Effectiveness and safety of Tolvaptan in infants with congenital heart disease.

BACKGROUND: Tolvaptan (TLV) is a selective vasopressin receptor 2 antagonist administered for congestive heart failure (CHF) after inadequate response to other diuretics. The effectiveness and safety of TLV have been evaluated well in adult patients. However, reports on its use in pediatric patients, especially infants, are scarce. METHODS: We retrospectively evaluated 41 children younger than 1 year of age who received TLV for CHF for congenital heart disease (CHD) between January 2010 and August 2021. We monitored the occurrence of adverse events, including acute kidney injury and hypernatremia, as well as laboratory data trends. RESULTS: Of the 41 infants included, 51.2% were male. The median age when TLV was initiated was 2 months, interquartile range (IQR) 1-4 months, and all infants had been administered other diuretics previously. The median dose of TLV was 0.1 mg/kg/day (IQR, 0.1-0.1). Urine output increased significantly after 48 h of treatment: baseline, 315 mL/day (IQR, 243-394); 48 h, 381 mL/day (IQR, 262-518) , p = 0.0004; 72 h, 385 mL/day (IQR, 301-569), p = 0.0013; 96 h, 425 mL/day (IQR, 272-524), p = 0.0006; and 144 h, 396 mL/day (IQR, 305-477), p = 0.0036. No adverse events were observed. CONCLUSIONS: Tolvaptan can be used safely and efficiently in infants with CHD. From the perspective of adverse effects, initiating administration at a lower dosage is preferable because this was found to be sufficiently effective.

Clear Evidence of LAMA5 Gene Biallelic Truncating Variants Causing Infantile Nephrotic Syndrome.

Background: Pathogenic variants in single genes encoding podocyte-associated proteins have been implicated in about 30% of steroid-resistant nephrotic syndrome (SRNS) patients in children. However, LAMA5 gene biallelic variants have been identified in only seven patients so far, and most are missense variants of unknown significance. Furthermore, no functional analysis had been conducted for all but one of these variants. Here, we report three patients with LAMA5 gene biallelic truncating variants manifesting infantile nephrotic syndrome, and one patient with SRNS with biallelic LAMA5 missense variants. Methods: We conducted comprehensive gene screening of Japanese patients with severe proteinuria. With the use of targeted next-generation sequencing, 62 podocyte-related genes were screened in 407 unrelated patients with proteinuria. For the newly discovered LAMA5 variants, we conducted in vitro heterotrimer formation assays. Results: Biallelic truncating variants in the LAMA5 gene (NM_005560) were detected in three patients from two families. All patients presented with proteinuria within 6 months of age. Patients 1 and 2 were siblings possessing a nonsense variant (c.9232C>T, p.[Arg3078*]) and a splice site variant (c.1282 + 1G>A) that led to exon 9 skipping and a frameshift. Patient 3 had a remarkable irregular contour of the glomerular basement membrane. She was subsequently found to have a nonsense variant (c.8185C>T, p.[Arg2720*]) and the same splice site variant in patients 1 and 2. By in vitro heterotrimer formation assays, both truncating variants produced smaller laminin α5 proteins that nevertheless formed trimers with laminin ß1 and γ1 chains. Patient 4 showed SRNS at the age of 8 years, and carried compound heterozygous missense variants (c.1493C>T, p.[Ala498Val] and c.8399G>A, p.[Arg2800His]). Conclusions: Our patients showed clear evidence of biallelic LAMA5 truncating variants causing infantile nephrotic syndrome. We also discerned the clinical and pathologic characteristics observed in LAMA5-related nephropathy. LAMA5 variant screening should be performed in patients with congenital/infantile nephrotic syndrome.