Publications by authors named "J V Torregrosa"

176 Publications

Bone Mineral Disease After Kidney Transplantation.

Calcif Tissue Int 2021 Mar 25. Epub 2021 Mar 25.

Nephrology Department, Centro Hospitalare, Universitário de Lisboa Central, Lisbon, Portugal.

Chronic kidney disease-mineral bone disorder (CKD-MBD) after kidney transplantation is a mix of pre-existing disorders and new alterations. The final consequences are reflected fundamentally as abnormal mineral metabolism (hypercalcemia, hypophosphatemia) and bone alterations [high or low bone turnover disease (as fibrous osteitis or adynamic bone disease), an eventual compromise of bone mineralization, decrease bone mineral density and bone fractures]. The major cause of post-transplantation hypercalcemia is the persistence of severe secondary hyperparathyroidism, and treatment options include calcimimetics or parathyroidectomy. On turn, hypophosphatemia is caused by both the persistence of high blood levels of PTH and/or high blood levels of FGF23, with its correction being very difficult to achieve. The most frequent bone morphology alteration is low bone turnover disease, while high-turnover osteopathy decreases in frequency after transplantation. Although the pathogenic mechanisms of these abnormalities have not been fully clarified, the available evidence suggests that there are a number of factors that play a very important role, such as immunosuppressive treatment, persistently high levels of PTH, vitamin D deficiency and hypophosphatemia. Fracture risk is four-fold higher in transplanted patients compared to general population. The most relevant risk factors for fracture in the kidney transplant population are diabetes mellitus, female sex, advanced age (especially > 65 years), dialysis vintage, high PTH levels and low phosphate levels, osteoporosis, pre-transplant stress fracture and high doses or prolonged steroids therapy. Treatment alternatives for CKD-MBD after transplantation include minimization of corticosteroids, use of calcium and vitamin D supplements, antiresorptives (bisphosphonates or Denosumab) and osteoformers (synthetic parathyroid hormone). As both mineral metabolism and bone disorders lead to increased morbidity and mortality, the presence of these changes after transplantation has to be prevented (if possible), minimized, diagnosed, and treated as soon as possible.
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http://dx.doi.org/10.1007/s00223-021-00837-0DOI Listing
March 2021

Cardiovascular calcifications in kidney transplant recipients.

Nephrol Dial Transplant 2021 Feb 23. Epub 2021 Feb 23.

Renal Division, ASST Santi Paolo e Carlo, Department of Health Sciences, University of Milan, Italy.

Vascular and valvular calcifications are highly prevalent in kidney transplant recipients and are associated with an increased risk of cardiovascular events, which represent the leading cause of long-term mortality in these patients. However, cardiovascular calcification has been traditionally considered as a condition mostly associated with advanced chronic kidney disease stages and dialysis, and comparatively fewer studies have assessed its impact after kidney transplantation. Despite partial or complete resolution of uremia-associated metabolic derangements, kidney transplant recipients are still exposed to several pro-calcifying stimuli that favour the progression of pre-existing vascular calcifications or their de novo development. Traditional risk factors, bone mineral disorders, inflammation, immunosuppressive drugs and deficiency of calcification inhibitors may all play a role, and strategies to correct or minimize their effects are urgently needed. The aim of this work is to provide an overview of established and putative mediators involved in the pathogenesis of cardiovascular calcification in kidney transplantation, and to describe the clinical and radiological features of these forms. We also discuss current evidence on preventive strategies to delay the progression of cardiovascular calcifications in kidney transplant recipients, as well as novel therapeutic candidates to potentially prevent their long-term deleterious effects.
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http://dx.doi.org/10.1093/ndt/gfab053DOI Listing
February 2021

Three Drug Combinations in the Treatment of Fit Elderly Multiple Myeloma Patients.

J Clin Med 2020 Nov 4;9(11). Epub 2020 Nov 4.

Service d'Hematologie et Therapie Cellulaire, and Inserm CIC U1402, 86000 Poitiers, France.

The multiple myeloma (MM) non transplant eligible (NTE) population is growing in line with the aging of the population in Western countries. Historically, this population has been known for having a greater risk of treatment related toxicity, and therefore drug development was slow and rather oriented towards the improvement of safety profile than the optimization of disease control. However, NTE MM patients, at least for the fit/non frail patients in recent years, seemed to have benefited more from a less palliative care to improve the depth of response and then prolong survival. NTE MM being a quite heterogeneous population, there are still a number of groups of patients that are in need of more efficient therapy, avoiding unnecessary toxicity, particularly for the frail patients. The use of triplet regimen with a melphalan-prednisone (MP) backbone has long been the standard of care for NTE MM, often dedicated to non-frail patients. New standards of care, triplet, and even quadruplet combinations, are emerging on the basis of the MP backbone but also on the more recently approved lenalidomide-dexamethasone (Rd) backbone. These developments were largely possible in line with the development of antibody-based immunotherapies (IT) in MM. The objective to improve outcomes with an acceptable safety profile will see other key therapeutic developments such as the dropping of dexamethasone early in the disease course or various attempts to allow permanent treatment discontinuation with a prolonged disease control. In that context, it is possible that immunomonitoring, minimal residual disease (MRD), and genomic risk-adaptation will become key elements of the treatment decisions on triplet-based regimens.
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http://dx.doi.org/10.3390/jcm9113554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694236PMC
November 2020

The impact of functional delayed graft function in the modern era of kidney transplantation - A retrospective study.

Transpl Int 2021 Jan 28;34(1):175-184. Epub 2020 Nov 28.

Nephrology and Renal Transplant Department, Hospital Clínic, Barcelona, Spain.

The dialysis-based definition of Delayed Graft Function (dDGF) is not necessarily objective as it depends on the individual physician's decision. The functional definition of DGF (fDGF, the failure of serum creatinine to decrease by at least 10% daily on 3 consecutive days during the first week post-transplant), may be more sensitive to reflect recovery after the ischemia-reperfusion injury. We retrospectively analyzed both definitions in 253 deceased donor kidney transplant recipients for predicting death-censored graft failure as primary outcome, using eGFR < 25 ml/min/1.73 m as a surrogate end-point for graft failure. Secondary outcome was a composite outcome that included graft failure as above and also patient's death. Median follow-up was 3.22 [2.38-4.21] years. Seventy-nine patients developed dDGF (31.2%) and 127 developed fDGF (50.2%). Sixty-three patients fulfilled criteria for both definitions (24.9%). At multivariable analysis, the two definitions were significantly associated with the primary [HR (95%CI) 2.07 (1.09-3.94), P = 0.026 for fDGF and HR (95%CI) 2.41 (1.33-4.37), P = 0.004 for dDGF] and the secondary composite outcome [HR (95%CI) 1.58 (1.01-2.51), P = 0.047 for fDGF and HR (95%CI) 1.67 (1.05-2.66), P = 0.028 for dDGF]. Patients who met criteria for both definitions had the worst prognosis, with a three-year estimates (95%CI) of survival from the primary and secondary outcomes of 2.31 (2.02-2.59) and 2.20 (1.91-2.49) years for fDGF+/dDGF+, in comparison with the other groups (P < 0.01 for trend). fDGF provides supplementary information about graft outcomes on top of the dDGF definition in a modern series of kidney transplantation.
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http://dx.doi.org/10.1111/tri.13781DOI Listing
January 2021

Clinical characteristics and risk factors for severe COVID-19 in hospitalized kidney transplant recipients: A multicentric cohort study.

Am J Transplant 2020 11 23;20(11):3030-3041. Epub 2020 Sep 23.

Nephrology Department, Hospital Universitari de Bellvitge, Barcelona, Spain.

Kidney transplant recipients might be at higher risk for severe coronavirus disease 2019 (COVID-19). However, risk factors for relevant outcomes remain uncertain in this population. This is a multicentric kidney transplant cohort including 104 hospitalized patients between March 4 and April 17, 2020. Risk factors for death and acute respiratory distress syndrome (ARDS) were investigated, and clinical and laboratory data were analyzed. The mean age was 60 years. Forty-seven patients (54.8%) developed ARDS. Obesity was associated to ARDS development (OR 2.63; P = .04). Significant age differences were not found among patients developing and not developing ARDS (61.3 vs 57.8 years, P = .16). Seventy-six (73%) patients were discharged, and 28 (27%) died. Death was more common among the elderly (55 and 70.8 years, P < .001) and those with preexisting pulmonary disease (OR 2.89, P = .009). At admission, higher baseline lactate dehydrogenase (257 vs 358 IU/mL, P = .001) or ARDS conferred higher risk of death (HR 2.09, P = .044). In our cohort, ARDS was equally present among young and old kidney recipients. However, the elderly might be at higher risk of death, along with those showing higher baseline LDH at admission.
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http://dx.doi.org/10.1111/ajt.16246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7436908PMC
November 2020

Use of De Novo mTOR Inhibitors in Hypersensitized Kidney Transplant Recipients: Experience From Clinical Practice.

Transplantation 2020 08;104(8):1686-1694

Nephrology and Renal Transplant Department, Hospital Clínic, Barcelona, Spain.

Background: It is commonly believed that mTOR inhibitors (mTORi) should not be used in high-immunological risk kidney transplant recipients due to a perceived increased risk of rejection. However, almost all trials that examined the association of optimal-dose mTORi with calcineurin inhibitor (CNI) have excluded hypersensitized recipients from enrollment.

Methods: To shed light on this issue, we examined 71 consecutive patients with a baseline calculated panel reactive antibody (cPRA) ≥50% that underwent kidney transplantation from June 2013 to December 2016 in our unit. Immunosuppression was based on CNI (tacrolimus), steroids and alternatively mycophenolic acid (MPA; n = 38), or mTORi (either everolimus or sirolimus, n = 33, target trough levels 3-8 ng/mL).

Results: Demographic and immunological risk profiles were similar, and almost 90% of patients in both groups received induction with lymphocyte-depleting agents. Cox-regression analysis of rejection-free survival revealed better results for mTORi versus MPA in terms of biopsy-proven acute rejection (hazard ratio [confidence interval], 0.32 [0.11-0.90], P = 0.031 at univariable analysis and 0.34 [0.11-0.95], P = 0.040 at multivariable analysis). There were no differences in 1-year renal function, Banff chronicity score at 3- and 12-month protocol biopsy and development of de novo donor-specific antibodies. Tacrolimus trough levels along the first year were not different between groups (12-mo levels were 8.72 ± 2.93 and 7.85 ± 3.07 ng/mL for MPA and mTORi group respectively, P = 0.277).

Conclusions: This single-center retrospective cohort analysis suggests that in hypersensitized kidney transplant recipients receiving tacrolimus-based immunosuppressive therapy similar clinical outcomes may be obtained using mTOR inhibitors compared to mycophenolate.
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http://dx.doi.org/10.1097/TP.0000000000003021DOI Listing
August 2020

Correction to: Panel Discussion: Some Aspects of the Management of Patients with X-Linked Hypophosphataemic Rickets.

Adv Ther 2020 08;37(8):3642

Departamento de Medicina, Universidad de Granada, UGC Endocrinología y Nutrición. Hospital Universitario San Cecilio, CIBERFES, Instituto de Salud Carlos III, Instituto de Investigación Biosanitaria de Granada, Granada, Spain.

In the original article, there is an error in age related reference.
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http://dx.doi.org/10.1007/s12325-020-01406-xDOI Listing
August 2020

Correction to: Panel Discussion: Some Aspects of the Management of Patients with X-Linked Hypophosphataemic Rickets.

Adv Ther 2020 07;37(7):3432

Departamento de Medicina, Universidad de Granada, UGC Endocrinología y Nutrición, Hospital Universitario San Cecilio, CIBERFES, Instituto de Salud Carlos III, Instituto de Investigación Biosanitaria de Granada, Granada, Spain.

In the original article, third author name has been published incorrectly.
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http://dx.doi.org/10.1007/s12325-020-01370-6DOI Listing
July 2020

Long-term results of a randomized study comparing parathyroidectomy with cinacalcet for treating tertiary hyperparathyroidism.

Clin Transplant 2020 08 3;34(8):e13988. Epub 2020 Jun 3.

Nephrology Department, Hospital Universitari de Bellvitge, University of Barcelona, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.

Tertiary hyperparathyroidism is a common cause of hypercalcemia after kidney transplantation (KT) and has been associated with renal dysfunction, bone mineral density loss, and increased risk of fracture and cardiovascular events. In a previous 12-month clinical trial, we demonstrated that subtotal parathyroidectomy was more effective than cinacalcet for controlling hypercalcemia. In the current study, we retrospectively evaluate whether this effect is maintained after 5 years of follow-up. In total, 24 patients had data available at 5 years, 13 in the cinacalcet group and 11 in the parathyroidectomy group. At 5 years, 7 of 11 patients (64%) in the parathyroidectomy group and 6 of 13 patients (46%) in the cinacalcet group (P = .44) showed normocalcemia. However, recurrence of hypercalcemia was only observed in the cinacalcet group (P = .016). Subtotal parathyroidectomy retained a greater reduction in intact parathyroid hormone (iPTH) compared with cinacalcet group. No differences were observed in kidney function and incidence of fragility fractures between both groups. Cinacalcet was discontinued in 5 out of 13 patients. In conclusion, in kidney transplant patients with tertiary hyperparathyroidism recurrence of hypercalcemia after 5-year follow-up is more frequent in cinacalcet than after subtotal parathyroidectomy.
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http://dx.doi.org/10.1111/ctr.13988DOI Listing
August 2020

The Role of Immunotherapy in Non-transplant Eligible Multiple Myeloma.

Front Oncol 2020 6;10:676. Epub 2020 May 6.

Service d'Hématologie et Thérapie cellulaire, Centre Hospitalier Universitaire de Poitiers, Poitiers, France.

As the global population is aging and survival in multiple myeloma (MM) is increasing, treating older MM patients, redefined as non-transplant eligible (NTE), is becoming more frequent. Yet, treating these patients remains a real challenge especially because of a marked heterogeneity in the population and an increased susceptibility to treatment toxicity. Indeed, the balance between efficacy and safety must be considered at all time throughout the treatment history for these patients. Therefore, younger and older patients were historically treated in a very different way, even though the safety profile of most anti-myeloma drugs has drastically improved over the years. The emergence of immunotherapy (IT) has largely widened the therapeutic options available in MM and above all has allowed a therapy at optimal dose, and therefore optimal activity, for all patients independently of their frailty features, with no increase in safety issues. Among the novel anti-myeloma IT-based agents, anti-CD38 monoclonal antibodies (mAbs) are now becoming the new backbone of treatment for NTE patients, in association with lenalidomide and dexamethasone. Moreover, several new IT-based drugs are currently being developed and investigated either alone or in association; such as new anti-CD38 mAbs, anti-CD38 mAbs with many different combinations, but also the CAR-T cells, bispecific T-cell engager (BiTEs), or antibody drug conjugate (ADC) targeting BCMA. One would expect that immunotherapy will ultimately change and even transform the MM landscape, even for elderly patients. Immunotherapy represents a shift in treatment paradigm in MM as it provides truly efficient drugs with a very favorable safety profile.
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http://dx.doi.org/10.3389/fonc.2020.00676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7218111PMC
May 2020

Panel Discussion: Some Aspects of the Management of Patients with X-Linked Hypophosphataemic Rickets.

Adv Ther 2020 05 31;37(Suppl 2):121-126. Epub 2020 Mar 31.

Departamento de Medicina, Universidad de Granada, UGC Endocrinología y Nutrición. Hospital Universitario San Cecilio, CIBERFES, Instituto de Salud Carlos III, Instituto de Investigación Biosanitaria de Granada, Granada, Spain.

X-linked hypophosphataemia (XLH) rickets is a rare disease frequently misdiagnosed and mismanaged. Despite having clinical guidelines that offers some therapeutic recommendations based on the clinical experience of experts, physicians still have questions about some important aspects of the diagnosis and treatment of XLH, such as when the disease should be suspected, who should be in charge of the diagnosis, what should be done once the disease is diagnosed, or what therapeutic options are currently available. The objective of this paper is to answer some of the more frequent questions related to the management of patients with XLH by a group of experts participating in a scientific conference on XLH held in Madrid.
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http://dx.doi.org/10.1007/s12325-019-01208-wDOI Listing
May 2020

Kidney Graft Outcomes in High Immunological Risk Simultaneous Liver-Kidney Transplants.

Liver Transpl 2020 04;26(4):517-527

Department of Nephrology and Renal Transplantation, Instituto Clínic de Nefrologia y Urologia, Hospital Clinic de Barcelona, Barcelona, Spain.

Recipients of simultaneous liver-kidney transplantations (SLKTs) have a lower risk of rejection compared with recipients of kidney transplants alone. However, there is disagreement about the impact of pretransplant anti-human leukocyte antigen sensitization on patient and kidney graft survival in the long term. The aim of the study was to evaluate the impact of the recipient immunological risk and comorbidities in renal graft outcomes on SLKT. We reviewed the SLKTs performed in our center from May 1993 until September 2017. Patient and graft survival were analyzed according to the immunological risk, comorbidities, liver and kidney rejection episodes, immunosuppression, and infections. A total of 20 recipients of SLKT were considered in the high immunological risk (HIR) group, and 68 recipients were included in the low immunological risk (LIR) control group. The prevalence of hepatitis C virus infection, second renal transplant, and time on dialysis prior to transplantation were significantly higher in the HIR group. The incidence of acute kidney rejection was higher in the HIR group (P<0.01). However, death-censored kidney graft survival as well as the estimated glomerular filtration rate at follow-up were not different between the 2 groups. Comorbidities, but not the immunological risk, impact negatively on patient survival. Despite the higher incidence of rejection in the HIR SLKT group, longterm renal function and graft survival were similar to the LIR group.
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http://dx.doi.org/10.1002/lt.25726DOI Listing
April 2020

Combination of calcineurin and mTOR inhibitors in kidney transplantation: a propensity score analysis based on current clinical practice.

J Nephrol 2020 Jun 18;33(3):601-610. Epub 2019 Dec 18.

Renal Transplant Unit, Hospital Clínic, Carrer Villaroel 170, 08023, Barcelona, Spain.

Introduction: The TRANSFORM study demonstrated that an immunosuppression based on a combination of calcineurin inhibitors and de-novo mTOR inhibitors (mTORi) is safe and effective in kidney transplant recipients. However, data that validate this approach in clinical practice are currently missing.

Materials And Methods: Analysis of 401 kidney transplant recipients transplanted from June 2013 to December 2016. All patients received tacrolimus with prednisone in combination with either mycophenolate (n = 186) or mTORi (either everolimus or sirolimus, n = 215). A propensity score to receive mTORi was calculated based on the inverse probability of treatment weighting (IPTW) from the following parameters: age and sex of donor and recipient, BMI, previous transplants, diabetes, cPRA, dialysis before transplantation, dialysis vintage, type of donor, ABO-incompatibility, HLA-mismatches, induction and ischemia time. Median follow-up was 2.6 [1.9; 3.7] years.

Results: Cox-regression analysis suggests good results for mTORi versus MPA in terms of 1-year biopsy-proven acute rejection (BPAR, P = 0.063), 1-year graft loss (P = 0.025) and patient survival (P < 0.001). Results observed for BPAR and graft failure were largely attributed to those patients that would have been excluded by the TRANSFORM because of some exclusion criteria (52.9% of the population, P = 0.003 for 1-year BPAR and P = 0.040 for graft loss). In patients who met selection criteria for TRANSFORM, no effect of treatment for BPAR or graft failure was observed, while the beneficial effect on overall survival persisted.

Conclusions: In a real-life setting, a protocol based on de-novo mTORi with tacrolimus and prednisone could be employed as a standard immunosuppressive regimen and was associated with good outcomes.
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http://dx.doi.org/10.1007/s40620-019-00675-2DOI Listing
June 2020

Developmental Differences in Platelet Inhibition Response to Prostaglandin E1.

Neonatology 2020 29;117(1):15-23. Epub 2019 Nov 29.

Servicio de Hematología y Oncología Médica, Hospital Universitario Morales Meseguer, Centro Regional de Hemodonación, IMIB-Arrixaca, CB15/00055-CIBERER, Murcia, Spain,

Background: The mechanisms underlying neonatal platelets hyporesponsiveness are not fully understood. While previous studies have demonstrated developmental impairment of agonist-induced platelet activation, differences in inhibitory signaling pathways have been scarcely investigated.

Objective: To compare neonatal and adult platelets with regard to inhibition of platelet reactivity by prostaglandin E1 (PGE1).

Methods: Platelet-rich plasma from umbilical cord (CB) or adult blood was incubated with PGE1 (0-1 μM). We assessed aggregation in response to adenosine diphosphate (ADP), collagen, and thrombin receptor activating peptide as well as cyclic adenosine 3'5'-monophosphate (cAMP) levels (ELISA). Gαs, Gαi2, and total- and phospho-protein kinase A (PKA) were evaluated in adult and CB ultrapure and washed platelets, respectively, by immunoblotting.

Results: Neonatal (vs. adult) platelets display hypersensitivity to inhibition by PGE1 of platelet aggregation induced by ADP and collagen (PGE1 IC50: 14 and 117 nM for ADP and collagen, respectively, vs. 149 and 491 nM in adults). They also show increased basal and PGE1-induced cAMP levels. Mechanistically, PGE1 acts by binding to the prostanoid receptor IP (prostacyclin receptor), which couples to the Gαs protein-adenylate cyclase axis and increases intracellular levels of cAMP. cAMP activates PKA, which phosphorylates different target inhibitor proteins. Neonatal platelets showed higher basal and PGE1-induced cAMP levels, higher Gαs protein expression, and a trend to increased PKA-dependent protein phosphorylation compared to adult platelets.

Conclusion: Neonatal platelets have a functionally increased PGE1-cAMP-PKA axis. This finding supports a downregulation of inhibitory when going from neonate to adult contributing to neonatal platelet hyporesponsiveness.
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http://dx.doi.org/10.1159/000504173DOI Listing
November 2020

Lead in terrestrial game birds from Spain.

Environ Sci Pollut Res Int 2020 Jan 21;27(2):1585-1597. Epub 2019 Nov 21.

Departamento de Ingeniería Rural y Agroalimentaria, Escuela Técnica Superior de Ingeniería Agronómica y del Medio Natural, Universidad Politécnica de Valencia, Camino de Vera s/n, 46022, Valencia, Spain.

We analysed exposure to Pb and its relationship with lead-based ammunition in seven species of terrestrial game birds-common woodpigeon (Columba palumbus), rock dove (Columba livia), stock dove (Columba oenas), European turtle-dove (Streptopelia turtur), red-legged partridge (Alectoris rufa), Barbary partridge (Alectoris barbara) and common quail (Coturnix coturnix)-from rural and urban areas in different parts of Spain (Valencia, Castilla-La Mancha, Castilla y León, Madrid, Islas Canarias and Navarra). A total of 530 liver samples were analysed, and the presence of Pb pellets was studied in the crop, gizzard and intestine; the state and appearance of these organs were also analysed. The number of specimens suspected to have ingested Pb shot was 28 (5.6%), and the geometric mean concentration of hepatic Pb was 0.054 μg g (wet weight, ww). A low percentage of samples (4.8%) were above the abnormal exposure threshold (0.65 μg g ww), and, in these specimens, renal Pb concentrations were determined. Common woodpigeons and rock doves from Madrid were found to have high concentrations of Pb in their livers, and, so, both species can be considered to be good bioindicators of Pb contamination in rural (common woodpigeons) and urban (rock doves) environments. Partridges bred for hunting may be more prone to ingesting pellets from the environment, a fact that should be taken into account in management decisions.
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http://dx.doi.org/10.1007/s11356-019-06827-yDOI Listing
January 2020

Improvement in wound healing, pain, and quality of life after 12 weeks of SNF472 treatment: a phase 2 open-label study of patients with calciphylaxis.

J Nephrol 2019 Oct 10;32(5):811-821. Epub 2019 Aug 10.

Sanifit Therapeutics, Palma, Spain.

Background: Calciphylaxis in end-stage renal disease is characterized by painful necrotic skin ulcers and high mortality. There are no approved therapies. SNF472, an intravenous formulation of myo-inositol hexaphosphate, inhibits the formation and growth of hydroxyapatite crystals, the final common pathway in the pathogenesis of vascular calcification.

Methods: In this open-label, single-arm study, calciphylaxis patients on thrice-weekly hemodialysis and standard care, received intravenous SNF472 3 times per week for 12 weeks. The primary endpoint was wound healing assessed using the quantitative Bates-Jensen Wound Assessment Tool (BWAT). Pain visual analog scale (VAS), quality of life (wound-QoL), and qualitative wound image review were secondary endpoints. Quantitative changes from baseline were analyzed by paired t-tests using multiple imputation to account for missing observations.

Results: Fourteen patients received SNF472. Improvements from baseline to week 12 were observed for mean BWAT score (- 8.1; P < 0.001), pain VAS (- 23.6 mm; P = 0.015) and wound-QoL global score (- 0.90; P = 0.003). Of the 9 patients with ulcerated lesions at baseline who completed treatment, wound image review showed improvement for 7. SNF472 was well tolerated with no serious treatment-related adverse events. The most common adverse events were infections which occur frequently in patients on hemodialysis. None of these were considered as treatment-related.

Conclusions: SNF472 was well-tolerated and improvements from baseline to week 12 in wound healing, pain, and quality of life were observed. A randomized, double-blind, placebo-controlled trial is planned to evaluate SNF472 in patients with calciphylaxis.
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http://dx.doi.org/10.1007/s40620-019-00631-0DOI Listing
October 2019

Osteoporosis, bone mineral density and CKD-MBD (II): Therapeutic implications.

Nefrologia 2019 May - Jun;39(3):227-242. Epub 2019 Feb 20.

Unidad de Gestión Clínica de Metabolismo Óseo, Hospital Universitario Central de Asturias, Instituto de Investigación Sanitaria del Principado de Asturias, REDinREN, Universidad de Oviedo, Oviedo, España.

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 (partI), 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.
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http://dx.doi.org/10.1016/j.nefro.2018.10.009DOI Listing
May 2020

Higher Proportion of Non-1-84 PTH Fragments in Peritoneal Dialysis Patients Compared to Hemodialysis Patients Using Solutions Containing 1.75 mmol/l Calcium.

Front Physiol 2018 20;9:1643. Epub 2018 Nov 20.

REDINREN, Madrid, Spain.

The prevalence of low- turnover bone disease (LTBD) in peritoneal dialysis (PD) patients is higher than in hemodialysis (HD) patients. LTBD patients may be at risk for vascular calcification, and cardiovascular disease. Current therapy for chronic kidney disease metabolic bone disorders (CKD-MBD) is guided by biochemical parameters, as bone biopsy is not used in routine clinical care. We assessed intact PTH (iPTH: 1-84PTH plus non-1-84PTH), 1-84PTH, and the 1-84PTH/non-1-84PTH ratio in 129 hemodialysis and 73 PD prevalent patients dialyzed with solutions containing 1.75 mmol/L calcium. Hemodialysis and PD patients presented similar iPTH and tCa values and prevalence of putative LTBD as defined according to KDOQI iPTH cut-off levels or 1-84 PTH levels. However, iCa accounted for a higher percentage of tCa in PD (53%) than in hemodialysis (39%) < 0.001, and the 1-84PTH/non-1-84PTH ratio was lower in PD than in hemodialysis patients (0.44 ± 0.12) vs. (0.60 ± 0.10), < 0.001. The prevalence of putative LTBD when using the coexistence of 1-84PTH/non-1-84PTH ratio < 1.0 and iPTH < 420 pg/m, was higher in PD than in hemodialysis patients (73 vs. 16% respectively, < 0.001). In a multivariate logistic regression analysis, dialysis modality was the main determinant of the 1-84PTH/non-1-84PTH ratio. Solutions containing 1.75 mmol/L calciums are associated to a higher proportion of non-1-84PTH fragments in PD than in HD patients. Different analytical criteria result in widely different estimates of LTBD prevalence, thus impairing the ability of clinicians to optimize therapy for CKD-MBD.
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http://dx.doi.org/10.3389/fphys.2018.01643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6262178PMC
November 2018

Calciphylaxis in patients with chronic kidney disease: A disease which is still bewildering and potentially fatal.

Nefrologia 2018 Nov - Dec;38(6):579-586. Epub 2018 Nov 8.

Servicio de Nefrología y Trasplante Renal, Hospital Clínic, Barcelona, España. Electronic address:

Calciphylaxis, also known as calcific uraemic arteriolopathy, is a rare syndrome that typically causes skin necrosis and usually affects dialysis patients. Its pathogenesis is multifactorial and is the consequence of many factors causing ectopic calcifications in patients with chronic kidney disease, such as calcium-phosphate metabolism disorders, hyper- or hypo-parathyroidism, diabetes, obesity, systemic inflammation and the use of vitamin K antagonists, among others. From a clinical point of view, calciphylaxis may progress from painful purpura to extensive areas of skin necrosis that can potentially lead to superinfection and the death of the patient due to sepsis. Treatment is primarily based on managing the wounds, eliminating all the possible precipitating factors of ectopic calcification and administering agents which are capable of inhibiting the process of calcification.
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http://dx.doi.org/10.1016/j.nefro.2018.05.007DOI Listing
October 2019

Osteoporosis, bone mineral density and CKD-MBD complex (I): Diagnostic considerations.

Nefrologia 2018 Sep - Oct;38(5):476-490. Epub 2018 Apr 24.

Unidad de Gestión Clínica de Servicio de Metabolismo Óseo, Hospital Universitario Central de Asturias, Instituto de Investigación del Principado de Asturias, REDinREN, Universidad de Oviedo, Oviedo, España.

Osteoporosis (OP) and chronic kidney disease (CKD) independently influence bone and cardiovascular health. A considerable number of patients with CKD, especially those with stages 3a to 5D, have a significantly reduced bone mineral density leading to a high risk of fracture and a significant increase in associated morbidity and mortality. Independently of classic OP related to age and/or gender, the mechanical properties of bone are also affected by inherent risk factors for CKD ("uraemic OP"). In the first part of this review, we will analyse the general concepts regarding bone mineral density, OP and fractures, which have been largely undervalued until now by nephrologists due to the lack of evidence and diagnostic difficulties in the context of CKD. It has now been proven that a reduced bone mineral density is highly predictive of fracture risk in CKD patients, although it does not allow a distinction to be made between the causes which generate it (hyperparathyroidism, adynamic bone disease and/or senile osteoporosis, etc.). Therefore, in the second part, we will analyse the therapeutic indications in different CKD stages. In any case, the individual assessment of factors which represent a higher or lower risk of fracture, the quantification of this risk (i.e. using tools such as FRAX) and the potential indications for densitometry in patients with CKD could represent an important first step pending new clinical guidelines based on randomised studies which do not exclude CKD patients, all the while avoiding therapeutic nihilism in an area of growing importance.
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http://dx.doi.org/10.1016/j.nefro.2017.12.006DOI Listing
October 2019

Fabry Nephropathy: An Evidence-Based Narrative Review.

Kidney Blood Press Res 2018 16;43(2):406-421. Epub 2018 Mar 16.

Nephrology and Renal Transplant Department, Hospital Clinic, University of Barcelona, RedInRen, Barcelona, Spain.

Fabry disease (FD) is a rare, X-linked disorder caused by mutations in the GLA gene encoding the enzyme α-galactosidase A. Complete or partial deficiency in this enzyme leads to intracellular accumulation of globotriaosylceramide (Gb3) and other glycosphingolipids in many cell types throughout the body, including the kidney. Progressive accumulation of Gb3 in podocytes, endothelial cells, epithelial cells, and tubular cells contribute to the renal symptoms of FD, which manifest as proteinuria and reduced glomerular filtration rate leading to renal insufficiency. A correct diagnosis of FD, although challenging, has considerable implications regarding treatment, management, and counseling. The diagnosis may be confirmed by demonstrating the enzyme deficiency in males and by identifying the specific GLA gene mutation in male and female patients. Treatment with enzyme replacement therapy, as part of the therapeutic strategy to prevent complications of the disease, may be beneficial in stabilizing renal function or slowing its decline, particularly in the early stages of the disease. Emergent treatments for FD include the recently approved chaperone molecule migalastat for patients with amenable mutations. The objective of this report is to provide an updated overview on Fabry nephropathy, with a focus on the most relevant aspects of its epidemiology, diagnosis, pathophysiology, and treatment options.
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http://dx.doi.org/10.1159/000488121DOI Listing
October 2018

Current aspects of Fabry's disease.

Med Clin (Barc) 2018 09 6;151(5):196-197. Epub 2018 Mar 6.

Servicio de Nefrología, Hospital Clinic, Barcelona, España. Electronic address:

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http://dx.doi.org/10.1016/j.medcli.2018.01.025DOI Listing
September 2018

Triple functioning renal allograft after repeated liver-kidney transplantation due to liver failure.

Nefrologia 2018 Nov - Dec;38(6):667-669. Epub 2018 Feb 1.

Nuclear Medicine Department, Hospital Clinic, Barcelona, Spain.

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http://dx.doi.org/10.1016/j.nefro.2017.11.014DOI Listing
October 2019

SNF472, a novel inhibitor of vascular calcification, could be administered during hemodialysis to attain potentially therapeutic phytate levels.

J Nephrol 2018 04 19;31(2):287-296. Epub 2018 Jan 19.

Nephrology and Renal Transplantation, Hospital Clínic, Barcelona, Spain.

Background: Cardiovascular calcification (CVC) is a major concern in hemodialysis (HD) and the loss of endogenous modulators of calcification seems involved in the process. Phytate is an endogenous crystallization inhibitor and its low molecular mass and high water solubility make it potentially dialyzable. SNF472 (the hexasodium salt of phytate) is being developed for the treatment of calciphylaxis and CVC in HD patients. We aimed to verify if phytate is lost during dialysis, and evaluate SNF472's behaviour during dialysis.

Methods: Dialyzability was assessed in vitro using online-hemodiafiltration and high-flux HD systems in blood and saline. SNF472 was infused for 20 min and quantified at different time points.

Results: Phytate completely dialyzed in 1 h at low concentrations (10 mg/l) but not when added at 30 or 66.67 mg/l SNF472. In bypass conditions, calcium was slightly chelated during SNF472 infusion but when the system was switched to dialysis mode the calcium in the bath compensated this chelation.

Conclusion: Phytate dialyses with a low clearance. The administration of SNF472 as an exogenous source of phytate allows to attain supra-physiological levels required for its potential therapeutic properties. As SNF472 is infused during the whole dialysis session, the low clearance would not affect the drug's systemic exposure.
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http://dx.doi.org/10.1007/s40620-018-0471-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5829128PMC
April 2018

Complex regional pain syndrome associated with erythropoietin therapy.

Nefrologia 2018 Jan - Feb;38(1):99-101. Epub 2017 Dec 6.

Unidad de Trasplante Renal, Hospital Clínic, Barcelona, España.

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http://dx.doi.org/10.1016/j.nefro.2017.01.002DOI Listing
October 2018

Down Regulation of the Munc18b-syntaxin-11 Complex and β1-tubulin Impairs Secretion and Spreading in Neonatal Platelets.

Thromb Haemost 2017 11 30;117(11):2079-2091. Epub 2017 Nov 30.

Servicio de Hematologia y Oncología Médica, Centro Regional de Hemodonación, Hospital Universitario Morales Meseguer, IMIB-Arrixaca, Murcia, Spain.

Neonatal platelets are hyporeactive and show impaired agonist-induced secretion despite no obvious abnormalities in their granules. Here, we examined, for the first time, the ultrastructure of neonatal and adult platelets following agonist activation. Under resting conditions, neonatal and adult platelets appeared ultrastructurally identical. Following agonist stimulation, however, noticeable degranulation occurred in adult platelets, while granules in neonatal platelets remained clearly visible and apparently unable to centralize or fuse. To investigate the underlying mechanisms, we first examined the expression levels of the main SNARE proteins, which mediate the membrane fusion events required for exocytosis. Neonatal platelets showed significantly reduced levels of syntaxin-11 and its regulator, Munc18b. Since granule centralization depends on contraction of the microtubule ring, we also examined the expression of its main component, β1-tubulin. Noteworthy, we found decreased mRNA and protein levels in neonatal platelets, while and isoforms were overexpressed, partially compensating for that deficiency. Finally, supporting the functional consequences of defective exocytosis, adhesion kinetic assays, performed in plasma-free medium, demonstrated delayed adhesion and spreading of neonatal platelets. This is the first report showing marked reductions of syntaxin-11-Munc18b complex and β1-tubulin in neonatal platelets, indicating that these proteins, required for platelet degranulation, are developmentally regulated.
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http://dx.doi.org/10.1160/TH17-04-0241DOI Listing
November 2017