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Inborn Errors of Metabolism
 

Inborn Errors of Metabolism

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  • so a t a short evaluation mortality rate was 27% and 71% of survivors with a normal development. But at a long follow-up mortality increaased up to 48% and more impressive most patients became mentally retarded. No difference was observed between UCD and OA.

Inborn Errors of Metabolism Inborn Errors of Metabolism Presentation Transcript

  • INBORN ERROR S OF METABOLISM Stefano Picca, MD D ept. of Nephrology and Urology, Dialysis Unit “ Bambino Gesù” Pediatric Research Hospital ROMA, Italy 5th International Conference on Pediatric C ontinuous Renal Replacement Therapy Orlando, FLA. 2008, June 19 – 21
    • INCIDENCE
    • Overall: 1:9160
    • Organic Acidurias: 1:21422
    • Urea Cycle Defects: 1:41506
    • Fatty Acids Oxidation Defects: 1:91599
    • AGE OF ONSET
    • Neonate: 40%
    • Infant: 30%
    • Child: 20%
    • Adult: 5-10% (?) Dionisi-Vici et al, J Pediatrics, 2002.
    “ SMALL MOLECULES” DISEASES INDUCING CONGENITAL HYPERAMMONEMIA
    • hyperammonemia is extremely toxic ( per se or through intracellular excess glutamine formation) to the brain causing astrocyte swelling, brain edema, coma, death or severe disability,
    • thus:
    • emergency treatment has to be started even before having a precise diagnosis since prognosis may depend on:
    • coma duration (total and/or before treatment)
    • (Msall, 1984; Picca, 2001; McBryde, 2006)
    • peak ammonium level
    • (Enns, 2007)
    • detoxification rapidity
    • (Schaefer, 1999)
    KEY POINTS FACING TO A HYPERAMMONEMIC NEWBORN
  • THE USUAL COURSE OF NEONATAL HYPERAMMONEMIA-1 PATIENT DIAGNOSIS TREATMENT home Mother: “sleeps too long” (May) Start Pharmacological Treatment peripheral hospital Hyperammonemia 3 rd level hospital Metabolic defect Starts (continues) Pharmacological Treatment DIALYSIS NO RESPONSE RESPONSE RE-FEEDING Metabolism expert Biochemistry Lab Neonatologist Nephrologist OUTCOME ANALYSIS
  • THE USUAL COURSE OF NEONATAL HYPERAMMONEMIA-2
    • Pharmacological
    • “ cocktail”
    NO RESPONSE RESPONSE Starts (continues) Pharmacological Treatment DIALYSIS RE-FEEDING OUTCOME ANALYSIS
    • AIMS
    •  precursors  catabolism  anabolism
    • stop protein
    • caloric intake  100 kcal/kg
    • insulin …and
    Pharmacological treatment before having a diagnosis
    • endogenous depuration
    • arginine 250 mg/Kg/2 hrs + 250 - 500 mg/Kg/day
    • carnitine 1g i.v. bolus 250 - 500 mg/Kg/day
    • vitamins (B12 1 mg,biotin 5-15 mg)
    • benzoate/phenylbutyrate 250 mg/Kg/2 hrs + 250 mg/Kg/day (UCD only?)
    • peroral carbamylglutamate 100 – 300 mg/kg
    Picca et al. Ped Nephrol 2001
  • THE USUAL COURSE OF NEONATAL HYPERAMMONEMIA-3
    • Pharmacological
    • “ cocktail”
    NO RESPONSE RESPONSE Starts (continues) Pharmacological Treatment DIALYSIS RE-FEEDING OUTCOME ANALYSIS
    • Waiting for…
  • 0 4 8 12 16 20 24 0 250 500 750 1000 2000 4000 6000 pNH 4 HOURS 0-4 HOURS MEDICAL TREATMENT IN NEONATAL HYPERAMMONEMIA Picca, 2002, unpublished (  mol/l) non-responders (dialysis) responders (med. treatment alone)
  • THE USUAL COURSE OF NEONATAL HYPERAMMONEMIA-4
    • Pharmacological
    • “ cocktail”
    NO RESPONSE RESPONSE Starts (continues) Pharmacological Treatment DIALYSIS RE-FEEDING OUTCOME ANALYSIS
    • Waiting for…
    • Dialysis
  • VC G KC PLASMA NH 4 (DIS)EQUILIBRIUM Modified from Sargent JA, Gotch FA, 1996. K D Ke
  • 0 10 20 30 40 50 60 0 20 40 60 80 100 CAVHD patients 0 10 20 30 40 50 60 0 20 40 60 80 100 HD patients TIME (hours) 0 10 20 30 40 50 60 0 20 40 60 80 100 CVVHD patients NH4p (percent of initial value) Picca et al. Ped Nephrol 2001
  • AMMONIUM CLEARANCE AND FILTRATION FRACTION USING DIFFERENT DIALYSIS MODALITIES. Picca et al., 2001
  • Dialysis in hyperammonemia: the “beyond ammonium removal” effects NH 4 removal GOOD BAD DIALYSIS Protein loss in the dialysate: 10-12 g/1.73m 2 /day (Maxvold, 2000) Dialysis-induced catabolism (Schulman, 2004) NH 4 scavengers (NaBz+NaPh) removal (Bunchman, 2007) Correction of AKI Citrulline removal (McBryde, 2004) Glutamine removal (McBryde, 2004)
  • Starts (continues) Pharmacological Treatment DIALYSIS NO RESPONSE RESPONSE RE-FEEDING THE USUAL COURSE OF NEONATAL HYPERAMMONEMIA-5
    • Pharmacological
    • “ cocktail”
    OUTCOME ANALYSIS
    • Waiting for…
    • Dialysis
    • Have we been
    • successful?
  • PROGNOSTIC INDICATORS: SURVIVAL
    • pre-treatment coma duration < 10 hrs
    Pela, 2008
    • pre-treatment coma duration < 33 hrs (no influence of post-treatment duration)
    • responsiveness to pharmacological therapy
    Picca, 2001
    • 50% pNH 4 decay time < 7 hrs
    • (catheter > 5F)
    Schaefer, 1999
    • pNH 4 at admission<180  mol/L
    Uchino, 1998
    • pNH 4 at admission<300  mol/L
    • Peak pNH 4 <480  mol/L
    Bachman, 2003
    • pNH 4 at admission<180  mol/L
    • Time to RRT<24 hrs
    • Medical treatment<24 hrs
    • BP> 5%ile at RRT initiation
    • HD initial RRT (trend)
    McBryde, 2006
  • SINP ITALIAN SOCIETY OF PEDIATRIC NEPHROLOGY   Italian Study Group “ Dialysis Treatment of Neonatal hyperammonemia” (Coord.: S. Picca, MD)
  • 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 0 1 2 3 4 5 6 patients years n= 48
  • DESCRIPTIVE (1) 0.28 39.0 39 GA 0.11 9.6 31 Apgar (5 min) 0.09 1.13 36 Creatinine (mg/dl) 0.18 8.45 31 Apgar (1 min) 0.6 14.0 47 Year of treatment (yrs after 1985) SEM Mean n Continuous Variable 2.4 18.3 44 Predialysis coma duration (hrs) 7.8 75.5 39 Coma total duration (hrs) 7.2 50.9 45 Dialysis duration (hrs) 1.8 11.4 37 pNH 4 dialysis 50% decay time (hrs) 141 1124 39 pNH 4 peak (  mol/L) 84 839 47 pNH 4 pre-dialysis (  mol/L) 103 685 46 pNH 4 pre-medical treatment (  mol/L) 1.7 -9.10 29 BE at admission 69.6 2985 46 BW at admission (g) 18.5 120.8 46 Age at admission (hrs) 67.6 3240 43 Birth BW (g)
  • DESCRIPTIVE (2) 6 CAVHD n Non continuous variable 12/ 27 (44%) Normal development at 2 years 23/39 (59%) Survival at 2 years * (*follow up N/A in 6 pts) 35/46 (76%) Survival at discharge 31/ 42 Intubation M 32/46 Gender 25 PD 3 HD 16 CVVHD
  • DEP. VARIABLE 1: SURVIVAL AT DISCHARGE
    • Year of treatment
    • Birth BW (g)
    • Age at admission (hrs)
    • BW at admission (g)
    • BE at admission
    • Creatinine (mg/dl)
    • pNH 4 pre-medical treatment (  mol/L)
    • pNH 4 pre-dialysis (  mol/L)
    • pNH 4 peak (  mol/L)
    • pNH 4 dialysis 50% decay time (hrs)
    • Dialysis duration (hrs)
    • Coma total duration (hrs)
    • Predialysis coma duration (hrs)
    • CAVHD
    • CVVHD
    • HD
    • DP
    • Gender
    • Intubation
    NS 0.056 0.62 0.25 0.93 0.075 NS NS 0.08 NS
  • 0 8 16 24 32 40 48 0 20 40 60 80 100 Ammonia Decay (%) Time (h) PD CVVH, HD, CAVH
  • PD vs. EXTRACORPOREAL 0.061 -8 ±154 302 ±80 pNH 4 increase (  mol/L) 0.914 829 ±128 848 ±112 pNH 4 pre-dialysis (  mol/L) <0.001 22 ± 3.9 75 ± 11 Dialysis duration (hrs) 0.017 24.3± 18.2 13.2 ± 2.3 Predialysis coma duration (hrs) 0.146 850 ±202 546 ±82 pNH 4 pre-medical treatment (  mol/L) p No PD n=21 PD n=25
  • DEP. VARIABLE 2: DEVELOPMENT AT 2 YEARS
    • Year of treatment
    • Birth BW (g)
    • Age at admission (hrs)
    • BW at admission (g)
    • BE at admission
    • Creatinine (mg/dl)
    • pNH 4 pre-medical treatment (  mol/L)
    • pNH 4 pre-dialysis (  mol/L)
    • pNH 4 peak (  mol/L)
    • pNH 4 dialysis 50% decay time (hrs)
    • Dialysis duration (hrs)
    • Coma total duration (hrs)
    • Predialysis coma duration (hrs)
    • CAVHD
    • CVVHD
    • HD
    • DP
    • Gender
    • Intubation
    0.017 (M-W); 0.056 (Regr. analysis) 0.15 0.073 NS NS NS
  • DEP. VARIABLE 3: UCD vs OA
    • Year of treatment
    • Birth BW (g)
    • Age at admission (hrs)
    • BW at admission (g)
    • BW loss from birth BW at admission (%)
    • BE at admission
    • pNH 4 pre-medical treatment (  mol/L)
    • pNH 4 pre-dialysis (  mol/L)
    • pNH 4 peak (  mol/L)
    • pNH 4 dialysis 50% decay time (hrs)
    • Creatinine (mg/dl)
    • Dialysis duration (hrs)
    • Coma total duration (hrs)
    • Predialysis coma duration (hrs)
    • CAVHD
    • CVVHD
    • HD
    • DP
    • Gender
    • Intubation
    NS 3126 ±91 vs 2765 ±88 p 0.018 -6.3 ±0.8 vs -12.2 ±1.0 p 0.018 -5.7 ±2 vs -14.6 ±1.9 p 0.023 997 ±124 vs 606 ±69 p 0.034 NS 779 ±121 vs 550±183 p 0.041
  • CONCLUSIONS-DIALYSIS
    • PD provides NH 4 clearance lower than HD and CRRT
    • However, in this series and in that of Schaefer (1999) detoxification rapidity was not significantly different from that of extracorporeal dialysis and patients treated with PD showed a trend toward a better survival
    • This may have been the consequence of a shorter coma duration and of a lower intoxication level before dialysis initiation
    • Extracorporeal should be the first-line dialysis modality in neonatal hyperammonemia
    • When HD and/or CRRT facilities are not available, PD should be considered. However, results are likely similar to those obtained with extracorporeal dialysis only in less intoxicated patients.
    • In our and in other series, dialysis modality did not affect the outcome in the presence of a long mean pre-treatment duration
    • In fact, p lasma ammonium level before every treatment and predialysis coma duration resulted to be the main determinants of survival both at short and long term
    • It is thus likely that the influence of detoxification rapidity on the outcome becomes evident when pre-treatment duration is shorter than that reported in our series, as reported by others (Schaefer 1999, Pela 2008)
    • However, as high intoxication level and long pre-treatment duration are the consequence of a delayed intervention, the need for an early diagnosis and treatment remains the crucial issue of neonatal hyperammonemia.
    CONCLUSIONS-OUTCOME
  • Short-term <2 nd year of life Mortality 27.5% Cognitive development Normal 71% Mild MR 4.7% Severe MR 23% Outcome Neonatal Onset pts Long-term >2 nd year of life (2-18 yrs) 48% 28.5% 9.5% 57% Deodato F et al, 2004 No significa nt difference between UCDs and OAs
  • ACKNOWLEDGEMENTS
    • Bambino Gesù Children Hospital:
    • Metabolic Unit : Carlo Dionisi-Vici, MD; Andrea Bartuli, MD; Gaetano Sabetta, MD
    • Clinical Biochemistry Lab : Cristiano Rizzo BSc, PhD; Anna Pastore BSc, PhD
    • NICU: all doctors and nurses
    • Dialysis Unit : Francesco Emma, MD, all doctors and nurses (thanks!)
    • In Italy:
    • SINP (Italian Society of Pediatric Nephrology)
    • All doctors from Pediatric Nephrology and NICUs of Genova, Milan, Turin, Padua, Florence, Naples, Bari.