renal tubular acidosis and other causes of normal anion gap metabolic acidosis

By Dr. Jagjit Khosla

RENAL TUBULAR ACIDOSIS

By Jagjit Khosla

Approach to a patient with Normal Anion Gap Metabolic Acidosis


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

-])


TYPES OF METABOLIC ACIDOSIS

Metabolic Acidosis

High Anion Gap Normal Anion Gap


ANION GAP


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


ANION GAPIf an acid is added to blood

Anion H+ Na+ HCO3-+

Na

Cl HCO3 UnHCO3


ANION GAP

Na

Cl UnHCO3

Cl- Other Anion

Normal Anion gap Metabolic Acidosis(Hyperchloremic)

High Anion gap Metabolic Acidosis


NORMAL ANION GAP METABOLIC ACIDOSIS


NORMAL AG METABOLIC ACIDOSIS

Normal Anion Gap Metabolic

Acidosis

(+) Urine Anion Gap (-) Urine Anion Gap


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+


URINE ANION GAP

Negative Positive

Increased renal NH4+ excretion

(Response to acidemia)

Failure of Kidneys to secrete NH4

+


NEGATIVE UAG - CAUSES

GI loss of HCO3IngestionDilutional

Post hypocapnia

1234

Type II RTA5



GI loss of HCO31- Diarrhoea- Intestinal or pancreatic fistula- Ureteral diversion- Villous adenoma



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



Cl-

Urea

Ureter

HCO3-

NH4+

Sigmoid ColonUrea-splitting organisms



GI loss of HCO3Ingestion

12

- Acetazolamide- Sevelamer- Cholestyramine- Toluene




123

- Due to rapid infusion of bicarbonate-free iv fluids




Post hypocapnia

1234

- Rapid correction of respiratory alkalosis by renal wasting of HCO3

- leading to transient acidosis




Post hypocapnia

1234

Type II RTA5


POSITIVE UAG - CAUSES

Type I RTAType IV RTA

12



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)


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


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


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


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



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



80% reabsorbed15% reabsorbed

5% excreted

HCO3

HCO3

HCO3

HCO3

100%



60% reabsorbed15% reabsorbed

25% excreted

HCO3

HCO3

HCO3

HCO3

100%

Decreased Proximal tubule reabsorption Cl-

K+


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


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


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


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


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


DISTAL ACIDIFICATION


Na+

K+

Na+ Channel

K+ Channel

3Na+

2K+

Na+K+ ATPase

Na+

-+K+ H+


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


TYPE I (DISTAL) RTA


Na+

K+

Na+ Channel

K+ Channel

3Na+

2K+

Na+K+ ATPase

Na+

-+K+ H+

4


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


TYPE I (DISTAL) RTAEtiology

Primary Idiopathic, Sporadic

Familial Autosomal dominant or recessive

Secondary Sjogren’s syndromeHypercalciuriaRheumatoid ArthritisHyperglobulinemiaIfosfamideAmphotericin BCirrhosisSLESickle Cell AnemiaObstructive UropathyLithiumRenal transplantation


TYPE IV RTAMechanisms- Reduced Aldosterone production

- Aldosterone resistance


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)


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

renal tubular acidosis and other causes of normal anion gap metabolic acidosis

Health & Medicine