New biomarkers of early and late graft dysfunction are needed in renal transplant to improve management of complications and prolong graft survival. A wide range of potential diagnostic and ...prognostic biomarkers, measured in different biological fluids (serum, plasma, urine) and in renal tissues, have been proposed for post-transplant delayed graft function (DGF), acute rejection (AR), and chronic allograft dysfunction (CAD). This review investigates old and new potential biomarkers for each of these clinical domains, seeking to underline their limits and strengths. OMICs technology has allowed identifying many candidate biomarkers, providing diagnostic and prognostic information at very early stages of pathological processes, such as AR. Donor-derived cell-free DNA (ddcfDNA) and extracellular vesicles (EVs) are further promising tools. Although most of these biomarkers still need to be validated in multiple independent cohorts and standardized, they are paving the way for substantial advances, such as the possibility of accurately predicting risk of DGF before graft is implanted, of making a "molecular" diagnosis of subclinical rejection even before histological lesions develop, or of dissecting etiology of CAD. Identification of "immunoquiescent" or even tolerant patients to guide minimization of immunosuppressive therapy is another area of active research. The parallel progress in imaging techniques, bioinformatics, and artificial intelligence (AI) is helping to fully exploit the wealth of information provided by biomarkers, leading to improved disease nosology of old entities such as transplant glomerulopathy. Prospective studies are needed to assess whether introduction of these new sets of biomarkers into clinical practice could actually reduce the need for renal biopsy, integrate traditional tools, and ultimately improve graft survival compared to current management.
Extracellular vesicles (EVs) are known immune-modulators exerting a critical role in kidney transplantation (KT). EV bioactive cargo includes graft antigens, costimulatory/inhibitory molecules, ...cytokines, growth factors, and functional microRNAs (miRNAs) that may modulate expression of recipient cell genes. As paracrine factors, neutrophil- and macrophage-derived EVs exert immunosuppressive and immune-stimulating effects on dendritic cells, respectively. Dendritic cell-derived EVs mediate alloantigen spreading and modulate antigen presentation to T lymphocytes. At systemic level, EVs exert pleiotropic effects on complement and coagulation. Depending on their biogenesis, they can amplify complement activation or shed complement inhibitors and prevent cell lysis. Likewise, endothelial- and platelet-derived EVs can exert procoagulant/prothrombotic effects and also promote endothelial survival and angiogenesis after ischemic injury. Kidney endothelial- and tubular-derived EVs play a key role in ischemia-reperfusion injury (IRI) and during the healing process; additionally, they can trigger rejection by inducing both alloimmune and autoimmune responses. Endothelial EVs have procoagulant/pro-inflammatory effects and can release sequestered self-antigens, generating a tissue-specific autoimmunity. Renal tubule-derived EVs shuttle pro-fibrotic mediators (TGF-β and miR-21) to interstitial fibroblasts and modulate neutrophil and T-lymphocyte influx. These processes can lead to peritubular capillary rarefaction and interstitial fibrosis-tubular atrophy. Different EVs, including those from mesenchymal stromal cells (MSCs), have been employed as a therapeutic tool in experimental models of rejection and IRI. These particles protect tubular and endothelial cells (by inhibition of apoptosis and inflammation-fibrogenesis or by inducing autophagy) and stimulate tissue regeneration (by triggering angiogenesis, cell proliferation, and migration). Finally, urinary and serum EVs represent potential biomarkers for delayed graft function (DGF) and acute rejection. In conclusion, EVs sustain an intricate crosstalk between graft tissue and innate/adaptive immune systems. EVs play a major role in allorecognition, IRI, autoimmunity, and alloimmunity and are promising as biomarkers and therapeutic tools in KT.
In this viewpoint, we summarize the relevance of thromboinflammation in COVID-19 and discuss potential mechanisms of endothelial injury as a key point for the development of lung and distant organ ...dysfunction, with a focus on direct viral infection and cytokine-mediated injury. Entanglement between inflammation and coagulation and resistance to heparin provide a rationale to consider other therapeutic approaches in order to preserve endothelial function and limit microthrombosis, especially in severe forms. These strategies include nebulized heparin, N-acetylcysteine, plasma exchange and/or fresh frozen plasma, plasma derivatives to increase the level of endogenous anticoagulants (tissue factor pathway inhibitor, activated protein C, thrombomodulin, antithrombin), dipyridamole, complement blockers, different types of stem cells, and extracellular vesicles. An integrated therapy including these drugs has the potential to improve outcomes in COVID-19.
To the Editor:
In reporting the results of the Randomized, Phase II Study to Evaluate the Safety and Pharmacokinetics of Oral Dabigatran Etexilate in Patients after Heart Valve Replacement ...(RE-ALIGN), Eikelboom et al. (Sept. 26 issue)
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conclude that the use of dabigatran, as compared with warfarin, showed no benefit and increased rates of thromboembolic and bleeding events among patients with mechanical heart valves.
We wonder whether baseline renal function was evaluated in patients who were receiving dabigatran and who had thromboembolic and bleeding complications. We also wonder whether there were differences in renal function between patients who had these complications . . .
Abstract
BACKGROUND AND AIMS
The development and massive use of mRNA COVID-19 vaccine BNT162b2 has raised new concerns on triggering de novo immune-mediated diseases, in particular rare diseases as ...glomerulonephritis (GN), even if the security profile is excellent and severe reactions have been rare. In literature few similar cases were recently described 1, 2. We report six cases of newly diagnosed GN after a two-dose regimen of SARS-CoV-2 vaccine, from a single tertiary care institution in Northern Italy.
METHOD
We described six cases of de novo GN occurring after massive use of Pfizer-BioNTech BNT162b2 COVID-19 vaccine from March 2021 to December 2021. All cases were biopsy proven. Baseline characteristics and laboratory findings, treatments and outcomes were based on review of medical records.
RESULTS
From April 2021, we observed two IgA nephropathies (IgA-N), one membranous nephropathy (MN), one membranoprolipherative GN (MPGN), one acute interstitial nephritis (aTIN) and one minimal change disease (MCD). Of note, one IgA-N presented with diffuse purpura as in IgA-vasculitis. The median age at vaccination was 52.8 years (min–max 18–67) and three (50%) were female; arterial hypertension was the most common comorbidity (50%). Only one subject contracted COVID-19 before vaccine (16.6%). None of the points showed any sign of renal disease before vaccine; at the time of disease onset, the median creatinine was 1.49 mg/dL (min–max 0.6–10.5 mg/dL) and proteinuria 3.0 g/24 h (min–max 0.9–13.8 g/24 h). All cases presented after the second dose (1 day to 6 months thereafter) and three (50%) were within 3 weeks from the vaccine. Of note, the aTIN developed after the vaccine during a long-time therapy with statins and relapsed after a rechallenge with a statin few months later. All the nephropathies were treated as per center practice, with an overall good response (four partial remissions and one complete remission). Given a target population of about 100 000–200 000 residents in our area, we could estimate an incidence rate of 4–8 cases/100 000 patient-years.
CONCLUSION
This small series has a lot of limitations including the small number of patients and we probably missed some cases in our area. Furthermore, we could not investigate a causal association, even if the timing of disease onset might be suspicious in three cases and the incidence seemed to be almost twice as the expected in Europe (about 2–4/100.000 patient-years). As for SARS-CoV-2 vaccines, it is likely that the mRNA vaccine will result in a more potent inflammatory stimulus than the one observed after inactivated virus-vaccine: maybe some patients had already a subclinical GN and the vaccine constituted a flare leading to the full-blown disease 3.
Abstract
Background. Patients on kidney replacement therapy comprise a vulnerable population and may be at increased risk of death from coronavirus disease 2019 (COVID-19). Currently, only limited ...data are available on outcomes in this patient population.
Methods. We set up the ERACODA (European Renal Association COVID-19 Database) database, which is specifically designed to prospectively collect detailed data on kidney transplant and dialysis patients with COVID-19. For this analysis, patients were included who presented between 1 February and 1 May 2020 and had complete information available on the primary outcome parameter, 28-day mortality.
Results. Of the 1073 patients enrolled, 305 (28%) were kidney transplant and 768 (72%) dialysis patients with a mean age of 60 ± 13 and 67 ± 14 years, respectively. The 28-day probability of death was 21.3% 95% confidence interval (95% CI) 14.3–30.2% in kidney transplant and 25.0% (95% CI 20.2–30.0%) in dialysis patients. Mortality was primarily associated with advanced age in kidney transplant patients, and with age and frailty in dialysis patients. After adjusting for sex, age and frailty, in-hospital mortality did not significantly differ between transplant and dialysis patients hazard ratio (HR) 0.81, 95% CI 0.59–1.10, P = 0.18. In the subset of dialysis patients who were a candidate for transplantation (n = 148), 8 patients died within 28 days, as compared with 7 deaths in 23 patients who underwent a kidney transplantation <1 year before presentation (HR adjusted for sex, age and frailty 0.20, 95% CI 0.07–0.56, P < 0.01).
Conclusions. The 28-day case-fatality rate is high in patients on kidney replacement therapy with COVID-19 and is primarily driven by the risk factors age and frailty. Furthermore, in the first year after kidney transplantation, patients may be at increased risk of COVID-19-related mortality as compared with dialysis patients on the waiting list for transplantation. This information is important in guiding clinical decision-making, and for informing the public and healthcare authorities on the COVID-19-related mortality risk in kidney transplant and dialysis patients.
Coronavirus disease 2019 (COVID-19) poses an unprecedented challenge to world health systems, substantially increasing hospitalization and mortality rates in all affected countries. Being primarily a ...respiratory disease, COVID-19 is mainly associated with pneumonia or minor upper respiratory tract symptoms; however, different organs can sustain considerable (if not terminal) damage because of coronavirus. Acute kidney injury is the most common complication of COVID-19-related pneumonia, and more than 20% of patients requiring ventilatory support develop renal failure. Additionally, chronic kidney disease is a major risk factor for COVID-19 severity and mortality. All these data demonstrate the relevance of renal function assessment in patients with COVID-19 and the need of early kidney-directed diagnostic and therapeutic approaches. However, the sole assessment of renal function could be not entirely indicative of kidney tissue status. In this viewpoint, we discuss the clinical significance and potential relevance of renal functional reserve evaluation in patients with COVID-19.
Abstract
Background and Aims
Very few information about COVID-19 in kidney transplant recipients (KTRs) are known and the available evidence are based on limited case series. In KTRs, Acute Kidney ...Injury (AKI) of different causes is known to be associated with a decreased graft survival: direct viral infection and local inflammation may potentially lead to a premature loss of graft function and to an increased risk of death in COVID-19 patients.
To evaluate prevalence, stage, causes of AKI and mortality in KTRs with a positive pharyngeal swab for SARS-CoV-2 in our transplant center located in a 500-bed University Hospital.
Method
In March-June 2020, we evaluated in 25 COVID-19 KTRs demographic and transplant characteristics, comorbidities, immunosuppressive therapies (IT). Patients were screened for type of symptoms, management of IT, complications and outcome. AKI was graded according to 2012 KDIGO guidelines and causes were investigated basing on both clinical and laboratory variables. AKI prevalence in KTRs was compared to that observed in the whole hospitalized COVID-19 patients.
Results
During the first wave of pandemic, a total of 945 patients were admitted to our hospital with a reported AKI prevalence of 37%. AKI classified using 2012 KDIGO guidelines associated with an increased mortality risk in the whole population.
In this setting, we observed that 25 KTRs followed-up in our University Hospital had a positive molecular diagnosis for COVID-19: median age was 58 years and 80% were males. Considering the most frequent comorbidities, 100% of KTRs had hypertension and 7/25 (29%) had diabetes. Clinical symptoms at enrollment were fever (95%), cough (47%), dyspnea (30%). Regarding IT, 100% of patients were taking CNI, 64% antimetabolite agents and 76% steroids. Of note, 19/25 patients (76%) were hospitalized and 6/19 (31.5%) were admitted to Intensive Care Unit (ICU). Mean length of hospital stay was 23 days. At admission, all KTRs stopped MMF and increased steroid doses, concomitantly decreasing CNI levels.
AKI occurred in 60% of KTRs (12/25), AKI KDIGO grading as follow: stage 1 4/12 (33.3%), stage 2 3/12 (25%), stage 3 5/12 (41.7%); development favored by low eGFR/increased serum creatinine (mean serum creatinine 2.06 mg/dl): 4/25 (16%) required hemodialysis and the most frequent cause of AKI was sepsis or septic shock. Overall mortality in KTRs was 37,5% (9/25): of note, 88% (8/9) of patients with a worse outcome had developed AKI.
Conclusion
AKI prevalence was significantly higher in KTRs than in non-transplanted COVID-19 patients. AKI development was associated with an increased risk of mortality: of note, mortality rate in KTRs was significantly higher than that observed in the non-transplanted patients. COVID-19 lead to a difficult management of IT, in particular for elevated tacrolimus levels due to associated antiviral and antibiotic therapies. COVID-19-associated AKI in KTRs may lead to an increased risk of rejection and premature loss of graft function with the need of skilled nephrological follow-up.
Kidney transplant recipients (KTRs), like other solid organ transplant recipients display a suboptimal response to mRNA vaccines, with only about half achieving seroconversion after two doses. ...However, the effectiveness of a booster dose, particularly in generating neutralizing antibodies (NAbs), remains poorly understood, as most studies have mainly focused on non‐neutralizing antibodies. Here, we have longitudinally assessed the humoral response to the SARS‐CoV‐2 mRNA vaccine in 40 KTRs over a year, examining changes in both anti‐spike IgG and NAbs following a booster dose administered about 5 months post‐second dose. We found a significant humoral response increase 5 months post‐booster, a stark contrast to the attenuated response observed after the second dose. Of note, nearly a quarter of participants did not achieve protective plasma levels even after the booster dose. We also found that the higher estimated glomerular filtration rate (eGFR) correlated with a more robust humoral response postvaccination. Altogether, these findings underscore the effectiveness of the booster dose in enhancing durable humoral immunity in KTRs, as evidenced by the protective level of NAbs found in 65% of the patients 5 months post‐ booster, especially those with higher eGFR rates.
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