H.Jalanko has documented that he has no relevant financial relationships to disclose or conflict of interest to resolve.

Transcription

1 H.Jalanko has documented that he has no relevant financial relationships to disclose or conflict of interest to resolve.

2 Management dilemmas in infants with congenital nephrotic syndrome (CNS) Hannu Jalanko Children s Hospital, University of Helsinki, Finland

3 Congenital nephrotic syndrome (CNS) Nephrotic syndrome manifesting during the first 3 months of age Heterogenous etiology Primary Genetic defects in podocyte genes Secondary Infections: syphilis, toxoplasmosis, HIV hepatitis B, malaria, CMV, rubella Autoimmune: maternal SLE, neutral endopeptidase antibodies, maternal steroid antibodichlorpheniramine treatment

4 Gene defects in CNS Nephrin (NPHS1) Podocin (NPHS2) Phospholipase Ce1 (PLCe1, NPHS3) Wilms tumor factor 1 (WT1) Laminin b2 (LAMB2) Slit diaphragm Unknown %

5 Diagnosis Clinical findings How severe proteinuria? Kidney function? Extrarenal problems? Syndrome? Neurology?? Genetic testing Which gene? What kind of mutations? Kidney biopsy FSGS, DMS, MC, CNF-type? Histology does not tell the etiology or prognosis!

6 Decision of active treatment Life-long therapy: nephrosis-dialysistransplantations May be difficult especially in patients with extrarenal co-morbidity What is best for the child and family? What are the medical and financial resources? Decision by a multidisciplinary team

7 Protein losses U-prot measurement after p-alb increased > g/l Albumin infusions Daily in severe CNS, less often in moderate CNS 20 % albumin up to 3-4 gr/kg/d + Furosemide What is the rigth albumin dose? Normal P-alb values? May lead to very large doses Enhanced losses Clinical findings? Oedema, weight, RR

8 Antiproteinuric therapy Angiotensin II harmful effect on podocyte function ACE-inhibitors and AT-II blockers Captopril 1-5 mg/kg/day; Losartan mg/kg/day Indomethacin 1-5 mg/kg/day combined with an ACE-inhibitor Several case reports on the positive effect in genetic and nongenetic CNS WT1, PLCe1, Podocin, Nephrin No responese in NPHS1 children with trunkating mutations

9 Glucocorticoids Glucocorticoids can stabilize podocyte actin network No CNS patient with a genetic defect has shown response to prednisone A 12 month old boy with PLCe1 mutations responded to prednisone Prednisone can be tried in small nephrotic infant in whom no gene defect has been found A patient waiting for the gene analysis: The change for postiive effect by prednisone is small

10 Cyclosprin A CsA stabilizes podocyte actin network Several reports on positive effect in older children with genetic SRNS, often together with ACEi. No reports on successful use of CsA in patients with genetic CNS (exception: partial response in 1 CNS with NPHS2 mut,) Exposure of CNS children to CsA not recommended

11 Infections Hypogammaglobulinemia Low IgG IgG-substitution probably not helpful Fast urinary loss, expensive Antibiotics Prophylaxis probably not helpful Aggressive treatment when infection suspected Vaccinations One published report on the effect in proteinuric CNS Vaccinations postponed to dialysis stage Infections caused by preventable pathogens are rare

12 Risk for thrombosis Thrombosis Low levels of antithrombotic factors Elevated levels of prothrombotic factors Thrombocytosis, increased aggregation (low PACAP) Prophylaxis Warfarin (INR= 2) ATIII (50 u/kg) in invasive procedures Aspirin if severe thrombocytosis Enoxaparin not helpful because of low AT III Thrombosis detected Heparin or enoxaparin+atiii

13 Endocrine problems Hypothyroidism Low total T3 and T4 due to losses of binding proteins TSH and Free T4 variable in nephrotic children Throxin substitution to CNS children (normalization of TSH) Adrenal insufficincy Case reports Hydrocortison trials in some CNF patients with repeated episodes of fever

14 Anemia Tendency for anemia varies in CNS patients Red blood cell transfusions should be avoided due to possible HLA-immunization EPO is lost into urine No systematic study on the effect of EPO treatment The Finnish experience: EPO not very potent Case report: Patients lose also transferrin and cobalamin into urine, which explains poor response (Toubiana 2009)

15 Options for renal replacement therapy in CNS Early Tx at nephrotic stage Successful in specialized centres Avoidance of dialysis complications May need intra-abdominal engraftment Risk of thrombotic complications Quite rarely used

16 Options for renal replacement therapy in CNS Early Tx at nephrotic stage Successful in specialized centres Avoidance of dialysis complications May need intra-abdominal engraftment Risk of thrombotic complications Quite rarely used Bilateral nephrectomy, short dialysis and early Tx Nephrectomies when 7 kg Protein losses stop Peritoneal dialysis for 3-6 months Extraperitoneal Tx when 10 kg

17 Options for renal replacement therapy in CNS Unilateral nephrectomy and late Tx Unilateral nephrectomy leads to reduction in protein losses May respond to ACEi therapy Easier management Enhanced development of ESRD Dialysis or pre-emptive Tx Tx at the age of 2-5 years

18 Middle-term outcome of Finnish type CNS EDTA-registy data (Holttä et al, in preparation) Finland Europe No of patients Age at RRT 0.7 yr 1.8 yr Age at Tx 1.6 yr 3.5 yr At 5 years post Tx Patient survival (90%) and graft survival (85%) equal egfr equal (around 60) Height equal ( SD, SD) The results equal to CAKUT patients

19 Long-term outcome of infant Tx UNOS data Tx in patients < 2 year provide excellent results with an estimated half-life of 28 years Finnish experience The measured GFR declines 2.2 ml/1.73m2 per year Most patients need a new graft kidney as young adults

20 Conclusions Understanding of the causes, pathophysiology and genetic diagnostics of CNS have improved dramatically Management of the nephrotic stage and dialysis still needs improvements Nutrition, growth, infection and thrombosis prophylaxis New antiproteinuric drugs? Transplantation Early and late Tx give equal results Re-transplantations later in life necessary