Difelikefalin improves itch-related sleep disruption in patients undergoing haemodialysis.

BACKGROUND: Poor sleep quality is associated with increased mortality and lower quality of life in patients with chronic kidney disease-associated pruritus (CKD-aP). Difelikefalin reduces itch in patients with CKD-aP undergoing haemodialysis. This post hoc analysis of Phase 3 studies (3105 and the pooled dataset from KALM-1 and KALM-2) evaluated whether itch reduction in CKD-aP improved sleep quality. METHODS: Itch intensity was assessed in patients undergoing haemodialysis, who had moderate-to-severe CKD-aP treated with intravenous difelikefalin (0.5 µg/kg, three times weekly) (N = 222, Study 3105; N = 426, KALM-1/-2) or placebo (N = 425, KALM-1/-2) for 12 weeks, using the Worst Itch Intensity Numerical Rating Scale (WI-NRS). Sleep quality was assessed using the sleep disability question of the 5-D itch scale (5­D SDQ) in all studies and, in Study 3105, with the Sleep Quality Numeric Rating Scale (SQ-NRS). RESULTS: Greater improvements in sleep quality were observed in patients with ≥ 3-point, versus < 3-point WI-NRS improvement using SQ-NRS in Study 3105 (mean [95% confidence interval]: -5.2 [-5.6, -4.8] vs -1.5 [-2.0, -1.0]) and 5-D SDQ in KALM-1/-2 (-1.8 [-2.1, -1.6] vs -0.8 [-1.1, -0.4]). SQ-NRS and WI-NRS scores correlated strongly at baseline and Week 12 in Study 3105 (Spearman correlation coefficient: 0.77 and 0.84, respectively). Correlations were also observed between 5-D SDQ and WI-NRS scores in Study 3105 and KALM­1/­2. CONCLUSIONS: In patients undergoing haemodialysis with moderate-to-severe CKD-aP, itch reduction with intravenous difelikefalin was associated with improved sleep quality. As disturbed sleep may contribute to mortality and morbidity in CKD-aP, difelikefalin may help to address a major clinical burden by improving sleep quality, secondary to itch relief.

Novel heterozygous COL4A3 mutation in a family with late-onset ESRD.

Thin basement membrane nephropathy (TBMN) and Alport syndrome (ATS) are genetically heterogeneous conditions characterized by structural abnormalities in the glomerular basement membrane (GBM). TBMN presents with hematuria, minimal proteinuria, and normal renal function. Although TBMN is an autosomal dominant disease (COL4A3 and COL4A4), ATS can be inherited X-linked (COL4A5), autosomal recessive, or autosomal dominant (both COL4A3 and COL4A4). The clinical course of TBMN is usually benign, whereas ATS typically results in end-stage renal disease (ESRD). Nevertheless, there is a broad spectrum of clinical phenotypes caused by mutations in COL4A3 or COL4A4. We report an Italian family who presented with hematuria and mild proteinuria. Mutational analysis showed a novel heterozygous mutation p.G291E in exon 15 of the COL4A3 gene. Many different mutations in COL4A3 and COL4A4 that cause TBMN have already been identified, but most genetic variability in these genes has been found to cause autosomal ATS. A valid genotype-phenotype correlation for TBMN or ATS is not yet known. Therefore, it is important to identify new mutations by direct sequencing to clarify their clinical importance, to assess the prognosis of the disease, and to avoid renal biopsy.