Uso terapéutico de las vesículas extracelulares en insuficiencia renal aguda y crónica

En la década de los 90 se descubrió un nuevo sistema de comunicación célula-célula, que consiste en la liberación de vesículas cargadas con partículas bioactivas (proteínas, mRNA, miRNA, metabolitos, etc.) en el espacio extracelular. Este tipo de comunicación se ha conservado durante la evolución, hecho que justificaría que la mayoría de los tipos celulares puedan generarlas. Estas vesículas extracelulares (VE) pueden regular diversos procesos fisiológicos, así como el desarrollo y progresión de enfermedades. En los últimos anos se ha extendido el estudio de las VE generadas principalmente por células madre adultas o embrionarias, células sanguíneas, células del sistema inmune y nervioso, así como células tumorales. El análisis de VE en fluidos corporales ha sido utilizado como herramienta de diagnóstico en cáncer y recientemente para distintas enfermedades renales. Sin embargo, en esta revisión pretendemos analizar la importancia, función y posible aplicación clínica de las VE generadas por células madre en enfermedades renales y en trasplantes

Renal transplantation in patients with hepatitis C virus antibody. A long national experience

Background. Renal transplantation is the best therapy for patients with hepatitis C virus (HCV) infection with end-stage renal disease. Patient and graft survival are lower in the long term compared with HCV-negative patients. The current study evaluated the results of renal transplantation in Spain in a long period (1990–2002), focusing on graft failure

A Descriptive Analysis of ATTR Amyloidosis in Spain from the Transthyretin Amyloidosis Outcomes Survey.

Introduction Transthyretin amyloidosis (ATTR amyloidosis) is a clinically heterogeneous disease caused by mutations in the transthyretin (TTR) gene or aggregation of wild-type transthyretin (ATTRwt). In Spain, there are two large endemic foci of ATTR amyloidosis caused by the Val30Met variant, with additional cases across the country; however, these data may be incomplete, as there is no centralized patient registry. The Transthyretin Amyloidosis Outcomes Survey (THAOS) is an ongoing, global, longitudinal, observational survey of patients with ATTR amyloidosis, including both inherited and wild-type disease, and asymptomatic patients with TTR mutations. This analysis aimed to gain a deeper understanding of the clinical profile of patients with ATTR amyloidosis in Spain. Methods This was a descriptive analysis of the demographic and clinical characteristics of symptomatic patients enrolled at six sites geographically dispersed throughout Spain (data cutoff: January 6, 2020). Patient data at enrollment, including genotype, demographics, and clinical presentation for symptomatic patients, were recorded. Patients were grouped by predominant phenotype based on clinical measures at enrollment: predominantly cardiac, predominantly neurologic, or mixed (cardiac and neurologic). Results There were 379 patients (58.0% male; 63.3% symptomatic) enrolled in the six THAOS sites in Spain. Predominant genotypes were the Val30Met mutation (69.1%) or ATTRwt (15.6%). Predominant phenotype distribution was neurologic (50.4%), mixed (35.8%), and cardiac (13.8%) for all symptomatic patients (n = 240); neurologic (67.8%), mixed (21.2%), and cardiac (11.0%) for symptomatic Val30Met (n = 146); and mixed (64.9%), cardiac (22.8%), and neurologic (12.3%) for symptomatic ATTRwt (n = 57). Symptomatic patients reported a range of ATTR amyloidosis signs and symptoms at enrollment, with autonomic neuropathy and sensory neuropathy common in all phenotypes. Conclusions These results from THAOS highlight the phenotypic heterogeneity associated with ATTR amyloidosis in Spain and the importance of comprehensive neurologic and cardiac evaluations in all patients with ATTR amyloidosis.post-print392 K

Renal transplantation in the modern immunosuppressive era in Spain: four-year results from a multicenter database focus on post-transplant cardiovascular disease

Producción CientíficaTo evaluate cardiovascular disease (CVD) after renal transplantation we established a CVD database (no-intervention) including all patients transplanted among 2000–2002 in 14 hospitals from Spain (Renal Forum Group) (n¼2600). They were prospective followed annually thereafter and we present herein the most important results concerning survival figures and CVD at four years. Mean recipient age was 49.7±13.7 years: 16% retransplanted and 12.5% hyperimmunized. Tacrolimus, mycophenolate mofetil, and steroids was used in 63%. Acute rejection (AR) rate at 1 year was 14.8%. Graft and patient survival at 48 months were 85.6% (death censored) and 91.7% respectively. The first cause of graft loss was vascular in the first year, death with function during the 2–3 years, and chronic allograft nephropathy at the 4th year. Donor age, time on dialysis, acute tubular necrosis (ATN), AR, SCr at 6 months, the use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers in the first year, and systolic blood pressure at 24 months were independent risk factors for graft loss at 4th year. The first cause of death was CVD (predominantly ischemic heart disease (IHD) in the first year). Recipient age, ATN, and SCr at 6 months were independent predictors of mortality. Despite worsening of donor age, comorbidity, and advanced age of recipients, survival figures at four years are considered good in our Spanish non-selected population. Cardiovascular mortality is the most important cause of death and graft loss particularly, IHD in the first year. Therefore, to decrease post-transplant mortality a careful cardiovascular evaluation and treatment in the waiting list and a close follow-up of patients after transplantation is mandatory

Preemptive simultaneous pancreas kidney transplantation has survival benefit to patients

Several organ allocation protocols give priority to wait-listed simultaneous kidney-pancreas (SPK) transplant recipients to mitigate the higher cardiovascular risk of patients with diabetes mellitus on dialysis. The available information regarding the impact of preemptive simultaneous kidney-pancreas transplantation on recipient and graft outcomes is nonetheless controversial. To help resolve this, we explored the influence of preemptive simultaneous kidney-pancreas transplants on patient and graft survival through a retrospective analysis of the OPTN/UNOS database, encompassing 9690 simultaneous transplant recipients between 2000 and 2017. Statistical analysis was performed applying a propensity score analysis to minimize bias. Of these patients, 1796 (19%) were transplanted preemptively. At ten years, recipient survival was significantly superior in the preemptive group when compared to the non-preemptive group (78.9% vs 71.8%). Dialysis at simultaneous kidney-pancreas transplantation was an independent significant risk for patient survival (hazard ratio 1.66 [95% confidence interval 1.32-2.09]), especially if the dialysis duration was 12 months or longer. Preemptive transplantation was also associated with significant superior kidney graft survival compared to those on dialysis (death-censored: 84.3% vs 75.4%, respectively; estimated half-life of 38.57 [38.33 -38.81] vs 22.35 [22.17 - 22.53] years, respectively). No differences were observed between both groups neither for pancreas graft survival nor for post-transplant surgical complications. Thus, our results sustain the relevance of early referral for pancreas transplantation and the importance of pancreas allocation priority in reducing patient mortality after simultaneous kidney-pancreas transplantation

Humoral and Cellular Immune Responses After a 3-dose Course of mRNA-1273 COVID-19 Vaccine in Kidney Transplant Recipients: A Prospective Cohort Study.

In kidney transplant recipients, there is discordance between the development of cellular and humoral response after vaccination against SARS-CoV-2. We sought to determine the interplay between the 2 arms of adaptive immunity in a 3-dose course of mRNA-1273 100 μg vaccine. Methods: Humoral (IgG/IgM) and cellular (N- and S-ELISpot) responses were studied in 117 kidney and 12 kidney-pancreas transplant recipients at the following time points: before the first dose, 14 d after the second dose' and before and after the third dose, with a median of 203 and 232 d after the start of the vaccination cycle, respectively. Results: After the second dose, 26.7% of naive cases experienced seroconversion. Before the third dose and in the absence of COVID-19, this percentage increased to 61.9%. After the third dose, seroconversion occurred in 80.0% of patients. Naive patients who had at any time point a detectable positivity for S-ELISpot were 75.2% of the population, whereas patients who maintained S-ELISpot positivity throughout the study were 34.3%. S-ELISpot positivity at 42 d was associated with final seroconversion (odds ratio' 3.14; 95% confidence interval' 1.10-8.96; P = 0.032). Final IgG titer was significantly higher in patients with constant S-ELISpot positivity (P < 0.001). Conclusions: A substantial proportion of kidney transplant recipients developed late seroconversion after 2 doses. Cellular immunity was associated with the development of a stronger humoral respons

Therapeutic application of extracellular vesicles in acute and chronic renal injury

A new cell-to-cell communication system was discovered in the 1990s, which involves the release of vesicles into the extracellular space. These vesicles shuttle bioactive particles, including proteins, mRNA, miRNA, metabolites, etc. This particular communication has been conserved throughout evolution, which explains why most cell types are capable of producing vesicles. Extracellular vesicles (EVs) are involved in the regulation of different physiological processes, as well as in the development and progression of several diseases. EVs have been widely studied over recent years, especially those produced by embryonic and adult stem cells, blood cells, immune system and nervous system cells, as well as tumour cells. EV analysis from bodily fluids has been used as a diagnostic tool for cancer and recently for different renal diseases. However, this review analyses the importance of EVs generated by stem cells, their function and possible clinical application in renal diseases and kidney transplantation

An update for atypical haemolytic uraemic syndrome: diagnosis and treatment. A consensus document

[EN]Haemolytic uraemic syndrome (HUS) is a clinical entitydefined as the triad of nonimmune haemolytic anaemia,thrombocytopenia, and acute renal failure, in which theunderlying lesions are mediated by systemic thromboticmicroangiopathy (TMA). Atypical HUS (aHUS) is a sub-typeof HUS in which the TMA phenomena are the consequenceof decreased regulation of the alternative complementpathway on cell surfaces due to a genetic cause. aHUS is anextremely rare disease that, despite the administration ofstandard treatment with plasma therapy, often progressesto terminal chronic renal failure with a high associated rateof mortality. In recent years, research has established thekey role that the complement system plays in the inductionof endothelial damage in patients with aHUS, through thecharacterisation of multiple mutations and polymorphismsin the genes that code for certain complement factors.Eculizumab is a monoclonal antibody that inhibits theterminal fraction of the complement protein, blocking theformation of a cell membrane attack complex. Inprospective studies in patients with aHUS, administeringeculizumab produces a rapid and sustained interruption inthe TMA process, with significant improvements in long-term renal function and an important decrease in the needfor dialysis or plasma therapy. In this document, we reviewand bring up to date the important aspects of this disease,with special emphasis on how recent advancements indiagnostic and therapeutic processes can modify thetreatment of patients with aHUS.[ES]El síndrome hemolítico urémico (SHU) es una entidad clínica definida por la tríada anemia hemolítica no inmune, trombocitopenia e insuficiencia renal aguda, en la que las lesiones subyacentes están mediadas por un proceso de microangiopatía trombótica (MAT) sistémica. El SHU atípico (SHUa) es un subtipo de SHU en el que los fenómenos de MAT son consecuencia de la pérdida de regulación de la vía alternativa del complemento sobre las superficies celulares de causa genética. El SHUa es una enfermedad ultra-rara que, pese al tratamiento estándar con terapia plasmática, frecuentemente evoluciona a la insuficiencia renal crónica terminal, con elevada mortalidad. En los últimos años, se ha establecido el papel clave que desempeña el sistema del complemento en la inducción de daño endotelial en los pacientes con SHUa, mediante la caracterización de múltiples mutaciones y polimorfismos en los genes que codifican determinados factores del complemento. Eculizumab es un anticuerpo monoclonal que inhibe la fracción terminal del complemento bloqueando la formación del complejo de ataque de membrana. En estudios prospectivos en pacientes con SHUa su administración ha demostrado la interrupción rápida y sostenida del proceso de MAT, con mejorías significativas de la función renal a largo plazo y con una reducción importante de la necesidad de diálisis o terapia plasmática. En el presente documento se revisan y actualizan los diversos aspectos de interés de esta enfermedad, con especial atención a cómo los recientes avances diagnósticos y terapéuticos pueden modificar el tratamiento de los pacientes con SHUa.The research carried out by Dr Rodriguez de Cordoba is financedby the Ministry of Economy and Competition (SAF2010-26583),the Autonomous Community of Madrid (S2010/BMD-2316), andthe Fundacion Renal Inigo Alvarez de Toledo.The authors would like to thank Alexion Pharmaceuticals fortheir logistic support in carrying out the consensus meetings,as well as editorial support through Ogilvy Healthworld.Peer reviewe

Uso terapéutico de las vesículas extracelulares en insuficiencia renal aguda y crónica

En la década de los 90 se descubrió un nuevo sistema de comunicación célula-célula, que consiste en la liberación de vesículas cargadas con partículas bioactivas (proteínas, mRNA, miRNA, metabolitos, etc.) en el espacio extracelular. Este tipo de comunicación se ha conservado durante la evolución, hecho que justificaría que la mayoría de los tipos celulares puedan generarlas. Estas vesículas extracelulares (VE) pueden regular diversos procesos fisiológicos, así como el desarrollo y progresión de enfermedades. En los últimos anos se ha extendido el estudio de las VE generadas principalmente por células madre adultas o embrionarias, células sanguíneas, células del sistema inmune y nervioso, así como células tumorales. El análisis de VE en fluidos corporales ha sido utilizado como herramienta de diagnóstico en cáncer y recientemente para distintas enfermedades renales. Sin embargo, en esta revisión pretendemos analizar la importancia, función y posible aplicación clínica de las VE generadas por células madre en enfermedades renales y en trasplantes

Increased anandamide induced relaxation in mesenteric arteries of cirrhotic rats. Role of cannabinoid and vanilloid receptors

Background and aims: Anandamide is an endocannabinoid that evokes hypotension by interaction with peripheral cannabinoid CB1 receptors and with the perivascular transient receptor potential vanilloid type 1 protein (TRPV1). As anandamide has been implicated in the vasodilated state in advanced cirrhosis, the study investigated whether the mesenteric bed from cirrhotic rats has an altered and selective vasodilator response to anandamide. Methods: We assessed vascular sensitivity to anandamide, mRNA and protein expression of cannabinoid CB1 receptor and TRPV1 receptor, and the topographical distribution of cannabinoid CB1 receptors in resistance mesenteric arteries of cirrhotic and control rats. Results: Mesenteric vessels of cirrhotic animals displayed greater sensitivity to anandamide than control vessels. This vasodilator response was reverted by CB1 or TRPV1 receptor blockade, but not after endothelium denudation or nitric oxide inhibition. Anandamide had no effect on distal femoral arteries. CB1 and TRPV1 receptor protein was higher in cirrhotic than in control vessels. Neither CB1 mRNA nor protein was detected in femoral arteries. Immunochemistry showed that CB1 receptors were mainly in the adventitia and in the endothelial monolayer, with higher expression observed in vessels of cirrhotic rats than in controls. Conclusions: These results indicate that anandamide is a selective splanchnic vasodilator in cirrhosis which predominantly acts via interaction with two different types of receptors, CB1 and TRPV1 receptors, which are mainly located in perivascular sensory nerve terminals of the mesenteric resistance arteries of these animals