PREDICTING IGA NEPHROPATHY PROGRESSION: A HISTOPATHOLOGICAL APPROACH USING PARIETAL EPITHELIAL CELLS AND PODOCYTE MARKERS - PARCC IgAN Score

IgA nephropathy (IgAN) presents with a highly variable clinical course. The heterogeneity of IgAN trajectories and the lack of detailed phenotyping remain obstacles for better outcome prediction and potentially endotype delineation. Although an international risk prediction tool has been developed based on demographic, clinical, and histological features, it does not incorporate molecular or pathophysiological data. Early glomerular alterations, such as parietal epithelial cell (PEC) activation or podocyte injury, may offer additional prognostic insights. 

However, this model does not incorporate mechanistic or molecular data and may not fully capture the biological heterogeneity underlying disease progression. Notably, patients with focal segmental glomerulosclerosis (FSGS), glomerulosclerosis, or crescentic lesions often experience more aggressive disease, yet histological scoring alone may fail to detect early cellular alterations with prognostic relevance.

Therefore, a sensitive assessment of mechanisms underlying such damage may improve disease stratification and outcome prediction. Even if cellular mechanisms underlying crescentic glomerulonephritis (cGN) and FSGS remain challenging to understand, it has been reported that activation of parietal epithelial cells (PEC) and the switch or loss of podocyte phenotype play key roles in these conditions.

The objectives of the project were  1. to characterize PEC and podocyte phenotypes in human IgAN using multiplex immunofluorescence. 2. To assess their associations with histological lesions and prognostic value beyond conventional clinical and pathological markers.

Kidney biopsies from 98 IgAN patients were analyzed using multiplex immunofluorescence to quantify PEC markers (CLDN1, CD9, CD44) and podocyte markers (p57/CDKN1C, WT1). 

Control glomeruli were obtained from pre-implantation kidney transplant biopsies (n = 18 glomeruli from 4 patients), performed immediately after vascular reperfusion.

Kidney biopsy specimens were reviewed and reclassified according to the Oxford MEST-C score: mesangial hypercellularity (M), endocapillary hypercellularity (E), segmental glomerulosclerosis (S), tubular atrophy/interstitial fibrosis (T), and crescents (C). An expert renal pathologist performed a centralized, anonymous review of all kidney biopsy slides.

Renal outcome was defined as a ≥50% decline in estimated glomerular filtration rate (eGFR) or progression to end-stage kidney disease (ESKD) at 5 years.

The Cox proportional hazards models evaluated associations between glomerular cell phenotypes, clinical parameters, histological lesions (MEST-C score), and renal prognosis. 

Model performance was evaluated using the Akaike Information Criterion (AIC), Harrell’s concordance index (C-index), and the integrated time-dependent area under the ROC curve (iAUC), which together assess model fit and discriminative ability over time.

To explore associations between glomerular cell phenotypes and baseline clinical parameters, Spearman correlation coefficients were calculated using per-patient averages of cell marker proportions. Correlations between individual or composite glomerular phenotypes and estimated glomerular filtration rate (eGFR) or proteinuria (PCR) were assessed.

During a median follow-up of 4.65 years (IQR: 2.07–8.49), 18 of 98 patients (18%) reached the primary renal outcome.

Age, sex and BMI distribution did not differ significantly between patients with good and poor renal outcomes at 5 years: median age at biopsy was 42 years vs. 41.3 years (P = 0.95), the proportion of male patients was respectively 28.7% vs. 44.4% (P = 0.13), median body mass index (BMI) 25.5 kg/m² vs. 24.0 kg/m² (P = 0.28). Compared to patients with good outcomes (n = 80), those with poor outcomes (n = 18) had lower baseline eGFR (20.5 ml/min per 1.73m² vs 50 ml/min per 1.73m², P < 0.0001) and higher proteinuria (0.40 g/mmol vs 0.14 g/mmol, P < 0.0001). They also showed lower serum albumin and albumin-to-creatinine ratio. Similarly, patients who progressed to poor renal outcomes had significantly higher mean arterial pressure (MAP) at biopsy (HR 1.36, 95% CI: 1.05–1.76).

Regarding glomerular markers, higher proportions of CLDN1⁺ cells (HR 1.18 [1.08–1.29], P = 0.0003), and activated PEC subsets (CLDN1⁺/CD44⁺, CLDN1⁺/CD9⁺, and CLDN1⁺/CD44⁺/CD9⁺) were all significantly associated with worse prognosis. The CLDN1⁺/CD44⁺/CD9⁺ population had the strongest association (HR 1.89 [1.35–2.64], P < 0.0001). Conversely, podocyte markers p57⁺ and WT1⁺ were less abundant in patients with poor outcomes (P < 0.0001 for both). The double-positive p57⁺/WT1⁺ population was also significantly reduced (1.73% vs 7.34%, HR 0.57 [0.45–0.74]).

Kaplan–Meier analysis by tertiles of glomerular expression showed that patients with the lowest p57 expression (T1 <9.43%) had the highest incidence of poor renal outcome, while those in the highest tertile (T3 >13.28%) had the lowest risk.

The reverse pattern was observed with CLDN1⁺/CD44⁺ cells: patients in the highest tertile (T3 > 2.98%) had the highest incidence of poor outcomes, and those in the lowest tertile (T1 < 0.49%) had the best prognosis.

Comparison of Multivariable Prognostic Models: The clinical model (eGFR, proteinuria, MAP) yielded an AIC of 117.71 and was used as a reference for comparison with extended models. Adding histological lesions (clinical + histological model) modestly improved model fit (AIC = 115.8), although association with T2 no longer reached statistical significance (P = 0.06).

In the new model, including all variables from the previous model plus p57⁺ and CLDN1⁺/CD44⁺ cells, only these two biomarkers remained significant: p57⁺ was associated with lower risk (HR 0.81 [0.67–0.98], P = 0.03) and CLDN1⁺/CD44⁺ associated with worse outcome (HR 1.09 [1.02–1.17], P = 0.02). This model showed improved fit (AIC = 106.51).

A stepwise selection identified the best model (AIC = 101.89), retaining only p57⁺ (HR 0.77, P = 0.0001) and CLDN1⁺/CD44⁺ cells (HR 3.32, P = 0.0001).

In this study, we analyzed kidney biopsies from patients with IgA nephropathy and identified specific molecular markers in two key glomerular cell types: parietal epithelial cells (PECs) and podocytes. 

Using predictive models, we showed that the presence of activated PECs and the loss of podocyte markers were associated with worse kidney outcomes. 

These findings may help clinicians better identify high-risk patients and tailor treatment strategies accordingly.

NB: part of the resulst of this abstract was presented at the 15th International Podocyte Conference