Impact of the first 24 h of continuous kidney replacement therapy on hemodynamics, ventilation, and analgo-sedation in critically ill children.

BACKGROUND: In a group of children admitted to the paediatric intensive care unit (PICU) receiving continuous kidney replacement therapy (CKRT), we aim to evaluate the data about their hemodynamic, ventilation and analgo-sedation profile in the first 24 h of treatment and possible associations with mortality. METHODS: Retrospective cohort study of children admitted to the PICU of the University Hospital of Padova undergoing CKRT between January 2011 and March 2021. Data was collected at baseline (T0), after 1 h (T1) and 24 h (T24) of CKRT treatment. The differences in outcome measures were compared between these time points, and between survivors and non-survivors. RESULTS: Sixty-nine patients received CKRT, of whom 38 (55%) died during the PICU stay. Overall, the vasoactive inotropic score and the adrenaline dose increased at T1 compared to T0 (p = 0.012 and p = 0.022, respectively). Compared to T0, at T24 patients showed an improvement in the following ventilatory parameters: Oxygenation Index (p = 0.005), Oxygenation Saturation Index (p = 0.013) PaO2/FiO2 ratio (p = 0.005), SpO2/FiO2 ratio (p = 0.002) and Mean Airway Pressure (p = 0.016). These improvements remained significant in survivors (p = 0.01, p = 0.027, p = 0.01 and p = 0.015, respectively) but not in non-survivors. No changes in analgo-sedative drugs have been described. CONCLUSIONS: CKRT showed a significant impact on hemodynamics and ventilation in the first 24 h of treatment. We observed a significant rise in the inotropic/vasoactive support required after 1 h of treatment in the overall population, and an improvement in the ventilation parameters at 24 h only in survivors.

Expanding the Spectrum of Extracorporeal Strategies in Small Infants with Hyperammonemia.

Hyperammonemia is a life-threatening condition mainly due to the neurotoxicity of ammonia. Ammonia scavengers may be insufficient, and extracorporeal treatment may be required. Continuous treatments are preferred, and a high-dose continuous renal replacement therapy (CRRT) must be prescribed to ensure a fast ammonia depletion. Many of the children with hyperammonemia are newborns, with lower blood volume than older children. The majority of the CRRT systems are adult-based, with large extracorporeal priming volumes and inadequate UF control. Recent strides have been made in the development of CRRT systems more suitable for young children with smaller sets to use in adult machines and dedicated monitors for neonates and infants. The main advantage of the machines for adults is the higher dialysis fluid flows, however with greater hemodynamic risks. Pediatric monitors have been designed to reduce the extracorporeal volume and to increase the precision of the treatment. However, they have substantial limitation in clearance performances. In this review, we discuss on current strategies to provide CRRT in newborns and small infants with hyperammonemia. We also presented our experience with the use of CARPEDIEM™ implemented in a CVVHDF modality, boosting the diffusive clearance with a post-replacement convective mechanism.

Acute paediatric kidney replacement therapies in Europe: demographic results from the EurAKId Registry.

BACKGROUND: Acute kidney injury (AKI), particularly that requiring dialysis, is a severe complication in hospitalized children that is associated with high morbidity and mortality. A prospective European AKI registry (EurAKId registry, NCT02960867) was created to describe the epidemiology and outcomes of paediatric patients treated with acute dialysis. METHODS: Children were recruited who were between 0 and 18 years of age and were treated both in and outside the paediatric intensive care unit (PICU) with peritoneal dialysis (PD), haemodialysis (HD) or continuous kidney replacement therapy (CKRT) for AKI or metabolic derangement, fluid overload (FO), sepsis or respiratory distress. Five age groups and 12 categories of primary diseases were defined. RESULTS: Data on 340 patients were analysed, of whom 86% received dialysis for AKI and 14% for reasons other than AKI. Boys accounted for 60% of the patients. Illness severity was greater in children with cardiac and haematologic diseases than those with kidney diseases. Most patients received dialysis in the PICU (84%). The most frequently used dialysis modality was CKRT (64%), followed by PD (14%) and HD (14%). The overall survival rate was 65%. Survival was significantly lower in children with three comorbidities than in children with no comorbidities (41% and 83%; P < 0.001). CONCLUSIONS: The EurAKId registry is the first prospective registry considering paediatric acute kidney replacement therapies (KRTs) in both critical and non-critical care settings, focusing on the three dialysis modalities in Europe. The clinical indications for KRT have expanded; our population was characterized by critically ill patients, primarily boys, who frequently received dialysis in the PICU with CKRT.

Renal transplantation in sensitized children and young adults: a nationwide approach.

Background: High levels of preformed anti-HLA antibodies dramatically diminish renal transplant outcomes. Most desensitization programmes guarantee good intermediate outcomes but quite disappointing long-term prognosis. The search for a fully compatible kidney increases time on the waiting list. Methods: In February 2011, a nationwide hyperimmune programme (NHP) was begun in Italy: all available kidneys are primarily proposed to highly sensitized patients with a panel reactive antibody above 80%. In this manuscript, we evaluate the outcome of paediatric patients transplanted with this approach. Results: Twenty-one patients were transplanted. Complete data are available for 20 patients. Mean age at transplantation was 14.5 years [standard deviation (SD) ± 5.5)]. Mean time on the waiting list was 29.3 months (SD ± 27.5). Median follow-up was 29.2 months (range: 11.2-59.3). The average number of HLA mismatches in these patients was 2.3 versus 3.7 in 48 standard patients transplanted in the same period (P < 0.001). Only one graft was lost. Two cases of humoral rejection occurred and were successfully treated. No cellular rejection was reported. Median creatinine clearance was 84, 88, 77 and 77 mL/min/1.73 m 2 respectively 1, 6, 12 and 24 months after transplant. Conclusions: Transplantation of sensitized patients avoiding prohibited antigens is feasible, at least in a selected cohort of patients. In order to be able to further improve this approach, which in our opinion is very successful, it would be necessary to expand the donor pool, possibly increasing the number of countries participating in the programme. In this series, time on the waiting list did not increase significantly. This allocation policy should ideally lead to an outcome comparable to that expected in standard patients, which is particularly desirable in young patients who have the longest life expectancy. Since long-term results of desensitization programmes are not (yet) convincing, we suggest that these programmes should be reserved for selected cases where compatible organs cannot be found within a reasonable time span.

Viral load of EBV DNAemia is a predictor of EBV-related post-transplant lymphoproliferative disorders in pediatric renal transplant recipients.

BACKGROUND: Post-transplant lymphoproliferative disorder (PTLD) is a severe complication of solid organ transplantation that can be classified into two major subtypes, namely, early lesions and non-early lesions, based on histopathological findings. In the vast majority of cases, proliferating cells are B lymphocytes and, most frequently, proliferation is induced by Epstein-Barr virus (EBV) infection. METHODS: The aim of our study was to evaluate the natural history of EBV infection and its possible evolution toward PTLD in a pediatric cohort of patients who received a renal transplant between January 2000 and December 2013. A total of 304 patients were evaluated for this study, of whom 103 tested seronegative for EBV at transplantation. RESULTS: Following transplantation, 50 of the 103 seronegative patients (48.5%) developed a first EBV infection, based on the results of PCR assays for EBV DNA, with 19 of these patients ultimately reverting to the negative state (<3000 copies/ml). Among the 201 seropositive patients only 40 (19.9%) presented a reactivation of EBV. Non-early lesions PTLD was diagnosed in ten patients, and early lesions PTLD was diagnosed in five patients. In all cases a positive EBV viral load had been detected at some stage of the follow-up. Having a maximum peak of EBV viral load above the median value observed in the whole cohort (59,909.5 copies/ml) was a significant and independent predictor of non-early lesions PTLD and all PTLD onset. CONCLUSIONS: A high PCR EBV viral load is correlated with the probability of developing PTLD. The definition of a reliable marker is essential to identify patients more at risk of PTLD and to personalize the clinical approach to the single patient.

Percutaneous endoscopic gastrostomy in children receiving peritoneal dialysis: A tertiary centre long-term experience and literature review.

BACKGROUND: Children with severe chronic kidney disease receiving maintenance peritoneal dialysis (PD) are often malnourished and may require nutritional supplementation. Recent PD guidelines address laparoscopic and open surgical gastrostomy as safe approaches in children established on PD, while existing evidence on percutaneous endoscopic gastrostomy (PEG) is still lacking; as well as the role of perioperative antibiotic and antifungal prophylaxis. Hence, this study aimed to report our experience with PEG placement in patients on PD and compare it with the available literature. METHODS: We retrospectively reviewed the medical records from patients on PD, who underwent PEG placement at a tertiary referral centre between 2000 and 2020. Data on perioperative management, complications and outcomes were retrieved. An extensive literature search was performed; studies describing PEG placement and perioperative prophylaxis in patients on PD were used as a comparison. Descriptive statistical analysis was conducted. RESULTS: Seven patients (five males) were included. Perioperative antibiotic and antifungal prophylaxis were standard practice. At a median follow-up of 27 months (10-75), the peritonitis rate was 0.2 patient/years. No statistical significance was found between the peritonitis rate before and after PEG placement (p = 0.2). Patients' demographics and postoperative complications were comparable to the reported studies. CONCLUSIONS: Based on our experience, our technique of PEG insertion with antimicrobial prophylaxis is feasible and associated with an acceptable complication risk in patients on PD. Further multicentric studies about surgical technique in patients on PD will be necessary to verify the feasibility of PEG and standardise the perioperative protocol.

Lumasiran treatment in pediatric patients with PH1: real-world data within a compassionate use program in Italy.

Background: Primary hyperoxaluria (PH) is a rare, severe genetic disorder, characterized by increased urinary excretion of calcium oxalate, which is responsible for kidney damage and systemic clinical manifestations. Since the year 2020, a new molecule, lumasiran, based on RNA interference (RNAi) technology, has been added to the traditional therapeutic approach. The aim of this analysis was to define the baseline characteristics of a PH1 pediatric population treated with lumasiran in a compassionate-use program setting, and to evaluate the medium-term efficacy of this drug in the routine clinical setting. Methods: A retrospective observational analysis was conducted in nine pediatric patients (male:female 5:4; median age at lumasiran start 1.9 years, range 0-14.1). Data concerning oxalate concentration in plasma and urine, kidney stones events, ultrasound and kidney function were collected during the study period (follow-up, mean ± standard deviation: 15.3 ± 5 months). Results: In this analysis, a reduction in the urinary oxalate to creatinine ratio (reduction range within the sixth month of treatment from 25.8% to 69.6%, median 51.2%) as well as plasma oxalate concentration under the limit of supersaturation of oxalate in all the patients. Only one patient presented new stone events; kidney ultrasonographic findings related to nephrocalcinosis remained stable in eight out of nine patients. Glomerular filtration rate remained stable during treatment. No adverse events related to lumasiran were noted. Conclusion: Data from this analysis support the efficacy and safety of lumasiran in a pediatric clinical setting, especially if administrated in early life.

Long-term Effects of Kidney Transplantation Compared With Dialysis on Intima-media Thickness in Children-Results From the 4C-T Study.

BACKGROUND: Children requiring kidney replacement therapy experience high burden of cardiovascular (CV) disease leading to increased mortality. Intima-media thickness (IMT) indicating atherosclerosis is a validated surrogate marker for future CV events. METHODS: We investigated the effect of different treatment modalities (dialysis, preemptive kidney transplantation (KTx), late KTx after dialysis) on IMT by multivariable linear mixed-effect modeling. Patients were enrolled in a prospective cohort study. RESULTS: A total of 261 analyzed children had a mean follow-up of 3 y. Children after preemptive and late KTx had lower levels of IMT when compared with dialysis. Using an interaction term, a significant progression of IMT over time was seen during dialysis (ß = 0.0053 mm/y, P   =  0.004). IMT before the start of therapy was the most influential determinant in all models. Low IMT was associated with maintenance steroid treatment after preemptive KTx. High IMT on dialysis was associated with higher systolic blood pressure, lower body mass index, lower serum albumin, and lower bicarbonate. CONCLUSIONS: IMT remained rather stable in children several years after KTx. In contrast, children on dialysis had higher IMT values, which increased over time. In these children, blood pressure control, calorie and protein intake, and acid-base homeostasis seem important. Taken together, children might profit from early transplantation to limit accumulation of CV risk.

Complex Bench Surgery Does Not Increase the Risk of Vascular Complications after Pediatric Kidney Transplantation.

INTRODUCTION: Vascular complications are severe complications of pediatric kidney transplantation (KT). We aimed to investigate whether a complex bench surgery (BS) affects the outcomes. METHODS: All pediatric KT performed at the University Hospital of Padua from 2015 to 2019 were analyzed, comparing those in which a standard BS was possible to those that necessitated a complex BS. The rates of vascular complications, patients' outcome, and graft survival were compared in the two groups. RESULTS: Eighty KTs were performed in 78 patients with a median age of 11 years (interquartile range [IQR] 4.3-14) and a median body weight of 24 kg (IQR 13-37). Thirty-nine donor kidneys (49%) needed a complex BS due to anomalies of renal veins in 12 (31%) and renal arteries in 16 (41%). The remaining 11 grafts (28%) underwent an elongation of the vein. There was no difference in the rate of primary graft non function (p = 0.97), delayed graft function (p = 0.72), and overall survival (p = 0.27). The rates of vascular complications, bleedings, and venous graft thrombosis were similar (p = 0.51, p = 0.59, p = 0.78, respectively). No arterial thrombosis or stenosis was reported. CONCLUSION: Complex BS did not compromise survival of the graft and did not put the allograft at risk of vascular complications, such as bleedings or thrombosis.

Urinary DKK3 as a biomarker for short-term kidney function decline in children with chronic kidney disease: an observational cohort study.

BACKGROUND: Childhood-onset chronic kidney disease is a progressive condition that can have a major effect on life expectancy and quality. We evaluated the usefulness of the kidney tubular cell stress marker urinary Dickkopf-related protein 3 (DKK3) in determining the short-term risk of chronic kidney disease progression in children and identifying those who will benefit from specific nephroprotective interventions. METHODS: In this observational cohort study, we assessed the association between urinary DKK3 and the combined kidney endpoint (ie, the composite of 50% reduction of the estimated glomerular filtration rate [eGFR] or progression to end-stage kidney disease) or the risk of kidney replacement therapy (ie, dialysis or transplantation), and the interaction of the combined kidney endpoint with intensified blood pressure reduction in the randomised controlled ESCAPE trial. Moreover, urinary DKK3 and eGFR were quantified in children aged 3-18 years with chronic kidney disease and urine samples available enrolled in the prospective multicentre ESCAPE (NCT00221845; derivation cohort) and 4C (NCT01046448; validation cohort) studies at baseline and at 6-monthly follow-up visits. Analyses were adjusted for age, sex, hypertension, systolic blood pressure SD score (SDS), BMI SDS, albuminuria, and eGFR. FINDINGS: 659 children were included in the analysis (231 from ESCAPE and 428 from 4C), with 1173 half-year blocks in ESCAPE and 2762 in 4C. In both cohorts, urinary DKK3 above the median (ie, >1689 pg/mg creatinine) was associated with significantly greater 6-month eGFR decline than with urinary DKK3 at or below the median (-5·6% [95% CI -8·6 to -2·7] vs 1·0% [-1·9 to 3·9], p<0·0001, in ESCAPE; -6·2% [-7·3 to -5·0] vs -1·5% [-2·9 to -0·1], p<0·0001, in 4C), independently of diagnosis, eGFR, and albuminuria. In ESCAPE, the beneficial effect of intensified blood pressure control was limited to children with urinary DKK3 higher than 1689 pg/mg creatinine, in terms of the combined kidney endpoint (HR 0·27 [95% CI 0·14 to 0·55], p=0·0003, number needed to treat 4·0 [95% CI 3·7 to 4·4] vs 250·0 [66·9 to ∞]) and the need for kidney replacement therapy (HR 0·33 [0·13 to 0·85], p=0·021, number needed to treat 6·7 [6·1 to 7·2] vs 31·0 [27·4 to 35·9]). In 4C, inhibition of the renin-angiotensin-aldosterone system resulted in significantly lower urinary DKK3 concentrations (least-squares mean 12 235 pg/mg creatinine [95% CI 10 036 to 14 433] in patients not on angiotensin-converting enzyme inhibitors or angiotensin 2 receptor blockers vs 6861 pg/mg creatinine [5616 to 8106] in those taking angiotensin-converting enzyme inhibitors or angiotensin 2 receptor blockers, p<0·0001). INTERPRETATION: Urinary DKK3 indicates short-term risk of declining kidney function in children with chronic kidney disease and might allow a personalised medicine approach by identifying those who benefit from pharmacological nephroprotection, such as intensified blood pressure lowering. FUNDING: None.

Early Use of Sotrovimab in Children: A Case Report of an 11-Year-Old Kidney Transplant Recipient Infected with SARS-CoV-2.

BACKGROUND: The use of virus-neutralizing monoclonal antibodies has been approved in fragile populations, including kidney transplant recipients, who are at risk of developing severe COVID-19. Sotrovimab is the only currently available anti-SARS-CoV-2 neutralizing monoclonal antibody with activity against the new Omicron variant of concern. While sotrovimab has been approved in adolescents and adults, studies regarding its efficacy and safety in children aged less than 12 years old and weighing less than 40 kg are still lacking. Here, we report a first case of a child, who was treated early with sotrovimab after a kidney transplant. CASE REPORT: At the end of January 2022, a 11-year-old male child underwent a deceased-donor kidney transplant and became infected with SARS-CoV-2 during the first day after surgery. Due to the increased risk of developing severe COVID-19, based on the predominance of Omicron and the patient's renal function, the child was treated with sotrovimab. The clinical course was successful and no adverse reactions were reported. CONCLUSIONS: For the first time, we report the well-tolerated use of sotrovimab in children under 12 years old. As the pandemic affects children across the globe, urgent data on sotrovimab dosing in children with a higher risk of developing severe COVID-19 are needed.

SARS-CoV2 Related Multi System Inflammatory Syndrome in a Child with Chronic Kidney Disease: Case Report.

Since April 2020, several paediatric cases were reported with a multisystemic inflammatory syndrome related with SARS-CoV2, called MIS-C. In this case report, we describe a 2-year-old male with end-stage renal disease (ESRD) in renal replacement therapy (RRT) with peritoneal dialysis and severe hypertension affected by a severe SARS-CoV2 related illness characterised by multiorgan failure and need for intensive care, with clinical and instrumental features compatible with MIS-C. Most paediatric patients with kidney disease experience mild SARS-CoV2 disease and to our knowledge, this is the first case of a child with chronic kidney disease suffering from MIS-C. We believe that chronic kidney disease together with dialysis status and severe hypertension play a crucial role on developing severe forms of SARS-CoV2 related disease.

Early childhood height-adjusted total kidney volume as a risk marker of kidney survival in ARPKD.

Autosomal recessive polycystic kidney disease (ARPKD) is characterized by bilateral fibrocystic changes resulting in pronounced kidney enlargement. Impairment of kidney function is highly variable and widely available prognostic markers are urgently needed as a base for clinical decision-making and future clinical trials. In this observational study we analyzed the longitudinal development of sonographic kidney measurements in a cohort of 456 ARPKD patients from the international registry study ARegPKD. We furthermore evaluated correlations of sonomorphometric findings and functional kidney disease with the aim to describe the natural disease course and to identify potential prognostic markers. Kidney pole-to-pole (PTP) length and estimated total kidney volume (eTKV) increase with growth throughout childhood and adolescence despite individual variability. Height-adjusted PTP length decreases over time, but such a trend cannot be seen for height-adjusted eTKV (haeTKV) where we even observed a slight mean linear increase of 4.5 ml/m per year during childhood and adolescence for the overall cohort. Patients with two null PKHD1 variants had larger first documented haeTKV values than children with missense variants (median (IQR) haeTKV 793 (450-1098) ml/m in Null/null, 403 (260-538) ml/m in Null/mis, 230 (169-357) ml/m in Mis/mis). In the overall cohort, estimated glomerular filtration rate decreases with increasing haeTKV (median (IQR) haeTKV 210 (150-267) ml/m in CKD stage 1, 472 (266-880) ml/m in stage 5 without kidney replacement therapy). Strikingly, there is a clear correlation between haeTKV in the first eighteen months of life and kidney survival in childhood and adolescence with ten-year kidney survival rates ranging from 20% in patients of the highest to 94% in the lowest quartile. Early childhood haeTKV may become an easily obtainable prognostic marker of kidney disease in ARPKD, e.g. for the identification of patients for clinical studies.

The European Rare Kidney Disease Registry (ERKReg): objectives, design and initial results.

BACKGROUND: The European Rare Kidney Disease Reference Network (ERKNet) recently established ERKReg, a Web-based registry for all patients with rare kidney diseases. The main objectives of this core registry are to generate epidemiological information, identify current patient cohort for clinical research, explore diagnostic and therapeutic management practices, and monitor treatment performance and patient's outcomes. The registry has a modular design that allows to integrate comprehensive disease-specific registries as extensions to the core database. The diagnosis (Orphacode) and diagnostic information (clinical, imaging, histopathological, biochemical, immunological and genetic) are recorded. Anthropometric, kidney function, and disease-specific management and outcome items informing a set of 61 key performance indicators (KPIs) are obtained annually. Data quality is ensured by automated plausibility checks upon data entry and regular offline database checks prompting queries. Centre KPI statistics and benchmarking are calculated automatically. RESULTS: Within the first 24 months since its launch, 7607 patients were enrolled to the registry at 45 pediatric and 12 specialized adult nephrology units from 21 countries. A kidney disease diagnosis had been established in 97.1% of these patients at time of enrolment. While 199 individual disease entities were reported by Orphacode, 50% of the cohort could be classified with 11, 80% with 43 and 95% with 92 codes. Two kidney diagnoses were assigned in 6.5% of patients; 5.9% suffered from syndromic disease. Whereas glomerulopathies (54.8%) and ciliopathies including autosomal dominant polycystic kidney disease (ADPKD) (31.5%) were the predominant disease groups among adults, the pediatric disease spectrum encompassed congenital anomalies of the kidney and urinary tract (CAKUT) (33.7%), glomerulopathies (30.7%), ciliopathies (14.0%), tubulopathies (9.2%), thrombotic microangiopathies (5.6%), and metabolic nephropathies (4.1%). Genetically confirmed diagnoses were reported in 24% of all pediatric and 12% adult patients, whereas glomerulopathies had been confirmed by kidney biopsy in 80.4% adult versus 38.5% pediatric glomerulopathy cases. CONCLUSIONS: ERKReg is a rapidly growing source of epidemiological information and patient cohorts for clinical research, and an innovative tool to monitor management quality and patient outcomes.

Usefulness of 99mTc-dimercaptosuccinic acid renal scan in the diagnosis and follow-up of acute tubulointerstitial nephritis in children.

BACKGROUND: Symptoms and signs of acute tubulointerstitial nephritis (ATIN) are nonspecific; therefore, renal biopsy is often necessary to clarify the diagnosis. The aim of this study was to evaluate the use of 99mTc-dimercaptosuccinic acid (DMSA) scintigraphy in the diagnosis and follow-up of ATIN. METHODS: We retrospectively reviewed the charts of five patients (nine renal units) with a median age of 14 years who underwent DMSA scan after a clinical and/or biopsy-proven diagnosis of ATIN. The exam was performed within 1 month after disease onset and repeated at a median time of 12 months after the acute phase. RESULTS: DMSA renal scans performed during the acute phase allowed the discovery of suggestive findings, including diffuse reduction of the renal uptake of radionuclide and presence of multiple 'cold' focal lesions in a corticomedullary distribution. The follow-up scintigraphy resulted normal in two patients who were treated with steroids and in one patient who presented a mild renal dysfunction in the acute phase. By contrast, the control scan showed persistent renal damage in one patient who was further readmitted because of hypertension and in one renal transplanted patient who presented a Stage 3 acute kidney injury in the acute phase. CONCLUSIONS: DMSA renal scan might be a reliable tool for an early non-invasive diagnosis of ATIN in children and might be particularly useful in those patients who are not candidates for a kidney biopsy. Moreover, DMSA scan gives accurate follow-up evaluation, as it allows monitoring of the evolution of acute renal parenchymal inflammation with potential risk of renal scar formation. Due to the small sample size, our findings warrant further validation in a larger study.