1. Electrolytes and pH disturbances : clinical signs to make a correct diagnosis and an early treatment G.S. Reusz First Department of Pediatrics Semmelweis University Budapest

2. Case 1 Six weeks old boy, Six weeks old boy, Uncontrolled gestation. Delivery at home. Uncontrolled gestation. Delivery at home. No postnatal screening No postnatal screening BW: 2200g actually: 1920g BW: 2200g actually: 1920g Admitted beause of failure to thrive, vomiting Admitted beause of failure to thrive, vomiting

3. Case 1 First inspection + laboratory fidings Physical aspect Physical aspect –Signs of deydration (fontanelles, dry tongue, decreased turgor) Blood gases Blood gases pH:7.18; pCO2:26 mmHg; aHCO3: 9.7 mmol/l; BE-17.5 mmol/l Electrolytes Electrolytes Na:149 K:6,3 Cl:109 mmol/l Differential diagnosis? Differential diagnosis? Pylorus stenosis? Pylorus stenosis? –Alkalosis, hypokalemia congenital adrenal hyperplasia (CAH) = pseudo-pylorus stenosis congenital adrenal hyperplasia (CAH) = pseudo-pylorus stenosis –Functional mineralocorticoid deficiency causes hyperkalemia Diabetes insipidus? Diabetes insipidus? –Thirsty, polyuria, despite of dehydration, high Na, normal pH normal K, RTA RTA –low K (could be – type IV?) ARF-CRF ARF-CRF

4. Laboratory data 2 RR: 126/70 RR: 126/70 Htk: 25% Htk: 25% Ca:1.72 P:2.6 mmol/l Ca:1.72 P:2.6 mmol/l Crea: 256 micromol/l Crea: 256 micromol/l Differential diagnosis? Differential diagnosis? ARF? ARF? CRF? CRF?

5. Physical exam. + US Physical examination Physical examination –Signs of deydration (fontanelles, dry tongue, decreased turgor) –Bilateral abdominal masses US US –Enlarged hyperechogenic kidneys –No sign of obstruction Dg: Dg: –ARPKD –CRF –Dehydration Differential diagnosis Differential diagnosis –Obstructive uropathy ? –ARPKD? –Other (Wilms tu, neuroblastoma) –Question of dehydration Acute worsening of underlying CRF Elevated creatnine Elevated creatnine –Prerenal component of azotemia –Decreased GFR AND dehydration

6. Treatment Directions of treatment Directions of treatment –Increase fluid intake –Treat Acidosis Acidosis Hypernatremia Hypernatremia Anemia Anemia Ca-P metabolism Ca-P metabolism Blood pressure Blood pressure Problems: Problems: NaHCO3 NaHCO3 –Sodium load –CNS? Hypernatremia Hypernatremia

7. Long term treatment NaHCO3: 8 mmol/day NaHCO3: 8 mmol/day NaCl: 31.5 mmol/day NaCl: 31.5 mmol/day Na total: 38.5 mmol=8.9 mmol/kg/day Na total: 38.5 mmol=8.9 mmol/kg/day calcitriol, calcium-carbonate calcitriol, calcium-carbonate Treatment if BP: amlodipine Treatment if BP: amlodipine Erythropoetin Erythropoetin

8. Last control: Blood gases Blood gases pH:7.35; pCO2 mmHg: 42; aHCO3: 24 mmol/l; BE:-1.5 electrolytes electrolytes Na:135 K:3.8 mmol/l Htk: 34% Htk: 34% Ca:2.2 P:1.5 mmol/l Ca:2.2 P:1.5 mmol/l Crea: 130 micromol/l Crea: 130 micromol/l RR: 105/66 mmHg RR: 105/66 mmHg

9. Comments

10. Case 2 One month old boy admitted because of failure to thrive, vomiting, weight loss in the last 2 weeks. One month old boy admitted because of failure to thrive, vomiting, weight loss in the last 2 weeks. Uncomplicated gestation BW: 3300 g Uncomplicated gestation BW: 3300 g Family history: his brother died 3 years ago at the age of 6 month. He suffered from postnatal hypoxia, followed by salt loosing kidney and electrolyte inbalance Family history: his brother died 3 years ago at the age of 6 month. He suffered from postnatal hypoxia, followed by salt loosing kidney and electrolyte inbalance Physical exam: severly dehidrated Physical exam: severly dehidrated –Fontanelle, tongue, turgor –Alert, reacts to painful stimuly

11. Laboratory data pH: 7.59, pCO2: 34 NaHCO3: 36.7 mmol/l BE: +12.9 mmol/l pH: 7.59, pCO2: 34 NaHCO3: 36.7 mmol/l BE: +12.9 mmol/l Na: 102, K: 2.1, Cl: 74 mmol/l, Na: 102, K: 2.1, Cl: 74 mmol/l, Ca: 2.67, P: 1.2 mmol/l osmolarity:243 mosmol/l Ca: 2.67, P: 1.2 mmol/l osmolarity:243 mosmol/l Crea:48 micromol/l TP:55 alb:38g/l Crea:48 micromol/l TP:55 alb:38g/l The dehydrated child has metabolic alkalosis with The dehydrated child has metabolic alkalosis with –hyponatraemia, –Hypochloraemia –hypokalaemia

12. Differential diagnsis 1. Pylorus stenosis 1. Pylorus stenosis –Usually less severe; physical and US examination 2. Salt loosing kidney (ex: tubular dysfunction due to hydronephrosis, ATN, metabolic disease). 2. Salt loosing kidney (ex: tubular dysfunction due to hydronephrosis, ATN, metabolic disease). –Alkalosis? 3. Salt loosing form of adrenogenital syndrome 3. Salt loosing form of adrenogenital syndrome –But: Functional mineralocorticoid deficiency causes hyperkalemia 4. Hyponatremic, hypokalemic, hypochloremic alkalosis: 4. Hyponatremic, hypokalemic, hypochloremic alkalosis: –Bartter syndromes

13. Ion transport at the loop of Henle

14. Pathophysiology of Bartter syndrome

15. Treatment NaCl (10-15 mmol/kg/day) NaCl (10-15 mmol/kg/day) KCl (10mmol/kg/day) KCl (10mmol/kg/day) Indomethacin (2 mg/kg/day) Indomethacin (2 mg/kg/day) Spironolacton (5 mg/kg/day) Spironolacton (5 mg/kg/day) His somatic and mental development is normal His somatic and mental development is normal Repeated need of hospitalization due to acute metabolic derailements following gastrointestinal and respiratory tract infections. Transient need of parenteral supplementation Repeated need of hospitalization due to acute metabolic derailements following gastrointestinal and respiratory tract infections. Transient need of parenteral supplementation

16. Comments

17. Case 3 8 month old boy 8 month old boy Admitted because vomiting, muscle weakness, lethargy Admitted because vomiting, muscle weakness, lethargy History of failure to thrive History of failure to thrive

18. Pysical aspect + lab Lethargic, severely dehidrated, Kussmaul- type breathing Lethargic, severely dehidrated, Kussmaul- type breathing pH: 7.19, pCO2: 22 mmHg, pH: 7.19, pCO2: 22 mmHg, NaHCO3: 10 mmol/l; BE: -19 mmol/l Na: 136, K: 3.1 mmol/l Na: 136, K: 3.1 mmol/l Ca: 1.9, P: 0.7 mmol/l Ca: 1.9, P: 0.7 mmol/l ALP: 1359 U/l, ALP: 1359 U/l, Crea: 46 micromol/l Crea: 46 micromol/l

19. First conclusions Acidosis Acidosis Electrolyte imbalance Electrolyte imbalance –K, Ca, P Normal creatinine Normal creatinine Elevated ALP Elevated ALP Next diagnostic steps? Next diagnostic steps?

20. Urine Urine: pH: 7.9 Protein:+, glucose:++ Urine: pH: 7.9 Protein:+, glucose:++ Collected urine: FeNa: 3% TPR: 67% Collected urine: FeNa: 3% TPR: 67% Acidosis, glycosuria, phosphate loss, aminoaciduria, proteinuria, hypercalciuria Acidosis, glycosuria, phosphate loss, aminoaciduria, proteinuria, hypercalciuria Dg: Fanconi syndrome Dg: Fanconi syndrome

21. 1930-ies: de Toni, Debré and Faconi renal rickets+glycosuria+hypophosphataemia =proximal tubular defect= aminoaciduria glycosuria hyperphosphaturia-hypophosphataemia bicarbonate wasting hypokalaemia proteinuria Clinical signs: polyuria, dehydration+disease-specific signs growth retardation, rickets, growth retardation, rickets, Fanconi syndrome

22. Fanconi syndrome. Aetiology: Inherited Inherited cystinosis cystinosis galactosaemia galactosaemia fructose intolerance fructose intolerance tyrosinaemia tyrosinaemia Wilsons disease Wilsons disease Lowe sy Lowe sy glycogenosis glycogenosis cytochrome-c oxidase def. cytochrome-c oxidase def. idiopathiic idiopathiic Acquired Acquired Lead poisoning Lead poisoning Solvent inhalation Solvent inhalation Azathioprine Azathioprine Gentamycine Gentamycine Streptozocine Streptozocine myeloma multiplex myeloma multiplex Sjögren sy Sjögren sy amyloidosis amyloidosis cysplatine cysplatine iphosphamide iphosphamide transplantation transplantation

23. Molecular mechanism of cystinosis Depletion of cystin by cysteamine a b c A: healthy lysosome B: cystinotic lysosome C: treatment by cysteamine

24. Clinical picture: Usually blond children, with white skin. Latency of several month, then: Usually blond children, with white skin. Latency of several month, then: polyuria, polydipsia, dehydration, acidosis, no weight gain polyuria, polydipsia, dehydration, acidosis, no weight gain 1-5g glycosuria, phosphate diabetes, gen. aminoaciduria, tubular proteinuria, acidosis seHCO3 12-15 mmol/l 1-5g glycosuria, phosphate diabetes, gen. aminoaciduria, tubular proteinuria, acidosis seHCO3 12-15 mmol/l Rickets Rickets leucocyte-cystine measurement leucocyte-cystine measurement

25. Clinical picture (cont) 3-6 y: photophoby (cornea-cristals+retina, blindness) 3-6 y: photophoby (cornea-cristals+retina, blindness) 7-8 y: ESRD 7-8 y: ESRD 5-10 y hypothyreosis 5-10 y hypothyreosis 12-40 y myopathy, swallowing difficulties 12-40 y myopathy, swallowing difficulties 13-40 y retina degeneration, blindness 13-40 y retina degeneration, blindness 18-40 y diabetes mellitus 18-40 y diabetes mellitus 18-40 y male hypogonadism 18-40 y male hypogonadism 21-40 y lung dysfunction 21-40 y lung dysfunction 21-40 y CNS calcification 21-40 y CNS calcification 21-40 y deterioration of CNS function 21-40 y deterioration of CNS function

26. 2 y

27. Cornea cristals

28. Rickets

29. Treatment Fluid: 3-3.5 l = cca. 250 ml/kg Fluid: 3-3.5 l = cca. 250 ml/kg K 350 mmol/day = 25 mmol/kg K 350 mmol/day = 25 mmol/kg HCO3300 mmol/day = 21.5 mmol/kg HCO3300 mmol/day = 21.5 mmol/kg Ca 2x250 mg Ca 2x250 mg P Sandoz4x500 mg P Sandoz4x500 mg Alpha-D350 microg/day Alpha-D350 microg/day Amilorid 1.25 mg Amilorid 1.25 mg HCTZ12.5 mg HCTZ12.5 mg L-Thyroxin25 microg L-Thyroxin25 microg Folic acid/iron supplementation Folic acid/iron supplementation Cystagone 5x250 mg Cystagone 5x250 mg Cysteamin eye drops 5x /day Cysteamin eye drops 5x /day

30. Effectivenes off treatment Kidney function Kidney function Growth Growth Organ damage Organ damage –eye –thyroidea –Glucose metabolism –gonads –CNS

31. Adequate treatment: n= 17 Partial treatment: n= 32 without therapy: n=67 Markello: N Engl J Med, Volume 328: 1993.1157-1162 Markello: N Engl J Med, Volume 328: 1993.1157-1162 GFR in function of age

32. Gahl: N Engl J Med, Volume 347(2).July 11, 2002.111-121 Cysteamin - Cysteamin + Kidney function and age

33. Prognosis depends on early diagnosis and early treatment Early cysteamin treatment could prevent deterioration of kidney function Early cysteamin treatment could prevent deterioration of kidney function Prevent the development of multiorgan damage Prevent the development of multiorgan damage Prevent complications secondary to Fanconi syndrome Prevent complications secondary to Fanconi syndrome Late introduction of cysteamine treatment can only slow down progression of established renal disease Late introduction of cysteamine treatment can only slow down progression of established renal disease In CRF: supportive treatment and transplantation In CRF: supportive treatment and transplantation

34. Comments