Immune responses following 3rd and 4th doses of heterologous and homologous COVID-19 vaccines in kidney transplant recipients.

Background: Solid organ transplant recipients have attenuated immune responses to SARS-CoV-2 vaccines. In this study, we report on immune responses to 3rd- (V3) and 4th- (V4) doses of heterologous and homologous vaccines in a kidney transplant population. Methods: We undertook a single centre cohort study of 724 kidney transplant recipients prospectively screened for serological responses following 3 primary doses of a SARS-CoV2 vaccine. 322 patients were sampled post-V4 for anti-spike (anti-S), with 69 undergoing assessment of SARS-CoV-2 T-cell responses. All vaccine doses were received post-transplant, only mRNA vaccines were used for V3 and V4 dosing. All participants had serological testing performed post-V2 and at least once prior to their first dose of vaccine. Findings: 586/724 (80.9%) patients were infection-naïve post-V3; 141/2586 (24.1%) remained seronegative at 31 (21-51) days post-V3. Timing of vaccination in relation to transplantation, OR: 0.28 (0.15-0.54), p=0.0001; immunosuppression burden, OR: 0.22 (0.13-0.37), p<0.0001, and a diagnosis of diabetes, OR: 0.49 (0.32-0.75), p=0.001, remained independent risk factors for non-seroconversion. Seropositive patients post-V3 had greater anti-S if primed with BNT162b2 compared with ChAdOx1, p=0.001.Post-V4, 45/239 (18.8%) infection-naïve patients remained seronegative. De novo seroconversion post-V4 occurred in 15/60 (25.0%) patients. There was no difference in anti-S post-V4 by vaccine combination, p=0.50. T-cell responses were poor, with only 11/54 (20.4%) infection-naive patients having detectable T-cell responses post-V4, with no difference seen by vaccine type. Interpretation: A significant proportion of transplant recipients remain seronegative following 3- and 4- doses of SARS-CoV-2 vaccines, with poor T-cell responses, and are likely to have inadequate protection against infection. As such alternative strategies are required to provide protection to this vulnerable group. Funding: MW/PK received study support from Oxford Immunotec.

Incidence, Risk Factors, and Effect on Allograft Survival of Glomerulonephritis Post-transplantation in a United Kingdom Population: Cohort Study.

Background: Post-transplant glomerulonephritis (PTGN) has been associated with inferior long-term allograft survival, and its incidence varies widely in the literature. Methods: This is a cohort study of 7,623 patients transplanted between 2005 and 2016 at four major transplant UK centres. The diagnosis of glomerulonephritis (GN) in the allograft was extracted from histology reports aided by the use of text-mining software. The incidence of the four most common GN post-transplantation was calculated, and the risk factors for disease and allograft outcomes were analyzed. Results: In total, 214 patients (2.8%) presented with PTGN. IgA nephropathy (IgAN), focal segmental glomerulosclerosis (FSGS), membranous nephropathy (MN), and membranoproliferative/mesangiocapillary GN (MPGN/MCGN) were the four most common forms of post-transplant GN. Living donation, HLA DR match, mixed race, and other ethnic minority groups were associated with an increased risk of developing a PTGN. Patients with PTGN showed a similar allograft survival to those without in the first 8 years of post-transplantation, but the results suggest that they do less well after that timepoint. IgAN was associated with the best allograft survival and FSGS with the worst allograft survival. Conclusions: PTGN has an important impact on long-term allograft survival. Significant challenges can be encountered when attempting to analyze large-scale data involving unstructured or complex data points, and the use of computational analysis can assist.

Rituximab use in adult glomerulopathies and its rationale / Uso do rituximabe em glomerulopatias em adultos e justificativas

Abstract Glomerulopathies are one of the leading causes of end-stage renal disease. In the last years, clinical research has made significant contributions to the understanding of such conditions. Recently, rituximab (RTX) has appeared as a reasonably safe treatment. The Kidney Disease: Improving Global Outcomes guidelines (KDIGO) recommended RTX only as initial treatment in antineutrophil cytoplasm antibody associated vasculitis (AAV) and in non-responders patients with lupus nephritis (LN), but these guidelines have not been updated since 2012. Nowadays, RTX seems to be at least as effective as other immunosuppressive regimens in idiopathic membranous nephropathy (IMN). In minimal-change disease, (MCD) this drug might allow a long-lasting remission period in steroid-dependent or frequently relapsing patients. Preliminary results support the use of RTX in patients with pure membranous LN and immunoglobulin-mediated membranoproliferative glomerulonephritis (MPGN), but not in patients with class III/IV LN or complement-mediated MPGN. No conclusion can be drawn in idiopathic focal segmental glomerulosclerosis (FSGS) and anti-glomerular basement membrane antibody glomerulonephritis (anti-GBM GN) because studies are small, heterogeneous, and scarce. Lastly, immunosuppression including RTX is not particularly useful in IgA nephropathy. This review presents the general background, outcomes, and safety for RTX treatment in different glomerulopathies. In this regard, we describe randomized controlled trials (RCTs) performed in adults, whenever possible. A literature search was performed using clinicaltrials.gov and PubMed.

Resumo As glomerulopatias figuram entre as principais causas de doença renal terminal. Nos últimos anos, a pesquisa clínica efetuou contribuições significativas para a compreensão desse grupo de patologias. Recentemente, o rituximabe (RTX) surgiu como um tratamento razoavelmente seguro. As diretrizes do Kidney Disease: Improving Global Outcomes (KDIGO) recomendam o RTX apenas como tratamento inicial na vasculite associada ao ANCA (VAA) e em pacientes não respondedores com nefrite lúpica (NL), embora não sejam atualizadas desde 2012. Atualmente, o RTX parece ser pelo menos tão eficaz quanto outros esquemas imunossupressores na nefropatia membranosa idiopática (NMI). Na doença por lesão mínima (DLM), o medicamento pode proporcionar um período de remissão duradouro em pacientes córtico-dependentes ou com recidivas frequentes. Resultados preliminares corroboram o uso de RTX em pacientes com NL membranosa pura e glomerulonefrite membranoproliferativa (GNMP) mediada por imunoglobulina, mas não em pacientes com NL classe III/IV ou GNMP mediada por complemento. Os achados a respeito de glomeruloesclerose segmentar e focal (GESF) idiopática e doença por anticorpo antimembrana basal glomerular (anti-MBG) não são conclusivos em função do pequeno número, porte e heterogeneidade dos estudos publicados até o presente momento. Por fim, a imunossupressão com RTX não é particularmente útil na nefropatia por IgA. A presente revisão apresenta o racional da prescrição de RTX nas diferentes glomerulopatias, desfechos e segurança. Nesse sentido, foram incluídos ensaios clínicos randomizados (ECRs) realizados em adultos, sempre que possível. Pesquisas bibliográficas foram realizadas nas bases de dados do clinictrials.gov e no PubMed.

Rituximab use in adult glomerulopathies and its rationale.

Glomerulopathies are one of the leading causes of end-stage renal disease. In the last years, clinical research has made significant contributions to the understanding of such conditions. Recently, rituximab (RTX) has appeared as a reasonably safe treatment. The Kidney Disease: Improving Global Outcomes guidelines (KDIGO) recommended RTX only as initial treatment in antineutrophil cytoplasm antibody associated vasculitis (AAV) and in non-responders patients with lupus nephritis (LN), but these guidelines have not been updated since 2012. Nowadays, RTX seems to be at least as effective as other immunosuppressive regimens in idiopathic membranous nephropathy (IMN). In minimal-change disease, (MCD) this drug might allow a long-lasting remission period in steroid-dependent or frequently relapsing patients. Preliminary results support the use of RTX in patients with pure membranous LN and immunoglobulin-mediated membranoproliferative glomerulonephritis (MPGN), but not in patients with class III/IV LN or complement-mediated MPGN. No conclusion can be drawn in idiopathic focal segmental glomerulosclerosis (FSGS) and anti-glomerular basement membrane antibody glomerulonephritis (anti-GBM GN) because studies are small, heterogeneous, and scarce. Lastly, immunosuppression including RTX is not particularly useful in IgA nephropathy. This review presents the general background, outcomes, and safety for RTX treatment in different glomerulopathies. In this regard, we describe randomized controlled trials (RCTs) performed in adults, whenever possible. A literature search was performed using clinicaltrials.gov and PubMed.

Health-related quality of life as predictor of mortality in end-stage renal disease patients: an observational study.

BACKGROUND: Health-related quality of life (HRQoL) is an important component of patient-centered outcomes and a useful parameter for monitoring quality of care. We assessed HRQoL, its determinants, and associations with mortality in patients with end-stage renal disease (ESRD). METHODS: Short Form-36 was used to assess HRQoL, its domain components, and physical (PCS) and mental (MCS) composite summary scores in altogether 400 (338 incident and 62 prevalent) dialysis patients with median age 64 years, 37% women, 24% diabetes mellitus (DM), 49% cardiovascular disease (CVD), and median estimated glomerular filtration rate (eGFR) of 5.3 (3.0-9.4) ml/min/1.732. Results were analyzed separately for 338 incident patients starting on hemodialysis (HD; 68%) or peritoneal dialysis (PD; 32%), and 62 prevalent PD patients. Mortality risk was analyzed during up to 60 months (median 28 months). RESULTS: Linear multivariate regression analysis showed that in incident dialysis patients, 1-SD higher PCS associated negatively with 1-SD higher age, DM and CVD, and positively with 1-SD higher hemoglobin and sodium (adjusted r2 = 0.17). In 62 prevalent PD patients, 1-SD higher PCS was negatively associated with 1-SD higher age. MCS was not associated to any of the investigated factors. Multivariate Cox regression analysis showed that in incident dialysis patients, 1-SD increase of PCS associated with lower all-cause mortality, hazard ratio 0.65 (95% confidence interval 0.52-0.81), after adjustments for age, sex, DM, CVD, plasma albumin, C-reactive protein and eGFR whereas 1-SD lower MCS did not associate with mortality. In PD patients, neither PCS nor MCS associated with mortality. CONCLUSIONS: MCS did not associate with any of the investigated clinical factors, whereas lower PCS associated with higher age, CVD, DM, and lower hemoglobin and sodium levels. MCS was not associated with mortality, whereas lower PCS associated with increased mortality risk. These results suggest that HRQoL - in addition to its role as patient-centered outcome - matters also for hard clinical outcomes in ESRD patients. Our knowledge about factors influencing MCS in ESRD patients is limited and should motivate further studies.

Health-related quality of life in peritoneal dialysis patients: A narrative review.

Health-related quality of life (HRQOL) is an important aspect of patients´ health that should be an integral part of the evaluation of patient-centered outcomes, not least because HRQOL associates with patients´ morbidity and mortality. This applies also to chronic kidney disease patients, including those dependent on renal replacement therapies, the type of which may influence patients´ perception of HRQOL. Several studies have addressed HRQOL in chronic kidney disease patients undergoing renal replacement therapies, especially transplanted patients and hemodialysis patients, while publications concerning peritoneal dialysis (PD) patients are scarcer. This review describes some of the methods used to assess HRQOL, factors influencing HRQOL in PD patients, HRQOL in PD vs hemodialysis, and the relation between HRQOL and patient outcomes. We conclude that assessment of HRQOL-often neglected at present-should be included as a standard measure of patient-centered outcomes and when monitoring the quality and effectiveness of renal care including PD treatment.

Thrombotic microangiopathy associated with Mycoplasma pneumoniae infection.

Thrombotic microangiopathy (TMA) comprises a process of sequential endothelial damage, microvascular thrombosis, consumptive thrombocytopenia and microangiopathic haemolytic anaemia that can affect several organs, including the kidney. A 36-year-old woman was presented with a petechial rash 3 weeks after an upper respiratory tract infection. Laboratory results showed normocytic normochromic anaemia, thrombocytopenia and evidence of TMA with decreased haptoglobin, elevated serum lactate dehydrogenase and a peripheral blood smear with numerous schistocytes. Treatment included daily plasmapheresis and prednisolone, with favourable clinical evolution. Antibodies anti-ADAMTS13 were positive, establishing the diagnosis of acquired thrombotic thrombocytopenic purpura. There was also serological evidence of a recent infection by Mycoplasma pneumoniae, and therefore the preceding respiratory tract infection by this agent was the most likely trigger for the disease. Due to the high mortality rate and poor outcomes, the prompt diagnostic and treatment are crucial in this rare disease. The identification of triggers related to this pathology can allow new therapeutic targets or preventive strategies.