Breakthrough Infections Following mRNA SARS-CoV-2 Vaccination in Kidney Transplant Recipients.

BACKGROUND: The clinical effectiveness of coronavirus disease 2019 (COVID-19) vaccination in kidney transplant (KT) recipients is lower than in the general population. METHODS: From April to October 2021, 481 KT recipients with COVID-19, included in the Spanish Society of Nephrology COVID-19 Registry, were analyzed. Data regarding vaccination status and vaccine type were collected, and outcomes of unvaccinated or partially vaccinated patients (n = 130) were compared with fully vaccinated patients (n = 351). RESULTS: Clinical picture was similar and survival analysis showed no differences between groups: 21.7% of fully vaccinated patients and 20.8% of unvaccinated or partially vaccinated died (P = 0.776). In multivariable analysis, age and pneumonia were independent risk factors for death, whereas vaccination status was not related to mortality. These results remained similar when we excluded patients with partial vaccination, as well as when we analyzed exclusively hospitalized patients. Patients vaccinated with mRNA-1273 (n = 213) showed a significantly lower mortality than those who received the BNT162b2 vaccine (n = 121) (hazard ratio: 0.52; 95% confidence interval, 0.31-0.85; P = 0.010). CONCLUSIONS: COVID-19 severity in KT patients has remained high and has not improved despite receiving 2 doses of the mRNA vaccine. The mRNA-1273 vaccine shows higher clinical effectiveness than BNT162b2 in KT recipients with breakthrough infections. Confirmation of these data will require further research taking into account the new variants and the administration of successive vaccine doses.

Renin-Angiotensin System Blockers and the Risk of COVID-19-Related Mortality in Patients with Kidney Failure.

BACKGROUND AND OBJECTIVES: There is concern about potential deleterious effects of angiotensin-converting enzyme inhibitors (ACEis) and angiotensin II receptor blockers (ARBs) in patients with coronavirus disease 2019 (COVID-19). Patients with kidney failure, who often use ACEis/ARBs, are at higher risk of more severe COVID-19. However, there are no data available on the association of ACEi/ARB use with COVID-19 severity in this population. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: From the European Renal Association COVID-19 database (ERACODA), we retrieved data on kidney transplant recipients and patients on dialysis who were affected by COVID-19, between February 1 and October 1, 2020, and had information on 28-day mortality. We used Cox proportional-hazards regression to calculate hazard ratios for the association between ACEi/ARB use and 28-day mortality risk. Additionally, we studied the association of discontinuation of these agents with 28-day mortality. RESULTS: We evaluated 1511 patients: 459 kidney transplant recipients and 1052 patients on dialysis. At diagnosis of COVID-19, 189 (41%) of the transplant recipients and 288 (27%) of the patients on dialysis were on ACEis/ARBs. A total of 88 (19%) transplant recipients and 244 (23%) patients on dialysis died within 28 days of initial presentation. In both groups of patients, there was no association between ACEi/ARB use and 28-day mortality in both crude and adjusted models (in transplant recipients, adjusted hazard ratio, 1.12; 95% confidence interval [95% CI], 0.69 to 1.83; in patients on dialysis, adjusted hazard ratio, 1.04; 95% CI, 0.73 to 1.47). Among transplant recipients, ACEi/ARB discontinuation was associated with a higher mortality risk after adjustment for demographics and comorbidities, but the association was no longer statistically significant after adjustment for severity of COVID-19 (adjusted hazard ratio, 1.36; 95% CI, 0.40 to 4.58). Among patients on dialysis, ACEi/ARB discontinuation was not associated with mortality in any model. We obtained similar results across subgroups when ACEis and ARBs were studied separately, and when other outcomes for severity of COVID-19 were studied, e.g., hospital admission, admission to the intensive care unit, or need for ventilator support. CONCLUSIONS: Among kidney transplant recipients and patients on dialysis with COVID-19, there was no significant association of ACEi/ARB use or discontinuation with mortality.

Predictors of outcome in a Spanish cohort of patients with Fabry disease on enzyme replacement therapy.

Fabry disease may be treated by enzyme replacement therapy (ERT), but the impact of chronic kidney disease (CKD) on the response to therapy remains unclear. The aim of the present study was to analyse the incidence and predictors of clinical events in patients on ERT. STUDY DESIGN: Multicentre retrospective observational analysis of patients diagnosed and treated with ERT for Fabry disease. The primary outcome was the first renal, neurological or cardiological events or death during a follow-up of 60 months (24-120). RESULTS: In 69 patients (42 males, 27 females, mean age 44.6±13.7 years), at the end of follow-up, eGFR and the left ventricular septum thickness remained stable and the urinary albumin: creatinine ratio tended to decrease, but this decrease only approached significance in patients on agalsidase-beta (242-128mg/g (p=0.05). At the end of follow-up, 21 (30%) patients had suffered an incident clinical event: 6 renal, 2 neurological and 13 cardiological (including 3 deaths). Events were more frequent in patients with baseline eGFR≤60ml/min/1.73m2 (log Rank 12.423, p=0.001), and this remained significant even after excluding incident renal events (log Rank 4.086, p=0.043) and in males and in females. Lower baseline eGFR was associated with a 3- to 7-fold increase the risk of clinical events in different Cox models. CONCLUSIONS: GFR at the initiation of ERT is the main predictor of clinical events, both in males and in females, suggesting that start of ERT prior to the development of CKD is associated with better outcomes.

[Teaching nephrology as part of a degree in medicine]. / La docencia de la nefrología en el grado de medicina.

The teaching of nephrology as part of a degree in medicine is potentially one of the most decisive factors when choosing a speciality. Until now, however, we have not had an overview of the teaching of nephrology in Spain. We have integrated information available in public databases with a survey and personal interviews with those responsible for teaching in Spanish medical faculties. In 2019, there were 44 universities offering a medicine degree in Spain, in 16 Autonomous Communities (34 of which were public and 10 private). For learning purposes, students have a number of hospital beds ranging from 0.2 to 4.7, and there are Autonomous Communities that have a higher proportion of students per inhabitant or per physician, such as Madrid or the Community of Navarra. In 16 universities there are tenured teaching staff (professors and lecturers), in 8 contracted medical lecturers, and in 2 assistant lecturers. In 21 medical faculties, theoretical and practical nephrology is taught by associate lecturers. The subject is taught between the third and fifth years of the degree, the median being the fourth year. It is usually integrated with another subject and only in the University of Navarra is it an independent subject, with 3 credits. The total number of hours devoted to theoretical teaching (both theoretical classes and seminars) is highly variable and ranges from 11 to 35, with a median of 17.5. Variability is observed in both the number of theoretical subjects (range 11 to 31) and seminars (range 0 to 9). Among the faculties that teach seminars, the ratio of theoretical topics to seminars ranges from 1.6 to 18. Most faculties evaluate clinical practices with various modalities and percentage of assessment. Knowledge is mostly assessed by a multiple choice exam. In conclusion, there is a high level of variability in the curriculum for the teaching of nephrology as part of a degree in medicine in Spain. Teaching staff who are tenured or who have a stable affiliation with universities make up just 23% of the total and, in many faculties, teaching depends exclusively on associate professors.

Mortality of hemodialysis patients is associated with their clinical situation at the start of treatment.

INTRODUCTION: Previous reports have shown very high mortality among hemodialyisis patients. Our goal was to analyze the mortality of patients in the Renal Registry of Patients who remained exclusively on hemodialysis treatment. METHODS: The cohort of patients who started treatment in the community of Castilla-La Mancha between 2010 and 2012 and remained on hemodialysis treatment was analysed until the end of 2017. Age, sex, primary kidney disease, vascular access, hemoglobin, Charlson index and serum albumin were included. RESULTS: Mortality rate was 63,4% after 5 years and 76% at the end of the study, with no difference between males and females, and was linked to an older age, urgent onset or in those with acute deterioration of chronic kidney disease, the use of catheters or albumin less than 3.5 g/dl. CONCLUSIONS: Mortality in patients who remain on hemodialysis is very high and is associated with non-modifiable factors such as age but also others that we can prevent or treat such as type of vascular access or nutrition status at the beginning of treatment.

Predictors of outcome in a Spanish cohort of patients with Fabry disease on enzyme replacement therapy.

Fabry disease may be treated by enzyme replacement therapy (ERT), but the impact of chronic kidney disease (CKD) on the response to therapy remains unclear. The aim of the present study was to analyse the incidence and predictors of clinical events in patients on ERT. STUDY DESIGN: Multicentre retrospective observational analysis of patients diagnosed and treated with ERT for Fabry disease. The primary outcome was the first renal, neurological or cardiological events or death during a follow-up of 60 months (24-120). RESULTS: In 69 patients (42 males, 27 females, mean age 44.6±13.7 years), at the end of follow-up, eGFR and the left ventricular septum thickness remained stable and the urinary albumin: creatinine ratio tended to decrease, but this decrease only approached significance in patients on agalsidase-beta (242-128mg/g (p=0.05). At the end of follow-up, 21 (30%) patients had suffered an incident clinical event: 6 renal, 2 neurological and 13 cardiological (including 3 deaths). Events were more frequent in patients with baseline eGFR≤60ml/min/1.73m2 (log Rank 12.423, p=0.001), and this remained significant even after excluding incident renal events (log Rank 4.086, p=0.043) and in males and in females. Lower baseline eGFR was associated with a 3- to 7-fold increase the risk of clinical events in different Cox models. CONCLUSIONS: GFR at the initiation of ERT is the main predictor of clinical events, both in males and in females, suggesting that start of ERT prior to the development of CKD is associated with better outcomes.

Teaching nephrology as part of a degree in medicine.

The teaching of nephrology as part of a degree in medicine is potentially one of the most decisive factors when choosing a speciality. Until now, however, we have not had an overview of the teaching of nephrology in Spain. We have integrated information available in public databases with a survey and personal interviews with those responsible for teaching in Spanish medical faculties. In 2019, there were 44 universities offering a medicine degree in Spain, in 16 Autonomous Communities (34 of which were public and 10 private). For learning purposes, students have a number of hospital beds ranging from 0.2 to 4.7, and there are Autonomous Communities that have a higher proportion of students per inhabitant or per physician, such as Madrid or the Community of Navarra. In 16 universities there are tenured teaching staff (professors and lecturers), in eight contracted medical lecturers, and in two assistant lecturers. In 21 medical faculties, theoretical and practical nephrology is taught by associate lecturers. The subject is taught between the third and fifth years of the degree, the median being the fourth year. It is usually integrated with another subject and only in the University of Navarra is it an independent subject, with three credits. The total number of hours devoted to theoretical teaching (both theoretical classes and seminars) is highly variable and ranges from 11 to 35, with a median of 17.5. Variability is observed in both the number of theoretical topics (range 11-31) and seminars (range 0-9). Among the faculties that teach seminars, the ratio of theoretical topics to seminars ranges from 1.6 to 18. Most faculties evaluate clinical practices with various modalities and percentage of assessment. Knowledge is mostly assessed by a multiple choice exam. In conclusion, there is a high level of variability in the curriculum for the teaching of nephrology as part of a degree in medicine in Spain. Teaching staff who are tenured or who have a stable affiliation with universities make up just 23% of the total and, in many faculties, teaching depends exclusively on associate professors.

Factors associating with differences in the incidence of renal replacement therapy among elderly: data from the ERA-EDTA Registry.

Background: The incidence of renal replacement therapy (RRT) in the general population ≥75 years of age varies considerably between countries and regions in Europe. Our aim was to study characteristics and survival of elderly RRT patients and to find explanations for differences in RRT incidence. Methods: Patients ≥75 years of age at the onset of RRT in 2010-2013 from 29 national or regional registries providing data to the European Renal Association-European Dialysis and Transplant Association Registry were included. Chi-square and Mann-Whitney U tests were used to assess variation in patient characteristics and linear regression was used to study the association between RRT incidence and various factors. Kaplan-Meier curves and Cox regression were employed for survival analyses. Results: The mean annual incidence of RRT in the age group ≥75 years of age ranged from 157 to 924 per million age-related population. The median age at the start of RRT was higher and comorbidities were less common in areas with higher RRT incidence, but overall the association between patient characteristics and RRT incidence was weak. The unadjusted survival was lower in high-incidence areas due to an older age at onset of RRT, but the adjusted survival was similar [relative risk 1.00 (95% confidence interval, 0.97-1.03)] in patients from low- and high-incidence areas. Conclusions: Variation in the incidence of RRT among the elderly across European countries and regions is remarkable and could not be explained by the available data. However, the survival of patients in low- and high-incidence areas was remarkably similar.

Markers of endothelial damage in patients with chronic kidney disease on hemodialysis.

Patients with Stage 5 chronic kidney disease who are on hemodialysis (HD) remain in a chronic inflammatory state, characterized by the accumulation of uremic toxins that induce endothelial damage and cardiovascular disease (CVD). Our aim was to examine microvesicles (MVs), monocyte subpopulations, and angiopoietins (Ang) to identify prognostic markers in HD patients with or without diabetes mellitus (DM). A total of 160 prevalent HD patients from 10 centers across Spain were obtained from the Biobank of the Nephrology Renal Network (Madrid, Spain): 80 patients with DM and 80 patients without DM who were matched for clinical and demographic criteria. MVs from plasma and several monocyte subpopulations (CD142+/CD16+, CD14+/CD162+) were analyzed by flow cytometry, and the plasma concentrations of Ang1 and Ang2 were quantified by ELISA. Data on CVD were gathered over the 5.5 yr after these samples were obtained. MV level, monocyte subpopulations (CD14+/CD162+ and CD142+/CD16+), and Ang2-to-Ang1 ratios increased in HD patients with DM compared with non-DM patients. Moreover, MV level above the median (264 MVs/µl) was associated independently with greater mortality. MVs, monocyte subpopulations, and Ang2-to-Ang1 ratio can be used as predictors for CVD. In addition, MV level has a potential predictive value in the prevention of CVD in HD patients. These parameters undergo more extensive changes in patients with DM.

Online Hemodiafiltration Reduces Bisphenol A Levels.

Several uremic toxins have been identified and related to higher rates of morbidity and mortality in dialysis patients. Bisphenol A (BPA) accumulates in patients with chronic kidney disease. The aim of this study is to demonstrate the usefulness of online hemodiafiltration (OL-HDF) in reducing BPA levels. Thirty stable hemodialysis patients were selected to participate in this paired study. During three periods of 3 weeks each, patients were switched from high-flux hemodialysis (HF-HD) to OL-HDF, and back to HF-HD. BPA levels were measured in the last session of each period (pre- and post-dialysis) using ELISA and HPLC. Twenty-two patients (mean age 73 ± 14 years; 86.4% males) were included. Measurements of BPA levels by HPLC and ELISA assays showed a weak but significant correlation (r = 0.218, P = 0.012). BPA levels decreased in the OL-HDF period of hemodialysis, in contrast to the HF-HD period when they remained stable (P = 0.002). In conclusion, OL-HDF reduced BPA levels in dialysis patients.

Study of glomerulonephritis evolution in Castilla-La Mancha (GLOMANCHA) between 1994 and 2008. / Estudio evolutivo de las glomerulonefritis en Castilla-La Mancha (GLOMANCHA) en el periodo 1994-2008.

BACKGROUND: Renal biopsy registries allow histopathological data to be collected to improve knowledge of different pathologies and their natural history. AIM: To analyse the data of the Castilla La Mancha Glomerulonephritis Registry (GLOMANCHA) and the evolution of the different biopsy-proven pathologies between 1994 and 2008. METHODS: The 6 most common biopsy-proven pathologies were collected during the 14 years of the study (941 biopsies) in the 5 participant centres of the autonomous community. In 2008, we assessed patient renal survival and mortality and we evaluated associated factors to each situation for each pathology. RESULTS: Of the 941 biopsies, 59% belonged to men, with a mean age of 48±18 years. At the time of the biopsy, the median glomerular filtration rate was 50.3 (25.5-76.3) ml/min/1,73 m(2) and median proteinuria was 3.4 (1.5-6.4) grams per day. The most common pathology were lupus nephropathy, followed by focal segmental glomerulosclerosis and membranous nephropathy. Lupus nephropathy and minimal change disease achieved the best renal prognosis during follow-up (mean 7.3±4.8 years). Rapidly progressive glomerulonephritis type 3 and focal segmental glomerulosclerosis had the worst renal prognosis. In addition, rapidly progressive glomerulonephritis type 3 presented the worst vital prognosis. CONCLUSIONS: In GLOMANCHA, we demonstrate the poor prognosis of rapidly progressive glomerulonephritis type 3, in contrast to minimal change disease or lupus nephropathy. Renal function is an independent predictor of renal survival and mortality in this study.

Present and future in the treatment of diabetic kidney disease.

Diabetic kidney disease is the leading cause of end-stage renal disease. Albuminuria is recognized as the most important prognostic factor for chronic kidney disease progression. For this reason, blockade of renin-angiotensin system remains the main recommended strategy, with either angiotensin converting enzyme inhibitors or angiotensin II receptor blockers. However, other antiproteinuric treatments have begun to be studied, such as direct renin inhibitors or aldosterone blockers. Beyond antiproteinuric treatments, other drugs such as pentoxifylline or bardoxolone have yielded conflicting results. Finally, alternative pathogenic pathways are being explored, and emerging therapies including antifibrotic agents, endothelin receptor antagonists, or transcription factors show promising results. The aim of this review is to explain the advances in newer agents to treat diabetic kidney disease, along with the background of the renin-angiotensin system blockade.

Cyclosporine A-induced apoptosis in renal tubular cells is related to oxidative damage and mitochondrial fission.

Cyclosporine A (CsA) nephrotoxicity has been linked to reactive oxygen species (ROS) production in renal cells. We have demonstrated that the antioxidant Vitamin E (Vit E) abolished renal toxicity in vivo and in vitro models. As one of the main sources of intracellular ROS are mitochondria, we studied the effects of CsA on several mitochondrial functions in LLC-PK1 cells. CsA induced ROS synthesis and decreased reduced glutathione (GSH). The drug decreased mitochondrial membrane potential (ΔΨm) and induced physiological modifications in both the inner (IMM) and the outer mitochondrial membranes (OMM). In the IMM, CsA provoked mitochondrial permeability transition pores (MPTP) and cytochrome c was liberated into the intermembrane space. CsA also induced pore formation in the OMM, allowing that intermembrane space contents can reach cytosol. Furthermore, CsA altered the mitochondrial dynamics, inducing an increase in mitochondrial fission; CsA increased the expression of dynamin related protein 1 (Drp1) that contributes to mitochondrial fission, and decreased the expression of mitofusin 2 (Mfn2) and optic atrophy protein 1 (Opa1), proteins involved in the fusion process. All these phenomena were related to apoptosis. These effects were inhibited when cells were treated with the antioxidant Vit E suggesting that they were mediated by the synthesis of ROS.

Gitelman syndrome during pregnancy: a therapeutic challenge.

We report a female patient diagnosed of Gitelman disease who suffered from severe hypokalemia and hypomagnesemia during pregnancy. We discuss the therapeutic approach and materno-fetal outcome.