Protocolized polyoma BK viral load monitoring and high-dose immunoglobulin treatment in children after kidney transplant.

Background: BKPyV virus nephropathy (BKPyVAN) is diagnosed in 5%-16% of pediatric renal transplant recipients (PRTR) and preceded by BKPyV-viruria and DNAemia. Despite the risk of irreversible transplant damage associated with BKPyVAN, evidence-based consensus guidelines for BKPyVAN prevention are still lacking. In this retrospective study, we examined the safety and efficacy of high-dose intravenous immunoglobulin (HD-IVIG) therapy for prevention of BKPyVAN in PRTR with significant BKPyV-viruria/DNAemia. Methods: Between January 2013 and December 2022, all PRTR under our care underwent routine urine and blood testing for BKPyV viral load, using specific polymerase chain reaction (PCR). BKPyV DNAemia, with <103 copies/mL, with BKPyV viruria <107 copies/mL, with no evidence of BKPyVAN, were managed with 50% dose reduction of mycophenolate mofetil (MMF). Patients showing no decline in BKPyV viral load within two months of MMF dose reduction were managed with HD-IVIG (2 g/kg). Results: Seventy patients were recruited during a ten-year period and 31/70 patients (44%) demonstrated significant post-transplantation BKPyV-viruria/DNAemia, while 13/31 (42%) patients were unresponsive to MMF dose reduction, and were administered HD-IVIG. Of these, 12/13 (92%) patients achieved BKPyV viral clearance within six months from completion of HD-IVIG therapy and 1/13 patient (8%) was unresponsive to HD-IVIG therapy, showing increased BKPyV viral load. There were no major adverse events associated with HD-IVIG, and none of our patients developed BKPyVAN during the study period. Conclusions: Prophylactic HD-IVIG therapy in PRTR with significant BKPyV-viruria/DNAemia unresponsive to MMF dose reduction is safe and might be effective in preventing BKPyVAN. Our findings remain to be established by large-scale prospective studies.

Innate Immunity and CKD: Is There a Significant Association?

Chronic kidney disease (CKD) constitutes a worldwide epidemic, affecting approximately 10% of the global population, and imposes significant medical, psychological, and financial burdens on society. Individuals with CKD often face elevated morbidity and mortality rates, mainly due to premature cardiovascular events. Chronic inflammation has been shown to play a significant role in the progression of CKD, as well as in the acceleration of CKD-related complications, including atherosclerosis, cardiovascular disease (CVD), protein-energy wasting, and the aging process. Over the past two decades, a substantial body of evidence has emerged, identifying chronic inflammation as a central element of the uremic phenotype. Chronic inflammation has been shown to play a significant role in the progression of CKD, as well as in the acceleration of CKD-related complications in dialysis patients, including atherosclerosis, CVD, protein-energy wasting, and the aging process. Remarkably, chronic inflammation also impacts patients with CKD who have not yet required renal replacement therapy. While extensive research has been conducted on the involvement of both the adaptive and innate immune systems in the pathogenesis of CKD-related complications, this wealth of data has not yet yielded well-established, effective treatments to counteract this ongoing pathological process. In the following review, we will examine the established components of the innate immune system known to be activated in CKD and provide an overview of the current therapeutic approaches designed to mitigate CKD-related chronic inflammation.

Diagnostic Utility of Exome Sequencing Among Israeli Children With Kidney Failure.

Introduction: Genetic etiologies are estimated to account for a large portion of chronic kidney diseases (CKD) in children. However, data are lacking regarding the true prevalence of monogenic etiologies stemming from an unselected population screen of children with advanced CKD. Methods: We conducted a national multicenter prospective study of all Israeli pediatric dialysis units to provide comprehensive "real-world" evidence for the genetic basis of childhood kidney failure in Israel. We performed exome sequencing and assessed the genetic diagnostic yield. Results: Between 2019 and 2022, we recruited approximately 88% (n = 79) of the children on dialysis from all 6 Israeli pediatric dialysis units. We identified genetic etiologies in 36 of 79 (45%) participants. The most common subgroup of diagnostic variants was in congenital anomalies of the kidney and urinary tract causing genes (e.g., EYA1, HNF1B, PAX2, COL4A1, and NFIA) which together explain 28% of all monogenic etiologies. This was followed by mutations in genes causing renal cystic ciliopathies (e.g., NPHP1, NPHP4, PKHD1, and BBS9), steroid-resistant nephrotic syndrome (e.g., LAGE3, NPHS1, NPHS2, LMX1B, and SMARCAL1) and tubulopathies (e.g., CTNS and AQP2). The genetic diagnostic yield was higher among Arabs compared to Jewish individuals (55% vs. 29%) and in children from consanguineous compared to nonconsanguineous families (63% vs. 29%). In 5 participants (14%) with genetic diagnoses, the molecular diagnosis did not correspond with the pre-exome diagnosis. Genetic diagnosis has a potential influence on clinical management in 27 of 36 participants (75%). Conclusion: Exome sequencing in an unbiased Israeli nationwide dialysis-treated kidney failure pediatric cohort resulted in a genetic diagnostic yield of 45% and can often affect clinical decision making.

Reduced Electroretinogram Responses in Morphologically Normal Retina in Patients with Primary Hyperoxaluria Type 1.

Purpose: To describe ocular findings in individuals with primary hyperoxaluria type 1 (PH1), focusing on the correlations between retinal anatomy and retinal function. To characterize the retinal alterations that occur at different disease stages by evaluating individuals with diverse degrees of renal impairment associated with PH1. Design: A cross-sectional study. Participants: Patients diagnosed with PH1 based on clinical criteria and genetic testing, treated in the Pediatric Nephrology Unit of the Ruth Children's Hospital, Rambam Health Care Campus, Haifa, Israel between 2013 and 2021. Methods: The ophthalmological assessment included a slit-lamp biomicroscopy of the anterior and posterior segment or indirect ophthalmoscopy. Electroretinography was employed for assessment of the retinal function, and retinal imaging included spectral-domain OCT and fundus autofluorescence. A systematic evaluation of the disease stage was based on clinical criteria including physical examination, purposeful imaging (X-ray, echocardiography, and US abdomen), and laboratory tests as needed. Main Outcome Measures: Anatomical and functional assessment of the retina in patients with PH1, and the relationship between retinal dysfunction and kidney impairment. Results: A total of 16 eyes were examined in the study of 8 children ranging in age from 4 to 19 years. Four eyes (25%) showed normal structural and functional retinal findings, 8 eyes (50%) presented functional impairment in the absence of pathological structural findings, and 4 eyes (25%) had advanced retinal damage that manifested as significant morphological and functional impairment. There was no direct relationship between the severity of the renal disease and the severity of the retinal phenotype. Conclusions: Subjects with PH1 present varying severity levels of the retinal phenotype, with possible discrepancy between the clinical retinal morphology and the retinal function noted on electroretinography. These findings raise questions about the molecular basis of the retinal manifestations in PH1. The presence of functional impairment in the absence of evident crystal deposition in the retina suggests that, in addition to oxalate crystal accumulation, other biomolecular processes may play a role in the development of retinopathy.

Acute hemodialysis therapy in neonates with inborn errors of metabolism.

BACKGROUND: Inborn errors of metabolism (IEM), including organic acidemias and urea cycle defects, are characterized by systemic accumulation of toxic metabolites with deleterious effect on the developing brain. While hemodialysis (HD) is most efficient in clearing IEM-induced metabolic toxins, data regarding its use during the neonatal period is scarce. METHODS: We retrospectively summarize our experience with HD in 20 neonates with IEM-induced metabolic intoxication (seven with maple syrup urine disease, 13 with primary hyperammonia), over a 16-year period, between 2004 and 2020. All patients presented with IEM-induced neurologic deterioration at 48 h to 14 days post-delivery, and were managed with HD in a pediatric intensive care setting. HD was performed through an internal jugular acute double-lumen catheter (6.5-7.0 French), using an AK-200S (Gambro, Sweden) dialysis machine and tubing, with F3 or FXpaed (Fresenius, Germany) dialyzers. RESULTS: Median (interquartile range) age and weight at presentation were 5 (3-8) days and 2830 (2725-3115) g, respectively. Two consecutive HD sessions decreased the mean leucine levels from 2281 ± 631 to 179 ± 91 µmol/L (92.1% reduction) in MSUD patients, and the mean ammonia levels from 955 ± 444 to 129 ± 55 µmol/L (86.5% reduction), in patients with hyperammonemia. HD was uneventful in all patients, and led to marked clinical improvement in 17 patients (85%). Three patients (15%) died during the neonatal period, and four died during long-term follow-up. CONCLUSIONS: Taken together, our results indicate that HD is safe, effective, and life-saving for most neonates with severe IEM-induced metabolic intoxication, when promptly performed by an experienced and multidisciplinary team. A higher resolution version of the Graphical abstract is available as Supplementary information.

[INTRAVENOUS IMMUNOGLOBULIN TREATMENT TO PREVENT BK NEPHROPATHY IN PEDIATRIC RENAL TRANSPLANT RECIPIENTS WITH BK VIRUS].

AIMS: In this retrospective study we examined the safety and efficacy of high-dose intravenous immunoglobulin (HD-IVIG) therapy in preventing BKVN in pediatric renal transplant recipients with BK-viremia/viruria. BACKGROUND: BK virus nephropathy (BKVN) is diagnosed in 5-16% of pediatric renal transplant recipients and is preceded by BK viremia/viruria. Despite irreversible renal damage associated with BKVN, there is a lack of evidence-based guidelines for preventive measures in patients with BK viremia/viruria. METHODS: All pediatric renal transplant recipients under our care underwent routine testing for urine and blood BK virus, using the polymerase chain reaction (PCR) technique. Patients exhibiting BK-viruria < 107 copies/milliliter (ml) and/or BK-viremia<103 copies/ml without any evidence of BKVN, were managed with 50% dose reduction of the immunosuppressive drug mycophenolate mofetil (MMF). Absence of BK viral load decline within two months from MMF dose reduction was managed with HD-IVIG (at 2 grams/kg body weight). RESULTS: The study included 62 patients over a 6-year period; 31 patients (50%) showed BK-viremia/viruria; 13/31 patients (42%) suffered from significant and persistent BK-viremia/viruria, unresponsive to MMF dose reduction, and were managed with HD-IVIG; 12/13 (92%) showed significant BK viral load reduction within 6 months from HD-IVIG therapy. Except for transient headache, no patient exhibited major adverse effects to HD-IVIG therapy, and none developed overt BKVN during the study period. CONCLUSIONS: Preventive HD-IVIG therapy in pediatric renal transplant recipients with BK viremia/viruria unresponsive to MMF dose reduction is safe and effective in preventing the development of BKVN. Additional large-scale studies are necessary to establish our findings.

A Novel Homozygous In-Frame Deletion in Complement Factor 3 Underlies Early-Onset Autosomal Recessive Atypical Hemolytic Uremic Syndrome - Case Report.

Background and Objectives: Atypical hemolytic uremic syndrome (aHUS) is mostly attributed to dysregulation of the alternative complement pathway (ACP) secondary to disease-causing variants in complement components or regulatory proteins. Hereditary aHUS due to C3 disruption is rare, usually caused by heterozygous activating mutations in the C3 gene, and transmitted as autosomal dominant traits. We studied the molecular basis of early-onset aHUS, associated with an unusual finding of a novel homozygous activating deletion in C3. Design Setting Participants & Measurements: A male neonate with eculizumab-responsive fulminant aHUS and C3 hypocomplementemia, and six of his healthy close relatives were investigated. Genetic analysis on genomic DNA was performed by exome sequencing of the patient, followed by targeted Sanger sequencing for variant detection in his close relatives. Complement components analysis using specific immunoassays was performed on frozen plasma samples from the patient and mother. Results: Exome sequencing revealed a novel homozygous variant in exon 26 of C3 (c.3322_3333del, p.Ile1108_Lys1111del), within the highly conserved thioester-containing domain (TED), fully segregating with the familial disease phenotype, as compatible with autosomal recessive inheritance. Complement profiling of the patient showed decreased C3 and FB levels, with elevated levels of the terminal membrane attack complex, while his healthy heterozygous mother showed intermediate levels of C3 consumption. Conclusions: Our findings represent the first description of aHUS secondary to a novel homozygous deletion in C3 with ensuing unbalanced C3 over-activation, highlighting a critical role for the disrupted C3-TED domain in the disease mechanism.

Induction of retinopathy by fibrillar oxalate assemblies.

The formation of metabolite fibrillar assemblies represents a paradigm shift in the study of human metabolic disorders. Yet, direct clinical relevance has been attributed only to metabolite crystals. A notable example for metabolite crystallization is calcium oxalate crystals observed in various diseases, including primary hyperoxaluria. We unexpectedly observed retinal damage among young hyperoxaluria patients in the absence of crystals. Exploring the possible formation of alternative supramolecular organizations and their biological role, here we show that oxalate can form ordered fibrils with no associated calcium. These fibrils inflict intense retinal cytotoxicity in cultured cells. A rat model injected with oxalate fibrils recaptures patterns of retinal dysfunction observed in patients. Antibodies purified from hyperoxaluria patient sera recognize oxalate fibrils regardless of the presence of calcium. These findings highlight a new molecular basis for oxalate-associated disease, and to our knowledge provide the first direct clinical indication for the pathogenic role of metabolite fibrillar assemblies.

Follicular Eruption With Folliculotropic Lymphocytic Infiltrates Associated With Iatrogenic Immunosuppression: Report and Study of 3 Cases, and Review of the Literature.

BACKGROUND: Several cases of folliculotropic mycosis fungoides, associated with immunosuppressive therapy, including calcineurin inhibitors, have been reported in solid organ transplant patients. We have encountered 3 patients on immunosuppressive therapy who developed follicular eruptions with folliculocentric infiltrates of nonatypical lymphocytes. OBJECTIVE: To characterize these follicular eruptions and review the literature. METHODS: Three patients, aged 7-15 years, who were treated with systemic immunosuppressive therapy developed follicular eruptions characterized histopathologically by folliculocentric lymphocytic infiltrates. These were studied clinically, histopathologically, immunophenotypically, and molecularly for T-cell receptor (TCR) gene rearrangement. RESULTS: All 3 cases were characterized histopathologically by folliculocentric infiltrates of nonatypical CD3 T lymphocytes with variable follicular exocytosis. Two cases also showed follicular mucinosis. Marked reduction in CD7 staining, and marked predominance of CD4 cells over CD8 cells was observed in all 3 cases. The TCR gene rearrangement studies were monoclonal in 2 cases. Oral calcineurin inhibitors (2 cyclosporine A and 1 tacrolimus) were part of the therapeutic regimen in all 3 patients. Their cessation along with local corticosteroid creams in 2 patients, and phototherapy with oral acitretin in one patient, was associated with complete clinical remission. CONCLUSIONS: Patients undergoing systemic immunosuppressive therapy that includes calcineurin inhibitors might develop follicular eruption with some immunophenotypical variations and a monoclonal TCR gene rearrangement but lack sufficient cytomorphological features of folliculotropic mycosis fungoides. Altering the immunosuppressive agent including calcineurin inhibitors may result in regression of the eruptions.

Long-term hemodialysis therapy in neonates and infants with end-stage renal disease: a 16-year experience and outcome.

BACKGROUND: Peritoneal dialysis is the preferred mode of renal replacement therapy in infants with end-stage renal disease (ESRD). Hemodialysis (HD) is seldom used in neonates and infants due to the risk of major complications in the very young. METHODS: Demographic, clinical, laboratory, and imaging data on all infants younger than 12 months with ESRD who received HD in our Pediatric Dialysis Unit between January 1997 and June 2013 were analyzed. RESULTS: Eighteen infants (n = 6 male) with ESRD (median age 3 months; median weight 4.06 kg) received HD through a central venous catheter (CVC) for a total of 543 months (median duration per infant 16 months). Seven of the infants (39%) were neonates, and five (28%) had serious comorbidities. There were five episodes of CVC infection, which is a rate of 0.3/1000 CVC days. Median catheter survival time was 320 days. Most infants had good oral intake, and only four (22%) required a gastric tube; 14 (78%) infants displayed normal growth. Fourteen (78%) infants had hypertension, of whom four (22%) had severe cardiac complications; eight (44%) showed delayed psychomotor development. Eleven (61%) of the infants, including six (86%) of the neonates, survived. Five (28%) infants underwent renal transplantation; 10-year graft survival was 80%. CONCLUSIONS: Based on these results, long-term HD in neonates and infants with ESRD is technically feasible, can be implemented without major complications, carries a very low rate of CVC infection and malfunction, and results in adequate nutrition, good growth, as well as good kidney graft and patient survivals. Future efforts should aim to prevent hypertension and its cardiac sequelae, improve neurodevelopmental outcome, and lower mortality rate in these infants.

Low infection rates and prolonged survival times of hemodialysis catheters in infants and children.

BACKGROUND AND OBJECTIVES: Hemodialysis (HD) catheter-related complications are regarded as the main cause of HD failure in infants and children with ESRD. In this study, we determined HD catheter infection rates and survival times in children. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We analyzed demographic, clinical, laboratory, and microbiologic data on all infants and children with ESRD who received HD therapy through a tunneled central venous catheter (CVC) in our Pediatric Dialysis Unit between January 2001 and December 2009. Our strict care of HD-CVCs makes no use of any kind of prophylactic antibiotic therapy. RESULTS: Twenty-nine children with ESRD (median age, 10 years) received HD through a CVC, for a total of 22,892 days during the study period. Eleven (38%) children were infants (<1 year of age) who received HD for a cumulative 3779 days (16% of total). Fifty-nine CVCs were inserted, of which 13 (22%) were in infants. There were 12 episodes of CVC infection-a rate of 0.52/1000 CVC days. Four (33%) episodes occurred in infants-a rate of 1.06/1000 CVC days. Only three (5%) of the CVCs were removed because of infection. Median catheter survival time for all children was 310 days and for infants was 211 days. CONCLUSIONS: Very low CVC infection rates (one infection per 5 CVC years) and prolonged CVC survival times (around 1 year) are achievable in infants and children with ESRD receiving HD therapy by adhering to a strict catheter management protocol and without using prophylactic antibiotic therapy.

Infected subgaleal hematoma in a neonate.

Subgaleal hematoma (SGH) is an infrequent finding in neonates, occurring mostly after vacuum extraction deliveries. SGH can cause anemia, hypovolemic shock, and death. To date, only one case of neonatal infected SGH has previously been reported. We describe a term neonate with severe polymicrobial infection complicating SGH, including anaerobic bacteria, and with unique imaging features.