#3589 OXALATE METABOLISM IN PRIMARY HYPEROXALURIA TYPE 1 TREATED WITH LUMASIRAN IMMEDIATELY AFTER BIRTH: STILL NOT EARLY ENOUGH

Abstract

Abstract Background and Aims Severe primary hyperoxaluria type 1 (PH1) with rapid onset nephrocalcinosis and renal function loss in early infancy required so far combined liver and kidney transplant. RNA interfering drugs are the new challenge for these children. Here we present the first case of a newborn affected by PH1 treated with RNA-interfering Lumasiran 6 hours after birth. Method Diagnosis of PH1 (homozygous mutation AGXT c.731T>C9 [p.Ile244Thr]) was done at 11 weeks of pregnancy on chorionic villus due to family history. Parents are first cousins, both heterozygous carriers of the mutation. Their first child is homozygous, affected by PH1, in dialysis for massive nephrocalcinosis since two months of life, kidney-liver transplanted at 14 months, with multiple comorbidities, severe retinal oxalate deposition, early ischemic stroke and post-transplant lympho-proliferative disease. Mother blood Oxalate, Glycolate and Urinary Oxalate during pregnancy proved normal (3 umol/L and 4 umol/L; 35 umol/mmol). Fetal morphology at ultrasound was normal, showing a male fetus large for gestational age, due to gestational diabetes, and polyhydramnios. At 37w cesarean section was performed. Birth weight 4120 g; Length 49.9 cm (99° centile for gestational age). Apgar score 9/9. Cord blood and amniotic fluid were obtained for Oxalate dosage and Sanger sequencing for diagnosis confirmation. Umbilical central venous line and bladder catheter were placed for immediate start of infusions and serial sampling. Results PH1 was confirmed due to Homozygous mutation AGXT c.731T>C9 [p.(Ile244Thr)]. Oxalate on cord blood was 15 umol/L (nv <10), on amniotic fluid 55 umol/L (nv 19-71), on first urine 401 umol/mmolCr (nv < 300 umol/mmolCr). Blood Oxalate at 6h of life rose to 32 umol/L, Glycolate to 107 umol/L and urinary Oxalate to 573 umol/mmolCr. Serum Creatinin was normal (0.3 mg/dl). At 6 hours of life the child was treated with Glycolate Oxidase RNAi Lumasiran at the dose 6 mg/kg subcutaneously, in combination with Pyridoxin 10 mg/kg/day. Hyperhydration (240 ml/kg/day) was maintained iv for 16 days in combination with oral water and potassium citrate (500 mg in 500 ml/day) above breast feeding. Blood Oxalate was serially assessed every 48 hrs showing a peak level of 108 umol/l (nv <10) at day 6, higher than the supersaturation level of 60 umol/L, then a gradual decline (65-56-62 umol/L at 10-20-30 days respectively). Lumasiran 6 mg/kd was repeated at 30 and 60 days according to schedule, then at 3 mg/kg every month. After the second dose of Lumasiran a steeper decline of blood Oxalate was observed (31-17 umol/L at 45-60 days respectively) reaching the upper normal limit of 12 umol/L after three doses, at 80 days. Urinary Oxalate in spite of Lumasiran early start rose until a maximum of 4173 umol/mmolCr (nv for age <300 umol/mmolCr) at 13 days and gradually declined to 765 umol/mmolCr at 80 days, after three doses. Blood and urine Glycolate initially paralleled Oxalate then increased after each Lumasiran dose. Renal ultrasound normal at birth, showed only minimal hyperechogenic spots during the first 2 months, then mild bilateral hyperechogenic papillary deposits without signs of nephrocalcinosis/stones. Renal function at 3 months of life is normal (serum Creatinine 0.2 mg/dl); child growth on the higher centiles (7 kg), with no adverse events. Conclusion Blood and urine Oxalate serial analysis in a severe case of PH1 treated immediately after birth show that Glycolate Oxidase inhibition has a latency of at least 15 days, even when no previous deposits are present. In these days extremely high level of urine and blood Oxalate, far higher than supersaturation level, are reached, in spite of normal renal function, hyperhydration, B6 and citrate supplementation. This case confirms that familiar severe forms of PH1 should be treated immediately after birth with Lumasiran in combination with aggressive supportive therapy to avoid irreversible nephrocalcinosis and renal failure. Prenatal treatment of these cases might be considered in future.