Abstract
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/1.73m2/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/1.73m2) 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.
Highlights
Earlier detection of progression risk in diabetic nephropathy will allow earlier intervention to reduce progression
In this report we assessed whether or not urinary pellet cell-specific mRNAs for podocytes might serve as early markers for detecting progression in a cohort of type 2 diabetics
The study was presaged by the observation that urinary pellet podocyte markers increased significantly prior to onset of albuminuria in a model of type 2 diabetes-associated nephropathy in the Zucker rat[37]
Summary
Earlier detection of progression risk in diabetic nephropathy will allow earlier intervention to reduce progression. Urinary pellet podocyte and tubular mRNA markers were increased in all diabetic groups in cross-sectional analysis. AUC analysis using K-fold cross validation to predict eGFR loss of ≥ 3 ml/ min/1.73m2/year showed that UPPod:CR and albuminuria each improved the AUC such that combined with clinical variables they gave an AUC = 0.70. In type 2 diabetics with micro- or macro-albuminuria UPPod:CR and albuminuria were good at predicting eGFR loss. Increased urinary albumin excretion represents the net difference between increased leak of albumin through the glomerular filtration barrier and the capacity of the proximal tubule to reabsorb filtered albumin from the tubular lumen Both glomerular and tubular mechanisms can contribute to net albumin excretion, suggesting that albuminuria will tend to be an insensitive and non-specific marker at early stages it will become more reliable as disease advances
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