Disparities in treatment and outcome of kidney replacement therapy in children with comorbidities: an ESPN/ERA Registry study.

Background: Data on comorbidities in children on kidney replacement therapy (KRT) are scarce. Considering their high relevance for prognosis and treatment, this study aims to analyse the prevalence and implications of comorbidities in European children on KRT. Methods: We included data from patients <20 years of age when commencing KRT from 2007 to 2017 from 22 European countries within the European Society of Paediatric Nephrology/European Renal Association Registry. Differences between patients with and without comorbidities in access to kidney transplantation (KT) and patient and graft survival were estimated using Cox regression. Results: Comorbidities were present in 33% of the 4127 children commencing KRT and the prevalence has steadily increased by 5% annually since 2007. Comorbidities were most frequent in high-income countries (43% versus 24% in low-income countries and 33% in middle-income countries). Patients with comorbidities had a lower access to transplantation {adjusted hazard ratio [aHR] 0.67 [95% confidence interval (CI) 0.61-0.74]} and a higher risk of death [aHR 1.79 (95% CI 1.38-2.32)]. The increased mortality was only seen in dialysis patients [aHR 1.60 (95% CI 1.21-2.13)], and not after KT. For both outcomes, the impact of comorbidities was stronger in low-income countries. Graft survival was not affected by the presence of comorbidities [aHR for 5-year graft failure 1.18 (95% CI 0.84-1.65)]. Conclusions: Comorbidities have become more frequent in children on KRT and reduce their access to transplantation and survival, especially when remaining on dialysis. KT should be considered as an option in all paediatric KRT patients and efforts should be made to identify modifiable barriers to KT for children with comorbidities.

Eltrombopag (thrombopoietin-receptor agonist) and plasmapheresis as rescue therapy of acute post-renal transplant immune thrombocytopenia in a child with Schimke immuno-osseous dysplasia-case report.

SIOD is rare disorder related to SMARCAL1 or SMARCAL2 gene mutation, including (among other comorbidities) T-cell immunodeficiency, nephrotic syndrome, and renal failure. Up to 22% of primary patients may develop various autoimmune disorders. We report the case of 11-year-old male with SIOD, who presented ITP at 2 years after renal transplantation with decrease in platelet count (from normal) to 56 000/µL and then (gradually) to 2000/µL. There was no effect of iv. methylprednisolone/dexamethasone. As the presence of antibodies against GPIIb/IIIa, GPIb, and GPIaIIa platelet glycoproteins was confirmed, patient was given 50 g of IVIG and then was put on plasmapheresis; however, both showed poor direct effect. As we were afraid to give rituximab (due to expected overimmunosuppression), we prescribed the oral TPO-receptor agonist (eltrombopag). Patient responded after 17 days of therapy, to the final dose of 50 mg/d (approx. 2 mg/kg). The antiplatelet antibodies disappeared after four plasmapheresis. Overall, the therapy was continued for 7 weeks and was stopped at platelet count of 433 000/µL. Platelet count remained stable in 8-month follow-up. Combination of plasmapheresis and TPO-receptor agonist was effective in post-renal transplant acute ITP in patient with SIOD.

Rituximab is not a "magic drug" in post-transplant recurrence of nephrotic syndrome.

UNLABELLED: Pediatric patients with end-stage renal failure due to severe drug-resistant nephrotic syndrome are at risk of rapid recurrence after renal transplantation. Treatment options include plasmapheresis, high-dose of cyclosporine A/methylprednisolone and more recently-rituximab (anti-B CD20 monoclonal depleting antibody). We report five patients with immediate (1-2 days) post-transplant recurrence of nephrotic syndrome, treated with this kind of combined therapy including 2-4 weekly doses of 375 mg/m(2) of rituximab. Only two (of five) patients have showed full long-term remission, while the partial remission was seen in two cases, and no clinical effect at all was achieved in one patient. The correlation between B CD19 cells depletion and clinical effect was present in two cases only. Severe adverse events were present in two patients, including one fatal rituximab-related acute lung injury. CONCLUSION: The anti-CD20 monoclonal antibody may be not effective in all pediatric cases of rapid post-transplant recurrence of nephrotic syndrome, and benefit/risk ratio must be carefully balanced on individual basis before taking the decision to use this protocol. WHAT IS KNOWN: • nephrotic syndrome may recur immediately after renal transplantation • plasmapheresis combined with pharmacotherapy is used as rescue management • rituximab was reported as effective drug both in primary and post-transplant nephrotic syndrome What is New: • rituximab may not be effective is several cases of post-transplant nephrotic syndrome due to variety of underlying mechanisms of the disease, which may be or not be responsive to this drug • there may be no correlation between drug-induced depletion of specific B cells and clinical effect; this might suggest B-cell independent manner of rituximab action.

Favorable four-yr outcome after renal transplantation in a patient with complement factor H antibody and CFHR1/CFHR3 gene mutation-associated HUS.

UNLABELLED: aHUS is a clinical challenge for successful renal transplantation. CASE REPORT: A 14-yr-old girl lost her kidneys at the age of 7, due to CFH antibodies and CFH-related protein (CFHR1/CFHR3) homozygous deletion-associated aHUS. CFH, CFI, and MCP gene mutations were excluded. The patient was a candidate for renal transplantation despite persistent presence of CFH antibodies (up to 539 AU/mL). Treatment with MMF, IVIG, and repeated PF (n = 8) was introduced while being placed on urgent waiting list. Three years after aHUS onset, the patient underwent the deceased donor renal transplantation "under cover" of PF, as PF was performed directly prior to surgery and, then, PFs were repeated up to overall 14 sessions. Quadruple immunosuppression (basiliximab + tacrolimus + MMF + prednisolone) was used. Moderate symptoms of aHUS (hemolysis, low platelets, and low C3) were present within first seven days post-transplant and then normalized with PF therapy. The patient remained stable during four yr of further follow-up after transplantation. CONCLUSION: Specific pre- and post-transplant management allowed successful renal transplantation in a CFH antibody-positive patient.

Do children with end-stage renal disease live shorter? Analysis of mortality on the basis of data from the Polish Registry of Renal Replacement Therapy in Children.

PURPOSE: The mortality of patients with end-stage renal disease (ESRD) is much higher than that of the general population. To date no data has been published on the mortality of children with ESRD in Poland. The aim of this study was to compare the risk of death for pediatric patients on renal replacement therapy (RRT) with that of the general pediatric population and to identify the risk factors of death. MATERIAL/METHODS: Data of 779 children with ESRD registered in the Polish Registry of Children on RRT was analyzed. The relative risk of death was calculated as the ratio of the mortality rate in ESRD patients to the mortality rate in age-adjusted general population. RESULTS: The mortality rate of children with ESRD was 74-fold higher than that of the age- and gender-adjusted general pediatric population (4.05 vs. 0.05/100 person-years). The highest mortality rate (4.53/100 patient-years) was found in the youngest age group. Younger age and duration of dialysis therapy were identified as mortality risk factors. The major causes of death in ESRD patients were infections and cardiovascular complications, whereas deaths in general child population were mainly due to accidents or congenital defects. CONCLUSIONS: The mortality in Polish children with ESRD is 74-fold higher than that of the general pediatric population. Infections, followed by cardiovascular complications, constitute the main causes of mortality in children subjected to RRT. The risk of death is the highest among children who started RRT at a younger age and in those subjected to long-term dialysis treatment.

Liver transplantation with ABO incompatible graft under immunoadsorption protocol--case report.

BACKGROUND: ABO incompatible liver transplantation is still controversial, but accepted in selected cases. Recently several authors reported use of the new technology aimed at elimination anti-donor ABO specific hemagglutinins to assist immunosuppression in preventing acute rejection after transplantation. CASE REPORT: We report two cases of liver transplantation in children with ABO incompatible graft under immunoadsorption protocol. Both patients were transplanted urgently (one due to acute decompensation of chronic liver failure and second due to acute liver failure) with ABO incompatible liver grafts. Both patients were in very poor general condition with deterioration of neurological status and there were no suitable ABO compatible grafts at the time. In both cases immunosuppressive protocol consisted of induction with basiliximab, followed by tacrolimus, mycophenolate mofetil and corticosteroids. Additionally in both patients 3 immunoadsorption sessions with Glycosorb ABO® system (Glycorex AB, Sweden), were performed. There were no any acute rejection episodes till now. The only problem observed after transplantation was mild anemia due to low grade hemolysis in the postoperative period. Both patients are alive and well with very good liver function 20 and 26 months after transplantation. CONCLUSIONS: Immunoadsorption therapy can be safely and effectively introduced in recipients of ABO incompatible donor liver.

Evaluation of the genetic background of standard-immunosuppressant-related toxicity in a cohort of 200 paediatric renal allograft recipients--a retrospective study.

BACKGROUND: Immunosuppressant toxicity is a limiting factor for the efficacy and safety of long-term therapy. Whether it stems solely from drug exposure, remains unclear. MATERIAL/METHODS: Overall, 207 children and adolescents at the mean age of 11+/-4.4, with primary renal allograft were analyzed. Immunosuppression regimens included CsA or TAC, combined with AZA or MMF and steroids. Drug-specific toxicities were diagnosed by renal biopsy and/or clinical criteria. Genotyping for MDR1, CYP3A5, IL1B, IL1RN, IL-6, IL-10, MCP-1, TGFB1, CCR5, VEGF and TNF-alpha gene polymorphisms was performed with the use of PCR and PCR-RFLP techniques. RESULTS: Nephrotoxicity was seen in 38.5% of patients treated with CsA and 29.5% - with TAC, while gingival hypertrophy was observed in 28% of CsA patients. Myelotoxicity was found in 3% of AZA-treated and 6.4% of MMF-treated patients. No significant correlation was seen between the patient's age, gender, type of pre-transplantation dialysis, donor age, graft origin or cold ischemia time, and the occurrence of drug-related toxicity. For CNIs, the drug exposure and the duration of treatment did not prove of significance either. TAC associated nephrotoxicity correlated with the CCR5 gene polymorphism, as the wt/32 genotype was found in 21% of patients with no detected toxicity (p<0.041) and in none of the nephrotoxicity cases. The presence of this genotype was also associated with significantly better graft function at 1 year post-transplant (GFR 115.104+/-28.40 vs 86.434+/-29.96; p=0.022). An association was seen between the MMF-induced myelotoxicity and the TNF-alpha G(-308)A polymorphism (p<0.005), but the MMF exposure was higher in patients who developed toxicity. CONCLUSIONS: Genetic background should be regarded one of the risk factors for immunosuppressant related toxicity in renal transplantation.

Multicentre prospective randomised trial of tacrolimus, azathioprine and prednisolone with or without basiliximab: two-year follow-up data.

A total of 192 children and adolescents undergoing renal transplantation were randomly chosen to receive tacrolimus, azathioprine and corticosteroids (TAS, n = 93) or tacrolimus, azathioprine, corticosteroids and two doses of basiliximab (TAS + B, n = 99). Six-month outcome data have previously been reported; this manuscript reports the 2-year data. Complete 2-year data were available on 164 (85.4%) of the original 192 patients. There was a single death in the TAS arm. Kaplan-Meier estimates of survival free of graft loss at 2 years were 94.9% in the TAS + B arm and 89.6% in the TAS arm [hazard ratio (HR) 0.52; 95% confidence interval (CI) 0.17 to 1.54, P = 0.23]. Estimates of survival free from rejection at 2 years were 75.2% in the TAS + B arm and 68.7% in the TAS arm (HR 0.81; 95% CI 0.46 to 1.40, P = 0.44). The mean estimated glomerular filtration rate (GFR) at 2 years, was 65.8 ml/min per 1.73 m(2) body surface area in the TAS arm and 66.7 ml/min per 1.73 m(2) in the TAS + B arm (P = 0.78). Blood pressure and cholesterol levels were similar in the two arms, and there was no evidence of a difference in the incidence of infection or malignancy. These data provide further evidence of a lack of benefit associated with the addition of basiliximab to a TAS regimen for European paediatric renal transplant recipients at low immunological risk.

Liver transplantation for fulminant Wilson's disease in children.

BACKGROUND: Fulminant Wilson's disease (FWD) is rare and fatal condition in children unless liver transplantation is performed, however introduction of new technologies could change this poor prognosis. The aim of our study was retrospective analysis of clinical course, treatment and outcome of children with FWD treated in our institution. MATERIAL/METHODS: Between 1999-2007 we've treated in our hospital 13 patients with mean age of 15.5 yrs with FWD. We performed retrospective analysis of clinical course, biochemical parameters, MELD/PELD score, Wilson score and Kings'-College criteria for LTx in acute liver failure in all these patients. Type of treatment and final outcome were analyzed, as well as qualification for transplantation was reevaluated in each case in accordance to pathological examination of explanted during transplantation livers. RESULTS: The initial symptoms of FWD were typically weakness, abdominal pain and developing later after 5-60 days (mean 20 days), jaundice. Eleven patients developed neurological symptoms with coma lasting for 2-11 days before transplantation or death. Maximal serum bilirubin concentration ranged between 4.5-71.6 mg% (mean 42.24 mg%), INR 2.9-10.0 (mean 5.4). MELD/PELD score was between 21-58 (mean 38), 10 patients fulfilled general King's-College criteria for transplantation in acute liver failure. Wilson's index ranged between 11 and 17 points (mean 13 points). In 11 children urgent liver transplantation (LTx) was performed, 1 child recovered on albumin dialysis and chelating treatment, 1 child died shortly after very late referral to our center. Actual follow-up of living patients is 0.36-7.43 years (mean 2.57 yrs), all are doing well with good liver function. CONCLUSIONS: FWD lead to death in almost all pediatric patients if LTx can not be performed, however early introduction of albumin dialysis (MARS) and chelating therapy allowed for survival without transplantation in single patient. It seems also that MARS therapy allows for at least prolongation of waiting time for LTx. Wilson's was slightly better predictor of need for LTx in our patients than classical King's-College criteria.

Clinical course of homozygous familial hypercholesterolemia during childhood: report on 4 unrelated patients with homozygous or compound heterozygous mutations in the LDLR gene.

Natural history of the disease in 4 unrelated Polish children with homozygous familial hypercholesterolemia (FH) is described. Their phenotypic homozygosity was established by identification of known LDLR gene mutations on both alleles, respectively: p.G592E & p.G592E in Patient 1; p.G592E & p.C667Y in Patient 2; p.S177L & p.R350X in Patient 3; and p.G592E & deletion in the promoter region, exons 1 and 2 in Patient 4. Heterozygosity of the mutations was revealed in all patients' mothers and fathers (obligatory heterozygotes) and in 1 out of 4 siblings studied. FH was diagnosed at the age of 4 months to 9 years by cholesterol screening among family members of patients with early cardiovascular disease episodes. At the time of FH detection, the children were asymptomatic. Only in 2, some skin eruptions were found. Antihyperlipidemic therapy was started, including a lipid-lowering diet, cholestyramine, and HMG-CoA inhibitors if necessary. No cardiovascular symptoms appeared during the observation up to the age of 18, 20, 19, and 17 years, respectively. An increase in external carotid artery diameter was found in a patient at the age of 9 years, and LDL-apheresis was introduced in his therapy. We conclude that the analysis of LDLR gene mutations in the studied FH children made it possible to identify 4 presymptomatic FH homozygotes and to introduce early appropriate treatment. Multicenter analysis of such persons would finally determine if the early lipid-lowering procedures can significantly reduce the risk of premature cardiovascular disease in homozygous FH.

[Continuous renal replacement therapy in children with acute renal failure--5 years of experience]. / Zastosowanie ciaglych metod leczenia nerkozastepczego u dzieci z ostra niewydolnoscia nerek--5 lat doswiadczen.

Continuous renal replacement therapy (CRRT) has became a modality of choice in chidren with acute renal failure (ARF), especially in cases of multiorgan failure (MOF) and in hemodynamically unstable patients in whom regular hemodialysis is difficult to reform. Newborns and infants with contraindications to peritoneal dialysis are another group of patients treated with CRRT. Retrospective analysis of CRRT therapy in 112 patients treated with (CVVHD, CVVH, CVVHDF, SCUF-continuous veno-venous hemodialysis/hemofiltration/ hemodiafiltration/ultrafiltration) between 2000-2005 is presented. Indication to CRRT was MOF (n=23, 20%), complications post-liver transplant (n=33, 29%), congenital metabolic defects (n=5, 4.5%), complications of cancer or chemotherapy (n=11, 9.8%) and other causes of ARF (n=40, 36.7%). Overall mortality was 36.6%. The highest rate was seen in children between 0-2 years of age (52,3%) and in patients with congenital metabolic diseases (80%). When adjusted to specific modality--the highest mortality was seen in patients treated with CVVHF (55.4%), while lower was in cases treated with CVVHD (37.8%) and CVVHDF (35.4%). Among older children higher mortality was seen in patients with mean arterial pressure (MAP) <70 mmHg (68.4%), compared to patients with MAP >70 mmHg (23.1%).

[Evaluation of pharmacokinetics and safety of valganciclovir oral suspension treatment in pediatric kidney graft recipients--preliminary report]. / Ocena farmakokinetyki i bezpieczenstwa stosowania walgancyklowiru w zawiesinie doustnej u dzieci po transplantacji nerki--doniesienie wstepne.

BACKGROUND: Invasive CMV disease in transplanted organ recipients is a life threatening condition. CMV infection is also known risk factor for acute rejection and chronic allograft nephropathy. The risk of CMV infection in pediatric population is high, especially in terms of primary infection. It can be significantly reduced under long term (3 months) prophylaxis with ganciclovir (GCV), available exclusively as parenteral drug. Since recently oral tablet pro-drug valganciclovir (VCV, Valcyte, Roche) is given in adult patients. This drug has proved similar efficacy and good bioavailability (roughly 70%), however there is no registered liquid form which can be precisely and safety administered in small children. MATERIAL AND METHOD: 10 children after kidney transplantation, aged 2-9.5 year (mean 5.1; SD +/- 2.3), body weight 8.5-19.5 kg (mean 14.6; SD +/- 3.5), with good graft function (serum creatinine 0.3-0.8 mg/dl) were given VCV oral suspension prepared in hospital pharmacy, using Valcyte tablets and commercially available vehicle (Paddock Laboratories, Inc) (60 mg/ml), 7.5 mg/kg b.w., 2-3 x/day. Through level (CO) of GCV in blood was measured in all patient, in 4 patient drug kinetics (4 measurements) was also analyzed preceded with evaluation of GCV elimination after intravenous infusion of GCV. RESULTS: There was no episode of drug toxicity nor drug withdrawal from other reason. CO (mean = 0.74 microg/ml; max. 1.15; min. 0.38; SD +/- 0.25) was close to predefined values (0.4-1.0 microg/ml). Concentration profile of GCV (Cmax 1.0-1.5 h post dose) was similar to profile observed in adult patient treated with VCG tablets. CONCLUSION: Treatment with VCV suspension provides precise dosage and seems to be safe in patient with low body weight. It enables ambulatory prophylaxis and treatment of CMV infection.

Successful treatment of a child with fulminant liver failure and coma caused by Amanita phalloides intoxication with albumin dialysis without liver transplantation.

FLF is a life-threatening disease. Hepatic coma exerts dramatic impact on patient survival. At present, LTx is the treatment modality of choice that provides significant improvement in outcome of most patients with FLF. Multiple attempts have been made to reduce mortality and improve the patient's condition. One of the new options is AD - MARS. We present the case of a 11-yr-old boy with FLF and hepatic coma who avoided the scheduled LTx because of rapid neurological and biochemical improvement immediately after three MARS sessions.

[Atypical osteitis in hemodialysed child with uncontrolled secondary hyperparathyroidism: a case report]. / Nietypowy przebieg zapalenia kosci zmienionych wskutek niekontrolowanej nadczynnosci przytarczyc u dziecka hemodializowanego--opis przypadku.

Ostitis in the course of secondary hyperparathyroidism can lead to heavy atypical skeletal changes. In 4-year old girl on hemodialysis, with hyperparathyroidism (iPTH level > 1500 pg/ml), despite specific pharmacological treatment, very pronounced skull and maxillary bone malformations developed within two months, which were the cause of problems with breathing. We observed also growing bones malformations concerning arms, legs, vertebral column and pelvis. Severe infectious ostitis with severe uremic osteodystrophy was diagnosed. After 3 months of antibiotic treatment (clindamycin) subtotal parathyreidectomy was performed. Control iPTH level was 111 pg/ml. In next weeks skull skeletal changes partially resolved, which was confirmed on computer tomography, and patients general condition improved. She has no longer difficulties with breathing.

[Clinical aspects of plasmapheresis therapy in children: single center experience]. / Kliniczne aspekty leczenia dzieci plazmafereza--doswiadczenie jednego osrodka.

Data concerning 576 plasmapheresis sessions (indications, anticoagulation applied, supplement type and acute complications) in children (mean body weight = 35 kg +/- 15; min 5 kg, max 75 kg) performed between 1990 and 2001 were analysed. INDICATIONS: Glomerulonephritis (GN)--185 (32%) (including recurrence after kidney transplantation--108, rapidly progressive GN--63, other GN--14), other immunological diseases--110 (19%) (systemic lupus erythematosus, Wegener's granulomatosis, myasthenia, Guillain-Barré syndrome, other), haemolytic-uraemic syndrome--104 (18%) (after kidney transplantation--50, atypical--54), Amanita poisoning 100 (17%), acute hepatic encephalopathy--41 (7%) (after liver transplantation--9), poisoning with drugs bound by plasma albumin--22 (4%) and complications in kidney graft recipients--14 (2%) (acute vascular rejection, parathormone toxicity). ANTICOAGULATION: Until the end of 1999--unfractionated heparin (in divided doses every 30 min--100 IU/kg/session on the average), from 2000 on--single dose of Fraxiparine (mean 70 IU anty-Xa/kg/session). SUPPLEMENT: Until 1995--Ringer solution + fresh frozen plasma, from 1996 on--Ringer solution + fresh frozen plasma or 4% albumin solution diluted in 5% dextrose (depending on indications, contraindications and fibrinogen concentration). COMPLICATIONS: Deaths in the course of plasmapheresis--0, others (rash, abdominal pain, headache, nausea and vomiting, blepharoedema, drop of arterial pressure, pruritus)--19 (3%), necessity of session termination because of patient condition (dyspnoea, urticaria, hypotension)--3 (0.5%) and technical problems--23 (4.5%) (filter damage--8, filter clotting--5, haemolysis--3, machine malfunction--5, problems with vascular access--2).