Kidney transplantation (KT) is the best treatment for end-stage kidney disease, with graft survival critically affected by the recipient's immune response. The role of the gut microbiome in modulating this immune response remains underexplored. Our study investigates how microbiome alterations might be associated with allograft rejection by analyzing the gut microbiome using 16S rRNA gene amplicon sequencing of a multicenter prospective study involving 562 samples from 245 individuals of whom 217 received KT. Overall, gut microbiome composition showed gradual recovery post-KT, mirroring chronic kidney disease (CKD)-to-health transition as indicated by an increase in Shannon diversity. Prior to graft rejection, we observed a decrease in microbial diversity and short-chain fatty acid-producing taxa. Functional analysis highlighted a decreased potential for short-chain fatty acid production in patients preceding the rejection event, validated by quantitative PCR for the production potential of propionate and butyrate. Postrejection analysis revealed normalization of these microbiome features. Comparison to published microbiome signatures from CKD patients demonstrated a partial overlap of the microbiome alterations preceding graft rejection with the alterations typically found in CKD. Our findings suggest that alterations in gut microbiome composition and function may precede and influence KT rejection, suggesting potential implications as biomarkers or for early therapeutic microbiome-targeting interventions.

We investigated factors associated with post-transplant growth in pediatric kidney transplant (KTx) recipients with a focus on plasma bicarbonate (HCO3−) and estimated the effect of alkali treatment on growth. In this study of the CERTAIN Registry, data were collected up to 5 years post-transplant. Generalized Additive Mixed Models were applied to assess the association between post-transplant growth and covariates. A trial-emulation analysis was performed to estimate the causal effect of alkali supplementation on growth. We report on 2147 primary KTx recipients with a median age at KTx of 10.2 (IQR 5.1;14.3) years. No statistically significant association was found between growth and HCO3− (p = 0.21), but the shape of the estimated conditional association showed a decreasing estimated growth with increasing HCO3−. Glucocorticoid treatment and allograft rejection showed an inverse association with growth. Living donor KTx, glomerulopathy, recombinant growth hormone use, low height z-score at KTx, younger age, and higher eGFR were positively associated with growth. The trial-emulation analysis included patients at 30 days and 3, 6, and 9 months post-transplant with HCO3− < 22 mmol/L and no prior alkaline treatment. Alkaline treatment was initiated in 194, 93, 47, and 25 patients, respectively. After adjustment for confounders, there was no significant difference in growth at 1-year post-transplant in treated and untreated patients. We found no association between HCO3− and growth nor evidence of improved growth after treatment of metabolic acidosis. Living donor KTx was positively associated with post-transplant growth, while there was an inverse association with allograft rejection.

CONTEXT:The pathophysiology of cystinosis-associated metabolic bone disease is complex. OBJECTIVE:We hypothesized a disturbed interaction between osteoblasts and osteoclasts. METHODS:This binational cross-sectional multicenter study included 103 patients with cystinosis (61% children) with chronic kidney disease (CKD) stages 1 to 5D/T at hospital clinics. Ten key bone markers were evaluated. RESULTS:Skeletal complications occurred in two-thirds of the patients, with adults having a 5-fold increased risk compared with children. Patients with CKD stages 1 to 3 showed reduced z-scores for serum phosphate and calcium and suppressed fibroblast growth factor 23 (FGF23) and parathyroid hormone levels, in conjunction with elevated bone-specific alkaline phosphatase levels. Serum phosphate was associated with estimated glomerular filtration rate, combined phosphate and active vitamin D treatment, and native vitamin D supplementation, while serum calcium was associated with age and dosage of active vitamin D. Sclerostin was generally elevated in children, and associated with age, FGF23 levels, and treatment with active vitamin D and growth hormone. The osteoclast marker tartrate-resistant acid phosphatase 5b was increased, and associated with age and treatment with active vitamin D. The ratio of soluble ligand of receptor activator of nuclear factor-κB (sRANKL) and osteoprotegerin (OPG), a surrogate for the regulation of osteoclastogenesis by osteoblasts, was decreased and associated with phosphate and 1,25(OH)2D3 levels. These changes were only partly corrected after transplantation. CONCLUSION:Bone health in cystinosis deteriorates with age, which is associated with increased osteoclast activity despite counter-regulation of osteoblasts via OPG/RANKL, which in conjunction with elevated sclerostin levels and persistent rickets/osteomalacia, may promote progressive bone loss.

In kidney transplant recipients (KTR), BK polyomavirus-associated nephropathy (BKPyVAN) is a major cause of graft loss. To facilitate the clearance of BKPyV-DNAemia, reduction of immunosuppression is currently the treatment of choice but may increase the risk of graft rejection. This international CERTAIN study was designed to determine the risk of alloimmune response and graft dysfunction associated with immunosuppression reduction for BKPyV treatment in 195 pediatric KTR. BKPyV-DNAemia was associated with a more than twofold increased risk of late T cell-mediated rejection (TCMR) (HR 2.22, p = 0.024), of de novo donor-specific HLA antibodies (dnDSA) and/or antibody-mediated rejection (ABMR) (HR 2.64, p = 0.002), and of graft function deterioration (HR 2.73, p = 0.001). Additional independent risk factors for dnDSA/ABMR development were a higher HLA mismatch (HR 2.72, p = 0.006) and re-transplantation (HR 6.40, p = 0.000). Other independent predictors of graft function deterioration were TCMR (HR 3.98, p = 0.003), higher donor age (HR 1.03, p = 0.020), and re-transplantation (HR 3.56, p = 0.013). These data indicate that reduction of immunosuppression for BKPyV-DNAemia management is associated with increased alloimmune response in pediatric KTR. Therefore, regular dnDSA screening and close monitoring of graft function in case of BKPyV-DNAemia followed by subsequent reduction of immunosuppressive therapy are recommended.

Einführung Die Clostridioides-difficile-Infektion (CDI) ist mit einer hohen Morbidität und Mortalität assoziiert. Auch wenn ihre Inzidenz in den letzten Jahren in Deutschland rückläufig ist, kann die individuelle Infektion trotz therapeutischen Fortschritts eine medizinische Herausforderung darstellen. Hier soll geklärt werden, welche Lücken verantwortliche Behandler/-innen in der Versorgung und in der Evidenzlage als besonders gravierend ansehen. Methoden In einem moderierten Workshop von in Deutschland tätigen CDI-Experten/-innen, wurden als relevant eingeschätzte Fragestellungen ermittelt. Eine bereits in fünf anderen Ländern (Australien, Frankreich, Großbritannien, Kanada und Italien) durchgeführte Befragung wurde ergänzend angepasst und von 27 Behandlern/-innen bearbeitet. Bei der Auswertung wurden die als besonders wichtig empfundenen Themen herausgearbeitet, die Aussagen der Fachgruppen verglichen und Meinungsänderungen berücksichtigt. Ergebnisse 27 vollständig ausgefüllte Fragebögen wurden ausgewertet. Verbesserungsbedarf wurde vorrangig bei der Verhinderung von CDI-Rezidiven (74,1%), sowie Therapie der Rezidive (55,6%) gesehen. Evidenzdefizite wurden bei der Behandlung von Rezidiven (55,6%) und der Identifikation der Risikofaktoren für Rezidive konstatiert (48,1%). Die Verbesserung der Versorgung mittels fäkalem Mikrobiota-Transfer (FMT) nannten 70,4%. Bei Leitlinien wurde mehr Klarheit (48,1%) und regelmäßigere Aktualisierung (40,7%) gewünscht. Für Patienten/-innen wurden bessere Aufklärung der über angemessenen Antibiotikaeinsatz (52,0%) und Wahlmöglichkeiten der FMT angestrebt (48,1%). Zusammenfassung Bei der Frage nach Verbesserungsbedarf in der Versorgung und Evidenzlücken bei der Behandlung von Patienten/-innen mit CDI ist die nationale Experten/-innensicht in Deutschland, wie auch die internationale Einschätzung ähnlich: Im Zentrum steht die Prävention und Therapie der rezidivierenden CDI. Die Problematik des Zugangs zum FMT ist eine deutsche Besonderheit, die verbesserungspflichtig erscheint.

Background Minimal change disease and primary focal segmental glomerulosclerosis in adults, along with idiopathic nephrotic syndrome in children, are immune-mediated podocytopathies that lead to nephrotic syndrome. Autoantibodies targeting nephrin have been found in patients with minimal change disease, but their clinical and pathophysiological roles are unclear.Methods We conducted a multicenter study to analyze antinephrin autoantibodies in adults with glomerular diseases, including minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, IgA nephropathy, antineutrophil cytoplasmic antibody-associated glomerulonephritis, and lupus nephritis, as well as in children with idiopathic nephrotic syndrome and in controls. We also created an experimental mouse model through active immunization with recombinant murine nephrin.Results The study included 539 patients (357 adults and 182 children) and 117 controls. Among the adults, antinephrin autoantibodies were found in 46 of the 105 patients (44%) with minimal change disease, 7 of 74 (9%) with primary focal segmental glomerulosclerosis, and only in rare cases among the patients with other conditions. Of the 182 children with idiopathic nephrotic syndrome, 94 (52%) had detectable antinephrin autoantibodies. In the subgroup of patients with active minimal change disease or idiopathic nephrotic syndrome who were not receiving immunosuppressive treatment, the prevalence of antinephrin autoantibodies was as high as 69% and 90%, respectively. At study inclusion and during follow-up, antinephrin autoantibody levels were correlated with disease activity. Experimental immunization induced a nephrotic syndrome, a minimal change disease-like phenotype, IgG localization to the podocyte slit diaphragm, nephrin phosphorylation, and severe cytoskeletal changes in mice.Conclusions In this study, circulating antinephrin autoantibodies were common in patients with minimal change disease or idiopathic nephrotic syndrome and appeared to be markers of disease activity. Their binding at the slit diaphragm induced podocyte dysfunction and nephrotic syndrome, which highlights their pathophysiological significance. (Funded by Deutsche Forschungsgemeinschaft and others.) Antinephrin autoantibodies occur in adults with minimal change disease and children with idiopathic nephrotic syndrome and appear to be disease activity markers. Their binding at slit diaphragms may induce podocyte dysfunction.

Abstract Background and Aims Cystinosis-associated metabolic bone disease (CMBD) is a major challenge in the treatment of patients with infantile nephropathic cystinosis (NC). Study data are limited due to small case numbers, lack of adults or patients on renal replacement therapy and/or inadequate assessment of bone health. Method We investigated markers for CMBD in all age groups (1-44 years; 61% children) and CKD stages 1-5D/T in the largest NC cohort to date with 103 German and Austrian NC patients. Skeletal comorbidity and concentrations of fibroblast growth factor 23 (FGF23), the osteoblast marker bone-specific alkaline phosphatase (BAP), the bone remodeling inhibitor sclerostin, the osteoclast marker tartrate-resistant acid phosphatase 5b (TRAP5b), the soluble receptor activator of nuclear factor kappa B ligand (sRANKL), osteoprotegerin (OPG) and the sRANKL/OPG ratio as surrogates for the regulation of osteoclastogenesis by osteoblasts were determined by ELISA, converted into age- and sex-specific z-scores and compared as a function of eGFR. Multivariable regression analyses were used to identify specific influencing factors associated with biochemical and clinical findings in pre-transplant NC patients. Results Skeletal complications occurred in two-thirds of patients, with the risk being five times higher in adults than in children. Pediatric and adult NC patients with CKD stages 1-4 showed hypophosphatemia and hypocalcemia associated with suppressed FGF23 and PTH levels and elevated BAP concentrations. This was associated with age, eGFR and treatment with phosphate and active vitamin D, suggesting more vigorous treatment of Fanconi syndrome in pre-transplant patients. As indicated by the increased TRAP5b and decreased sRANKL/OPG ratio, osteoclast activity was increased despite counterregulation by osteoblasts, which in conjunction with increased sclerostin activity may have contributed to the progressive bone loss and skeletal comorbidity in our patient cohort. Conclusion Bone health in NC progressively deteriorates with age, largely due to persistent rickets/osteomalacia associated with inadequate treatment of Fanconi syndrome and increased osteoclast activity despite osteoblast counterregulation via OPG/RANKL. Our data suggest that a primary osteoclast defect in NC promotes increased bone resorption, limiting maximal bone mass and leading to progressive bone loss and increased skeletal comorbidity.

Cystinosis is a rare autosomal-recessive lysosomal storage disease that progressively affects multiple organs beginning with the kidneys. Patients require lifelong multidisciplinary care for the management of kidney disease and progressive extra-renal manifestations, and thus, they are especially fragile and vulnerable during transition from pediatric to adult care. Previous documents have provided guidance to help the medical transition of these highly burdened patients. Patients and their families often experience great psychological distress and face significant social challenges; for these reasons, they often need help from psychologists, social workers, and other psychosocial professionals. Due to the rarity of the disease, most psychosocial professionals have no expertise in this disorder and require advice. To this end, a steering committee (SC) composed of six experts, including pediatric nephrologists, psychologists, and social workers with experience in the care for patients with cystinosis, have identified and addressed seven key questions related to psychosocial challenges of the disease and the burden of treatment. Ten additional international experts (the extended faculty, EF) were invited to answer these questions. Since robust evidence is lacking, as in many rare diseases, conclusions were based on collective agreement between members of the SC and the EF, and the consolidated answers were summarized into expert opinion statements. The present document contains information on the concerns and psychosocial burden of patients with cystinosis and of their caregivers, and provides practical advice for timely and appropriate support to facilitate the transition to adult care.

Background. Kidney transplantation (KTx) from small donors is associated with inferior graft survival in registry studies, whereas single-center studies show favorable results. Methods. We compared 175 pediatric KTx from small donors <= 20 kg (SDKTx) with 170 age-matched recipients from adult donors (ADKTx) from 20 centers within the Cooperative European Paediatric Renal Transplant Initiative registry. Graft survival and estimated glomerular filtration rate (eGFR) were analyzed by Cox regression and mixed models. Detailed data on surgical and medical management were tested for association with graft survival. Results. One-year graft survival was lower after SDKTx compared with ADKTx (90.9% versus 96.5%; odds ratio of graft loss, 2.92; 95% confidence interval [CI], 1.10-7.80; P = 0.032), but 5-y graft survival was comparable (90.9% versus 92.7%; adjusted hazard ratio of graft loss 1.9; 95% CI, 0.85-4.25; P = 0.119). SDKTx recipients had an annual eGFR increase of 8.7 +/- 6.2 mL/min/1.73 m2 compared with a decrease of 6.9 +/- 5.7 mL/min/1.73 m2 in ADKTx recipients resulting in a superior 5-y eGFR (80.5 +/- 25.5 in SDKTx versus 65.7 +/- 23.1 mL/min/1.73 m2 in ADKTx; P = 0.008). At 3 y posttransplant, eGFR after single SDKTx was lower than after en bloc SDKTx (86.6 +/- 20.4 versus 104.6 +/- 35.9; P = 0.043) but superior to ADKTx (68.1 +/- 23.9 mL/min/1.73 m2). Single-kidney SDKTx recipients had a lower rate of hypertension at 3 y than ADKTx recipients (40.0% versus 64.7%; P = 0.008). Conclusions. Compared with ADKTx, 5-y graft function is superior in SDKTx and graft survival is similar, even when performed as single KTx. Utilizing small donor organs, preferably as single kidneys in experienced centers, is a viable option to increase the donor pool for pediatric recipients.

Homozygous familial hypercholesterolaemia is a life-threatening genetic condition, which causes extremely elevated LDL-C levels and atherosclerotic cardiovascular disease very early in life. It is vital to start effective lipid-lowering treatment from diagnosis onwards. Even with dietary and current multimodal pharmaceutical lipid-lowering therapies, LDL-C treatment goals cannot be achieved in many children. Lipoprotein apheresis is an extracorporeal lipid-lowering treatment, which is used for decades, lowering serum LDL-C levels by more than 70% directly after the treatment. Data on the use of lipoprotein apheresis in children with homozygous familial hypercholesterolaemia mainly consists of case-reports and case-series, precluding strong evidence-based guidelines. We present a consensus statement on lipoprotein apheresis in children based on the current available evidence and opinions from experts in lipoprotein apheresis from over the world. It comprises practical statements regarding the indication, methods, treatment goals and follow-up of lipoprotein apheresis in children with homozygous familial hypercholesterolaemia and on the role of lipoprotein(a) and liver transplantation.

Die Gallengangsatresie ist eine seltene Cholangiopathie unklarer Ätiologie und stellt die häufigste Ursache für eine Lebertransplantation im Kindesalter dar. Um den Zeitpunkt einer möglichen Transplantation hinauszuzögern oder diese zu vermeiden, sollte so früh wie möglich eine Kasai-Hepatoportoenterostomie (KPE) durchgeführt werden. Trotzdem überleben nur knapp 20–30

Allograft loss after pediatric kidney transplantation (KTx) is highest in adolescents and young adults. Non-adherence and Health Care Transition (HCT) are important factors, but others do also contribute. Patients were randomized 1:1. The intervention group (IG) included a central case manager, a communication app, and joined transition rounds for one year before and one after transfer. Primary endpoint was the coefficient of variation (CoV) of the trough level of the calcineurin inhibitor as a surrogate marker for medication adherence associated with graft loss. Least square (LS) mean differences and corresponding 95% confidence intervals (CIs) were estimated using an ANCOVA model. 220 patients were assessed for eligibility. 49 patients were randomized to the intervention group and 53 to the control group (CG). We analyzed 84 patients in the modified intention-to-treat analysis (38IG,46CG) and 60 in the per protocol analysis (25IG,35CG) No difference in CoV was observed. We saw low numbers of graft-related events and observed no differences with respect to quality of life. BTP did not improve adherence and other outcome parameters. Non-adherent patients may have decided not to take part, as adherence of participants was already good at study start. It thus is a future challenge to design multicenter trials on HCT that include multiple interventions.

Introduction Clostridioides difficile infection (CDI), as a nosocomial disease, is associated with high morbidity and mortality. Even though the incidence of CDI has been declining in Germany in recent years, the individual infection may pose a medical challenge despite therapeutic advances. The aim here is to clarify which gaps practitioners consider to be particularly serious in care and in the existing evidence base. Methods In a moderated workshop of German CDI experts the topics considered as relevant were identified. A survey already conducted in five other countries (Australia, France, Great Britain, Canada, and Italy) was adapted and processed by 27 practitioners. During the evaluation, the topics perceived as particularly important were identified, the statements of the specialist groups were compared and changes in opinion were considered. Results 27 fully completed questionnaires were evaluated. The need for improvement was primarily seen in the prevention of CDI recurrences (74.1%) and the treatment of recurrences (55.6%). Evidence deficits were noted in the treatment of recurrences (55.6%) and identification of risk factors for recurrences (48.1%). Improving care via fecal microbiota transfer (FMT) was named by 70.4%. For guidelines, more clarity (48.1%) and more regular updates (40.7%) were desired. For patients, better education on appropriate antibiotic use (52.0%) and choice of FMT were desired (48.1%). Summary The German expert view and the international assessment is similar, when asked about the need for improvement in care and evidence gaps in the treatment of patients with CDI: The focus is on prevention and therapy of recurrent CDI. The problem of access to FMT is a German peculiarity that seems to need improvement.

Despite significant medical and technical improvements in the field of dialysis, the morbidity and mortality among patients with chronic kidney disease (CKD) stage 5 on dialysis remains extremely high. Hemodiafiltration (HDF), a dialysis method that combines the two main principles of hemodialysis (HD) and hemofiltration—diffusion and convection—has had a positive impact on survival when delivered with a high convective dose. Improved outcomes with HDF have been attributed to the following factors: HDF removes middle molecular weight uremic toxins including inflammatory cytokines, increases hemodynamic stability, and reduces inflammation and oxidative stress compared to conventional HD. Two randomized trials in adults have shown improved survival with HDF compared to high-flux HD. A large prospective cohort study in children has shown that HDF attenuated the progression of cardiovascular disease, improved bone turnover and growth, reduced inflammation, and improved blood pressure control compared to conventional HD. Importantly, children on HDF reported fewer headaches, dizziness, and cramps; had increased physical activity; and improved school attendance compared to those on HD. In this educational review, we discuss the technical aspects of HDF and results from pediatric studies, comparing outcomes on HDF vs. conventional HD. Convective volume, the cornerstone of treatment with HDF and a key determinant of outcomes in adult randomized trials, is discussed in detail, including the practical aspects of achieving an optimal convective volume.

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.

AimsWe investigated the relationship between metabolic acidosis over time and allograft outcome in pediatric kidney transplantation.MethodsThis registry study collected data up to 10 years posttransplant. Survival analysis for a composite endpoint of graft loss or estimated glomerular filtration rate (eGFR) ≤30 mL/min per 1.73 m2 or ≥50% decline from eGFR at month 3 posttransplant was performed. The association of HCO3-<22 mmol/L (metabolic acidosis) and HCO3-<18 mmol/L (severe metabolic acidosis) with allograft outcome was investigated using stratified Cox models and marginal structural models. Secondary analyses included the identification of risk factors for metabolic acidosis and the relationship between alkali supplementation and allograft outcome.ResultsWe report on 1911 patients, of whom 347 reached the composite endpoint. The prevalence of metabolic acidosis over time ranged from 20.4% to 38.9%. In the adjusted Cox models, metabolic acidosis (hazard ratio [HR],2.00; 95% confidence interval [CI], 1.54 to 2.60) and severe metabolic acidosis (HR,2.49; 95%CI, 1.56 to 3.99) were associated with allograft dysfunction. Marginal structural models showed similar results (HR,1.75; 95%CI, 1.32 to 2.31 and HR,2.09; 95%CI, 1.23 to 3.55, respectively). Older age was associated with a lower risk of metabolic acidosis (odds ratio (OR) 0.93 per year older; 95% CI, 0.91 to 0.96) and severe metabolic acidosis (OR, 0.89; 95% CI, 0.84 to 0.95). Patients with uncontrolled metabolic acidosis had the worst outcome compared to those without metabolic acidosis and without alkali (HR, 3.70; 95% CI, 2.54 to 5.40)ConclusionThe degree of metabolic acidosis is associated with allograft dysfunction.

Introduction Data on age-related differences in rejection rates, infectious episodes and tacrolimus exposure in pediatric kidney transplant recipients (pKTR) on a tacrolimus-based immunosuppressive regimen are scarce. Methods We performed a large-scale analysis of 802 pKTR from the CERTAIN registry from 40 centers in 14 countries. Inclusion criteria were a tacrolimus-based immunosuppressive regimen and at least two years of follow-up. The patient population was divided into three age groups (infants and young children <6 years, school-aged children 6-12 years, and adolescents >12 years) to assess age-related differences in outcome. Results Median follow-up was 48 months (IQR, 36-72). Within the first 2 years post-transplant, infants and young children had a significantly higher incidence of infections (80.6% vs. 55.0% in adolescents, P<0.001) and a significantly higher number of cumulative hospital days (median 13 days vs. 7 days in adolescents, P < 0.001). Adolescents had a significantly higher rate of biopsy-proven acute rejection episodes in the first year post-transplant (21.7%) than infants and young children (12.6%, P=0.007). Infants and young children had significantly lower tacrolimus trough levels, lower tacrolimus concentration-to-dose ratios as an approximation for higher tacrolimus clearance, and higher tacrolimus intra-patient variability (all P < 0.01) than adolescents. Conclusions This largest study to date in European pKTR on a tacrolimus-based immunosuppressive regimen shows important age-related differences in rejection rates, infection episodes, tacrolimus exposure and clearance. These data suggest that immunosuppressive therapy in pKTR should be tailored and personalized according to the age-specific risk profiles of this heterogeneous patient population. The data may also serve as a benchmark for future studies with novel immunosuppressive drugs.