Renal trajectories in the french RaDiCo Alport syndrome cohort

<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Background and Aims</jats:title> <jats:p>Alport syndrome (AS) is increasingly diagnosed thanks to the availability of molecular genetics analysis. Age at kidney failure varies widely according to sex and genotypes as has been reported in several series. However much less is known regarding the earlier stages of renal disease progression, response to RAS inhibition (RASi) and eGFR slopes, which are of utmost importance to designing future therapeutical trials. We report data from a French national cohort of AS patients to better characterize the response to RASi and kidney function decline in a real-world setting.</jats:p> </jats:sec> <jats:sec> <jats:title>Method</jats:title> <jats:p>RaDiCo/Eurbio-Alport is a multicenter retrospective and prospective observational cohort of AS involving 36 adult and pediatric nephrology centers across France. Patient enrollment took place from May 2017 to June 2022. ​​Diagnosis of AS was confirmed based on one or more criteria: molecular genetics, renal biopsy findings by electron microscopic or abnormal expression of type IV collagen chains on skin or renal biopsy. We analyzed UPCR values before and after RASi initiation at predefined intervals: M12 (4–18 months), M24 (18–30 months), M36 (30–42 months), M60 (48–72 months), M84 (72–96 months), M120 (108–132 months), and post-M120. UPCR changes from baseline were tested using one-tailed Wilcoxon signed-rank tests. We modeled the eGFR slope for each patient who had two consecutive eGFR values below 90 mL/min/1.73 m² with at least three eGFR measurements and a follow-up duration of at least two years. The eGFR was evaluated using the EKFC equation validated across ages (2–90 years). The eGFR slopes were estimated using linear regression. We analyzed the eGFR slopes across genetic groups and compared the median slopes in predefined baseline UPCR categories (&lt;50, 50–100, 100–200, &gt;200 in mg/mmol).</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>A total of 643 patients were included: 203 in the male X-linked group (MX), 179 in the female X-linked group (FX), 95 in the autosomal dominant group (AD), 65 in the autosomal recessive group (AR), and 99 with unknown inheritance mode. 50–100, 100–200, &gt;200 in mg/mmol).</jats:p> <jats:p>Proteinuria Response to RASi. We analyzed patients treated with RASi with available UPCR measurements. The median baseline age was 18 (10, 36). Table 1 presents the number of patients, median UPCR at each RASi treatment interval and corresponding p-values. Compared to baseline, UPCR decreased significantly (−51%) at M12, and then increased progressively over time indicating an escape to RAS inhibition.</jats:p> <jats:p>Individual eGFR Slopes. We estimated the eGFR slopes for 194 patients, at median baseline age of 30 (16, 46) and a follow-up of 7.1 (4.4, 15.0) years. The median yearly eGFR decline in mL/min/1.73 m² was −2.1 (−4.2, −0.5) overall, with subgroup values of −2.4 (−4.0, −1.1) in AD (n = 32), −3.4 (−4.3, −0.9) in AR (n = 19), −1.0 (−2.4, 0.3) in FX (n = 69), and −3.6 (−7.2, −1.1) in MX (n = 86).</jats:p> <jats:p>Table 2 presents comparisons of baseline UPCR, baseline eGFR and eGFR slopes across UPCR categories. The results emphasized the impact of baseline UPCR, even at low levels, on eGFR decline.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusion</jats:title> <jats:p>Our data bring a real-world focus on the effect of RASi in a large cohort of AS patients showing the time frame of escape from the antiproteinuric effect. We show the heterogeneity of eGFR slopes according to sex and genotype. Importantly we show the gradual impact of UPCR on eGFR slope, starting as early as 50 mg/mol. In all, these data will be of utmost value in helping design future therapeutical trials.</jats:p> </jats:sec>