Urinary podocyte mRNAs precede microalbuminuria as a progression risk marker in human type 2 diabetic nephropathy

• Published in: Scientific reports Vol. 10; no. 1; p. 18209
• Main Authors: Fukuda, Akihiro, Minakawa, Akihiro, Kikuchi, Masao, Sato, Yuji, Nagatomo, Masanao, Nakamura, Shuji, Mizoguchi, Tetsu, Fukunaga, Naoya, Shibata, Hirotaka, Naik, Abhijit S., Wiggins, Roger C., Fujimoto, Shouichi
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23.10.2020; Nature Publishing Group
• Subjects: 692/163; 692/4022; 692/53; Albuminuria - urine; Aquaporin 2; Biomarkers - urine; Creatinine; Cross-Sectional Studies; Diabetes; Diabetes mellitus; Diabetes Mellitus, Type 2 - complications; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - urine; Diabetic Nephropathies - complications; Diabetic Nephropathies - genetics; Diabetic Nephropathies - urine; Diabetic nephropathy; Disease Progression; Epidermal growth factor receptors; Female; Glomerular Filtration Rate; Humanities and Social Sciences; Humans; Male; mRNA; multidisciplinary; Nephropathy; Podocytes - metabolism; Risk Factors; RNA, Messenger - metabolism; Science; Science (multidisciplinary)
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-75320-1

Earlier detection of progression risk in diabetic nephropathy will allow earlier intervention to reduce progression. The hypothesis that urinary pellet podocyte mRNA is a more sensitive progression risk marker than microalbuminuria was tested. A cross sectional cohort of 165 type 2 diabetics and 41 age and sex-matched controls were enrolled. Podocyte stress (Urinary pellet podocin:nephrin mRNA ratio), podocyte detachment (Urinary pellet podocin mRNA:creatinine ratio: UPPod:CR) and a tubular marker (Urinary pellet aquaporin 2:creatinine ratio) were measured in macro-albuminuric, micro-albuminuric and norm-albuminuric groups. eGFR was reassessed after 4 years in 124 available diabetic subjects. Urinary pellet podocyte and tubular mRNA markers were increased in all diabetic groups in cross-sectional analysis. After 4 years of follow-up univariable and multivariate model analysis showed that the only urinary markers significantly related to eGFR slope were UPPod:CR ( P  < 0.01) and albuminuria ( P  < 0.01). AUC analysis using K-fold cross validation to predict eGFR loss of ≥ 3 ml/min/1.73m 2 /year showed that UPPod:CR and albuminuria each improved the AUC similarly such that combined with clinical variables they gave an AUC = 0.70. Podocyte markers and albuminuria had overlapping AUC contributions, as expected if podocyte depletion causes albuminuria. In the norm-albuminuria cohort (n = 75) baseline UPPod:CR was associated with development of albuminuria ( P  = 0.007) and, in the tertile with both normal kidney function (eGFR 84 ± 11.7 ml/min/1.73m 2 ) and norm-albuminuria at baseline, UPPod:CR was associated with eGFR loss rate ( P  = 0.003). In type 2 diabetics with micro- or macro-albuminuria UPPod:CR and albuminuria were equally good at predicting eGFR loss. For norm-albuminuric type 2 diabetics UPPod:CR predicted both albuminuria and eGFR loss.