Pediatric kidney transplantation: is it safe to perform during night-time or day-off?

PURPOSE: To investigate the impact of after-hours surgery on the outcomes of pediatric kidney transplantation (KT). METHODS: Medical records of pediatric KTs performed at a single institution between 2013 and 2021 were retrospectively reviewed. The population was split into three groups according to the incision time and calendar: ordinary day (8.00 AM - 6.30 PM), day-off, and night-time (6.30 PM - 8.00 AM). The following endpoints were compared: ischemia times, length of surgery, complications, delayed graft function (DGF), primary graft non-function (PGNF), and eGFR at three-month follow-up. RESULTS: Ninety-six non-living donor KTs were performed, median age 11 (IQR 4.3-14) years and median body weight 26 (IQR 13-50) kg. Forty-one (43%) were performed during night-time and 28 (29%) during day-off. Ischemia times were similar (p = 0.769, p = 0.536). Day-off KTs presented an extended length of surgery (p = 0.011). Thirty-two complications were reported in 31 KTs. No difference in the overall rate of complications, DGF, PNGF, and three-month eGFR was found (p = 0.669, p = 0.383, p = 0.949, p = 0.093). Post-operative bleedings were more common in days-off (p = 0.003). CONCLUSION: The number of pediatric KTs performed during after-hours was considerable. Even though similar outcomes were reported, more caution should be focused on the KTs performed in days-off to avoid severe complications.

New Insights into Pediatric Kidney Transplant Rejection Biomarkers: Tissue, Plasma and Urine MicroRNAs Compared to Protocol Biopsy Histology.

The early identification of a subclinical rejection (SCR) can improve the long-term outcome of the transplanted kidney through intensified immunosuppression. However, the only approved diagnostic method is the protocol biopsy, which remains an invasive method and not without minor and/or major complications. The protocol biopsy is defined as the sampling of allograft tissue at pre-established times even in the absence of an impaired renal function; however, it does not avoid histological damage. Therefore, the discovery of new possible biomarkers useful in the prevention of SCR has gained great interest. Among all the possible candidates, there are microRNAs (miRNAs), which are short, noncoding RNA sequences, that are involved in mediating numerous post-transcriptional pathways. They can be found not only in tissues, but also in different biological fluids, both as free particles and contained in extracellular vesicles (EVs) released by different cell types. In this study, we firstly performed a retrospective miRNA screening analysis on biopsies and serum EV samples of 20 pediatric transplanted patients, followed by a second screening on another 10 pediatric transplanted patients' urine samples at one year post-transplant. In both cohorts, we divided the patients into two groups: patients with histological SCR and patients without histological SCR at one year post-transplantation. The isolated miRNAs were analyzed in an NGS platform to identify different expressions in the two allograft states. Although no statistical data were found in sera, in the tissue and urinary EVs, we highlighted signatures of miRNAs associated with the histological SCR state.

Use of Tocilizumab in the treatment of chronic active antibody-mediated rejection in pediatric kidney transplant recipients.

Chronic active antibody-mediated rejection is one of the leading causes of graft failure and traditional therapies have unclear efficacy. Recent studies suggested that Tocilizumab could stabilize renal function and improve microvascular inflammation. Here we report the outcomes of Tocilizumab therapy in 6 pediatric kidney transplant recipients with biopsy-proven chronic active antibody-mediated rejection resistant to standard treatments. All patients received monthly Tocilizumab infusions for 6 months and were monitored for renal function (creatinine, estimated glomerular filtration rate (eGFR), proteinuria) and Human Leukocyte Antigens (HLA) and non-HLA antibodies at baseline and 3 and 6 months after Tocilizumab initiation. For each patient, a follow-up biopsy was scheduled at the end of the treatment. Renal function did not show stabilization or improvement (mean eGFR 37 ml/min/1.73 m2 pre-Tocilizumab and 27 ml/min/1.73 m2 3 months after-Tocilizumab) and proteinuria remained stable. Moreover, Tocilizumab had no impact on HLA and non-HLA antibodies. Graft loss was observed in 3 patients (50 %) and 4 patients who underwent post-treatment biopsy showed a worsening in overall chronicity scores. In our pediatric series, rescue therapy with Tocilizumab did not appear to be effective in modifying the natural history of chronic active antibody-mediated rejection.

Metabolic Acidosis Is Associated With an Accelerated Decline of Allograft Function in Pediatric Kidney Transplantation.

Introduction: We investigated the relationship between metabolic acidosis over time and allograft outcome in pediatric kidney transplantation (KTx). Methods: This registry study collected data up to 10 years posttransplant. Survival analysis for a composite end point of graft loss or estimated glomerular filtration rate (eGFR) ≤ 30 ml/min per 1.73 m2 or ≥50% decline from eGFR at month 3 posttransplant was performed. The association of serum bicarbonate concentration (HCO3 -) < 22 mmol/l (metabolic acidosis) and HCO3 - < 18 mmol/l (severe metabolic acidosis) with allograft outcome was investigated using stratified Cox models and marginal structural models. Secondary analyses included the identification of risk factors for metabolic acidosis and the relationship between alkali supplementation and allograft outcome. Results: We report on 1911 patients, of whom 347 reached the composite end point. The prevalence of metabolic acidosis over time ranged from 20.4% to 38.9%. In the adjusted Cox models, metabolic acidosis (hazard ratio [HR], 2.00; 95% confidence interval [CI], 1.54-2.60) and severe metabolic acidosis (HR, 2.49; 95% CI, 1.56-3.99) were associated with allograft dysfunction. Marginal structural models showed similar results (HR, 1.75; 95% CI, 1.32-2.31 and HR, 2.09; 95% CI, 1.23-3.55, respectively). Older age was associated with a lower risk of metabolic acidosis (odds ratio [OR] 0.93/yr older; 95% CI, 0.91-0.96) and severe metabolic acidosis (OR, 0.89; 95% CI, 0.84-0.95). Patients with uncontrolled metabolic acidosis had the worst outcome compared to those without metabolic acidosis and without alkali (HR, 3.70; 95% CI, 2.54-5.40). Conclusion: The degree of metabolic acidosis is associated with allograft dysfunction.

Steroid-Resistant Nephrotic Syndrome due to NPHS2 Variants Is Not Associated With Posttransplant Recurrence.

Introduction: Unlike idiopathic nephrotic syndrome (NS), hereditary podocytopathies are not expected to recur after kidney transplantation. However, some reports of posttransplant recurrence of NS in patients carrying variants in the NPHS2 gene have been described, notably with the p.Arg138Gln variant, which is more prevalent in Europe. The objective of this study was to assess the risk of recurrence after kidney transplantation in a large cohort of patients with biallelic NPHS2 pathogenic variants. Methods: Since January 2010, 61 patients identified at Necker-Enfants Malades Hospital and 56 enrolled in the PodoNet Registry with biallelic variants in the NPHS2 gene were transplanted and were compared with 44 transplanted children with steroid-resistant NS (SRNS) without any identified pathogenic variant. Results: Of the 117 patients, 23 carried the p.Arg138Gln variant in the homozygous state and 16 in the compound heterozygous state. The other 78 patients carried different variants in the homozygous (n = 44) or compound heterozygous state. Only 1 patient with NPHS2-related SRNS experienced posttransplant recurrence (median follow-up of cohort 8.5 years [2.5-15]). Conversely, 7 of 44 patients (16%) without any identified pathogenic variant recurred within a maximum of 7 days after transplantation (median follow-up 8.9 years [0.6-13.9]). Conclusion: In this large cohort, the risk of patients with causative variants in the NPHS2 gene to develop NS recurrence after kidney transplantation was extremely low. This is coherent with the pathophysiology of intrinsic slit-diaphragm disease. These data are reassuring and should be considered when counselling patients, making living kidney donation, whether related or not, a safe choice.

[Congenital Nephrotic Syndrome: Role of Podxl Gene].

In the last decades, our understanding of the genetic disorders of inherited podocytopathies has advanced immensely; this has been possible thanks to the development of next-generation sequencing technologies that offer the possibility to evaluate targeted genes at a lower cost than in the past. Identifying new genetic mutations has helped to recognize the key role of the podocyte in the health of the glomerular filter and to understand the mechanisms that regulate the cell biology and pathology of the podocyte. Here we describe a patient with congenital nephrotic syndrome due to a mutation in PODXL. This gene encodes podocalyxin, a podocyte-specific surface sialomucin known to maintain the characteristic architecture of the foot processes and the patency of the filtration slits.