CLINICAL PREDICTORS AND OUTCOMES OF IMMUNOGLOBULIN A NEPHROPATHY VERSUS ALPORT SYNDROME: A RETROSPECTIVE COMPARATIVE COHORT STUDY

Immunoglobulin A Nephropathy (IgAN) and Alport syndrome (AS), particularly the autosomal dominant form of AS (ADAS), may present similarly with microscopic haematuria, proteinuria and preserved kidney function. While kidney biopsy and genetic testing are the gold standards for diagnosis of IgAN and AS respectively, both carry attendant risks and costs, making initial selection of the most appropriate diagnostic test challenging. Differentiating between IgAN and AS is hence clinically important but difficult.

We aim to compare the clinical characteristics and outcomes of patients with IgAN and AS presenting with similar clinical phenotypes, to identify potential clinical predictors that may distinguish between the two conditions, to guide the most appropriate initial diagnostic test.

We conducted a retrospective comparative cohort study with a case-control analytic approach using data from two existing cohorts: low-risk biopsy-proven IgAN patients (defined as estimated glomerular filtration rate ≥ 60 ml/min/1.73 m² and sub-nephrotic range proteinuria < 3.5g/day) who were selected from the EXIST study, and genetically confirmed AS patients from the Clinical Implementation Pilot for Glomerular Diseases (CIP GLOM) cohort. Comparative analyses were performed between IgAN and (i) all AS patients, and (ii) those with ADAS. Predictors of IgAN were identified using univariable and multivariable logistic regression.

We included 47 patients with low-risk IgAN and 36 with AS, of which the majority were autosomal dominant (n=27, 75.0%). AS patients were younger at recruitment (median 29.5 vs 48.2 years, p<0.001), and at time of initial disease presentation (median 15.5 vs 37.0 years, p<0.001). Hypertension and A3 albuminuria were significantly more common in IgAN than in AS (40.4% vs. 8.3%, p < 0.001; 97.9% vs. 30.6%, p < 0.001, respectively). Variables significant on univariable logistic regression analysis were included in the multivariable model, except age at recruitment (excluded for collinearity) and albuminuria (excluded due to model non-convergence). In the final multivariable logistic regression model predicting diagnosis, older age at presentation (OR 1.06, 95% CI 1.02-1.10, p<0.001) and presence of hypertension (OR 7.01, 95% CI 1.71-28.81, p=0.007) were associated with higher odds of IgAN compared to AS. Similar associations were observed when the model was restricted to comparison between IgAN and ADAS alone. There were no differences in the composite endpoint (development of kidney failure requiring kidney replacement therapy, a decline in estimated glomerular filtration rate (eGFR) to <15mL/min/1.73m2, or death) between both groups.

Patients with IgA Nephropathy were older at presentation and more likely to have hypertension compared to those with Alport syndrome, regardless of mode of inheritance. No difference in composite kidney and mortality outcomes were observed between the two groups of patients. These findings highlight the potential utility of integrating these clinical predictors in guiding diagnostic stratification to select the most appropriate initial diagnostic test, though validation in larger cohorts is warranted.