In IgA Nephropathy, Glomerulosclerosis Is Associated with Increased Urinary CD80 Excretion and Urokinase-Type Plasminogen Activator Receptor-Positive Podocyturia

Abstract

Background: Podocyturia may determine the evolution to podocytopenia, glomerulosclerosis, and renal failure. According to the Oxford classification of IgA nephropathy (IgAN), the S1 lesion describes glomerulosclerosis. Urokinase-type plasminogen activator receptor (uPAR) participates in podocyte attachment, while CD80 increases in glomerulosclerosis. We measured uPAR-positive urinary podocytes and urinary CD80 (uCD80) in controls and in IgAN subjects with M1E0S0T0 and M1E0S1T0 Oxford scores to assess a potential association between podocyturia, inflammation, and glomerulosclerosis. Methods: The groups were as follows: controls (G1), n = 20 and IgAN group (G2), n = 39, subdivided into M1E0S0T0 (G2A), n = 21 and M1E0S1T0 (G2B), n = 18. Among the included variables, we determined uPAR-positive podocytes/gram of urinary creatinine (gUrCr) and uCD80 ng/gUrCr. Biopsies with interstitial fibrosis and tubular atrophy <10% were included. Results: Groups were not different in age and gender; urinary protein-creatinine (uP/C) ratio, Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equation, uPAR-positive podocytes/gUrCr, and uCD80 were significantly increased in G2 versus G1. G2A and G2B were not different in age, gender, hypertension, and follow-up. G2B displayed significantly higher uP/C, uPAR-positive podocytes, uCD80, and lower CKD-EPI versus G2A. Strong significant correlations were encountered between uCD80 and podocyturia in G2A and G2B. However, when G1 was compared to G2A and G2B separately, the differences with respect to uP/C, uPAR-positive podocytes, and podocyturia were significantly stronger versus G2B than versus G2A. Conclusions: IgAN presents elevated uCD80 excretion and uPAR-positive podocyturia, while CD80 correlates with podocyturia. Glomerulosclerosis (S1) at the time of biopsy is associated with higher uP/C, lower renal function, increased uPAR-positive podocyturia, and CD80 excretion, and is independent of M1. In IgAN, uPAR may participate in podocyte detachment.

IgA nephropathy: “State of the art”: a report from the 15th International Symposium on IgA Nephropathy celebrating the 50th anniversary of its first description

“…16 Podocyturia and podocyte-specific molecules shed into the urine may yet prove valuable tools for pathophysiologic investigations in IgAN, but such studies have suffered from lack of standardization, cellular instability, and lack of suitable podocyte markers. 17,18 Debate also continues over the importance of vascular lesions in IgAN, in particular those associated with endothelial injury and thrombotic microangiopathy. 19,20 The reported fraction of IgAN patients with morphologic lesions of thrombotic microangiopathy varies greatly from 2% to 50%.…”

“…23,24 A number of putative IgAN-specific biomarkers were discussed, including serum levels of Gd-IgA1, Gd-IgA1-specific autoantibodies, and IgA-IgG immune complexes; urinary Gd-IgA1, CD89, CD71, and podocyte urokinase-type plasminogen activator receptor. 18,[25][26][27] Each of these biomarkers now needs to be evaluated in the new risk prediction model that provides a study platform to see whether they add value in predicting risk and guiding clinical decision making in IgAN.…”

Podocyturia: Potential applications and current limitations

“…In nephrotic urines, plasmin is elevated due to the upregulated action of uPA, and its receptor uPAR is highly expressed in urinary podocytes[ 21 , 22 ]. These findings suggest that uPAR is involved in podocyte detachment, probably via activation of αVβ3-integrin[ 16 , 23 , 24 ]. Employing immunofluorescent microscopy, we have demonstrated that in patients with IgA nephropathy and Fabry disease, uPAR is present in the cytoplasm of urinary podocytes.…”

“…Employing immunofluorescent microscopy, we have demonstrated that in patients with IgA nephropathy and Fabry disease, uPAR is present in the cytoplasm of urinary podocytes. In the case of IgA nephropathy, the number of uPAR + detached podocyte is significantly higher than controls and in patients with glomerular sclerotic lesions compared to those without (M1E0S1T0 vs M1E0S0T0 according to Oxford classification)[ 24 ]. Moreover, by western blot analysis as well as by PCR techniques we have confirmed the presence of elevated concentrations of uPAR in Fabry podocytes[ 23 ].…”

A Personalized Update on IgA Nephropathy: A New Vision and New Future Challenges

“…Urokinase-type plasminogen activator receptor (uPAR) may participate in podocyte attachment. uPAR could play a fundamental role in the process of irreversible podocyte detachment through progression to kidney failure via glomerular podocytopenia and glomerulosclerosis [68]. In this sense, the use of amiloride could be useful to avoid podocyte detachment by blocking uPAR synthesis.…”