Myocarditis following COVID-19 mRNA vaccinations: Twin and sibling case series.

ImportanceMyocarditis and myopericarditis are well described adverse events of special interest (AESI) following COVID-19 vaccinations. Whilst the aetiology is still being investigated; there is evidence that genetic predisposition may be a risk factor for the development of myocarditis. Furthermore, hormones are thought to contribute to sex-specific differences in myocarditis, skewed toward a larger risk in adolescent males. Objective: This unique sibling case series may help highlight potential mechanisms and prognostic factors in the development of myocarditis following COVID-19 vaccination in adolescent males. In this context, twin and familial studies provide a unique epidemiological perspective to investigate the interplay between genetic predisposition and other factors. Participants: Observational case series of all siblings reported to SAEFVIC with chest pain following COVID-19 vaccinations in Victoria, Australia. Exposure: mRNA vaccination (Comirnaty BNT162b2 COVID-19 (Pfizer-BioNTech) and Spikevax mRNA-1273 (Moderna). Findings: Our case series comprises 6 young males; two sets of monozygotic twins and one set of fraternal brothers following reports of chest pain associated with COVID-19 mRNA vaccination. Five patients were diagnosed with myocarditis as per Brighton Collaboration Criteria (Level 2). The remaining sibling, who did not have myocarditis, was subsequently diagnosed with pubertal delay. Conclusions: Understanding the genetic and hormonal risk factors and aetiology for myocarditis associated with COVID-19 vaccines is paramount. Further evaluation of specific genetic targets or biomarkers is required to understand the implications of population vaccine policy, particularly for adolescent and young adult males at highest risk for this AESI.

[Clinicopathologic features and prognosis of patients with IgA nephropathy superimposed on transplant glomerulopathy].

Objective: To observe the clinicopathologic features and prognostic of patients with IgA nephropathy (IgAN) superimposed on transplant glomerulopathy (TG+ IgAN). Methods: Electronic medical records of Jinling Hospital were searched for TG+ IgAN patients that was diagnosed during January 2004 to December 2016. Clinicopathologic features and prognoses information were retrieved and analyzed. The primary outcome was initiation of replacement therapy or an eGFR declined to<15 ml·min(-1)·(1.73m(2))(-1). Results: A total of 49 patients with pathologically confirmed TG+ IgAN were enrolled in this study. The median time from renal transplantation to allograft biopsy was 85 months. There were 131 patients with TG in the control group. There was no statistical difference in the age, gender, and immunosuppressive regimen during renal biopsy in the two groups. In TG+ IgAN patients, the median serum creatinine level was 175 µmol/L, the median urinary protein was 1.45 g/24 h, and 16.3% of the patients had nephrotic range proteinuria, the incidence of microscopic hematuria was 40.8%, and the average hemoglobin was 105 g/L. In terms of pathology, the degree of glomerular mesangial matrix hyperplasia in the TG+ IgAN group was significantly heavier compared with TG group (P=0.004), and the degree of hyaline degeneration of the small arteries was lighter (P=0.043). There was no significant difference in interstitial inflammation (i), tubulitis (t), glomerulitis (g), peritubular capillaritis (ptc) and intimal arteritis (v). Calculated by Kaplan-Meier method, the median survival time of 49 patients with TG+ IgAN was 36.9 months, and there was no difference in survival rate of allografts compared with TG group. Conclusions: Compared with TG patients without IgA, TG+ IgAN patients had higher incidence of microscopic hematuria, more severe glomerular mesangial matrix hyperplasia, and no significant differences in other clinicopathological features. The prognosis of TG+ IgAN patients was not significantly different from those without IgAN.

Retrospective evaluation of the effect of mycophenolate mofetil dosage on survival of kidney grafts based on biopsy results.

INTRODUCTION: Plasma concentration monitoring is commonly used to adjust immunosuppressant dosage in transplant recipients, but adjustment is often based on clinical experience rather than rigorous quantitative indicators. METHODS: We examined the effect of mycophenolate mofetil (MMF) dosage on graft survival by pathologic and immunologic analysis of 88 kidney recipients who were given a postoperative immunosuppressive regimen of tacrolimus (FK506), MMF, and corticosteroids. Patients were given a conventional dosage (≥1.5 g/d; n = 40) or a reduced dosage (n = 48) of MMF owing to postoperative adverse side effects. RESULTS: The reduced-dose group included patients given low doses (≤1.0 g/d; n = 27), ultra-low doses (≤0.5 g/d; n = 15), and those who discontinued MMF (n = 6). The dose reduction group had increased acute rejection, chronic rejection, and graft dysfunction, poorer pathologic scores, and increased cell infiltration of graft tissue (CD4, CD8, CD68, and CD138 positivity) and expression of interleukin-2R and HLA-DR. Finally, hazard analysis indicated that patients given low doses and ultra-low doses of MMF had poorer long-term kidney grafts survival (hazard ratios of 1.52 and 1.78, respectively). CONCLUSIONS: These results indicate the importance of using an appropriate dosage of MMF in kidney transplant recipients.

Effect of CYP3A5 genotype on renal allograft recipients treated with tacrolimus.

OBJECTIVE: Tacrolimus concentrations are associated with CYP3A5 genotype. The purpose of this study was to evaluate the outcomes and drug concentrations/doses among a posttransplant population with various CYP3A5 genotypes within 12 months. METHODS: Sixty seven kidney recipients receiving immunosuppression with tacrolimus + mycophenolate mofetil + prednisolone were grouped according to their CYP3A5 genotypes (*1/*1; *1/*3; *3/*3). The initial dose of tacrolimus (0.15 mg/kg/d) was adjusted according to achieve a target therapeutic window. All patients underwent a protocol biopsy at 1 month posttransplantation. We assayed serum creatinine and tacrolimus blood trough concentrations to calculate the concentration per dosage during follow-up. We also investigated the incidence of acute rejection episodes and the nephrotoxicity of tacrolimus according to the renal biopsy. RESULTS: There was no significant difference among serum creatinine concentrations. Tracrolimus blood concentrations showed a significant difference at day 7 and 1 month with no significant difference at 3, 6, or 12 months among the three groups. The CYP3A5*3/*3 group showed the largest concentration per dosage (C/D) and CYP3A5*1/*1, the smallest C/D. There was a significant difference among the three groups. The occurrence of an acute rejection episode within 3 months showed a significant difference among the three groups but not from 3 to 12 months after transplantation. Nephrotoxicity was greatest among the CYP3A5*3/*3 group. CONCLUSION: CYP3A5 influenced the blood concentrations of tacrolimus. Our study suggested to choose the initial dosage according to the CYP3A5 genotype to obtain a better outcome and reduce the incidences of acute rejection episodes and nephrotoxicity.

Prognostic effect of lymphocyte subgroup CD4+ and CD8+ cells in peripheral blood in renal transplant patients with cytomegalovirus viremia.

OBJECTIVE: Our aim was to evaluate the prognostic effect of peripheral blood lymphocyte subgroup CD4+ and CD8+ cells on renal transplant patients with cytomegalovirus (CMV) viremia. MATERIALS AND METHODS: Using 41 renal transplant patients with CMV-PCR(+) in peripheral blood and stable values of serum creatinine (SCr), we evaluated the changes in lymphocyte subgroup CD4+ and CD8+ cells with onset of antiviral therapy with gancyclovir for treatment of pneumonia. We compared patients with or without pneumonia. RESULTS: The lower the peripheral blood lymphocyte subgroup CD4+ and CD8+ cell numbers, the higher the incidence of CMV pneumonia. The numbers of CD4+ and CD8+ cells at 1 month posttransplantation and at the time of CMV-PCR(+) detection were significantly lower than those before transplantation in the CMV pneumonia group (P < .01) and also in the nonpneumonia group. CONCLUSIONS: The decrease in peripheral blood lymphocyte subgroup CD4+ and CD8+ cells after renal transplantation in patients with CMV viremia showed prognostic value for pneumonia. Increased CD4+ and CD8+ cells in peripheral blood combined with preemptive therapy may reduce the incidence of pneumonia among patients with CMV viremia.

Therapeutic effect of Tripterygium wilfordii on proteinuria associated with sirolimus in renal transplant recipients.

Sirolimus (SRL) is a potent immunosuppressive drug used to prevent acute allograft rejection after renal transplantation. Nevertheless, the occurrence of proteinuria has recently been recognized among patients on SRL-based therapy. The aim of this study was to investigate the therapeutic effects of Tripterygium wilfordii Hook F. (T II) on proteinuria associated with SRL in renal transplant recipients. According to accepting T II, 36 recipients were divided into 2 groups: T II group (n = 21) and valsartan group (n = 15). The T II group was administered 1 mg/kg/d, and the valsartan group, 80 mg twice per day for 12 months. Efficiency was then evaluated. Complete remission: proteinuria decreased by >50%; partial remission: proteinuria decreased by 20% to 50%; ineffective: proteinuria decreased by <20%. Upon 12-month follow-up, the total effective rates in the T II group and the valsartan group were 95.2% and 86.7% (P < .05), respectively. Twenty of 21 patients with proteinuria in the T II group were negative at 3-month follow-up with disappearance of edema. There were some adverse events that had greater incidence rates in the valsartan group compared with the T II group, such as hyperkalemia (26.7% vs 4.8%). We concluded that the application of T II markedly reduced proteinuria associated with SRL in renal transplant patients.

A single-dose daclizumab induction protocol in renal allograft recipients: a Chinese single center experience.

This study prospectively compared immunoprophylaxis with a single dose of daclizumab versus no induction in kidney transplant recipients treated with a cyclosporine, mycophenolate mofetil, and prednisone-based immunosuppression regimen seeking to observe the impact of a single-dose regimen for prevention of acute rejection among Chinese renal allograft recipients. A total of 118 renal transplant recipients were randomized into a daclizumab induction therapy group (daclizumab group, n = 58) and a no induction group (control group, n = 60). The daclizumab group received a single-dose (1 mg/kg of ideal body weight by intravenous infusion) 2 hours before the operation. There was no induction therapy in the control group. There was no significant difference in the baseline parameters at randomization between the two groups. The mean time to the first episode of acute rejection was 41.2 +/- 3.2 days for the daclizumab group versus 11.2 +/- 4.6 days for the control group. The number of first biopsy-confirmed acute rejection episodes during the 6-months after transplantation was significantly different in the daclizumab (7,12.1%) versus the control group (14,23.3%; P < .001). At the end of 12 months, patient and graft survivals were 100% in the groups with or without daclizumab. We noted that the incidence of infection, including serious infection was similar, in the daclizumab group to that in the control group, 17.2% and 20.0%, respectively. This study showed that a single-dose of daclizumab effectively prevented acute rejection in Chinese renal allograft recipients.