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CD4+-T-cell Derived Inflammatory Mediators as Biomarkers for Diagnosis of Acute Interstitial Nephritis.

Record Type:	Electronic resources : Monograph/item
Title/Author:	CD4+-T-cell Derived Inflammatory Mediators as Biomarkers for Diagnosis of Acute Interstitial Nephritis./
Author:	Moledina, Dennis G.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2018,
Description:	93 p.
Notes:	Source: Dissertations Abstracts International, Volume: 80-09, Section: B.
Contained By:	Dissertations Abstracts International80-09B.
Subject:	Medicine. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=13841702
ISBN:	9780438907669

CD4+-T-cell Derived Inflammatory Mediators as Biomarkers for Diagnosis of Acute Interstitial Nephritis.
Moledina, Dennis G.

CD4+-T-cell Derived Inflammatory Mediators as Biomarkers for Diagnosis of Acute Interstitial Nephritis. - Ann Arbor : ProQuest Dissertations & Theses, 2018 - 93 p.

Source: Dissertations Abstracts International, Volume: 80-09, Section: B.

Thesis (Ph.D.)--Yale University, 2018.

This item must not be added to any third party search indexes.

Background Acute interstitial nephritis (AIN) is a common cause of acute kidney disease (AKD). While it is one of the few treatable causes of AKD, AIN can lead to permanent kidney damage if it is not diagnosed and treated promptly. Since there is no typical sign, symptom, or non-invasive diagnostic test for AIN, current diagnosis requires a high index of clinical suspicion for this disease and often a kidney biopsy for confirmation. A noninvasive diagnostic biomarker for AIN could lead to timely clinical management of this disease and prevent occurrence of permanent kidney damage. I hypothesize that AIN is an allergic reaction to drugs, which is mediated by CD4+T-cells and predict that cytokines derived from these cells would be higher in AIN participants than those without AIN. Methods Since the diagnosis of AIN can only be established by histological examination of kidney tissue, fIenrolled patients who underwent a kidney biopsy for evaluation of AKD. From 2015 to 2017, I enrolled 155 consecutive participants at two Yale-affiliated academic hospitals in New Haven, CT. A diagnosis of AIN was established by agreement of at least two out of three renal pathologists, who were blinded to clinical scenario and clinical biopsy reports. I created a multivariable model for adjudicated AIN diagnosis using interstitial histological features reported by individual pathologists. In aim 1, I measured cytokines derived from CD4+T cells [Th1: interferon (IFN)-γ, interleukin (IL)-2, and tumor necrosis factor (TNF)-α; Th2: IL-4, IL-5, IL-9, and IL-13] in banked plasma and urine samples collected before the biopsy. I used Mesoscale Discovery multiplex platform, which is a modified sandwich immunoassay. I tested the univariable association of cytokines with AIN and with interstitial histological features. In aim 2, I created two "AIN diagnostic indices" by fitting multivariable logistic regression models for outcome of AIN. I used currently available clinical features and diagnostic tests as predictors to create "AIN diagnostic index 1." Next, I added novel biomarkers to AIN diagnostic index 1. I reported discrimination of multivariable models using area under receiver-operating characteristic curve (AUC) and compared sequential models using likelihood ratio test. Results Of the 155 study participants, 35 (23%) had AIN, whereas 120 had other diagnoses including acute tubular injury (n=36), diabetic kidney disease (n=15), arterionephrosclerosis (n=19), glomerular disease (n=40), and others (n=10). I noted moderate inter-rater agreement for AIN diagnosis (Fleiss Kappa 0.40) and interstitial eosinophils (0.46), whereas the inter-rater agreement was lower for interstitial infiltrate (0.26) and tubulitis (0.27). A multivariable model containing these three interstitial features reported by individual pathologists had an AUC of 0.89 (95% CI, 0.85-0.93) for adjudicated AIN diagnosis. As compared with participants without AIN, those with AIN had higher median (interquartile range) urine TNF-α [1.07 (0.31-6.53) vs. 0.26 (0.17-0.78), P<0.001] and IL-9 [0.56 (0.22-1.12) vs. 0.25 (0.10-0.55), P=0.01]. Urine TNF-α and IL-9 levels were also higher in participants with higher severity of interstitial histological features. These results were consistent across all sensitivity analyses including adjusting for urine concentration, comparing AIN to those with acute tubular injury, and using alternate AIN definitions. Urine IL-2 levels were higher in some but not all analyses, whereas the other urinary cytokines were comparable between participants with AIN and those without AIN. Plasma cytokines were comparable between participants with AIN and those without AIN. The clinical nephrologist's pre-biopsy suspicion for AIN had an AUC for adjudicated AIN diagnosis of 0.60 (0.51-0.69). AIN diagnostic index 1, consisting of participant sex, a marker of allergic reaction (blood eosinophil count), and a marker of glomerular injury (proteinuria), had an AUC of 0.71 (0.61-0.82). Addition of TNF-α and IL-9 to AIN diagnostic index 1 improved the AUC to 0.82 (0.73-0.90; P<0.001). Conclusions Urine cytokines TNF-α and IL-9 were higher in participants with AIN than in those without AIN. These biomarkers significantly improved discrimination for AIN compared with clinical nephrologists' prebiopsy suspicion of AIN and a model containing clinically available variables. Given that the pathway determining cytokines in the Th1- (IFN-γ) and Th2- (IL-4, IL-13) pathway were comparable between AIN and controls, my results indicate that Th1/Th2-cells may not be the primary mediators of this disease. In contrast, given the consistently higher IL-9 and TNF-α in participants with AIN, this disease is likely to be mediated by Th9derived IL-9-dependent activation of mast cells, which produce TNF-α. This is consistent with the role of Th9 cells and mast cells in other allergic diseases and could be further evaluated in future studies.

ISBN: 9780438907669Subjects--Topical Terms:

641104
Medicine.

CD4+-T-cell Derived Inflammatory Mediators as Biomarkers for Diagnosis of Acute Interstitial Nephritis.
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100 1 $a Moledina, Dennis G. $3 3437902
245 1 0 $a CD4+-T-cell Derived Inflammatory Mediators as Biomarkers for Diagnosis of Acute Interstitial Nephritis.
260 1 $a Ann Arbor : $b ProQuest Dissertations & Theses, $c 2018
300 $a 93 p.
500 $a Source: Dissertations Abstracts International, Volume: 80-09, Section: B.
500 $a Publisher info.: Dissertation/Thesis.
500 $a Advisor: Parikh, Chirag R.
502 $a Thesis (Ph.D.)--Yale University, 2018.
506 $a This item must not be added to any third party search indexes.
506 $a This item must not be sold to any third party vendors.
520 $a Background Acute interstitial nephritis (AIN) is a common cause of acute kidney disease (AKD). While it is one of the few treatable causes of AKD, AIN can lead to permanent kidney damage if it is not diagnosed and treated promptly. Since there is no typical sign, symptom, or non-invasive diagnostic test for AIN, current diagnosis requires a high index of clinical suspicion for this disease and often a kidney biopsy for confirmation. A noninvasive diagnostic biomarker for AIN could lead to timely clinical management of this disease and prevent occurrence of permanent kidney damage. I hypothesize that AIN is an allergic reaction to drugs, which is mediated by CD4+T-cells and predict that cytokines derived from these cells would be higher in AIN participants than those without AIN. Methods Since the diagnosis of AIN can only be established by histological examination of kidney tissue, fIenrolled patients who underwent a kidney biopsy for evaluation of AKD. From 2015 to 2017, I enrolled 155 consecutive participants at two Yale-affiliated academic hospitals in New Haven, CT. A diagnosis of AIN was established by agreement of at least two out of three renal pathologists, who were blinded to clinical scenario and clinical biopsy reports. I created a multivariable model for adjudicated AIN diagnosis using interstitial histological features reported by individual pathologists. In aim 1, I measured cytokines derived from CD4+T cells [Th1: interferon (IFN)-γ, interleukin (IL)-2, and tumor necrosis factor (TNF)-α; Th2: IL-4, IL-5, IL-9, and IL-13] in banked plasma and urine samples collected before the biopsy. I used Mesoscale Discovery multiplex platform, which is a modified sandwich immunoassay. I tested the univariable association of cytokines with AIN and with interstitial histological features. In aim 2, I created two "AIN diagnostic indices" by fitting multivariable logistic regression models for outcome of AIN. I used currently available clinical features and diagnostic tests as predictors to create "AIN diagnostic index 1." Next, I added novel biomarkers to AIN diagnostic index 1. I reported discrimination of multivariable models using area under receiver-operating characteristic curve (AUC) and compared sequential models using likelihood ratio test. Results Of the 155 study participants, 35 (23%) had AIN, whereas 120 had other diagnoses including acute tubular injury (n=36), diabetic kidney disease (n=15), arterionephrosclerosis (n=19), glomerular disease (n=40), and others (n=10). I noted moderate inter-rater agreement for AIN diagnosis (Fleiss Kappa 0.40) and interstitial eosinophils (0.46), whereas the inter-rater agreement was lower for interstitial infiltrate (0.26) and tubulitis (0.27). A multivariable model containing these three interstitial features reported by individual pathologists had an AUC of 0.89 (95% CI, 0.85-0.93) for adjudicated AIN diagnosis. As compared with participants without AIN, those with AIN had higher median (interquartile range) urine TNF-α [1.07 (0.31-6.53) vs. 0.26 (0.17-0.78), P<0.001] and IL-9 [0.56 (0.22-1.12) vs. 0.25 (0.10-0.55), P=0.01]. Urine TNF-α and IL-9 levels were also higher in participants with higher severity of interstitial histological features. These results were consistent across all sensitivity analyses including adjusting for urine concentration, comparing AIN to those with acute tubular injury, and using alternate AIN definitions. Urine IL-2 levels were higher in some but not all analyses, whereas the other urinary cytokines were comparable between participants with AIN and those without AIN. Plasma cytokines were comparable between participants with AIN and those without AIN. The clinical nephrologist's pre-biopsy suspicion for AIN had an AUC for adjudicated AIN diagnosis of 0.60 (0.51-0.69). AIN diagnostic index 1, consisting of participant sex, a marker of allergic reaction (blood eosinophil count), and a marker of glomerular injury (proteinuria), had an AUC of 0.71 (0.61-0.82). Addition of TNF-α and IL-9 to AIN diagnostic index 1 improved the AUC to 0.82 (0.73-0.90; P<0.001). Conclusions Urine cytokines TNF-α and IL-9 were higher in participants with AIN than in those without AIN. These biomarkers significantly improved discrimination for AIN compared with clinical nephrologists' prebiopsy suspicion of AIN and a model containing clinically available variables. Given that the pathway determining cytokines in the Th1- (IFN-γ) and Th2- (IL-4, IL-13) pathway were comparable between AIN and controls, my results indicate that Th1/Th2-cells may not be the primary mediators of this disease. In contrast, given the consistently higher IL-9 and TNF-α in participants with AIN, this disease is likely to be mediated by Th9derived IL-9-dependent activation of mast cells, which produce TNF-α. This is consistent with the role of Th9 cells and mast cells in other allergic diseases and could be further evaluated in future studies.
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