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.

Background and Aims The impairing effect of chronic kidney disease-associated pruritus (CKD-aP) on the quality of life (QoL) of patients undergoing haemodialysis (HD) is well-established. The aim of this post-hoc analysis was to assess the impact of itch relief on QoL, as measured by the 5-D itch scale, in patients with CKD-aP enrolled in the Phase 3 KALM-1 and -2 clinical trials. This study also aimed to confirm the use of ≥5-point reduction in 5-D itch scale total score as a threshold for clinically meaningful improvement in itch-related QoL, by comparing to notable improvement on the Patients’ Global Impression of Change (PGI-C) scale. Method Data were pooled from 851 patients with moderate-to-severe CKD-aP undergoing HD in the KALM-1 and -2 trials testing difelikefalin vs placebo. Sustained responders were defined as patients who achieved a ≥3-point improvement in the weekly mean 24-hour Worst Itching Intensity Numerical Rating Scale [WI-NRS] score at Week 12 of the study, whereas non-sustained responders were defined as patients that reported a ≥3-point improvement in any week of the study but not at Week 12. Improvements in QoL, as measured by the mean change in 5-D itch scale total score from baseline to Week 12, were compared in sustained responders vs non-sustained responders. Data were analysed by ANCOVA multiple imputation, with a missing-at-random assumption. The mean change in 5-D itch scale total score was analysed in relation to patients’ reporting on the five categories of the PGI-C scale. Results In pooled analysis, 305 patients undergoing HD with CKD-aP qualified as sustained responders, whereas 128 patients were non-responders. Reduction in 5-D itch scale total score over 12 weeks was significantly higher in sustained responders compared with non-sustained responders (least squares [LS] mean ±standard error; –7.1±0.2 vs –4.0±0.3, LS mean difference –3.0±0.3, p<0.001) (Figure 1). Greater reductions in 5-D itch scale total score were observed in patients reporting more substantial improvements in PGI-C. Specifically, patients reporting much, or very much, improvement in PGI-C scored ≥5-point reduction on the 5-D itch scale (mean ±standard error; –5.3±0.2 and –8.2±0.3, respectively) (Figure 2). Conclusion This study observed a greater improvement in QoL, as measured by the 5-D itch scale total score, in patients with CKD-aP who reported a clinically meaningful reduction in itch, as measured by WI-NRS, at Week 12. These results also support the use of ≥5-point reduction in the 5-D itch scale total score as a threshold for clinically meaningful improvement in the QoL of patients with CKD-aP. As only sustained responders exceeded this threshold, these data suggest that continued treatment of itch may be necessary to maximally improve QoL in these patients.

Background and Aims Chronic kidney disease-associated pruritus (CKD-aP) is a serious condition that greatly impacts patients’ quality of life (QoL). Moderate-severe pruritus affects up to 47% of patients undergoing haemodialysis (HD) [1]. The aim of this analysis was to assess the impact of itch relief on the disease and social functioning domains of the Skindex-10 questionnaire in a post hoc analysis of the difelikefalin (DFK) Phase 3 studies in patients with CKD-aP undergoing HD. Method Patients with moderate-to-severe CKD-aP (mean Worst Itch Numerical Rating Scale [WI-NRS] score ≥4 [KALM-1] or ≥5 [Study 3105 and KALM-2]) undergoing HD were enrolled and randomised 1:1 to receive intravenous DFK 0.5 µg/kg or placebo (KALM-1 and -2) or open-label DFK (Study 3105) 3 times/week for 12 weeks. Data from all patients who completed the studies were included in the present analysis irrespective of study drug exposure; data were pooled for patients receiving DFK and placebo from the KALM studies. The 12-week change from baseline in the Skindex-10 questionnaire subdomains were assessed for disease (Q1–3) and social functioning (Q7–10). Change from baseline in the mood/emotional distress domain has previously been reported (Q4–6) [2]. Results Skindex-10 scores were available for 914 patients (KALM studies: n = 720; Study 3105: n = 194). At Week 12, patients with a clinically relevant (WI-NRS ≥3-point) change (decrease) in itch (KALM: n = 305; 3105: n = 143) reported a relative mean (± standard error) corresponding improvement of 59.7%±2.0 (KALM) and 65.9%±2.6 (3105) from baseline in the disease domain of Skindex-10, compared with 18.4%±2.3 and 30.7%±4.4 of patients with <3-point WI-NRS improvement (KALM: n = 415 [Figure A]; 3105: n = 51 [Figure B]). In addition, a much greater improvement in QoL was reported for the social functioning domain for patients with ≥3-point WI-NRS improvement, compared with patients with <3-point improvement (66.2%±3.5 vs 11%±7.6 in the KALM studies; 75.5%±4.0 vs 49.4%±8.5 in Study 3105). Overall, the patients with ≥3-point WI-NRS change reported relative mean improvement from baseline ranging from 64%±2.3 to 70.2%±2.6 across the total Skindex-10 scale compared with 15.1%±4.8 to 35.4%±5.5 of patients with <3-point improvement at Week 12 across all studies. Conclusion In this post hoc analysis, patients with CKD-aP undergoing HD who reported a clinically meaningful reduction in itch intensity also achieved a substantially greater improvement in both the disease and social functioning domains of Skindex-10, as well as overall itch-related QoL.