Urine podocin:nephrin mRNA ratio (PNR) as a podocyte stress biomarker

Fukuda, Akira; Wickman, Larysa; Venkatareddy, Madhusudan; Wang, Su Q.; Chowdhury, Mosharaf; Wiggins, Jocelyn; Shedden, Kerby; Wiggins, Roger C.

doi:10.1093/ndt/gfs313

Cited by 72 publications

(86 citation statements)

References 44 publications

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“…Furthermore, podocyte stress was also increased in the older group, as assessed by comparing two mRNA species from the same cell that we have previously reported as reflecting podocyte stress (the urine podocin-to-nephrin mRNA ratio). 32 Thus, in older age, podocytes are more stressed and podocytes are detaching in greater amounts.…”

Section: Resultsmentioning

confidence: 99%

Glomerular Aging and Focal Global Glomerulosclerosis

Hodgin¹,

Bitzer²,

Wickman

et al. 2015

Journal of the American Society of Nephrology

181

237

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Kidney aging is associated with an increasing proportion of globally scarred glomeruli, decreasing renal function, and exponentially increasing ESRD prevalence. In model systems, podocyte depletion causes glomerulosclerosis, suggesting age-associated glomerulosclerosis could be caused by a similar mechanism. We measured podocyte number, size, density, and glomerular volume in 89 normal kidney samples from living and deceased kidney donors and normal poles of nephrectomies. Podocyte nuclear density decreased with age due to a combination of decreased podocyte number per glomerulus and increased glomerular volume. Compensatory podocyte cell hypertrophy prevented a change in the proportion of tuft volume occupied by podocytes. Young kidneys had high podocyte reserve (podocyte density .300 per 10 6 mm 3 ), but by 70-80 years of age, average podocyte nuclear density decreased to, ,100 per 10 6 mm 3 , with corresponding podocyte hypertrophy. In older age podocyte detachment rate (urine podocin mRNA-to-creatinine ratio) was higher than at younger ages and podocytes were stressed (increased urine podocin-to-nephrin mRNA ratio). Moreover, in older kidneys, proteinaceous material accumulated in the Bowman space of glomeruli with low podocyte density. In a subset of these glomeruli, mass podocyte detachment events occurred in association with podocytes becoming binucleate (mitotic podocyte catastrophe) and subsequent wrinkling of glomerular capillaries, tuft collapse, and periglomerular fibrosis. In kidneys of young patients with underlying glomerular diseases similar pathologic events were identified in association with focal global glomerulosclerosis. Podocyte density reduction with age may therefore directly lead to focal global glomerulosclerosis, and all progressive glomerular diseases can be considered superimposed accelerators of this underlying process.

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Section: Resultsmentioning

confidence: 99%

Glomerular Aging and Focal Global Glomerulosclerosis

Hodgin¹,

Bitzer²,

Wickman

et al. 2015

Journal of the American Society of Nephrology

181

237

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“…Proteins encoded by these genes may be detected in plasma and urine and provide a noninvasive means to measure organ function in a cell-lineage-specific manner. In contrast to ubiquitously expressed molecules involved in fibrosis and inflammation, which are currently the most common source of candidate biomarkers for chronic diseases, cell-lineage-specific biomarkers are less likely to be confounded by extrarenal processes and should provide superior diagnostic specificity (Fukuda et al 2012). This has been demonstrated in the context of podocyte failure in model systems and human disease (Sato et al 2009), and nanodissection provides an opportunity to expand the scope of podocyte-specific transcripts analyzed in a complex mixture of urinary cells by these approaches.…”

Section: Discussionmentioning

confidence: 99%

Defining cell-type specificity at the transcriptional level in human disease

et al. 2013

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Cell-lineage–specific transcripts are essential for differentiated tissue function, implicated in hereditary organ failure, and mediate acquired chronic diseases. However, experimental identification of cell-lineage–specific genes in a genome-scale manner is infeasible for most solid human tissues. We developed the first genome-scale method to identify genes with cell-lineage–specific expression, even in lineages not separable by experimental microdissection. Our machine-learning–based approach leverages high-throughput data from tissue homogenates in a novel iterative statistical framework. We applied this method to chronic kidney disease and identified transcripts specific to podocytes, key cells in the glomerular filter responsible for hereditary and most acquired glomerular kidney disease. In a systematic evaluation of our predictions by immunohistochemistry, our in silico approach was significantly more accurate (65% accuracy in human) than predictions based on direct measurement of in vivo fluorescence-tagged murine podocytes (23%). Our method identified genes implicated as causal in hereditary glomerular disease and involved in molecular pathways of acquired and chronic renal diseases. Furthermore, based on expression analysis of human kidney disease biopsies, we demonstrated that expression of the podocyte genes identified by our approach is significantly related to the degree of renal impairment in patients. Our approach is broadly applicable to define lineage specificity in both cell physiology and human disease contexts. We provide a user-friendly website that enables researchers to apply this method to any cell-lineage or tissue of interest. Identified cell-lineage–specific transcripts are expected to play essential tissue-specific roles in organogenesis and disease and can provide starting points for the development of organ-specific diagnostics and therapies.

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“…[1][2][3][4][5][14][15][16][17] As outlined in the introduction, these concepts are collectively captured as the podocyte depletion hypothesis. No other mechanism of progression of glomerular diseases that is independent of podocyte injury and depletion has yet been proven to exist.…”

Section: Discussionmentioning

confidence: 99%

“…4,14 Model systems demonstrate that throughout the progression process podocytes continue to detach and appear in the urine, where they can be monitored noninvasively through quantitation of urine pellet mRNAs. [14][15][16][17] All progressors includes all patients with biopsy-proven GNs who halved their eGFR and/or progressed to ESRD requiring RRTs. eGFR progressors had biopsy-proven GNs who halved their eGFR during the observation period.…”

mentioning

confidence: 99%

Urine Podocyte mRNAs, Proteinuria, and Progression in Human Glomerular Diseases

Wickman¹,

Afshinnia²,

Wang³

et al. 2013

Journal of the American Society of Nephrology

113

121

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Model systems demonstrate that progression to ESRD is driven by progressive podocyte depletion (the podocyte depletion hypothesis) and can be noninvasively monitored through measurement of urine pellet podocyte mRNAs. To test these concepts in humans, we analyzed urine pellet mRNAs from 358 adult and pediatric kidney clinic patients and 291 controls (n=1143 samples). Compared with controls, urine podocyte mRNAs increased 79-fold (P,0.001) in patients with biopsy-proven glomerular disease and a 50% decrease in kidney function or progression to ESRD. An independent cohort of patients with Alport syndrome had a 23-fold increase in urinary podocyte mRNAs (P,0.001 compared with controls). Urinary podocyte mRNAs increased during active disease but returned to baseline on disease remission. Furthermore, urine podocyte mRNAs increased in all categories of glomerular disease evaluated, but levels ranged from high to normal, consistent with individual patient variability in the risk for progression. In contrast, urine podocyte mRNAs did not increase in polycystic kidney disease. The association between proteinuria and podocyturia varied markedly by glomerular disease type: a high correlation in minimalchange disease and a low correlation in membranous nephropathy. These data support the podocyte depletion hypothesis as the mechanism driving progression in all human glomerular diseases, suggest that urine pellet podocyte mRNAs could be useful for monitoring risk for progression and response to treatment, and provide novel insights into glomerular disease pathophysiology.

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Urine podocin:nephrin mRNA ratio (PNR) as a podocyte stress biomarker

Abstract: We concluded that the PNR, used in combination with proteinuria, will be worth testing for its clinical diagnostic and decision-making utility.

Cited by 72 publications

References 44 publications

Glomerular Aging and Focal Global Glomerulosclerosis

Glomerular Aging and Focal Global Glomerulosclerosis

Defining cell-type specificity at the transcriptional level in human disease

Urine Podocyte mRNAs, Proteinuria, and Progression in Human Glomerular Diseases

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