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Fabry disease or also called Anderson-Fabry disease (FD) is a rare disease caused by pathogenic variants in the GLA gene, located on the X chromosome. This gene is involved in the metabolism of glycosphingolipids and its pathogenic variants cause a deficit or absence of α-galactosidase A causing the deposition of globotriaosylceramide throughout the body. Females have a variable phenotypic expression and a better prognosis than males. This is due to the X chromosome inactivation phenomenon. We present a clinical case of Fabry disease in a female with predominantly renal involvement and demonstrate how the X chromosome inactivation phenomenon is tissue dependent, showing preferential inactivation of the mutated allele at the renal level. Resumen: La enfermedad de Fabry o también llamada de Anderson-Fabry (EF) es una enfermedad rara, causada por variantes patogénicas en el gen GLA, localizado en el cromosoma X. Este gen interviene en el metabolismo de los glucoesfingolípidos y variantes patogénicas en el mismo causan déficit o ausencia de la α-galactosidasa A ocasionando el depósito de globotriaosilceramida en todo el organismo. Las mujeres presentan una expresión fenotípica variable y de mejor pronóstico que los varones. Esto es debido al fenómeno de inactivación del cromosoma X. Presentamos un caso clínico de enfermedad de Fabry en una mujer con afectación predominantemente renal y demostramos cómo el fenómeno de la inactivación del cromosoma X es tejido dependiente, mostrando una inactivación preferencial del alelo mutado a nivel renal.

Resumen: La enfermedad de Fabry o también llamada de Anderson-Fabry (EF) es una enfermedad rara, causada por variantes patogénicas en el gen GLA, localizado en el cromosoma X. Este gen interviene en el metabolismo de los glucoesfingolípidos y variantes patogénicas en el mismo causan déficit o ausencia de la α-galactosidasa A, ocasionando el depósito de globotriaosilceramida en todo el organismo. Las mujeres presentan una expresión fenotípica variable y de mejor pronóstico que los varones. Esto es debido al fenómeno de inactivación del cromosoma X. Presentamos un caso clínico de enfermedad de Fabry en una mujer con afectación predominantemente renal y demostramos cómo el fenómeno de la inactivación del cromosoma X es tejido dependiente, mostrando una inactivación preferencial del alelo mutado a nivel renal. Abstract: Fabry disease or also called Anderson–Fabry disease (FD) is a rare disease caused by pathogenic variants in the GLA gene, located on the X chromosome. This gene is involved in the metabolism of glycosphingolipids and its pathogenic variants cause a deficit or absence of α-galactosidase A causing the deposition of globotriaosylceramide throughout the body. Females have a variable phenotypic expression and a better prognosis than males. This is due to the X chromosome inactivation phenomenon. We present a clinical case of Fabry disease in a female with predominantly renal involvement and demonstrate how the X chromosome inactivation phenomenon is tissue dependent, showing preferential inactivation of the mutated allele at the renal level.

Monoclonal gammopathy of renal significance includes all renal disorders caused by a monoclonal immunoglobulin secreted by a non-malignant B-cell clone. Patients with MGRS do not, by definition, meet criteria for multiple myeloma, with haematological disorders generally considered to be monoclonal gammopathy of undetermined significance. Nevertheless, the renal involvement can be serious and require specific treatment. Monoclonal gammopathy of renal significance is associated with a wide spectrum of disorders, including the recently discovered C3 glomerulopathy. Development of C3 glomerulopathy in the context of monoclonal gammopathy of renal significance after kidney transplantation is uncommon and very few cases have been published to date. We report on three cases of C3 glomerulopathy in the context of de novo monoclonal gammopathy after kidney transplantation. Resumen: La gammapatía monoclonal de significado renal incluye todas las enfermedades renales causadas por una inmunoglobulina monoclonal secretada por un clon de célula B no maligno. Por definición, los pacientes con gammapatía monoclonal de significado renal no cumplen criterios de mieloma múltiple y la alteración hematológica es generalmente considerada gammapatía monoclonal de significado incierto. No obstante, la dolencia que pueden causar a nivel renal puede ser importante, requiriendo un tratamiento específico. El espectro de la gammapatía monoclonal de significado renal es amplio, incluyendo una entidad reciente como la nefropatía C3. El desarrollo de una nefropatía C3 en el contexto de una gammapatía monoclonal de significado renal tras el trasplante renal no es frecuente y hasta el momento ha sido poco descrita. A continuación presentamos 3 casos de nefropatía C3 asociados a una gammapatía monoclonal de aparición de novo tras el trasplante renal. Keywords: Monoclonal gammopathy, Kidney transplant, C3 glomerulopathy, Palabras clave: Gammapatía monoclonal, Trasplante renal, Nefropatía C3

Resumen: La gammapatía monoclonal de significado renal incluye todas las enfermedades renales causadas por una inmunoglobulina monoclonal secretada por un clon de célula B no maligno. Por definición, los pacientes con gammapatía monoclonal de significado renal no cumplen criterios de mieloma múltiple y la alteración hematológica es generalmente considerada gammapatía monoclonal de significado incierto. No obstante, la dolencia que pueden causar a nivel renal puede ser importante, requiriendo un tratamiento específico. El espectro de la gammapatía monoclonal de significado renal es amplio, incluyendo una entidad reciente como la nefropatía C3. El desarrollo de una nefropatía C3 en el contexto de una gammapatía monoclonal de significado renal tras el trasplante renal no es frecuente y hasta el momento ha sido poco descrita. A continuación presentamos 3 casos de nefropatía C3 asociados a una gammapatía monoclonal de aparición de novo tras el trasplante renal. Abstract: Monoclonal gammopathy of renal significance includes all renal disorders caused by a monoclonal immunoglobulin secreted by a non-malignant B-cell clone. Patients with MGRS do not, by definition, meet criteria for multiple myeloma, with haematological disorders generally considered to be monoclonal gammopathy of undetermined significance. Nevertheless, the renal involvement can be serious and require specific treatment. Monoclonal gammopathy of renal significance is associated with a wide spectrum of disorders, including the recently discovered C3 glomerulopathy. Development of C3 glomerulopathy in the context of monoclonal gammopathy of renal significance after kidney transplantation is uncommon and very few cases have been published to date. We report on three cases of C3 glomerulopathy in the context of de novo monoclonal gammopathy after kidney transplantation. Palabras clave: Gammapatía monoclonal, Trasplante renal, Nefropatía C3, Keywords: Monoclonal gammopathy, Kidney transplant, C3 glomerulopathy

Pretransplant graft inflammation could be involved in the worse prognosis of deceased donor (DD) kidney transplants. A2A adenosine receptor (A2AR) can stimulate anti-inflammatory M2 macrophages, leading to fibrosis if injury and inflammation persist. Pre-implantation biopsies of kidney donors (47 DD and 21 living donors (LD)) were used to analyze expression levels and activated intracellular pathways related to inflammatory and pro-fibrotic processes. A2AR expression and PKA pathway were enhanced in DD kidneys. A2AR gene expression correlated with TGF-β1 and other profibrotic markers, as well as CD163, C/EBPβ, and Col1A1, which are highly expressed in DD kidneys. TNF-α mRNA levels correlated with profibrotic and anti-inflammatory factors such as TGF-β1 and A2AR. Experiments with THP-1 cells point to the involvement of the TNF-α/NF-κB pathway in the up-regulation of A2AR, which induces the M2 phenotype increasing CD163 and TGF-β1 expression. In DD kidneys, the TNF-α/NF-κB pathway could be involved in the increase of A2AR expression, which would activate the PKA–CREB axis, inducing the macrophage M2 phenotype, TGF-β1 production, and ultimately, fibrosis. Thus, in inflamed DD kidneys, an increase in A2AR expression is associated with the onset of fibrosis, which may contribute to graft dysfunction and prognostic differences between DD and LD transplants.

Delayed graft function (DGF) increases the risk of graft loss by up to 40%, and recent developments in kidney donation have increased the risk of its occurrence. Lowering the risk of DGF, however, is challenging due to a complicated etiology in which ischemia-reperfusion injury (IRI) leads to acute tubular necrosis. Among various strategies explored, the choice of induction therapy is one consideration. Rabbit antithymocyte globulin (rATG [Thymoglobuline]) has complex immunomodulatory effects that are relevant to DGF. In addition to a rapid and profound T-cell depletion, rATG inhibits leukocyte migration and adhesion. Experimental studies of rATG have demonstrated attenuated IRI-related tissue damage in reperfused tissues, consistent with histological evidence from transplant recipients. Starting rATG intraoperatively instead of postoperatively can improve kidney graft function and reduce the incidence of DGF. rATG is effective in preventing acute rejection in kidney transplant recipients at high immunological risk, supporting delayed calcineurin inhibitor (CNI) introduction which protects the graft from early insults. A reduced rate of DGF has been reported with rATG (started intraoperatively) and delayed CNI therapy compared to IL-2RA induction with immediate CNI in patients at high immunological risk, but not in lower-risk patients. Overall, induction with rATG induction is the preferred choice for supporting delayed introduction of CNI therapy to avoid DGF in high-risk patients but shows no benefit versus IL-2RA in lower-risk individuals. Evidence is growing that intraoperative rATG ameliorates IRI, and it seems reasonable to routinely start rATG before reperfusion.

This Guide for Living Donor Kidney Transplantation (LDKT) has been prepared with the sponsorship of the Spanish Society of Nephrology (SEN), the Spanish Transplant Society (SET), and the Spanish National Transplant Organization (ONT). It updates evidence to offer the best chronic renal failure treatment when a potential living donor is available. The core aim of this Guide is to supply clinicians who evaluate living donors and transplant recipients with the best decision-making tools, to optimise their outcomes.Moreover, the role of living donors in the current KT context should recover the level of importance it had until recently. To this end the new forms of incompatible HLA and/or ABO donation, as well as the paired donation which is possible in several hospitals with experience in LDKT, offer additional ways to treat renal patients with an incompatible donor.Good results in terms of patient and graft survival have expanded the range of circumstances under which living renal donors are accepted. Older donors are now accepted, as are others with factors that affect the decision, such as a borderline clinical history or alterations, which when evaluated may lead to an additional number of transplantations.This Guide does not forget that LDKT may lead to risk for the donor. Pre-donation evaluation has to centre on the problems which may arise over the short or long-term, and these have to be described to the potential donor so that they are able take them into account. Experience over recent years has led to progress in risk analysis, to protect donors’ health. This aspect always has to be taken into account by LDKT programmes when evaluating potential donors.Finally, this Guide has been designed to aid decision-making, with recommendations and suggestions when uncertainties arise in pre-donation studies. Its overarching aim is to ensure that informed consent is based on high quality studies and information supplied to donors and recipients, offering the strongest possible guarantees. Resumen: Esta guía de recomendaciones para el TR de donante vivo (TRDV) es un documento elaborado con el patrocinio de la Sociedad Española de Nefrología, la Sociedad Española de Trasplantes y la Organización Nacional de Trasplantes que actualiza la calidad de la evidencia disponible para ofrecer el mejor tratamiento de la insuficiencia renal crónica cuando se disponga de un donante vivo potencial. El objetivo principal de esta guía es proporcionar a los profesionales con responsabilidad en los estudios previos del donante vivo y del receptor trasplantado, las mejores herramientas para tomar decisiones en beneficio del donante vivo y del receptor del trasplante.Además, en el contexto actual del TR, el donante vivo debe recuperar el protagonismo que alcanzó en un pasado reciente. Para ello, las nuevas modalidades de donación HLA y/o ABO incompatible, así como la donación cruzada disponibles en diversos centros con experiencia en TRDV, son oportunidades adicionales para el tratamiento de enfermos renales que tienen un donante incompatible.Los buenos resultados en supervivencia del paciente y del injerto están ampliando las circunstancias de aceptación de donantes vivos de riñón, incluyendo donantes de mayor edad y otros con algunos condicionantes que incluyen antecedentes o alteraciones límite que, cuando son evaluados con criterios objetivos, pueden aportar un numero adicional de trasplantes.No se ha obviado en esta guía que el TRDV puede representar algún riesgo para el que dona. Estos problemas que pueden aparecer a corto o largo plazo tienen que ser objeto principal de valoración previa a la donación y presentados al potencial donante para que en ejercicio de su autonomía los asuma o rechace. La experiencia acumulada en los últimos años ha permitido avanzar en el análisis de riesgos para preservar la salud de los donantes, aspecto que debe estar siempre presente en los responsables de programas de TRDV cuando se procede al estudio de idoneidad de un potencial donante.Finalmente, esta guía ha sido estructurada para facilitar la toma de decisiones con recomendaciones y sugerencias ante incertidumbres derivadas de los resultados en los exhaustivos estudios predonación. Y todo ello, con el objetivo de que el consentimiento informado que debe certificar la calidad de los estudios y la información proporcionada a donante y receptor, alcancen las mayores garantías posibles.

Resumen: Esta guía de recomendaciones para el TR de donante vivo (TRDV) es un documento elaborado con el patrocinio de la Sociedad Española de Nefrología, la Sociedad Española de Trasplantes y la Organización Nacional de Trasplantes que actualiza la calidad de la evidencia disponible para ofrecer el mejor tratamiento de la insuficiencia renal crónica cuando se disponga de un donante vivo potencial. El objetivo principal de esta guía es proporcionar a los profesionales con responsabilidad en los estudios previos del donante vivo y del receptor trasplantado, las mejores herramientas para tomar decisiones en beneficio del donante vivo y del receptor del trasplante.Además, en el contexto actual del TR, el donante vivo debe recuperar el protagonismo que alcanzó en un pasado reciente. Para ello, las nuevas modalidades de donación HLA y/o ABO incompatible, así como la donación cruzada disponibles en diversos centros con experiencia en TRDV, son oportunidades adicionales para el tratamiento de enfermos renales que tienen un donante incompatible.Los buenos resultados en supervivencia del paciente y del injerto están ampliando las circunstancias de aceptación de donantes vivos de riñón, incluyendo donantes de mayor edad y otros con algunos condicionantes que incluyen antecedentes o alteraciones límite que, cuando son evaluados con criterios objetivos, pueden aportar un numero adicional de trasplantes.No se ha obviado en esta guía que el TRDV puede representar algún riesgo para el que dona. Estos problemas que pueden aparecer a corto o largo plazo tienen que ser objeto principal de valoración previa a la donación y presentados al potencial donante para que en ejercicio de su autonomía los asuma o rechace. La experiencia acumulada en los últimos años ha permitido avanzar en el análisis de riesgos para preservar la salud de los donantes, aspecto que debe estar siempre presente en los responsables de programas de TRDV cuando se procede al estudio de idoneidad de un potencial donante.Finalmente, esta guía ha sido estructurada para facilitar la toma de decisiones con recomendaciones y sugerencias ante incertidumbres derivadas de los resultados en los exhaustivos estudios predonación. Y todo ello, con el objetivo de que el consentimiento informado que debe certificar la calidad de los estudios y la información proporcionada a donante y receptor, alcancen las mayores garantías posibles. Abstract: This guide for living donor renal transplantation (LDRT) has been prepared with the sponsorship of the Spanish Society of Nephrology (SEN), the Spanish Transplant Society (SET), and the Spanish National Transplant Organization (ONT). It updates evidence to offer the best chronic renal failure treatment when a potential living donor is available. The core aim of this guide is to supply clinicians who evaluate living donors and transplant recipients with the best decision-making tools, to optimise their outcomes.Moreover, the role of living donors in the current RT context should recover the level of importance it had until recently. To this end the new forms of incompatible HLA and/or ABO donation, as well as the paired donation which is possible in several hospitals with experience in LDRT, offer additional ways to treat renal patients with an incompatible donor.Good results in terms of patient and graft survival have expanded the range of circumstances under which living renal donors are accepted. Older donors are now accepted, as are others with factors that affect the decision, such as a borderline clinical history or alterations, which when evaluated may lead to an additional number of transplantations.This guide does not forget that LDRT may lead to risk for the donor. Pre-donation evaluation has to centre on the problems which may arise over the short or long-term, and these have to be described to the potential donor so that they are able to take them into account. Experience over recent years has led to progress in risk analysis, to protect donors’ health. This aspect always has to be taken into account by LDRT programmes when evaluating potential donors.Finally, this guide has been designed to aid decision-making, with recommendations and suggestions when uncertainties arise in pre-donation studies. Its overarching aim is to ensure that informed consent is based on high quality studies and information supplied to donors and recipients, offering the strongest possible guarantees.

Resumen: El hiperparatiroidismo secundario es uno de los componentes integrales de las alteraciones del metabolismo óseo-mineral en la enfermedad renal crónica (ERC) o complejo chronic kidney disease-mineral bone disorder. Se ha demostrado que en el desarrollo y progresión del hiperparatiroidismo secundario intervienen muchos factores, estrechamente interrelacionados, pero la presencia e importancia de la hiporrespuesta (o resistencia) a la acción de la hormona paratiroidea (PTH) es poco comprendida. En esta revisión analizaremos sus antecedentes, factores que intervienen, así como alguno de los mecanismos moleculares que podrían explicarla. La presencia de resistencia a la acción biológica de la PTH no es única en la ERC, ya que también se presenta para otras hormonas, habiéndose incluso usado el término de «uremia como una enfermedad de receptores». Esta hiporrespuesta a la PTH tiene importantes implicaciones clínicas, dado que no solo permite explicar parte de la patogenia progresiva de la hipersecreción de PTH e hiperplasia paratiroidea, sino también la creciente prevalencia de enfermedad ósea adinámica en la población con ERC. De este modo, subrayamos la importancia de controlar, sin normalizar completamente, los niveles de PTH en los distintos estadios de ERC, dado que un cierto incremento de sus niveles supone inicialmente una adaptación clínica. Futuros estudios a nivel molecular sobre la uremia, o la reciente descripción del efecto directo del fosfato sobre la actividad del receptor sensor de calcio como sensor de fosfato, podrían resultar valiosos incluso más allá de explicar la hiporrespuesta a la PTH en la ERC. Abstract: Secondary hyperparathyroidism (SHPT) is an integral component of the chronic kidney disease–mineral and bone disorder (CKD–MBD). Many factors have been associated with the development and progression of SHPT but the presence of skeletal or calcemic resistance to the action of PTH in CKD has often gone unnoticed. The term hyporesponsiveness to PTH is currently preferred and, in this chapter, we will not only review the scientific timeline but also some of the molecular mechanisms behind. Moreover, the presence of resistance to the biological action of PTH is not unique in CKD since resistance to other hormones has also been described (“uremia as a receptor disease”). This hyporesponsiveness carries out important clinical implications since it explains, at least partially, not only the progressive nature of the pathogenesis of CKD-related PTH hypersecretion and parathyroid hyperplasia but also the increasing prevalence of adynamic bone disease in the CKD population. Therefore, we underline the importance of PTH control in all CKD stages, but not aiming to completely normalize PTH levels since a certain degree of SHPT may represent an adaptive clinical response. Future studies at the molecular level, i.e. on uremia, or the recent description of the calcium-sensing receptor as a phosphate sensor, may become of great value beyond their significance to explain just the hyporesponsiveness to PTH in CKD.

Secondary hyperparathyroidism (SHPT) is an integral component of the chronic kidney disease-mineral and bone disorder (CKD-MBD). Many factors have been associated with the development and progression of SHPT but the presence of skeletal or calcemic resistance to the action of PTH in CKD has often gone unnoticed. The term hyporesponsiveness to PTH is currently preferred and, in this chapter, we will not only review the scientific timeline but also some of the molecular mechanisms behind. Moreover, the presence of resistance to the biological action of PTH is not unique in CKD since resistance to other hormones has also been described (“uremia as a receptor disease”). This hyporesponsiveness carries out important clinical implications since it explains, at least partially, not only the progressive nature of the pathogenesis of CKD-related PTH hypersecretion and parathyroid hyperplasia but also the increasing prevalence of adynamic bone disease in the CKD population. Therefore, we underline the importance of PTH control in all CKD stages, but not aiming to completely normalize PTH levels since a certain degree of SHPT may represent an adaptive clinical response. Future studies at the molecular level, i.e. on uremia or the recent description of the calcium-sensing receptor as a phosphate sensor, may become of great value beyond their significance to explain just the hyporesponsiveness to PTH in CKD. Resumen: El hiperparatiroidismo secundario (HPS) es uno de los componentes integrales de las alteraciones del metabolismo óseo-mineral en la enfermedad renal crónica (ERC) o complejo CKD-MBD («Chronic Kidney Disease-Mineral Bone Disorder»). Se ha demostrado que en el desarrollo y progresión del HPS intervienen muchos factores, estrechamente interrelacionados, pero la presencia e importancia de hiporrespuesta (o resistencia) a la acción de la hormona paratiroidea (PTH) es poco comprendida. En esta revisión analizaremos sus antecedentes, factores que intervienen, así como alguno de los mecanismos moleculares que podrían explicarla. La presencia de resistencia a la acción biológica de la PTH no es única en la ERC ya que también se presenta para otras hormonas, habiéndose incluso usado el término de “uremia como una enfermedad de receptores”. Esta hiporrespuesta a la PTH tiene importantes implicaciones clínicas, dado que no sólo permite explicar parte de la patogenia progresiva de la hipersecreción de PTH e hiperplasia paratiroidea, sino también la creciente prevalencia de enfermedad ósea adinámica en la población con ERC. De este modo, subrayamos la importancia de controlar, sin normalizar completamente, los niveles de PTH en los distintos estadios de ERC dado que un cierto incremento de sus niveles supone inicialmente una adaptación clínica. Futuros estudios a nivel molecular sobre la uremia o la reciente descripción del efecto directo del fosfato sobre la actividad del receptor sensor de calcio como sensor de fosfato, podrían resultar valiosos incluso más allá de explicar la hiporrespuesta a la PTH en la ERC.

Background: In an earlier monocentric study, we have developed a novel non-invasive test system for the prediction of renal allograft rejection, based on the detection of a specific urine metabolite constellation. To further validate our results in a large real-world patient cohort, we designed a multicentric observational prospective study (PARASOL) including six independent European transplant centers. This article describes the study protocol and characteristics of recruited better patients as subjects.Methods: Within the PARASOL study, urine samples were taken from renal transplant recipients when kidney biopsies were performed. According to the Banff classification, urine samples were assigned to a case group (renal allograft rejection), a control group (normal renal histology), or an additional group (kidney damage other than rejection).Results: Between June 2017 and March 2020, 972 transplant recipients were included in the trial (1,230 urine samples and matched biopsies, respectively). Overall, 237 samples (19.3%) were assigned to the case group, 541 (44.0%) to the control group, and 452 (36.7%) samples to the additional group. About 65.9% were obtained from male patients, the mean age of transplant recipients participating in the study was 53.7 ± 13.8 years. The most frequently used immunosuppressive drugs were tacrolimus (92.8%), mycophenolate mofetil (88.0%), and steroids (79.3%). Antihypertensives and antidiabetics were used in 88.0 and 27.4% of the patients, respectively. Approximately 20.9% of patients showed the presence of circulating donor-specific anti-HLA IgG antibodies at time of biopsy. Most of the samples (51.1%) were collected within the first 6 months after transplantation, 48.0% were protocol biopsies, followed by event-driven (43.6%), and follow-up biopsies (8.5%). Over time the proportion of biopsies classified into the categories Banff 4 (T-cell-mediated rejection [TCMR]) and Banff 1 (normal tissue) decreased whereas Banff 2 (antibody-mediated rejection [ABMR]) and Banff 5I (mild interstitial fibrosis and tubular atrophy) increased to 84.2 and 74.5%, respectively, after 4 years post transplantation. Patients with rejection showed worse kidney function than patients without rejection.Conclusion: The clinical characteristics of subjects recruited indicate a patient cohort typical for routine renal transplantation all over Europe. A typical shift from T-cellular early rejections episodes to later antibody mediated allograft damage over time after renal transplantation further strengthens the usefulness of our cohort for the evaluation of novel biomarkers for allograft damage.

Resumen: La osteoporosis (OP) y la enfermedad renal crónica (ERC) influyen independientemente en la salud ósea. Numerosos pacientes con ERC presentan una disminución de densidad mineral ósea (DMO), un elevado riesgo de fracturas por fragilidad ósea y un incremento de su morbimortalidad. Con el envejecimiento de la población estos hechos no son dependientes solo de la «osteodistrofia renal» sino también de la OP asociada. Dado que la DMO tiene capacidad predictiva en pacientes con ERC (parte I), ahora analizaremos las implicaciones terapéuticas derivadas. Análisis post hoc de estudios aleatorizados han mostrado que fármacos como alendronato, risedronato, raloxifeno, teriparatida o denosumab tienen una eficacia comparable a la población general en pacientes con una disminución leve-moderada del filtrado glomerular (especialmente ERC-3). Estos estudios tienen limitaciones, pues incluyen mayoritariamente mujeres «sanas», sin diagnóstico conocido de ERC y habitualmente con parámetros normales de laboratorio; sin embargo, también existen datos positivos preliminares en estadios más avanzados (ERC-4) y más limitados en ERC-5D. Por todo ello, al menos en ausencia de alteraciones significativas del metabolismo mineral (i.e., hiperparatiroidismo severo), el beneficio potencial de dichos fármacos debería ser considerado en pacientes que presenten un riesgo de fractura elevado o muy elevado. Es novedad importante que las nuevas guías no condicionan su uso a la práctica de una biopsia ósea previa y que el beneficio/riesgo de estos fármacos podría estar justificado. Sin embargo, debemos considerar que la mayoría de estudios no son consistentes y tienen un bajo grado de evidencia, por lo que la indicación farmacológica (riesgo/beneficio) debe ser individualizada y prudente. Abstract: Osteoporosis (OP) and chronic kidney disease (CKD) both independently affect bone health. A significant number of patients with CKD have decreased bone mineral density (BMD), are at high risk of fragility fractures and have an increased morbidity and mortality risk. With an ageing population, these observations are not only dependent on “renal osteodystrophy” but also on the associated OP. As BMD predicts incident fractures in CKD patients (part I), we now aim to analyse the potential therapeutic consequences. Post-hoc analyses of randomised studies have shown that the efficacy of drugs such as alendronate, risedronate, raloxifene, teriparatide and denosumab is similar to that of the general population in patients with a mild/moderate decline in their glomerular filtration rate (especially CKD-3). These studies have some flaws however, as they included mostly “healthy” women with no known diagnosis of CKD and generally with normal lab test results. Nevertheless, there are also some positive preliminary data in more advanced stages (CKD-4), even though in CKD-5D they are more limited. Therefore, at least in the absence of significant mineral metabolism disorders (i.e. severe hyperparathyroidism), the potential benefit of these drugs should be considered in patients with a high or very high fracture risk. It is an important change that the new guidelines do not make it a requirement to first perform a bone biopsy and that the risk/benefit ratio of these drugs may be justified. However, we must also be aware that most studies are not consistent and the level of evidence is low. Consequently, any pharmacological intervention (risk/benefit) should be prudent and individualised. Palabras clave: Osteoporosis, CKD-MBD, Densidad mineral ósea, Fracturas, ERC, DEXA, Bisfosfonatos, Denosumab, Romosozumab, Keywords: Osteoporosis, CKD-MBD, Bone mineral density, Fractures, CKD, DEXA, Bisphosphonates, Denosumab, Romosozumab

Osteoporosis (OP) and chronic kidney disease (CKD) both independently affect bone health. A significant number of patients with CKD have decreased bone mineral density (BMD), are at high risk of fragility fractures and have an increased morbidity and mortality risk. With an aging population, these observations are not only dependent on “renal osteodystrophy” but also on the associated OP. As BMD predicts incident fractures in CKD patients (part I), we now aim to analyze the potential therapeutic consequences. Post hoc analyses of randomized studies have shown that the efficacy of drugs such as alendronate, risedronate, raloxifene, teriparatide and denosumab is similar to that of the general population in patients with a mild/moderate decline in their glomerular filtration rate (especially CKD-3). These studies have some flaws however, as they included mostly “healthy” women with no known diagnosis of CKD and generally with normal lab test results. Nevertheless, there are also some positive preliminary data in more advanced stages (CKD-4), even though in CKD-5D they are more limited. Therefore, at least in the absence of significant mineral metabolism disorders (i.e. severe hyperparathyroidism), the potential benefit of these drugs should be considered in patients with a high or very high fracture risk. It is an important change that the new guidelines do not make it a requirement to first perform a bone biopsy and that the risk/benefit ratio of these drugs may be justified. However, we must also be aware that most studies are not consistent and the level of evidence is low. Consequently, any pharmacological intervention (risk/benefit) should be prudent and individualized. Resumen: La osteoporosis (OP) y la enfermedad renal crónica (ERC) influyen independientemente en la salud ósea. Numerosos pacientes con ERC presentan una disminución de densidad mineral ósea (DMO), un elevado riesgo de fracturas por fragilidad ósea y un incremento de su morbimortalidad. Con el envejecimiento de la población estos hechos no son dependientes solo de la «osteodistrofia renal» sino también de la OP asociada. Dado que la DMO tiene capacidad predictiva en pacientes con ERC (parte I), ahora analizaremos las implicaciones terapéuticas derivadas. Análisis post hoc de estudios aleatorizados han mostrado que fármacos como alendronato, risedronato, raloxifeno, teriparatida o denosumab tienen una eficacia comparable a la población general en pacientes con una disminución leve-moderada del filtrado glomerular (especialmente ERC-3). Estos estudios tienen limitaciones, pues incluyen mayoritariamente mujeres «sanas», sin diagnóstico conocido de ERC y habitualmente con parámetros normales de laboratorio; sin embargo, también existen datos positivos preliminares en estadios más avanzados (ERC-4) y más limitados en ERC-5D. Por todo ello, al menos en ausencia de alteraciones significativas del metabolismo mineral (i.e., hiperparatiroidismo severo), el beneficio potencial de dichos fármacos debería ser considerado en pacientes que presenten un riesgo de fractura elevado o muy elevado. Es novedad importante que las nuevas guías no condicionan su uso a la práctica de una biopsia ósea previa y que el beneficio/riesgo de estos fármacos podría estar justificado. Sin embargo, debemos considerar que la mayoría de estudios no son consistentes y tienen un bajo grado de evidencia, por lo que la indicación farmacológica (riesgo/beneficio) debe ser individualizada y prudente. Keywords: Osteoporosis, CKD-MBD, Bone mineral density, Fractures, CKD, DEXA, Bisphosphonates, Denosumab, Romosozumab, Palabras clave: Osteoporosis, CKD-MBD, Densidad mineral ósea, Fracturas, ERC, DEXA, Bisfosfonatos, Denosumab, Romosozumab

Previous results from our group and others have shown that urinary pellet expression of miR155-5p and urinary CXCL-10 production could play a key role in the prognosis and diagnosis of acute rejection (AR) in kidney transplantation patients. Here, a logistic regression model was developed using NONMEM to quantify the relationships of miR155-5p urinary expression, CXCL-10 urinary concentration and tacrolimus and mycophenolic acid (MPA) exposure with the probability of AR in adult kidney transplant patients during the early post-transplant period. Owing to the contribution of therapeutic drug monitoring to achieving target exposure, neither tacrolimus nor MPA cumulative exposure was identified as a predictor of AR in the studied population. Even though CXCL-10 urinary concentration showed a trend, its effect on AR was not significant. In contrast, urinary miR155-5p expression was prognostic of clinical outcome. Monitoring miR155-5p urinary pellet expression together with immunosuppressive drug exposure could be very useful during routine clinical practice to identify patients with a potential high risk of rejection at the early stages of the post-transplant period. This early risk assessment would allow for the optimization of treatment and improved prevention of AR.