RENAL TUBULAR ACIDOSIS- RTA types and features

Gives an idea about RTa

1. Dr.Sujatha.M Junior resident Pediatrics AIIMS, Jodhpur MODERATOR : Dr. ALIZA MITTAL RENAL TUBULAR ACIDOSIS

2. Objectives Definition Physiology  pathology and types Etiology Clinical features Differential diagnosis Investigations and approach Management

3. Case vignettes Can Present like any of the above…!!! HIGH INDEX OF SUSPICION IS REQUIRED..!!

4. DEFINITION Group of tubular transport defects with inability to appropriately acidify urine with resultant non – anion gap (hyperchloremic) metabolic acidosis with normal or near normal GFR

5. AR isolated pRTA AR dRTA AD dRTA AR dRTA

6. Proximal tubule AR isolated pRTA

7. Distal tubule AR dRTA AD dRTA AR dRTA

8. Physiology and pathology Impaired bicarbonate reabsorption in PCT Impaired excretion of H+ ions in DCT Combination of both Absence of impairment on GFR

9. Types Type I – Distal RTA Type II – Proximal RTA Type III – Combined (rare – not used now) Type IV – Hyperkalemic Etiology Clinical presentation Management

10. Type I RTA – distal rta etiology – inherited forms Dominant SCL4A1 gene AE 1 protein defective No non-renal malformation Recessive AE 1 – hemolytic anemia H+ - ATPase B1 subunit – early hearing loss A4 subunit – no or delayed hearing loss

11. ACQUIRED

12. Electrolyte abnormalities Hypokalemia Hypercalciuria Hypocitraturia Normal anion gap metabolic acidosis

13. Type II RTA – proximal RTA ETIOLOGY – inherited Dominant Isolated – mutations not known Fanconi syndrome – mutations not known X – linked Dent disease – renal chloride channel defect – CLCN 5 gene

14. Recessive Isolated – band keratopathy, cataract, glaucoma, enamel defects, intellectual impairment, basal ganglia calcification – NBC 1 defect – SLC4A4 mutations Fanconi syndrome : global dysfunction of tubule Cystinosis Tyrosinemia type 1 Fanconi bickel syndrome Wilson disease Galactosemia Hereditary fructose intolerance Lowe syndrome Glycogen storage Disorder type 1 Mitochondrial disorders

15. ACQUIRED

16. Electrolyte abnormalities Hypokalemia Glucosuria Aminoaciduria Phosphaturia Citraturia Tubular proteinuria Hypouricemia Uricosuria Normal anion gap metabolic acidosis

17. Type III RTA or mixed RTA Not used now Carbonic anhydrase II mutations (8q22) Manifests with features of both distal and proximal rta Features – rta , osteopetrosis, cerebral calcifications, mental retardation GUIBAUD VAINSEL SYNDROME

18. Type IV RTA or hyperkalemic RTA Intact ability to lower urine pH with hyperkalemic acidosis Voltage defect – insufficient negative intra-tubular potential at the level of CCD ( hyperkalemic distal RTA) Rate defect – aldosterone deficiency or resistance ( type 4 RTA) Inhibition of ammoniagenesis

19. Physiology and pathology

20. Clinical features Failure to thrive (growth retardation) Irritability, anorexia, weakness Polyuria, polydipsia Salt craving Recurrent episodes of dehydration Rachitic features Muscle weakness, neck flop, transient paralysis Nephrocalcinosis and stones Hearing loss - sensorineural Other associated syndromic features – cystinosis, tyrosinemia, galactosemia, SLE, Sjogren, MSK, etc

21. Look for these also…

22. Differential diagnosis Saline administration

23. Approach to RTA

24. Bicarbonate loading test Oral / iv bicarbonate given and measure urine pH in samples collected under mineral oil Loading till urine pH >7.5 and plasma bicarb > 22 to 24 mEQ /L Fractional excretion of bicarbonate Urine to blood CO2 gradient

25. Calcium – creatinine ratio Hypercalciuria – U. calcium > 4mg/kg/day Urine Ca-Creatinine ratio: 0-6 months < 0.8 6-12 months < 0.6 1-2 years < 0.4 > 2 years < 0.2

26. Tubular maximum of Phosphate FePO 4 2- - 5 to 12 % Tubular reabsorption – 88 to 95 % FePO 4 2- = urine phosphate x plasma creatinine x 100 plasma phosphate x urine creatinine tubular reabsorption = 100 – fractional excretion Tubular maximum for phosphate corrected for GFR ( Bijovet index) = plasma phosphate – urine phosphate x plasma creatinine urine creatinine Normal TmP /GFR = 2.8 – 4.4 mg/dl

27. Bijovet nomogram

28. Induced systemic acidosis Furosemide 1 mg/kg with fludrocortisone 0.025 mg/kg is given early morning Urine pH after 6 hours >5.3 indicates impaired distal acidification Fludrocortisone furosemide test AMMONIUM CHLORIDE TEST – similar test - NOT USED NOW WIDELY

29. Interpretation In cases of distal rta , even on overwhelming the system by administration of fludrocortisone and furosemide, urinary acidification will not be achieved If the urine pH is < 5.3 after FF test, distal rta is ruled out

30. TRANSTUBULAR POTASSIUM GRADIENT IN TYPE 4 RTA Index of K+ gradient in distal tubular lumen and interstitium TTKG = urine potassium x plasma osmolality plasma potassium x urine osmolality Normal – 6 to 12 In presence of hyperkalemia – should rise >10 Low TTKG < 8 suggests hypoaldosteronism or resistance to aldosterone ‘ Fludrocortisone administration  rise in TTKG >7 suggests hypoaldosteronism

31. Management – goals Correction of acidosis Treatment of Rickets Monitor for growth failure Monitor hearing, kidney function Look for associated co-morbidities in the form of syndromes

32. Treatment

33. Take home message RTA – lack of bicarbonate absorption in PCT or lack of H+ secretion in DCT Features – failure to thrive, weakness, polyuria, rickets High index of suspicion needed for diagnosis Urine pH –to be measured by pH meter, no use of dipsticks for the same Urine pH < 5.3 after ff test rules out distal RTA TmP /GFR - essential to label phosphaturia, hypophosphatemia alone doesn’t imply phosphate wasting Screening for underlying cause to be done Treatment – correction of acidosis, rickets, monitor growth

34. References Nelson’s textbook pediatrics – 21 st edition Pediatric nephrology – Arvind bagga – 6 th edition Evaluation of renal tubular acidosis. – NC Indian J Pediatr . 2007 Jul;74(7):679-86. Renal Tubular Acidosis: The Clinical Entity -JUAN RODRI ´GUEZ SORIANO Department of Pediatrics , Hospital de Cruces, Vizcaya, Spain. J Am Soc Nephrol 13: 2160–2170, 2002 Renal Tubular Acidosis - Jonathan Pelletier, MD,* Rasheed Gbadegesin , MD, MBBS,† Betty Staples, MD* *Department of Pediatrics and †Department of Pediatric Nephrology, Duke Children’s Hospital and Health Center , Durham, NC AAP review