#2883 Kidney outcomes and effects of proteinuria in Alport syndrome: a longitudinal analysis of 1175 patients from the UK National Registry of Rare Kidney Diseases (RaDaR)

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Abstract Background and Aims Alport syndrome (AS) is often characterised by pathogenic variants in type IV collagen genes COL4A3/4/5. Previous genotype-phenotype studies have shown patients with certain genotypes reach kidney failure (KF) at a younger age. However, more detailed understanding of the trajectory of eGFR decline for AS patients, and whether this differs by genetic or clinical factors such as genotype or proteinuria control is lacking. Here, we examine KF and eGFR slope and describe associations between proteinuria and kidney outcomes in a large cohort of AS patients, using data from the UK National Registry of Rare Kidney Diseases (RaDaR). Method RaDaR has data linkage with the UK Renal Registry for Kidney Replacement Therapy initiation data, renal units for laboratory results and regional genetics hubs for clinical genetic reports. For analyses relating to mutation type, patients with variants reported by accredited clinical labs as “Pathogenic” or “Likely Pathogenic” by American College of Medical Genetics criteria were included. eGFR slope was estimated for each CKD stage using multi-level linear models to account for individual patient trajectories, and included a covariate to test for differences between mutation types categorised as “Classical” (Male X-linked AS, Digenic and COL4A3/4 homozygous/2x mutations) vs. “Heterozygous” (Female X-linked AS, COL4A3/4 heterozygous) genotypes. Proteinuria progression was investigated by modelling each patient's uPCR by age using linear mixed models, stratified by genotype. Kaplan Meier analysis was used to estimate time from eGFR 90/60/45 mL/min/1.73 m2 to KF or death and compared using logrank statistics. Results were stratified by proteinuria level in the year prior to eGFR 90/60/45 mL/min/1.73 m2. Results The cohort comprised 1175 patients, 584 (50%) female. Clinical genetic reports were available for 535/1175 (46%) patients, of whom 459 (86%) had Pathogenic or Likely Pathogenic variants identified, 198 classical (n = 45 COL4A3/4 homozygous/2x mutations, n = 151 Male X-linked AS, n = 2 Digenic), and 261 heterozygous genotypes (n = 116 Female X-linked AS, n = 145 COL4A3/4 heterozygotes). Overall, median uPCR increased until CKD stage 5: Stage 1: 84.7 mg/mmol (IQR 25.0–231.4), 2: 132.5 (37.0–298.0), 3a: 132 (41.0–301.0), 3b: 187.3 (69.0–385.0), 4: 237.9 (121.9–426.5) and 5: 211.1 (118.8–336.4), however results from the linear mixed model, stratifying by genetic mutation type demonstrated that only patients with autosomal recessive (p = 0.005) and Male X-linked (p < 0.0005) disease experienced a significant progressive increase in proteinuria. Median uPCR in the year prior to reaching eGFR 90/60/45 ml/min/1.73 m2 was 158, 254 and 268 mg/mmol respectively. Compared to those with below median uPCR, patients with above median proteinuria had significantly worse kidney survival with hazard ratios of 5.3 (95% CI 1.5–19.0, p = 0.0097), 3.6 (95% CI 1.5–8.7, p = 0.0048) and 6.5 (95% CI 3.0–13.9, p < 0.0001) from eGFR thresholds of 90, 60 and 45 ml/min/1.73 m2 respectively (Fig. 1). Patients with classical genotypes had higher annual eGFR loss during each CKD stage compared to those with heterozygous genotypes (Fig. 2), most markedly in CKD stage 4 (Classical vs Heterozygous genotypes: −9.1(95% CI −10.9 to −7.3) vs −3.8 ml/min/1.73 m2/year (−5.5 to −2.1)). For patients with heterozygous genotypes, mean eGFR loss was similar throughout CKD stages 1, 2 and 3a at −0.9 ml/min/1.73 m2/year, increasing in later CKD stages. Conclusion These analyses demonstrate differences in eGFR trajectory by genotype in AS: compared with those with heterozygous genotypes, patients with classical genotypes exhibited rising proteinuria levels early in disease and had faster eGFR loss throughout their clinical course. eGFR loss accelerated in both groups on reaching CKD stage 4 and lower proteinuria levels were strongly associated with better renal outcomes at all eGFR thresholds. These findings could inform design and interpretation of clinical trials in AS.

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