Elevated levels of IL-6 in IgA nephropathy patients are induced by an epigenetically driven mechanism modulated by viral and bacterial RNA.

BACKGROUND: Immunoglobulin A nephropathy (IgAN) is the most frequent primary glomerulonephritis and the role of IL-6 in pathogenesis is becoming increasingly important. A recent whole genome DNA methylation screening in IgAN patients identified a hypermethylated region comprising the non-coding RNA Vault RNA 2-1 (VTRNA2-1) that could explain the high IL-6 levels. METHODS: The pathway leading to IL-6 secretion controlled by VTRNA2-1, PKR, and CREB was analyzed in peripheral blood mononuclear cells (PBMCs) isolated from healthy subjects (HS), IgAN patients, transplanted patients with or without IgAN. The role of double and single-strand RNA in controlling the pathway was investigated. RESULTS: VTRNA2-1 was downregulated in IgAN compared to HS and in transplanted IgAN patients (TP-IgAN) compared to non-IgAN transplanted (TP). The loss of the VTRNA2-1 natural restrain in IgAN patients caused PKR hyperphosphorylation, and consequently the activation of CREB by PKR, which, in turn, led to high IL-6 production, both in IgAN and in TP-IgAN patients. IL-6 levels could be decreased by the PKR inhibitor imoxin. In addition, PKR is normally activated by bacterial and viral RNA, and we found that both the RNA poly(I:C), and the COVID-19 RNA-vaccine stimulation significantly increased the IL-6 levels in PBMCs from HS but had an opposite effect in those from IgAN patients. CONCLUSION: The discovery of the upregulated VTRNA2-1/PKR/CREB/IL-6 pathway in IgAN patients may provide a novel approach to treating the disease and may be useful for the development of precision nephrology and personalized therapy by checking the VTRNA2-1 methylation level in IgAN patients.

Kinetics of humoral immune response and severity of infection after three doses of SARS-CoV-2 mRNA vaccine in a large cohort of kidney transplant recipients.

BACKGROUND: COVID-19 in kidney transplant recipients is associated with high morbidity and mortality. In this study we aimed to evaluate: (i) the seroconversion rate after BNT162b2 (Pfizer-BioNTech) SARS-CoV-2 vaccine, (ii) factors associated with humoral response, (iii) clinical outcome of COVID-19 in kidney transplanted patients. METHODS: We enrolled a cohort of 743 kidney transplant recipients followed up from March 2020 until April 2022. A subset of 336 patients, who received three-doses of SARS-CoV-2 vaccine, was analyzed in terms of kinetics of humoral immune response and compared to a control group of 94 healthcare workers. Antibody response was tested before vaccination (T0), 15 and 90 days after the second dose (T1 and T2), on the day of the third dose (T3) and one month after the third dose (T4). RESULTS: We observed that 66 out of 743 subjects had COVID-19 infection pre-vaccination: 65.2% had severe symptoms, 27.3% were hospitalized (9 deaths), none were asymptomatic. After three doses, 51 patients had COVID-19 infection, 60.8% were asymptomatic, 27.5% reported mild symptoms, 3.9% showed severe symptoms, 7.8% were hospitalized (2 deaths). In the subset of 336 vaccinated patients, an antibody level > 0.8 U/ml was detected at T1, that increased at T2 and T3, peaking at T4. Independent factors associated with a negative antibody titer at T4 were decreasing estimated glomerular filtration rate, time from transplantation, and antimetabolites (all p < 0.001) and age (p = 0.007). CONCLUSIONS: The kinetics of humoral response after three doses of vaccine in kidney transplant patients is characterized by a late but effective immune response against SARS-CoV-2, reducing morbidity and mortality.

Efficacy of sustained low-efficiency dialysis in the management of topiramate intoxication: case report.

Guidelines on the use of dialysis treatment in patients with chronic kidney disease (CKD) and TPM (Topiramate) intoxication are controversial. A 51-year-old man with epilepsy and CKD was carried to our emergency department for dysuria and sickness. He chronically assumed TPM 100 mg 3/day. Creatinine level was 2.1 mg/dL, blood urea nitrogen 70 mg/dL, and inflammation indexes were increased. We started empirical antibiotic therapy and rehydration. The day two he had diarrhea and an acute insurgence of dizziness, confusion, and bicarbonate levels reduction. Brain CT resulted negative for acute events. During the night his mental status worsened, and urinary output results were about 200 mL in 12h. EEG showed desynchronized brain bioelectric activity. Thereafter, there was an episode of seizure and then anuria, hemodynamic instability, and loss of consciousness. Creatinine value was 5.39 mg/dL with a serious metabolic acidosis non-anion gap. We decided to start 6-hours Sustained Low Efficiency Hemo-Dia-Filtration (SLE-HDF). We assisted in the recovery of consciousness and later in the improvement of kidney function after 4 hours of treatment. TPM levels before SLE-HDF resulted in 123.1 µg/mL. At the end of treatment resulted in 30 µg/mL. To our knowledge, this is the first report of TPM involuntary intoxication in a patient affected by CKD who survived such a high TPM concentration treated with renal replacement therapy. SLE-HDF resulted in moderate elimination of TPM and acidemia resolution, continuous monitoring patient's vital parameters in relation to his hemodynamic instability, since blood flow and dialysate flow are lower than conventional hemodialysis.

Therapeutic Approach for Recurrent Focal Segmental Glomerulosclerosis in Pediatric Renal Transplant Recipients: A Single-Center Experience.

INTRODUCTION: Recurrence of focal segmental glomerulosclerosis (FSGS) after kidney transplantation (KTx) develops in 40% of patients, leading to graft loss in half of cases. Extracorporeal apheretic treatments, combined with immunosuppressive drugs, seem to be the most promising therapies, but at now limited reports are available, mainly in pediatric patients. OBJECTIVE: We aimed to assess the efficacy of immunoadsorption (IA) to treat recurrent FSGS in pediatric patients. METHODS: We report a case series of 4 pediatric patients (aged 4-12 years) followed at our institution for early recurrent FSGS after KTx. FSGS recurrence was treated with early and intensive apheretic treatments IA. RESULTS: After IA initiation, a partial remission (PR) of proteinuria at 24-month follow-up was achieved only in 1 patient. The others showed a mild reduction of nephrotic proteinuria, without PR, but gained a significant improvement in clinical signs of nephrotic syndrome (reduction of edema, increased serum albumin, and total protein levels). After a median follow-up of 38 (22-48) months, renal function was almost stable over time in all patients, except one who returned to hemodialysis after 22 months. No severe IA-related complications occurred. CONCLUSIONS: According to our clinical experience, IA revealed as a safe and effective therapy to treat patients with recurrent FSGS after KTx and it could maintain stable renal function in 75% of patients.

Severe COVID-19 by SARS-CoV-2 Lineage B.1.1.7 in Vaccinated Solid-Organ Transplant Recipients: New Preventive Strategies Needed to Protect Immunocompromised Patients.

BACKGROUND: Solid-organ transplant (SOT) recipients are at a high risk of severe COVID-19, and are priority for vaccination. Here, we describe three cases of severe COVID-19 caused by SARS-CoV-2 B.1.1.7 lineage in vaccinated SOT recipients. METHODS: Three SOT patients were hospitalized in the Policlinico Hospital of Bari (southern Italy) and underwent nasopharyngeal swabs for molecular detection of SARS-CoV-2 genes and spike protein mutations by real-time PCR. One sample was subjected to whole-genome sequencing. RESULTS: One patient was a heart transplant recipient and two were kidney transplant recipients. All were hospitalized with severe COVID-19 between March and May 2021. Two patients were fully vaccinated and one had received only one dose of the BNT162b2 mRNA vaccine. All the patients showed a high viral load at diagnosis, and molecular typing revealed the presence of B.1.1.7 lineage SARS-CoV-2. In all three cases, prolonged viral shedding was reported. CONCLUSIONS: The three cases pose concern about the role of the B.1.1.7 lineage in severe COVID-19 and about the efficacy of COVID-19 vaccination in immunocompromised patients. Protecting immunocompromised patients from COVID-19 is a challenge. SOT recipients show a suboptimal response to standard vaccination, and thus, an additive booster or a combined vaccination strategy with mRNA, protein/subunit, and vector-based vaccines may be necessary. This population should continue to practice strict COVID-19 precautions post-vaccination, until new strategies for protection are available.

High levels of gut-homing immunoglobulin A+ B lymphocytes support the pathogenic role of intestinal mucosal hyperresponsiveness in immunoglobulin A nephropathy patients.

BACKGROUND: Immunoglobulin A nephropathy (IgAN) is the most frequent primary glomerulonephritis. The role of the microbiota and mucosal immunity in the pathogenesis of IgAN remains a key element. To date, the hypothetical relationship between commensal bacteria, elevated tumour necrosis factor (TNF) superfamily member 13 [also known as B-cell activating factor (BAFF)] levels, perturbed homoeostasis of intestinal-activated B cells and intestinal IgA class switch has not been clearly shown in IgAN patients. METHODS: We studied the intestinal-renal axis connections, analysing levels of BAFF, TNF ligand superfamily member 13 (APRIL) and intestinal-activated B cells in IgAN patients, healthy subjects (HSs) and patients with non-IgA glomerulonephritides. RESULTS: IgAN patients had increased serum levels of BAFF cytokine, correlating with higher amounts of five specific microbiota metabolites, and high APRIL cytokine serum levels. We also found that subjects with IgAN have a higher level of circulating gut-homing (CCR9+ ß7 integrin+) regultory B cells, memory B cells and IgA+ memory B cells compared with HSs. Finally, we found that IgAN patients had high levels of both total plasmablasts (PBs) and intestinal-homing PBs. Interestingly, PBs significantly increased in IgAN but not in patients with other glomerulonephritides. CONCLUSIONS: Our results demonstrate a significant difference in the amount of intestinal-activated B lymphocytes between IgAN patients and HSs, confirming the hypothesis of the pathogenic role of intestinal mucosal hyperresponsiveness in IgAN. The intestinal-renal axis plays a crucial role in IgAN and several factors may contribute to its complex pathogenesis and provide an important area of research for novel targeted therapies to modulate progression of the disease.