Prenatal diagnosis of primary hyperoxaluria type 1 (homozygous AGXT c.731T>C9 [p.(Ile244Thr)] mutation) was made at 11 weeks of pregnancy through chorionic villus sampling performed due to family history.

The parents, who were first cousins and heterozygous carriers, had had a first child affected by primary hyperoxaluria type 1 five years earlier, who reached kidney failure in the second month of life, requiring intensive hemodialysis. Liver and kidney transplantation was performed at 13 months of age, however after one month the kidney graft was lost due to disease recurrence presumably to the mobilization of the systemic oxalate deposits. Multiple comorbidities occurred, a second kidney transplant was required and the child developed post-transplant lymphoproliferative disease.

The second pregnancy was closely monitored by a multidisciplinary team; maternal blood and urine oxalate and glycolate levels were normal. The fetus, large for gestational age, due to gestational diabetes, had normal morphology. A cesarean section at 37 weeks resulted in the birth of a 4120 g male infant, Apgar score 9/9. The child underwent serial blood and urine oxalate measurements starting from the cord blood and amniotic fluid, which highlighted a rapid increase in oxalate in the first hours.

At 6 h of life, to prevent nephrocalcinosis development, the child was treated with glycolate oxidase RNA interference lumasiran 6 mg/kg subcutaneously, associated with pyridoxin 10 mg/kg/day. Sanger sequencing confirmed both the homozygous mutation AGXT c.731T>C9 [p.(Ile244Thr)], which is only partially responsive to vitamin B6, and the diagnosis of primary hyperoxaluria type 1.

Intravenous hyperhydration (240 mL/kg/day) was maintained for 16 days, together with oral water and potassium citrate (500 mg in 500 mL/day) in addition to breastfeeding.

Blood and urine oxalate and glycolate were assessed every 48 h for the first week, then every ten days and subsequently before each administration of lumasiran, using ion chromatography and liquid chromatography-tandem mass spectrometry, respectively. Certified standard solutions were used for calibration. Nine-point calibration curves with internal standard (glycolic acid 13C2) were used for the determination of plasma and urine glycolate. A single point calibration curve with internal standard (bromide) was used for the determination of plasma and urine oxalate. Urinary creatinine was determined using an enzymatic colorimetric method. Liver and kidney function, acid–base parameters and electrolytes were assessed before each lumasiran administration.

Lumasiran 6 mg/kg was repeated at 30 and 60 days, then the dose was reduced to 3 mg/kg every month, according to schedule and to 6 mg/kg every 90 days after the patient reached a weight of 10 kg.

Cord blood oxalate was 15 μmol/L (normal < 10 μmol/L), and amniotic fluid oxalate and glycolate were 55 μmol/L (normal 19–71 μmol/L) and 2 μmol/L (normal 66–109 µmol/L), respectively. The first urine test showed an oxalate/creatinine ratio of 401 µmol/mmol (normal < 360 µmol/mmol) and a glycolate/creatinine (UGly/Cr) ratio of 6 µmol/mmol (normal < 50 µmol/mmol).

At 6 h of life, before the first lumasiran dose, blood oxalate had risen to 32 µmol/L, urine oxalate/creatinine to 573 µmol/mmol and urine glycolate/creatinine to 15 µmol/mmol (Fig. 1A, B). Blood glycolate was 107 µmol/L.

Oxalate and glycolate concentrations in a newborn affected by primary hyperoxaluria type 1 treated with lumasiran starting from 6 h of life. A Blood oxalate and glycolate concentrations. B Spot urine oxalate and glycolate to creatinine. Ox oxalate, CaOx calcium oxalate, Gly glycolate

Despite treatment, blood oxalate peaked at 108 µmol/L on day 6, higher than the calcium oxalate saturation limit, roughly corresponding to a blood oxalate concentration of 50 µmol/L. Serum creatinine was normal (0.3 mg/dL).

A gradual decline (65 to 56 to 62 µmol/L at 10, 20 and 30 days, respectively) was observed (Fig. 1A). After the second dose of lumasiran, a further steeper decline of blood oxalate was observed (31 and 17 µmol/L at 45 and 60 days, respectively), reaching the safer upper limit of 12 µmol/L after three doses at 80 days, and the fully normal value of 6 µmol/L from the fourth dose onward (Fig. 1A). However, despite the early start of lumasiran, urine oxalate/creatinine rose to a maximum of 4173 µmol/mmol (normal value for age < 360 µmol/mmol) at 13 days and gradually declined to 765 µmol/mmol at 80 days, after three treatment doses, and to 335 µmol/mmol, the upper level of the normal range after four doses (Fig. 1B), later falling into the normal range at all samplings.

The 24-h urinary excretion of oxalate measured on days 2 and 6 of life was 360 and 400 µmol/day, respectively.

Blood and urine glycolate initially paralleled oxalate, then increased after each lumasiran dose until the third dose, gradually declining afterward (Figs. 1A, B).

Kidney ultrasound was normal at birth and showed only minimal and hyperechogenic spots during the first 2 months. Over 24 months of follow-up, serial ultrasound showed a complete absence of kidney oxalate deposits, and the kidney function remained normal (serum creatinine 0.2 mg/dL) as well as physiological development and growth.

No adverse events were reported.