RESUMEN
Delayed Graft Function (DGF) is defined as the need for dialysis during the first week after transplantation. DGF is frequent and mostly derived from the ischemia/reperfusion cascade to which the graft is subjected throughout the transplantation process. A graft biopsy is recommended after 7 days of DGF to exclude an episode of acute rejection. Note that DGF per se is associated with an increased risk of acute graft rejection, as well as with a shorter long-term graft survival. Several strategies are being studied to mitigate the ischaemic damage, thereby improving graft quality. Among these, cellular therapy using mesenchymal stromal cells (MSC) is promising, in particular via the administration of MSC in the machine perfusion during the preservation of the graft. We will discuss here the different definitions of DGF and the main predictive factors of DGF, as well as the impact on the graft outcomes. The current strategies to prevent DGF will be briefly reviewed.
La reprise retardée de fonction du greffon rénal (DGF en anglais pour Delayed Graft Function), définie notamment par la nécessité de dialyse durant la 1ère semaine après transplantation, reste un événement fréquent. La DGF résulte principalement des phénomènes d'ischémie/reperfusion auxquels le greffon est soumis tout au long du processus de transplantation. Néanmoins, une biopsie du greffon est préconisée après 7 jours de DGF afin d'exclure une cause non ischémique telle qu'un rejet aigu. La DGF est per se associée à un risque accru de rejet du greffon, ainsi qu'à une moins bonne survie du greffon rénal au long cours. Plusieurs stratégies sont étudiées afin d'atténuer les dommages ischémiques et améliorer la qualité du greffon. Parmi celles-ci, la thérapie cellulaire par cellules stromales mésenchymateuses est prometteuse, notamment via l'administration de celles-ci dans la machine de perfusion lors de la préservation du greffon. Nous aborderons les différentes définitions de la DGF ainsi que ses principaux facteurs prédictifs, l'impact sur le devenir du greffon et, brièvement, les stratégies actuelles dans le cadre de la prévention de la DGF.
Asunto(s)
Trasplante de Riñón , Humanos , Trasplante de Riñón/efectos adversos , Riñón , Funcionamiento Retardado del Injerto/prevención & control , Funcionamiento Retardado del Injerto/etiología , Supervivencia de Injerto , Rechazo de Injerto/prevención & control , Rechazo de Injerto/patología , Isquemia , Factores de Riesgo , Resultado del TratamientoRESUMEN
Various properties of mesenchymal stromal cells (MSCs) might be particularly of interest after liver transplantation (LT). In this article, we report the long-term results of a prospective, controlled, and first-in-human phase 1 study evaluating the safety of a single MSC infusion after LT. A total of 10 LT recipients treated with standard immunosuppression received 1.5 to 3 × 106 /kg third-party unrelated MSCs on postoperative day 3 and were prospectively compared with a control group of 10 LT recipients. Primary endpoints were set to prospectively detect potentially delayed adverse effects of MSC infusion, particularly the occurrence of infections and cancers. Secondary endpoints of liver graft and patient survival, graft rejection and function, occurrence of bile duct complications, and development of donor-specific anti-human leukocyte antigen (HLA) antibodies (DSA) against liver or MSC donors were studied. The median follow-up was 85 months. There was no difference in overall rates of infection or cancer at 5 years of follow-up between the 2 groups. There was also no difference in secondary endpoints. The prevalence of de novo liver DSAs related to HLA mismatches was twice as high in the MSC group compared with the control group. All of the de novo class II HLA antibodies against MSCs were linked to a shared HLA mismatch between the liver and MSCs. This study confirms the safety of a single MSC infusion after LT. The potential benefits of MSC injections in the context of organ transplantation have yet to be demonstrated by larger prospective studies. The development of anti-HLA antibodies against an MSC donor should be further evaluated, especially in cases of shared HLA mismatches between graft and MSC donors, despite the fact that no deleterious effect has been detected.
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Trasplante de Células Madre Hematopoyéticas , Trasplante de Hígado , Células Madre Mesenquimatosas , Estudios de Seguimiento , Rechazo de Injerto/diagnóstico , Rechazo de Injerto/epidemiología , Rechazo de Injerto/prevención & control , Supervivencia de Injerto , Antígenos HLA , Humanos , Trasplante de Hígado/efectos adversos , Estudios ProspectivosRESUMEN
Mesenchymal stromal cells (MSCs) exhibit anti-inflammatory and immune-regulatory properties, and preclinical studies suggest a potential benefit in solid organ transplantation. We report on the 1-year follow-up of an open-label phase I-II trial of a single infusion of third-party MSC post-kidney transplantation, in addition to standard immunosuppression. Ten kidney transplant recipients from deceased donors received third-party bone marrow MSCs (â¼2 × 106/kg) on day 3 ± 2 post-transplant and were compared to 10 concurrent controls. No adverse effects were noted at MSC injection. One participant with a history of cardiac disease had a non-ST-elevation myocardial infarction approximately 3 hours after MSC infusion. Incidences of opportunistic infections and acute rejection were similar. At day 7 post-transplant, estimated glomerular filtration rate (eGFR) in MSC-treated recipients reached 48.6 ml/min/1.73m2, compared to 32.5 ml/min/1.73m2 in controls and 29.3 ml/min/1.73m2 in our overall cohort of kidney transplant recipients. No difference in eGFR was found at 1 year. MSC-treated recipients showed increased frequencies of regulatory T cells at day 30, with no significant change in B cell frequencies compared to concurrent controls. Four MSC-treated participants developed antibodies against MSC or shared kidney-MSC HLA, with only 1 with MFI >1500. A single infusion of third-party MSC following kidney transplantation appears to be safe, with one cardiac event of unclear relationship to the intervention. MSC therapy is associated with increased regulatory T cell proportion and with improved early allograft function. Long-term effects, including potential immunization against MSC, remain to be studied.
Asunto(s)
Rechazo de Injerto/prevención & control , Terapia de Inmunosupresión/métodos , Fallo Renal Crónico/cirugía , Trasplante de Riñón/efectos adversos , Trasplante de Células Madre Mesenquimatosas/efectos adversos , Administración Intravenosa , Anciano , Aloinjertos/inmunología , Aloinjertos/fisiopatología , Linfocitos B , Femenino , Estudios de Seguimiento , Tasa de Filtración Glomerular , Rechazo de Injerto/inmunología , Rechazo de Injerto/fisiopatología , Humanos , Terapia de Inmunosupresión/efectos adversos , Riñón/inmunología , Riñón/fisiopatología , Recuento de Linfocitos , Masculino , Trasplante de Células Madre Mesenquimatosas/métodos , Persona de Mediana Edad , Estudios Prospectivos , Linfocitos T Reguladores/inmunología , Trasplante Homólogo/efectos adversos , Trasplante Homólogo/métodos , Resultado del TratamientoRESUMEN
Renal segmental metabolism is reflected by the complex distribution of the main energy pathways along the nephron, with fatty acid oxidation preferentially used in the cortex area. Ischemia/reperfusion injury (IRI) is due to the restriction of renal blood flow, rapidly leading to a metabolic switch toward anaerobic conditions. Subsequent unbalance between energy demand and oxygen/nutrient delivery compromises kidney cell functions, resulting in a complex inflammatory cascade including the production of reactive oxygen species (ROS). Renal IRI especially involves lipid accumulation. Lipid peroxidation is one of the major events of ROS-associated tissue injury. Here, we briefly review the current knowledge of renal cell lipid metabolism in normal and ischemic conditions. Next, we focus on renal lipid-associated injury, with emphasis on its mechanisms and consequences during the course of IRI. Finally, we discuss preclinical observations aiming at preventing and/or attenuating lipid-associated IRI.
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Lesión Renal Aguda/metabolismo , Riñón/irrigación sanguínea , Riñón/metabolismo , Metabolismo de los Lípidos , Peroxidación de Lípido , Circulación Renal , Daño por Reperfusión/metabolismo , Lesión Renal Aguda/patología , Lesión Renal Aguda/fisiopatología , Lesión Renal Aguda/prevención & control , Animales , Antiinflamatorios/farmacología , Antioxidantes/farmacología , Humanos , Quelantes del Hierro/farmacología , Riñón/efectos de los fármacos , Riñón/patología , Metabolismo de los Lípidos/efectos de los fármacos , Peroxidación de Lípido/efectos de los fármacos , Estrés Oxidativo , Especies Reactivas de Oxígeno/metabolismo , Daño por Reperfusión/patología , Daño por Reperfusión/fisiopatología , Daño por Reperfusión/prevención & control , Transducción de SeñalRESUMEN
Acute kidney injury (AKI) represents a worldwide public health issue of increasing incidence, with a significant morbi-mortality. AKI treatment mostly relies on supportive manoeuvres in the absence of specific target-oriented therapy. The pathophysiology of AKI commonly involves ischaemia/reperfusion (I/R) events, which cause both immune and metabolic consequences in renal tissue. Similarly, at the time of kidney transplantation (KT), I/R is an unavoidable event which contributes to early graft dysfunction and enhanced graft immunogenicity. Mesenchymal stromal cells (MSCs) represent a heterogeneous population of adult, fibroblast-like multi-potent cells characterized by their ability to differentiate into tissues of mesodermal lineages. Because MSC have demonstrated immunomodulatory, anti-inflammatory and tissue repair properties, MSC administration at the time of I/R and/or at later times has been hypothesized to attenuate AKI severity and to accelerate the regeneration process. Furthermore, MSC in KT could help prevent both I/R injury and acute rejection, thereby increasing graft function and survival. In this review, summarizing the encouraging observations in animal models and in pilot clinical trials, we outline the benefit of MSC therapy in AKI and KT, and envisage their putative role in renal ischaemic conditioning.
Asunto(s)
Enfermedades Renales/terapia , Trasplante de Células Madre Mesenquimatosas/métodos , Daño por Reperfusión/terapia , Adulto , Animales , Humanos , Riñón/irrigación sanguínea , Riñón/fisiopatología , Enfermedades Renales/etiología , Enfermedades Renales/fisiopatología , Daño por Reperfusión/complicaciones , Daño por Reperfusión/fisiopatologíaRESUMEN
Introduction: [18F]FDG PET/CT noninvasively disproves acute kidney allograft rejection (AR) in kidney transplant recipients (KTRs) with suspected AR. However, the correlation of biopsy-based Banff vs. PET/CT-based scores of acute inflammation remains unknown, as does the prognostic performance of [18F]FDG PET/CT at one year post suspected AR. Methods: From 2012 to 2019, 114 [18F]FDG-PET/CTs were prospectively performed in 105 adult KTRs who underwent per cause transplant biopsies. Ordinal logistic regression assessed the correlation between the extent of histological inflammation and the mean standardized [18F]FDG uptake values (mSUVmean). Functional outcomes of kidney allografts were evaluated at one year post per cause biopsy and correlated to mSUVmean. Results: A significant correlation between mSUVmean and acute Banff score was found, with an adjusted R 2 of 0.25. The mSUVmean was significantly different between subgroups of "total i", with 2.30 ± 0.71 in score 3 vs. 1.68 ± 0.24 in score 0. Neither the function nor the survival of the graft at one year was statistically related to mSUVmean. Discussion: [18F]FDG-PET/CT may help noninvasively assess the severity of kidney allograft inflammation in KTRs with suspected AR, but it does not predict graft outcomes at one year.
RESUMEN
Introduction: Mesenchymal stromal cells (MSCs) have particular properties that are of interest in organ transplantation, including the expansion of regulatory T cells (Tregs), a key factor in transplant tolerance induction. However, the most effective immunosuppressive drug to associate with MSCs has yet to be defined. Additionally, the impact of the association of everolimus with MSCs on Treg expansion, and on the induction of liver graft tolerance, has never been studied. The aim of this study was to evaluate the effects of MSCs in combination, or not, with everolimus on Treg expansion and in a model of rejection after liver transplantation (LT) in the rat. Methods: Firstly, 24 Lewis rats were assigned to 4 groups (n=6 in each group) receiving intravenous MSCs or saline injection at day (D)9 with/without subcutaneous everolimus from D0 to D14. Analysis of circulating Tregs was performed at D0, D14 and D28. In a second set of experiment, 30 Lewis rats were randomized in 3 groups 48hours after LT with a Dark Agouti rat liver: everolimus (subcutaneous for 14 days), MSCs (intravenous injection at post-operative day 2 and 9), or both everolimus and MSCs. Rejection of the liver graft was assessed by liver tests, histology and survival. Results: Individually, MSC infusion and everolimus promoted Treg expansion in rats, and everolimus had no negative impact on Treg expansion in combination with MSCs. However, in the LT model, injections of MSCs two and nine days following LT were not effective at preventing acute rejection, and the combination of MSCs with everolimus failed to show any synergistic effect when compared to everolimus alone. Conclusion: Everolimus may be used in association with MSCs. However, in our model of LT in the rat, post-transplant MSC injections did not prevent acute rejection, and the association of MSCs with everolimus did not show any synergistic effect.
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Trasplante de Hígado , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Animales , Everolimus/farmacología , Rechazo de Injerto/patología , Trasplante de Hígado/efectos adversos , Complicaciones Posoperatorias , Ratas , Ratas Endogámicas Lew , Linfocitos T ReguladoresRESUMEN
Background: Kidney damage has been reported in patients with COVID-19. Despite numerous reports about COVID-19-associated nephropathy, the factual presence of the SARS-CoV-2 in the renal parenchyma remains controversial. Methods: We consecutively performed 16 immediate (≤3 hours) postmortem renal biopsies in patients diagnosed with COVID-19. Kidney samples from five patients who died from sepsis not related to COVID-19 were used as controls. Samples were methodically evaluated by three pathologists. Virus detection in the renal parenchyma was performed in all samples by bulk RNA RT-PCR (E and N1/N2 genes), immunostaining (2019-nCOV N-Protein), fluorescence in situ hybridization (nCoV2019-S), and electron microscopy. Results: The mean age of our COVID-19 cohort was 68.2±12.8 years, most of whom were male (69%). Proteinuria was observed in 53% of patients, whereas AKI occurred in 60% of patients. Acute tubular necrosis of variable severity was found in all patients, with no tubular or interstitial inflammation. There was no difference in acute tubular necrosis severity between the patients with COVID-19 versus controls. Congestion in glomerular and peritubular capillaries was respectively observed in 56% and 88% of patients with COVID-19, compared with 20% of controls, with no evidence of thrombi. The 2019-nCOV N-Protein was detected in proximal tubules and at the basolateral pole of scattered cells of the distal tubules in nine out of 16 patients. In situ hybridization confirmed these findings in six out of 16 patients. RT-PCR of kidney total RNA detected SARS-CoV-2 E and N1/N2 genes in one patient. Electron microscopy did not show typical viral inclusions. Conclusions: Our immediate postmortem kidney samples from patients with COVID-19 highlight a congestive pattern of AKI, with no significant glomerular or interstitial inflammation. Immunostaining and in situ hybridization suggest SARS-CoV-2 is present in various segments of the nephron.
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Lesión Renal Aguda , COVID-19 , Lesión Renal Aguda/diagnóstico , Anciano , Anciano de 80 o más Años , COVID-19/complicaciones , Capilares/patología , Humanos , Hibridación Fluorescente in Situ , Glomérulos Renales/patología , Masculino , Persona de Mediana Edad , Necrosis , SARS-CoV-2RESUMEN
BACKGROUND: Proteinuria has been commonly reported in patients with COVID-19. However, only dipstick tests have been frequently used thus far. Here, the quantification and characterization of proteinuria were investigated and their association with mortality was assessed. METHODS: This retrospective, observational, single center study included 153 patients, hospitalized with COVID-19 between March 28th and April 30th, 2020, in whom total proteinuria and urinary α1-microglobulin (a marker of tubular injury) were measured. Association with mortality was evaluated, with a follow-up until May 7th, 2020. RESULTS: According to the Kidney Disease Improving Global Outcomes staging, 14% (n = 21) of the patients had category 1 proteinuria (< 150 mg/g of urine creatinine), 42% (n = 64) had category 2 (between 150 and 500 mg/g) and 44% (n = 68) had category 3 proteinuria (over 500 mg/g). Urine α1-microglobulin concentration was higher than 15 mg/g in 89% of patients. After a median follow-up of 27 [14;30] days, the mortality rate reached 18%. Total proteinuria and urinary α1-microglobulin were associated with mortality in unadjusted and adjusted models. This association was stronger in subgroups of patients with normal renal function and without a urinary catheter. CONCLUSIONS: Proteinuria is frequent in patients with COVID-19. Its characterization suggests a tubular origin, with increased urinary α1-microglobulin. Tubular proteinuria was associated with mortality in COVID-19 in our restropective, observational study.
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COVID-19/complicaciones , Proteinuria/epidemiología , Anciano , Anciano de 80 o más Años , Bélgica/epidemiología , Biomarcadores/orina , COVID-19/epidemiología , COVID-19/orina , Femenino , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , Pronóstico , Proteinuria/etiología , Proteinuria/orina , Estudios Retrospectivos , Tasa de Supervivencia/tendenciasRESUMEN
Over the past decade, the clinical application of mesenchymal stromal cells (MSCs) has generated growing enthusiasm as an innovative cell-based approach in solid organ transplantation (SOT). These expectations arise from a significant number of both transplant- and non-transplant-related experimental studies investigating the complex anti-inflammatory, immunomodulatory, and tissue-repair properties of MSCs. Promising preclinical results have prompted clinical trials using MSC-based therapy in SOT. In the present review, the general properties of MSCs are summarized, with a particular emphasis on MSC-mediated impact on the immune system and in the ischemic conditioning strategy. Next, we chronologically detail all clinical trials using MSCs in the field of SOT. Finally, we envision the challenges and perspectives of MSC-based cell therapy in SOT.
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Rechazo de Injerto/prevención & control , Terapia de Inmunosupresión/métodos , Trasplante de Células Madre Mesenquimatosas/métodos , Células Madre Mesenquimatosas/citología , Trasplante de Órganos/métodos , Animales , Rechazo de Injerto/inmunología , HumanosRESUMEN
Mesenchymal stromal cells (MSC) have been demonstrated to attenuate renal ischemia/reperfusion (I/R) damage in rodent models. The mechanisms of such nephro-protection remain largely unknown. Furthermore, the optimal timing of MSC administration has been poorly investigated. Here, we compare the impact of MSC injection 7 days before (MSCD - 7) versus 1 day after (MSCD + 1) renal I/R in rats. Control groups received equivalent volumes of saline at similar time-points (SD - 7 and SD + 1). Right nephrectomy was performed, and left renal ischemia lasted 45 min. After 48-hour reperfusion, we observed significantly improved renal function parameters, reduced apoptotic index and neutrophil/macrophage infiltration in kidney parenchyma, and lower expression of tubular damage markers and pro-inflammatory cytokines in MSCD - 7 in comparison to MSCD + 1 and saline control groups. Next, comparative high-throughput RNA sequencing of MSCD - 7 vs. SD - 7 non-ischemic right kidneys highlighted significant down-regulation of fatty acid biosynthesis and up-regulation of PPAR-α pathway. Such a preferential regulation towards lipid catabolism was associated with decreased levels of lipid peroxidation products, i.e. malondialdehyde and 4-hydroxy-2-nonenal, in MSCD - 7 versus SD - 7 ischemic kidneys. Our findings suggest that MSC pretreatment may exert protective effects against renal I/R by modulating lipid metabolism in rats.
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Lesión Renal Aguda/etiología , Lesión Renal Aguda/metabolismo , Metabolismo de los Lípidos , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas/metabolismo , Daño por Reperfusión/metabolismo , Lesión Renal Aguda/diagnóstico , Lesión Renal Aguda/terapia , Animales , Apoptosis , Biopsia , Proliferación Celular , Modelos Animales de Enfermedad , Ácidos Grasos/metabolismo , Perfilación de la Expresión Génica , Pruebas de Función Renal , Peroxidación de Lípido , Masculino , Células Madre Mesenquimatosas/citología , Ratas , Daño por Reperfusión/diagnóstico , Daño por Reperfusión/terapia , Factores de Tiempo , Transcriptoma , Resultado del TratamientoRESUMEN
Kidney transplantation (KTx) represents the best available treatment for patients with end-stage renal disease. Still, full benefits of KTx are undermined by acute rejection (AR). The diagnosis of AR ultimately relies on transplant needle biopsy. However, such an invasive procedure is associated with a significant risk of complications and is limited by sampling error and interobserver variability. In the present review, we summarize the current literature about non-invasive approaches for the diagnosis of AR in kidney transplant recipients (KTRs), including in vivo imaging, gene expression profiling and omics analyses of blood and urine samples. Most imaging techniques, like contrast-enhanced ultrasound and magnetic resonance, exploit the fact that blood flow is significantly lowered in case of AR-induced inflammation. In addition, AR-associated recruitment of activated leukocytes may be detectable by 18F-fluoro-deoxy-glucose positron emission tomography. In parallel, urine biomarkers, including CXCL9/CXCL10 or a three-gene signature of CD3ε, IP-10 and 18S RNA levels, have been identified. None of these approaches has been adopted yet in the clinical follow-up of KTRs, but standardization of procedures may help assess reproducibility and compare diagnostic yields in large prospective multicentric trials.
RESUMEN
Kidney transplantation (KTx) represents the best available treatment for patients with end-stage renal disease. Still, the full benefits of KTx are undermined by acute rejection (AR). The diagnosis of AR ultimately relies on transplant needle biopsy. However, such an invasive procedure is associated with a significant risk of complications and is limited by sampling error and interobserver variability. In the present review, we summarize the current literature about non-invasive approaches for the diagnosis of AR in kidney transplant recipients (KTRs), including in vivo imaging, gene-expression profiling and omics analyses of blood and urine samples. Most imaging techniques, such as contrast-enhanced ultrasound and magnetic resonance, exploit the fact that blood flow is significantly lowered in case of AR-induced inflammation. In addition, AR-associated recruitment of activated leucocytes may be detectable by 18F-fluorodeoxyglucose positron emission tomography. In parallel, urine biomarkers, including CXCL9/CXCL10 or a three-gene signature of CD3ε, CXCL10 and 18S RNA levels, have been identified. None of these approaches has yet been adopted in the clinical follow-up of KTRs, but standardization of analysis procedures may help assess reproducibility and comparative diagnostic yield in large, prospective, multicentre trials.
RESUMEN
Ischemia/reperfusion injury (IRI) represents a worldwide public health issue of increasing incidence. IRI may virtually affect all organs and tissues and is associated with significant morbidity and mortality. Particularly, the duration of blood supply deprivation has been recognized as a critical factor in stroke, hemorrhagic shock, or myocardial infarction, as well as in solid organ transplantation (SOT). Pathophysiologically, IRI causes multiple cellular and tissular metabolic and architectural changes. Furthermore, the reperfusion of ischemic tissues induces both local and systemic inflammation. In the particular field of SOT, IRI is an unavoidable event, which conditions both short- and long-term outcomes of graft function and survival. Clinically, the treatment of patients with IRI mostly relies on supportive maneuvers since no specific target-oriented therapy has been validated thus far. In the present review, we summarize the current literature on mesenchymal stromal cells (MSC) and their potential use as cell therapy in IRI. MSC have demonstrated immunomodulatory, anti-inflammatory, and tissue repair properties in rodent studies and in preliminary clinical trials, which may open novel avenues in the management of IRI and SOT.
Asunto(s)
Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas/citología , Daño por Reperfusión/terapia , Animales , Antígenos de Superficie/metabolismo , Isquemia Encefálica/terapia , Tratamiento Basado en Trasplante de Células y Tejidos , Humanos , Enfermedades Renales/etiología , Enfermedades Renales/terapia , Hepatopatías/etiología , Hepatopatías/terapia , Células Madre Mesenquimatosas/metabolismo , Daño por Reperfusión Miocárdica/terapia , Fenotipo , Daño por Reperfusión/etiologíaRESUMEN
Kidney transplantation represents the best treatment of end-stage renal disease. In addition to the degree of human leukocyte antigen matching, long-term graft survival is influenced by the quality of the graft before its transplantation. Quality criteria include the level of ischemic damage caused by the transplantation per se. Renal ischemic preconditioning (IP) consists of different approaches to prevent ischemia/reperfusion (I/R) damage induced by the interruption and recovery of renal circulation, as observed during transplantation. Distinct animal models show promising results regarding the efficiency of PCI to preserve kidney structure and function in I/R conditions. Characterizing the cellular cascades involved in I/R led to the identification of putative targets of renal IP, including the adenosine monophosphate-activated protein kinase (AMPK). AMPK is a ubiquitous energy sensor, which has been implicated in the maintenance of epithelial cell polarization under energy deprivation. Among others, the anti-diabetic drug, metformin, is a potent activator of AMPK. Here, we summarize the in vitro and in vivo data about the role of AMPK in renal IP. Defining the pharmacological conditions of IP would help to improve the quality of the renal graft before its transplantation, thereby increasing its long-term survival.
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Proteínas Quinasas Activadas por AMP/fisiología , Precondicionamiento Isquémico , Trasplante de Riñón , Riñón/irrigación sanguínea , Daño por Reperfusión/prevención & control , Proteínas Quinasas Activadas por AMP/efectos de los fármacos , Aminoimidazol Carboxamida/análogos & derivados , Aminoimidazol Carboxamida/farmacología , Aminoimidazol Carboxamida/uso terapéutico , Animales , Metabolismo Energético/fisiología , Activación Enzimática/efectos de los fármacos , Células Epiteliales/enzimología , Células Epiteliales/ultraestructura , Supervivencia de Injerto , Humanos , Isquemia/etiología , Isquemia/fisiopatología , Fallo Renal Crónico/cirugía , Trasplante de Riñón/métodos , Metformina/farmacología , Metformina/uso terapéutico , Estrés Oxidativo , Ratas , Ratas Sprague-Dawley , Circulación Renal , Ribonucleótidos/farmacología , Ribonucleótidos/uso terapéutico , Transducción de Señal/efectos de los fármacosRESUMEN
Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis is an autosomal-recessive disease caused by mutations in the CLDN16 or CLDN19 genes, which encode tight junction-associated proteins, claudin-16 and -19. The resultant tubulopathy leads to urinary loss of Mg(2+) and Ca(2+), with subsequent nephrocalcinosis and end-stage renal disease (ESRD). An 18-year-old boy presented with chronic kidney disease and proteinuria, as well as hypomagnesaemia, hypercalciuria and nephrocalcinosis. A kidney biopsy revealed tubular atrophy, interstitial fibrosis and segmental sclerosis of some glomeruli. Two novel mutations in the CLDN16 gene were identified: c.340C>T (nonsense) and c.427+5G>A (splice site). The patient reached ESRD at 23 and benefited from kidney transplantation.