Browsing by Subject "Proteinuria"

Now showing 1 - 4 of 4
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    Altered O-glycomes of Renal Brush-Border Membrane in Model Rats with Chronic Kidney Diseases
    (MDPI, 2021-10-21) Yu, Aiying; Zhao, Jingfu; Zhong, Jieqiang; Wang, Junyao; Yadav, Shiv Pratap S.; Molitoris, Bruce A.; Wagner, Mark C.; Mechref, Yehia; Medicine, School of Medicine
    Chronic kidney disease (CKD) is defined as a decrease in renal function or glomerular filtration rate (GFR), and proteinuria is often present. Proteinuria increases with age and can be caused by glomerular and/or proximal tubule (PT) alterations. PT cells have an apical brush border membrane (BBM), which is a highly dynamic, organized, and specialized membrane region containing multiple glycoproteins required for its functions including regulating uptake, secretion, and signaling dependent upon the physiologic state. PT disorders contribute to the dysfunction observed in CKD. Many glycoprotein functions have been attributed to their N- and O-glycans, which are highly regulated and complex. In this study, the O-glycans present in rat BBMs from animals with different levels of kidney disease and proteinuria were characterized and analyzed using liquid chromatography tandem mass spectrometry (LC-MS/MS). A principal component analysis (PCA) documented that each group has distinct O-glycan distributions. Higher fucosylation levels were observed in the CKD and diabetic groups, which may contribute to PT dysfunction by altering physiologic glycoprotein interactions. Fucosylated O-glycans such as 1-1-1-0 exhibited higher abundance in the severe proteinuric groups. These glycomic results revealed that differential O-glycan expressions in CKD progressions has the potential to define the mechanism of proteinuria in kidney disease and to identify potential therapeutic interventions.
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    Bevacizumab-induced hypertension and proteinuria: a genome-wide study of more than 1000 patients
    (Springer Nature, 2022) Quintanilha, Julia C.F.; Wang, Jin; Sibley, Alexander B.; Jiang, Chen; Etheridge, Amy S.; Shen, Fei; Jiang, Guanglong; Mulkey, Flora; Patel, Jai N.; Hertz, Daniel L.; Dees, Elizabeth Claire; McLeod, Howard L.; Bertagnolli, Monica; Rugo, Hope; Kindler, Hedy L.; Kelly, William Kevin; Ratain, Mark J.; Kroetz, Deanna L.; Owzar, Kouros; Schneider, Bryan P.; Lin, Danyu; Innocenti, Federico; Medicine, School of Medicine
    Background: Hypertension and proteinuria are common bevacizumab-induced toxicities. No validated biomarkers are available for identifying patients at risk of these toxicities. Methods: A genome-wide association study (GWAS) meta-analysis was performed in 1039 bevacizumab-treated patients of European ancestry in four clinical trials (CALGB 40502, 40503, 80303, 90401). Grade ≥2 hypertension and proteinuria were recorded (CTCAE v.3.0). Single-nucleotide polymorphism (SNP)-toxicity associations were determined using a cause-specific Cox model adjusting for age and sex. Results: The most significant SNP associated with hypertension with concordant effect in three out of the four studies (p-value <0.05 for each study) was rs6770663 (A > G) in KCNAB1, with the G allele increasing the risk of hypertension (p-value = 4.16 × 10-6). The effect of the G allele was replicated in ECOG-ACRIN E5103 in 582 patients (p-value = 0.005). The meta-analysis of all five studies for rs6770663 led to p-value = 7.73 × 10-8, close to genome-wide significance. The most significant SNP associated with proteinuria was rs339947 (C > A, between DNAH5 and TRIO), with the A allele increasing the risk of proteinuria (p-value = 1.58 × 10-7). Conclusions: The results from the largest study of bevacizumab toxicity provide new markers of drug safety for further evaluations. SNP in KCNAB1 validated in an independent dataset provides evidence toward its clinical applicability to predict bevacizumab-induced hypertension.
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    Changes in proteinuria and albuminuria with initiation of antiretroviral therapy: data from a randomized trial comparing tenofovir disoproxil fumarate/emtricitabine versus abacavir/lamivudine
    (Ovid Technologies (Wolters Kluwer) - Lippincott Williams & Wilkins, 2014-09-01) Wyatt, Christina M.; Kitch, Douglas; Gupta, Samir K.; Tierney, Camlin; Daar, Eric S.; Sax, Paul E.; Ha, Belinda; Melbourne, Kathleen; McComsey, Grace A.; AIDS Clinical Trials Group Study A5224s Team; Department of Medicine, IU School of Medicine
    BACKGROUND: Antiretroviral therapy (ART) is associated with improved kidney function; however, the nucleotide reverse transcriptase inhibitor (NRTI) tenofovir disoproxil fumarate (TDF) has been associated with decreased kidney function and proteinuria. METHODS: We examined changes in urine protein:creatinine (UPCR) and urine albumin:creatinine (UACR) ratios in 245 ART-naive participants in A5202 randomized in a substudy to blinded NRTI (abacavir/lamivudine, ABC/3TC, n = 124 or TDF/emtricitabine, TDF/FTC, n = 121) with open-label protease inhibitor (PI) atazanavir/ritonavir or nonnucleoside reverse transcriptase inhibitor (NNRTI) efavirenz. RESULTS: At baseline, 18% of participants had clinically significant proteinuria (UPCR ≥200 mg/g), and 11% had clinically significant albuminuria (UACR ≥30 mg/g). The prevalence of clinically significant proteinuria and albuminuria decreased from baseline to week 96 in all treatment groups. In intention-to-treat analyses, there was a significant effect of NRTI component on fold change in UPCR (P = 0.011) and UACR (P = 0.018) from baseline to week 96, with greater improvements in participants randomized to ABC/3TC. There was no significant effect of NNRTI/PI component on fold change in UPCR (P = 0.23) or UACR (P = 0.88), and no significant interactions between NRTI and NNRTI/PI components. CONCLUSIONS: In this prespecified secondary analysis, ART initiation was associated with improvements in proteinuria and albuminuria, with significantly greater improvements in participants randomized to ABC/3TC versus TDF/FTC. These are the first data from a randomized trial to suggest that initiation of TDF/FTC may not be associated with the same degree of improvement in proteinuria and albuminuria that have been reported with other regimens. Future studies should consider the long-term clinical significance of these findings.
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    Changes in the Expression of Renal Brush Border Membrane N-Glycome in Model Rats with Chronic Kidney Diseases
    (MDPI, 2021-11-11) Yu, Aiying; Zhao, Jingfu; Yadav, Shiv Pratap S.; Molitoris, Bruce A.; Wagner, Mark C.; Mechref, Yehia; Medicine, School of Medicine
    Chronic kidney disease (CKD) is defined by a reduced renal function i.e., glomerular filtration rate (GFR), and the presence of kidney damage is determined by measurement of proteinuria or albuminuria. Albuminuria increases with age and can result from glomerular and/or proximal tubule (PT) alterations. Brush-border membranes (BBMs) on PT cells play an important role in maintaining the stability of PT functions. The PT BBM, a highly dynamic, organized, specialized membrane, contains a variety of glycoproteins required for the functions of PT. Since protein glycosylation regulates many protein functions, the alteration of glycosylation due to the glycan changes has attracted more interests for a variety of disease studies recently. In this work, liquid chromatography-tandem mass spectrometry was utilized to analyze the abundances of permethylated glycans from rats under control to mild CKD, severe CKD, and diabetic conditions. The most significant differences were observed in sialylation level with the highest present in the severe CKD and diabetic groups. Moreover, high mannose N-glycans was enriched in the CKD BBMs. Characterization of all the BBM N-glycan changes supports that these changes are likely to impact the functional properties of the dynamic PT BBM. Further, these changes may lead to the potential discovery of glycan biomarkers for improved CKD diagnosis and new avenues for therapeutic treatments.