolic acidosis

The anion gap acidosis

• Uremia (mild)• Ingestions

– Methanol– Ethylene glycol

• Ketoacidosis– DKA– Starvation– Alcoholic

• Sepsis

• L-Lactic acidosis– Salicylate intoxication– Ischemia– Cyanide intoxication

• Nitroprusside

– Malignancy– Metformin– Liver failure– Thiamine deficiency

• D-Lactic acidosis• Pyroglutamic acidosis

GOLDMARK

• G Glycols

• O Oxoproline: pyroglutamic acidosis

• L L-lactic acidosis

• D D-Lactic acidosis

• M Methanol

• A Aspirin

• R Renal failure

• K Ketoacidosis

AN Mehta, JB Emmett , M Emmett, Lancet, 372, 9642, p 892, 2008

Lactic acidosis

Lactic acidosis

• Type A– Tissue hypoxia

• Shock– Septic– Hemorrhagic– Neurogenic– Cardiogenic

• Respiratory failure• Anemia• CO poisoning

• Type B– Mitochondria

failure• Cyanide• Malignancy• Medications

– Anti-HIV– Metformin– Aspirin

• Thiamine deficiency

D-lactate

Ketoacidosis, a consequence of using fat as energy

Diabetic ketoacidosis

• Type 1 diabetes• No ability to

produce insulin• Without

exogenous insulin patients are dependent on ketones for energy

• So despite blood sugars 4-10x normal, patients act as if they are hypoglycemic

Diabetic ketoacidosis

ingestions

AspirinCauses type B lactic acidosis

Stimulates respiration so it also causes respiratory alkalosis

Methanol ingestion

Metabolic alkalosis

Addition of bicarbonate

• One ampule of Na Bicarbonate is 50 mmol of HCO3

• One 325 mg pill is 4 mmol of HCO3

• One tsp of baking soda is 60 mmol of HCO3

Contraction alkalosis

• Volume deficiency increases the kidneys excretion of hydrogen ions

• Enhanced sodium reabsorption in the proximal tubule increases reclaiming filtered bicarbonate

• Increased angiotensin increases AT2 which stimulates aldosterone

• Aldosterone increases intercalated cell hydrogen secretion, increasing synthesis of new bicarbonate

Excess mineralcorticoid activity• Secondary hyperaldosteronism

• Primary hyperaldosteronism

• Cushing’s syndrome

• Congenital adrenal hyperplasia

• Hyperreninism (renal artery stenosis)

• Licorice

Metabolic alkalosis can be divided into chloride responsive and chloride resistant categories

Saline responsive patients have a low urine chloride (less than 20 mmol/L)

Saline resistant patients have high urine chloride (greater than 20 mmol/L)

Chloride responsive

Chloride unresponsive