Coronavirus disease 2019 (COVID-19) outbreak has significantly upended solid organ transplant (SOT) practice around the world. Early reports confirmed the heavy burden of COVID-19 in SOT recipients ...with mortality rates reaching up to 35%. Because most transplant recipients harbored multiple comorbidities known to be associated with a severe course of COVID-19, the true impact of immunosuppression by itself remained an unsolved issue. Transplant societies have initially recommended to postpone nonurgent renal transplantations, while trying to maintain life-saving transplant programs, such as heart, lung, and liver transplantations. The pandemic thus resulted in an unprecedented and sudden drop of transplant activity worldwide. Moreover, the best treatment strategy in infected patients was challenging. Both reduction of immunosuppression and use of targeted therapies aiming at counteracting severe acute respiratory syndrome coronavirus 2 infection were the 2 faces of the therapeutic armamentarium. Recent controlled studies have better delineated the basis of mitigating and management strategies to improve patients' outcome. Nevertheless, and given the persistence of circulating virus, evidence-based recommendations in SOT recipients remain unclear. The resumption of transplant activity should be tailored with careful selection of both donors and recipients. Transplant decision should be made on a case-by-case basis after thorough assessment of the risks and benefits.
Atypical hemolytic uremic syndrome (aHUS) is a rare, possibly life-threatening disease characterized by platelet activation, hemolysis and thrombotic microangiopathy (TMA) leading to renal and other ...end-organ damage. We originally conducted two phase 2 studies (26 weeks and 1 year) evaluating eculizumab, a terminal complement inhibitor, in patients with progressing TMA (trial 1) and those with long duration of aHUS and chronic kidney disease (trial 2). The current analysis assessed outcomes after 2 years (median eculizumab exposure 100 and 114 weeks, respectively). At all scheduled time points, eculizumab inhibited terminal complement activity. In trial 1 with 17 patients, the platelet count was significantly improved from baseline, and hematologic normalization was achieved in 13 patients at week 26, and in 15 patients at both 1 and 2 years. The estimated glomerular filtration rate (eGFR) was significantly improved compared with baseline and year 1. In trial 2 with 20 patients, TMA event-free status was achieved by 16 patients at week 26, 17 patients at year 1, and 19 patients at year 2. Criteria for hematologic normalization were met by 18 patients at each time point. Improvement of 15 ml/min per 1.73 m2 or more in eGFR was achieved by 1 patient at week 26, 3 patients at 1 year, and 8 patients at 2 years. The mean change in eGFR was not significant compared with baseline, week 26, or year 1. Eculizumab was well tolerated, with no new safety concerns or meningococcal infections. Thus, a 2-year analysis found that the earlier clinical benefits achieved by eculizumab treatment of aHUS were maintained at 2 years of follow-up.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background Atypical hemolytic uremic syndrome (aHUS) is a rare genetic life-threatening disease of chronic uncontrolled complement activation leading to thrombotic microangiopathy (TMA) and severe ...end-organ damage. Eculizumab, a terminal complement inhibitor approved for aHUS treatment, was reported to improve hematologic and renal parameters in 2 prior prospective phase 2 studies. This is the largest prospective study of eculizumab in aHUS to date, conducted in an adult population. Study Design Open-label single-arm phase 2 trial. Setting & Participants Patients 18 years or older with aHUS (platelet count <150 × 103 /μL, hemoglobin ≤ lower limit of normal, lactate dehydrogenase ≥1.5 × upper limit of normal ULN, and serum creatinine ≥ ULN) were included in this multicenter multinational study. Intervention Intravenous eculizumab (900 mg/wk for 4 weeks, 1,200 mg at week 5 and then every 2 weeks) for 26 weeks. Outcomes & Measurements Primary end point was complete TMA response within 26 weeks, defined as hematologic normalization (platelet count ≥150 × 103 /μL, LDH ≤ ULN), and preservation of kidney function (<25% serum creatinine increase from baseline), confirmed by 2 or more consecutive measurements obtained 4 or more weeks apart. Results 41 patients were treated; 38 (93%) completed 26 weeks of treatment. 30 (73%) were included during their first TMA manifestation. 30 (73%) had complete TMA response. Platelet counts and estimated glomerular filtration rates increased from baseline ( P < 0.001). All 35 patients on baseline plasma exchange/plasma infusion discontinued by week 26. Of 24 patients requiring baseline dialysis, 5 recovered kidney function before eculizumab initiation and 15 of the remaining 19 (79%) discontinued dialysis during eculizumab treatment. No patients lost existing transplants. Quality-of-life measures were significantly improved. Two patients developed meningococcal infections; both recovered, and 1 remained on eculizumab treatment. Limitations Single-arm open-label design. Conclusions Results highlight the benefits of eculizumab in adult patients with aHUS: improvement in hematologic, renal, and quality-of-life parameters; dialysis discontinuation; and transplant protection.
This study shows that the mTORC pathway is central to the antiphospholipid syndrome. Among patients with kidney transplants and antiphospholipid syndrome, 70% of those treated with sirolimus had ...long-term functioning allografts versus 12% of those not treated with sirolimus.
The antiphospholipid syndrome is an autoimmune disease characterized by the presence of circulating antiphospholipid antibodies that result in vascular thrombosis and obstetrical complications.
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The syndrome may be isolated or may occur in association with autoimmune disorders, such as systemic lupus erythematosus. Thrombotic events represent the major complication of the antiphospholipid syndrome,
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and to date, long-term anticoagulation has been the only treatment shown to reduce vascular complications. However, that regimen does not prevent organ deterioration and death in high-risk patients, particularly those in whom catastrophic antiphospholipid syndrome develops.
In addition to the thrombotic complications, vascular cellular infiltrates and fibrosis of the . . .
Antibody-mediated rejection (ABMR) can occur in patients with preexisting anti-HLA donor-specific antibodies (DSA) or in patients who develop
DSA. However, how these processes compare in terms of ...allograft injury and outcome has not been addressed. From a cohort of 771 kidney biopsy specimens from two North American and five European centers, we performed a systematic assessment of clinical and biologic parameters, histopathology, circulating DSA, and allograft gene expression for all patients with ABMR (
=205). Overall, 103 (50%) patients had preexisting DSA and 102 (50%) had
DSA. Compared with patients with preexisting DSA ABMR, patients with
DSA ABMR displayed increased proteinuria, more transplant glomerulopathy lesions, and lower glomerulitis, but similar levels of peritubular capillaritis and C4d deposition.
DSA ABMR was characterized by increased expression of IFN
-inducible, natural killer cell, and T cell transcripts, but less expression of AKI transcripts compared with preexisting DSA ABMR. The preexisting DSA ABMR had superior graft survival compared with the
DSA ABMR (63% versus 34% at 8 years after rejection, respectively;
<0.001). After adjusting for clinical, histologic, and immunologic characteristics and treatment, we identified
DSA ABMR (hazard ratio HR, 1.82 compared with preexisting DSA ABMR; 95% confidence interval 95% CI, 1.07 to 3.08;
=0.03); low eGFR (<30 ml/min per 1.73 m
) at diagnosis (HR, 3.27; 95% CI, 1.48 to 7.23;
<0.001); ≥0.30 g/g urine protein-to-creatinine ratio (HR, 2.44; 95% CI, 1.47 to 4.09;
<0.001); and presence of cg lesions (HR, 2.25; 95% CI, 1.34 to 3.79;
=0.002) as the main independent determinants of allograft loss. Our findings support the transplant of kidneys into highly sensitized patients and should encourage efforts to monitor patients for
DSA.
Antibodies may have different pathogenicities according to IgG subclass. We investigated the association between IgG subclasses of circulating anti-human HLA antibodies and antibody-mediated kidney ...allograft injury. Among 635 consecutive kidney transplantations performed between 2008 and 2010, we enrolled 125 patients with donor-specific anti-human HLA antibodies (DSA) detected in the first year post-transplant. We assessed DSA characteristics, including specificity, HLA class specificity, mean fluorescence intensity (MFI), C1q-binding, and IgG subclass, and graft injury phenotype at the time of sera evaluation. Overall, 51 (40.8%) patients had acute antibody-mediated rejection (aABMR), 36 (28.8%) patients had subclinical ABMR (sABMR), and 38 (30.4%) patients were ABMR-free. The MFI of the immunodominant DSA (iDSA, the DSA with the highest MFI level) was 6724±464, and 41.6% of patients had iDSA showing C1q positivity. The distribution of iDSA IgG1-4 subclasses among the population was 75.2%, 44.0%, 28.0%, and 26.4%, respectively. An unsupervised principal component analysis integrating iDSA IgG subclasses revealed aABMR was mainly driven by IgG3 iDSA, whereas sABMR was driven by IgG4 iDSA. IgG3 iDSA was associated with a shorter time to rejection (P<0.001), increased microcirculation injury (P=0.002), and C4d capillary deposition (P<0.001). IgG4 iDSA was associated with later allograft injury with increased allograft glomerulopathy and interstitial fibrosis/tubular atrophy lesions (P<0.001 for all comparisons). Integrating iDSA HLA class specificity, MFI level, C1q-binding status, and IgG subclasses in a Cox survival model revealed IgG3 iDSA and C1q-binding iDSA were strongly and independently associated with allograft failure. These results suggest IgG iDSA subclasses identify distinct phenotypes of kidney allograft antibody-mediated injury.
Adrenocortical carcinomas (ACC) are a rare tumor type with a poor five-year survival rate and limited treatment options.
Understanding of the molecular pathogenesis of this disease has been aided by ...genomic analyses highlighting alterations in TP53, WNT, and IGF signaling pathways. Further elucidation is needed to reveal therapeutically actionable targets in ACC.
In this study, global DNA methylation levels were assessed by the Infinium HumanMethylation450 BeadChip Array on 18 ACC tumors and 6 normal adrenal tissues. A new, non-linear correlation approach, the discretization method, assessed the relationship between DNA methylation/gene expression across ACC tumors.
This correlation analysis revealed epigenetic regulation of genes known to modulate TP53, WNT, and IGF signaling, as well as silencing of the tumor suppressor MARCKS, previously unreported in ACC.
DNA methylation may regulate genes known to play a role in ACC pathogenesis as well as known tumor suppressors.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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•Chronic HBV infection no longer influences 10-year patient or graft survival in kidney transplant recipients.•Chronic HCV infection still negatively impacts 10-year patient and graft ...survival.•The negative effect of chronic HCV infection is removed by sustained viral suppression.•Antiviral therapy should be systematically proposed for HBV- and/or HCV-infected kidney transplant recipients/candidates.
Before antiviral therapy, kidney transplant recipients infected with hepatitis B virus (HBV) or hepatitis C virus (HCV) had poor outcomes. Since the 90s, nucleos(t)ide analogues have been widely used in HBV-infected patients, while interferon-based therapy was rarely used in HCV-infected patients. The aim of this study was to assess the impact of HBV and HCV on patient and graft survival, according to viral replication status.
Data from January 1993 to December 2010 were extracted from the French national database CRISTAL. A total of 31,433 kidney transplant recipients were included, of whom 575, 1,060 and 29,798 had chronic hepatitis B, C, or were not infected, respectively.
Ten-year survival was lower in HCV-infected (71.3%) than in HBV-infected (81.2%, p = 0.0004) or non-infected kidney transplant recipients (82.7%, p <0.0001). Ten-year kidney graft survival was lower in HCV-infected (50.6%) than in HBV-infected (62.3%, p <0.0001) or non-infected kidney transplant recipients (64.7%, p <0.0001). A random analysis of the medical records of 184 patients with HBV and 504 patients with HCV showed a control of viral replication in 94% and 35% of cases, respectively. Ten-year patient and graft survival in patients with detectable HCV RNA was lower than in their matching controls. Conversely, patients with HCV and undetectable HCV RNA had higher 10-year survival than their matched controls without significant differences in graft survival.
Chronic HBV infection does not impact 10-year patient and kidney graft survival thanks to control of viral replication with nucleos(t)ide analogues. In kidney transplant recipients infected with HCV, patients with detectable RNA had worse outcomes, whereas the outcomes of those with undetectable RNA were at least as good as non-infected patients. Thus, direct-acting antivirals should be systematically offered to HCV-infected patients.
Previously, infections with hepatitis B or hepatitis C virus led to poor outcomes in kidney transplant recipients. However, the outcomes of kidney transplants in patients with viral suppression are as good as those for kidney transplants in non-infected patients. Antiviral therapy should be systematically proposed to hepatitis B and/or hepatitis C-infected kidney transplant recipients or candidates to prevent the deleterious hepatic and extrahepatic impact of chronic viral replication. Recent access to direct-acting antivirals in patients with hepatitis C virus and renal dysfunction provides exciting new opportunities.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Mitochondrial DNA (mtDNA) mutations and polymorphisms contribute to many complex diseases, including cancer. Using a unique mouse model that contains nDNA from one mouse strain and homoplasmic ...mitochondrial haplotypes from different mouse strain(s)-designated Mitochondrial Nuclear Exchange (MNX)-we showed that mtDNA could alter mammary tumor metastasis. Because retrograde and anterograde communication exists between the nuclear and mitochondrial genomes, we hypothesized that there are differential mtDNA-driven changes in nuclear (n)DNA expression and DNA methylation. Genome-wide nDNA methylation and gene expression were measured in harvested brain tissue from paired wild-type and MNX mice. Selective differential DNA methylation and gene expression were observed between strains having identical nDNA, but different mtDNA. These observations provide insights into how mtDNA could be altering epigenetic regulation and thereby contribute to the pathogenesis of metastasis.
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