Renal - Acid-Base Disorders

Distal RTA Associated Clinical Features

- Hypokalemia, - Nephrocalcinosis due to hypercalciuria (bone demineralization) - Hypocitraturia (low citrate)

Treatment of Renal Failure Acidosis

Chronic, Mild Acidosis Treat with Na-Bicarbonate

Lecture Q: 42yo man with history of alcoholism admitted after three day drinking binge. He feels weak, with nausea and persistent vomiting. Exam: Thin, BP 96/46, P100, RR 10 LabsABG pH 7.55; HCO3 39; PCO2 46 Na: 136; K: 2.8 Cl: 84; HCO3: 39 BUN: 32; Creatining: 1.6 *What is the most appropriate therapy?* a.) Oral acetazolamide b.) IV normal saline c.) IV normal saline plus KCl d.) IV 5% dextrose e.) IV potassium chloride

ABG pH 7.55; HCO3 39; PCO2 46 - pH 7.55 alkalemic - HCO3 39 implies Metabolic Alkalosis - PCO2 46 implies compensatory Respiratory Acidosis Dx: Metabolic Alkalosis with compensatory Respiratory acidosis *c.) IV normal saline plus KCl* - *K is important!!!!!*

Chronic Metabolic Alkalosis

Ability of Proximal Tubule to reabsorb HCO3 is increased, which maintains the alkalosis - prevents further Na and HCO3 loss to maintain the ECV

DKA Accumulation of Ketoacids

Accumulation of Ketoacids (acetoacetic acid, β-hydroxybutyric acid) generates an amino gap metabolic acidosis *Volume Depletion* that accompanies DKA may --> tissue underperfusion and *simultaneous lactic acidosis* **Degree of elevation of anion gap may be less than expected from the serum [HCO3]; may be due to urinary excretion of ketoacids or a concomitant metabolic alkalosis from vomiting

Hyperchloremic (*Non-Gap*) Metabolic Acid

Add HCl (Hydrochloric Acid) to the blood - Buffered by HCO3 --> HCO3 drops - Cl level is increased HCO3 and Cl cancel each other out Anion Gap stays the same!

Bicarbonate therapy

Aims to replace lost buffer in lactic acidosis and improve pH - controversial; may have deleterios effects - NaHCO3 should be considered when Pt is very acidotic (pH<7.1 or [HCO3] <8 mmol/L

ABG (Arterial Blood Gas) Basics

Arterial pH Serum Bicarbonate Arterial PCO2 Appropriateness of compensatory responses

Aspirin Poisoning Acidosis

Aspirin poisoning --> complex acid base disturbances Characteristically: - *Respiratory alkalosis* from direct stimulation of respiratory center - Mild *anion gap metabolic acidosis* (due to accumulation of organic acids, lactic acids, and ketoacids - NOT salicylic acid!!!)

Lactic Acidosis: Glycolysis

Cellular metabolism requires ATP for energy, much of which is produced from carb metabolism. In the absence of O2 as an electron receptor, glucose metabolism would stop as NAD+ (a cofactor for glycolysis) is converted to NADH. In humans this does not happen as the *NADH can be recycled by the conversion of Pyruvate --> Lactic Acid by Lactate Dehydrogenase*

Delta/Delta

Change in Serum Anion Gap/Change in Bicarbonate

Osmolal Gap

Difference between measured *Plasma Osmolality* and *Calclulated Osmolality* - High Osmolal Gap imples presence of unmeasured osmoles (alcohol, methanol, ethylene glycol, ketones)

GI vs RTA Non-Gap Acidosis

Distinguished by UAG Positive value = RTA Very Negative value = GI HCO3 Loss - (Note in diarrhea the urine pH may be high due to hypokalemic induced increased generation of NH3 and excess buffering of free urinary hydrogen ion)

Diuretics --> Alkalosis

Diuretic use --> volume depletion due to urinary loss of NaCl with resulting *secondary hyperaldosteronism* - Increased aldosterone, along w/ increased delivery of Na to CCD --> *enhanced reabsorption of Na+* at this site --> *increased excretion of K and H+* Hypokalemia promotes proximal tubule ammoniagenesis, and a metabolic alkalosis results from excretion of extra NH4+.

Methanol and Ethylene Glycol: Early Clinical Signs of Intoxication

Drunkenness - Progression to coma - Nausea - Blindness (Methanol) - Oxalate Crystalluria - Acute Renal Failure (Ethylene Glycol) - Anion Gap Metabolic Acidosis (may be SEVERE)

Primary Hyperaldosteronism (Conn Syndrome)

Due to either *bilateral adrenal hyperplasia or an adrenal tumour (usually adenoma) producing aldosterone* Typically presents with hypertension with hypokalemia and a mild metabolic alkalosis - much more common cause of hypertension than is usually appreciated

Type IV Renal Tubular Acidosis

Due to impaired aldosterone secretion or aldosterone resistance Results in a *mild non-anion gap metabolic acidosis in the setting of hyperkalemia*

Osmotic Diuresis in DKA

Elevated Serum BG raises serum osmolality --> H2O shifts from cells to ECF --> Osmotic diuresis occurs with significant loss of H2O, Na, and K Hyperglycemia is exacerbated by the osmotic diuresis induced pre-renal uremia --> impairs urinary glucose excretion.

Treatment for Methanol and Ethylene Glycol Poisoning Acidosis

Emergency treatment = inhibit metabolism of the alcohols using: - Ethanol - Fomepizole - Hemodialysis

Urine Anion Gap

Estimate of Urine Ammonium Excretion: UAG = UNa+UK+UCl *Normal: -20 - -50mmol/L* reflecting urine NH4+ Excretion with Cl-

Distal RTA

Excretion of NH4Cl requires: - generation of ammonium from glutamine in the proximal tubule - medullary recycling of ammonia - generation of a negative intra-tubule potential in the CCD - secretion of H+ by the apical H+- ATPase Abnormalities in any of these areas can result in a distal RTA

Proximal RTA

Failure to reabsorb HCO3 can result in *bicarbonate wasting and non-anion gap metabolic acidosis* - May also be an impairment of proximal ammoniagenesis, resulting in a more positive urine anion gap Proximal RTA usually occurs w/ other *evidence of proximal tubular dysfunction (glucosuria, aminoaciduria and phosphate wasting)* (Fanconi syndrome(, but may be isolated Most Common Cause of Proximal RTA: *Multiple Myeloma*

H+ Secretion

H+ is excreted by kidney mostly as NH4Cl - Amount of NaH2PO4 is relatively fixed and increased acid loads are excreted predominantly as NH4Cl

DKA: Lack of Insulin and Free Fatty Acids (FFAs)

Lack of insulin activates lipolysis in adipocytes --> release of FFA's --> FFA's enter mitochondria --> FFA *oxidation to Acetyl-CoA* --> Acetyl CoA enters Kreb Cycle to produce ATP - Large amounts of Acetyl CoA --> *conversion of Acetyl CoA to Ketoacids in the liver as a source of energy for brain and kidneys*

Lactic Acid Buffering

Lactic acid is buffered by *serum bicarbonate* --> generation of lactate (hence the positive anion gap in lactic acidosis). - Normal serum lactate levels: 1-1.5mmol/l - Lactic acidosis lactate: >4-5mmol/l in an acidemic patient W/ recovery, the lactate can be metabolized by the liver back to pyruvate and thence H2O and CO2.

Metabolic Alkalosis

Less critical than acidosis as generation of Alkaloids is slow and kidneys readily excrete HCO3 - Impairment of renal excretion is almost always required before significant metabolic alkalosis can develop

"Hallmark" of Metabolic Acidosis

Low HCO3!! Can Occur via: 1.) Addition of Acid - lactic acid, sulfiric acid, etc - bicarbonate buffers the acid and drops 2.) Loss of Base - diarrhea, diarrhea has a lot of HCO3 in it = loss of HCO3 via fecalexcretion

Respiratory Response to Metabolic Alkalosis

Lungs compensate via Hypoventilation, which retains CO2 and lowers pH toward normal - PCO2 should drop 0.6mmHg per 1mmol increase in HCO3

Kussmaul Respiration

Marked increase in ventilation (both increased respiratory rate and depth) when acidosis is severe

Mixed Respiratory/Metabolic Acid-Base Disorder

May be present if change in PCO2 is inappropriate for change in HCO3 (or vice versa) e.g. Metabolic Acidosis w/ Serum [HCO3] = 16 - expect PCO2 to drop by ~8mmHg - if actual PCO2 has dropped 20mmHg --> implies presence of an additional respiratory alkalosis (e.g. metabolic acidosis and respiratory alkalosis in aspirin intoxication)

Primary Hyperaldosteronism (Conn Syndrome) --> Alkalosis

Mechanism of metabolic alkalosis similar to diuretic use, except the *increased distal delivery of Na* is due to the *volume expanded state in the setting of aldosterone action* - *Hypokalemia* is similarly important in augmenting *proximal tubule ammoniagenesis*

Metabolic Acidosis Clinical Case *DETERMINE THE CAUSE*: *History*: A 26yo man with a 10yr history of diabetes mellitus attends the ER following a 3 day history of feeling unwell. He complains of nausea and abdominal pain. He has recently broken up with his girlfriend and she is worried he may have taken something to harm himself. *Examination*: he is drowsy, BP 96/62 and his respiratory rate is increased ("blow off") *Investigations* Arterial Blood Gas reveals pH 7.22; HCO3 12; PCO2 30 - *BG 150mg/dl and urine ketones neg - Ethylene glycol level 124 mg/dl*

Metabolic acidosis with compensatory respiratory alkalosis *Anion Gap = 25* --> Indicates Raised Anion Gap Metabolic Acidosis Normal BG and Neg Urine Ketones = not DKA Ethylene Glycol level = Antifreeze poisoning! *Treatment*: - IV fluids - Antagonize alcohol dehydrogenase (ethanol infusion or fomepizole) - Urgent hemodialysis

Clinical Presentation of DKA

Pts typically present with decreased level of consciousness, Kussmaul breathing, Hyperglycemia, and severe metabolic acidosis - Arterial pH may be <7.0!

D-Lactic Acidosis

Rarely in sick pts with bacterial overgrowth in bowel, gut organisms produce *d-lactic acid* (Type A and B due to L-lactic acid) - D-Lactic Acid cannot be metabolized by L-Lactic Dehydrogenase --> Lactic Acidosis Important to *consider when cause of Anion Gap Metabolic Acidosis is unclear* - D-Lactate not measured by standard assays for lactic acid

Specific Diagnosis* of Proximal RTA

Requires the *finding of high urine pH (>7.5) and high fractional excretion of HCO3 (>15%) during a HCO3 infusion*

Respiratory vs Kidney Compensation

Respiratory compensates FAST, Kidneys take several days

Proximal RTA In clinical terms...

Serum HCO3 level is reset to a new level at which compensatory renal mechanisms are able to fully reabsorb and prevent further loss of HCO3in the urine (i.e. a lowered tubular threshold for HCO3 reabsorption). When this is reached all the filtered HCO3 can be reabsorbed and the urine pH becomes appropriately acidic (urine pH < 5.5). *Typical serum HCO3 in proximal RTA is 16-18mmol/l* Correcting the acidosis may prove difficult as *raising the serum HCO3 leads to an increase of filtered HCO3 and wasting of bicarbonate in the urine* *Specific diagnosis* of proximal RTA requires the *finding of high urine pH (>7.5) and high fractional excretion of HCO3 (>15%) during a HCO3 infusion*

Most Common Cause of Distal RTA in Adults

Sjogren's syndrome - reduces the expression of H+ATPase in the intercalated cells in the CCD

Alkalosis: Aldosterone Excess

Stimulates Na reabsorption in principal cells of CCD --> increased H+ secretion by intercalated cells - This is the mechanism behind cases of metabolic alkalosis associated with ECV expansion (sometimes called *saline resistant met alkalosis*)

Alkalosis: Chloride Depletion

Stimulates distal H+ secretion

Renal Failure - Anions that Accumulate

Sulfate Phosphate Urate Hippurate

Mixed Metabolic Acid Base Disorders:The Delta:Delta

THIS WILL NOT BE ON THE EXAM!!!! KNOW WHAT Delta:Delta IS, BUT DO NOT NEED TO APPLY IT!!!!

Primary Hyperaldosteronism (Conn Syndrome) Treatment

Treatment consists of antagonism of the aldosterone effects with *spironolactone or eplerenone* for bilateral adrenal hyperplasia, and surgery, if indicated, for an aldosterone secreting adrenal adenoma.

Treatment of Type A Lactic Acidosis

Treatment directed at underlying cause of lactic acidosis w/ aim of increasing tissue O2 delivery *Principle Intervention*: Measures to correct shock - O2 therapy (may be needed in systemic hypoxia) - Bicarbonate therapy (replace buffer and improve pH) = controversial and may have deleterios effects

Metabolic Acidosis Treatment Goals

Treatment should be aimed at: - Stopping the production of H+ (e.g. insulin in ketoacidosis, O2 therapy in lactic acidosis) - Treating serious threats associated with acidosis (e.g. hemodialysis for ethylene glycol poisoning) - Managing dangerous K+ abnormalities (e.g. hypokalemia in RTA can be exacerbated by treating the acidosis)

Treatment of Diuretic Induced Alkalosis

Treatment with NaCl and KCl will allow the kidneys to excrete the excess bicarbonate.

Treatment of Vomiting Induced Alkalosis

Treatment with normal saline and KCl will expand the ECV and allow the kidneys to excrete the excess bicarbonate correcting the alkalosis.

Gap Acidosis

e.g. addition of 5mmol/L of Lactic Acid Each H+ from LActic Acid is buffered by a single HCO3 molecule (produces Sodim Lactate and H2CO3) and then excreted in the lungs - leads to a decrease in HCO3 (in this case, 5 Lactic Acids = decrease of 5 HCO3's) *Decrease in HCO3 --> Increase in Anion Gap* CHANGE in Anion Gap is roughly = to Change in HCO3

Normal Value for the Anion Gap Depends On...

is dependent on the *serum protein concentration* and approximates to 3 x [albumin] (g/dl). - In hypoalbuminaemic condition where serum albumin concentration 3g/dl, the expected anion gap for this person would be 9. ??????????

Metabolic Acidosis

is usually present if the *serum HCO3 <22* Rarely, this may be a compensatory response to a chronic respiratory alkalosis (eg. pregnancy) in which case the pH will be > 7.4

Ureteral Diversion Into Bowel

may also generate a non-anion gap metabolic acidosis from HCO3/Cl exchange and gut reabsorption of NH4Cl.

Starvation

may lead to mild ketosis

Detection of Ketoacids in Urine

presence of ketoacids in the urine can be detected by dipsticks, however, it should be recognized that many dipstick tests for ketoacids do not detect β-hydroxybutyrate which may be the predominant ketone body.

Failure to lower PCO2 by 1mmol per mmol of HCO3 implies...

presence of simultaneous respiratory acidosis (*Mixed Acid-Base Disturbance*)

Fanconi Syndrome

proximal tubular dysfunction (glucosuria, aminoaciduria and phosphate wasting)

Poisoning-Related Ketoacidosis

should be considered in the patient with an *anion gap metabolic acidosis* and an *increased plasma osmolal gap* Due to: - Methanol - Ethylene Glycol - Aspirin

Step 5: Assess the Anion Gap

the calculated difference between cations and anions in the blood - roughly equal to the *negative charge contributed by proteins* AG = (Na+K) - (Cl+HCO3) = ~16 - K varies very little so instead use: *AG = (Na+) - (Cl+HCO3) = ~12*

Renal Failure Acidosis

# of functioning nephrons decreases --> kidney's ability to excrete acid fails --> accumulation of anions results in *raised anion gap* Acidosis usually Not severe - only becomes apparent when GFR <25 mls/min UNLESS there is a significant non-anion gap acidosis from interstitial disease - Accumulation of : Sulfate, Phosphate, Urate, Hippurate

Simple vs Mixed Acid Base Disorder

*Clinical Case* pH 7.22; HCO3 12; PCO2 30 HCO3 drop from 24 ->12 PCO2 drop from 40 ->30 Roughly 1:1 change - Appropriate drop in PCO2 for this degree of metabolic acidosis *Mixed Disorder (Combined Met acidosis and Resp alkalosis)* pH 7.37; HCO3 12; PCO2 21 HCO3 drop from 24->12 PCO2 drop from 40->21 pH higher than expected (close to normal!) for normal respiratory compensation - Excessive decrease in PCO2 suggesting an additional respiratory stimulus (e.g. salicylate toxicity - aspirin)

Most Common Cause of Type IV Renal Tubular Acidosis

*Hyporeninemic hypoaldosteronism* seen in patients with diabetes mellitus - Type IV RTA is usually associated with renal impairment. Note: Patients are often able to appropriately lower their urine pH < 5.3, however, the *UAG is inappropriately low due to impaired ammoniagenesis*

"Hallmark" of Metabolic Alkalosis

*Increased HCO3* Caused by: 1.) Loss of Acid - GI Tract - Kidneys 2.) Gain of Base

Lecture Q: *"What does this Arterial Blood Gas reveal?" pH 7.22; HCO3 12 mEq/L; PCO2 30mmHg* a.) Metabolic Acidosis b.) Metabolic Alkalosis c.) Respiratory Acidosis d.) Respiratory Alkalosis e.) Who cares...I'm not an acid base nerd!

*Metabolic Acidosis* (with compensatory respiratory alkalosis)

Assessment Flow Chart

*Metabolic Acidosis*: - Low HCO3, Acidemia/Low pH *Respiratory Acidosis*: - PaCO2 High, Acidemia/Low pH *Metabolic Alkalosis*: - High HCO3, Alkalemia/High pH *Respiratory Alkalosis*: - PaCO2 Low, Alkalemia/High pH

Degree of Compensation: *Metabolic Disorders*

*Metabolic Acidosis*: Every *1mmol/L drop in [HCO3]* expect *1mmHg drop in PCO2* (from 40) *Metabolic Alkalosis*: Every *1mmol/L rise in [HCO3]* expect *0.6mmHg rise in PCO2*

Degree of Compensation: *Respiratory Disorders*

*Respiratory Acidosis*: *Acute*: Every *10mmHg rise in PCO2* Expect *1mmol rise in HCO3* *Chronic*: Every *10mmHg rise in PCO2* Expect *3.5mmol rise in HCO3* *Respiratory Alkalosis*: *Acute*: Every *10mmHg fall in PCO2* Expect *2mmol fall in HCO3* *Chronic*: Every *10mmHg fall in PCO2* Expect *4mmol fall in HCO3*

Lecture Q: What does this Arterial Blood Gas reveal: *pH 7.31; HCO3 31mEq/L; PCO2 64 mmHg* a.) Metabolic Acidosis b.) Metabolic Alkalosis c.) Respiratory Acidosis d.) Respiratory Alkalosis

- Arterial pH 7.31 implies Acidemia - PCO2 high (normal 40) implies Respiratory Acidosis - HCO3 high (normal 24) implies Metabolic Alkalosis *Respiratory acidosis with compensatory metabolic alkalosis*

Alkalosis: ECV Depletion

- Decreased GFR - Increased Proximal NaHCO3 reabsorption - Stimulates RAAS

Other Causes of Renal Salt Wasting

- Renal interstitial disease - Osmotic diuresis - (rarely) Bartter's and Gitelman's Syndromes

Glycolysis ATP Output

1 glucose metabolized by glycolysis (Kreb's cycle + oxidative phosphorylation) --> 36-38moles of ATP

Factors that prevent the kidney from excreting the excess alkali (*Maintenance of Alkalosis*)

1.) *ECV depletion* (↓GFR, ↑ proximal NaHCO3 reabsorption, stimulates RAAS) 2.) *Cl- depletion* (stimulates distal H+ secretion) 3.) *Aldosterone excess* (stimulates Na reabsorption in principal cells of CCD --> increased H+ secretion by intercalated cells) - This is the mechanism behind cases of metabolic alkalosis associated with ECV expansion (sometimes called *saline resistant met alkalosis*)

Treatment of DKA

1.) *IV Fluids and K* Replacement - correction of metabolic abnormalities 2.) Phosphate replacement in some cases 3.) *Insulin Therapy*: allows metabolism of keto-anions to HCO3 to replenish buffer - Although a marked acidosis may be present in Ketoacidosis, *generation of acid from ketogenesis is Slow* and Rapid correction of pH with Bicarbonate is rarely required and may be detrimental!

Why measure the serum anion gap?

1.) *Identify the cause of a metabolic acidosis* 2.) Identify a mixed metabolic acid base disorder (delta / delta) 3.) Response to Rx / low anion gap

Renal Tubular Acidosis

1.) *Proximal RTA*: inability to reabsorb filtered HCO3 2.) *Distal RTA*: impaired excretion of ammonium chloride (NH4Cl)

Causes of Lactic Acidosis

1.) *Type A - Anaerobic Metabolism due to Tissue Hypoxia* - Shock - Lunng Problem - Hemoglobin Problem - Increased O2 Requirement 2.) *Type B - Impaired Lactic Acid Metabolism w/o Hypoxia* - Liver Problems - Mitochondrial Disroders - Impaired PDH 3.) *D-Lactic Acidosis* - Bacterial overgrowth in bowel

A sustained increase in [HCO3] can only occur if two factors are present

1.) A source of alkali (*Generation of Alkalosis*) - Usually vomiting or renal H+ loss (diuretics) 2.) Factors that prevent the kidney from excreting the excess alkali (*Maintenance of Alkalosis*)

Metabolic Acidosis Clinical Case: *History*: A 26yo man with a 10yr history of diabetes mellitus attends the ER following a 3 day history of feeling unwell. He complains of nausea and abdominal pain. He has recently broken up with his girlfriend and she is worried he may have taken something to harm himself. *Examination*: he is drowsy, BP 96/62 and his respiratory rate is increased ("blow off") *Investigations* Arterial Blood Gas reveals pH 7.22; HCO3 12; PCO2 30

1.) Arterial pH 7.22 implies Acidemia 2.) HCO3 low (normal 24) implies Metabolic Acidosis 3.) PCO2 low (normal 40) implies Respiratory Alkalosis Dx: *Metabolic acidosis with compensatory respiratory alkalosis*

Ketoacidosis

1.) Diabetic Ketoacidosis (DKA) 2.) Alcoholic Ketoacidosis

Causes of *Low Anion Gap*

1.) Hypoalbuminaemia 2.) Positively Charged Paraproteinaemia (Myeloma) 3.) Addition of Halides to Serum (rare) - Rarely *cationic* proteins (e.g. myeloma) can cause a falsely elevated anion gap.

Compensation in Metabolic Acidosis vs Respiratory Acidosis

1.) In metabolic acidosis (low pH, low HCO3), alveolar ventilation increases creating a respiratory alkalosis (low PCO2) in order to return pH toward the normal range 2.) In Respiratory acidosis (low pH, high PCO2), kidneys excrete H+ and create a metabolic alkalosis (high HCO3) in order to return pH toward the normal range

Other Testing for Gap Acidosis (to distinguish root cause)

1.) Lactic Acidosis - look for hypotension, tissue ischemia - lactate levels 2.) Ketoacidosis - Diabetes: hyperglycemia, serum/urine ketones) - Starvation, alcoholic ketoacidosis 3.) Renal failure - serum creatinine 4.) Poisoning - toxicology screen - Serum osmolal gap

Causes of Gap Metabolic Acid

1.) Lactic Acidosis 2.) Ketoacidosis 3.) Renal Failure 4.) Poisoning - Methanol - Ethylene Glycol - Aspirin

Causes of Metabolic Acidosis

1.) Raised Anion Gap [Na-(Cl+HCO3) >12] - Lactic Acidosis - Ketoacidosis - Renail Failure - Poisoning 2.) Non-Anion Gap (Hyperchloremic Metabolic Acidosis) - GI HCO3 loss - Renal Tubular Acidosis

7-Step Assesment of Acid-Base Status

1.) What is pH 2.) Check Serum Bicarbonate 3.) Check Arterial PCO2 4.) Assess Compensatory Responses 5. Assess Anion Gap 6.) Assess the Delta/Delta 7.) Identify Underlying Cause of Acid-Base Disturbance

Anion Gap is Calculated for 2 Main Reasons

1.) to help determine etiology of a metabolic acidosis 2.) to determine if a complex metabolic disorder is present (e.g. in a pt with metabolic acidosis from DKA (Diabetic Ketoacidosis) and a simultaneous metabolic alkalosis from vomiting)

Typical serum HCO3 in Proximal RTA

16-18mmol/l

Calculated Osmolality

2 x [Na] + [glucose/18] + [urea/2.8] *Normal: <10mOsm*

Primary Hyperaldosteronism (Conn Syndrome) Screening

A good screening test for primary aldosteronism is the *aldosterone/renin ratio* which will show a *raised aldosterone level and low renin level* giving a high ratio.

Treatment of Aspirin Poisoning Acidosis

Alkali Therapy Hemodialysis

Lecture Q: *What is the likely diagnosis for a 22yo woman with a metabolic acidosis?* Na: 140 K: 5.1 Cl: 112 HCO3: 15 BUN: 15 Creatining: 0.5 a.) Diabetic Ketoacidosis b.) Lactic acidosis c.) Renal tubular acidosis d.) Aspirin poisoning

Anion Gap: (140+5.1)-(112+16) = 17.1

Type A Lactic Acidosis

Any condition that *impairs O2 delivery to tissues* leads to *anaerobic glycolysis with formation of Lactate* (Lactic Acidosis). Often seen in ill pts with hypotension due to sepsis, hypovolemia, or cardiogenic shock. - Pt in the ICU w/ sepsis syndrome who has problems with gas exchange and oxygen delivery to tissues from hypotension which are not readily reversed, is likely to have a *persistent metabolic acidosis*

Untreated Renal Failure Acidosis May Lead to...

Bone demineralization Skeletal Muscle Wasting May promote progression of the underlying renal disease

Metabolic Alkalosis Clinical Manifestations

Clinical manifestations of metabolic alkalosis are related to the *alkalemia* as well as the underlying cause of the disorder: 1.) * Musculoskeletal symptoms* - cramps, weakness) - often due to hypokalemia 2.) *Cardiovascular symptoms* - hypotension - from Volume Depletion - arrhythmias from Hypokalemia - Alkalemia itself can also result in cardiac arrhythmias due to *ventricular irritability* 3.) *CNS symptoms* - disorientation, lethargy, seizures - Can develop, and are usually due to the alkalemia itself

Acute Type A Lactic Acidosis

Commonly seen during marked physical exertion ("the burn") when enhanced energy needs temporarily outstrip O2 delivery - Rapidly Reversed as O2 debt is replaced

Distal Hydrogen Secretion

Controlled by aldosterone and distal flow Na / H2O - Na+ reabsorption creates luminal electronegativity promoting K+ and H+ secretion - Secreted H+ combines with NH3 --> NH4+ --> Excreted in the Urine

Correction of Acidosis in Proximal RTA

Correcting the acidosis may prove difficult as *raising the serum HCO3 leads to an increase of filtered HCO3 and wasting of bicarbonate in the urine*

How Serious is the Metabolic Acidosis?

Depends on many things: - Volume status - Rate of generation of acid - Presence of hypoxia - Degree of respiratory compensation - Any associated K disorders

Metabolic Alkalosis and Hypokalemia

Hypokalemia is almost universally associated with a metabolic alkalosis and both have similar causes!!!!

Step 6 - Assess the Delta/Delta

If HCO3 were the only buffer there would be a 1:1 relationship between increase in anion gap and fall in serum [HCO3] in an anion gap metabolic acidosis. W/ mild degrees of acidosis this is the case. However, *as the acid load increases, H+ can be buffered by other buffers* (predominantly intracellular) and the *change in anion gap is usually greater than the change in HCO3*

Delta/Delta in Mixed Respiratory Acid-Base Disorder

If delta/delta is much greater than expected (i.e. > 1.5:1) it suggests the simultaneous presence of an *underlying metabolic alkalosis* (which raises the [HCO3]) and an *anion-gap metabolic acidosis* (e.g. vomiting in patient with diabetic ketoacidosis) - Rarely a patient may have a normal [HCO3] and the only clue to a metabolic acidosis is the raised anion gap.

Low Delta/Delta

If delta/delta is much less than expected (i.e. < 1:1) it implies the presence of a *non-anion gap acidosis* in addition to the *anion gap metabolic acidosis* (e.g. lactic acidosis with simultaneous renal tubular acidosis).

Urine Electrolytes in Metabolic Alkalosis

If the kidneys are working appropriately the normal response to a decreased EABV is to retain Na+ and the urine [Na] is typically low (<20mmol/l) - In metabolic alkalosis there may be an *obligate loss of Na with bicarbonate in the urine*, and in this setting, a *more accurate assessment of volume status can be determined from a low urine chloride (<20mmol/l)*

Type IV Renal Tubular Acidosis Mechanism

Impaired aldosterone action --> impaired Na reabsorption in the CCD and diminished generation of the negative intraluminal potential --> *failure of H+ secretion by intercalated cells in the CCD* - Also a failure of potassium secretion by principal cells in the CCD - Hyperkalemia generates an intracellular acidosis in proximal tubular epithelial cells which impairs ammonium generation

Urine Anion Gap in Renal Tubular Acidosis

In RTA there is a failure ir NH4+ excretion and the UAG has a *positive value* - enables distinction between GI HCO3 loss and RTA

Alcoholic Ketoacidosis

In alcohol abuse ketoacidosis may develop in pts who have been *vomiting and are volume depleted* - *insulin deficiency* may be due to* intense SNS stimulation* - IV fluids alone will reverse the Ketoacidosis (*dextrose* to stimulate insulin release and *saline* to replace volume defecit)

Unmeasured Anions in a Gap Metabolic Acidosis

In each form of Gap Acidosis, an unmeasured anion is being added to the blood (See Chart)

Step 4: Assess Compensatory Responses

In order to maintain pH Kidneys try to compensate to respiratory acid-base disorders and lungs try to compensate for metabolic disorders *Compensation NEVER Over-Corrects pH!* (As a rule, compensation restores pH toward normal, but Not completely TO normal) - If pH is acidemic (pH < 7.4), acidosis is the primary acid-base disorder and if pH is alkalemic (pH > 7.4), alkalosis is the primary

Urine Anion Gap in Metabolic Acidosis

In states of metabolic acidosis, NH4Cl excretion should increase and Urine Anion Gap should become progressively *more negative* (-17 to -100mmol/L), reflecting increased NH4+

Insulin and Glucose

Insulin is required to allow the movement of glucose into most cells (excluding brain and liver) via specific glucose transporters (e.g. GLUT1). This permits glucose metabolism and the production of ATP.

GI HCO3 Loss

Intestinal secretions below stomach contain a total base concentration of ~60mmol/L *Diarrhea --> leads to loss of base --> metabolic acidosis* - Unmeasured anions are not added to serum so there is NO CHANGE in Anion Gap - Kidneys can compensate so acidosis is rarely marked in this setting unless there is *concomitant renal impairment, possibly due to volume depletion* - Diminished distal delivery of Na to the CCD may also result in impaired renal excretion of K and H+

Distal RTA Treatment

More pronounced metabolic acidosis can develop (serum [HCO3] may fall less than 10mmol/l) with a urine pH that is always greater than 5.3). Treatment of the acidosis requires *Less HCO3 therapy* as the max required will only be that necessary to *supply enough buffer to balance the daily net acid load* (~1mmol/kg/day). Note: Correction of hypokalemia should be performed before *correction of acidosis as correction of pH will drive K into cells and can exacerbate hypokalemia*

Lecture Q: *What is the likely diagnosis for a 22yo woman with a metabolic acidosis* Na: 140 K: 5.1 Cl: 112 HCO3: 16 BUN: 10 Creatinine: 0.5 a.) DKA b.) Lactic Acidosis c.) Renal Tubular Acidosis d.) Aspirin Poisoning

Na - (Cl + HCO3) = 140 - (112 + 16) = 12; normal anion gap --> *Non-Gap Acidosis* *c.) Renal Tubular Acidosis* - Other option is diarrhea

Normal HCO3 Rabsorption

Normal Serum [HCO3] = 24mmol/L w/ daily GFR ~180L --> implies ~4300mmol of HCO3 must be reabsorbed by the tubules to prevent loss of buffer in urine 90% of HCO3 reabsorption occurs in the *proximal tubule*

Step 2: Check the Serum Bicarbonate (HCO3)

Normal: 22-30mmol/L HCO3<22 = Metabolic Acidosis HCO3>30 = Metabolic Alkalosis

Step 3: Check Arterial PCO2

Normal: 35-45mmHg PCO2>40mmHg = Respiratory Acidosis PCO2<40mmHg = Respiratory Alkalosis

Step 1: What is the pH?

Normal: 7.35-7.45 pH <7.35 = Acidemia pH>7.45 = Alkalemia Normal pH = either no acid-base disturbance, or a complex disorder where acidosis and alkalosis exactly cancel each other out

Predominant Anions and Cations in the Body

Note the concentrations of most are low & do not contribute greatly to the anion gap.

Type B Lactic Acidosis

Occurs in pts with *abnormal lactate metabolism* with adequate O2 delivery. - much less common than Type A Usually due to: - *drug effect* (e.g. Metformin, HIV meds) - *inborn errors of metabolism* - *Mitochondrial Dysfunction*

Diabetic Ketoacidosis (DKA)

Occurs in pts with Type I DM who have absent or low insulin --> Glucose can't enter cells, Serum BG increases, and cells resort to Fatty Acid Oxidation for energy. FA Oxidation produces ketoacids which accumulate and generate anion gap metabolic acidosis.

Step 7: Identify the Underlying Cause of Acid-Base Disturbance

Once the type of acid-base disorder has been identified it is important to establish the underlying cause of the disorder.

Methanol and Ethylene Glycol

Potentially fatal alcohols taken for intoxicating effects or suicide Metabolism by ADH produces *Formic Acid* (methanol) or *Glycolic and Oxalic Acids* (Ethylene Glycol) responsible for the anion gap metabolic acidosis, which may be Severe.

Administration or Ingestion of sodium bicarbonate.

Under normal conditions, the kidneys are able to excrete excess bicarbonate and a metabolic alkalosis will not develop simply by the administration or ingestion of sodium bicarbonate.

Causes of Metabolic Alkalosis

Usually divided into those with a Decreased EABV or Increased EABV 1.) *Volume depletion* - Vomiting - Diuretics 2.) *Volume expansion/hypertension* - Primary Hyperaldosteronism (Conn Syndrome) Assessment of the *volume status is critical* to determining the cause of metabolic alkalosis. The vast majority of metabolic alkaloses are due to *vomiting or diuretic use*.

Metformin

Widely used hypoglycemic agent which may cause Type B Lactic Acidosis - occurs more commonly in pts with renal impairment - should be discontinued if serum creatinine >1/5mg/dl or before interventions that may compromise renal function (e.g. IV contrast studies)

Hyperventilation in Response to Acidosis

[H+] is determined by the ratio of PCO2 to HCO3 - Appropriate respiratory response to metabolic acidosis (↓HCO3) is to hyperventilate ("blow-off CO2") - PCO2 ↓ by 1 mmHg per 1 mmol drop in HCO3

Vomiting --> Alkalosis

[HCl] in gastric juice = 125mmol/L - Several L/day may be lost via vomiting or nasogastric suction - Associated volume depletion from NaHCO3 loss in urine --> inability of kidneys to excrete excess HCO3 In this setting, pH usually high (>6.0) Note: Urine Na may not be as low as predicted in the setting of volume depletion due to obligate urine loss of Na with HCO3.

Osmolal gap >25 in setting of Anion Gap Metabolic Acidosis

highly suggestive of methanol or ethylene glycol poisonong

In general acidosis is becoming dangerous if:

pH <7.2 HCO3 single-digit (<10) Consequences may be: depressed myocardial contractility and impaired enzyme function