Hepatitis E virus infection of transplanted kidneys.

Immunocompromised patients are at risk of chronic hepatitis E (HEV) infection. Recurrent T cell and borderline rejections in a pediatric patient with high HEV copy numbers led us to study HEV infection within renal transplants. To investigate the frequency of renal HEV infection in transplanted patients, 15 samples from patients with contemporaneous diagnoses of HEV infection were identified at our center. Ten samples had sufficient residual paraffin tissue for immunofluorescence (IF) and RNA-fluorescence-in-situ-hybridization (RNA-FISH). The biopsy of the pediatric index patient was additionally sufficient for tissue polymerase chain reaction and electron microscopy. HEV RNA was detected in paraffin tissue of the index patient by tissue polymerase chain reaction. Subsequently, HEV infection was localized in tubular epithelial cells by IF, RNA-FISH, and electron microscopy. One additional biopsy from an adult was positive for HEV by RNA-FISH and IF. Focal IF positivity for HEV peptide was observed in 7 additional allografts. Ribavirin therapy was not successful in the pediatric index patient; after relapse, ribavirin is still administered. In the second patient, successful elimination of HEV was achieved after short-course ribavirin therapy. HEV infection is an important differential diagnosis for T cell rejection within transplanted kidneys. Immunostaining of HEV peptide does not necessarily prove acute infection. RNA-FISH seems to be a reliable method to localize HEV.

[Improved Care and Treatment Options for Patients with Hyperphagia-Associated Obesity in Bardet-Biedl Syndrome]. / Verbesserte Versorgungs-und Behandlungsoptionen für Patienten mit Hyperphagie-assoziierter Adipositas bei Bardet-Biedl-Syndrom.

Bardet-Biedl syndrome (BBS) is a rare, autosomal recessive multisystem disease. The pathophysiological origin is a dysfunction of the primary cilium. Clinical symptoms are heterogeneous and variable: retinal dystrophy, obesity, polydactyly, kidney abnormalities, hypogenitalism and developmental delays are the most common features. By the approval of the melanocortin 4 receptor agonist setmelanotide, a drug therapy for BBS-associated hyperphagia and obesity can be offered for the first time. Hyperphagia and severe obesity represent a considerable burden and are associated with comorbidity and increased mortality risk. Due to the limited experience with setmelanotide in BBS, a viable comprehensive therapy concept is to be presented. Therapy decision and management should be conducted in expert centers. For best therapeutic effects with setmelanotide adequate information of the patient about the modalities of the therapy (daily subcutaneous injection) and possible adverse drug events are necessary. Furthermore, the involvement of psychologists, nutritionists and nursing services (support for the application) should be considered together with the patient. The assessment of therapy response should be carried out with suitable outcome measurements and centrally reported to an adequate register.

Outcome of infantile nephropathic cystinosis depends on early intervention, not genotype: A multicenter sibling cohort study.

Infantile nephropathic cystinosis (INC) is an inheritable lysosomal storage disorder characterized by lysosomal cystine accumulation, progressive kidney disease, and multiple extrarenal complications (ERCs). Cysteamine postpones the onset of end-stage kidney disease (ESKD) and reduces the incidence of ERCs; however, cysteamine is generally initiated upon establishment of the renal Fanconi syndrome (FS) and partial loss of kidney function, whereas data on long-term effects of cysteamine administered from neonatal age are lacking. An international multicenter retrospective cohort study of siblings with INC was set up to investigate the outcome in relation to age at initiation of cysteamine versus CTNS genotype, with attention to patients treated with cysteamine from neonatal age. None of the siblings treated from neonatal age (n = 9; age 10 ± 6 years) had reached ESKD, while 22% of their index counterparts (n = 9; age 14 ± 5 years) had commenced renal replacement therapy. Siblings treated with cysteamine from the onset of symptoms at a younger age compared with their index counterparts, reached ESKD at a significant older age (13 ± 3 vs. 10 ± 3 years, p = 0.002). In contrast, no significant difference in ERCs was observed between sibling and index patients, independently from the age at initiation of cysteamine. The CTNS genotype had no impact on the overall outcome in this cohort. In INC, presymptomatic treatment with cysteamine results in a better renal outcome in comparison to treatment initiated from the onset of symptoms. This justifies including cystinosis into newborn screening programs. SYNOPSIS: In infantile nephropathic cystinosis, presymptomatic treatment with cysteamine improves the renal outcome which justifies the inclusion of cystinosis into newborn screening programs.

Emulation of the control cohort of a randomized controlled trial in pediatric kidney transplantation with Real-World Data from the CERTAIN Registry.

BACKGROUND: Randomized controlled trials in pediatric kidney transplantation are hampered by low incidence and prevalence of kidney failure in children. Real-World Data from patient registries could facilitate the conduct of clinical trials by substituting a control cohort. However, the emulation of a control cohort by registry data in pediatric kidney transplantation has not been investigated so far. METHODS: In this multicenter comparative analysis, we emulated the control cohort (n = 54) of an RCT in pediatric kidney transplant patients (CRADLE trial; ClinicalTrials.gov NCT01544491) with data derived from the Cooperative European Paediatric Renal Transplant Initiative (CERTAIN) registry, using the same inclusion and exclusion criteria (CERTAIN cohort, n = 554). RESULTS: Most baseline patient and transplant characteristics were well comparable between both cohorts. At year 1 posttransplant, a composite efficacy failure end point comprising biopsy-proven acute rejection, graft loss or death (5.8% ± 3.3% vs. 7.5% ± 1.1%, P = 0.33), and kidney function (72.5 ± 24.9 vs. 77.3 ± 24.2 mL/min/1.73 m2 P = 0.19) did not differ significantly between CRADLE and CERTAIN. Furthermore, the incidence and severity of BPAR (5.6% vs. 7.8%), the degree of proteinuria (20.2 ± 13.9 vs. 30.6 ± 58.4 g/mol, P = 0.15), and the key safety parameters such as occurrence of urinary tract infections (24.1% vs. 15.5%, P = 0.10) were well comparable. CONCLUSIONS: In conclusion, usage of Real-World Data from patient registries such as CERTAIN to emulate the control cohort of an RCT is feasible and could facilitate the conduct of clinical trials in pediatric kidney transplantation. A higher resolution version of the Graphical abstract is available as Supplementary information.

Timing of reconstruction of the lower urinary tract in pediatric kidney transplant recipients: A CERTAIN multicenter analysis of current practice.

BACKGROUND: Preexistent LUTD are considered a hostile environment, which might negatively impact KTx survival. In such cases, surgical reconstruction of the bladder is required. However, there is still disagreement on the optimal timing of the reconstruction procedure. METHODS: This is a multicenter analysis of data from the CERTAIN Registry. Included were 62 children aged 8.18 ± 4.90 years, with LUTD. Study endpoints were the duration of initial posttransplant hospitalization, febrile UTIs, and a composite failure endpoint comprising decline of eGFR, graft loss, or death up to 5 years posttransplant. Outcome was compared to matched controls without bladder dysfunction. RESULTS: Forty-one patients (66.1%) underwent pretransplant and 14 patients (22.6%) posttransplant reconstruction. Bladder augmentation was performed more frequently in the pretransplant (61%) than in the posttransplant group (21%, p = .013). Outcome in the pre- and posttransplant groups and in the subgroups of patients on pretransplant PD with major bladder surgery either pre- (n = 14) or posttransplant (n = 7) was comparable. Outcomes of the main study cohort and the matched control cohort (n = 119) were comparable during the first 4 years posttransplant; at year 5, there were more events of transplant dysfunction in the study cohort with LUTD than in controls (p = .03). CONCLUSIONS: This multicenter analysis of the current practice of LUTD reconstruction in pediatric KTx recipients shows that pre- or posttransplant surgical reconstruction of the lower urinary tract is associated with a comparable 5-year outcome.

Health care transition from pediatric to adult care: an evidence-based guideline.

For consistent quality of treatment of young people with chronic health care needs, a structured health care transition (HCT) from pediatric medicine to adult medical care is essential. Currently, most countries have no guidelines on HCT based on systematic evidence research. To close this gap, guidance to support HCT was developed in Germany. Twenty-two experts in the management of adolescents and young adults with different chronic conditions and three patient representatives were invited to take part in the guideline group. Based on a systematic literature search recommendations for HCT were drafted. Where evidence was lacking, recommendations were developed using collective expert consensus. The consensus process was independently moderated using a Delphi approach. The final draft was reviewed and endorsed by all major German medical societies. The clinical recommendations provide guidance for all chronic somatic diseases. After assessment of HCT readiness, an individualized plan for HCT should be drawn up. Key elements here are a responsible coordinator, age-adapted patient education, involvement of caregivers, web-based interventions, joint visits, and a structured summary for the receiving physician. The aim is the gradual transfer of responsibility for disease management to the young person themselves.    Conclusion: As only a few randomized controlled studies on HCT are available, evidence-based statements are possible for some but not all areas of HCT. However, this guideline may help to develop globally accepted standards. These standards should be established and implemented. The aim should be a reimbursement by individual national health systems to allow appropriate support for young people. What is Known: • Health care transition from pediatric to adult care is primarily organized in local settings, partly based on disease-specific guidelines. •There have been no national guidelines in Germany until now. What is New: • Here we present the general evidence-based guidelines of the German Association of Scientific Medical Societies for health care transition. • These might serve as a blueprint for further national or international health care transition guidelines.

Steering Transplant Immunosuppression by Measuring Virus-Specific T Cell Levels: The Randomized, Controlled IVIST Trial.

BACKGROUND: Pharmacokinetic monitoring is insufficient to estimate the intensity of immunosuppression after transplantation. Virus-specific T cells correlate with both virus-specific and general cellular immune defense. Additional steering of immunosuppressive therapy by virus-specific T cell levels might optimize dosing of immunosuppressants. METHODS: In a multicenter, randomized, controlled trial, we randomized 64 pediatric kidney recipients to a control group with trough-level monitoring of immunosuppressants or to an intervention group with additional steering of immunosuppressive therapy by levels of virus-specific T cells (quantified by cytokine flow cytometry). Both groups received immunosuppression with cyclosporin A and everolimus in the same target range of trough levels. Primary end point was eGFR 2 years after transplantation. RESULTS: In the primary analysis, we detected no difference in eGFR for the intervention and control groups 2 years after transplantation, although baseline eGFR 1 month after transplantation was lower in the intervention group versus the control group. Compared with controls, patients in the intervention group received significantly lower daily doses of everolimus and nonsignificantly lower doses of cyclosporin A, resulting in significantly lower trough levels of everolimus (3.5 versus 4.5 µg/L, P<0.001) and cyclosporin A (47.4 versus 64.1 µg/L, P<0.001). Only 20% of patients in the intervention group versus 47% in the control group received glucocorticoids 2 years after transplantation (P=0.04). The groups had similar numbers of donor-specific antibodies and serious adverse events. CONCLUSIONS: Steering immunosuppressive therapy by virus-specific T cell levels in addition to pharmacokinetic monitoring seems safe, results in a similar eGFR, and personalizes immunosuppressive therapy by lowering exposure to immunosuppressive drugs, likely resulting in lower drug costs. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: IVIST trial, https://www.clinicaltrialsregister.eu/ctr-search/search?query=2009-012436-32 and ISRCTN89806912.

Prevalence of Mental Disorders in a German Kidney Transplant Population: Results of a KTx360°-Substudy.

In patients after kidney transplantation (KTx) an increased rate of affective and anxiety disorders has been observed. Repeatedly, a relationship between mental health issues and increased morbidity and mortality in KTx recipients has been reported. However, information on the prevalence of mental disorders in KTx patients is scarce. As part of the structured multimodal follow-up program (KTx360°), mental disorders were examined in 726 patients after KTx through structured diagnostic interviews using the Mini-DIPS Open Access. Overall, 27.5% had a current and 49.2% a lifetime mental disorder. Only 14.5% with a current mental disorder reported to be in treatment. Affected patients were younger, more often female, reported more symptoms of anxiety and depression and less perceived social support. While comparable to the rate in general population samples, the prevalence of mental disorders should attract attention. The low treatment rate requires an improved identification of afflicted patients and provision of specialist treatment.ISRCTN registry, https://doi.org/10.1186/ISRCTN29416382 , date of registry: 03.05.2017.

An international cohort study spanning five decades assessed outcomes of nephropathic cystinosis.

Nephropathic cystinosis is a rare disease secondary to recessive mutations of the CTNS gene encoding the lysosomal cystine transporter cystinosin, causing accumulation of cystine in multiple organs. Over the years, the disease has evolved from being a fatal condition during early childhood into a treatable condition, with patients surviving into adulthood. Data on cystinosis are limited by the rarity of the disease. Here, we have investigated factors associated with kidney and growth outcome in a very large cohort of 453 patients born between 1964 and 2016 and followed in Belgium, Germany, Austria, France, Italy, Spain, The Netherlands, Turkey and United Kingdom. From the 1970s to the 1990s, the median increase in kidney survival was 9.1 years. During these years, cysteamine, a cystine-depleting agent, was introduced for the treatment of cystinosis. Significant risk factors associated with early progression to end-stage kidney disease assessed by Cox proportional multivariable analysis included delayed initiation of cysteamine therapy and higher mean leucocyte cystine levels. No significant effect on kidney function was observed for gender, pathogenic variant of the CTNS gene, and the prescription of indomethacin or renin angiotensin system blockers. Significantly improved linear growth was associated with early use of cysteamine and lower leukocyte cystine levels. Thus, our study provides strong evidence in favor of early diagnosis and optimization of cystine depletion therapy in nephropathic cystinosis.

Three-year outcomes from the CRADLE study in de novo pediatric kidney transplant recipients receiving everolimus with reduced tacrolimus and early steroid withdrawal.

CRADLE was a 36-month multicenter study in pediatric (≥1 to <18 years) kidney transplant recipients randomized at 4 to 6 weeks posttransplant to receive everolimus + reduced-exposure tacrolimus (EVR + rTAC; n = 52) with corticosteroid withdrawal at 6-month posttransplant or continue mycophenolate mofetil + standard-exposure TAC (MMF + sTAC; n = 54) with corticosteroids. The incidence of composite efficacy failure (biopsy-proven acute rejection [BPAR], graft loss, or death) at month 36 was 9.8% vs 9.6% (difference: 0.2%; 80% confidence interval: -7.3 to 7.7) for EVR + rTAC and MMF + sTAC, respectively, which was driven by BPARs. Graft loss was low (2.1% vs 3.8%) with no deaths. Mean estimated glomerular filtration rate at month 36 was comparable between groups (68.1 vs 67.3 mL/min/1.73 m2 ). Mean changes (z-score) in height (0.72 vs 0.39; P = .158) and weight (0.61 vs 0.82; P = .453) from randomization to month 36 were comparable, whereas growth in prepubertal patients on EVR + rTAC was better (P = .050) vs MMF + sTAC. The overall incidence of adverse events (AEs) and serious AEs was comparable between groups. Rejection was the leading AE for study drug discontinuation in the EVR + rTAC group. In conclusion, though AE-related study drug discontinuation was higher, an EVR + rTAC regimen represents an alternative treatment option that enables withdrawal of steroids as well as reduction of CNIs for pediatric kidney transplant recipients. ClinicalTrials.gov: NCT01544491.

Precise variant interpretation, phenotype ascertainment, and genotype-phenotype correlation of children in the EARLY PRO-TECT Alport trial.

Early initiation of therapy in patients with Alport syndrome (AS) slows down renal failure by many years. Genotype-phenotype correlations propose that the location and character of the individual's variant correlate with the renal outcome and any extra renal manifestations. In-depth clinical and genetic data of 60/62 children who participated in the EARLY PRO-TECT Alport trial were analyzed. Genetic variants were interpreted according to current guidelines and criteria. Genetically solved patients with X-linked inheritance were then classified according to the severity of their COL4A5 variant into less-severe, intermediate, and severe groups and disease progress was compared. Almost 90% of patients were found to carry (likely) pathogenic variants and classified as genetically solved cases. Patients in the less-severe group demonstrated a borderline significant difference in disease progress compared to those in the severe group (p = 0.05). While having only limited power according to its sample size, an obvious strength is the precise clinical and genetic data of this well ascertained cohort. As in published data differences in clinical progress were shown between patients with COL4A5 less-severe and severe variants. Therefore, clinical and segregational data are important for variant (re)classification. Genetic testing should be mandatory allowing early diagnosis and therapy of AS.

Adherence in pediatric renal recipients and its effect on graft outcome, a single-center, retrospective study.

BACKGROUND: In recent years, treatment-adherence gained increasing attention in nearly every area of medicine including transplant medicine. Medication adherence following solid organ transplantation is known to be indispensable for a satisfactory allograft survival. METHODS: We examined 60 patients between the ages of four months and 20 years who underwent kidney transplantation at Hannover Medical School between January 2011 and August 2017. Age at transplantation varied from 4 months to 20 years. 12 patients (20%) already underwent their second solid organ transplantation. 5 patients (8.3%) had a combined kidney-liver-transplantation. We used two different methods for rating adherence: An objective one based on the coefficient of variation (CoV%) of immunosuppressant trough levels, and a subjective questionnaire answered by the patients themselves, their parents or legal custodians, the treating pediatrician, as well as by the attending psychologist. RESULTS: The CoV% in our study was by-trend higher in those patients who suffered from a biopsy-proven rejection (x̅CoV% = 35.7, σ CoV% = 30.1 in patients with rejection vs. x̅ CoV% = 26.0, σ CoV% = 10.5 in patients without rejection). Furthermore, the psychologist's assessment correlated significantly both with rejections as well as with the formation of de novo donor-specific antibodies (dnDSA) while the pediatrician's rating showed no correlation (Prejections  = 0.005 and PdnDSA  = 0.03 for psychologist's rating vs. Prejections  = 0.50 and PdnDSA  = 0.50 for pediatrician). CONCLUSIONS: Apart from underlining the importance of medication adherence, the present research stresses the role of a multi-disciplinary treatment approach to support pediatric renal transplant recipients and their families.

Course of renal allograft function after diagnosis and treatment of post-transplant lymphoproliferative disorders in pediatric kidney transplant recipients.

BACKGROUND: Post-transplant lymphoproliferative disease (PTLD) is a life-threatening complication in renal transplant recipients. Immunomodulatory and chemotherapeutic treatment potentially affect allograft function. The aim of this study was to evaluate graft function of pediatric kidney transplant recipients following diagnosis and standardized treatment of PTLD. METHODS: Patients were identified from the German Ped-PTLD registry, and data on renal function were retrospectively retrieved from patient charts. For PTLD treatment, immunosuppressive therapy was reduced and all children received rituximab (375 mg/m2 ) for up to six doses. Two patients required additional low-dose chemotherapy. Renal allograft function was monitored by consecutive measurements of estimated glomerular filtration rate (eGFR) at defined time points. Follow-up was up to 60 months after PTLD. RESULTS: Twenty patients were included in this cohort analysis. Median time from transplantation to PTLD was 2.4 years. Histopathology showed monomorphic lesions in 16 and polymorphic in 4 patients. Two patients experienced PTLD relapse after 2 and 14 months. Range-based analysis of variance showed stable allograft function in 17 of 20 patients (85%). Mean eGFR increased during early treatment phase. One patient experienced graft rejection 5.3 years after diagnosis of PTLD. Another patient developed recurrence of primary renal disease (focal-segmental glomerulosclerosis) and lost his renal allograft 3.8 years post-transplant (2.0 years after PTLD diagnosis). CONCLUSION: Treatment of PTLD with rituximab with or without low-dose chemotherapy in combination with reduced immunosuppression, mostly comprising of an mTOR inhibitor-based, calcineurin inhibitor-free regimen, is associated with stable graft function and favorable graft survival in pediatric renal transplant patients.

Surgical complications in pediatric kidney transplantation-Incidence, risk factors, and effects on graft survival: A retrospective single-center study.

The field of pediatric kidney transplantation remains challenging due to an ongoing lack of size-matched grafts and anatomical peculiarities. In the current study, we investigated the incidence of surgical complications in pediatric recipients, with a focus on risk factors and effects on graft outcome. We retrospectively reviewed all 2386 kidney transplantations at our institution from January 2005 until December 2018. Of these, 221 transplants were performed in pediatric recipients, defined as under the age of 18 years. Donor-recipient body surface area ratios were calculated to evaluate the effects of size mismatching. Regression analyses were performed to identify independent risk factors for surgical complications and graft survival, respectively. Perioperative surgical complications requiring revision were observed in 34 (15.4%) cases. Leading cause for revision were vascular complications such as thrombosis or stenosis (n = 15 [6.8%]), which were significantly more frequent in case of young donors, (ie, donor age <6 years; OR: 4.281; CI-95%:1.385-13.226; P = .012), previous nephrectomy (OR: 3.407; CI-95%:1.019-11.387; P = .046), and en-bloc grafts (OR: 4.923; CI-95%:1.355-17.884; P = .015), followed by postoperative hemorrhage (n = 10 [4.5%]), ureteral complications (n = 8 [3.6%]), and lymphoceles (n = 7 [3.2%]). Median follow-up was 84.13 (0.92-175.72) months. One-, 5-, and 10-year graft survival rates were 97.1%, 88.9%, and 65.1%, respectively. Except for vascular complications (HR: 4.727; CI-95%:1.363-16.394; P = .014), none of the analyzed surgical morbidities significantly influenced graft survival. In conclusion, pediatric kidney transplantation achieves excellent long-term results. However, meticulous surgical technique and continuous postoperative monitoring are imperative for early detection and treatment of imminent vascular complications, especially in case of young donors and en-bloc grafts.

Clinical practice recommendations for recurrence of focal and segmental glomerulosclerosis/steroid-resistant nephrotic syndrome.

Recurrence of primary disease is one of the major risks for allograft loss after pediatric RTx. The risk of recurrence of FSGS/SRNS after pediatric RTx in particular can be up to 86% in idiopathic cases. There is a need for consensus recommendations on its prevention and treatment. The CERTAIN study group has therefore performed a thorough literature search based on the PICO model of clinical questions to formulate educated statements to guide the clinician in the process of decision-making. A set of educated statements on prevention and treatment of FSGS/SRNS after pediatric RTx has been generated after careful evaluation of available evidence and thorough panel discussion. We do not recommend routine nephrectomy prior to transplantation; neither do we recommend abstaining from living donation. Special attendance needs to be given to those patients who had already experienced graft loss due to FSGS/SRNS recurrence. Early PE or IA with or without high-dose CsA and/or rituximab seems to be most promising to induce remission. The educated statements presented here acknowledge that FSGS/SRNS recurrence after pediatric RTx remains a major concern and is associated with shorter graft survival or even graft loss. The value of any recommendation needs to take into account that evidence is based on cohorts that differ in ethnicity, pre-transplant history, immunosuppressive regimen, definition of recurrence (eg, clinical and/or histological diagnosis) and treatment modalities of recurrence.

Virus-specific T cells in pediatric renal transplantation.

After pediatric kidney transplantation, immunosuppressive therapy causes an increased risk of severe viral complications, especially from cytomegalovirus (CMV), BK polyomavirus (BKPyV) or Epstein-Barr virus (EBV), and less frequent from adenovirus (ADV). However, suitable predictive markers for the individual outcome of viral infections are missing and the therapeutic management remains a challenge to the success of pediatric kidney transplantation. Virus-specific T cells are known for controlling viral replication and there is growing evidence that virus-specific T cells may serve as a prognostic marker to identify patients at risk for viral complications. This review provides an overview of the usability of virus-specific T cells for improving diagnostic and therapeutic management of viral infections with reference to the necessity of antiviral prophylaxis, timing of pre-emptive therapy, and dosing of immunosuppressive medication after pediatric kidney transplantation. Several studies demonstrated that high levels of virus-specific T cells are associated with decrease of virus load and favorable outcome, whereas lack of virus-specific T cells coincided with virus-induced complications. Accordingly, the additional monitoring of virus-specific T cells aims to personalize the management of antiviral therapy, identify overimmunosuppression, and avoid unnecessary therapeutic interventions. Prospective randomized trials in pediatric kidney recipients comparing standard antiviral and immunosuppressive regimens with T cell-guided therapeutic interventions are needed, before monitoring of virus-specific T cells is implemented in the routine care of pediatric kidney graft recipients.

Distribution and management of the pediatric refugee population with renal replacement: A German pediatric cohort.

With migration rising, the pediatric nephrology community is faced with challenges concerning the management of end-stage kidney disease (ESKD) in the pediatric refugee population. Data on the care of the pediatric refugee cohort on renal replacement therapy (RRT) is not available. A survey conducted by us in 2018 showed that the group of refugee children arriving to Germany during the years 2015-2017 accounts for approximately 20% of the total pediatric dialysis population in Germany. Provision of (medical) care for these children and their families is often hampered by psychosocial problems, cultural differences, language barriers, and administrative issues. Treating centers need to provide additional human as well as financial and logistic resources. In this educational review, we raise awareness and discuss possible challenges occurring in the treatment of refugee children with ESKD.

Endurance-oriented training program with children and adolescents on maintenance hemodialysis to enhance dialysis efficacy-DiaSport.

OBJECTIVE: Pediatric patients spend significant time on maintenance hemodialysis (HD) and traveling. They are often not capable of participating in sports activities. To assess the effects of exercise training during HD on dialysis efficacy in children and adolescents, we set up a multi-center randomized controlled trial (RCT). METHODS: Patients on HD, age 6 to 18 years, were randomized either to 3× weekly bicycle ergometer training or to no training during HD for 12 weeks. Change in single-pool Kt/V (spKt/V) was the primary outcome parameter. RESULTS: We randomized 54 patients of whom 45 qualified (23 in the intervention and 22 in the waiting control group, 14.5 ± 3.01 years, 32 male and 13 female) for the intention-to-treat (ITT) population. Only 26 patients finished study per-protocol (PP). Training was performed for an average of 11.96 weeks (0.14-13.14) at 2.08 ± 0.76 times per week and for a weekly mean of 55.52 ± 27.26 min. Single-pool Kt/V was similar in the intervention compared to the control group (1.70 [0.33] vs. 1.79 [0.55]) at V0 and (1.70 [0.36] vs. 1.71 [0.51]) at V1; secondary endpoints also showed no difference in both ITT and PP analysis. No significant adverse events were reported. No bleeding or needle dislocation occurred in 1670 training sessions. CONCLUSIONS: Intradialytic bicycle training is safe, but does not improve dialysis efficacy and physical fitness. However, the study can be considered underpowered, particularly because of high dropout rates. Future studies need better strategies to increase motivation and compliance and other more effective/intensive exercise measures should be evaluated. TRIAL REGISTRATION: The trial was registered in ClinicalTrials.Gov ( Clinicaltrials.gov identifier: NCT01561118) on March 22, 2012.

Use and preferences regarding internet-based health care delivery in patients with chronic kidney disease.

BACKGROUND AND OBJECTIVES: Internet-based technologies play an increasingly important role in the management and outcome of patients with chronic kidney disease (CKD). The healthcare system is currently flooded with digital innovations and internet-based technologies as a consequence of the coronavirus disease 2019 (COVID-19) pandemic. However, information about the attitude of German CKD-patients with access to online tools towards the use of remote, internet-based interactions such as video conferencing, email, electronic medical records and apps in general and for health issues in particular, are missing. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: To address the use, habits and willingness of CKD patients in handling internet-based technologies we conducted a nationwide cross-sectional questionnaire survey in adults with CKD. RESULTS: We used 380 questionnaires from adult CKD patients (47.6% on dialysis, 43.7% transplanted and 8.7% CKD before renal replacement therapy) for analysis. Of these 18.9% denied using the internet at all (nonusers). Nonusers were significantly older (74.4 years, SD 11.4) than users (54.5 years, SD 14.5, p < 0.001), had a lower educational level than users (≥ 12 years: 6.9% versus 47.1%, p < 0.001) and were more often on dialysis. Within the group of internet users only a minority (2.6%) was using video conferencing with their physician, only 11.7% stated that they were using email to report symptoms and 26.6% were using the internet to schedule appointments. Slightly more than one-third of internet users (35.1%) are concerned that their personal medical data are not safe when submitted via the internet. CONCLUSIONS: Within our group of German CKD-patients we found that almost one out of five patients, especially older patients and patients with a lower educational level, did not use the internet at all. The majority of internet users reported in our survey that they have not used internet-based technologies within a medical context so far, but are willing to consider it. Therefore, it seems to be important to introduce and teach motivated CKD-patients the use and benefits of simple and safe internet-based health care technologies.

A multicenter, randomized, placebo-controlled, double-blind phase 3 trial with open-arm comparison indicates safety and efficacy of nephroprotective therapy with ramipril in children with Alport's syndrome.

Children with Alport syndrome develop renal failure early in life. Since the safety and efficacy of preemptive nephroprotective therapy are uncertain we conducted a randomized, placebo-controlled, double-blind trial in 14 German sites of pediatric patients with ramipril for three to six years plus six months follow-up to determine these parameters. Pretreated children and those whose parents refused randomization became an open-arm control, which were compared to prospective real-world data from untreated children. The co-primary endpoints were safety (adverse drug reactions) and efficacy (time to progression). Out of 66 oligosymptomatic children, 22 were randomized and 44 joined the open-arm comparison. Ramipril therapy showed no safety issues (total of 216.4 patient-years on ramipril; adverse event rate-ratio 1.00; 95% confidence interval 0.66-1.53). Although not significant, our results cautiously showed that ramipril therapy was effective: in the randomized arm, Ramipril decreased the risk of disease progression by almost half (hazard ratio 0.51 (0.12-2.20)), diminished the slope of albuminuria progression and the decline in glomerular filtration. In adjusted analysis, indications of efficacy were supported by prospective data from participants treated open label compared with untreated children, in whom ramipril again seemed to reduce progression by almost half (0.53 (0.22-1.29)). Incorporating these results into the randomized data by Bayesian evidence synthesis resulted in a more precise estimate of the hazard-ratio of 0.52 (0.19-1.39). Thus, our study shows the safety of early initiation of therapy and supports the hope to slow renal failure by many years, emphasizing the value of preemptive therapy. Hence, screening programs for glomerular hematuria in children and young adults could benefit from inclusion of genetic testing for Alport-related gene-variants.