1,721,011 research outputs found
Extra-renal adverse effects of mTOR inhibitors: know them to optimize their use in renal transplantation.
No full textThe mammalian target of rapamycin inhibitors (mTOR-I) sirolimus and everolimus represents a class of immunosuppressive drugs largely used in renal transplantation. The main mechanism of action of these drugs is the inhibition of the mammalian target of rapamycin (mTOR), a regulatory protein kinase involved in lymphocyte proliferation. Additionally, the inhibition of the crosstalk among mTORC1, mTORC2 and PI3K confers the anti-neoplastic activities of these drugs. Because of their specific pharmacological characteristics and their relative lack of nephrotoxicity, these inhibitors are a valid option to calcineurine inhibitors (CNIs) for maintenance immunosuppression in renal transplant recipients with chronic allograft damage. However, as other immunosuppressive drugs, mTOR-I may induce the development of several adverse effects (e.g., pulmonary toxicity, hematological disorders, dismetabolism, lymphedema) that need to be early diagnosed and treated to avoid severe illness in renal transplant patients. All these side effects are most of the time reversible and dose related. Therefore, it is unquestionable that these particular drugs should be administered at the lowest dose able to maintain relatively low trough levels, in order to increase their importance and specific therapeutic effects minimizing or avoiding drug toxicities. Utilization of low dosages of mTOR-I should be encouraged not only in CNI-combined schemas, but also when administered alone in CNI-free immunosuppressive protocol
Monoclonal antibody therapy and renal transplantation: focus on adverse effects.
Full text linkA series of monoclonal antibodies (mAbs) are commonly utilized in renal transplantation as induction therapy (a period of intense immunosuppression immediately before and following the implant of the allograft), to treat steroid-resistant acute rejections, to decrease the incidence and mitigate effects of delayed graft function, and to allow immunosuppressive minimization. Additionally, in the last few years, their use has been proposed for the treatment of chronic antibody-mediated rejection, a major cause of late renal allograft loss. Although the exact mechanism of immunosuppression and allograft tolerance with any of the currently used induction agents is not completely defined, the majority of these medications are targeted against specific CD proteins on the T or B cells surface (e.g., CD3, CD25, CD52). Moreover, some of them have different mechanisms of action. In particular, eculizumab, interrupting the complement pathway, is a new promising treatment tool for acute graft complications and for post-transplant hemolytic uremic syndrome. While it is clear their utility in renal transplantation, it is also unquestionable that by using these highly potent immunosuppressive agents, the body loses much of its innate ability to mount an adequate immune response, thereby increasing the risk of severe adverse effects (e.g., infections, malignancies, haematological complications). Therefore, it is extremely important for clinicians involved in renal transplantation to know the potential side effects of monoclonal antibodies in order to plan a correct therapeutic strategy minimizing/avoiding the onset and development of severe clinical complications
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Downregulation of nuclear-encoded genes of oxidative metabolism in dialyzed chronic kidney disease patients.
Full text linkBACKGROUND:Mitochondria, essential eukaryotic cells organelles defined as the "powerhouse of the cell" because of their ability to produce the vast majority of energy necessary for cellular metabolism, may have a primary role in the oxidative stress-related intracellular machinery associated to chronic kidney disease (CKD).METHODS:To better assess this research assumption, we decided to study the key factors regulating mitochondrial oxidative metabolism in CKD patients in peritoneal dialysis (PD, n = 15) using several bio-molecular methodologies.RESULTS:RT-PCR experiments demonstrate that the expression level of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) and nuclear respiratory factor-1 (NRF-1), two genes primarily involved in mitochondrial biogenesis and functions, were significantly hypo-expressed in peripheral blood mononuclear cells of PD patients compared to healthy subjects (HS, n = 15). Additionally, mRNA levels of several PGC1-α downstream target genes (TFAM, COX6C,COX7C, UQCRH and MCAD) were profoundly down-regulated in PD cells. TFAM protein analysis confirmed gene-expression results. High plasmatic concentration of Malondialdehyde found in PD patients, confirmed the contribution of the oxidative stress to these biological effects. Finally, Nuclear factor erythroid-derived 2-like 2 (NRF2 or NFE2L2), a transcription factor for numerous antioxidant/detoxifying enzymes and one of its target genes, superoxide dismutase-2 mitochondrial (SOD2) were up-regulated in PD compared to HS.CONCLUSIONS:Our results revealed, for the first time, that CKD-PD patients' PBMC, through a complex intracellular biochemical machinery, are able to modulate their mitochondrial functions probably in the attempt to reduce oxidative metabolic damage and to turn on a valuable defense cellular strategy against oxidative stress
Pharmacogenetics: a promising tool to personalize immunosuppressive therapy in renal transplantation.
No full textIl trapianto renale rappresenta la terapia d’elezione per la malattia renale allo stadio terminale, una condizione clinica caratterizzata da gravi alterazioni biologiche/biochimiche che richiedono una terapia sostitutiva della funzione renale per garantire la sopravvivenza dei pazienti. Il trapianto è seguito, nella maggior parte dei casi, da un significativo miglioramento della qualità di vita dei pazienti, da una riduzione delle spese mediche e da un prolungamento della vita. Tuttavia i pazienti nefro-trapiantati devono assumere diversi farmaci immunosoppressori (inibitori della calcineurina, inibitori di mTOR e antimetaboliti) caratterizzati da un basso indice terapeutico, che, in alcuni casi, potrebbero determinare importanti effetti collaterali. Per evitare tossicità e reazioni avverse al farmaco, è importante che gli immunosoppressori siano somministrati correttamente sulla base dei livelli ematici degli stessi. Tuttavia questa metodologia risulta spesso poco riproducibile e poco efficiente. Inoltre, come in gran parte descritto, differenze ereditarie nel metabolismo e nella disposizione dei farmaci, e la variabilità genetica nei bersagli terapeutici (es recettori) possono inficiare significativamente i loro effetti e la tossicità. Pertanto, numerosi studi si stanno focalizzando sulla identificazione di biomarcatori utili per personalizzare la terapia sulla base delle caratteristiche genetiche dei pazienti. In questo contesto, riteniamo che le tecniche "omiche" potrebbero rappresentare in futuro potenti strumenti che, se impiegate regolarmente, potrebbero contribuire a raggiungere questo obiettivo
IDENTIFICATION OF MOLECULAR BIOMARKERS FOR EARLY DIAGNOSIS OF DELAYED GRAFT FUNCTION IN RENAL TRANSPLANT RECIPIENTS
No full textIntroduction and Aims: Delayed graft function (DGF) is the most common complication affecting kidney allografts in the immediate post-transplant period. Defined as the necessity for dialysis in the first week after surgery, DGF occurs in 20% to 50% of patients receiving a first cadaver graft. DGF is usually the result of ischemic damage to the graft before or during harvesting, and it is further aggravated by the reperfusion syndrome, a multifactorial event in which polymorphonuclear (PMN) cells play a major role. This condition is often associated with an increased
risk of premature graft failure and residual graft dysfunction. Factors related to the donor and prerenal, renal, or postrenal transplant factors related to the recipient can contribute to this condition. However, at the state of art, the systemic biological
machinery associated to this condition is still not completely known.
Methods: Therefore, aims of our study have been to identify, by combining an innovative high-throughput technology (HG-U133A, microarray, Affymetrix) with classical bio-molecular approaches, specific DGF transcriptomic fingerprints (DGF biomarkers). To this purpose, we compared the genomic profile (around 15,000 genes) of 7 patients with DGF with that of 7 patients with early graft function (EGF). This comparison was performed using PMN isolated by whole blood at the time of transplantation (T0) and after one day (T1) post-transplantation. Subsequently, we
applied several statistical algorithms and functional analysis by Gene-Set Enrichment Analysis (GSEA), to identify biological processes able to discriminate DGF versus EGF at both T0 and T1.
Results: Bioinformatics showed that two pathways: a) NLS BEARING SUBSTRATE IMPORT INTO NUCLEUS (19 annotated genes) and b) PROTEIN IMPORT INTO THE NUCLEUS (32 annotated genes) were significantly up-regulated, at both T0
and T1, in DGF compared to EGF (p<0.009/FDR<30 and p<0.004/FDR<35, respectively). RT-PCR performed on an independent cohort of patients (n:25 with DGF and n:25 with EGF) confirmed microarray results. Both the identified pathways
are primary involved in the transport of substrates from cytoplasm to nucleus.
Conclusions: Our approach may help researchers to improve the overall biological knowledge of DGF; moreover, it may introduce new potential biomarkers useful to early identify risk patients for DGF and to select new research topics and potential targets for future therapeutic approaches
DISREGOLAZIONE DELLA BIOSINTESI E DEL METABOLISMO DEI PROTEOGLICANI/GLICOSAMINOGLICANI NEI SOGGETTI UREMICI: UNO STUDIO DI GENOMICA FUNZIONALE
No full textINTRODUZIONE. Recenti dati della letteratura suggeriscono che i glicosaminoglicani e proteoglicani svolgono un ruolo chiave nello sviluppoe nella regolazione degli stati infiammatori cronici ed esercitanoun ruolo biologico attivo nella patogenesi del danno cardiovascolare.MATERIALI E METODI. Pertanto, per definire il coinvolgimento diquesti sistemi biologici nella progressione del danno renale cronicoe nella genesi delle comorbidità associate, abbiamo utilizzato unapproccio combinato tra tecnologia di screening genomico (microarraysu RNA estratto da linfomonociti periferici) e biologia molecolareclassica. In particolare, abbiamo misurato le variazioni trascrittomicherelative a 210 geni codificanti per proteine coinvoltenella biosintesi e nel metabolismo di proteoglicani/glicosaminoglicani.L’analisi microarray è stata condotta su un training-group[n=24 emodializzati (ED), n=18 peritoneodializzati (PD), n=9 pazienticon insufficienza renale cronica II-III stadio K/DOQI (IRC II-III) e n=5soggetti normali (NORM)] mentre la validazione biologica su untesting-group (n=24 ED, n=18 PD, n=11 IRC IV-V, n=12 IRC II-III e n=12NORM). L’analisi bioinformatica è stata effettuata utilizzando algoritmistatistici parametrici e non parametrici, il calcolo del FDR mediante1000 permutazioni e l'analisi dei link biologici con i softwarer-project e Gene-Set Enrichment Analysis (GSEA).RISULTATI E CONCLUSIONI. L’analisi microarray/statistica rivelavache i NORM e i pazienti con IRC II-III avevano un pattern di espressionegenico simile (p=0.54), ma differivano significativamente daED e PD (p<0.001, FDR<5%). ED e PD avevano livelli di espressionedell’RNA sovrapponibili (p=0.36). 34 geni risultavano iper-espressinei gruppi di pazienti ED e PD [tra questi: vascular endothelialgrowth factor A (VEGFA), Eparanase (HPSE) e Versicano (VCAN)].L’analisi dell’ attività plasmatica dell'Eparanase, misurato con metodicaELISA, nel testing-group, confermava i risultati dello studiogenomico (NORM e IRC II-III versus IRC IV-V, HD e PD, p<0.001).I nostri dati mostrano una chiara disregolazione del metabolismodei proteoglicani e glicosaminoglicani nei soggetti con grave deficitdella funzione renale e identificano nuovi biomarkers (per esempioEparanase) potenzialmente associati allo sviluppo di comorbidità(infiammazione, aterosclerosi) e utilizzabili come nuovi target terapeutici
DISTURBI PSICOLOGICI, QUALITÀ DI VITA E PRODUZIONE DI CITOCHINE NEI PAZIENTI IN EMODIALISI
No full textIntroduzione. I pazienti ED presentano spesso disturbi psicologici che influenzano negativamente la qualità di vita (QOL). In altre condizioni morbose croniche, le citochine infiammatorie giocano un ruolo patogenetico nei disturbi ansioso/depressivi associati. Il contatto sangue-superfici artificiali e lo stato uremico cronico favoriscono l’attivazione dei leucociti
mononucleati e il rilascio di citochine infiammatorie. Si può ipotizzare che l’aumentato rilascio di citochine infiammatorie possa favorire il manifestarsi di disturbi psicologici nei pazienti ED.
Scopi. Valutare l’incidenza di disturbi psicologici e la QOL di un gruppo di pazienti ED e di correlare questi dati con la produzione leucocitaria di citochine infiammatorie.
Metodi. Pazienti: 30 pazienti ED e 20 pazienti affetti da malattia renale cronica stadio I/II (K-DOQI). La presenza di disturbi psicologici è stata valutata con test psicometrico HADS (Hospital Anxiety Depression Scale) con il quale si ottiene uno score totale (HADS-T, range 0-42), uno score dei sintomi depressivi (HADS-D, range 0-21) e uno score dei sintomi di ansia (HADS-A, range 0-21). Per HADS-D o HADS-A è stato considerato un cut-off ≥ 8. La QOL è stata valutata con il test KDQOL-SF TM 1.3 modificato (range 0-100). Con tre domande di questo test si genera uno score dei disturbi cognitivi (KDQOL-FC), validato nei pazienti ED. I prelievi ematici pre-dialitici effettuati in Li-eparina. Il sangue è stato diluito 1:5 con RPMI/eparina e incubato per 24 ore in presenza di LPS di E. coli (10 o 100 ng/ml). Sui surnatanti cellulari è stato effettuato il dosaggio ELISA per IL-1β, IL-6 e TNF-α. I valori sono stati espressi sia come concentrazione (ng/ml), che normalizzati per n. di leucociti mononucleati (ng/106 cellule). Sono anche stati valutati parametri di efficienza dialitica (Kt/V sec. Daugirdas), albuminemia, fosfatemia.
Risultati. Gli score HADS-T, HADS-D e HADS-A erano più elevati nei pazienti ED, ma la differenza non era statisticamente significativa. Tuttavia, i sintomi depressivi erano presenti in una maggiore % di pazienti ED (50%) rispetto ai controlli (20%, p<0.0001), mentre i sintomi di ansia erano comparabili nei due gruppi (43% verso 45% risp.). La QOL era peggiore nei pazienti ED (63.7 ± 14.8) rispetto ai controlli (74.9 ± 11.9; p=0.006) e correlava inversamente con HADS-T, HADS-D e HADS-A (p<0.0001 per tutti). Non si osservavano variazioni significative di Kt/V, albuminemia o fosfatemia nei pazienti con o senza sintomi di depressione o di ansia. La produzione normalizzata di citochine era significativamente più elevata nei pazienti ED rispetto ai controlli (IL-1β 4.13±2.65 vs 2.78±1.81; p=0.05; IL-6 15.59±7.61 vs. 10.34±5.39; p=0.010; TNF-α 14.35±6.42 vs. 7.17±2.61; p<0.0001). I pazienti con i sintomi di ansia o depressione presentavano livelli medi di IL-6 più alti (19.1±6.8 e 17.9±8.2 risp.) rispetto a quelli senza sintomi di ansia o depressione (12.9±7.0 e 13.3±6.5 risp.), ma la differenza era statisticamente significativa solo per l’ansia (p=0.026). Infine, lo score KDQOL-FC correlava inversamente con la concentrazione di IL-6 (p=0.04) e la concentrazione di TNF-α (p=0.016).
Conclusioni. Nei pazienti ED i disturbi psicologici sono frequenti e condizionano negativamente la QOL. I sintomi sono indipendenti dalla efficienza dialitica. I leucociti dei
pazienti ED producono elevati livelli di citochine infiammatorie e l’IL-6 e il TNF-
α sembrano giocare un ruolo patogenetico nei disturbi psicologici dei pazienti ED
From pharmacogenetics to pharmacogenomics: the birth of a new era of personalized medicine in nephrology
No full textRecent evidence suggests that adverse drug reactions are a major cause of death and hospital admissions in Europe and the United States. Environmental/ non-genetic as well as genetic factors are responsible for the great interpatient variability in drug metabolism and in the molecular interactions between drugs and therapeutic targets. By means of pharmacogenetic approaches, several genetic settings have been linked to the effects and toxicity of many agents used in clinical nephrology. However, these strategies, which analyze single genes or candidate pathways, cannot be considered ideal because the overall pharmacological effects of drugs typically are not dependent on monogenic traits. Therefore, to identify the multigenetic influence on drug response, researchers and clinicians from different fields of medicine and pharmacology have started to perform pharmacogenomic studies employing innovative whole-genome, high-throughput technologies. In nephrology, only few pharmacogenomics reports have been published to date, suggesting the need to enlarge the number of projects and increase the research budget for this important research field. In the future, we would expect that by applying the knowledge about an individual's inherited response to drugs, nephrologists will be able to prescribe medications based on each person's genetic makeup, to carefully monitor the efficacy and toxicity of a given drug, and to modify the dose and number of medications to obtain predefined clinical outcomes
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