3. INTRODUCTION
Metabolic acidosis is a clinical disturbance characterized by an increase in
plasma acidity, low blood pH (<7.35)
It occurs when the body produces excessive quantities of acid or when the
kidneys are not removing enough acid from the body (increased
production of hydrogen ions or the inability of the body to form
bicarbonate (HCO3) in the kidney
If unchecked, leads to acidemia with varying consequences
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4. INTRODUCTION
Usually, is a sign of an underlying disease process and identification of this
underlying condition is essential to initiate appropriate therapy
Causes are diverse
Consequences can be serious including coma and death
Understanding the regulation of acid-base balance requires appreciation
of the fundamental definitions
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5. DEFINITION OF TERMS
An acid is a substance that can donate hydrogen ions (H+)
A base is a substance that can accept H+
Buffers
Prevent sudden and large swings in pH , resist pH changes
Consist of a weak base and acid
Chemical buffers- Phosphate buffer, bicarbonate buffer, ammonia buffer
Acidemia refers to a pH < 7.35 (normal range 7.35-7.45)
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6. RENAL PHYSIOLOGY
Kidneys regulate plasma osmolarity by modulating the amount of water,
solutes, and electrolytes in the blood
They ensure long term acid-base balance
Normally the kidneys secrete H+ into the urine which are lost from the body
during urination
If blood is too acidic, more H+ are lost and vice versa if too basic
Mechanism of urine formation- Glomerular filtration, tubular reabsorption and
tubular secretion
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7. ACIDIFICATION OF URINE
Urine acidification and bicarbonate reabsorption take place in several
segments of the nephron; proximal tubule, loop of Henle, distal tubule,
and collecting ducts where most acidification occurs
Kidneys normally maintain acid-base balance by excreting the acid ions
and reabsorbing the bicarbonate ions (base) which serves to neutralize the
acid produced by the body
During the elaboration of an acid urine, the distal nephron (DCT and
Collecting duct) reabsorb that portion of the filtered HCO3 escaping
proximal reabsorption, titrtate luminal buffers and lower urine pH
The secretion of H+ occurs by a primary active mechanism which involves
the extrusion of H+ across the luminal cell membrane by an electrogenic
H+ pump driven by the hydrolysis of ATP
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9. ANION GAP
Na + Unmeasured cations = Cl + HCO3 + Unmeasured anions
Anion gap is the quantity of anions not balanced by cations
Usually due to negatively charged plasma proteins as the charges of the
other unmeasured cations and anions tend to balance out
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10. CAUSES OF METABOLIC ACIDOSIS
4 main causes;
Increase in the generation of H+ from endogenous and exogenous acids
(Lactate, ketones) or exogenous acids (salicylate, methanol, ethylene glycol)
Inability of the kidneys to excrete the hydrogen from dietary protein intake
(type 1 and 4 Renal tubular acidosis)
The loss of bicarbonate due to wasting through the kidneys (type 2 RTA) or
through the GIT (diarrhoea)
The kidneys response to alkalosis
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11. HIGH ANION GAP
High AG if over 12mEq/L
Causes;
Lactic acidosis
Ketoacidosis
CKD
Ingestions; Salicylte, methanol, ethylene glycol, propylene, paraldehyde, metformin,
phenformin
Massive rhabdomyolysis
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12. NORMAL ANION GAP
The number of bicarbonate ions decrease
To compensate the amount of lost bicarbonate ions, the body absorbs
chloride ions
As a result, the anion gap remains normal but the amount of chloride ions
increases
Also known as hyperchloremic acidosis
Hyperchloremic acidosis occurs basically due to these conditions;
Severe diarrhoea
Renal tubular acidosis
Rarer causes; uterosigmoid or pancreatic fistulas, acetazolamide use, Addison‘s
disease
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13. URINE ANION GAP
In severe diarrhoea, bicarbonate is lost in the stool, reducing the amount of
anions, resulting in acidity
GI and renal losses can be distinguished via urinary anion gap analysis;
Urine AG = Urine Na + Urine K – Urine Cl
A positive value suggests a low urinary NH4+, and indicates renal bicarbonate
loss (RTA)
Negative values suggests a high urinary NH4+, found with GI causes
(diarrhoea)
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14. HYPERCHLOREMIC ACIDOSIS
Loss of bicarbonate stores through diarrhoea or renal tubular wasting
leads to a metabolic acidosis state characterized by increased plasma
chloride concentration and decreased plasma bicarbonate concentration
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15. RENAL TUBULAR ACIDOSIS
RTA is a condition that results from the kidneys being unable to appropriately
acidify the urine resulting in the accumulation of acid in the body
A metabolic acidosis occuring secondary to decreased renal acid secretion in
the absence of marked decreases in GFR, and characterized by a normal AG are
collectively referred to as Renal Tubular Acidoses
Results in growth retardation, kidney stones, bone disease, CKD
Types;
RTA type 1- Distal RTA
RTA type 2- Proximal RTA
RTA type 3- Combined Proximal and Distal RTA
RTA type 4- Hyperkalemic
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16. TYPE 1 (DISTAL RTA)
In the distal nephron, primarily the collecting duct, the urine pH reaches its
lowest values
Distal tubule is responsible for generating new bicarbonate under influence of
aldosterone
Damage to alpha-intercalated cells of distal tubule causes no new generation
of bicarbonate and thus, no hydrogen ions
This raises the urine pH due to inadequate acid secretion
It is associated with hypokalaemia due to failure of H+/ATPase
Also known as the classic type
The deficiency is secondary to 2 main pathophysiologic mechanisms;
A secretory defect
A permeability defect
When secretory defect predominates, the decreased secretion of protons (H+)
fails to maximally decrease the urinary pH
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17. TYPE 1
Other mechanisms include decreased functioning of H+/ATPase, increased
leak of protons from the tubules back into the lumen as seen in
amphotericin B toxicity
Causes (Inherited);
Autosomal dominant; mutations of SLC4A1 gene
Autosomal recessive with deafness; mutations in the gene ATP6V1B expressed
in alpha=intercalated cells of distal tubule and cochlear, having distal RTA and
sensorineural deafness
Autosomal recessive without deafness; mutations in ATP6V0A4
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18. TYPE 1(Causes-Acquired)
Autoimmune diseases are the commonest cause in adults; SLE, Sjogren
syndrome, RA, SSc, thyroiditis, hepatitis and PBC
Genetic association; Marfan‘s syndrome, Ehler Danlos syndrome, sickle cell
disease, congenital obstruction of the urinry tract
Nephrocalcinosis; chronic hypercalcemia, medullary sponge kidney
Tubulointerstitial diseases; chronic pyelonephritis, chronic interstitial nephritis,
obstructive uropathy, renal transplant ejection
Hypergammaglobulinemic states; monoclonal gammopathy, multiple
myeloma, amyloidosis, crryoglobulinemia, CLD
Drugs; lithium, amphotericin B, NSAIDs, lead, antiviirals
Miscellaneous; diopathic, familial hypercalciuria, glue sniffing (inhalation of
recreation drug)
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19. TYPE 2 (PROXIMAL)
Normally, 85% to 95% of bicarbonate is reabsorbed at the proximal tubule
and only 10% absorbed at the distal tubule
Due to a bicarbonate leak, impaired proximal HCO3 reabsorption in
proximal tubule results in excess HCO3 in urine leading to metabolic
acidosis
Often associated with Fanconi syndrome and is rarer than type 1
Hypokalaemia is common due to osmotic diuresis because of decreased
HCO3 reabsorption causing increased flow rate to the tubules and causing
increased K+ excretions
Carbonic anhydrase inhibitors impair proximal bicarbonate reabsorption,
tenofovir, ifosfamide can cause Fanconi syndrome
Genetic causes; autosomal recessive, autosomal dominant
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21. TYPE 3 (MIXED)
Rare
Mostly affects children from Arabic, North African and Middle Eastern
descent
Due to mutations of CA II resulting in carbonic anhydrase II deficiency
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22. TYPE 4 (HYPERKALEMIC)
Ammonium excretion requires the renal synthesis of ammonia and the
secretion of hydrogen ions from the collecting tubular cells into the
tubular lumen where they are trapped as ammonium (NH4+)
Hypoaldesteronism causes hyperkalemia and metabolic acidosis
Hyperkalaemia impairs ammonia genesis in the proximal tubule and
reduces the availability of NH3 to buffer urinary hydrogen ions and
decreases hydrogen ion excretion in urine
The failure to acidify urine is due to inadequate amount rather than
complete absence of NH3 available for buffering of protons
Even if only a few protons are secreted distally, urine pH would fall and this
is why these patients have a urine pH < 5.5
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23. TYPE 4
Deficiency of or resistance to aldosterone is the most common cause of
hyperkalaemic dRTA
Most common cause of type 4 RTA in adults is hyporeninemic
hypoaldosteronism which is frequently observed among patients with mild to
moderate CKD, especially if due to diabetic nephropathy
Resistance to the action of aldosterone is observed in patients with a chronic
tubulointerstitial disease, those on potassium-sparing diuretics and rare
congenital disorder called pseudohypoaldosteronism
Addison disease, bilateral adrenalectomy, certain enzymatic defects, NSAID
use, HIV, Renal transplant
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24. CLINICAL FEATURES
Symptoms of metabolic acidosis are not specific
The respiratory centre in the brainstem is stimulated and hyperventilation
develops in an effort to compensate for the acidosis
As a result; varying degrees of dyspnoea
Chest pain, headache, confusion, generalized weakness, and bone pain
Nausea, vomiting and loss of appetite
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25. Important points in the history..
Age of onset, family history may point toward inherited disorders which
usually start in childhood
Visual symptoms, including dimming, photophobia, scotomata- methanol
ingestion
Renal stones- RTA or chronic diarrhoea
Tinnitus, blurred vision, and vertigo- Salicylate poisoning
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26. Important points in the history..
Diarrhoea- GI losses of HCO
History of DM, alcoholism, starvation- accumulation of ketoacids
Polyuria, increased thirst, epigastric pain, vomiting- DKA
Nocturia, pruritus, polyuria, anorexia, decline in urine output- Renal failure
Ingestion of toxins or drugs- Salicylates, acetazolamide,cyclosporine,
ethylene glycol, methanol, metformin, topiramate
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27. SIGNS
The best recognized sign of metabolic acidosis is kussmaul respirations, a
form of hyperventilation that serves to increase minute ventilatory volume.
Characterized by an increase in tidal volume rather than respiratory rate.
Appreciated as deliberate, slow and deep breathing
Chronic metabolic acidosis in children stunted growth and rickets
Coma and hypotension in acute severe metabolic acidosis
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28. SIGNS
Non specific; and depend on the underlying cause
Some examples; xerosis, scratch marks, pallor, drowsiness, fetor, asterixis,
pericardial rub for renal failure, dry mucous membranes and fruity smell
for DKA
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29. HISTORY AND PHYSICAL FOR THE
RTAs
Type 1 Distal;
rickets, growth failure, osteomalacia
Hypercalciuria, hypocitaturia (citrate is reabsorbed as a buffer for hydrogen
ions)
Alkaline urine
Nephrocalcinosis (calcium phosphate stones)
Recurrent UTIs
ESRD
Muscle weakness, arrhythmia from hypokalaemia
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30. HISTORY AND PHYSICAL FOR THE
RTAs
Type 2 Proximal
Osteomalacia
Hypokalaemia
Hypophosphatemic rickets
Loss of glucose, urate, and amino acids in the urine
Type 3 Mixed
Guibaud-Vainsel syndrome
Osteopetrosis
Cerebral calcification, Mental retardation
Facial dysmorphism, conductive hearing loss, blindness due to nerve compression
Type 4 Hyperkalemic
Hyperkalaemia, metabolic acidosis
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32. Calculations
Anion gap
Osmolar gap
Appropriate PCO2 change based on serum bicarbonate
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33. INTERPRETATION STEPS
Determine the main acid-base problem
1. Determine the acid-base status (pH lower than 7.35)
Metabolic or Respiratory
2. Bicarbonate < 20mEq/L
Metabolic acidosis
3. Calculate anion gap
Normal AG; 8 – 16mEq/L (5 -7 using newer lab analyzers)
4. Assess if respiratory compensation is adequate
5. Determine if patients history and physical fits the proposed diagnosis of type
and causes of metabolic acidosis
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34. URINE pH and AG
dRTA – urinary pH > 5.5, urinary AG positive
pRTA – urinary pH < 5.5, urinary AG positive
Type 4 RTA - urinary pH < 5.5, urinary AG positive
Diarrhoea – urinary pH variable, urinary AG negative
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35. WORK UP
1st clue to metabolic acidosis is a decreased serum bicarbonate
concentration observed from an EUCr
Remember that a decreased serum bicarbonate can be observed as a
compensatory response to respiratory alkalosis
Bicarbonate of less than 15mEq/L almost always is due to at least in part,
metabolic acidosis
Only definitive way to diagnose metabolic acidosis is by simultaneous
measurement of serum electrolytes and arterial blood gases, whcih shows
pH and PaCO to be low
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36. A low serum HCO3 and pH of less than 7.40 upon ABG analysis confirms
metabolic acidosis
Calculate the anion gap (AG) to help with the differential diagnosis and
diagnose mixed disorders
In general, a high-AG acidosis is present if AG is greater than 10-12mEq/L
and a non-AG acidosis is present if the AG is less than or equal to 10-12
mEq/L.
The AG decreases by 2.5mEq for every 1g/dl decrease in serum albumin
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37. Osmolar gap (OG) = Measured serum osmolality - Calculated serum osmolality
Normal is about 10-15mOsm/kg
Calculated plasma osmolality (P) = {2 X Na}+{Glucose in mg/dl}/18+{BUN in mg/dl}/2.8
If AG is elevated, calculate osmolar gap
OG > 15mOsm/kg indicates the presence of abnormal unmeasured os motically active
molecules
Most common causes; ethanol, methanol, ethylene glycol, isopropanolol
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38. EVALUATION OF RTAs
(General)
Consider RTAs in any patient with an otherwise unexplained normal anion
gap (hyperchloremic) metabolic acidosis
Measure blood pH
Plasma potassium; low in type 1 and type 2 and high in type 4
BUN/Cr; normal or near normal (rules out renal failure as the cause of
acidosis)
Urine anion gap (Na + K) – Cl (positive gap signifies low NH4Cl excretion
which causes a decrease inchloride in urine along with hyperchloemic
metabolic acidosis suggesting RTA
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39. EVALUATION OF RTAs
(Specific)
Acid load test confirms diagnosis of distal RTA
Bicarbonate infusion test
Urine Na; type 4 RTA presents with persistently high urine Na despite
restricted Na diet because of aldosterone deficiency or resistance
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40. TREATMENT
Treatment of GI causes of hyperchloremic acidosis is aimed at;
Administration of saline solutions to repair volume losses
Early administration of potassium
Treatment of acidosis with bicarbonate-containing solutions is
accompanied by potassium replacement to avoid severe hypokalemia
Generally, identify underlying disease entity, give specific therapy
However therapy for hyperchloremic RTA still needed
Goals of therapy; reduce rate of progression to CKD, neutralize metabolic
bone disease and in children, improve growth
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41. TREATMENT/ MANAGEMENT OF THE
RTAs (Hypokalaemic dRTA)
Treatment consists of long-term alkali administrationin amounts sufficient to
counterbalance endogenous acid productionand any bicarbonaturia that may
be present
Oral bicarbonate replacement at 1-2 mEq/kg per day by sodium bicarbonate
or potassium citrate
Potassium citrate necessary for patients with hypokalaemia, nephrolithiasis or
nephrocalcinosis
Sought and treat underlying conditions
Most bicarbonate is absorbed in the proximal tubule so distal RTA is relatively
easy to correct
Spironolactone can be used to maintain normokalaemia
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42. TREATMENT/ MANAGEMENT OF THE
RTAs (Proximal RTA)
High doses of bicarbonate greater than 5 to 15 mEq/kg per day are required to
treat type 2 RTA
Raising the serum bicarbonate concentration will increase the filtered
bicarbonate load above the proximal tubule‘s reduced absorptive capacity,
resulting in a marked bicarbonate diuresis so a larger amount of alkali is
required to account for these urine losses
Increased bicarbonate concentration in urine induced by alkali therapy also
increases urinary potassium losses
Administration of potassium salts must accompany or precede as it minimizes
the degree of hypokalemia associated with alkali therapy
Can be dificult to treat because alkali administration results in prompt and
marked bicarbonaturia and potassium wasting
Thiazide diuretics cause extracellular volume depletion which will enhance
bicarbonate reabsorption in type 2 RTA
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43. TREATMENT/ MANAGEMENT OF THE
RTAs (Hyperkalaemic dRTA)
Identify entities amenable to intervention such as obstructive uropathy
Most patients can be managed with a limitation of dietary potassium to 40 to
60 mEq per day
Avoid foods and drugs that may contain high potassium content
Cation exchange resins may be helpful in hyperkalaemia
Distal sodium delivery is increased if patients increase ingestion of dietary salt
Fludrocortisone 0.1mg per day is effective in managing hyperkalaemia
associated with aldosterone deficiency. However it is not usually used due to
hypertension, heart failure and oedema exacerbated in patients with renal
insufficiency
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44. Hypophosphatemia due to decreased proximal phosphate reabsorption
and reduced activation of vitamin D also occurs in some patients and may
be a major contributor to the development of bone disease
Thus phosphate and vitamin D supplementation may be required to
normalize the serum phosphate and reverse metabolic bone disease
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45. PROGNOSIS
Morbidity and mortality in metabolic acidosis are primarily related to the
underlying condition and the acid-base derangement
Prognosis is poor if the derangements are large and vitals are unstable
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46. CONCLUSION
Metabolic acidosis is a clinical disturbance characterized by an increase in
plasma acidity (pH < 7.35 and a low HCO3 level)
It is usually a sign of an underlying disease process
Identify underlying and initiate appropriate therapy
Treatment is case dependent and lab tests include; arterial blood gas,
electrolytes, toxin levels
The overall prevalence in the population is uncertain
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47. REFERENCES
Roth KS, Chan JC. Renal tubular acidosis; a new look at an old problem.
Clin Pediatr (Phila). 2001 Oct;40(10):533-43 (Pub Med)
Trepiccione F, Prosperi F, Hubner CA, Chambrey R. New findings on the
Pathogenesis of Distal Renal Tubular Acidosis. Kidney Dis (Basel). 2017
Dec;3(3):98-105 (Pub Med)
Johnson RJ, Feehally J, Floege J, Marcello T. Comprehensive Clinical
Nephrology. 5e. Philadelphia, PA; Elsevier/Saunders 2015
Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson J, Loscalzo J. eds.
Harrison‘s Principles of Internal Medicine, 18e. New York; McGraw Hill;
2012.
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