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By Dr. Jagjit Khosla
RENAL TUBULAR ACIDOSIS
By Jagjit Khosla
Approach to a patient with Normal Anion Gap Metabolic Acidosis
By Dr. Jagjit Khosla
METABOLIC ACIDOSIS
Definition- Blood pH <7.35 (Acidemia) - [HCO3
-]
- [PaCO2] (1.2 mm Hg fall in [PaCO2] for every 1 meq/L reduction in [HCO3
-])
By Dr. Jagjit Khosla
TYPES OF METABOLIC ACIDOSIS
Metabolic Acidosis
High Anion Gap Normal Anion Gap
By Dr. Jagjit Khosla
ANION GAP
By Dr. Jagjit Khosla
ANION GAPNa+ + Unmeasured cations = Cl- + HCO3
- + Unmeasured anionsOr, Unmeasured anions – Unmeasured cations = Na+ - (Cl- + HCO3
-)
Anion Gap = Na+ - (Cl- + HCO3-)
DefinitionAnion gap is Quantity of anions not balanced by cations- usually due to the NEGATIVELY CHARGED PLASMA PROTEINS as the charges of the other unmeasured cations and anions tend to balance out.
Na
Cl HCO3 UnNormal Anion Gap (10 – 12 mM/L)
Note : - Adjust for Hypoalbuminemia
By Dr. Jagjit Khosla
ANION GAPIf an acid is added to blood
Anion H+ Na+ HCO3-+
Na
Cl HCO3 UnHCO3
By Dr. Jagjit Khosla
ANION GAP
Na
Cl UnHCO3
Cl- Other Anion
Normal Anion gap Metabolic Acidosis(Hyperchloremic)
High Anion gap Metabolic Acidosis
By Dr. Jagjit Khosla
NORMAL ANION GAP METABOLIC ACIDOSIS
By Dr. Jagjit Khosla
NORMAL AG METABOLIC ACIDOSIS
Normal Anion Gap Metabolic
Acidosis
(+) Urine Anion Gap (-) Urine Anion Gap
By Dr. Jagjit Khosla
Cl
URINE ANION GAPUNa+ + UK+ + Unmeasured cations = UCl- + Unmeasured anions
Or, Unmeasured anions – Unmeasured cations = (UNa+ + UK+) - UCl-
Urine Anion Gap (UAG) = (UNa+ + UK+) - UCl-
- NH4+ is the primary unmeasured cation which is not balanced by anions.
- UAG as indirect assay for renal NH4+ excretion
Na K NH4+
By Dr. Jagjit Khosla
URINE ANION GAP
Negative Positive
Increased renal NH4+ excretion
(Response to acidemia)
Failure of Kidneys to secrete NH4
+
By Dr. Jagjit Khosla
NEGATIVE UAG - CAUSES
GI loss of HCO3IngestionDilutional
Post hypocapnia
1234
Type II RTA5
By Dr. Jagjit Khosla
NEGATIVE UAG - CAUSES
GI loss of HCO31- Diarrhoea- Intestinal or pancreatic fistula- Ureteral diversion- Villous adenoma
By Dr. Jagjit Khosla
NEGATIVE UAG - CAUSES
GI loss of HCO31Pancreas
Ileum
Colon
Pancreas
Ileum
Colon
HCO3-
HCO3-
Cl-
HCO3-
Cl-
K+ HCO3-
Normal Diarrhea
Cl-
Flooding the colon with HCO3-
instead of Cl- drives K+ secretion
By Dr. Jagjit Khosla
NEGATIVE UAG - CAUSES
Cl-
Urea
Ureter
HCO3-
NH4+
Sigmoid ColonUrea-splitting organisms
By Dr. Jagjit Khosla
NEGATIVE UAG - CAUSES
GI loss of HCO3Ingestion
12
- Acetazolamide- Sevelamer- Cholestyramine- Toluene
By Dr. Jagjit Khosla
NEGATIVE UAG - CAUSES
GI loss of HCO3IngestionDilutional
123
- Due to rapid infusion of bicarbonate-free iv fluids
By Dr. Jagjit Khosla
NEGATIVE UAG - CAUSES
GI loss of HCO3IngestionDilutional
Post hypocapnia
1234
- Rapid correction of respiratory alkalosis by renal wasting of HCO3
- leading to transient acidosis
By Dr. Jagjit Khosla
NEGATIVE UAG - CAUSES
GI loss of HCO3IngestionDilutional
Post hypocapnia
1234
Type II RTA5
By Dr. Jagjit Khosla
POSITIVE UAG - CAUSES
Type I RTAType IV RTA
12
By Dr. Jagjit Khosla
RENAL TUBULAR ACIDOSIS
By Dr. Jagjit Khosla
RENAL TUBULAR ACIDOSIS
DefinitionDisorders affecting the overall ability of the renal tubules either to secrete hydrogen ions or to retain bicarbonate ions
Types- Type I (Distal)- Type II (Proximal)- Type IV (Hypoaldosteronism)
By Dr. Jagjit Khosla
RENAL ACID-BASE HOMEOSTASIS
- Proximal Acidification Reabsorption of HCO3
- in Proximal tubule
- Distal Acidification H+ secretion in Collecting tubule
Type II RTA
Type I & Type IV RTA
By Dr. Jagjit Khosla
PROXIMAL ACIDIFICATIONProximal Tubule Cell Tubular Lumen
Na+
H+
H20 CO2
3HCO3-
Na+
CA II
3Na+
2K+
Na+K+ ATPase
H+ HCO3-+
H2CO3
CO2 H2O+
Carbonic Anhydrase IV
+
H+HCO3- +
H2CO3
Na+H+ Exchanger
Na+ HCO3-
Cotransporter
Na+
Blood
By Dr. Jagjit Khosla
TYPE II (PROXIMAL) RTAProximal Tubule Cell Tubular Lumen
Na+
H+
H20 CO2
3HCO3-
Na+
CA II
3Na+
2K+ H+ HCO3-+
H2CO3
CO2 H2O+
Carbonic Anhydrase IV
+
H+HCO3- +
H2CO3
Na+H+ Exchanger
Na+ HCO3-
Cotransporter
Na+
1
2
5
6
3
4
Na+K+ ATPase
Blood
By Dr. Jagjit Khosla
TYPE II (PROXIMAL) RTA
• Fanconi’s syndrome - Loss of Glucose, Calcium, phosphate, citrate, uric acid, lysozymes, light chain immunoglobins, and amino acids.
• Isolated HCO3 wasting is rarely identified.
Isolated HCO3 wasting
Generalised Proximal tubular
dysfunction
By Dr. Jagjit Khosla
TYPE II (PROXIMAL) RTA
Primary disorders• Idiopathic, sporadic• Familial disorders
– Cystinosis– Tyrosinemia– Hereditary fructose intolerance– Galactosemia– Glycogen storage disease(Type I)– Wilson’s disease– Lowe’s syndrome– Carbonic Anhydrase deficiency
Secondary disorders• Multiple myeloma• Drugs
– Tenofovir– Carbonic anhydrase inhibitors– Ifosfamide
• Amyloidosis• Heavy metals poisoning (Lead,
Cadmium, Hg, Cu)• Vitamin D deficiency• Renal transplantation• Paroxysmal nocturnal
hemoglobinuria
By Dr. Jagjit Khosla
TYPE II (PROXIMAL) RTA
80% reabsorbed15% reabsorbed
5% excreted
HCO3
HCO3
HCO3
HCO3
100%
By Dr. Jagjit Khosla
TYPE II (PROXIMAL) RTA
60% reabsorbed15% reabsorbed
25% excreted
HCO3
HCO3
HCO3
HCO3
100%
Decreased Proximal tubule reabsorption Cl-
K+
By Dr. Jagjit Khosla
TYPE II (PROXIMAL) RTAFeatures• U. HCO3- (FeHCO3 > 15%)• U. pH <5.5, • S. [HCO3
-] 12-20• U. Na+
• U. K+ - HypokalemiaMechanism of enhanced K+ excretion- Increased distal Na+ delivery - Sodium wasting induced secondary hyperaldosteronism
By Dr. Jagjit Khosla
TYPE II (PROXIMAL) RTAEffect on Potassium excretionWithout alkali therapy
Principal Cell LumenBlood
Na+
K+
Na+ Channel
K+ Channel
3Na+
2K+
Na+K+ ATPase
Na+
-+K+
Aldosterone
By Dr. Jagjit Khosla
TYPE II (PROXIMAL) RTAEffect on Potassium excretionWith alkali therapy
Increased S. [HCO3-]
Increased filtered load above proximal reabsorptive capacity
Increased distal sodium and water delivery
Enhanced distal potassium excretion
Note : Alkali therapy in proximal RTA should be accompanied with potassium to prevent hypokalemia
By Dr. Jagjit Khosla
DISTAL ACIDIFICATION
• Collecting tubule (CT) is the major site of H+ secretion
• Made up of : – Cortical Collecting tubule – H+ secretion coupled with Na+
reabsorption– Medullary Collecting tubule – H+ secretion independent of
Na+ reabsorption
• Alpha-intercalated cells are main cells involved in H+ secretion
By Dr. Jagjit Khosla
DISTAL ACIDIFICATIONAlpha Intercalated cell Lumen
K+
H+
H2CO3
H20CO2 +
HCO3-
CA II
Cl-
H+
Blood
3Na+
2K+
Na+K+ ATPase
H+ ATPase
H+ K+ ATPase
H+
HPO42- NH3
H2PO4- NH4
+
Anion Exchanger
By Dr. Jagjit Khosla
DISTAL ACIDIFICATION
Principal Cell LumenBlood
Na+
K+
Na+ Channel
K+ Channel
3Na+
2K+
Na+K+ ATPase
Na+
-+K+ H+
By Dr. Jagjit Khosla
TYPE I (DISTAL) RTAAlpha Intercalated cell Lumen
K+
H+
H2CO3
H20CO2 +
HCO3-
CA II
Cl-
H+
Blood
3Na+
2K+
Na+K+ ATPase
H+ ATPase
H+ K+ ATPase
H+
HPO42- NH3
H2PO4- NH4
+
Anion Exchanger
1
23
By Dr. Jagjit Khosla
TYPE I (DISTAL) RTA
Principal Cell LumenBlood
Na+
K+
Na+ Channel
K+ Channel
3Na+
2K+
Na+K+ ATPase
Na+
-+K+ H+
4
By Dr. Jagjit Khosla
TYPE I (DISTAL) RTAMechanisms- Defective H+-K+ ATPase (Classic Hypokalemic dRTA)
- Defective H+ ATPase (Normokalemic dRTA)
- Gradient defect (Backleak of secreted H+ e.g. Amphotericin B)
- Voltage depended defect (Hyperkalemic dRTA)
- Abnormal Anion Exchange
By Dr. Jagjit Khosla
TYPE I (DISTAL) RTAEtiology
Primary Idiopathic, Sporadic
Familial Autosomal dominant or recessive
Secondary Sjogren’s syndromeHypercalciuriaRheumatoid ArthritisHyperglobulinemiaIfosfamideAmphotericin BCirrhosisSLESickle Cell AnemiaObstructive UropathyLithiumRenal transplantation
By Dr. Jagjit Khosla
TYPE IV RTAMechanisms- Reduced Aldosterone production
- Aldosterone resistance
By Dr. Jagjit Khosla
TYPE IV RTAEtiology
Decreased aldosterone production
Hyporeninemic hypoaldosteronism- Renal disease, most often diabetic nephropathy- Nonsteroidal anti-inflammatory drugs- Calcineurin inhibitors- Volume expansion, as in acute glomerulonephritisMedications - ACE inhibitors, angiotensin II receptor blockers, and direct renin inhibitorsHeparinPrimary adrenal insufficiencySevere illnessInherited disordersCongenital isolated hypoaldosteronismPseudohypoaldosteronism type 2 (Gordon's syndrome)
By Dr. Jagjit Khosla
TYPE IV RTAEtiology
Aldosterone resistance
Inhibition of the epithelial sodium channel- Potassium-sparing diuretics, such as spironolactone, eplerenone, amiloride, and triamterine- Antibiotics, trimethoprim and pentamidinePseudohypoaldosteronism type 1
By Dr. Jagjit Khosla
By Dr. Jagjit Khosla