Histogenomics: Association of Gene Expression Patterns With Histological Parameters in Kidney Biopsies

Perco, Paul; Kainz, Alexander; Wilflingseder, Julia; Soleiman, Afschin; Mayer, Bernd; Oberbauer, Rainer

doi:10.1097/tp.0b013e318191b4c0

Cited by 38 publications

(26 citation statements)

References 36 publications

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“…50,51 Coupled with the excellent 5-year graft survival for this group, the results suggest that early IF of LD KTx, although common and linked with increased inflammatory activity, 9,26,52 may be self-limiting or associated with alternative immunologic pathways in the majority of cases. 53 In contrast to some gene expression studies of biopsies for cause, 29,35,36,40,54 we found in early surveillance biopsies with IF alone or IFϩi that neither TLDA nor microarray analyses demonstrated broadly increased expression of transcripts related to extracellular matrix or profibrotic pathways. Furthermore, although in some settings alterations in "kidney response to injury" genes (termed lowPIPKAT genes in this study) have been linked with early graft damage, 10,50,52 we found that virtually all of the altered gene expression in the IFϩi grafts may be attributed to the infiltrating cells.…”

Section: Discussioncontrasting

confidence: 47%

“…Thus, in specific circumstances, the information provided by gene expression analyses may be used to enhance rather than replace that provided by graft pathology. Finally, in common with the work published by others in the field, 18,20,23,25,29,40,54,56 our TLDA and microarray analyses contribute to a growing publicly available databank of expression profiles from KTx recipients with diverse characteristics and provide a basis for ongoing mechanistic investigation of renal allograft injury and repair.…”

Section: Discussionmentioning

confidence: 97%

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Fibrosis with Inflammation at One Year Predicts Transplant Functional Decline

Park

Griffin

Cornell³

et al. 2010

Journal of the American Society of Nephrology

196

168

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Lack of knowledge regarding specific causes for late loss of kidney transplants hampers improvements in long-term allograft survival. Kidney transplants with both interstitial fibrosis and subclinical inflammation but not fibrosis alone after 1 year have reduced survival. This study tested whether fibrosis with inflammation at 1 year associates with decline of renal function in a low-risk cohort and characterized the nature of the inflammation. We studied 151 living-donor, tacrolimus/mycophenolate-treated recipients without overt risk factors for reduced graft survival. Transplants with normal histology (n ϭ 86) or fibrosis alone (n ϭ 45) on 1-year protocol biopsy had stable renal function between 1 and 5 years, whereas those with both fibrosis and inflammation (n ϭ 20) exhibited a decline in GFR and reduced graft survival. Immunohistochemistry confirmed increased interstitial T cells and macrophages/dendritic cells in the group with both fibrosis and inflammation, and there was increased expression of transcripts related to innate and cognate immunity. Pathway-and pathologic process-specific analyses of microarray profiles revealed that potentially damaging immunologic activities were enriched among the overexpressed transcripts (e.g., Toll-like receptor signaling, antigen presentation/dendritic cell maturation, IFN-␥-inducible response, cytotoxic T lymphocyte-associated and acute rejection-associated genes). Therefore, the combination of fibrosis and inflammation in 1-year protocol biopsies associates with reduced graft function and survival as well as a rejection-like gene expression signature, even among recipients with no clinical risk factors for poor outcomes. Early interventions aimed at altering rejection-like inflammation may improve long-term survival of kidney allografts.

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Section: Discussioncontrasting

confidence: 47%

Section: Discussionmentioning

confidence: 97%

Fibrosis with Inflammation at One Year Predicts Transplant Functional Decline

Park

Griffin

Cornell³

et al. 2010

Journal of the American Society of Nephrology

196

168

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“…Our current understanding of the molecular mechanisms underlying post-transplant AKI is mainly based on investigations of IRI [33] and of zero-hour kidney transplant biopsies [34], [35], [36]. To our knowledge only one study so far analyzed the transcriptome of human renal allograft biopsies during AKI [20] which was also used as independent validation set for findings of the current study.…”

Section: Discussionmentioning

confidence: 99%

Molecular Pathogenesis of Post-Transplant Acute Kidney Injury: Assessment of Whole-Genome mRNA and MiRNA Profiles

et al. 2014

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Acute kidney injury (AKI) affects roughly 25% of all recipients of deceased donor organs. The prevention of post-transplant AKI is still an unmet clinical need. We prospectively collected zero-hour, indication as well as protocol kidney biopsies from 166 allografts between 2011 and 2013. In this cohort eight cases with AKI and ten matched allografts without pathology serving as control group were identified with a follow-up biopsy within the first twelve days after engraftment. For this set the zero-hour and follow-up biopsies were subjected to genome wide microRNA and mRNA profiling and analysis, followed by validation in independent expression profiles of 42 AKI and 21 protocol biopsies for strictly controlling the false discovery rate. Follow-up biopsies of AKI allografts compared to time-matched protocol biopsies, further baseline adjustment for zero-hour biopsy expression level and validation in independent datasets, revealed a molecular AKI signature holding 20 mRNAs and two miRNAs (miR-182-5p and miR-21-3p). Next to several established biomarkers such as lipocalin-2 also novel candidates of interest were identified in the signature. In further experimental evaluation the elevated transcript expression level of the secretory leukocyte peptidase inhibitor (SLPI) in AKI allografts was confirmed in plasma and urine on the protein level (p<0.001 and p = 0.003, respectively). miR-182-5p was identified as a molecular regulator of post-transplant AKI, strongly correlated with global gene expression changes during AKI. In summary, we identified an AKI-specific molecular signature providing the ground for novel biomarkers and target candidates such as SLPI and miR-182-5p in addressing AKI.

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“…Nephrology researchers have begun to employ these innovative high-throughput procedures to identify the whole basal expression profile of normal or pathological human kidney [100], to select biomarkers predicting acute and chronic allograft outcomes [101,102] and to assess more clearly the intricate molecular pathways associated to the pathogenesis and onset of several immunological renal diseases [103,104]. On the contrary, only few reports to date have been published describing the multi-genetic influence on drug response in nephrology.…”

Section: Pharmacogenomics and Immunosuppressive Drugs Used In Clinicamentioning

confidence: 99%

Pharmacogenomics: a new paradigm to personalize treatments in nephrology patients

Zaza

Granata

Sallustio

et al. 2009

Clinical and Experimental Immunology

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SummaryAlthough notable progress has been made in the therapeutic management of patients with chronic kidney disease in both conservative and renal replacement treatments (dialysis and transplantation), the occurrence of medication-related problems (lack of efficacy, adverse drug reactions) still represents a key clinical issue. Recent evidence suggests that adverse drug reactions are major causes of death and hospital admission in Europe and the United States. The reasons for these conditions are represented by environmental/non-genetic and genetic factors responsible for the great inter-patient variability in drugs metabolism, disposition and therapeutic targets. Over the years several genetic settings have been linked, using pharmacogenetic approaches, to the effects and toxicity of many agents used in clinical nephrology. However, these strategies, analysing single gene or candidate pathways, do not represent the gold standard, being the overall pharmacological effects of medications and not typically monogenic traits. Therefore, to identify multi-genetic influence on drug response, researchers and clinicians from different fields of medicine and pharmacology have started to perform pharmacogenomic studies employing innovative whole genomic high-throughput technologies. However, to date, only few pharmacogenomics reports have been published in nephrology underlying the need to enhance the number of projects and to increase the research budget for this important research field. In the future we would expect that, applying the knowledge about an individual's inherited response to drugs, nephrologists will be able to prescribe medications based on each person's genetic make-up, to monitor carefully the efficacy/toxicity of a given drug and to modify the dosage or number of medications to obtain predefined clinical outcomes.

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Histogenomics: Association of Gene Expression Patterns With Histological Parameters in Kidney Biopsies

Abstract: In summary, we identified biomarkers in transplant kidney biopsies, which are predictive for medium-term allograft function.

Cited by 38 publications

References 36 publications

Fibrosis with Inflammation at One Year Predicts Transplant Functional Decline

Fibrosis with Inflammation at One Year Predicts Transplant Functional Decline

Molecular Pathogenesis of Post-Transplant Acute Kidney Injury: Assessment of Whole-Genome mRNA and MiRNA Profiles

Pharmacogenomics: a new paradigm to personalize treatments in nephrology patients

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