rta 18.05.16

Seminar on

Renal Tubular Acidosis

Seminar on

Renal Tubular

Acidosis

Renal Tubular

Acidosis

Introduction.

Acid-base balance.

Anion gap.

Presented by –

Dr. Shahrina Afroze Tisha.

MD Resident,

Dept. of Pediatric Nephrology,

Bangladesh Institute of Child Health.

Case scenario 1

Abdullah, 1 year 2 months old boy, presented with polyuria, polydipsia and failure to thrive for 3 months. Mother also complaints of persistent vomiting for last 2 months. For these, he was conservatively treated but there was no significant improvement. On examination,the child was irritable, dehydrated. There was poor weight gain(7 kg) and widening of wrists and ankle.

Investigation:Hb- 10.2 gm/dl.Na+- 142.55.K+- 1.53.Cl- 111.46.Anion gap- 13.49.S. Ca+- 6.7 mg/dl.ALP- 197 u/l.PTH- 178.3 pg/ml.S. Creatinine- 0.50 mg/dl.PH- 7.28.HCO3- 10.9.Urinary PH- 6.59.

Case Scenario 2

The child aged 2 years, presented with the complaints of failure to thrive. His birth weight was 2.7 kg. He did well in the first 3 months and then had problems with persistent vomiting. He had poor weight gain as well. He was given conservative management for the next 3-4 months. There was no major improvement seen thereafter also.

EXAMINATION:

weight 6.9 kg, height 73 cm, BP 92/60 mm of hg

The child was unable to walk yet and was irritable all the time. He had poor appetite. There was no hepatospleenomegaly, rash or joint pains.

InvestigationsHemoglobin: 9.2 g/dlTLC: 11000/ULPLC: 1.9 laks/ULNa+: 135 meq/lK+: 2.8 meq/lCL: 116 meq/lAnion gap- 13.8Urea: 12 g/dlCreatinine: 0.7 mg/dlVenous blood gas: PH- 7.2Bicarbonate: 8.2Urine: PH- 6

Discussion

Both cases the investigations clearly showed metabolic acidosis with a normal anion gap associated with hypokalamia and hyperchloremia. These are the classical features of Renal Tubular Acidosis.

Normal Acid base Homeostasis

Acid base homeostasis requires the integration of at least 3 organ systems, including the liver, the lungs and the kidneys.

The liver metabolizes protein that produces H+ ion.

The lungs remove CO2 and thereby H+ reflecting HCO3 ions role as an extracellular buffer.

The kidney generate new HCO3 to replace the HCO3 consumed during the buffering process.

Metabolic Acidosis

Definition:

Loss of Bicarbonate(HCO3) or gain of Hydrogen(H+) is called Metabolic acidosis.

Signs and symptoms:

Symptoms are not specific. Patient may present with nausea, vomiting, abdominal pain, chest pain, palpitations, headache, deep rapid breathing called kussmaulrespirations,

Muscle weakness, bone pain and joint pain. Extreme acidemia may lead to neurological like lethargy, stupor, coma, seizures and cardiac, like arrythmia, hypotension complications.

Compensatory mechanism:

Alveolar hyperventilation to increase pulmonary CO2 excretion and reduced PCO2 level.

Limits of compensation: PCO2= 15.

Types

Anion Gap

Definition:

The anion gap is the difference in the measured cations and the measured anions in serum, plasma or urine. It represents anions other than bicarbonate and chloride required to balance sodium’s positive charge.

Normal Anion gap: 12 ± 2 mEq/l.

• It is calculated by subtracting the serum concentration of chloride and bicarbonate from the concentration of sodium and potassium.

• Anion Gap=Serum (Na++K+) - (Cl- + HCO3).

Anion Gap Increases:

• When the plasma concentration of K+,Ca++,Mg+ is decreased.

• When the concentration of or the charge on plasma is increased.

• When organic anions e.g Lactate or foreign anions e.g ethylene glycol accumulates in the blood.

• Ketoacidosis, Lactic acidosis.

Anion Gap Decreases: When cataions are increased or when plasma albumin decreased.

DD of MA

Loss of bicarbonate MA with normal AG Addition of acids MA with increased AG

GIT loss of bicarbonate Diarrhea, fistula or drainage,

surgery for NEC, ileal loop

conduit, use of anion

exchange resin.

Increased acid production Increased βhydroxybutyric

acid&acetoacetic acid

production,

Starvation or fasting,

Ethanol intoxication.

Renal loss of bicarbonate Renal tubular acidosis Increased lactic acid

production

Tissue hypoxia, muscular

exercise, ethanol ingestion,

systemic disease−leukemia,

diabetes, cirrhosis,

pancreatitis, inborn errors of

metabolism−CHO, urea cycle,

amino acid, organic acid.

Other causes Addition of HCL, NH4Cl,

Arginine, lysine.

Hyper alimentation.

Dilutionalacidisis.

Organic acidosis Methanol, ethylene glycol,

paraldehyde, salicylate,

NSAID,etc. intoxication,

methylmalonicaciduria,

Increased sulphuric acid Methionine administration

Decreased acid excretion AKF

CKD

Urinary Anion Gap

According to Principle of Electronutrility

• Sum of urinary cataions= sum of urinary anions

• Urinary Na+ + K+ + NH4+ =Cl- + HCO3-

• Urinary Anion Gap: (Na+ + K +)-Cl- = -NH4+

• Urinary Anion Gap gives us a fair estimation of NH4+ excretion as NH4 combines with Cl- to form NH4Cl and excreted through urine.

• Normal value of Urinary Anion Gap is 30 to 35 mEq/L.

POSITIVE UAG:

RTA (type i and iv).

Diabetic ketoacidsis.

Normal UAG or low –ve:

Diarrhoea.

RTA (type ii).

Definition.

Classification.

Causes.

Pathophysiology.

Presented by –

Dr. Kanta Halder.

MD Resident,

Dept. of Pediatric Nephrology,

Bangladesh Institute of Child Health.

Renal Tubular Acidosis

Renal tubular acidosis comprises a group of transport defects characterized by inability to acidify urine appropriately resulting in metabolic acidosis.

Classification

Renal tubular acidosis can be classified into 4 types –

1. Type I: Distal RTA (dRTA) or Classic RTA.

2. Type II: Proximal RTA (pRTA).

3. Type IV: Hyperkalemic.

4. Type III: Mixed dRTA & pRTA.

Causes of pRTA (Type II)

Primary

Sporadic.

Inherited.

Fanconi Syndrome.

Cystinosis.

Tyrosinemia.

Galactosemia.

Wilson disease.

Lowe syndrome.

Secondary

Multiple myeloma.

Carbonic anhydraseinhibitor.

Drugs: Aminoglycosides, Valproate.

Heavy metal: Lead, Mercury.

Primary hyperparathyroidism.

Causes of dRTA (Type I)

Primary

Sporadic/ Idiopathic.

Inherited/ Familial.

Autosomal dominant.

Autosomal recessive.

Secondary

Systemic lupus erythematosus.

Sjögren syndrome.

Sickle cell anemia.

Obstructive uropathy.

Reflux nephropathy.

Nephrocalcinosis.

Drugs: Amphotericin B, Lithum.

Causes of Type IV RTA

Aldosteron deficiency without renal disease:

Adrenal TB.

Adrenal necrosis.

Aldosteron deficiency in chronic renal insufficiency:

Obstructive uropathy.

Interstitial nephritis.

Nephrocalcinosis.

Aldosteron resistance:

Post-transplantation.

Amiloride, spironolactrone, ACE inhibitors.

Heparin, NSAIDs, calcineurin inhibitors.

HCO3 reabsorption in Proximal

Renal Tubule

• The Na-K-ATPase located in the basolateralmembrane generates and maintains the lowintracellular sodium concentration.

• Protons are excreted into the tubule lumen bythe sodium-proton exchanger (NHE3) wherethey combine with bicarbonate to formcarbonic acid.

• In the presence of carbonic anhydrase IV(CAIV) the carbonic acid is hydrolyzed to waterand carbon dioxide which enter the cell andrecombine to form carbonic acid by the actionof intracellular carbonic anhydrase II (CAII).

• The carbonic acid ionizes into a proton whichis then excreted into the lumen andbicarbonate which is transported by thesodium-bicarbonate symporter (NBC1) intothe blood stream.

Pathophysiology of pRTA

• Primary defect: Defective reabsorption of HCO3 ⁻, less HCO3 ⁻ reabsorption in PT.

• HCO3 ⁻ binds mainly with Na+ .

• Increase Na+ delivery in DT.

• Aldosterone secretion is stimulated.

• Hypokalaemia & Metabolic acidosis.

Acid sectetion in intercalated cell in

distal nephrons

• Protons are excreted into the tubule lumen by the proton-ATPase and are buffered by ammonia or titratable acid (mostly phosphate).

• Inside the cell, carbonic anhydrase II (CAII)provides the protons and bicarbonatethrough the hydration of carbon dioxide toform carbonic acid.

• Bicarbonate is excreted into the blood stream by action of the chloride bicarbonate exchanger (AE1) on the basolateral membrane.

• Chloride homeostasis is maintained by the potassium-chloride cotransporter (KCC4) and the chloride channel (ClC-Kb).

Pathophysiology of dRTA

Reduced proton secretion in distal tubule:

• “weak pump”inability for H+ pump to achieve a steep H+ ion gradient between tubular cell and lumen resulting decreased secretion of proton.

• “Leaky membrane” causes back diffusion of H+( due to Amphotericin B).

• “Low pump activity” insufficient distal H+

pumping capacity due to tubular damage.

Pathophysiology of Type IV RTA

The underlying defect here is the impaired cation exchange in the distal tubules with reduced secretion of H⁺ and K⁺.

Pathophysiology:

• Aldosteron deficiency/ distal tubular resistance to aldosteron→ impaired Na⁺/K⁺−H⁺ exchange mechanism→ decrease K⁺ & H⁺ secretion→ acidosis& hyperkalemia.

RTA Video.

Clinical features.

Presented by –

Dr. Sabrina Akter.

MD Resident,

Dept. of Pediatric Nephrology,

Bangladesh Institute of Child Health.

Clinical manifestation

Type 1 (DISTAL) RTA:

Failure to thrive.

Polyuria & polydipsia.

Rachitic manifestation.

Osteomalasia.

Muscle weakness.

Nausia, vomiting.

Nephrolithiasis.

Nephrocalcinosis.

Sensorineural deafness(AR dRTA).

Rachitic manifestation

Head:

Box like square head.

Craniotabs.

Chest:

Pigeon chest deformity.

Rachitic rosary( at costochondral junction).

Harrison sulcus.

Extrimity:

Widening of wrist and ankle.

Anterior bowing of leg.

Limb deformities:

coxa vara.

genu valgum.

genu varum.

Features of Fanconi Syndrome

Diffuse proximal tubular dysfunction leading to excess urinary loss of –

Glucose : glucosuria with normal blood glucose level

Phosphate : hypophosphataemia, rickets,osteomalacia

Amino acid : no obvious clinical consequence

HCO3- : leading to p RTA

K+ : hypokalaemia

• Na+, CL- & water : polyuria & polydipsia

recurrent episodes of

dehydration .

Tubular proteinuria: loss of low molecular weight protein including retinol binding protein.

Clinical features of type-ii RTA

• Global dysfunction of PT→proximalRTA→phosphaturia, glucosuria, aminoaciduria →polyurea, polydipsia.

• Global dysfunction of PT →phosphaturia→rickets& osteomalacia, →FTT & growth retardation→ recurrent dehydration.

• Global dysfunction of PT →hypokalemia→muscleweakness.

Type iii RTA

C/F of both p RTA & dRTA.

Osteopetrosis.

Cerebral calcification.

Mental retardation.

Type iv RTA

Growth retardation.

Polyuria & polydipsia.

S/S of Obstructive uropathy.

Pyelonephritis.

Bone diseases are generally absent.

Nephrocalcinosis

Diagnosis.

Presented by –

Dr. Faria Ahmed Asha.

MD Resident,

Dept. of Pediatric Nephrology,

Bangladesh Institute of Child Health.

Lab diagnosis of RTA

RTA should be suspected when metabolicacidosis is accompanied by hyperchloremiaand a normal plasma anion gap (Na+ - [Cl- +HCO3-] = 8 to 16 mmol/L) in a patientwithout evidence of gastrointestinal HCO3-losses and who is not taking acetazolamideor ingesting exogenous acid.

Urine pHS. K+

NaHCO3 loading

Urine pH <5.5S. K+ low/

NormalU-B CO2

>20mmHgFEHCO3 > 10-

15%

Urine pH >5.5S. K+

low/NormalU-B CO2

<20mmHgFEHCO3 <5%

Urine pH >5.5S. K+

high/NormalU-B CO2

< / >20mmHgFEHCO3 <5%

Urine pH <5.5S. K+

high/NormalU-B CO2

>20mmHgFEHCO3 <5 -10%

Proximal RTA

Classic type 1

RTA

Hyperkalemic type 1

RTA

Type 4 RTA

Functional evaluation of proximal

bicarbonate absorption

Fractional excretion of bicarbonate

• Urine ph monitoring during IVadministration of sodium bicarbonate (3-5ml/kg).

• Levels of bicarbonate & creatinine aremeasured in blood & random urinespecimen.

• FEHCO3 = (urine HCO3 × Plasma creatinine)÷ (plasma HCO3 × urine creatinine) × 100.

Interpretation

Normal ProximalRTA

Distal RTA

Hyperkalemic RTA

FEHCO3 < 5% > 15% < 5% < 5-10%

Functional Evaluation of Distal

Urinary Acidification and

Potassium Secretion

• Urine pH.

• Urine anion gap.

• Urine osmolal gap.

• Urine Pco2.

• TTKG.

• Urinary citrate.

62

Urine pH

• Urine pH is useful for assessing theoverall integrity of distal urinaryacidification.

• In humans, the minimum urine pH that canbe achieved is 4.5 to 5.0.

• Ideally urine ph should be measured in afresh morning urine sample.

• A low urine ph does not ensure normaldistal acidification and vice versa.

63

NH4CL loading test / urinary

acidification test

• Administration of NH4Cl induces a metabolicacidosis to which the kidney responds withmaximum urinary acidification.

• Measure baseline urine pH & acid-base statusin a venous sample.

• Then give NH4Cl 0.1 – 0.15g/kg p/o over 30-45min with fruit juice.

• The pH of each urine specimen is measuredover the next 6 hours.

Interpretation

Proximal RTA

Distal RTA Type IV RTA

Urine pH< 5.5 > 5.5 < 5.5

Urine Anion Gap

• Urine AG = Urine (Na + K - Cl).

• The urine AG has a negative value in most patients with a normal AG metabolic acidosis.

• Patients with renal failure, type 1 (distal) renal tubular acidosis (RTA), or hypoaldosteronism(type 4 RTA) are unable to excrete ammonium normally. As a result, the urine AG will have a positive value.

• There are, however, two settings inwhich the urine AG cannot be used.

• When the patient is volume depletedwith a urine sodium concentrationbelow 25 meq/L.

• When there is increased excretion ofunmeasured anions

Interpretation

Normal Proximal RTA

Distal RTA

Type 4 RTA

UAG 30-35 mEq/l

Normal positive positive

Urine osmolal gap

• When the urine AG is positive and it is unclearwhether increased excretion of unmeasuredanions is responsible, the urine ammoniumconcentration can be estimated fromcalculation of the urine osmolal gap.

• UOG is more useful than the UAG inestimating urinary NH4+ excretion.

• UOG=Uosm - 2 x ([Na + K]) + [urea/6+glucose/18].

• UOG of >100 represents intact NH4 secretion.

Urine PCO2

• Measure of distal acid secretion.

• In pRTA, unabsorbed HCO3 reacts withsecreted H+ ions to form H2CO3 thatdissociate slowly to form CO2 inmedullary CT.

Interpretation

Proximal RTA

Distal RTA Type 4 RTA

U-B PCO2

mmHg> 20 < 20 >20

TTKG ( Transtubular K gradient)

• TTKG is a concentration gradient between thetubular fluid at the end of the cortical collectingtubule and the plasma.

• TTKG = [Urine K ÷ (Urine osmolality / Plasmaosmolality)] ÷ Plasma K.

• Normal value is 8 and above.• Value <7 in a hyperkalemic patient indicates

hypoaldosteronism.• This formula is relatively accurate as long as the

urine osmolality exceeds that of the plasmaurine sodium concentration is above 25 meq/L

Urine citrate

• The proximal tubule reabsorbs most (70-90%)of the filtered citrate.

• Acid-base status plays the most significantrole in citrate excretion.

• Alkalosis enhances citrate excretion, whileacidosis decreases it.

• Citrate excretion is impaired by acidosis,hypokalemia,high–animal protein diet andUTI.

Laboratory findings in different type

of RTA

Parameter Proximal

(type 2 ) RTA

Distal ( type 1

) RTA

Hyperkalemic

( type 4 ) RTA

UAG Negative positive Positive

Urine PH < 5.5 > 5.5 < 5.5

Urine NH4 low Low Low

Urine Ca++ Normal High Normal/ Low

Plasma K+ Low Low High

FEHCO3 > 10% < 5% 5 to 10%

PCO2 mmHg > 20 < 10 >20

Treatment.

Follow up.

Prognosis.

Presented by –

Dr. Jonaki Khatun.

MD Resident,

Dept. of Pediatric Nephrology,

Bangladesh Institute of Child Health.

Treatment of RTA

Type- 1 RTA( Distal)

Correction of acidosis:

• Sodium bicarbonate: 5-10 mEq/kg/day.

• Citrate- sodium/potassium(polycitra).

• Shohl solution(1 mEq/ml).

Correction of hypokalemia:

• Hypokalemia should be treated before correction of acidosis.

Cont…

With adequate correction of acidosis, renal potassium losses are reduced but some patients require prolonged potassium supplements.

Vitamin- D: If there is rickets and osteopenia.

Thiazide diuretics: If hypercalciuria persist after correction of acidosis.

Type- 2 RTA(Proximal)

Correction of acidosis:

• Alkali supplimentation (5- 20 mEq/kg/day).

• Thiazide diuretics with potassium supplimentation: increasing proximal bicarbonate reabsorption.

Cont..

Phosphate supplement: 1-3 gm/kg/day.

• Joule solution

• Neutral phosphate solution

• Vit- D

Treatment of underlying cause.

Type- IV RTA.

Avoidance of potassium containing food, fruits and drugs.

Mineralocorticoid suppliment.

Thiazide diuretics.

Cont..

Loop diuretics: May be used in Aldosteron resistant cases.

Potassium exchange regins (Kayexalate) may be required.

Fanconi syndrome.

Adequate hydration:Patient may need 0.9% saline.

Correction of acidosis.

Suppliments of sodium, potassium, bicarbonate and phosphate.

Administration of moderate doses of Vit- D.

Follow Up

Assesment of growth.

Blood level of:

Electrolytes.

pH.

HCO3.

USG screening for nephrocalcinosis in distal RTA.

Prognosis

o Usually depends on nature of underlying disease.

o Patients with treated isolated proximal or distal RTA generally demonstrate improvement in growth , provided S. HCO3 level maintained in the normal range.

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