The development of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines and therapeutics will depend on understanding viral immunity. We studied T cell memory in 42 patients ...following recovery from COVID-19 (28 with mild disease and 14 with severe disease) and 16 unexposed donors, using interferon-γ-based assays with peptides spanning SARS-CoV-2 except ORF1. The breadth and magnitude of T cell responses were significantly higher in severe as compared with mild cases. Total and spike-specific T cell responses correlated with spike-specific antibody responses. We identified 41 peptides containing CD4
and/or CD8
epitopes, including six immunodominant regions. Six optimized CD8
epitopes were defined, with peptide-MHC pentamer-positive cells displaying the central and effector memory phenotype. In mild cases, higher proportions of SARS-CoV-2-specific CD8
T cells were observed. The identification of T cell responses associated with milder disease will support an understanding of protective immunity and highlights the potential of including non-spike proteins within future COVID-19 vaccine design.
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FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Nephronophthisis (NPH) is the most prevalent genetic cause for ESRD in children. However, little is known about the prevalence of NPH in adult-onset ESRD. Homozygous full gene deletions of the
gene ...encoding nephrocystin-1 are a prominent cause of NPH. We determined the prevalence of NPH in adults by assessing homozygous
full gene deletions in adult-onset ESRD.
Adult renal transplant recipients from five cohorts of the International Genetics and Translational Research in Transplantation Network (iGeneTRAiN) underwent single-nucleotide polymorphism genotyping. After quality control, we determined autosomal copy number variants (such as deletions) on the basis of median log2 ratios and B-allele frequency patterns. The findings were independently validated in one cohort. Patients were included in the analysis if they had adult-onset ESRD, defined as start of RRT at ≥18 years old.
We included 5606 patients with adult-onset ESRD; 26 (0.5%) showed homozygous
deletions. No donor controls showed homozygosity for this deletion. Median age at ESRD onset was 30 (range, 18-61) years old for patients with NPH, with 54% of patients age ≥30 years old. Notably, only three (12%) patients were phenotypically classified as having NPH, whereas most patients were defined as having CKD with unknown etiology (
=11; 42%).
Considering that other mutation types in
or mutations in other NPH-causing genes were not analyzed, NPH is a relatively frequent monogenic cause of adult-onset ESRD. Because 88% of patients had not been clinically diagnosed with NPH, wider application of genetic testing in adult-onset ESRD may be warranted.
ABSTRACT
Background
Kidney transplant survival benefits are not observed for around 8 months after transplantation because of a higher complications rate in early post-transplant periods. This study ...compares survival of patients awaiting transplantation with survival of transplant recipients and non-listed dialysis patients in Ireland.
Methods
In this retrospective analysis, the relative-risk (RR) of death was assessed with time-dependent, non-proportional hazards analysis, with adjustment for age, cause of end-stage kidney disease (ESKD), time from first treatment for ESKD to placement on the waiting list and year of initial placement on the list.
Results
A total of 3597 patients were included. Annual death rates per 100 patient-years at risk for all patients on dialysis, waiting-list patients and transplant recipients were 16.5, 2.4 and 1.2, respectively. Death rate was highest among diabetics. The relative risk of death for all patients on dialysis was five times higher than the waiting-list patients RR, 4.90; 95% confidence interval (CI), 3.70-6.52; P < 0.001. Time to survival equilibration was 1 year. Thereafter, the 5-year mortality risk was estimated to be 47% lower than that of the patients on the waiting list (RR, 0.53; 95% CI, 0.37-0.77; P = 0.001).
Conclusions
Transplant recipients had a higher risk of death initially, but a better long-term survival. Time to death risk equilibration was longer compared with other studies. This could be explained by better survival rates in our waiting-list cohort.
The term C3 glomerulopathy describes renal disorders characterized by the presence of glomerular deposits composed of C3 in the absence of significant amounts of Ig. On the basis of electron ...microscopy appearance, subsets of C3 glomerulopathy include dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). The full spectrum of histologic change observed in C3 glomerulopathy has yet to be defined and pathologic predictors of renal outcome within this patient population remain largely unknown. This study thus characterized a large C3 glomerulopathy cohort and identified clinicopathologic predictors of renal outcome.
All patients with kidney biopsies fulfilling criteria for C3 glomerulopathy from two quaternary renal centers within the United Kingdom and Ireland between 1992 and 2012 were retrospectively reviewed. We recorded histologic, demographic, and clinical data and determined predictors of ESRD using the Cox proportional hazards model.
Eighty patients with C3 glomerulopathy were identified: 21 with DDD and 59 with C3GN. Patients with DDD were younger, more likely to have low serum C3 levels, and more likely to have crescentic GN than patients with C3GN. Patients with C3GN were older and had more severe arteriolar sclerosis, glomerular sclerosis, and interstitial scarring than patients with DDD. Of 70 patients with available follow-up data, 20 (29%) progressed to ESRD after a median of 28 months. Age >16 years, DDD subtype, and crescentic GN were independent predictors of ESRD within the entire cohort. Renal impairment at presentation predicted ESRD only among patients with DDD.
Although detailed serologic and genetic data are lacking, this study nevertheless identifies important clinicopathologic distinctions between patients with DDD and C3GN. These include independent predictors of renal outcome. If replicated in other cohorts, these predictors could be used to stratify patients, enabling application of emerging mechanism-based therapies to patients at high risk for poor renal outcome.
Type 1 diabetes affects over nine million individuals globally, with approximately 40% developing diabetic kidney disease. Emerging evidence suggests that epigenetic alterations, such as DNA ...methylation, are involved in diabetic kidney disease. Here we assess differences in blood-derived genome-wide DNA methylation associated with diabetic kidney disease in 1304 carefully characterised individuals with type 1 diabetes and known renal status from two cohorts in the United Kingdom-Republic of Ireland and Finland. In the meta-analysis, we identify 32 differentially methylated CpGs in diabetic kidney disease in type 1 diabetes, 18 of which are located within genes differentially expressed in kidneys or correlated with pathological traits in diabetic kidney disease. We show that methylation at 21 of the 32 CpGs predict the development of kidney failure, extending the knowledge and potentially identifying individuals at greater risk for diabetic kidney disease in type 1 diabetes.
Kidney grafts from donors who died of stroke and related traits have worse outcomes relative to grafts from both living donors and those who died of other causes. We hypothesise that deceased donors, ...particularly those who died of stroke, have elevated polygenic burden for cerebrovascular traits. We further hypothesise that this donor polygenic burden is associated with inferior graft outcomes in the recipient.
Using a dataset of 6666 deceased and living kidney donors from seven different European ancestry transplant cohorts, we investigated the role of polygenic burden for cerebrovascular traits (hypertension, stroke, and intracranial aneurysm (IA)) on donor age of death and recipient graft outcomes.
We found that kidney donors who died of stroke had elevated intracranial aneurysm and hypertension polygenic risk scores, compared to healthy controls and living donors. This burden was associated with age of death among donors who died of stroke. Increased donor polygenic risk for hypertension was associated with reduced long term graft survival (HR: 1.44, 95% CI 1.07, 1.93) and increased burden for hypertension, and intracranial aneurysm was associated with reduced recipient estimated glomerular filtration rate (eGFR) at 1 year.
Collectively, the results presented here demonstrate the impact of inherited factors associated with donors' death on long-term graft function.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Abstract Background and purpose Late‐onset mitochondrial disorders are diagnostically challenging with significant heterogeneity in disease presentation. A case is reported of a 67‐year‐old gentleman ...who presented with a 3‐month history of seizures, recurrent encephalopathy, ataxia and weight loss, preceded by recent initiation of haemodialysis for end‐stage chronic kidney disease. Methods Extensive work‐up including serological, cerebrospinal fluid, magnetic resonance imaging and electroencephalography was performed. Whole exome sequencing and muscle biopsy confirmed the diagnosis. Results Magnetic resonance imaging brain demonstrated a single non‐enhancing T2 fluid attenuated inversion recovery hyperintense cortical/subcortical signal change in the right temporal lobe and cerebellar atrophy. Given the subacute presentation of uncertain aetiology, he was empirically treated for autoimmune/paraneoplastic encephalitis. Despite radiological resolution of the cortical abnormality 2 weeks later, there was no clinical improvement. Further collateral history unveiled a mildly ataxic gait and longstanding hearing loss suggestive of a genetic cause. Whole exome sequencing revealed a likely pathogenic, heteroplasmic mitochondrial DNA variant in the MT‐TV gene, m.1659T>C, present at higher levels of heteroplasmy in muscle (91%) compared to other mitotic tissues. A high fat/protein diet and multivitamins including co‐enzyme Q10 were commenced. Treatment of the nutritional deficiency and avoidance of intermittent fasting due to unreliable oral intake secondary to encephalopathy probably contributed to the clinical improvement seen over the ensuing few months, with resolution of his encephalopathy and return to his baseline gait and weight. Conclusion An adult case is reported with an acute neurological presentation mimicking encephalitis, caused by a heteroplasmic m.1659T>C MT‐TV variant, previously reported once in a child who displayed a different clinical phenotype.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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