ACID BASE PATHOPHYSIOLOGY AND DISEASE STATES

The Four Cardinal Acid Base Disorders M acidosis M alkalosis R acidosis R alkalosis Disorder pHpCO 2 [HCO 3 - ]            

Metabolic Acidosis: The “Anion Gap” Na + Cl - HCO 3 - Alb -  [Na + ] - ([Cl - ] + [HCO 3 - ]) ~ mM/L

Na + + Cl - + H + + HCO 3 - Na + + Cl - + H 2 CO 3 Na + + Cl - + CO 2 + H 2 O What happens after HCl addition: Na + + Cl -

Metabolic Acidosis: The “Anion Gap” Na + Cl - HCO 3 - Alb -  [Na + ] - ([Cl - ] + [HCO 3 - ]) Na + Cl - HCO 3 - Alb - Nl Anion gap M acidosis

Na + + A - + Cl - + H + + HCO 3 - Na + + A - + Cl - + H 2 CO 3 Na + + A - + Cl - + CO 2 + H 2 O What happens after AH addition where “A” is a retained anion: Na + + A - + Cl -

Metabolic Acidosis: The “Anion Gap” Na + Cl - HCO 3 - Alb - Na + Cl - HCO 3 - Alb -  [Na + ] - ([Cl - ] + [HCO 3 - ]) Nl Anion gap M acidosis Na + Cl - HCO 3 - Alb - A-A- High Anion gap M acidosis

Clinician short-hand you should know: Na +  Cl -  BUN K +  HCO 3 -  creatinine Glucose 140  105   25 

140  105  30 Glucose  25   105  27 Glucose  6   113  33 Glucose  16  1.4 And now, it’s time for: “Calculate That Gap” 140 -( ) = 10 = normal ( ) = 30 = high ( ) = 10 = normal

Differential Dx of high-anion gap acidosis: "SLUMPED": Salicylates Lactic acidosis Uremia Methanol intoxication Paint sniffing (toluene) Ethylene glycol intoxication DKA or alcoholic ketoacidosis

Usually: mixed respiratory alkalosis & metabolic acidosis (rare: metab pure acidosis) Toxic at < 5 mEq/l, so no anionic contrib to AG No increase in osmolal gap ([ASA] < 5 mM) Salicylates - ± Hx aspirin ingestion, nausea, tinnitus, unexplained hyperventilation, noncardiogenic pulmonary edema, elevated prothrombin time

Treatment for salicylate intoxication: Un-ionized form (protonated) enters the brain and is excreted poorly So….alkalinize (HCO3 infusion) to maximize renal excretion (dialysis)

Lactic acidosis - Type A = increased O2 demand or decreased O2 delivery Type B = Malignancies (lymphoma) Phenformin, metformin hepatic failure acute respiratory alkalosis (salicylates) HAART congenital (glycogen storage disease type I) etc

Uremia is indicated by BUN, creatinine (chronicity by kidney size and Hct). Methanol - presents with ± abdominal pain, vomiting, headache; CT: BL putamen infarcts visual disturbance (optic neuritis)

Normal retina (left); optic neuritis (right) Methanol intoxication: neurological effects Putamen infarcts

Anion gap may be > 50 Osmolal gap > 10 mOsm

No increase in osmolal gap Paint sniffing (“huffing”) (toluene) may present as either anion gap acidosis or normal gap acidosis Anion = hippurate

Ethylene glycol - presents with ± CNS disturbances, cardiovascular collapse, respiratory failure, renal failure Oxalate crystals (octahedral or dumbell) in urine are diagnostic Anion gap may be > 50 Osmolal gap > 10 mOsm

“The rotund rodents chew through brake lines and radiator hoses in search of a fix of ethylene glycol…” “Marmots have an amazing ability to handle toxic substances. To tranquilize them, they need the same dose as a bear, and a bear will be down for 40 minutes while a marmot will be back up in 5. If you have to redrug them, it’s really hard to make them unconscious again.” National Wildlife Feb/Mar, 2002

Oxalate crystals “back of the envelope”

1.Ethanol infusion to compete with alcohol dehydrogenase (dialysis) OR 2.“Antizol” (fomepizole) (inhibits ADH) load, then 10 mg/kg q12 x 4 Treatment for methanol & ethylene glycol intoxication:

Diabetic ketoacidosis - Key clinical features are: type I DM (i.e. no insulin) a trigger: e.g. sepsis, fracture, stroke hyperglycemia ECF vol depletion & renal insufficiency acetoacetic- and  hydroxybutyric- acids

Alcoholic ketoacidosis - key clinical features are recent stopping ingestion of ethanol, hypoglycemia, and contracted ECF (usually due to vomiting)

THE SERUM OSMOLALITY CAN HELP WITH THE DIAGNOSIS IN HIGH ANION GAP ACIDOSES Step 1: Calculate Osm = 2[Na + ] + glucose/18 + BUN/2.8 Step 2: Measure Osm (freezing point depression) 3. Osmolal gap (measured - calc) should be ≤ 10 Osm gap due to small, osmotically-active molecules: mannitol (no acidosis) ethanol (acidosis = AKA) isopropanol (a "drunk" with ketones, but no acidosis) methanol (acidosis) ethylene glycol (acidosis)

Does metabolic acidosis cause hyperkalemia via H + /K + exchange?

Na + + Lact - + Cl - + H + + HCO 3 - Na + + Lact - + Cl - + H 2 CO 3 Lact - HCO 3 - Na + + Cl - + HCO 3 - (normal HCO 3 -,normal gap) Acute lactic acidosis from seizures (“closed” system”; lactate reabsorbed) Na + + Lact - + Cl - (low HCO 3 -,high gap) Na + + Lact - + Cl - + CO 2 + H 2 O Na + + Cl - + HCO 3 -

Time (minutes) Acute lactic acidosis from seizures (“closed” system”; lactate reabsorbed) Seizure [K + ] [HCO 3 - ] pH A. Gap

Principles of K + /H + Exchange: 1. Occurs if anion is impermeable 2. Limited if anion is permeable (“organic”) K+K+ H+H+ Cl - H+H+ A-A- K+K+

1. GI bicarbonate loss: diarrhea villous adenoma pancreatic, biliary, small bowel fistulae uretero-sigmoidostomy obstructed uretero-ileostomy Causes of a “normal anion gap” (A.K.A. “hyperchloremic”) metabolic acidosis

Pancreas Ileum Colon Pancreas Ileum Colon Diarrhea Causes Loss of HCO 3 - And a Normal Anion Gap Acidosis And Hypokalemia HCO 3 - Cl - HCO 3 - Cl - K+K+ HCO 3 - NormalDiarrhea Cl -

Flooding the colon or CCD with HCO 3 - instead of Cl - drives K + secretion Na + K+K+ K+K+ Cl - HCO 3 - K+K+

Pancreas Ileum Pancreatic fistula or transplant: loss of HCO 3 - Skin or urinary bladder HCO 3 - Cl -

Ileal loop Obstructed Uretero-ileostomy Causes a Normal Anion Gap Acidosis Obstructed ileal loop HCO 3 - Ureter Skin Cl - Ileostomy bag Cl -

The underlying assumption is that NH 4 + is excreted and maintains electroneutrality: ([Na + ] + [K + ] + [NH 4 + ]) - [Cl - ] = 0 Since NH 4 + is unmeasured, a negative urine anion gap indicates NH 4 + Cl excretion (i.e. normal renal tubule acidification) How to differentiate GI HCO 3 - loss from renal HCO 3 - loss? Use the urinary anion gap

A positive urine anion gap ~ no NH 4 + Cl excretion (i.e. low renal tubule acidification) Normal acidotic: closed circles Diarrhea: closed triangles Type 1 or IV RTA: open circles Battle et al, NEJM 1988

2. Ingestions & infusions ammonium chloride hyperalimentation (arginine/lysine-rich) 3. Renal bicarbonate (or equivalent) loss proximal RTA distal RTA type IV RTA early renal failure acetazolamide hydrated DKA Causes of a “normal anion gap” (A.K.A. “hyperchloremic”) metabolic acidosis

Proximal RTA (“Type II”) HCO 3 - (1) Na + (3) HCO 3 - H+H+ CO 2 H2OH2O + H+H+ Na + HCO 3 - glucose amino acids urate phosphate Defective Na + - dependent resorption = Fanconi’s Syndrome

InheritanceGene product Clinical features Genetically-Defined Proximal RTAs Autosomal recessive SLC4A4NBC1Prox RTA corneal Ca ++ pancreatitis Autosomal recessive CA2Carbonic Anhydrase II Proximal Or distal Or “hybrid” RTA; osteopetrosis; cerebral Ca ++

HCO 3 - in moles/time filtered GFR x [HCO 3 - ] plasma = “filtered load of HCO 3 - ” HCO 3 - Tm U HCO3 V Type II Renal Tubular Acidosis (“Proximal RTA”) New HCO 3 Tm U HCO3 V

Type II Renal Tubular Acidosis (“RTA”) HCO 3 -

Net acid excretion = urinary NH urinary “titratable acid” (H 2 PO 4 - ) - urinary HCO 3 - H+H+ NH 4 + NH 3 + HCO H 2 CO 3 HPO H 2 PO 4 - Not titratable; need to measure Present in Prox RTA Titratable acid

Flooding of CCD with HCO 3 - exceeds its resorptive capacity; HCO 3 - becomes “a poorly resorbed anion” Na + K+K+ K+K+ Principal cell  IC cell  IC cell HCO 3 - Cl - HCO 3 - Cl - H+H+ ATP ADP + P i H+H+ ATP ADP + P i Cl - pH min = 5 HCO 3 -

Glomerulus Prox tubule CCD How Diarrhea and Proximal RTA Are Alike Pancreas Ileum Colon K+K+ HCO 3 - K+K+

Urine pH in proximal RTA

Fractional excretion of HCO 3 - in proximal RTA

Diminished proximal resorption of HCO 3 - Plasma [HCO 3 - ] mEq/L Urine pH depends on plasma [HCO 3 - ] & GFR relative to proximal HCO 3 - Tm Fractional HCO 3 - excretion high (15-20%) at nl plasma [HCO 3 - ] Plasma [K + ] reduced, worsens with HCO 3 - therapy Dose of daily HCO 3 - required: mEq/kg/d Non-renal: rickets or osteomalacia Features of Proximal Renal Tubular Acidosis (“Type II”)

3. Renal bicarbonate (or equivalent) loss proximal RTA distal RTA type IV RTA early renal failure acetazolamide hydrated DKA Causes of a “normal anion gap” (A.K.A. “hyperchloremic”) metabolic acidosis

Distal RTA Na + K+K+ K+K+ Principal cell  IC cell  IC cell HCO 3 - Cl - HCO 3 - Cl - H+H+ ATP ADP + P i H+H+ ATP ADP + P i Cl - Aldosterone amphotericin Auto-immune

Hypo- kalemia in distal RTA: H + no longer shunts Na + current so K + must do so Na + K+K+ K+K+ Principal cell  IC cell  IC cell HCO 3 - Cl - HCO 3 - Cl - H+H+ ATP ADP + P i H+H+ ATP ADP + P i Cl - Aldosterone

Urine pH in distal RTA

Fractional excretion of HCO 3 - in distal RTA

Diminished distal H + secretion (autoimmune) or backleak of secreted H + (ampho-B) Plasma [HCO 3 - ] may be below 10 mEq/L Urine pH always > 5.5 Fractional HCO 3 - <3% at nl plasma [HCO 3 - ] Plasma [K + ] reduced Dose of daily HCO 3 - required: 1-2 mEq/kg/d Non-renal: nephrocalcinosis, renal stones Features of Classic Distal Renal Tubular Acidosis (“Type I”)

InheritanceGene product Clinical features Genetically-Defined Type I Distal RTAs-1 Autosomal recessive SLC4A1AE1 (G710D)  V850) Acute illness or growth failure in childhood ± deafness Autosomal dominant SLC4A1AE1 (A858D R589S R589H) Milder; Hearing is OK

InheritanceGene product Clinical features Genetically-Defined Type I Distal RTAs-2 Autosomal recessive ATP6  1 58 kDa subunit: vacuolar H + ATPase Distal RTA; sensori- neural hearing loss Autosomal recessive ATP6N1B116 kDa subunit: vacuolar H + ATPase Distal RTA; no hearing loss

3. Renal bicarbonate (or equivalent) loss proximal RTA distal RTA type IV RTA early renal failure acetazolamide hydrated DKA Causes of a “normal anion gap” (A.K.A. “hyperchloremic”) metabolic acidosis

Hyporenin- hypo aldosteronism Na + K+K+ K+K+ Principal cell  IC cell  IC cell HCO 3 - Cl - HCO 3 - Cl - H+H+ ATP ADP + P i H+H+ ATP ADP + P i Cl - Aldosterone Diabetes is the main cause

Urine pH generally < 5.5 as if the H + gradient is OK but the H + “throughput” is poor Plasma [HCO 3 - ] usually above 15 mEq/L Major problem: hyperkalemia suppresses ammoniagenesis Hypoaldosteronism (“Type IV RTA”)

Total Body K+ Excess Decreases Proximal Tubule Acidification and Ammoniagenesis via Intracellular Alkalosis 2. Total body K+ excess K+K+ 3. K+ entry into proximal tubule cells HCO 3 - (1) Na + (3) HCO 3 - H+H+ CO 2 H2OH2O + H+H+ Na + H+H+ 4. Alkalinization of prox tubule cell by K + /H + exchange 1. Failed CCD K + secretion

“ Voltage” type Hyperkalemic Distal RTA Na + K+K+ K+K+ Principal cell  IC cell  IC cell HCO 3 - Cl - HCO 3 - Cl - H+H+ ATP ADP + P i H+H+ ATP ADP + P i Cl - Aldosterone Obstruction Sickle Cell Amiloride Trimethoprim Pentamidine “PHA”

Urine pH Lasix + amiloride Lasix

Urine pH generally > 5.5 as if the H + gradient is poor AND the H + “throughput” is poor Plasma [HCO 3 - ] usually above 15 mEq/L Again: hyperkalemia suppresses ammoniagenesis “Voltage type” Hyperkalemic Distal RTA

InheritanceGene product Clinical features Genetically-Defined Hyperkalemic Distal RTAs-1 Autosomal dominant MLRMineralo- corticoid receptor PHA* I: Hyperkalemic distal RTA * “PHA” = Pseudohypoaldosteronism

InheritanceGene product Clinical features Genetically-Defined Hyperkalemic Distal RTAs-1 Autosomal recessive SNCC1A  ENaC PHA I Autosomal recessive SNCC1B  ENaC PHA I Autosomal recessive SNCC1G  ENaC PHA I

Aldosterone deficiency or resistance (“voltage”) Plasma [HCO 3 - ] usually above 15 mEq/L Urine pH depends: generally < 5.5 in hypoaldosteronism generally > 5.5 in voltage defect Fractional HCO 3 - excretion <3% at nl plasma [HCO 3 - ] Plasma [K + ] elevated Dose of daily HCO 3 - required: 1-3 mEq/kg/d Non-renal: none Features of the Hyperkalemic Distal RTAs

Normal Gap Acidosis With Nl Creatinine Urinary anion gap Negative (high NH 4 + ) GI HCO 3 - loss Proximal RTA acetazolamide Positive (low NH 4 + ) Urine pH & plasma [K + ] Urine pH < 5.5 & high[K + ] Hypo- aldosteronism RTA(type IV) Urine pH > 5.5 & low/nl[K + ] Distal RTA (“Type I”): secretory or gradient defect Voltage Defect Urine pH > 5.5 & high[K + ]

2. Ingestions & infusions ammonium chloride hyperalimentation (arginine/lysine-rich) 3. Renal bicarbonate (or equivalent) loss proximal RTA distal RTA type IV RTA early renal failure acetazolamide hydrated DKA Causes of a “normal anion gap” (A.K.A. “hyperchloremic”) metabolic acidosis

Excretion of the Daily Acid Load is Decreased in Chronic Renal Failure (CRF) or Distal Renal Tubular Acidosis (dRTA) Kim et al, AJKD 1996 Chronic Renal Failure dRTA Acid-loaded controls

2. Ingestions & infusions ammonium chloride hyperalimentation (arginine/lysine-rich) 3. Renal bicarbonate (or equivalent) loss proximal RTA distal RTA type IV RTA early renal failure acetazolamide hydrated DKA Causes of a “normal anion gap” (A.K.A. “hyperchloremic”) metabolic acidosis

Renal handling of acetoacetate in the dog Schwab and Lotspeich 1954 Self-inhibition of absorption

Renal handling of acetoacetate And  -OH butyrate in the rat Ferrier et al, 1992 Endogenous levels: Good resorption Elevated levels: Poor resorption Self-inhibition of absorption

Na + + AcAc - + Cl - + H + + HCO 3 - Na + + AcAc - + Cl - + H 2 CO 3 Na + + AcAc - + Cl - + CO 2 + H 2 O Na + + Cl - Renal loss of filtered AcAc - Pathophysiology of normal anion gap acidosis in diabetic ketoacidosis

Dumping of keto-anions with hydration in DKA Adrogué 1984

DKAs admitted hydrated have non-anion gap acidosis Adrogué 1984

The Four Cardinal Acid Base Disorders M acidosis M alkalosis R acidosis R alkalosis Disorder pHpCO 2 [HCO 3 - ]            

Vomiting H + loss Plasma pH and HCO 3 Distal K + secretion K + depletion High HCO 3 Tm NH 3 /NH 4 + secretion CCD HCO 3 resorption Renal HCO 3 resorption H + /K + ATPase pCO 2 K + loss, K + intake

Vomiting High HCO 3 Tm CCD HCO 3 resorption Renal HCO 3 resorption H + loss Plasma pH and HCO 3 Distal K + secretion K + depletion NH 3 /NH 4 + secretion H + /K + ATPase pCO 2 K + loss, K + intake Na + loss ECF volume Sympathetic tone GFR GFR x P HCO 3 Renin Local Ang II Systemic Ang II Aldosterone Low filtered HCO 3 load

Na + loss ECF volume Sympathetic tone GFR GFR x P HCO 3 Renin Local Ang II Systemic Ang II Aldosterone Vomiting High HCO 3 Tm CCD HCO 3 resorption Renal HCO 3 resorption H + loss Plasma pH and HCO 3 Distal K + secretion K + depletion NH 3 /NH 4 + secretion H + /K + ATPase pCO 2 K + loss, K + intake Low filtered HCO 3 load Chloride loss TG feedback Distal chloride delivery CCD HCO 3 Secretion (  IC cell)

Na + loss ECF volume Sympathetic tone GFR Filtered HCO 3 Renin Local Ang II Systemic Ang II Vomiting High HCO 3 Tm CCD HCO 3 resorption Renal HCO 3 resorption H + loss Plasma pH and HCO 3 Distal K + secretion K + depletion NH 3 /NH 4 + secretion H + /K + ATPase pCO 2 K + loss, K + intake Low filtered HCO 3 load Chloride loss TG feedback Distal chloride delivery CCD HCO 3 secretion Aldosterone

DIFFERENTIAL DIAGNOSIS OF METABOLIC ALKALOSIS USING URINE Cl Normal Urine [Cl - ] Mineralocorticoidism RAS, aldosteronism 11-  DH deficiencies Bartter’s Diuretics (early) Severe K + depletion Diuretics (late) Low Urine [Cl - ] Vomiting NG suction Posthypercapnia Low Cl - intake Cystic fibrosis

The Four Cardinal Acid Base Disorders M acidosis M alkalosis R acidosis R alkalosis Disorder pHpCO 2 [HCO 3 - ]            

Minute ventilation pCO 2 pO 2 Central chemoreceptors ventilation Carotid & aortic bodies The Drives to Ventilation: CO 2 and O 2

Causes of Respiratory Acidosis Chronic 10 mm Hg  pCO 2  3.5 mEq/L  HCO 3 - Acute 10 mm Hg  pCO 2  1 mEq/L  HCO 3 - Asthma Pulmonary edema Cardiac arrest Drug overdose Sleep apnea Chronic Obstructive Pulmonary Disease (COPD) Neuromuscular (e.g. Lou-Gehrig’s) Obesity/Pickwickian

NH 4 + Na + Chronically Elevated pCO 2 Stimulates Formation of New HCO 3 - by Ammoniagenesis H+H+ H+H+ Na + NH 3 NH 4 + HCO 3 - Glutamine NH 3 + CO 2 + H 2 O Glutaminase Proximal tubule

pCO 2 isobars HCO 3 - pH Acute vs Chronic Respiratory Acidosis

The Four Cardinal Acid Base Disorders M acidosis M alkalosis R acidosis R alkalosis Disorder pHpCO 2 [HCO 3 - ]            

Causes of Respiratory Alkalosis Chronic 10 mm Hg  pCO 2  3-5 mEq/L  HCO 3 - Acute 10 mm Hg  pCO 2  2 mEq/L  HCO 3 - Fear Pain Acid-base exams… Anxiety Altitude; Psychosis Sepsis; Stiff lungs Liver failure Salicylates Pregnancy Neurological Iatrogenic (wrong ventilator setting)

HCO 3 - in moles/time filtered GFR x [HCO 3 - ] plasma = “filtered load of HCO 3 - ” HCO 3 - Tm U HCO3 V Chronic Reduction in pCO2 Lowers HCO 3 - Tm New HCO 3 Tm U HCO3 V

145  95   25  1.8 RA-ABG: 7.50 /pCO2 33 /pO2 105 EXTRA CREDIT: WHAT IS THE ACID-BASE DISTURBANCE? 3. But the pCO2 is too low for a normal HCO 3 - = respiratory alkalosis This is the “Triple Ripple” 1. Anion gap is high (20) = addition of organic acid (“footprints”) 2. pH is high = alkalosis must be superimposed on Anion Gap acidosis but respiratory alkalosis would lower HCO 3 - so must be metabolic alkalosis (vomiting?)

End of Patho-Physiology Section (Acid-Base Part 2) OR

NH 4 + NH 4 + undergoes counter-current multiplication-1

Descending limb Ascending limb Counter-Current Multiplication 1. At the start: all cups have 10 pennies; 2. All new incoming cups have 10 pennies