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High volume hemofiltration (HVHF) could remove from plasma inflammatory mediators involved in sepsis-associated acute kidney injury (SA-AKI). The IVOIRE trial did not show improvements of outcome and organ dysfunction using HVHF. The aim of this study was to evaluate in vitro the biological effects of plasma of patients treated by HVHF or standard volume hemofiltration (SVHF). We evaluated leukocyte adhesion, apoptosis and functional alterations of endothelial cells (EC) and tubular epithelial cells (TEC). In vitro data were correlated with plasma levels of TNF-α, Fas-Ligand (FasL), CD40-Ligand (CD40L), von Willebrand Factor (vWF) and endothelial-derived microparticles. An experimental model of in vitro hemofiltration using LPS-activated blood was established to assess cytokine mass adsorption during HVHF or SVHF. Plasma concentrations of TNF-É, FasL, CD40L and von Willebrand Factor (vWF) were elevated at the start (d1h0) of both HVHF and SVHF, significantly decreased after 6 h (d1h6), remained stable after 12 h (d1h12) and then newly increased at 48 h (d3h0). Plasma levels of all these molecules were similar between HVHF- and SVHF-treated patients at all time points considered. In addition, the levels of endothelial microparticles remained always elevated, suggesting the presence of a persistent microvascular injury. Plasma from septic patients induced leukocyte adhesion on EC and TEC through up-regulation of adhesion receptors. Moreover, on EC, septic plasma induced a cytotoxic and anti-angiogenic effect. On TEC, septic plasma exerted a direct pro-apoptotic effect via Fas up-regulation and caspase activation, loss of polarity, altered expression of megalin and tight junction molecules with an impaired ability to internalize albumin. The inhibition of plasma-induced cell injury was concomitant to the decrease of TNF-α, Fas-Ligand and CD40-Ligand levels. The protective effect of both HVHF and SVHF was time-limited, since a further increase of circulating mediators and plasma-induced cell injury was observed after 48 h (d3h0). No significant difference of EC/TEC damage were observed using HVHF- or SVHF-treated plasma. The in vitro hemofiltration model confirmed the absence of a significant modulation of cytokine adsorption between HVHF and SVHF. In comparison to SVHF, HVHF did not increase inflammatory cytokine clearance and did not reverse the detrimental effects of septic plasma-induced EC and TEC injury. Further studies using adsorptive membranes are needed to evaluate the potential role of high dose convective therapies in the limitation of the harmful activity of plasma soluble factors involved in SA-AKI.Trial registration IVOIRE randomized clinical trial; ClinicalTrials.gov (NCT00241228) (18/10/2005).
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Células Endoteliales , Células Epiteliales , Hemofiltración , Sepsis , Humanos , Sepsis/terapia , Células Endoteliales/metabolismo , Hemofiltración/métodos , Células Epiteliales/metabolismo , Masculino , Lesión Renal Aguda/terapia , Lesión Renal Aguda/etiología , Femenino , Persona de Mediana Edad , Apoptosis , Anciano , Túbulos Renales/metabolismo , Citocinas/metabolismo , Citocinas/sangre , Adhesión CelularRESUMEN
INTRODUCTION: Despite major advances in the field of dialysis, there are still some unmet needs such as reducing inflammation through adequate depuration. It is well known that the wide spectrum of pro-inflammatory and pro-atherosclerotic uremic toxins are inefficiently removed by current dialysis techniques. Adsorption seems to be an extra tool to remove toxins, but its effect and optimization have not been widely studied. The aim of this report was to present preliminary results regarding the possibility of performing hemodiafiltration with a highly adsorptive polymethylmethacrylate membrane. METHODS: The study was first conducted in 10 patients in which the safety and feasibility of hemodiafiltration with PMMA BG-U 2.1 membrane were tested through measurement of hemolysis indices, transmembrane pressures, and dialysis adequacy. Twenty patients were prospectively observed for 18-month period in which they consecutively underwent standard hemodialysis, standard post-dilution hemodiafiltration, and polymethylmethacrylate-based post-dilution hemodiafiltration. Protein-bound uremic toxins concentrations and inflammatory markers were measured throughout the observed period. RESULTS: HDF-PMMA was inferior to HDF in convective volume, but KT/V was similar, and no differences were noted in operating pressures during the two treatments. During HDF-PMMA period of treatment, we observed a significant reduction of CPR levels, and HDF-PMMA was superior to all other treatments in hepcidin removal even if this did not significantly affect hemoglobin levels. HDF-PMMA could significantly reduce indoxyl sulfate (indoxyl) concentration over a period of 6 months but not for p-cresyl sulfate (p-cresyl). CONCLUSION: PMMA BG-U 2.1 membrane can be safely and efficiently used in hemodiafiltration. Moreover, as these preliminary results show, adding adsorption properties to convection and diffusion enabled an increased removal of indoxyl uremic toxin associated to a reduction in inflammation markers as CRP and hepcidin without any negative impact on albumin levels.
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INTRODUCTION: Acute kidney injury (AKI) frequently develops in patients receiving cancer therapy and requires a wide differential diagnosis due to possible role of unique cancer and drug-related factors, in addition to common pre- and post-renal causes. Rapid development of new molecular targeted anti-cancer drugs and immunotherapies has opened unprecedented possibilities of treatment at the price of an increased spectrum of renal side effects. AREAS COVERED: The present review aims at providing a state-of-the-art picture of AKI in cancer patient (PubMed and Embase libraries were searched from inception to January 2024), with a focus on differential diagnosis and management of diverse clinical settings. Reports of parenchymal AKI due to glomerular, microvascular, tubular and interstitial damage have been constantly increasing. Complex electrolyte and acid-base disorders can coexist. The role of renal biopsy and possible therapeutic approaches are also discussed. EXPERT OPINION: Onconephrology has become an important subspecialty of clinical nephrology, requiring constantly updated skills and a high degree of interdisciplinary integration to tackle diagnostic challenges and even therapeutic and ethical dilemmas. Integrated onconephrological guidelines and availability of biomarkers may provide new tools for management of this unique type of patients in the near future.
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Lesión Renal Aguda , Antineoplásicos , Neoplasias , Humanos , Lesión Renal Aguda/etiología , Lesión Renal Aguda/tratamiento farmacológico , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Neoplasias/complicaciones , Diagnóstico Diferencial , Biomarcadores , Terapia Molecular Dirigida/efectos adversos , Inmunoterapia/métodos , Inmunoterapia/efectos adversos , BiopsiaRESUMEN
Despite the recent advances in dialysis technology, mortality rate of chronic uremic patients still remains excessively high: of note, in comparison to age- and sex-matched healthy controls, this frail population shows a higher incidence of infections, cancer, cognitive decline, and, in particular, major adverse cardiovascular events (MACE) that represent nowadays the first cause of mortality. Several traditional and nontraditional factors contribute to this increased risk for MACE and accelerated cellular senescence: among these, inflammation has been shown to play a key role. The costimulatory pathway CD40-CD40 Ligand (CD40L) is harmfully activated during inflammation and uremia-associated clinical complications: in particular, the soluble form of CD40L (sCD40L) can bind to the CD40 receptor triggering a cascade of detrimental pathways in immune and nonimmune cells. In this narrative review, we summarize the current concepts of the biological role of the CD40-CD40L pathway in uremia-associated organ dysfunction, focusing on the above-described main causes of mortality. Moreover, we discuss the interaction of the CD40-CD40L pathway with extracellular vesicles, microparticles recently identified as new uremic toxins. The biological effects of sCD40L in MACE, cognitive decline, infections, and cancer will be also briefly commented. Last, based on recent studies and ongoing clinical trials, we herein describe the modulatory activity of adsorptive dialysis membranes in polymethylmethacrylate on CD40-CD40L detrimental activation.
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A meeting entitled Renal BIopsy for Kidney Transplantation Therapy (ReBIrth) took place on May 31st, 2022 in Bologna, Italy. The meeting drew together nephrologists, surgeons, and pathologists and recognized as experts in the field of kidney transplantation in Italy. In this paper, we present our experience working with kidney transplants in the current era of immunosuppression therapy. The primary aim is to report the histopathological characteristics of failed kidney allografts after a consensus of experts reviewed the cases on a wholeslide imaging digital platform. Regardless of the cases discussed, digital pathology was reliable in identifying all the morphological and immunohistochemical features required to improve the correct use of immunosuppressive therapy to prevent graft failure and optimize patient management.
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Trasplante de Riñón , Nefrología , Humanos , Trasplante de Riñón/efectos adversos , Trasplante de Riñón/métodos , Riñón/cirugía , Riñón/patología , Terapia de Inmunosupresión , BiopsiaRESUMEN
Extracellular vesicles form a complex intercellular communication network, shuttling a variety of proteins, lipids, and nucleic acids, including regulatory RNAs, such as microRNAs. Transfer of these molecules to target cells allows for the modulation of sets of genes and mediates multiple paracrine and endocrine actions. EVs exert broad pro-inflammatory, pro-oxidant, and pro-apoptotic effects in sepsis, mediating microvascular dysfunction and multiple organ damage. This deleterious role is well documented in sepsis-associated acute kidney injury and acute respiratory distress syndrome. On the other hand, protective effects of stem cell-derived extracellular vesicles have been reported in experimental models of sepsis. Stem cell-derived extracellular vesicles recapitulate beneficial cytoprotective, regenerative, and immunomodulatory properties of parental cells and have shown therapeutic effects in experimental models of sepsis with kidney and lung involvement. Extracellular vesicles are also likely to play a role in deranged kidney-lung crosstalk, a hallmark of sepsis, and may be key to a better understanding of shared mechanisms underlying multiple organ dysfunction. In this review, we analyze the state-of-the-art knowledge on the dual role of EVs in sepsis-associated kidney/lung injury and repair. PubMed library was searched from inception to July 2022, using a combination of medical subject headings (MeSH) and keywords related to EVs, sepsis, acute kidney injury (AKI), acute lung injury (ALI), and acute respiratory distress syndrome (ARDS). Key findings are summarized into two sections on detrimental and beneficial mechanisms of actions of EVs in kidney and lung injury, respectively. The role of EVs in kidney-lung crosstalk is then outlined. Efforts to expand knowledge on EVs may pave the way to employ them as prognostic biomarkers or therapeutic targets to prevent or reduce organ damage in sepsis.
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Extracellular vesicles (EV) are emerging mediators in several diseases. However, their role in the pathophysiology of antibody-mediated allograft rejection (AMR) has been poorly investigated. Here, we investigated the role of EV isolated from AMR patients in inducing tubular senescence and endothelial to mesenchymal transition (EndMT) and analyzed their miRNA expression profile. By multiplex bead flow cytometry, we characterized the immunophenotype of plasma AMR-derived EV and found a prevalent platelet and endothelial cell origin. In vitro, AMR-derived EV induced tubular senescence by upregulating SA-ß Gal and CDKN1A mRNA. Furthermore, AMR-derived EV induced EndMT. The occurrence of tubular senescence and EndMT was confirmed by analysis of renal biopsies from the same AMR patients. Moreover, AMR-derived EV induced C3 gene upregulation and CFH downregulation in tubular epithelial cells, with C4d deposition on endothelial cells. Interestingly, RNase-mediated digestion of EV cargo completely abrogated tubular senescence and EndMT. By microarray analysis, miR-604, miR-515-3p, miR-let-7d-5p, and miR-590-3p were significantly upregulated in EV from AMR group compared with transplant controls, whereas miR-24-3p and miR-29a-3p were downregulated. Therefore, EV-associated miRNA could act as active player in AMR pathogenesis, unraveling potential mechanisms of accelerated graft senescence, complement activation and early fibrosis that might lead to new therapeutic intervention.
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Vesículas Extracelulares , MicroARNs , Células Endoteliales/metabolismo , Células Epiteliales/metabolismo , Vesículas Extracelulares/metabolismo , Humanos , MicroARNs/genética , ARN Mensajero/metabolismoRESUMEN
Current treatment of primary and secondary glomerulopathies is hampered by many limits and a significant proportion of these disorders still evolves towards end-stage renal disease. A possible answer to this unmet challenge could be represented by therapies with stem cells, which include a variety of progenitor cell types derived from embryonic or adult tissues. Stem cell self-renewal and multi-lineage differentiation ability explain their potential to protect and regenerate injured cells, including kidney tubular cells, podocytes and endothelial cells. In addition, a broad spectrum of anti-inflammatory and immunomodulatory actions appears to interfere with the pathogenic mechanisms of glomerulonephritis. Of note, mesenchymal stromal cells have been particularly investigated as therapy for Lupus Nephritis and Diabetic Nephropathy, whereas initial evidence suggest their beneficial effects in primary glomerulopathies such as IgA nephritis. Extracellular vesicles mediate a complex intercellular communication network, shuttling proteins, nucleic acids and other bioactive molecules from origin to target cells to modulate their functions. Stem cell-derived extracellular vesicles recapitulate beneficial cytoprotective, reparative and immunomodulatory properties of parental cells and are increasingly recognized as a cell-free alternative to stem cell-based therapies for different diseases including glomerulonephritis, also considering the low risk for potential adverse effects such as maldifferentiation and tumorigenesis. We herein summarize the renoprotective potential of therapies with stem cells and extracellular vesicles derived from progenitor cells in glomerulonephritis, with a focus on their different mechanisms of actions. Technological progress and growing knowledge are paving the way for wider clinical application of regenerative medicine to primary and secondary glomerulonephritis: this multi-level, pleiotropic therapy may open new scenarios overcoming the limits and side effects of traditional treatments, although the promising results of experimental models need to be confirmed in the clinical setting.
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Vesículas Extracelulares , Glomerulonefritis , Células Endoteliales , Vesículas Extracelulares/metabolismo , Glomerulonefritis/metabolismo , Glomerulonefritis/terapia , Humanos , Medicina Regenerativa/métodos , Células Madre/metabolismoRESUMEN
Acute kidney injury is a frequent complication of hospitalized patients and significantly increases morbidity and mortality, worsening costs and length of hospital stay. Despite this impact on healthcare system, treatment still remains only supportive (dialysis). Stem cell-derived extracellular vesicles are a promising option as they recapitulate stem cells properties, overcoming safety issues related to risks or rejection or aberrant differentiation. A growing body of evidence based on pre-clinical studies suggests that extracellular vesicles may be effective to treat acute kidney injury and to limit fibrosis through direct interference with pathogenic mechanisms of vascular and tubular epithelial cell damage. We herein analyze the state-of-the-art knowledge of therapeutic approaches with stem cell-derived extracellular vesicles for different forms of acute kidney injury (toxic, ischemic or septic) dissecting their cytoprotective, regenerative and immunomodulatory properties. We also analyze the potential impact of extracellular vesicles on the mechanisms of transition from acute kidney injury to chronic kidney disease, with a focus on the pivotal role of the inhibition of complement cascade in this setting. Despite some technical limits, nowadays the development of therapies based on stem cell-derived extracellular vesicles holds promise as a new frontier to limit acute kidney injury onset and progression.
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Lesión Renal Aguda , Vesículas Extracelulares , Insuficiencia Renal Crónica , Lesión Renal Aguda/patología , Lesión Renal Aguda/terapia , Células Epiteliales/patología , Vesículas Extracelulares/patología , Humanos , Insuficiencia Renal Crónica/terapia , Células MadreRESUMEN
A causal link between viral infections and autoimmunity has been studied for a long time and the role of some viruses in the induction or exacerbation of systemic lupus erythematosus (SLE) in genetically predisposed patients has been proved. The strength of the association between different viral agents and SLE is variable. Epstein-Barr virus (EBV), parvovirus B19 (B19V), and human endogenous retroviruses (HERVs) are involved in SLE pathogenesis, whereas other viruses such as Cytomegalovirus (CMV) probably play a less prominent role. However, the mechanisms of viral-host interactions and the impact of viruses on disease course have yet to be elucidated. In addition to classical mechanisms of viral-triggered autoimmunity, such as molecular mimicry and epitope spreading, there has been a growing appreciation of the role of direct activation of innate response by viral nucleic acids and epigenetic modulation of interferon-related immune response. The latter is especially important for HERVs, which may represent the molecular link between environmental triggers and critical immune genes. Virus-specific proteins modulating interaction with the host immune system have been characterized especially for Epstein-Barr virus and explain immune evasion, persistent infection and self-reactive B-cell "immortalization". Knowledge has also been expanding on key viral proteins of B19-V and CMV and their possible association with specific phenotypes such as antiphospholipid syndrome. This progress may pave the way to new therapeutic perspectives, including the use of known or new antiviral drugs, postviral immune response modulation and innate immunity inhibition. We herein describe the state-of-the-art knowledge on the role of viral infections in SLE, with a focus on their mechanisms of action and potential therapeutic targets.
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Citomegalovirus/inmunología , Retrovirus Endógenos/inmunología , Herpesvirus Humano 4/inmunología , Inmunidad Innata/inmunología , Lupus Eritematoso Sistémico/inmunología , Parvovirus B19 Humano/inmunología , Síndrome Antifosfolípido/inmunología , Síndrome Antifosfolípido/virología , Autoinmunidad/inmunología , Infecciones por Citomegalovirus/patología , Retrovirus Endógenos/fisiología , Infecciones por Virus de Epstein-Barr/patología , Herpesvirus Humano 4/fisiología , Interacciones Huésped-Patógeno/fisiología , Humanos , Lupus Eritematoso Sistémico/virología , Infecciones por Parvoviridae/patología , Parvovirus B19 Humano/fisiologíaRESUMEN
Emerging evidence indicates that reactivation of BK polyomavirus (BKPyV) in the kidney and urothelial tract of kidney transplant recipients (KTRs) may be associated with cancer in these sites. In this retrospective study of a single center cohort of KTRs (n = 1307), 10 clear cell renal cell carcinomas and 5 urinary bladder carcinomas were analyzed from 15 KTRs for the presence of BKPyV infection through immunohistochemistry and fluorescent in situ hybridization (FISH). Three of these patients had already exhibited biopsy-proven polyomavirus-associated nephropathies (PyVAN). Although the presence of BKPyV large-T antigen was evident in the urothelium from a kidney removed soon after PyVAN diagnosis, it was undetectable in all the formalin-fixed and paraffin-embedded (FFPE) blocks obtained from the 10 kidney tumors. By contrast, large-T antigen (LT) labeling of tumor cells was detected in two out of five bladder carcinomas. Lastly, the proportion of BKPyV DNA-FISH-positive bladder carcinoma nuclei was much lower than that of LT-positive cells. Taken together, our findings further strengthen the association between BKPyV reactivation and cancer development in KTRs, especially bladder carcinoma.
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Virus BK , Neoplasias Renales/virología , Trasplante de Riñón/efectos adversos , Infecciones por Polyomavirus/virología , Urotelio/virología , Adulto , Antígenos Virales de Tumores/análisis , Femenino , Humanos , Hibridación Fluorescente in Situ , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Receptores de Trasplantes , Urotelio/patologíaRESUMEN
New biomarkers of early and late graft dysfunction are needed in renal transplant to improve management of complications and prolong graft survival. A wide range of potential diagnostic and prognostic biomarkers, measured in different biological fluids (serum, plasma, urine) and in renal tissues, have been proposed for post-transplant delayed graft function (DGF), acute rejection (AR), and chronic allograft dysfunction (CAD). This review investigates old and new potential biomarkers for each of these clinical domains, seeking to underline their limits and strengths. OMICs technology has allowed identifying many candidate biomarkers, providing diagnostic and prognostic information at very early stages of pathological processes, such as AR. Donor-derived cell-free DNA (ddcfDNA) and extracellular vesicles (EVs) are further promising tools. Although most of these biomarkers still need to be validated in multiple independent cohorts and standardized, they are paving the way for substantial advances, such as the possibility of accurately predicting risk of DGF before graft is implanted, of making a "molecular" diagnosis of subclinical rejection even before histological lesions develop, or of dissecting etiology of CAD. Identification of "immunoquiescent" or even tolerant patients to guide minimization of immunosuppressive therapy is another area of active research. The parallel progress in imaging techniques, bioinformatics, and artificial intelligence (AI) is helping to fully exploit the wealth of information provided by biomarkers, leading to improved disease nosology of old entities such as transplant glomerulopathy. Prospective studies are needed to assess whether introduction of these new sets of biomarkers into clinical practice could actually reduce the need for renal biopsy, integrate traditional tools, and ultimately improve graft survival compared to current management.
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Funcionamiento Retardado del Injerto/diagnóstico , Rechazo de Injerto/diagnóstico , Supervivencia de Injerto/inmunología , Trasplante de Riñón/efectos adversos , Insuficiencia Renal/diagnóstico , Tolerancia al Trasplante/inmunología , Inteligencia Artificial , Biomarcadores/sangre , Ácidos Nucleicos Libres de Células/sangre , Ácidos Nucleicos Libres de Células/genética , Biología Computacional/métodos , Funcionamiento Retardado del Injerto/sangre , Funcionamiento Retardado del Injerto/genética , Funcionamiento Retardado del Injerto/inmunología , Diagnóstico Precoz , Vesículas Extracelulares/química , Vesículas Extracelulares/metabolismo , Rechazo de Injerto/sangre , Rechazo de Injerto/genética , Rechazo de Injerto/inmunología , Humanos , Riñón/metabolismo , Riñón/patología , Medicina de Precisión/métodos , Insuficiencia Renal/sangre , Insuficiencia Renal/genética , Insuficiencia Renal/inmunologíaRESUMEN
Extracellular vesicles (EVs) are known immune-modulators exerting a critical role in kidney transplantation (KT). EV bioactive cargo includes graft antigens, costimulatory/inhibitory molecules, cytokines, growth factors, and functional microRNAs (miRNAs) that may modulate expression of recipient cell genes. As paracrine factors, neutrophil- and macrophage-derived EVs exert immunosuppressive and immune-stimulating effects on dendritic cells, respectively. Dendritic cell-derived EVs mediate alloantigen spreading and modulate antigen presentation to T lymphocytes. At systemic level, EVs exert pleiotropic effects on complement and coagulation. Depending on their biogenesis, they can amplify complement activation or shed complement inhibitors and prevent cell lysis. Likewise, endothelial- and platelet-derived EVs can exert procoagulant/prothrombotic effects and also promote endothelial survival and angiogenesis after ischemic injury. Kidney endothelial- and tubular-derived EVs play a key role in ischemia-reperfusion injury (IRI) and during the healing process; additionally, they can trigger rejection by inducing both alloimmune and autoimmune responses. Endothelial EVs have procoagulant/pro-inflammatory effects and can release sequestered self-antigens, generating a tissue-specific autoimmunity. Renal tubule-derived EVs shuttle pro-fibrotic mediators (TGF-ß and miR-21) to interstitial fibroblasts and modulate neutrophil and T-lymphocyte influx. These processes can lead to peritubular capillary rarefaction and interstitial fibrosis-tubular atrophy. Different EVs, including those from mesenchymal stromal cells (MSCs), have been employed as a therapeutic tool in experimental models of rejection and IRI. These particles protect tubular and endothelial cells (by inhibition of apoptosis and inflammation-fibrogenesis or by inducing autophagy) and stimulate tissue regeneration (by triggering angiogenesis, cell proliferation, and migration). Finally, urinary and serum EVs represent potential biomarkers for delayed graft function (DGF) and acute rejection. In conclusion, EVs sustain an intricate crosstalk between graft tissue and innate/adaptive immune systems. EVs play a major role in allorecognition, IRI, autoimmunity, and alloimmunity and are promising as biomarkers and therapeutic tools in KT.
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Vesículas Extracelulares/inmunología , Vesículas Extracelulares/metabolismo , Sistema Inmunológico/inmunología , Sistema Inmunológico/metabolismo , Riñón/inmunología , Trasplantes/inmunología , Trasplantes/metabolismo , Citocinas/metabolismo , Células Endoteliales/metabolismo , Riñón/metabolismo , Enfermedades Renales , Trasplante de Riñón , Túbulos Renales/metabolismo , Macrófagos/metabolismo , Células Madre Mesenquimatosas/metabolismo , Daño por Reperfusión/inmunología , Daño por Reperfusión/metabolismo , Daño por Reperfusión/fisiopatología , Linfocitos T/inmunología , Trasplantes/fisiopatologíaRESUMEN
BACKGROUND: TCF7L2 rs7903146 C>T polymorphism is associated with diabetes in the general population but its independent impact on cardiovascular disease is debated. On this basis, we investigated its association with major adverse cardiac events (MACE) in a single-center cohort of non-diabetic kidney transplant recipients (KTRs). METHODS: Patients with pretransplant diabetes were excluded and patients who developed post-transplant diabetes were censored at time of diagnosis. RESULTS: rs7903146 C>T polymorphism appeared to modulate the risk of MACE: 5-year prevalence was 0.8% in CC patients, 7.2% in CT patients and 9.7% in TT patients (P<.001). TCF7L2 rs7903146 was an independent predictor of MACE in a multivariate Cox regression model (for each T allele, HR: 2.99, 95%CI: 1.62-5.52, P<.001), together with history of cardiac ischemic events (HR: 8.69, 95%CI: 3.57-21.16, P<.001), DGF (HR: 2.42, 95%CI: 0.98-5.95, P=.056) and HLA-mismatches (for each mismatch: HR: 1.55, 95%CI: 1.00-2.43, P=.053). Introduction of rs7903146 C>T polymorphism into a model based on these clinical variables significantly increased predictive power for MACE (P=.003). CONCLUSIONS: TCF7L2 rs7903146 T allele may be strongly and independently associated with MACE in non-diabetic KTRs. These findings suggest the possibility of employing this SNP to more accurately stratify cardiological risk in KTRs.
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Fallo Renal Crónico/cirugía , Trasplante de Riñón/efectos adversos , Isquemia Miocárdica/etiología , Polimorfismo de Nucleótido Simple , Complicaciones Posoperatorias , Proteína 2 Similar al Factor de Transcripción 7/genética , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Isquemia Miocárdica/patología , Proyectos Piloto , Pronóstico , Estudios Retrospectivos , Factores de RiesgoRESUMEN
BACKGROUND: Several genetic polymorphisms modulate the risk of posttransplant diabetes mellitus (PTDM), a complication associated with an increased morbidity and mortality after kidney transplantation; however, their clinical utility is still undefined. METHODS: Genetic analysis was performed in 464 kidney transplantation recipients to evaluate whether transcription factor 7-like 2 (TCF7L2) rs7903146 gene polymorphism is associated with the risk of PTDM and a meta-analysis of similar studies including our results was performed (total kidney transplantation recipients, n = 3105). A predictive model of PTDM was built on the basis of this polymorphism and clinical parameters. RESULTS: In our cohort, 163 patients possessed the CC genotype of rs7903146 (35.1%), 237 were CT (51.1%), and 64 were TT (13.8%): their 2 years PTDM incidence was, respectively, 7.8%, 11.9%, and 22.7%. At multivariate analysis, age (per year; hazard ratio [HR], 1.029; 95% confidence interval [95% CI], 1.005-1.054; P = 0.017), body mass index (25.0-29.9 vs <25.0; HR, 2.43; 95% CI, 1.40-4.23; P = 0.0018; ≥30 vs <25.0; HR, 5.70; 95% CI, 2.77-11.74; P < 0.0001), TCF7L2 rs7903146 (per each T allele; HR, 1.81; 95% CI, 1.26-2.59; P = 0.001) and previous transplants (HR, 2.80; 95% CI, 1.39-5.64; P = 0.004) emerged as independent predictive factors for PTDM.Meta-analysis of present and 5 previous studies showed higher risk of PTDM in carriers of rs7903146 TT genotype (odds ratio, 1.95; 95% CI, 1.39-2.74; P < 0.0001) and absence of heterogeneity among studies (I = 0%).Inclusion of this polymorphism in a predictive model appeared to improve its ability to stratify patients according to the risk of PTDM. CONCLUSIONS: In renal transplant patients, TCF7L2 rs7903146 is strongly and independently associated with PTDM and might hold the potential to identify patients at risk for this complication.
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Diabetes Mellitus/genética , Trasplante de Riñón/efectos adversos , Polimorfismo Genético , Proteína 2 Similar al Factor de Transcripción 7/genética , Adulto , Anciano , Distribución de Chi-Cuadrado , Diabetes Mellitus/diagnóstico , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Heterocigoto , Homocigoto , Humanos , Italia , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Análisis Multivariante , Oportunidad Relativa , Fenotipo , Modelos de Riesgos Proporcionales , Factores de Riesgo , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: Often the reduced contrast enhancement on CT renal imaging is radiologically interpreted as acute pyelonephritis (PNA), but it is the task of the clinician to assess a possible differential diagnosis such as a renal infarct and look for a cause. METHODS: In our experience (2010-2013), we hospitalized 51 patients with radiological imaging consistent with acute pyelonephritis in native kidneys. However, three of these cases result, after a second look, to be ischemic lesions, only sometimes complicated by over-infections (Tabella 1). FIRST CASE: a woman hospitalized for fever and flank pain with blood culture positive for Klebsiella Pneumoniae. Antibiotic therapy allowed a clinical-laboratory improvement, but after 45 days persisted a focal wedge to the CT scan. The labs showed a anemia due to a sickle cell disease (SLC). The overview was finally interpreted as a renal infarct secondary to a sickle cell anemia, initially complicated by over-infection. SECOND CASE: a men hospitalized for a acute flank pain. The CT scan showed a left renal infarct and a partial renal artery thrombosis, resulting in abuse of cannabinoids and LAC positivity.Third case: a woman hospitalized for flank pain and slight movement of inflammatory markers. CT showed a cuneiform area in the right kidney not vascularized, that did not resolved after prolonged antibiotic therapy. The labs evidence a heterozygous mutation of prothrombin and MTHFR causing the renal infarction. CONCLUSIONS: 6% of radiographic imaging consistent with acute pyelonephritis concealed an underlying infarct, due to a unknown state of thrombophilia. The presence of hypovascular imaging to the TC scan, therefore, requires a differential diagnosis between PNA and infarct, especially in the case of atypical development.
Asunto(s)
Infarto/diagnóstico por imagen , Riñón/irrigación sanguínea , Pielonefritis/diagnóstico por imagen , Tomografía Computarizada por Rayos X , Enfermedad Aguda , Adulto , Diagnóstico Diferencial , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Inactivating mutations of the calcium-sensing receptor (CaSR), of the G-protein subunit α11 (GNA11) and of the adaptor-related protein complex 2, sigma 1 subunit (AP2S1) genes are responsible for familial hypocalciuric hypercalcaemia (FHH). The aim of this study was to analyse prevalence and pathogenicity of CaSR, GNA11 and AP2S1 mutations in patients with an FHH phenotype and to compare them with a sample of patients with primary hyperparathyroidism (PHPT) in order to identify the most useful laboratory parameter for a differential diagnosis. METHODS: Patients with an FHH phenotype were studied with polymerase chain reaction amplification and direct sequencing of the entire CaSR, GNA11 and AP2S1 coding sequences. Novel mutations were introduced in a Myc-tagged human wild-type (WT) CaSR cDNA-expressing vector, and functional assay was performed on human embryonic kidney cells evaluating expression and function of mutated proteins. RESULTS: Among 16 FHH patients, none had an inactivating GNA11 or AP2S1 mutation while 3 (18.8%) carried a CaSR mutation and 10 (62.5%) at least one CaSR polymorphism. Within the latter group, 7 of 10 patients had more than one polymorphism (4.1 ± 2.1 per patient). Two novel CaSR mutations [c.2120A>T (E707V) and c.2320G>A (G774S)] were identified: the E707V mutation prevented CaSR expression (western blot), whereas the G774S mutation determined a reduced receptor sensitivity to calcium (IP3 assay). PHPT patients showed significantly (P < 0.001) higher serum calcium, parathyroid hormone, urinary calcium and calcium-creatinine clearance ratio (CCCR) and significantly lower serum phosphate than FHH ones. CONCLUSIONS: FHH should be clearly differentiated by PHPT to avoid unnecessary surgery: CCCR could be a useful screening tool while genetic analysis should include the two novel CaSR mutations herein described. The role of multiple polymorphisms deserves further investigation in patients with an FHH phenotype.