Simultaneous or sequential kidney-liver transplantation in primary hyperoxaluria.

BACKGROUND: Primary hyperoxaluria type 1 is responsible for pediatric kidney failure in 1 to 2% of cases. Novel therapies based on RNA interference are changing the natural history of the disease. However, for those who do progress to kidney failure, and for patients living in countries that cannot afford these expensive therapies, liver-kidney transplantation may remain the only efficient therapy. METHODS: The aim of the study was to evaluate the outcome of patients with primary hyperoxaluria type 1 who received simultaneous or sequential liver-kidney transplantation. We retrospectively evaluated 10 patients, five of whom received a simultaneous transplantation, and five underwent sequential transplantation, with a median postponement of the kidney transplantation of 8 months (range 4-20). Among the patients, 5 were from medium-low income countries. RESULTS: Median follow up was 3.2 years (range 1.6-11). Median estimated glomerular filtration rate at 6 and 12 months was 81.2 (range: 45.7-108.8) and 79.3 ml/min/1.73m2 (range 54.7-112.1) in patients who underwent simultaneous transplantation, and 45.7 (range 34.5-86.7) and 38.3 ml/min/1.73m2 (range 29.9-77.5) in those with sequential transplantation (p:NS). Biopsies performed at 6 and 12 months showed precipitation of calcium oxalate crystals in 7 patients, demonstrating the recurrence of deposition despite the delay between liver and kidney transplantation. No differences in kidney function or in post-transplant renal oxalate precipitation were observed between patients that underwent bilateral nephrectomy and those who did not. As of their most recent follow up, none of the patients has lost their kidney graft. CONCLUSIONS: Our study shows that by adapting the transplant strategy to individual cases, patients with primary hyperoxaluria type 1 can be successfully treated.

Factors influencing circuit lifetime in paediatric continuous kidney replacement therapies - results from the EurAKId registry.

BACKGROUND: Continuous kidney replacement therapy (CKRT) has recently become the preferred kidney replacement modality for children with acute kidney injury (AKI). We hypothesise that CKRT technical parameters and treatment settings in addition to the clinical characteristics of patients may influence the circuit lifetime in children. METHODS: The study involved children included in the EurAKId registry (NCT02960867), who underwent CKRT treatment. We analysed patient characteristics and CKRT parameters. The primary end point was mean circuit lifetime (MCL). Secondary end points were number of elective circuit changes and occurrence of dialysis-related complications. RESULTS: The analysis was composed of 247 children who underwent 37,562 h of CKRT (median 78, IQR 37-165 h per patient). A total of 1357 circuits were utilised (3, IQR 2-6 per patient). MCL was longer in regional citrate anticoagulation (RCA), compared to heparin (HA) and no anticoagulation (NA) (42, IQR 32-58 h; 24, IQR 14-34 h; 18, IQR 12-24 h, respectively, p < 0.001). RCA was associated with longer MCL regardless of the patient's age or dialyser surface. In multivariate analysis, MCL correlated with dialyser surface area (beta = 0.14, p = 0.016), left internal jugular vein vascular access site (beta = -0.37, p = 0.027), and the use of HA (beta = -0.14, p = 0.038) or NA (beta = -0.37, p < 0.001) vs. RCA. RCA was associated with the highest ratio of elective circuit changes and the lowest incidence of complications. CONCLUSION: Anticoagulation modality, dialyser surface, and vascular access site influence MCL. RCA should be considered when choosing first-line anticoagulation for CKRT in children. Further efforts should focus on developing guidelines and clinical practice recommendations for paediatric CKRT.

Impact of CytoSorb and CKRT on hemodynamics in pediatric patients with septic shock: the PedCyto study.

Background: There is a lack of data to support the use of hemoadsorption in pediatric septic shock. The aim of our study was to assess the effectiveness and safety of CytoSorb therapy in this setting. Methods: Phase II interventional single arm pilot study in which 17 consecutive children admitted with septic shock who required continuous kidney replacement therapy (CKRT) and weighed ≥10 kg were included. A CytoSorb (CytoSorbents Inc, New Jersey, USA) hemoadsorption cartridge was added to the CKRT every 24 h for a maximum of 96 h. A control group of 13 children with septic shock treated with CKRT but not hemoadsorption at Children's Hospital Bambino Gesù and enrolled in the EuroAKId register was selected as an historical cohort. The primary outcome of the study was a reduction in vasopressor or inotrope dose of >50% from baseline by the end of CytoSorb therapy. Secondary outcomes included hemodynamic and biological changes, changes in severity scores, and 28-day mortality. Results: There were significant decreases in the Vasoactive Inotropic Score (VIS) and the Pediatric Logistic Organ Dysfunction 2 (PELOD-2) score at 72 and 96 h from the start of the CytoSorb therapy compared to baseline; the reductions were larger in the hemoadsorption group than in the control group (historical cohort). 28-day mortality was lower, although not significantly, in the hemoadsorption group when compared to the control group (5/17 [29%] vs. 8/13 [61%] OR 0.26 [95% CI: 0.05-1.2]; p = 0.08). Conclusions: CytoSorb therapy may have some benefits in pediatric patients with septic shock. Future larger randomized trials are needed in this setting. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT05658588, identifier (Clinicaltrials.gov NCT05658588).

Impact of Continuous Kidney Replacement Therapy and Hemoadsorption with CytoSorb on Antimicrobial Drug Removal in Critically Ill Children with Septic Shock: A Single-Center Prospective Study on a Pediatric Cohort.

Background: Extracorporeal therapies (ET) are increasingly used in pediatric settings as adjuvant therapeutic strategies for overwhelming inflammatory conditions. Although these treatments seem to be effective for removing inflammatory mediators, their influence on antimicrobials pharmacokinetic should not be neglected. Methods: A prospective observational study of children admitted to the pediatric intensive care unit (PICU) with a diagnosis of sepsis/septic shock. All critically ill children received hemoadsorption treatment with CytoSorb (CS) in combination with CKRT. Therapeutic drug monitoring has been performed on 10 critically ill children, testing four antimicrobial molecules: meropenem, ceftazidime, amikacin and levofloxacin. In order to evaluate the total and isolated CKRT and CS contributions to antibiotic removal, blood samples at each circuit point (post-hemofilter, post-CS and in the effluent line) were performed. Therefore, the clearance and mass Removal (MR) of the hemofilter and CS were calculated. Results: Our preliminary report describes a different impact of CS on these target drugs removal: CS clearance was low for amikacine (6-12%), moderate for ceftazidime (43%) and moderate to high for levofloxacine (52-72%). Higher MR and clearance were observed with CKRT compared to CS. To the best of our knowledge, this is the first report regarding pharmacokinetic dynamics in critically ill children treated with CKRT and CS for septic shock.

A simplified protocol of regional citrate anticoagulation with phosphate-containing solutions in infants and children treated with continuous kidney replacement therapy.

BACKGROUND: Regional citrate anticoagulation (RCA) is the preferred modality of anticoagulation used in continuous kidney replacement therapy (CKRT) in adults and less extensively in children. Potential metabolic complications limit widespread use in infants, neonates, and in children with liver failure. METHODS: We report our experience with a simplified protocol in 50 critically ill children, infants, and neonates, some of them with liver failure, with commercially available solutions containing phosphorous and higher concentration of potassium and magnesium. RESULTS: RCA allowed attainment of a mean filter lifetime of 54.5 ± 18.2 h, 42.5% of circuits lasted more than 70 h, and scheduled change was the most frequent cause of CKRT interruption. Patient Ca++ and circuit Ca++ were maintained in the target range with mean values of 1.15 ± 0.13 mmol/l and 0.38 ± 0.07 mmol/l, respectively. No session had to be stopped because of metabolic complications. The most frequent complications were hyponatremia, hypomagnesemia, and metabolic acidosis mostly related to primary disease and critical illness. No session had to be stopped because of citrate accumulation (CA). Transitory CA occurred in 6 patients and was managed without requiring RCA interruption. No patients with liver failure presented CA episodes. CONCLUSIONS: In our experience, RCA with commercially available solutions was easily applied and managed in critically ill children, even in patients with low weight or with liver failure. Solutions containing phosphate and higher concentrations of magnesium and potassium allowed reduction of metabolic derangement during CKRT. Prolonged filter life was ensured with no detrimental effects on patients and reduced staff workload. A higher resolution version of the Graphical abstract is available as Supplementary information.

Preliminary Evaluation of Sedentary Lifestyle in Italian Children after Solid Transplant: What Role Could Physical Activity Play in Health? It Is Time to Move.

BACKGROUND: Advances in the medical-surgical field have significantly increased survival after solid organ transplantation in the pediatric population. However, these patients are predisposed to the development of long-term complications (e.g., cardiovascular disease). The therapeutic role of physical activity (PA) to counteract these complications is well known. The purpose of the study was to investigate the level of PA in a pediatric population after solid organ transplantation. METHODS: In the first 4 weeks at the beginning of the school year, the Physical Activity Questionnaire for Older Children and Adolescents was administered to young patients who had previously undergone solid transplants at our institute. RESULTS: Questionnaires of 49 patients (57.1% female, mean age 13.2 ± 3.5 years) were analyzed and 32.7% of subjects did not perform any exercise during school physical education classes. Only 24% practiced a moderate quantity of exercise in the previous week (2-3 times/week) and 72% engaged in sedentary behaviors during weekends. CONCLUSIONS: Preliminary data confirmed that young recipients are still far from meeting the minimum indications of the World Health Organization on PA and sedentary behavior. It will be necessary to increase their involvement in PA programs in order not only to increase their life expectancy but also to improve their quality of life.

Reversible glomerular damage in disseminated intravascular coagulation.

BACKGROUND: Brain death secondary to traumatic brain injury is one of the main sources of organs for transplantation but it can be associated with disseminated intravascular coagulation, which has been considered a relative contraindication for kidney donation. METHODS: We describe two successful pediatric cases of kidney transplantation from a single donor with disseminated intravascular coagulation. RESULTS: A 17-year-old male donor died from head injury and both kidneys were offered to our center. Within 24 h, donor's Hb and platelets dropped to 8.3 g/dl and 32 000/mcl, respectively, serum creatinine reached 2.01 mg/dl, and urinalysis showed proteinuria (300 mg/dl). Pre-implant biopsy showed massive occlusion of glomerular capillaries by fibrin thrombi containing fragmented red blood cells and inflammatory cells, and acute tubular damage. Arterioles and small arteries were spared. A diagnosis of DIC was made. The kidneys were transplanted in a 16-year-old girl and a 13-year-old boy. Slow recovery of graft function was observed in both recipients. On post-operative day 3, platelets dropped to a minimum value of 66 000 and 86 000/mcl, respectively. Diuresis was always present. On day 4, platelets started to rise. Six months later, both recipients attained normal renal function. A six-month protocol biopsy showed no microthrombi or other signs of disseminated intravascular coagulation. CONCLUSIONS: Despite the limited data available in literature, the outcome of these two cases is positive. Thus, pre-implant kidney biopsy, even if it reveals massive thrombotic occlusion of glomerular capillaries compatible with diagnosis of disseminated intravascular coagulation, should not be considered an absolute contraindication to transplantation.

A clinical approach to children with C3 glomerulopathy.

C3 glomerulopathy is a relatively new clinical entity that represents a challenge both to diagnose and to treat. As new therapeutic agents that act as complement inhibitors become available, many with an oral formulation, a better understanding of this disease and of the underlying complement dysregulation driving it has become increasingly useful to optimize patient care. Moreover, recent advances in research have clarified the role of complement in other glomerular diseases in which its role was less established, namely in immune-complex membranoproliferative glomerulonephritis (IC-MPGN), ANCA-vasculitis, IgA nephropathy, and idiopathic membranous nephropathy. Complement inhibitors are being studied in adult and adolescent clinical trials for these indications. This review summarizes current knowledge and future perspectives on every aspect of the diagnosis and management of C3 glomerulopathy and elucidates current understanding of the role of complement in this condition and in other glomerular diseases in children. An overview of ongoing trials involving therapeutic agents targeting complement in glomerular diseases is also provided.

Returning to dialysis after kidney allograft failure: the experience of the Italian Registry of Paediatric Chronic Dialysis.

BACKGROUND: The need for dialysis after kidney allograft failure (DAGF) is among the top five reasons for dialysis initiation, making this an important topic in clinical nephrology. However, data are scarce on dialysis choice after transplantation and clinical outcomes for DAGF in children. METHODS: Patients receiving chronic dialysis < 18 years were recorded from January 1991 to January 2019 by the Italian Registry of Pediatric Chronic Dialysis (IRPCD). We investigated factors influencing choice of dialysis modality, patient outcome in terms of mortality, switching dialysis modality, and kidney transplantation. RESULTS: Among 118 patients receiving DAGF, 41 (35%) were treated with peritoneal dialysis (PD), and 77 (65%) with haemodialysis (HD). Significant predictors for treatment with PD were younger age at dialysis start (OR 0.85 per year increase [95%CI 0.72-1.00]) and PD use before kidney transplantation (OR 8.20 [95%CI 1.82-37.01]). Patients entering DAGF in more recent eras (OR 0.87 per year increase [95%CI 0.80-0.94]) and with more than one dialysis modality before kidney transplantation (OR 0.56 for being treated with PD [0.12-2.59]) were more likely to be initiated on HD. As compared to patients on HD, those treated with PD exhibited increased but non-significant mortality risk (HR 2.15 [95%CI 0.54-8.6]; p = 0.28) and higher prevalence of dialysis-related complications during DAGF (p = 0.002) CONCLUSIONS: Patients entering DAGF in more recent years are more likely to be initiated on HD. In this specific population of children, use of PD seems associated with a more complicated course. A higher resolution version of the Graphical abstract is available as Supplementary information.

Ofatumumab rescue treatment in post-transplant recurrence of focal segmental glomerulosclerosis.

BACKGROUND: Treatment of post-transplant focal segmental glomerulosclerosis (FSGS) recurrence is still debated. The use of the fully human anti-CD20 monoclonal antibody ofatumumab has been suggested. CASE-DIAGNOSIS/TREATMENT: Two boys with FSGS received a kidney transplantation at the age of 15 years from a deceased and a living donor. Maintenance therapy consisted of calcineurin inhibitors, antiproliferative agents, and prednisone. Early post-transplant FSGS recurrence was observed after 2 and 3 days. Rituximab infusion and plasmapheresis sessions were performed with transient clinical improvement in the first patient, and no apparent response in the second patient. Both patients were treated with two ofatumumab infusions, which induced in patient #1 a complete and stable remission for more than 12 months and in patient #2 a partial remission with a progressive reduction of proteinuria and normalization of serum protein levels. CONCLUSIONS: Ofatumumab may be a therapeutic option for post-transplant FSGS recurrence in patients who respond poorly to rituximab.

Renal Tubular Dysfunction Fully Accounts for Plasma Biochemical Abnormalities in Type 1A Pseudohypoparathyroidism.

Context: Type 1A pseudohypoparathyroidism (PHP-1A) is characterized by target organ resistance to PTH. Patients can present with various dysmorphic features; however, renal failure has not been classically described. Case Description: A female patient came to our attention at the age of 7 years with characteristic signs of PTH resistance (i.e., hypocalcemia, hyperphosphatemia, and high serum PTH levels). She also presented with hypothyroidism, early-onset obesity, short metacarpal bones, and multiple subcutaneous ossifications, leading to a clinical diagnosis of pseudohypoparathyroidism. In addition to her genetic condition, she had bilateral renal hypodysplasia that was slowly progressing to end-stage kidney disease. She received a kidney transplant at the age of 16 years and, after transplantation, experienced rapidly normalized calcium, phosphate, and PTH levels, allowing f withdrawal of vitamin D supplementation. Conclusions: To the best of our knowledge, ours is the first report of a patient with PHP-1A undergoing kidney transplantation. Normalization of biochemical parameters after the procedure demonstrated that renal tubular resistance to PTH is sufficient to explain the calcium/phosphate abnormalities observed in PHP-1A.

Hypercoagulability and nephrotic syndrome.

Patients with nephrotic syndrome are at increased risk for thromboembolic events such as deep venous and arterial thrombosis, renal vein thrombosis and pulmonary embolism. This thrombophilic phenomenon has been attributed to a "hypercoagulable" state in which an imbalance between naturally occurring pro-coagulant/pro-thrombotic factors and anti-coagulant/antithrombotic factors promotes in situ thrombosis in deep veins or arteries. Management of thromboembolic events may be divided in prophylactic and therapeutic strategies. Hypoalbuminemia is the most significant independent predictor factor of thrombotic risk, especially for values <2 g/dL. However, the most important question in these patients is whether to anticoagulate prophylactically or not. The decision depends on type of glomerulonephritis, proteinuria severity, other predisposing factors and prior history of thrombosis. Reviewing the recent literature, we suggest the best therapeutic management of anticoagulation for patients with nephrotic syndrome, focusing on prophylactic strategies.