2. Objectives
• Review causes of Non-anion gap
Metabolic Acidosis
• Physiology & functional anatomy of
kidney
• Approach to RTA
• Distinguish RTA Types 1, 2 and 4
• Treatment of RTAs
3. Anion-Gap
• This Gap refers to the difference between
the concentration of Cations (Na+ ,k+)and
concentration of Anion (Cl- and HCO3
- )in
the blood.
• It consists for the most part of proteins in
the anionic form, HPO4
2-,SO4
2- and organic
acids.
• Normal values 09 - 14mEq/L.
5. METABOLIC ACIDOSIS
• Loss of bicarbonate leads to systemic acidemia,
which produces low arterial ph and low serum hco3
• The appropriate compensation is increased respiration
leading to a reduced pCO2.
• In general, the expected degree of pCO2 reduction is
calculated as
Expected pCO2 = 1.5 × [HCO3
-] + 8 ± 2
7. Differential Diagnosis of High AG Metabolic Acidosis
“MUDPILES”
• Methanol
• Uremia
• DKA
• Paraldehyde
• INH
• Lactic acidosis
• Ethylene glycol
• Salicylates
8. Non-anion gap Metabolic Acidosis
• “USED CAR”
• U Uretero-Sigmoid Diversions.
– Accum of urine in colon reab chloride & water by intestine secretion of
bicarb into intestine
• S Saline administration.
• E Endocrinopathies.
– Addisons, Spirinolactone, Triamterene, Amiloride, Primary
Hyperparathyroidism
• D Diarrhoea.
• C Carbonic Anhydrase Inhibitors.
• A hyper-Alimentation.
• R Renal Tubular Acidosis
9. • The mechanisms of the above items causing a
non-anion gap metabolic acidosis are as follows:
• Ureterosigmoid Connection :Recall that urine
contains large amounts of chloride.
• But now instead of losing the chloride in the
urine, the chloride is passed into the sigmoid
colon.
• This large amount of chloride is then exchanged
in the sigmoid colon for HCO3, which is then lost
in the stool (GI loss of HCO3).
10. • Diarrhoea:In the case of diarrhoea, as you get
increasing amount of dehydration, excess lactate
is produced (because of insufficient oxygen
delivery).
• You might expect to get a metabolic acidosis,
but dehydration also causes a contraction
alkalosis which can normalize the pH or even
drive the pH up causing alkalosis.
• Carbonic Anhydrase inhibitors: Renal
reclaimation and generation of HCO3 depends on
carbonic anhydrase.
• So the carbonic anhydrase inhibitors cause loss
of HCO3 in the urine.
11. • So, CA-I's interfere with renal tubular
function and therefore cause RTA.
• Eg. Acetazolamide, topiramate.
• Ingesting large amounts of chloride (in
the form of CaCl or NH4Cl) : A large
amount of Cl makes it to the sigmoid
colon where it is exchanged for
HCO3 which is then excreted by the
GI tract (GI loss).
12. • Pancreatic fistula: Bicarbonate-rich fluid
excreted into the intestines where it is lost (GI
loss of HCO3).
• Parenteral nutrition (TPN): There is an
additional mechanism by which NH4Cl causes a
non-AG metabolic acidosis.
• It is similar to the mechanism by which TPN
causes a non-AG metabolic acidosis.
• Either the NH4Cl or the amino acids in TPN are
meatbolized to HCl which causes a transient
non-AG metabolic acidosis.
13. • The decreased pH and decreased
HCO3 stimulate renal tubular reabsorption
and generation of HCO3 (secretion of H+).
• You only end up with a metabolic acidosis
if the addition of acid overrides the ability
of the renal tubules to secrete H+ and
generate NH3
+ for excretion in the urine,
usually a short-lived process.
14. Metabolic acidosis
High Anion-Gap:
• Acids associated with an
unmeasured anion are
produced or exogenously
gained
• Treatment:
– Correct underlying cause
– (Bicarbonate: severe
acidemia)
Non-anion gap:
• Bicarbonate, chloride
• “Hyperchloremic” acidosis
• Renal vs. GI loss of
HCO3-
• Treatment:
– Bicarbonate therapy
15. URINARY ANION GAP (UAG)
– Acc to Principle of electro-neutrality:
• Sum of urinary cations = Sum of urinary anions
• Na+ + K+ + Ca2+ + Mg2+ + NH4
+ = Cl-+SO4
2-+PO4
3- etc.
• On usual diets, excretion of Ca2+, Mg2+, SO4
2-, PO4
3- and
other organic ions is fairly constant. Also, urinary Na+,
K+, Cl- can be easily measured but NH4
+ and other ions
are usually unmeasured and since the contribution of
HCO3
- to urinary anion is negligible unless the urine is
alkaline, therefore,
• Urinary Na+ + K+ + NH4
+ = Cl- + other anions
• Urinary Na+ + K+ - Cl- = -NH4
+ + other anions
• from a practical point of view: urinary anion gap i.e.
( Na+ + K+ - Cl- = -NH4
+ ) and this gives us a fair
estimation of NH4
+ ion excretion.
Normal value of urinary anion gap is 30-35 meq/L.
16. Urine anion gap (UAG)
Urine anion gap = [Na+] + [K+] – [Cl-]
• Normal: zero or positive
• GI causes: “neGUTive” UAG
• Impaired renal acid excretion (RTA): positive
or zero
• Often not necessary b/c clinically obvious
(diarrhoea)
17. • Positive UAG
– RTA (because of decreased NH4
+ production
but greater excretion of sodium salts of
acids)
– DKA
– toluene poisoning,
– alcoholic ketoacidosis.
• Negative UAG
– Diarrhoea
20. Physiology of Nephron:
Reabsorbs: 65%
of filtered Na+, Cl-
, HCO3
- & K+ and
100% Glucose
and amino acids.
Secretes:Organic
acids, Bases, and
H+ ions.
Proximal
Tubule
Early DCT
Thin LOH
Highly permeable to
water & moderately
permeable to most
solutes, have few
mitochondria so little
active transport
Thick Ac LOH
Reabsorbs
: 25% of
filtered
Na, Cl, Mg
Secretes:
H+
Reabsorbs
Na, Cl, Mg
Impermeab
le to water
& Urea
Late DCT
& CTs
Principal
Cells:
Reabsorbs
Na and
secretes K.
Intercalated
Cells
reabsorbs K+
& HCO3
- and
Secretes H+.
Water
absorption is
controlled by
ADH
22. Distal Convoluted Tubule
& Collecting Ductules
One HCO3- ion is absorbed for each
Hydrogen ion secreted & a Cl- ion is
passively diffused (secreted) with
Hydrogen ion.
kAE1
27. Approach towards Diagnosis
of RTA
• PLASMA ANION GAP
– Since all types of RTA are associated with a normal
plasma anion gap, it is the initial step in evaluation
of metabolic acidosis
• URINARY ANION GAP (UAG)
– The next step is to distinguish RTA from extra renal
causes. Urinary anion gap (net charge) provides an
estimate of urinary NH4
+ ion excretion.
– RTA=Positive UAG
28. • URINE pH
– assesses overall integrity of distal urinary
acidification and provides an estimate of the
number of free H+ ions in the urine secreted in
response.
– In the presence of systemic acidosis present
spontaneously or induced by ammonium chloride
(NH4Cl) loading, the urinary pH is <5.5 normally.
– If the pH >5.5 (during metabolic acidosis) it
suggests defective distal secretion of H+
– Acidic Urine
• Proximal RTA
– Alkaline Urine
• Distal RTA
• Acute/Chronic Diarrhea
• UTI (with urea splitting organisms).
29. • AMMONIUM CHLORIDE (NH4Cl) LOADING TEST
– Administration of oral NH4Cl (0.1mg/kg) challenge
might be given followed by measurement of urine
pH every hour for the next 8 hours to look for
kidney's response to the induced metabolic acidosis.
Normally, a fall in plasma total HCO3
- levels by 3-
5meq/L induces urinary pH to be <5.5
– If in the presence of metabolic acidosis:
•Urinary pH <5.5
–Normal response (rules out Distal RTA )
•Urinary pH >5.5
–Distal RTA – likely
30. • BICARBONATE LOADING TEST:
– Sodium bicarbonate is administered as half strength
intravenous infusion at 3 ml/min, while measuring urine pH
in timed samples every 30-60 minutes apart. A steady state
is achieved after 3 to 4 hours of start of infusion, and the
test terminated when three urinary samples with pH > 7.5
are collected.
• Interpretation of this test allows characterization of
type of RTA :
– Urine To Blood CO2 Gradient
• In alkaline urine (i.e after a NaHCO3 loading) urine pCO2
increases due to distal H+ secretion and is considered a
sensitive indicator of distal acidification. After achieving a urine
pH >7.5 and plasma HCO3
- levels > 23-25 meq/L, difference
between the urine and blood pCO2 (i.e. U-B pCO2) is measured
as:-
– U-B PCO2 >20mmHg - Normal / Proximal RTA
– U-B PCO2 <10mmHg - Distal RTA
Cont……
31. – Fractional Excretion of Bicarbonate (FeHCO3%):
• is an important marker of proximal tubular
handling of bicarbonate. Normally, proximal
tubules reabsorb most of the filtered bicarbonate
(i.e. Fractional excretion is < 5%). The fractional
excretion of bicarbonate is calculated following
adequate alkalinization as shown:-
• FeHCO3% =Urine HCO3
- x Plasma creatinine x100
Plasma HCO3
- x Urine creatinine
– FeHCO3 < 5% - Normal / Distal RTA
– FeHCO3 > 5% - Proximal RTA
– In hyperchloremic distal RTA - FeHCO3 varies from 5-
10%.
32. • NEWER INVESTIGATIONS:
– Tests for Phosphate Handling:
• Fractional excretion of PO4 (FePO4 %)
• Bijovet Index (TmPO4/GFR)
• Trans tubular potassium gradient (TTKG)
– Frusemide Test:
• Response to frusemide helps determine the
possible site and mechanism of defect in type 1
RTA.
33. • FePO4 = Urine PO4 * Serum creatinine
*100/ serum PO4 * urine creatinine
• Bijovet Index =TmPO4/GFR (Tubular
maximum)
• This index represents the blood
concentration above which most
phosphate is excreted & below which
most is reabsorbed.
• Normal value is 2.8 – 4.2
34. Response on Urine pH and K+ ion excretion following
Frusemide administration in normal subjects and patients
with dRTA
Defect Site of
Defect
Urine pH
during
acidosis
Urine pH
after
Frusemide
K+ Excre.
baseline
K+ Excre.
Frusemide
Normal None <5.5 Further
Decline
Normal Increased
H+ ATPase
defect
Diffuse,
cortical CT
>5.5 >5.5 Normal Increased
H+ ATPase
defect
Medullary
CT alone
>5.5 <5.5 Normal Increased
Voltage
defect
Cortical CT >5.5 >5.5 Decreased Unchanged
35. • Renal tubular acidosis (RTA) is a disease
state characterized by a normal anion gap
(hyperchloremic) metabolic acidosis in the
setting of normal or near-normal
glomerular filtration rate with defects in
tubular H secretion & urinary acidification.
Definition
36. Type 1 RTA
• First described, classical form
• The problem is inability to maximally
acidify urine
• Distal defect decreased H+ secretion
• H+ builds up in blood (acidotic)
• K+ secreted instead of H+ (hypokalemia)
• Urine pH > 5.5
• Hypercalciuria
• Renal stones
37. Pathophysiology:
• Metabolic acidosis secondary to decreased
secretion of H+ ions in the absence of a
marked decrease in the glomerular filtration
rate (GFR) is characteristic of distal RTA.
• Patients with distal RTA have
inappropriately low H+ ion excretion when
compared with the normal rate of acid
production.
• The deficiency here is secondary to either a
– secretory (rate) defect or a gradient
(permeability) defect.
38. • secretory defect:- the rate of secretion of H+ ions
is low for the degree of acidosis. It is due to
defective function of
– H+ ATPase,
– H+/K+ ATPase or
– Cl-/HCO3
- exchanger
– (“weak pump”).
• Gradient (permeability) defect:- there is normal
secretion of H+ ions but an increased back leak
resulting in dissipation of the pH gradient
• (“leaky-membrane”)
• as seen in RTA due to amphotericin B.
• The low titrable acidity and NH4
+ secretion in distal
RTA leads to systemic acidosis.
39. • Hypokalemia:
– Increased potassium losses in the tubular lumen
– Urinary Na+ losses and volume contraction aldosterone
production increased tubular K+ secretion and decreased
proximal K+ reabsorption.
• Nephrocalcinosis:
– Chronic acidosis decreased tubular reabsorption of Ca2+
renal hypercalciuria and hyperparathyroidism.
– Acidosis and hypokalemia stimulate the proximal tubular
reabsorption of citrate and decrease its urinary excretion.
– This hypercalciuria, hypocitraturia and alkaline urine leads to
calcium phosphate stone formation in the kidneys
(nephrocalcinosis and nephrolithiasis).
41. Clinical Profile:-
• Failure to thrive, Growth retardation (MC).
• Polyuria, Polydipsia
• Nephrocalcinosis, Nephrolithiasis
• Rachitic manifestations (later in childhood)
• Weakness, Transient paralysis (due to
Hypokalemia)
• Sporadic or autosomal recessive cases
may have associated SNHL that may
present at birth or later
45. Type 1 RTA Treatment
• Electrolyte abnormalities should always be
corrected before treating acidosis. Acidosis
is corrected by administration of alkali
solutions. Initial dose is 2-3meq/kg/day
and can be increased until the blood
bicarbonate levels become normal.
• The amount of bicarbonate required to
maintain acid base status may be as high
as 5-10meq/kg/day and the duration of
therapy is usually lifelong.
46. Various alkali solutions used are:
– Sodium bicarbonate solution (7.5%)
– Citrate solutions:
– Polycitra solution (2 meq/ml)
• 110 gm Potassium Citrate, 66.8 gm Citric acid, 100
gm Sodium Citrate, 1 L water
• 1 ml=2 meq base
– Shohl solution (1 meq/ml)
• 140 gm Citric acid, 90 gm Sodium Chloride 1 L
water
1 ml = 1 meq base.
– Potassium alkali salts should be used if hypokalemia is a
persistent problem. In case of associated rickets/osteopenia,
VitaminD supplementation may be given.
The relatives of patients with idiopathic type1 / RTA should be
screened for this disorder as timely intervention can prevent
growth retardation in children.
47. Type 2 RTA (Proximal RTA)
• Proximal defect
• Decreased reabsorption of HCO3-
• HCO3
- wasting, net H+ excess
• Urine pH < 5.5, although high initially
• K+: low to normal
48. Pathophysiology:
• Primary defect:
– reduced renal threshold for HCO3
-
bicarbonaturia.
• Proposed mechanisms
– defective pump secretion or function of the
H+/ATPase, Na+/H+ antiporter, Na+/K+
ATPase or the deficiency of carbonic
anhydrase in the brush border membrane
increased urinary loss of HCO3
-systemic
acidosis.
49. • Type 2 RTA, also called proximal, is caused by
failure of bicarbonate reabsorption in the
proximal tubule resulting in HCO3 loss in the
urine systemic acidosis
• The mechanisms of H+ secretion in the distal
tubule is intact so urine pH is <5.5 even though
the HCO3 is lost in urine.
• The bicarbonate is replaced in the circulation by
Cl-, resulting in hyperchloremia.
• Increased sodium delivery to the distal tubule
increases aldosterone secretion, resulting in
hypokalemia.
• Ultimately, a new steady state is reached in
which serum HCO3
- is decreased, and, hence, the
filtered load, distal delivery, and urinary excretion
of HCO3
- are all reduced.
50. • The acidosis is self-limited because acid
production and excretion are equivalent
at this reduced pH; the plasma HCO3
-
remains at 15 to 20 mEq/L.
• Because urinary citrate levels are not
reduced, stone formation does not
occur despite increased urinary
calcium.
• This condition is more common in
children, and it can lead to growth
retardation and metabolic bone disease
53. Clinical Profile:
• Failure to thrive, growth retardation (mc).
• Polyuria, Polydipsia
• Dehydration (due to sodium, H2O Losses)
• Rachitic Manifestations.
• (Common in fanconi syndrome because
of Hypophosphatemia)
• Irritability, listlessness, anorexia or
preference for savory foods.
54. Type 2 RTA (Treatment)
• Alkali supplementation(NaHCO3) remains the
treatment of choice. Children with proximal RTA
require large amounts of alkali per day
(approximately 5-20 meq/kg/day).
• Thiazide diuretic can be used in conjunction with
low salt diet to reduce the amount of bicarbonate
required.
• Thiazides act by causing extracellular fluid
contraction and increasing proximal bicarbonate
reabsorption.
• Potassium supplementation is done to compensate
for the increased potassium excretion caused by
thiazides.
55. • Phosphate supplements and moderate doses of Vitamin D
may be required.
Phosphate supplements Strength:
(a) Joulie solution 1ml= 30mg
(b) Neutral phosphate solution 1ml=20mg
• Specific therapy for an underlying disorder (cysteamine for
cystinosis, D-penicillamine for Wilson disease and lactose free
diet in galactosemia) is indicated in few patients.
56. RICKETS ASSOCIATED WITH
RTA
• Rickets may be present in RTA ,
particularly type 2 proximal RTA.
• Hypophosphatemia and phosphaturia is
common in that, causing rickets.
• Bone demineralization without overt
rickets is usually detected in type 1 distal
RTA.
57. • This metabolic bone disease may be
characterized by bone pain, growth
retardation,osteopenia and occasionally
pathologic fractures.
• Bone demineralization in distal RTA
probably relates to dissolution of bone
because the calcium carbonate in bone
serves as a buffer against the metabolic
acidosis due to the hydrogen ions retained
by patients
58. Treatment
• DISTAL RTA: administration of sufficient
bicarbonate to reverse acidosis reverses bone
dissolution and the hypercalciuria.
• PROXIMAL RTA: treatment with both
bicarbonate and oral phosphate supplements
heal rickets.
• In RTA,vitamin D levels are reduced in relation
to the degree of renal impairment.Vitamin D is
required to offset the secondary
hyperparathyroidism that complicates oral
phosphate therapy.
59. Type 4 RTA:
The underlying defect here
is the impaired cation
exchange in the distal
tubules with reduced
secretion of H+ and K+
(hyperkalaemic acidosis).
60. Type 4 RTA
• Impaired Aldosterone secretion or distal tubule
resistance to Aldosterone
• Impaired function of Na+/K+-H+ (cation)
exchange mechanism
• Decreased H+ and K+ secretion plasma
buildup of H+ and K+ (hyperkalemia)
• Urine pH < 5.5 (because the distal tubule H+
pump functions normally )
• Aldosterone increases Na+ reabsorption
(pseudohypoaldosteronism) and results in a
negative intratubular potential.
• Other factor that causes a decreased H+
excretion in type 4 RTA is the inhibition of
ammoniagenesis due to hyperkalemia
62. Type IV RTA
ACUTE CHRONIC
OBSTRUTIVE
UROPATHY
•ACUTE
PYELONEPHRITIS
•ACUTE URINARY
OBSTRUCTION
ALDOSTERONE
UNRESPONSIVENESS
ACIDOSIS
HYPERKALEMIA
63. Clinical Profile:
• Growth retardation (MC)
• Polyuria, polydipsia, dehydration.
• Signs and symptoms of obstructive
uropathy and features of
pyelonephritis.
• Bone diseases are generally absent.
64. Type 4 RTA (Treatment)
• The main goal of therapy here is to reduce serum
potassium levels (as acidosis improves once the
hyperkalemic block of ammonium production is
removed).
• Children are put on a low potassium diet and any drug
suppressing aldosterone production is discontinued.
• Mineralocorticoid supplementation with fludrocortisone
will improve hyperkalemia and acidosis.
• In children with hypertension or heart failure
mineralocorticoids are contraindicated, potassium
exchange resins (e.g Kayexelate), however, may be
required.
65. What happened to Type 3 RTA?
• Very rare
• Used to designate mixed dRTA and pRTA
of uncertain etiology
• Now describes genetic defect in Type 2
carbonic anhydrase (CA2), found in both
proximal, distal tubular cells and bone
• This terminology is no longer used.
66. VARIOUS TYPES OF RTA
Proximal RTA
(Type 2)
Distal RTA (type 1) Type 4 RTA
Plasma K+ Normal/Low Normal/low High
Urine pH <5.5 >5.5 <5.5
UAG Positive positive Positive
Urine NH4
+ Low low Low
Fractional HCO3
-
excretion
>10-15% <5% 5-10%
U-B pCO2 mmHg >20 <20 >20
Urine Ca2+ Normal High Norma/ low
Other tubular
defects
Often Present Absent Absent
Nephrocalcinosis Absent Present Absent
Bone disease common Often present Absent
67. FOLLOW UP:
A regular follow up must be done for:
• - Assessment of growth
• - Blood levels of electrolytes, pH and
bicarbonate levels
• - Ultrasound screening for
nephrocalcinosis in subjects with distal
RTA.
68. Prognosis:
• Usually depends on the nature of underlying
disease. Subjects with RTA usually demonstrate
a dramatic improvement in growth provided
serum bicarbonate levels are maintained within
the normal range.
• Patients of fanconi syndrome and systemic
illnesses may have difficulties with growth
failure, rickets and various signs and symptoms
pertaining to their disease.
70. Take Home Points
• Review causes of Non-anion gap Metabolic
Acidosis
– Renal vs. GI losses
– “USED CAR”
• Distinguish RTA Types 1, 2 and 4
– See Table + Some clues:
– Type 1: renal stones, hypercalciuria, high urine pH
despite metabolic acidosis
– Type 2: think acetazolamide and bicarbonate wasting;
Fanconi syndrome
– Type 4: aldosterone deficiency and hyperkalemia
• Mainstay of treatment of RTA
– Bicarbonate therapy
