1. A child with oedema Constantinos J. Stefanidis “A. Kyriakou” Children's Hospital Athens, Greece

2. What is the diagnosis ? Urine protein 4+ Urine blood 2-3+ Hct 42 % Na 134 mEq/l K 4.2 mEq/l Urea 22 mg/dl Creat. 0.5 mg/dl John B. 4 year old boy with a two day history of puffiness around the eyes. Physical examination BP 105/75mmHg HR 85/min Feet: mild pitting oedema Alb. 2.2 g/L Chol. 270 mg/dl Family doctor diagnosed an “allergic reaction” Abdomen: N Chest: N Genitalia: N

3. Idiopathic nephrotic syndrome (NS) n Oedema n Low plasma albumin <25 g/L n Severe proteinuria >40 mg/m 2 /hr or Pr : Cr >200 mg/mmol (1.8 mg/mg) NS may be accompanied by: haematuria, arterial hypertension and decreased GFR (NS with a nephritic course) John should be admitted at the Hospital ?

4. All children with newly diagnosed NS should be admitted at the Hospital. The goals are: n n Removal of fluid overload. n n Reduction and disappearance of proteinuria. n n Prevention of complications (infection, thrombosis).

5. Why John has oedema ??? n n Removal of fluid overload. n n Reduction and disappearance of proteinuria. n n Prevention of complications (infection, thrombosis). Management

6. IntravascularspaceInterstitialspace Massive protein loss Hypoalbuminaemia Renin-ATII-aldosterone axis and ADH Increased reabsorption of Na and H 2 0 Hypovolaemia Deterioration of oedema “Underfill” theory of oedema formation Hypovolaemia Oedema

7. Donckerwolcke RA et al Kidney Int 1997 Intravasular space in patients with NS n n No evidence of reactive stimulation of vasoactive axis of renin-ATII-aldosterone and/or ADH before the establishment of overt hypoalbuminaemia Schrier RW et al Kidney Int 1998 n n Sodium retention seems to occur in early relapse of the NS

8. IntravascularspaceInterstitialspace “Overfill” theory of oedema formation* Collecting duct of patients with NS are 'resistant' to the action of the atrial natriuretic peptide ??? Primary Na retention * Schrier RW et al Kidney Int 1998 Intravascular volume expansion Oedema Transcapillary movement of fluid

9. In most patients with NS : Hypovolaemia Hypoalbuminaemia Oedema n n In the early stages the 'underfill' mechanism operate. n n In a later period a new steady state will be reached with a normal or expanded blood volume ('overfill’ mechanism). Donckerwolcke RA et al Kidney Int 1997 Intravascular volume expansion Oedema Transcapillary movement of fluid Primary renal Na and H 2 0 retention

10. John should have an albumin infusion??? n n Abdominal pain n n Hypotension n n Oliguria n n Evidence of renal failure No because he has no signs of hypovolemia i.e.: Laboratory findings of hypovolemia : n n High hematocrit n n Low urine Na (1-2 mmol/L) n n UK/UK+Na x 100% < 20% ?

11. Diuretics: In significant oedema and absence of hypovolemia Frusemide and spironolactone 1mg/kg/day. John should have diuretics??? Hypertension Correction of hypervolemia or hypovolemia. Nifedipine 0,5-1 mg/kg/day and /or atenolol 0,5-1 mg/kg/day.

12. n n Removal of fluid overload. n n Reduction and disappearance of proteinuria. n n Prevention of complications (infection, thrombosis). Management For how long John should have prednisolone ?

13. Prednisone (pz): 60 mg/m 2 /day (or 2mg/kg ideal body weight). Not exceeding a total dose of 80mg/day for one month. The 2nd month 40 mg/m 2 of pz in a single dose every 48 hrs. (Total treatment period of 2 months). France: One month course of daily, followed by 2 months of alternate day pz (2mg/kg). Then pz is decreased by 0.5mg/kg every 2 weeks. (Total treatment period of 4-5 months). Germany: 6 weeks course of daily, followed by 6 weeks of alternate day pz. (Total treatment period of 3 months). Initial steroid therapy. The protocol of the International Study of Kidney Diseases in Children From the late 60's until 80's the ISKDC provided a classification of NS

14. Early non-responder: proteinuria does not normalize within 4 weeks of daily pz therapy Relapse: Proteinuria > 40mg/d/m 2 (or Albustix 2+ or >) on three consecutive days. Definitions Frequent relapses: >2 relapses within 6 months of initial response. Steroid dependence: 2 consecutive replapses occuring during pz treatment or within 14 days of its cessation.

15. Prednizone 60 mg/m 2 /24hrs + 40 mg/m 2 /48hrs Brodehl J Clin Nephrol 1991 Initial steroid therapy and frequency of relapses (%)

16. International Study of Kidney Diseases in Children NS with minimal changes (90%) Focal segmental glo- merulosclerosis (8%) Diffuse mesangial proliferative glomeruglomerulo- nephritis (2%) J Pediatr 1981 Steroid sensitivity rather than histology is the major determinant of prognosis. Webb N et al. Am J Kidney Dis 1996

17. Pretreatment indications Age 12 years Nephritic findings (macroscopic hematuria or microscopic and hypertension) Renal failure The frequency of relapses alone is not an indication for biopsy. Webb N et al. Am J Kidney Dis 1996 John has hematuria should he have a renal biopsy ? 23% of children with MCNS and 67 % with FSGS had microscopic hematuria ISKD J Pediatr 1981 Post treatment indication of renal biopsy Steroid resistance Frequent relapses before cyclosporin

18. n n Removal of fluid overload. n n Reduction and disappearance of proteinuria. n n Prevention of complications (infection, thrombosis). Management John should have antibiotics and/or anticoagulation treatment ???

19. Antibiotics In the oedematous child with gross ascites oral penicillin 125-250 mg BID. Diet Salt restriction. Normal protein intake. Calorie control. Activity The child should be mobilized. What about his diet and activity ??? Prevention of thrombosis by correction of hypovolemia.

20. Parents should have a booklet with information about the disease. Children with NS should receive immunization as normal unless they have been taking pz daily for more than one week. Life vaccines can be given only if the child is on a low dose pz. What parents should know about NS ? Parents should know that NS is a chronic disease and they should get prepared for possible relapses. Parents should be informed that chickenpox and measles are major threats and should go to the Hospital if their child is exposed.

21. Ehrich JHH Drukker A Rec Adv Pediatr 1999 Key points for clinical practice Childhood NS is a chronic disease and cannot be left untreated. Steroid-sensitive NS, the most frequently form of childhood NS is a relatively mild form of the disease virtually without long term impairment of glomerular filtration rate. Steroid-sensitive NS tends to relapse. This requires clear therapeutic strategies to try and keep the patients in long lasting remissions and to minimise the adverse effects of long- term corticosteroid therapy. Relapses should be detected at home before the onset of symptomatic NS by daily 'dipstix' for urinary protein.