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Kidney transplant recipients require a lifelong protocol of immunosuppressive therapy to prevent graft rejection. However, these same medications leave them susceptible to opportunistic infections. One pathogen of particular concern is human polyomavirus 1, also known as BK virus (BKPyV). This virus attacks kidney tubule epithelial cells and is a direct threat to the health of the graft. Current standard of care in BK virus-infected transplant recipients is reduction in immunosuppressant therapy, to allow the patient's immune system to control the virus. This requires a delicate balance; immune suppression must be strong enough to prevent rejection, yet weak enough to allow viral clearance. We seek to model viral and immune dynamics with the ultimate goal of applying optimal control methods to this problem. In this paper, we begin with a previously published model and make simplifying assumptions that reduce the number of parameters from 20 to 14. We calibrate our model using newly available patient data and a detailed sensitivity analysis. Numerical results for multiple patients are given to show that the newer model reflects observed dynamics well. [ABSTRACT FROM AUTHOR]

Chronic kidney disease is a really important heath issue, and transplantation is an intervention that can greatly increase patient quality of life and survival. The aim of this study was to perform a comprehensive evaluation of the BK virus, CMV, and EBV in kidney transplant recipients (KTRs); to assess the prevalence of infections; and to test if our detection method would be feasible for use in follow-ups with KTRs. A total of 157 KTRs registered at the Clinical Hospital "Dr. C. I. Parhon", Iași, Romania, were selected using specific inclusion/exclusion criteria. We tested the blood samples from each patient for BK, EBV, and CMV using a multiplex real-time PCR (qPCR) assay and the TaqMan PCR principle. The highest prevalence was detected for BKV (11/157, 7%), followed by CMV (9/157, 5.7%) and EBV (5/157, 3.2%). By simultaneously detecting three possible nephropathic viruses and oncogenes in KTRs using multiplex real-time PCR, we aimed to optimize their monitoring and follow-up. The prevalence of the tested nephropathogenic viruses—BKV, CMV, and EBV—was comparable to that analyzed in other studies. We demonstrate that the use of qPCR for viral detection in KTRs is a robust, cost-effective method for case monitoring. [ABSTRACT FROM AUTHOR]

BK viremia (BKPyV-DNAemia) and nephropathy (BKPyVAN) are significant causes of morbidity and mortality in kidney transplant recipients (KTRs). Vitamin D supports immune function, yet low 25-hydroxyvitamin D [25(OH)D] is common among KTRs. The association between serum 25(OH)D, measured 61 days to 2 years post-transplant, and subsequent incident BKPyV-DNAemia and BKPyVAN was examined in KTRs without previous BKPyV-DNAemia or BKPyVAN, respectively. Out of 3308 KTRs, 399 (12%) were vitamin D deficient [25(OH)D ≤ 20 ng/mL], and 916 (27.7%) were insufficient [25(OH)D 21–29 ng/mL]. A total of 184 KTRs developed BKPyV-DNAemia and 44 developed BKPyVAN. The incidence rate (/100 person-years) for BKPyV-DNAemia was 2.88 in the 25(OH)D sufficient group, 2.22 in the insufficient group, and 2.37 in the deficient group. The incidence rate (/100 person-years) for BKPyVAN was 0.30 in the 25(OH)D sufficient group, 0.75 in the insufficient group, and 1.28 in the deficient group. Vitamin D deficiency (adjusted hazard ratio [aHR] compared to 25(OH)D sufficiency: 3.92; 95% CI: 1.66–9.23) and insufficiency (aHR: 2.22; 95% CI: 1.11–4.45) remained significantly associated with the incidence of BKPyVAN after adjustment for baseline characteristics. Low serum 25(OH)D was associated with an increased risk of BKPyVAN but not BKPyV-DNAemia. [ABSTRACT FROM AUTHOR]

Background/Objectives: With kidney transplant immunosuppression, physicians must balance preventing rejection with minimizing infection and malignancy risks. Steroids have been a mainstay of these immunosuppression regimens since the early days of kidney transplantation, yet their risks remain debated. Our study looks at the clinical outcomes of patients undergoing early steroid withdrawal (ESW) vs. steroid continuous (SCI) maintenance immunosuppression in adult kidney transplant recipients. Methods: A retrospective case-control study, utilizing propensity score-matching, was performed using the US Collaborative Network Database within TriNetX to evaluate renal transplant outcomes at one year in first-time kidney transplant adult patients (>18 years old) who were prescribed an ESW regimen (no steroids after post-transplant day 7 with maintenance tacrolimus [tac] + mycophenolic acid [MMP]/mycophenolate mofetil [MMF]) vs. SCI (tac + MMF/MMP + prednisone). Cohorts were matched on demographics, comorbidities, previously described risk factors for rejection, and induction immunosuppression. Primary outcomes included viral infections, pyelonephritis, and sepsis. Secondary outcomes included renal transplant rejection, death-censored allograft failure (eGFR < 15 mL/min), patient mortality, delayed graft function, and diabetes mellitus. Results: A total of 2056 patients were in each cohort after matching (mean age: 50.7–51 years, 17.9–20.0% African American, 60–60.6% male.) The SCI cohort had a significantly higher cumulative incidence of composite viremia (18 vs. 28.1%, ESW vs. SCI, p < 0.01) driven by CMV, EBV, and BK virus. Post-transplant diabetes mellitus was significantly higher in the SCI cohort (3.21% vs. 5.49%, ESW vs. SCI, p < 0.01). Delayed graft function was also higher in the SCI cohort (19.55% vs. 22.79%, ESW vs. SCI, p < 0.01). Pyelonephritis (2.3 vs. 4.91%, ESW vs. SCI, p < 0.01) and sepsis (2.15 vs. 5.95%, ESW vs. SCI, p < 0.01) were higher in the SCI cohort. Rejection rates were similar between ESW and SCI (29 vs. 31%, ESW vs. SCI, p = 0.41). There were significantly higher incidences of graft failure (4.9 vs. 9.9%, ESW vs. SCI, p < 0.01) and mortality (0.8 vs. 2.1%, ESW vs. SCI, p < 0.01) in the SCI cohort. Conclusions: This well-matched case-control study suggests that ESW is associated with lower infectious outcomes, mortality, and graft failure without increasing rejection risk, supporting the potential benefits of ESW in kidney transplant patients. [ABSTRACT FROM AUTHOR]

Despite the high prevalence of BK polyomavirus (BKPyV) and the associated risk for BKPyV-associated nephropathy (BKPyVAN) in kidney transplant (KTX) recipients, many details on viral processes such as replication, maturation, assembly and virion release from host cells have not been fully elucidated. VP1 is a polyomavirus-specific protein that is expressed in the late phase of its replicative cycle with important functions in virion assembly and infectious particle release. This study investigated the localization and time-dependent changes in the distribution of VP1-positive viral particles and their association within the spectrum of differing cell morphologies that are observed in the urine of KTX patients upon active BKPyV infection. We found highly differing recognition patterns of two anti-VP1 antibodies with respect to intracellular and extracellular VP1 localization, pointing towards independent binding sites that were seemingly associated with differing stages of virion maturation. Cells originating from single clones were stably cultured out of the urine sediment of KTX recipients with suspected BKPyVAN. The cell morphology, polyploidy, virus replication and protein production were investigated by confocal microscopy using both a monoclonal (mAb 4942) and a polyclonal rabbit anti-VP1-specific antibody (RantiVP1 Ab). Immunoblotting was performed to investigate changes in the VP1 protein. Both antibodies visualized VP1 and the mAb 4942 recognized VP1 in cytoplasmic vesicles exhibiting idiomorphic sizes when released from the cells. In contrast, the polyclonal antibody detected VP1 within the nucleus and in cytoplasm in colocalization with the endoplasmic reticulum marker CNX. At the nuclear rim, VP1 was recognized by both antibodies. Immunoblotting revealed two smaller versions of VP1 in urinary decoy cell extracts, potentially from different translation start sites as evaluated by in silico analysis. Oxford Nanopore sequencing showed integration of BKPyV DNA in chromosomes 3, 4 and 7 in one of the five tested primary cell lines which produced high viral copies throughout four passages before transcending into senescence. The different staining with two VP1-specific antibodies emphasizes the modification of VP1 during the process of virus maturation and cellular exit. The integration of BKPyV into the human genome leads to high virus production; however, this alone does not transform the cell line into a permanently cycling and indefinitely replicating one. [ABSTRACT FROM AUTHOR]

Since the significance of viral infections in children and adolescents with nephrotic syndrome (NS) is yet to be defined, this study intended to estimate the occurrence, pattern, and outcomes of some DNA viral infections in children with NS. Methods: A prospective study was conducted to determine the genome identification of the viruses Epstein-Barr (EBV), human cytomegalovirus (HCMV), human herpesvirus 6 (HHV-6 type A and type B) and 7 (HHV-7), polyomavirus (BKV), and human adenovirus (HAdV) in plasma and urine samples of pediatric patients with NS. Results: A total of 35 patients aged 1 to 18 years with NS and under immunosuppressant drugs participated in the study. Plasma and urine samples were collected at regular intervals during a median follow-up of 266 days (range 133–595), and DNA was analyzed to detect the selected DNA viruses. Eleven patients (31.4%) had active virus infections, and patterns were classified as coinfection, recurrent, and consecutive. Of these, six patients (54.5%) presented viral coinfection, six (54.5%) viral recurrence, and seven patients (63.3%) had viral consecutive infection. Ten of the eleven patients with active infection had a proteinuria relapse (91%) and eight (72.7%) were hospitalized (p = 0.0022). Active HCMV infection was the most frequent infection and was observed in six patients (54.5%), three of the eleven patients (27.2%) had suspected HCMV disease in the gastrointestinal tract, and one had HHV-7 coinfection. The frequency of other infections was: 9% for HHV-6, 45.5% for BKV, 27.3% for HHV-7, 18.2% for EBV, and 18.2% for HAdV. Conclusion: viral infections, especially HCMV, can be an important cause of morbidity and nephrotic syndrome relapse in children. [ABSTRACT FROM AUTHOR]

Background/Objectives: The novel coronavirus disease 2019 (COVID-19) has led to significant morbidity and mortality among kidney transplant recipients. SARS-CoV-2 has been hypothesized to cause an unusual immunological dysregulation triggering alloimmunity and leading to graft rejection. Methods: This prospective observational cohort study assessed 321 kidney transplant recipients who had COVID-19 infection. After the infection, patients' sera were tested for the presence of anti-HLA de novo DSA and non-DSA specificities. Logistic regression analysis and a stepwise multivariable logistic regression analysis were used to analyze the independent risk factors associated with the development of antibodies, adjusting for known confounders. The variables evaluated were acute COVID-19 characteristics (i.e., presentation, and need for hospitalization), demographic characteristics (i.e., age, gender, and primary renal disease), clinical characteristics (i.e., various comorbidities), and post-COVID-19 sequelae. Results: Anti-HLA de novo DSA developed in 18.7% of patients, while anti-HLA class I and class II non-DSA antibodies developed de novo in 84 (26.3%) and 83 (25.9%) patients, respectively. The development of DSA, HLA-DQ, and HLA-DR antibodies was predicted by the history of graft rejection. Obesity appeared to be protective against the emergence of de novo DSA. De novo DSA and HLA-DR antibody formation was positively linked with intravenous immunoglobulin use, CMV-hyperimmune globulin use, and decreased doses of immunosuppression during acute infection. Better allograft function during the acute disease was a protective factor against the formation of HLA-DQ and HLA-DR antibodies. Positive predictors of de novo DSA development were graft biopsy and the reactivation of EBV after infection. Conclusions: These findings suggest that the SARS-CoV-2 virus has an immunomodulatory effect and may be associated with an increased mortality in this population. [ABSTRACT FROM AUTHOR]

The John Cunningham virus (JCV) is a polyomavirus that usually infects people at a young age and does not cause any symptoms in immunocompetent individuals. However, in immunocompromised individuals, such as kidney transplant recipients, JCV can cause severe and potentially fatal disease. Unfortunately, JCV has not been researched as extensively as the BK virus and is not mentioned in relevant kidney transplant guidelines. This lack of attention to JCV can lead to less consideration in kidney transplant patients' care. Surveillance using locally available diagnostic methods is of the utmost importance. The presence of JCV can be diagnosed with urine decoy cells, viruria, or viremia verified by the PCR method. A low threshold for considering JCV as a possible cause of any neurological or renal dysfunction in kidney transplant recipients must be maintained. In such cases, kidney and brain biopsy are indicated. Maintaining the appropriate immunosuppression while avoiding over-immunosuppression to prevent JCV disease is crucial, and the approach should be individual, according to overall immunological risk. We hypothesize that the presence of the JCV can indicate overt immunosuppression and identify kidney transplant recipients more prone to opportunistic infections and diseases, including some malignancies. To explore that, future observational studies are needed. [ABSTRACT FROM AUTHOR]

Background/Objectives: In the absence of an effective antiviral treatment for BK polyomavirus (BKPyV), a better understanding of the epidemiology and time course of BKPyV replication after kidney transplantation is needed to limit the virus's impact on the graft outcome. Methods: In a 7-year study, we screened more than 430 kidney transplant recipients and analyzed the time course and virological characteristics of BKPyV replication. Results: Urinary viral replication was observed in 116 (27%) of the 430 patients, and 90 of the 116 (78%) had viral DNAemia. Thirty-eight patients (8.8%) were presumed to have nephropathy (DNAemia > 4 log10 copies/mL). Of the patients with BKPyV replication, 48%, 60%, 71%, and 80% were first found to be positive one, two, three, and four months post-transplantation. The initial viral load in the urine was below 7 log10 copies/mL in 100% of the patients with viral replication first detected before the first month, and this proportion was 57% when viral replication was first detected after the first month. When the BKPyV replication was first detected in a urine sample at month 3 or later, 81.5% of patients had concomitant BKPyV DNAemia. The predominant viral subtype was Ib2 (60%), and there was no apparent relationship between the subtype and the time course of BKPyV replication. Conclusions: Urinary BKPyV replication occurs early after renal transplantation and in most patients will increase to a level requiring therapeutic intervention. Close monitoring for BKPyV in the early post-transplantation period would enable the pre-emptive adjustment of the immunosuppression regimen. [ABSTRACT FROM AUTHOR]

Our previous study showed that the Epstein–Barr virus (EBV) may be the etiology for some patients with interstitial cystitis/bladder pain syndrome (IC/BPS); hence, the current study aimed to investigate the urinary viral spectrum in patients with IC/BPS and the clinical efficacy of valacyclovir. Twenty-eight patients were prospectively enrolled for valacyclovir 500 mg twice a day for 4 weeks. Urine samples were collected from IC/BPS patients and 30 controls. The primary outcome was the difference in the visual analog scale (VAS) pain score, and secondary outcomes included changes in the urinary viral spectrum and urinary inflammatory cytokine level (ClinicalTrials.gov Identifier: NCT05094414). Urinary EBV was detected in 14.2% IC/BPS patients but not in the controls. Urinary John Cunningham virus and BK virus were detected in 18 (64.3%) and 2 (7.1%) patients with IC/BPS, respectively, with similar prevalences noted for the controls. No cytomegalovirus, varicella-zoster virus, or herpes simplex virus was detected in the urine samples. The VAS pain score in patients with IC/BPS significantly decreased after 4 weeks (from 7.5 [5.52–9.0] to 5 [1.5–6.0], p = 0.0003). Urinary EBV was undetectable in any sample after valacyclovir treatment, and the decreases in urinary interleukin (IL)-1β (from 0.66 [0.55–0.82] pg/mL to 0.58 [0.55–0.64] pg/mL, p = 0.0034), IL-8 (from 6.81 [2.38 to 29.1] pg/mL to 4.33 [1.53–11.04] pg/mL, p = 0.0361), IL-10 (from 1.06 [0.94–1.18] pg/mL to 0.92 [0.88–1.02], p = 0.0086), and tumor necrosis factor-α (from 1.61 [1.50–1.72] pg/mL to 1.50 [1.44–1.55] pg/mL, p = 0.0079) were significant. Valacyclovir could relieve bladder pain, eliminate urinary EBV, and reduce bladder inflammation. [ABSTRACT FROM AUTHOR]

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system (CNS) caused by reactivation of dormant JC polyomavirus (JCPyV). PML was mainly observed in immunocompromised individuals, such as HIV-positive patients, autoimmune disease patients, and cancer patients. Given that the presence of anti-JCPyV antibodies in serum is a risk indicator for PML development, it is essential to monitor anti-JCPyV antibody levels. In the present study, we established reporter-based single-infection neutralization assays for JCPyV and the genetically similar BK polyoma virus (BKPyV). We then confirmed the lack of cross-reactivity between the two viruses using test sera obtained from mice immunized with plasmids encoding the JCPyV or BKPyV capsid. Next, we compared neutralization antibody titers in sera from healthy donors, patients with multiple sclerosis (MS), and HIV-positive patients using an in-house enzyme-linked immunosorbent assay (ELISA) with JCPyV-like particles (virus-like particles; VLPs). A positive correlation was demonstrated between the neutralization titer (75% infectious concentration; IC75) against JCPyV and the antibody titer obtained by VLP-based JCPyV ELISA. This assay system may be applied to detect antibodies against other PyVs by generation of pseudoviruses using the respective capsid expression plasmids, and is expected to contribute to the surveillance of PyV as well as basic research on these viruses. [ABSTRACT FROM AUTHOR]

Background and Objectives: Kidney transplant recipients are at risk of developing more severe forms of COVID-19 infection. The aim of this study was to compare the clinical course of COVID-19 infection among kidney transplant patients and a control group. Materials and Methods: We examined 150 patients hospitalized with COVID-19 infection. Patients were divided into study (kidney transplant recipients, n = 53) and control (without a history of kidney transplantation, n = 97) groups. Demographics, clinical characteristics, treatment data, and clinical outcomes were assessed. Results: The median patient age was 56.0 (46.0–64.0) years, and seventy-seven patients (51.3%) were men. The median Charlson comorbidity index was higher in the study group (3.0 vs. 2.0, p < 0.001). There was a higher incidence of hypoxemia in the control group upon arrival (52.6% vs. 22.6%, p = 0.001) and a higher NEWS index median (2.0 vs. 1.0 points, p = 0.009) and incidence of pneumonia during hospitalization (88.7% vs. 73.6%, p = 0.023). In the study group, there were more cases of mild (26.4% vs. 11.3%, p = 0.023) and critically severe forms of COVID-19 infection (26.4% vs. 3.1%, p < 0.001), kidney failure was more prevalent (34.0% vs. 1.0%, p < 0.001), and a greater number of patients were transferred to the intensive care unit (22.6% vs. 3.1%, p < 0.001) and died (18.9% vs. 1.0%, p < 0.001). Multivariable analysis revealed that treatment in the intensive care unit correlated with a higher mortality rate than transplantation itself (HR = 20.71, 95% CI 2.01–213.33, p = 0.011). Conclusions: The course of the COVID-19 disease in kidney transplant recipients is heterogeneous and can be more severe than in the general population. Even though patients may be hospitalized with fewer symptoms, complications and death are more likely to occur. [ABSTRACT FROM AUTHOR]

Background: Delayed graft function (DGF) is common after kidney transplantation from deceased donors and may significantly affect post-transplant outcomes. This study aimed to evaluate whether an innovative approach, based on the administration of the intravenous prostaglandin analogue iloprost, could be beneficial in reducing the incidence of DGF occurring after kidney transplantation from deceased donors. Methods: This prospective, randomized (1:1), placebo-controlled study enrolled all consecutive patients who received a kidney transplant from a deceased donor from January 2000 to December 2012 and who were treated in the peri-transplant period with the prostaglandin analogue iloprost at 0.27 μg/min through an elastomeric pump (treatment group) or with a placebo (control group). Results: A total of 476 patients were included: DGF was reported in 172 (36.1%) patients in the entire cohort. The multivariate analysis showed that the donor's age > 70 years (OR 2.50, 95% confidence interval (CI): 1.40–3.05, p < 0.001), cold ischemia time > 24 h (OR 2.60, 95% CI: 1.50–4.51, p < 0.001), the donor's acute kidney injury (OR 2.71, 95% CI: 1.61–4.52, p = 0.021) and, above all, the recipient's arterial hypotension (OR 5.06, 95% CI: 2.52–10.1, p < 0.0001) were the strongest risk factors for developing post-transplant DGF. The incidence of DGF was 21.4% in the treatment group and 50.9% in the control group (p < 0.001). Interestingly, among patients who developed DGF, those who received iloprost had a shorter duration of post-transplant DGF (10.5 ± 8.3 vs. 13.4 ± 6.7, days, p = 0.016). Conclusions: This study showed that the use of a continuous infusion of iloprost could safely and effectively reduce the incidence of DGF in recipients of deceased-donor kidneys, allowing a better graft functionality as well as a better graft survival. [ABSTRACT FROM AUTHOR]

We evaluated the diagnostic performance of the STANDARD i-Q COVID-19 Ag Test, which was developed to detect viral antigens, using nasal and oral swabs. Sixty positive and 100 negative samples were analyzed. We determined the distribution of the Ct values according to the day of sample collection after symptom onset, the diagnostic performance of the total samples and subgroups separated by Ct value or time of sample collection, and the Ct value at which maximal accuracy was expected. No differences were observed in Ct values, except for the samples obtained on the day of symptom onset. The diagnostic sensitivity and specificity of the oral swabs were 75.0 and 100.0%, respectively, whereas those of the nasal swabs were 85.0 and 98.0%, respectively. The sensitivity was higher in samples with a high viral load collected earlier than those collected later, although the difference was not significant. False-negative results were confirmed in all samples with a Ct value ≥ 30.0. These results indicate that tests using oral and nasal swabs are helpful for diagnosing acute symptomatic cases with suspected high viral loads. Our tests exhibited relatively low sensitivity but high specificity rates, indicating the need to assess negative antigen test results. [ABSTRACT FROM AUTHOR]

Anti-rejection medications are essential in preventing organ rejection amongst solid organ transplant recipients; however, these agents also cause profound immunosuppression, predisposing lung transplant recipients (LTRs) to infectious complications. The timely management including prevention, diagnosis, and treatment of such infectious complications is vital to prevent significant morbidity and mortality in solid organ transplant recipients and allograft dysfunction. LTRs are inundated with microbes that may be recognized as commensals in hosts with intact immune systems. Bacterial infections are the most common ones, followed by viral pathogens. Indications of a brewing infectious process may be subtle. Hence, the importance of adapting vigilance around isolated hints through symptomatology and signs is pivotal. Signals to suggest an infectious process, such as fever and leukocytosis, may be dampened by immunosuppressive agents. One must also be vigilant about drug interactions of antibiotics and immunosuppressive agents. Treatment of infections can become challenging, as antimicrobials can interact with immunosuppressive agents, and antimicrobial resistance can surge under antimicrobial pressure. Transplant infectious disease physicians work in concert with transplant teams to obtain specimens for diagnostic testing and follow through with source control when possible. This heavily impacts medical decisions and fosters a multidisciplinary approach in management. Furthermore, the reduction of immunosuppression, although it augments the risk of allograft rejection, is as crucial as the initiation of appropriate antimicrobials when it comes to the management of infections. [ABSTRACT FROM AUTHOR]

Polyomaviruses are widespread, with BK viruses being most common in humans who require immunosuppression due to allotransplantation. Infection with BK polyomavirus (BKV) may manifest as BK virus-associated nephropathy and hemorrhagic cystitis. Established diagnostic methods include the detection of polyomavirus in urine and blood by PCR and in tissue biopsies via immunohistochemistry. In this study, 79 patients with pathological renal retention parameters and acute kidney injury (AKI) were screened for BK polyomavirus replication by RNA extraction, reverse transcription, and virus-specific qPCR in urine sediment cells. A short fragment of the VP2 coding region was the target of qPCR amplification; patients with (n = 31) and without (n = 48) a history of renal transplantation were included. Urine sediment cell immunofluorescence staining for VP1 BK polyomavirus protein was performed using confocal microscopy. In 22 patients with acute renal injury, urinary sediment cells from 11 participants with kidney transplantation (KTX) and from 11 non-kidney transplanted patients (nonKTX) were positive for BK virus replication. BK virus copies were found more frequently in patients with AKI stage III (n = 14). Higher copy numbers were detected in KTX patients having experienced BK polyoma-nephropathy (BKPyVAN) in the past or diagnosed recently by histology (5.6 × 109–3.1 × 1010). One patient developed BK viremia following delayed graft function (DGF) with BK virus-positive urine sediment. In nonKTX patients with BK copies, decoy cells were absent; however, positive staining of cells was found with epithelial morphology. Decoy cells were only found in KTX patients with BKPyVAN. In AKI, damage to the tubular epithelium itself may render the epithelial cells more permissive for polyoma replication. This non-invasive diagnostic approach to assess BK polyomavirus replication in urine sediment cells has the potential to identify KTX patients at risk for viremia and BKPyVAN during AKI. This method might serve as a valuable screening tool for close monitoring and tailored immunosuppression decisions. [ABSTRACT FROM AUTHOR]

Introduction: Kidney transplantation stands out as the optimal treatment for patients with end-stage kidney disease, provided they meet specific criteria for a secure outcome. With the exception of identical twin donor–recipient pairs, lifelong immunosuppression becomes imperative. Unfortunately, immunosuppressant drugs, particularly calcineurin inhibitors like tacrolimus, bring about adverse effects, including nephrotoxicity, diabetes mellitus, hypertension, infections, malignancy, leukopenia, anemia, thrombocytopenia, mouth ulcers, dyslipidemia, and wound complications. Since achieving tolerance is not feasible, patients are compelled to adhere to lifelong immunosuppressive therapies, often involving calcineurin inhibitors, alongside mycophenolic acid or mTOR inhibitors, with or without steroids. Area covered: Notably, these drugs, especially calcineurin inhibitors, possess narrow therapeutic windows, resulting in numerous drug-related side effects. This review focuses on the prevalent immunosuppressive drug-related side effects encountered in kidney transplant recipients, namely nephrotoxicity, post-transplant diabetes mellitus, leukopenia, anemia, dyslipidemia, mouth ulcers, hypertension, and viral reactivations (cytomegalovirus and BK virus). Additionally, other post-kidney-transplantation drugs such as valganciclovir may also contribute to adverse events such as leukopenia. For each side effect, we propose preventive measures and outline appropriate treatment strategies. [ABSTRACT FROM AUTHOR]

Surveillance of the renal allograft recipient is essential when monitoring renal function to detect the early onset of rejection and alter therapeutic treatments to treat acute rejection or other causes and improve long-term graft function. If renal function begins to deteriorate, a renal biopsy is often indicated to assess the Banff grade of potential rejection or other causes, especially in the setting of polyoma BK viral load elevation. Although BK infection in the allograft is asymptomatic, reactivation of the virus is known to be associated with the acceleration of pathologic change and a poor outcome in the allograft. BK reactivation in a transplant kidney is not uncommon, and determining inflammation related to the virus versus acute rejection is paramount for appropriate immunosuppressive therapy management. We identified a concomitant polyoma BK virus and West Nile Virus (WNV) infection in two renal transplant patients which, to our knowledge, has not previously been reported. However, other concomitant infections have been reported in renal allografts including BK virus and cytomegalovirus (CMV), CMV and hepatitis C (HCV), and HCV and human immunodeficiency virus (HIV). As WNV has become endemic in many regions of the United States, and since the transmission of the virus via transplanted organs is associated with significant morbidity and mortality, it may be prudent to consider serologic screening for WNV in living donors prior to organ procurement. Regardless, the observation we made and report here should underscore the potential for concomitant viral infections that may be masked when a renal allograft has a significant inflammatory response to BK virus. [ABSTRACT FROM AUTHOR]

Belatacept, a CTLA4-Ig, was designed to prevent rejection and graft loss in kidney transplant recipients. This immunotherapy showed a long-term clinical benefit mainly on renal function and better glycemic control but was also associated with a higher number of severe infectious diseases, particularly CMV disease, and lymphoproliferative disease. Therapeutic drug monitoring usually guides the benefit–risk assessment of long-term immunosuppression. In this study, an analytical method by LC-MS/MS was developed in 20 microL of plasma for the belatacept quantification. Intra- and inter-assay precision and accuracy were lower than 20% for the limit of quantification, and 15% for higher concentrations. The method was implemented in our lab and provided data about the inter-variability (N = 108) and intra-variability (N = 33) of belatacept concentrations in kidney transplant recipients with a stable renal function, after conversion from a CNI- to a belatacept-based regimen. [ABSTRACT FROM AUTHOR]

Kidney transplantation is the preferred therapeutic option for end-stage renal disease; however, the alloimmune response is still the leading cause of renal allograft failure. To better identify immunologic disparities in order to evaluate HLA compatibility between the donor and the recipient, the concept of eplet load has arisen. Regular kidney function monitoring is essential for the accurate and timely diagnosis of allograft rejection and the appropriate treatment. Donor-derived cell-free DNA (dd-cfDNA) has been proposed as a potential biomarker of acute rejection and graft failure in kidney transplantation. The proportion of plasma dd-cfDNA was determined in forty-two kidney patients at 1 month after transplantation. A total of eleven (26.2%) patients had a dd-cfDNA proportion of ≥1.0%. The only pretransplant variable related to dd-cfDNA > 1.0% was the HLA class II eplet mismatch load, mainly the HLA-DQB1 eplet mismatch load. Furthermore, dd-cfDNA was able to discriminate the patients with antibody-mediated rejection (AbMR) (AUC 87.3%), acute rejection (AUC 78.2%), and troubled graft (AUC 81.4%). Increased dd-cfDNA levels were associated with kidney allograft deterioration, particularly rejection, as well as a greater HLA class II eplet mismatch load. Consequently, combining dd-cfDNA determination and HLA eplet mismatch load calculation should improve the assessment of the risk of short- and long-term allograft damage. [ABSTRACT FROM AUTHOR]

With increasing knowledge of immunologic factors and with the advent of potent immunosuppressive agents, the last several decades have seen significantly improved kidney allograft survival. However, despite overall improved short to medium-term allograft survival, long-term allograft outcomes remain unsatisfactory. A large body of literature implicates acute and chronic rejection as independent risk factors for graft loss. In this article, we review measures taken at various stages in the kidney transplant process to minimize the risk of rejection. In the pre-transplant phase, it is imperative to minimize the risk of sensitization, aim for better HLA matching including eplet matching and use desensitization in carefully selected high-risk patients. The peri-transplant phase involves strategies to minimize cold ischemia times, individualize induction immunosuppression and make all efforts for better HLA matching. In the post-transplant phase, the focus should move towards individualizing maintenance immunosuppression and using innovative strategies to increase compliance. Acute rejection episodes are risk factors for significant graft injury and development of chronic rejection thus one should strive for early detection and aggressive treatment. Monitoring for DSA development, especially in high-risk populations, should be made part of transplant follow-up protocols. A host of new biomarkers are now commercially available, and these should be used for early detection of rejection, immunosuppression modulation, prevention of unnecessary biopsies and monitoring response to rejection treatment. There is a strong push needed for the development of new drugs, especially for the management of chronic or resistant rejections, to prolong graft survival. Prevention of rejection is key for the longevity of kidney allografts. This requires a multipronged approach and significant effort on the part of the recipients and transplant centers. [ABSTRACT FROM AUTHOR]

We evaluated the overall performance of the Cobas 6800 BKV test in detecting BK virus (BKV). We examined the imprecision of the Cobas 6800 BKV test and compared the qualitative and quantitative results obtained from the Cobas 6800 BKV test and the Real-Q BKV quantification assay. We assessed 88 plasma and 26 urine samples collected between September and November 2022 from patients with BKV infection using the Real-Q BKV quantitative assay. The lognormal coefficient of variation indicated that the inter-assay precision of the Cobas 6800 BKV test ranged from 13.86 to 33.83%. A strong correlation was observed between the quantitative results obtained using the Cobas 6800 BKV test and the Real-Q BKV quantification assay for plasma samples. The Spearman's rank correlation coefficients (ρ) for plasma, polymerase chain reaction (PCR) media-stabilized urine, and raw urine samples were 0.939, 0.874, and 0.888, respectively. Our analyses suggest that the Cobas 6800 BKV test is suitable for clinical applications owing to the strong correlation between the results obtained using this test and the Real-Q BKV quantification assay in plasma and urine samples. Furthermore, utilizing fresh raw urine samples can be a viable approach for the Cobas 6800 BKV test as it is less labor- and time-intensive. [ABSTRACT FROM AUTHOR]

Background and Objectives: Although ocular disorders can occasionally impact people with HIV over the course of their illness, HIV/AIDS is unmistakably a multisystem disorder. A physician can rule out a wide range of ophthalmic problems with the assistance of an ophthalmologist, from adnexal disorders to posterior segment diseases, including those affecting the optic tract and optic nerve. Materials and Methods: Based on patient medical data from the "St. Parascheva" Clinical Hospital of Infectious Diseases in Iasi, we carried out a retrospective clinical investigation on patients with HIV/AIDS and ophthalmological conditions who were hospitalized in northeastern Romania. We seek to draw attention to the characteristics and ophthalmological comorbidities of HIV/AIDS patients. The studied period was between 1 January 1991 and 31 December 2022. Results: There were a total of 38 recorded cases of ophthalmological manifestations in the HIV-infected patients. The research group's average age was 37.31 years old (standard deviation 9.5693917). Males were primarily impacted, having lower total CD4+ T-lymphocyte levels based on sex and CD4+ T-lymphocyte levels overall. The HIV viral load was 999 268.13 copies/mL on average (standard deviation 1,653,722.9). Of all the patients, we found out that 17 had congenital eye diseases (44.73%) and the others (21, 55.26%) developed ophthalmological diseases. CMV Retinitis was found most frequently, in eight patients (21.05%), followed by Myopia in seven patients (18.42%). Conclusions: The key to the management of HIV-positive patients is a multidisciplinary approach and access to antiretroviral therapy. Anyone who is HIV-positive and experiences ocular symptoms at any time should be directed to seek professional ophthalmologic treatment as soon as feasible. A therapeutic holdup could result in irreversible vision loss. Long-term coordination is required to combat this disease, improving communication between the ophthalmology and infectious disease fields. [ABSTRACT FROM AUTHOR]

C3 glomerulonephritis (C3GN) is a rare cause of end-stage kidney disease and frequently recurrent in allografts following kidney transplantation (KT). Herein, we describe the case of a kidney transplant recipient who developed recurrent C3GN along with BK-virus-associated nephropathy (BKVAN) following KT. A 33-year-old man diagnosed with membranoproliferative glomerulonephritis 17 years ago underwent preemptive KT with a donor kidney from his aunt. Proteinuria gradually increased after 3 months following KT, and graft biopsy was performed 30 months after KT. Histopathological examination revealed recurrent C3GN. The dosages of triple immunosuppressive maintenance therapy agents were increased. Subsequently, serum C3 levels recovered to normal levels. However, at 33 months following KT, the BK viral load increased and graft function gradually deteriorated; a second graft biopsy was performed at 46 months following KT, which revealed BKVAN and decreased C3GN activity. The dosages of immunosuppressive agents were decreased; subsequently, BKVAN improved and graft function was maintained with normal serum C3 levels at 49 months following KT. This case indicates that C3GN is highly prone to recurrence following KT and that immunosuppressive therapy for C3GN increases the risk of BKVAN. [ABSTRACT FROM AUTHOR]

Infectious agents can pose a significant challenge in kidney transplantation, as they have the potential to cause direct infections in the transplanted kidney. These infections can lead to a decline in kidney function and reduce the longevity of the transplanted kidney. Common post-transplant allograft infections include bacterial pyelonephritis and the BK virus infection, while adenovirus, JC virus, and cytomegalovirus are less frequent but can also lead to significant allograft dysfunctions. The histopathological features of these infections are characterized by the infiltration of inflammatory cells in the kidney interstitial area and the presence of viral nuclear inclusions or cytopathic changes in the renal tubular epithelial cells. The confirmation of causative organisms can be achieved by immunohistochemical staining or the visualization of viral particles using electron microscopic examination. However, these methods typically require a longer turnaround time and are not readily available in developing countries, unlike standard hematoxylin-eosin staining. Notably, the differential diagnosis of interstitial inflammation in kidney allografts almost always includes T cell-mediated rejection, which has a different treatment approach than allograft infections. The aim of this review was to prompt clinicians to identify diverse pathological alterations as observed in kidney allograft biopsies, thereby facilitating further investigations and the management of suspected kidney allograft infections. [ABSTRACT FROM AUTHOR]

Background: Reactivation of JC and BK polyomaviruses during immunosuppression can lead to adverse clinical outcomes. In renal transplant recipients, BKV-associated nephropathy can result in graft loss, while in patients with autoimmune disorders, prolonged immunomodulatory drug use can cause rare onset of progressive multifocal leukoencephalopathy due to JCV reactivation. In such patients, accurate BK and JC viral load determinations by molecular technologies are important for diagnosis and clinical management; however, comparability across centres requires effective standardisation of diagnostic molecular detection systems. In October 2015, the WHO Expert Committee for Biological Standardisation (ECBS) established the 1st WHO International Standards (ISs) for use as primary-order calibrants for BKV and JCV nucleic acid detection. Two multi-centre collaborative studies confirmed their utility in harmonising agreement across the wide range of BKV and JCV assays, respectively. Previous Illumina-based deep sequence analysis of these standards, however, identified deletions in different regions, including the large T-antigen coding region. Hence, further detailed characterization was warranted. Methods: Comprehensive sequence characterisation of each preparation using short- and long-read next-generation sequencing technologies was performed with additional corroborative independent digital PCR (dPCR) determinations. Potential error rates associated with long-read sequencing were minimised by applying rolling circle amplification (RCA) protocols for viral DNA (circular dsDNA), generating a full validation of sequence identity and composition and delineating the integrity of full-length BK and JC genomes. Results: The analysed genomes displayed subpopulations frequently characterised by complex gene re-arrangements, duplications and deletions. Conclusions: Despite the recognition of such polymorphisms using high-resolution sequencing methodologies, the ability of these reference materials to act to enhance assay harmonisation did not appear significantly impacted, based on data generated by the 2015 WHO collaborative studies, but highlights cautionary aspects of IS generation and commutability for clinical molecular diagnostic application. [ABSTRACT FROM AUTHOR]

The BK virus (BKV) causes severe hemorrhagic cystitis in hematopoietic stem cell transplant (HSCT) recipients. To eliminate reactivated BKV, symptomatic patients can be treated with a reduction of the immunosuppressive therapy, with the antiviral drug cidofovir, or with virus-specific T cells (VSTs). In the current study, we compared the effect of VSTs to other treatment options, following up specific T cells using interferon-gamma ELISpot assay. We observed BKV large T-specific cellular responses in 12 out of 17 HSCT recipients with BKV-related cystitis (71%). In recipients treated with VSTs, 6 out of 7 showed specific T-cell responses, and that number in those without VSTs was 6 out of 10. In comparison, 27 out of 50 healthy controls (54%) responded. In HSCT recipients treated for BKV-related cystitis, absolute CD4+ T-cell numbers and renal function correlated with BKV-specific cellular responses (p = 0.03 and 0.01, respectively). In one patient, BKV-specific cellular immunity could already be detected at baseline, on day 35 after HSCT and prior to VSTs, and remained increased until day 226 after VSTs (78 vs. 7 spots increment). In conclusion, the ELISpot appears to be suitable to sensitively monitor BKV-specific cellular immunity in HSCT recipients, even early after transplantation or in the long term after VSTs. [ABSTRACT FROM AUTHOR]

Rates of late allograft loss have improved slowly in the last decades. Well described traditional risk factors that influence allograft survival include cardiovascular events, rejection, infections and post-transplant neoplasia. Here, we critically evaluate the influence of several non-immunological, non-traditional risk factors and describe their impact on allograft survival and cardiovascular health of kidney transplant recipients. We assessed the following risk factors: arterial stiffness, persistent arteriovenous access, mineral bone disease, immunosuppressive drugs residual levels variability, hypomagnesemia, glomerular pathological alterations not included in Banff criteria, persistent inflammation and metabolic acidosis. [ABSTRACT FROM AUTHOR]

Renal complications of HIV infection are common and histologically diverse. Besides HIV-associated nephropathy, which is the most well-defined glomerular disorder, immune-complex-mediated glomerulonephritis (HIVICK) is also encountered in the setting of HIV infection and may occasionally present with "lupus-like" features by light microscopy and immunofluorescence. Management of HIVICK remains controversial and mainly focuses on HIV viremia suppression with combined antiretroviral therapy. Immunosuppressive therapy may be used in order to mitigate the renal inflammation induced by the immune complex deposition. Data regarding the use of immunosuppressants in HIVICK are very limited, mostly including corticosteroids and mycophenolate acid analogues. Herein, we present the case of a 40-year-old HIV-infected Caucasian man with nephrotic syndrome, renal impairment, and a "lupus-like" membranous pattern in the kidney biopsy, who achieved a partial response of his proteinuria with a tacrolimus-based regimen in combination with antiretroviral therapy. [ABSTRACT FROM AUTHOR]

Background: No specific antiviral drug can effectively treat BKV reactivation after kidney transplantation. Thus, we evaluated stepwise-reduced immunosuppression to treat BKV reactivation. Methods: 341 kidney-transplant recipients were monitored for BKV infection (BKV-viremia, BKV-viruria). Positive samples with a significant virus load were nested PCR-genotyped in the VP1 region. In 97/211 patients presenting BKV viremia ≥104 copies/mL and/or BKV viruria ≥107 copies/mL, or BKV-nephropathy immunosuppression (i.e., mycophenolate mofetil [MMF]) was reduced by 50%. If viral load did not decrease within 28 days, MMF dose was further reduced by 25%, although calcineurin-inhibitor (CNI) therapy remained unchanged. If BKV viral load did not decrease within another 28 days, MMF was withdrawn and replaced by everolimus combined with reduced CNIs. Results: Only 41/97 BKV (+) cases completed the 6-month follow-up. Among these, 29 (71%) were in the BKV-I group and 12 (29%) were in BKV-IV. BKV viruria and BKV viremia were significantly decreased from 9.32 to 6.09 log10 copies/mL, and from 3.59 to 2.45 log10 copies/mL (p < 0.001 and p = 0.024, respectively). 11/32 (34.4%) patients were cleared of BKV viremia; 2/32 (6.3%) patients were cleared of BKV in both serum and urine, and 9/9 (100%) only had BKV viruria but did not develop BKV viremia. eGFR remained stable. No patient with BKV-related nephropathy had graft loss. There was a significant inverse relationship between changes in eGFR and serum BKV load (r = −0.314, p = 0.04). Conclusions: This stepwise immunosuppressive strategy proved effective at reducing BKV viral load in kidney transplant recipients that had high BKV loads in serum and/or urine. Renal function remained stable without rejection. [ABSTRACT FROM AUTHOR]

BK virus-associated nephropathy (PvAN) increases the risk of graft failure justifying treatment. Conversion to mammalian target of rapamycin inhibitors (mTORi) and Human polyclonal immunoglobulins (IVIg) could prevent the risk of PvAN. Our retrospective study assessed the efficacy of mTORi associated with IVIg therapy (mTORi±IVIg group) versus standard immunosuppression reduction to clear BKV DNAemia. Among forty-three kidney-transplanted patients with positive BKV DNAemia, we included twenty-six patients in the mTORi±IVIg group and reduced immunosuppression therapy for seventeen patients. We focused on BKV DNAemia clearance on the first-year. Renal function, rejection rate, evolution to PvAN, and complications of immunosuppression were assessed. BKV DNAemia decreased faster and significantly in the control group as compared to the mTORi±IVIg group (p < 0.001). Viral clearance was significantly higher in the control group compared to the mTORi±IVIg group (88% vs. 58%; p = 0.033). Death-censored graft loss, rejection rates and kidney-graft function at 12 months did not significantly differ. Multivariate analyses significantly associated BKV DNAemia clearance with reducing immunosuppression (OR = 0.11 (0.06–0.9), p = 0.045), female kidney donor (OR = 0.10 (0.01–0.59/)], p = 0.018) and time to first DNAemia, (OR = 0.88 (0.76–0.96), p = 0.019). In our study, the standard treatment for BKV DNAemia had better outcomes than an mTORi±IVIg conversion. [ABSTRACT FROM AUTHOR]

Kidney transplant recipients who are at increased risk for COVID-19 infection and associated morbidity and mortality have been shown to be prone to an impaired humoral immune response to a standard vaccination schedule against COVID-19 with two doses of SARS-CoV-2 mRNA vaccines. In this study, response rate of 94 kidney transplant recipients without detectable seroconversion after two doses of a mRNA vaccine who were offered a timely third mRNA vaccine after completion of the standard vaccination schedule was retrospectively analyzed. After a median of 28 days, antibody titers against the S1 spike protein showed a non-response rate of 53%. No significant risk factors for non-response could be identified. The responders showed a high variation in antibody titers (median 73.9 BAU/mL, IQR 221.5). In conclusion, a third booster mRNA vaccine in non-responding kidney transplant recipients leads to a detectable humoral immune response in approximately half of the patients. In the seroconversion group, antibody titers were highly variable, indicating that even non-responders to the standard vaccination schedule might develop a significant humoral immune response after a timely booster vaccine. [ABSTRACT FROM AUTHOR]

Kidney transplant candidates and kidney transplant recipients (KTRs) are at particular risk of severe complications of COVID-19 disease. In Western countries, mortality in affected hospitalized KTRs ranges between 19% and 50%. COVID-19 vaccination remains the most important measure to prevent the severity of infection in candidates and recipients of kidney transplant. However, the uraemic condition may affect the vaccine-induced immunity in patients with advanced chronic kidney disease (CKD) and in KTRs. Retention of uraemic toxins, dysbiosis, dysmetabolism, and dialysis can diminish the normal response to vaccination, leading to dysfunction of inflammatory and immune cells. In KTRs the efficacy of vaccines may be reduced by the immunosuppressive medications, and more than half of kidney transplant recipients are unable to build an immune response even after four administrations of anti-COVID-19 vaccines. The lack of antibody response leaves these patients at high risk for SARS-CoV-2 infection and severe COVID-19 disease. The aim of the present review is to focus on the main reasons for the impaired immunological response among candidates and kidney transplant recipients and to highlight some of the present options available to solve the problem. [ABSTRACT FROM AUTHOR]

Viral infections can be a serious complication of therapy in children with acute lymphoblastic leukemia (ALL). In this study, we focused on the incidence and the profile of viral infection in children with ALL treated in 17 pediatric oncology centers in Poland in the two-year periods of 2018–2019 and 2020–2021. We also compared the frequency of viral infections in 2018–2019 to that in 2020–2021. In 2020–2021, a total of 192 children with ALL had a viral infection during intensive chemotherapy. A total number of 312 episodes of viral infections were diagnosed. The most common infections detected in the samples were: COVID-19 (23%), rhinovirus (18%), and respiratory syncytial virus (14%). COVID-19 and BK virus infections were the reason for the death 1% of all patients. In 2018–2019, a total of 53 ALL patients who had a viral infection were reported and 72 viral events were observed, mainly adenovirus (48.6%), rotavirus (31.9%), and herpes zoster (8.3%). No deaths were reported during this period. The cumulative incidence of viral infections in 2018–2019 was 10.4%, while for 2020–2021, it was 36.7%. In conclusion, a high incidence of COVID-19 infection was observed among pediatric patients with ALL in Poland. The mortality rate in our material was low. The viral profile in ALL children undergoing chemotherapy can be useful for clinicians to improve prophylactic and therapeutic strategies. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) is projected to become the fifth global cause of death by 2040 as a result of key shortcomings in the current methods available to diagnose and treat kidney diseases. In this regard, the novel holobiont concept, used to describe an individual host and its microbial community, may pave the way towards a better understanding of kidney disease pathogenesis and progression. Microbiota-modulating or -derived interventions include probiotics, prebiotics, synbiotics and postbiotics. As of 2019, the concept of postbiotics was updated by the International Scientific Association of Probiotics and Prebiotics (ISAPP) to refer to preparations of inanimate microorganisms and/or their components that confer a health benefit to the host. By explicitly excluding purified metabolites without a cellular biomass, any literature making use of such term is potentially rendered obsolete. We now review the revised concept of postbiotics concerning their potential clinical applications and research in kidney disease, by discussing in detail several formulations that are undergoing preclinical development such as GABA-salt for diet-induced hypertension and kidney injury, sonicated Lactobacillus paracasei in high fat diet-induced kidney injury, GABA-salt, lacto-GABA-salt and postbiotic-GABA-salt in acute kidney injury, and O. formigenes lysates for hyperoxaluria. Furthermore, we provide a roadmap for postbiotics research in kidney disease to expedite clinical translation. [ABSTRACT FROM AUTHOR]

Autoimmune hemolytic anemia (AIHA) is a rare complication following heart transplantation and has been attributed to several etiologies including infections, immunosuppressive medications, and post-transplant lymphoproliferative disorders. We report a 23-year-old male presenting 22 years after heart transplantation with severe AIHA. Laboratory findings were notable for positive IgG autoantibody against RBCs and high titer Epstein-Barr virus (EBV) viremia. Shortly after the first unit of irradiated RBC transfusion and high dose steroids, the patient developed acute dyspnea and hypoxia requiring intubation. Further workup demonstrated that the patient had Methicillin-sensitive Staphylococcus aureus (MSSA) pneumonia (PNA) and bacteremia, requiring antibiotics. Patient was subsequently treated with high-dose steroids, IVIG, as well as rituximab. Following treatment, the patient was successfully extubated and eventually showed complete resolution of the anemia. This case is novel as it represents AIHA likely secondary to EBV viremia in a post-cardiac transplant patient complicated by a severe transfusion reaction. In this circumstance, rituximab in conjunction with standard of care remains an effective treatment of choice. [ABSTRACT FROM AUTHOR]

Antibody-mediated rejection (AMR) of liver allograft transplantation was considered as anecdotal for many decades. However recently, AMR has gained clinical awareness as a potential cause of chronic liver injury, leading to liver allograft fibrosis and eventual graft failure. (1) Methods: Literature on chronic AMR (cAMR) in pediatric post-liver transplant patients was reviewed for epidemiologic data, physiopathology, diagnosis, and treatment approaches. (2) Results: Accurate incidence of cAMR in pediatric liver transplantation remains unknown. Diagnostic criteria of cAMR were suggested by the Banff Working Group in 2016 and are based on standardized histopathological findings, C4d staining pattern, associated with the presence of donor-specific antibodies (DSA). Physio-pathological mechanisms are not clear for the technically difficult-to-obtain animal models reproducing cAMR. Treatment protocols are not established, being limited to case reports and case series, based on experience in ABO incompatible transplantation and kidney transplantation. Immunosuppression compliance with adequate dose adjustment may prevent cAMR. Conversion of Cyclosporine to Tacrolimus may improve pathological findings if treated in early phase. The association of steroids, Mycophenolate Mofetil (MMF) and mTOR inhibitors have shown some synergistic effects. Second-line treatments such as intravenous immunoglobulin (IVIG) and plasma exchange may decrease antibody titers based on ABO incompatible transplant protocols. The use of anti-CD20 (Rituximab) and proteasome inhibitors (Bortezomib) is controversial due to the lack of qualified studies. Therefore, multicenter randomized trials are needed to establish the best therapeutic strategy. In refractory cases, re-transplantation is the only treatment for allograft failure. (3) Conclusions: This literature review collects recent clinical, histopathological, and therapeutical advances of cAMR in liver allograft transplantation of pediatric patients. There are many physio-pathological aspects of cAMR to be clarified. Further efforts with multicenter prospective protocols to manage patients with cAMR are needed to improve its outcome. [ABSTRACT FROM AUTHOR]

BK virus maintains a latent infection that is ubiquitous in humans. It has a propensity for reactivation in the setting of a dysfunctional cellular immune response and is frequently encountered in kidney transplant recipients. Screening for the virus has been effective in preventing progression to nephropathy and graft loss. However, it can be a diagnostic and therapeutic challenge. In this in-depth state-of-the-art review, we will discuss the history of the virus, virology, epidemiology, cellular response, pathogenesis, methods of screening and diagnosis, evidence-based treatment strategies, and upcoming therapeutics, along with the issue of re-transplantation in patients. [ABSTRACT FROM AUTHOR]

Background: Solid organ rejection post-SARS-CoV-2 vaccination or COVID-19 infection is extremely rare but can occur. T-cell recognition of antigen is the primary and central event that leads to the cascade of events that result in rejection of a transplanted organ. Objectives: To describe the results of a systematic review for solid organ rejections following SARS-CoV-2 vaccination or COVID-19 infection. Methods: For this systematic review and meta-analysis, we searched Proquest, Medline, Embase, Pubmed, CINAHL, Wiley online library, Scopus and Nature through the Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) guidelines for studies on the incidence of solid organ rejection post-SARS-CoV-2 vaccination or COVID-19 infection, published from 1 December 2019 to 31 May 2022, with English language restriction. Results: One hundred thirty-six cases from fifty-two articles were included in the qualitative synthesis of this systematic review (56 solid organs rejected post-SARS-CoV-2 vaccination and 40 solid organs rejected following COVID-19 infection). Cornea rejection (44 cases) was the most frequent organ observed post-SARS-CoV-2 vaccination and following COVID-19 infection, followed by kidney rejection (36 cases), liver rejection (12 cases), lung rejection (2 cases), heart rejection (1 case) and pancreas rejection (1 case). The median or mean patient age ranged from 23 to 94 years across the studies. The majority of the patients were male (n = 51, 53.1%) and were of White (Caucasian) (n = 51, 53.7%) and Hispanic (n = 15, 15.8%) ethnicity. A total of fifty-six solid organ rejections were reported post-SARS-CoV-2 vaccination [Pfizer-BioNTech (n = 31), Moderna (n = 14), Oxford Uni-AstraZeneca (n = 10) and Sinovac-CoronaVac (n = 1)]. The median time from SARS-CoV-2 vaccination to organ rejection was 13.5 h (IQR, 3.2–17.2), while the median time from COVID-19 infection to organ rejection was 14 h (IQR, 5–21). Most patients were easily treated without any serious complications, recovered and did not require long-term allograft rejection therapy [graft success (n = 70, 85.4%), graft failure (n = 12, 14.6%), survived (n = 90, 95.7%) and died (n = 4, 4.3%)]. Conclusion: The reported evidence of solid organ rejections post-SARS-CoV-2 vaccination or COIVD-19 infection should not discourage vaccination against this worldwide pandemic. The number of reported cases is relatively small in relation to the hundreds of millions of vaccinations that have occurred, and the protective benefits offered by SARS-CoV-2 vaccination far outweigh the risks. [ABSTRACT FROM AUTHOR]

(1) Background: Following renal transplantation, infection with cytomegalovirus (CMV) is a common and feared complication. mTOR-inhibitor (mTOR-I) treatment, either alone or in combination with calcineurininhibitors (CNIs), significantly reduces the CMV incidence after organ transplantation. As of now, there is no information on which mTOR-I, sirolimus (SIR) or everolimus (ERL), has a stronger anti-CMV effect. (2) Methods: The current literature was searched for prospective randomized controlled trials in renal transplantation. There were 1164 trials screened, of which 27 could be included (11,655 pts.). We performed a network meta-analysis to analyze the relative risk of different types of mTOR-I treatment on CMV infection 12 months after transplantation compared to CNI treatment. (3) Results: Four different types of mTOR-I treatment were analyzed in network meta-analyses—SIR mono, ERL mono, SIR with CNI, ERL with CNI. The mTOR-I treatment with the strongest anti-CMV effect compared to a regular CNI treatment was ERL in combination with a CNI (relative risk (RR) 0.27, confidence interval (CI) 0.22–0.32, p < 0.0001). The other mTOR-I therapy groups showed a slightly decreased anti-CMV efficacy (SIR monotherapy (mono): RR 0.35, CI 0.22–0.57, p < 0.001; SIR with CNI: RR 0.43, CI 0.29–0.64, p < 0.0001; ERL mono: RR 0.46, CI 0.22–0.93, p = 0.031). (4) Conclusions: The anti-CMV effect of both mTOR-Is (SRL and ERL) is highly effective, irrespective of the combination with other immunosuppressive drugs. Certain differences with respect to the potency against the CMV could be found between SRL and ERL. Data gained from this analysis seem to support that a combination of ERL and CNI has the most potent anti-CMV efficacy. [ABSTRACT FROM AUTHOR]

With the vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), studies are describing cases of glomerulonephritis arising after vaccination. We present the first case of a kidney transplant patient who, after mRNA vaccination against SARS-CoV-2, developed nephrotic proteinuria and renal dysfunction, with a biopsy diagnostic of collapsing glomerulonephritis. No other triggers for this glomerulonephritis were identified. Antibodies against the spike protein were negative, but the patient developed a specific T-cell response. The close time between vaccination and the proteinuria suggests a possible determinant role of vaccination. We should be aware of nephropathies appearing after COVID-19 vaccination in kidney transplant recipients also. [ABSTRACT FROM AUTHOR]

Poliomavirus BK virus (BKV) is highly infective, causing asymptomatic infections during childhood. After the initial infection, a stable state of latent infection is recognized in kidney tubular cells and the uroepithelium with negligible clinical consequences. BKV is an important risk factor for BKV-associated diseases, and, in particular, for BKV-associated nephropathy (BKVN) in renal transplanted recipients (RTRs). BKVN affects up to 10% of renal transplanted recipients, and results in graft loss in up to 50% of those affected. Unfortunately, treatments for BK virus infection are restricted, and there is no efficient prophylaxis. In addition, consequent immunosuppressive therapy reduction contributes to immune rejection. Increasing surveillance and early diagnosis based upon easy and rapid analyses are resulting in more beneficial outcomes. In this report, the current status and perspectives in the diagnosis and treatment of BKV in RTRs are reviewed. [ABSTRACT FROM AUTHOR]

Sudan ebolavirus (SUDV) is one of four members of the Ebolavirus genus known to cause Ebola Virus Disease (EVD) in humans, which is characterized by hemorrhagic fever and a high case fatality rate. While licensed therapeutics and vaccines are available in limited number to treat infections of Zaire ebolavirus, there are currently no effective licensed vaccines or therapeutics for SUDV. A well-characterized animal model of this disease is needed for the further development and testing of vaccines and therapeutics. In this study, twelve cynomolgus macaques (Macaca fascicularis) were challenged intramuscularly with 1000 PFUs of SUDV and were followed under continuous telemetric surveillance. Clinical observations, body weights, temperature, viremia, hematology, clinical chemistry, and coagulation were analyzed at timepoints throughout the study. Death from SUDV disease occurred between five and ten days after challenge at the point that each animal met the criteria for euthanasia. All animals were observed to exhibit clinical signs and lesions similar to those observed in human cases which included: viremia, fever, dehydration, reduced physical activity, macular skin rash, systemic inflammation, coagulopathy, lymphoid depletion, renal tubular necrosis, hepatocellular degeneration and necrosis. The results from this study will facilitate the future preclinical development and evaluation of vaccines and therapeutics for SUDV. [ABSTRACT FROM AUTHOR]

Objectives: The purpose of this study was to identify the SNP sites and determine the BKV genotype circulating in kidney-transplant Vietnamese recipients based on the VP1 gene region. Methods: 344 samples were collected from post-kidney-transplant recipients at the 103 Vietnam Military Hospital to investigate the number of BKV infections. Positive samples with a sufficient virus concentration were analyzed by nested PCR in the VP1 region, sequencing detected genotyping and single-nucleotide polymorphism. Results: BKV infection was determined in 214 patients (62.2%), of whom 11 (5.1%) were diagnosed with BKV-associated nephropathy. Among the 90 BKV-I strains sequenced, 89 (98.88%) were strains of I/b-1 and 1 (1.12%) was strain I/b-2. The 60 BKV-IV strains had a greater diversity of subgroups, including 40% IV/a-1, 1.66% IV/a-2, 56.68% IV/c-1, and 1.16% IV/c-2. Additionally, of 11 cases diagnosed with BKVN, seven belonged to subgroup I/b-1 (63.6%) and four to subgroup IV/c-1 (36.4%). Moreover, 22 specific SNPs that were genotype I or IV were determined in this Vietnamese population. Specifically, at position 1745, for the Vietnamese BKV-IV strains, the SNP position (A→G) appeared in 57/60 samples (95%). This causes transformation of the amino acid N→S. This SNP site can enable detection of genotype IV in Vietnam. It represents a unique evolution pattern and mutation that has not been found in other international strains. Conclusion: The BKV-I genotype was more common than BKV-IV; however, mutations that occur on the VP1 typing region of BKV-IV strains were more frequent than in BKV-I strains. [ABSTRACT FROM AUTHOR]

The chicken astrovirus (CAstV) is a ubiquitous enteric RNA virus that has been associated mainly with conditions, such as the runting-stunting syndrome, severe kidney disease, visceral gout, and white chick syndrome, in broiler-type chickens worldwide. Sequence analysis of the capsid genes' amino acids of the strains involved in these conditions reveals a genetic relationship and diversity between and within the CAstV genogroups and subgroups based on phylogenetic analysis, genetic distance (p-dist), and pathogenicity. While the two genogroups (A and B) are demarcated phylogenetically, their pairwise amino acid sequence identity is 39% to 42% at a p-dist of 0.59 to 0.62. Group-A consists of three subgroups (Ai, Aii, and Aiii) with an inter- and intra-subgroup amino acid identity of 78% to 82% and 92% to 100%, respectively, and a p-dist of 0.18 to 0.22. On the other hand, the six subgroups (Bi, Bii, Biii, Biv, Bv, and Bvi) in Group-B, with a p-dist of 0.07 to 0.18, have an inter- and intra-subgroup amino acid identity of 82% to 93% and 93% to 100%, respectively. However, these groupings have little to no effect on determining the type of CAstV-associated pathology in chickens. [ABSTRACT FROM AUTHOR]

This document is a correction notice for an article published in the Journal of Clinical Medicine. The original publication contained a mistake in Table 1, where the percentage of patients who had undergone radiation therapy was incorrectly stated as 66% instead of 34%. The corrected table is provided in the document. The authors state that this correction does not affect the scientific conclusions of the study. [Extracted from the article]

In immunosuppressed patients, BKPyV-variants emerge carrying rearranged non-coding control-regions (rr-NCCRs) that increase early viral gene region (EVGR) expression and replication capacity. BKPyV also encodes microRNAs, which have been reported to downregulate EVGR-encoded large T-antigen transcripts, to decrease viral replication in infected cells and to be secreted in exosomes. To investigate the interplay of NCCR and microRNAs, we compared archetype- and rr-NCCR-BKPyV infection in cell culture. We found that laboratory and clinical rr-NCCR-BKPyV-strains show higher replication rates but significantly lower microRNA levels than archetype virus intracellularly and in exosomes. To investigate whether rr-NCCR or increased EVGR activity modulated microRNA levels, we examined the (sp1-4)NCCR-BKPyV, which has an archetype NCCR-architecture but shows increased EVGR expression due to point mutations inactivating one Sp1 binding site. We found that microRNA levels following (sp1-4)NCCR-BKPyV infection were as low as in rr-NCCR-variants. Thus, NCCR rearrangements are not required for lower miRNA levels. Accordingly, Sp1 siRNA knock-down decreased microRNA levels in archetype BKPyV infection but had no effect on (sp1-4)- or rr-NCCR-BKPyV. However, rr-NCCR-BKPyV replication was downregulated by exosome preparations carrying BKPyV-microRNA prior to infection. To explore the potential relevance in humans, urine samples from 12 natalizumab-treated multiple sclerosis patients were analysed. In 7 patients, rr-NCCR-BKPyV were detected showing high urine BKPyV loads but low microRNAs levels, whereas the opposite was seen in 5 patients with archetype BKPyV. We discuss the results in a dynamic model of BKPyV replication according to NCCR activity and exosome regulation, which integrates immune selection pressure, spread to new host cells and rr-NCCR emergence. [ABSTRACT FROM AUTHOR]

Polyomaviruses are non-enveloped, dsDNA viruses that are common in mammals, including humans. All polyomaviruses encode the large T-antigen and small t-antigen proteins that share conserved functional domains, comprising binding motifs for the tumor suppressors pRb and p53, and for protein phosphatase 2A, respectively. At present, 13 different human polyomaviruses are known, and for some of them their large T-antigen and small t-antigen have been shown to possess oncogenic properties in cell culture and animal models, while similar functions are assumed for the large T- and small t-antigen of other human polyomaviruses. However, so far the Merkel cell polyomavirus seems to be the only human polyomavirus associated with cancer. The large T- and small t-antigen exert their tumorigenic effects through classical hallmarks of cancer: inhibiting tumor suppressors, activating tumor promoters, preventing apoptosis, inducing angiogenesis and stimulating metastasis. This review elaborates on the putative roles of human polyomaviruses in some of the emerging hallmarks of cancer. The reciprocal interactions between human polyomaviruses and the immune system response are discussed, a plausible role of polyomavirus-encoded and polyomavirus-induced microRNA in cancer is described, and the effect of polyomaviruses on energy homeostasis and exosomes is explored. Therapeutic strategies against these emerging hallmarks of cancer are also suggested. [ABSTRACT FROM AUTHOR]