Background
Podocalyxin (PODXL) is a highly sialylated adhesion glycoprotein that plays an important role in podocyte's physiology. Recently, missense and nonsense dominant variants in the PODXL gene ...have been associated with focal segmental glomerulosclerosis (FSGS), a leading cause of nephrotic syndrome and kidney failure. Their histologic description, however, was superficial or absent.
Methods
We performed exome sequencing on a three‐generation family affected by an atypical glomerular nephropathy and characterized the disease by light and electron microscopy.
Results
The disease was characterized by FSGS features and glomerular basement membrane duplication. Six family members displayed chronic proteinuria, ranging from mild manifestations without renal failure, to severe forms with end‐stage renal disease. Exome sequencing of affected twin sisters, their affected mother, healthy father, and healthy maternal uncle revealed a new nonsense variant cosegregating with the disease (c.1453C>T, NM_001018111) in the PODXL gene, which is known to be expressed in the kidney and to cause nephropathy when mutated. The variant is predicted to lead to a premature stop codon (p.Q485*) that results in the loss of the intracytoplasmic tail of the protein.
Conclusion
This is the first description of a peculiar association combining a PODXL stop‐gain variant and both FSGS and membranoproliferative glomerulonephritis features, described by light and electron microscopy.
This study describes the association of a genetic Podocalyxin (PODXL) variant with a familial glomerular nephropathy characterized by focal segmental glomerulosclerosis and membranoproliferative glomerulonephritis features. This finding expands the phenotypic spectrum associated to PODXL variants and highlights the importance to screen the PODXL gene for deleterious variants in similar disease forms.
The ZEBRA (Z EBV replication activator) protein is the major transcription factor of EBV, expressed upon EBV lytic cycle activation. An increasing body of studies have highlighted the critical role ...of EBV lytic infection as a risk factor for lymphoproliferative disorders, such as post-transplant lymphoproliferative disease (PTLD). We studied 108 transplanted patients (17 PTLD and 91 controls), retrospectively selected from different hospitals in France and in the Netherlands. The majority of PTLD were EBV-positive diffuse large B-cell lymphomas, five patients experienced atypical PTLD forms (EBV-negative lymphomas, Hodgkin’s lymphomas, and T-cell lymphomas). Fourteen patients among the seventeen who developed a pathologically confirmed PTLD were sZEBRA positive (soluble ZEBRA, plasma level above 20 ng/mL, measured by an ELISA test). The specificity and positive predictive value (PPV) of the sZEBRA detection in plasma were 98% and 85%, respectively. Considering a positivity threshold of 20 ng/mL, the sensitivity of the sZEBRA was 82.35% and the specificity was 94.51%. The mean of the sZEBRA values in the PTLD cases were significantly higher than in the controls (p < 0.0001). The relevance of the lytic cycle and, particularly, the role of ZEBRA in lymphomagenesis is a new paradigm pertaining to the prevention and treatment strategies for PTLD. Given the high-specificity and the predictive values of this test, it now appears relevant to investigate the lytic EBV infection in transplanted patients as a prognostic biomarker.
While cardiovascular disease has been associated with an increased risk of coronavirus disease 2019 (COVID-19), no studies have described its clinical course in patients with aortic stenosis who had ...undergone transcatheter aortic valve replacement (TAVR). Numerous observational studies have reported an association between the A blood group and an increased susceptibility to SARS-CoV-2 infection. Our objective was to investigate the frequency and clinical course of COVID-19 in a large sample of patients who had undergone TAVR and to determine the associations of the ABO blood group with disease occurrence and outcomes. Patients who had undergone TAVR between 2010 and 2019 were included in this study and followed-up through the recent COVID-19 outbreak. The occurrence and severity (hospitalization and/or death) of COVID-19 and their associations with the ABO blood group served as the main outcome measures. Of the 1125 patients who had undergone TAVR, 403 (36%) died before 1 January 2020, and 20 (1.8%) were lost to follow-up. The study sample therefore consisted of 702 patients. Of them, we identified 22 cases (3.1%) with COVID-19. Fourteen patients (63.6%) were hospitalized or died of disease. Multivariable analysis identified the A blood group (vs. others) as the only independent predictor of COVID-19 in patients who had undergone TAVR (odds ratio (OR) = 6.32; 95% confidence interval (CI) = 2.11−18.92; p = 0.001). The A blood group (vs. others; OR = 8.27; 95% CI = 1.83−37.43, p = 0.006) and a history of cancer (OR = 4.99; 95% CI = 1.64−15.27, p = 0.005) were significantly and independently associated with disease severity (hospitalization and/or death). We conclude that patients who have undergone TAVR frequently have a number of cardiovascular comorbidities that may work to increase the risk of COVID-19. The subgroup with the A blood group was especially prone to developing the disease and showed unfavorable outcomes.
Kidney transplant recipients (KTRs) displays marked inter-individual variations in magnitude of immune responses to anti-SARS-CoV-2 vaccination. The aim of this large single-center study was to ...identify the predictive factors for serological response to the mRNA-1273 vaccine in KTRs. We also devised a score to optimize prediction with the goal of implementing a personalized vaccination strategy. The study population consisted of 564 KTRs who received at least two doses of the mRNA-1273 vaccine. Anti-RBD IgG titers were quantified one month after each vaccine dose and until six months thereafter. A third dose vaccine was given when the antibody titer after the second dose was <143 BAU/mL. A score to optimize prediction of vaccine response was devised using the independent predictors identified in multivariate analysis. The seropositivity rate after the second dose was 46.6% and 22.2% of participants were classified as good responders (titers ≥ 143 BAU/mL). On analyzing the 477 patients for whom serology testing was available after the second or third dose, the global seropositivity rate was 69% (good responders: 46.3%). Immunosuppressive drugs, graft function, age, interval from transplantation, body mass index, and sex were associated with vaccine response. The devised score was strongly associated with the seropositivity rate (AUC = 0.752, p < 0.0001) and the occurrence of a good antibody response (AUC = 0.785, p < 0.0001). Notably, antibody titers declined over time both after the second and third vaccine doses. In summary, a high burden of comorbidities and immunosuppression was correlated with a weaker antibody response. A fourth vaccine dose and/or pre-exposure prophylaxis with monoclonal antibodies should be considered for KTRs who remain unprotected.
Conversion from calcineurin-inhibitors (CNIs) to belatacept can help kidney-transplant (KT) recipients avoid CNI-related nephrotoxicity. The risk of associated opportunistic infections (OPIs) is ...ill-defined. We conducted a multicentric cohort study across 15 French KT-centers in a real-life setting. Between 07-2010 and 07-2019, 453 KT recipients were converted from CNI- to belatacept-based therapy at 19 0.13–431 months post-transplantation. Most patients, i.e., 332 (79.3%), were converted after 6-months post-transplantation. Follow-up time after conversion was 20.1 +/− 13 months. OPIs developed in 42(9.3%) patients after 14 +/− 12 months post-conversion. Eight patients (19%) had two OPI episodes during follow-up. Incidences of CMV DNAemia and CMV disease were significantly higher in patients converted before 6-months post-KT compared to those converted later (i.e., 31.6% vs. 11.5%; p < 0.001; and 11.6% vs. 2.4%, p < 0.001, respectively). Cumulative incidence of OPIs was 6.5 OPIs/100 person–years. Incidence of CMV disease was 2.8/100 person–years, of pneumocystis pneumonia 1.6/100 person–years, and of aspergillosis 0.2/100 person–years. Multivariate analyses showed that estimated glomerular filtration (eGFR) < 25 mL/min/1.73 m2 at conversion was independently associated with OPIs (HR = 4.7 (2.2 − 10.3), p < 0.001). The incidence of EBV DNAemia was 17.3 events /100 person–years. At 1-year post-conversion, mean eGFR had significantly increased from 32.0 +/− 18 mL/min/1.73 m2 to 42.2 +/− 18 mL/min/1.73 m2 (p < 0.0001). Conversion to belatacept is an effective strategy with a low infectious risk.
Background The reasons that decreased glomerular filtration rate (GFR) might alter the clinical efficacy of clopidogrel are poorly understood. Study Design In this study, we sought to evaluate ...whether decreased GFR alters platelet response to clopidogrel in patients receiving a maintenance dose of clopidogrel (75 mg/d for at least 8 days). Settings & Participants 126 consecutive patients categorized by estimated GFR: stages 1-2 (>60 mL/min/1.73 m2 ; n = 29), stage 3a (45-59 mL/min/1.73 m2 ; n = 21); stage 3b (30-44 mL/min/1.73 m2 ; n = 26), stage 4 (15-29 mL/min/1.73 m2 ; n = 14), and stage 5 (<15 mL/min/1.73 m2 ; n = 36) were prospectively enrolled. Predictor Residual platelet reactivity, defined in the VASP (Vasodilator Stimulated Phosphoprotein) flow cytometry test as platelet reactivity index (PRI) ≥61% and in the VerifyNow turbidimetric-based assay as a value >235 PRU (adenosine diphosphate receptor reaction units) or percentage of platelet inhibition <15%. Outcomes We examined factors associated with low response to clopidogrel using logistic regression. Results A significant relationship between estimated GFR, PRI, PRU, and percentage of inhibition was found. The prevalence of residual platelet reactivity was highest in patients with GFR stage 5. PRI ≥61% occurred in 52.8% of patients with stage 5 versus 30.8% of stage 3b and 24.1% of stages 1-2 ( P = 0.1). PRU >235 was found in 63.6% of patients with stage 5 versus 36.8% of stage 3b and 17.2% of stages 1-2 ( P = 0.005). Inhibition <15% affected 66.7% of patients with stage 5 versus 21.1% of stage 3b and 17.2% of stages 1-2 ( P < 0.001). In the multivariable model, GFR stage 5 (adjusted prevalence ratio PR, 3.10; 95% CI, 1.23-9.43; P = 0.02), and obesity (adjusted PR, 1.92; 95% CI, 1.34-2.23; P = 0.004) were the sole predictors of residual platelet reactivity. Limitations Interference of hemodialysis with the pharmacokinetics of clopidogrel could not be excluded. Conclusion GFR stage 5 is associated with substantial impairment of platelet inhibition independently of diabetes mellitus.
The life expectancy of patients who have dementia and are initiated on dialysis in the United States has not been described in the medical literature. A retrospective cohort study was conducted of ...272,024 Medicare/Medicaid primary patients in the US Renal Data System who were started on ESRD therapy between April 1, 1995, and December 31, 1999, and followed through December 31, 2001. Cox regression was used to calculate adjusted hazard ratios for risk for death after initiation of dialysis for patients whose dementia was diagnosed before the initiation of dialysis as shown by Medicare claims. The average time to death for patients with dementia was 1.09 versus 2.7 yr (P < 0.001) with an adjusted hazard ratio of 1.87 (95% confidence interval 1.77 to 1.98). The 2-yr survival for patients with dementia was 24 versus 66% for patients without dementia (P < 0.001 via log rank test). Dementia that is diagnosed before initiation on dialysis is an independent risk factor for subsequent death. Such patients should be considered for time-limited trials of dialysis and careful discussion in choosing whether to pursue initiation of dialysis or palliative care.
We here report on the first observation of a C3 mutation that is related to atypical hemolytic and uremic syndrome (aHUS), which occurred in a pancreatic islet transplant patient. Immunosuppressive ...treatments, such as calcineurin inhibitors, have been linked to undesirable effects like nephrotoxicity.
A 40-year-old man with brittle diabetes, who was included in the TRIMECO trial, became insulin-independent 2 months after pancreatic islet transplantation. About 15 months after islet transplantation, the patient exhibited acute kidney injury due to aHUS. Despite plasma exchange and eculizumab treatment, the patient developed end-stage renal disease. A genetic workup identified a missense variant (p.R592Q) in the C3 gene. In vitro, this C3 variant had defective Factor I proteolytic activity with membrane proteins as cofactor proteins, which was thus classified as pathogenic. About 1 year after the aHUS episode, kidney transplantation was carried out under the protection of the specific anti-C5 monoclonal antibody eculizumab. The patient had normal kidney function, with preserved pancreatic islet function 4 years later.
Pancreatic islet transplantation could have triggered this aHUS episode, but this link needs to be clarified. Although prophylactic eculizumab maintains kidney allograft function, its efficacy still needs to be studied in larger populations.
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