Burkhard Toenshoff

• Heidelberg University

Background Approximately 50% of patients with chronic kidney disease due to C3 glomerulopathy (C3G) or primary immune‐complex membranoproliferative glomerulonephritis (IC‐MPGN) will require dialysis and/or kidney transplantation (KTx) within the first 10 years of disease onset. Currently, there are no guidelines regarding the indications for KTx or...

Background Chronic kidney disease (CKD) seriously affects the well-being and shortens the life expectancy of children and adolescents, but its progression is challenging to predict. Therefore, there is an urgent need for biomarkers that can identify children at risk of faster CKD progression. Alport syndrome (AS) is the most common monogenetic glom...

Background A pre-transplant prediction model using commonly available factors is valuable for optimizing donor selection, communication, and counselling for pediatric kidney transplant (PKT) recipients. This study aims to externally validate a Dutch PKT prediction model and assess its international applicability. Methods Data from the Dutch-, CERT...

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...

The 1‐ and 5‐year patient and graft survival rates of pediatric kidney transplant recipients have improved considerably in recent years. Regardless of early success, kidney transplantation is challenged by suboptimal long‐term allograft and patient survival. Many kidney transplants are lost due to immune (rejection) and nonimmune allograft injuries...

The pivotal role of the cell entry receptor ACE2 for SARS‐CoV‐2 infection is well‐established. When ACE2 is shed from cell surface into plasma as soluble ACE2 (sACE2), it can effectively neutralize SARS‐CoV‐2. This longitudinal prospective cohort study analyzed sACE2 activity in 1192 participants, aged 4 months to 81 years, 3 and 12 months after SA...

Background We developed a blended training program at a tertiary pediatric center based on hospital-specific emergency guidelines, profession-specific Virtual Patients (VPs), and interprofessional team training. Using this novel approach, we addressed differing educational needs of medical and nursing staff and intrinsic cognitive overload among pa...

Background: The heterogeneous clinical presentation of graft microvascular inflammation poses a major challenge to successful kidney transplantation. The effect of microvascular inflammation on allograft outcomes is unclear. Methods: We conducted a cohort study that included kidney-transplant recipients from more than 30 transplantation centers...

Background 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. Methods This international CERTAIN study was designed to d...

This study by the Cooperative European Paediatric Renal Transplant Initiative (CERTAIN) was designed to determine the incidence, risk factors, current management strategies, and outcomes of antibody-mediated rejection (ABMR) in pediatric kidney transplant recipients (pKTR). We performed an international, multicenter, longitudinal cohort study of da...

Introduction Data on age-related differences in rejection rates, infectious episodes, and tacrolimus exposure in pediatric kidney transplant recipients (pKTRs) on a tacrolimus-based immunosuppressive regimen are scarce. Methods We performed a large-scale analysis of 802 pKTRs from the Cooperative European Paediatric Renal Transplant Initiative (CE...

Background Complement 3 glomerulopathy (C3G) and immune complex membranoproliferative glomerulonephritis (IC-MPGN) are ultra-rare chronic kidney diseases with an overall poor prognosis, with approximately 40–50% of patients progressing to kidney failure within 10 years of diagnosis. C3G is characterized by a high rate of disease recurrence in the t...

Context The pathophysiology of cystinosis-associated metabolic bone disease is complex. Objective We hypothesized a disturbed interaction between osteoblasts and osteoclasts. Design Binational cross-sectional multicenter study. Setting Hospital clinics. Patients One hundred and three patients with cystinosis (61% children) with chronic kidney d...

Background Infantile nephropathic cystinosis (INC) is a rare lysosomal storage disorder, mostly and often firstly affecting the kidneys, together with impaired disharmonious growth and rickets, eventually resulting in progressive chronic kidney disease (CKD). With the introduction of cysteamine therapy, most pediatric patients reach adulthood with...

Background Data on age-related differences in rejection rates, infectious episodes and tacrolimus exposure in pediatric kidney transplant recipients (pKTR) on a uniform tacrolimus-based immunosuppressive regimen are scarce. Methods We therefore performed a large-scale analysis of 802 pKTR from the CERTAIN registry from 40 centers in 14 countries....

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...

Introduction Hepatocyte nuclear factor 1-beta (HNF1B) gene variants or the chromosome 17q12 deletion (17q12del) represent the most common monogenic cause of developmental kidney disease. Although neurodevelopmental disorders have been associated with the 17q12del, specific genotype-phenotype associations with respect to kidney function evolution ha...

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 E...

Introduction We investigated the relationship between metabolic acidosis over time and allograft outcome in pediatric kidney transplantation (KTx). Methods This registry study collected data up to 10 years posttransplant. Survival analysis for a composite end point of graft loss or estimated glomerular filtration rate (eGFR) ≤ 30 ml/min per 1.73 m...

A major challenge in kidney transplantation (KT) is the large interpatient variability in the pharmacokinetics of immunosuppressive drugs. Here, we explored the role of the gut microbiome in interindividual variation in immunosuppressive drug metabolism. Analysis of 38 fecal communities, including 10 from KT recipients, and 45 bacterial species aga...

Background This study by the Cooperative European Paediatric Renal Transplant Initiative (CERTAIN) was designed to determine the incidence, risk factors, current management strategies and outcomes of antibody-mediated rejection (ABMR) in pediatric kidney transplant recipients (pKTR). Methods We performed an international, multicenter, longitudinal...

Introduction Primary hyperoxaluria (PH) is a rare genetic disorder of hepatic glyoxylate metabolism. Nedosiran is an RNA interference (RNAi) therapeutic that the US Food and Drug Administration has approved for treatment of PH1. PHYOX3 is a trial evaluating monthly nedosiran in patients with PH. Methods In this PHYOX3 interim analysis, participant...

Background A structured transition of adolescents and young adults with chronic autoinflammatory and autoimmune disorders from the pediatric to the adult health care system is important. To date, data on the time, processes, outcome, resources required for the necessary components of the transition process and the associated costs are lacking. Met...

Background Tacrolimus, a calcineurin inhibitor (CNI), is currently the first-line immunosuppressive agent in kidney transplantation. The therapeutic index of tacrolimus is narrow due to due to the substantial impact of minor variations in drug concentration or exposure on clinical outcomes (i.e., nephrotoxicity), and it has a highly variable intra-...

Background Little is known about the time-varying determinants of kidney graft failure in children. Methods We performed a retrospective study of primary pediatric kidney transplant recipients (<18 years) from the Eurotransplant registry (1990-2020). Piece-wise exponential additive mixed models were applied to analyze time-varying recipient, donor...

Background Vesicoureteral reflux (VUR) is common in children and adolescents undergoing kidney transplantation (KTx) and may adversely affect allograft kidney function. Methods To explore the current management of symptomatic native and allograft VUR in pediatric KTx recipients, an online survey was distributed to European surgical transplant prof...

Background Early onset de novo focal segmental glomerular sclerosis (FSGS) in the kidney allograft in patients without FSGS in the native kidney is a rare disorder in children. It usually occurs mostly beyond the first year after kidney transplantation and often leads to graft loss. Standardized treatment protocols have not yet been established. C...

Background: The structured transition of adolescents and young adults with chronic kidney disease (CKD) from pediatric to adult care is important, but data on the time and resources required for the necessary components of the transition process and the associated costs are lacking. Methods: In a prospective single-center cohort study of 52 pati...

Background: Infantile nephropathic cystinosis (INC) is a systemic lysosomal storage disease causing intracellular cystine accumulation, resulting in renal Fanconi syndrome, progressive kidney disease (CKD), rickets, malnutrition, and myopathy. An INC-specific disproportionately diminished trunk length compared to leg length poses questions regardi...

Predicting long-term kidney allograft failure is an unmet need for clinical care and clinical trial optimization in children. We aimed to validate a kidney allograft failure risk prediction system in a large international cohort of pediatric kidney transplant (kTx) recipients. Patients from 20 centers from Europe and the United States, transplanted...

Background: We developed a blended training program at a tertiary pediatric center based on hospital-specific emergency guidelines, profession-specific Virtual Patients (VPs), and interprofessional team training. Using this novel approach, we addressed differing educational needs of medical and nursing staff and intrinsic cognitive overload among p...

The urinary albumin- and protein-to-creatinine ratios (UACR and UPCR, respectively) are key endpoints in most clinical trials assessing risk of progression of chronic kidney disease (CKD). For the first time, the current study compares the UACR versus the UPCR head-to-head at early stages of CKD, taking use of the hereditary podocytopathy Alport sy...

In March 2022, KDIGO held a virtual controversies conference to address the important but rarely examined phase during which the kidney transplant is failing or has failed. In addition to discussing the definition of the failing allograft, four broad areas were considered in the context of a declining functioning graft: prognosis and kidney failure...

Because it is currently not possible to induce specific tolerance, transplantation requires immunosuppressive therapies. The goal is to use immunosuppressive agents that are potent, selective, and reversible, with reliable delivery and long-term safety. A careful balance is required to find the dose that prevents rejection of the graft, while minim...

[This corrects the article DOI: 10.3389/fimmu.2023.1092335.].

Introduction Patient data are increasingly available in (multi)national registries, especially for rare diseases. This study aims to provide an overview of current European registries of paediatric kidney transplantation (PKT) care, their coverage, and their focus. Based on these data, we assess whether the current status is optimal for achieving o...

Introduction Rejection remains the main cause of allograft failure in paediatric kidney transplantation and is driven by donor-recipient HLA mismatching. Modern computational algorithms enable assessment of HLA mismatch immunogenicity at the molecular level (molecular-mismatch, molMM). Whilst molMM has been shown to correlate with alloimmune outcom...

Data on cross-neutralization of the SARS-CoV-2 omicron variant more than one year after SARS-CoV-2 infection are urgently needed, especially in children, to predict the likelihood of reinfection and to guide vaccination strategies. In a prospective observational cohort study, we evaluated live-virus neutralization of the SARS-CoV-2 omicron (BA.1) v...

Background: Vesico-ureteral reflux (VUR) is considered to be a risk factor for recurrent febrile urinary tract infections and impaired renal transplant survival. Methods: An online survey supported by the European Society for Paediatric Nephrology was designed to evaluate current management strategies of VUR in native and transplanted kidneys of...

Background Data on humoral immune response to standard COVID-19 vaccination are scarce in adolescent patients and lacking for children below 12 years of age with chronic kidney disease including kidney transplant recipients. Methods We therefore investigated in this retrospective two-center study (DRKS00024668; registered 23.03.2021) the humoral i...

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 kid...

X-linked Alport syndrome (AS) caused by hemizygous disease-causing variants in COL4A5 primarily affects males. Females with a heterozygous state show a diverse phenotypic spectrum ranging from microscopic hematuria to end-stage kidney disease (ESKD) and extrarenal manifestations. In other X-linked diseases, skewed X-inactivation leads to preferenti...

Background Long COVID in children and adolescents remains poorly understood due to a lack of well-controlled studies with long-term follow-up. In particular, the impact of the family context on persistent symptoms following SARS-CoV-2 infection remains unknown. We examined long COVID symptoms in a cohort of infected children, adolescents, and adult...

Background Methylmalonic acidemia (MMAemia) is characterized by accumulation of methylmalonic acid (MMA) in all body tissues. To minimize disease-related complications, isolated kidney (KTx), liver (LTx) or combined liver-kidney transplantation (LKTx) have been suggested. However, the impact of these different transplant strategies on outcome are u...

Introduction Little is known about the consequences of deranged chronic kidney disease–mineral and bone disorder (CKD-MBD) parameters on kidney allograft function in children. We examined a relationship between these parameters over time and allograft outcome. Methods This registry study from the Cooperative European Paediatric Renal Transplant In...

During its lifetime, the renal allograft is at continuous risk for the development of rejection due to HLA and non-HLA incompatibility with the recipient which is why lifelong immunosuppressive therapy is required. The goal of immunosuppressive therapy posttransplantation in pediatric renal transplant recipients is to prevent acute and chronic reje...

Long-term data on the humoral immune response and cross-neutralization against variants of concern in children more than one year after SARS-CoV-2 infection are currently missing and urgently needed in order to predict the likelihood of reinfections and guide vaccination strategies.

Nedosiran is an investigational RNA interference agent designed to inhibit expression of hepatic lactate dehydrogenase, the enzyme thought responsible for the terminal step of oxalate synthesis. Oxalate overproduction is the hallmark of all genetic subtypes of primary hyperoxaluria (PH). In this double‐blind, placebo‐controlled study, we randomly a...

Infantile nephropathic cystinosis, due to impaired transport of cystine out of lysosomes, occurs with an incidence of 1 in 100–200,000 live births. It is characterized by renal Fanconi syndrome in the first year of life and glomerular dysfunction progression to end-stage kidney disease by approximately 10 years of age. Treatment with oral cysteamin...

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. In...

Introduction Nephronophthisis (NPH) comprises a group of rare disorders accounting for up to 10% of end-stage kidney disease (ESKD) in children. Prediction of kidney prognosis poses a major challenge. We assessed differences in kidney survival, impact of variant type, and the association of clinical characteristics with declining kidney function....

An association between certain ABO/Rh blood groups and susceptibility to SARS-CoV-2 infection has been proposed for adults, although this remains controversial. In children and adolescents, the relationship is unclear due to a lack of robust data. Here, we investigated the association of ABO/Rh blood groups and SARS-CoV-2 in a multi-center study co...

BACKGROUND AND AIMS Kidney allograft loss is a common cause of end-stage renal disease but accurate prediction models of kidney allograft loss are lacking in children. The iBOX system has been broadly validated among adults. We aimed to validate the iBOX system in a large international cohort of pediatric kTx recipients. METHOD In this observation...

Background Infantile nephropathic cystinosis (INC) is a rare lysosomal storage disorder resulting in progressive chronic kidney disease (CKD) and a variety of extrarenal manifestations. This orphan disease remains a challenge for patients, their families and health care providers. There is currently no comprehensive study on patients' clinical cour...

The study conference of the German Society for Pediatric Nephrology (GPN), which has been held for almost 50 years, is the most important instrument of cooperative research in German pediatric nephrology. It has made a significant contribution to improving clinical care and strengthens the cooperation between the pediatric nephrology centers. Many...

Seroconversion after COVID‐19 vaccination is impaired in kidney transplant recipients. Emerging variants of concern such as the B.1.617.2 (delta) and the B.1.1.529 (omicron) variant pose an increasing threat to these patients. In this observational cohort study, we measured anti‐S1 IgG, surrogate neutralizing, and anti‐receptor‐binding domain antib...

Background To describe treatment practices for juvenile proliferative lupus nephritis (LN) class III and IV of pediatric rheumatologists and nephrologists in Germany and Austria in preparation for a treat-to-target treatment protocol in LN.Methods Survey study by members of the Society for Pediatric and Adolescent Rheumatology (GKJR) and the German...

Background: Decision-making in the field of pediatric dialysis requires evidence from clinical trials, but, similar to other fields of pediatric medicine, might be affected by a low trial publication rate. Methods: We analyzed the current publication rate, the time to publication, and factors that might be associated with both rate of and time t...

Background: The quality of medical care for pediatric kidney transplant recipients depends on sound evidence from published clinical trials. Methods: We examined the publication rate, time to publication, and factors associated with publication of studies in pediatric kidney transplantation registered on ClinicalTrials.gov from 1999 to 2020. Re...

Background: Asymptomatic hyperuricemia is frequently observed in pediatric kidney transplant recipients; symptomatic hyperuricemia, however, is a rare complication. Only few data are available in this patient population. We, therefore, investigated the prevalence of hyperuricemia and its association with kidney transplant function and blood pressu...

Background: There are several databases across the world that collect pediatric KT data. We compare the hospitalization outcomes for pediatric KT recipients from a large Canadian transplant center (SickKids database; The Hospital for Sick Children Kidney Transplantation Institutional Database), United States (NAPRTCS), and Europe (CERTAIN registry...

Background Tacrolimus (Tac) intraindividual variability (TacIPV) in pediatric kidney transplant patients is only poorly understood. We investigated the impact of TacIPV on de novo donor-specific HLA antibodies ( dn DSA) development and allograft rejection in Caucasian pediatric recipients of a living or deceased donor kidney with low immunological...

COVID-19 course and immunity differ in children and adults. We analyzed immune response dynamics in 28 families up to 12 months after mild or asymptomatic infection. Unlike adults, the initial response is plasmablast-driven in children. Four months after infection, children showed an enhanced specific antibody response and a lower but detectable S1...

Children with infantile nephropathic cystinosis (INC), an inherited lysosomal storage disease resulting in cystine accumulation in all body cells, are prone to progressive chronic kidney disease (CKD), impaired growth and reduced weight gain; however, systematic anthropometric analyses are lacking. In this prospective multicenter study we investiga...

Background and objectives Antibody response after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination is impaired in kidney transplant recipients. Emerging variants, such as B.1.617.2 ( δ ), are of particular concern because of their higher transmissibility and partial immune escape. Little is known about protection against the...

Zusammenfassung Hintergrund und Ziel Die im Rahmen der COVID-19-Pandemie erlassenen Maßnahmen zum Infektionsschutz führten zu tiefgreifenden Einschränkungen und Veränderungen im sozialen, (vor-)schulischen, familiären und Freizeitbereich. Die vorliegende Studie untersucht das Ausmaß an psychischer Belastung von Kindern, Jugendlichen und ihren Fami...

Resolving the role of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission in households with members from different generations is crucial for containing the current pandemic. We conducted a large-scale, multicenter, cross-sectional seroepidemiologic household transmission study in southwest Germany during May 11-August 1, 202...

Background: Approximately 1700 children per year with end-stage kidney disease undergo kidney transplantation in Europe and the United States of America; 30%-50% are living donor kidney transplantations. There may be immunological differences between paternal and maternal donors due to transplacental exchange of cells between the mother and fetus...

Background The extent to which children and adolescents contribute to SARS-CoV-2 transmission remains not fully understood. Novel high-capacity testing methods may provide real-time epidemiological data in educational settings helping to establish a rational approach to prevent and minimize SARS-CoV-2 transmission. We investigated whether pooling o...

Background: Long-term persistence of antibodies against SARS-CoV-2, particularly the SARS-CoV-2 Spike Trimer, determines individual protection against infection and potentially viral spread. The quality of children's natural humoral immune response following SARS-CoV-2 infection is yet incompletely understood but crucial to guide pediatric SARS-CoV...

Idiopathic nephrotic syndrome is the most frequent glomerular disease in children in most parts of the world. Children with steroid-sensitive nephrotic syndrome (SSNS) generally have a good prognosis regarding the maintenance of normal kidney function even in the case of frequent relapses. The course of SSNS is often complicated by a high rate of r...

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...

When mycophenolic acid (MPA) was originally marketed for immunosuppressive therapy, fixed doses were recommended by the manufacturer. Awareness of the potential for a more personalized dosing has led to development of methods to estimate MPA area under the curve based on the measurement of drug concentrations in only a few samples. This approach is...

Background Non-HLA antibodies against endothelial targets have been implicated in the pathogenesis of antibody-mediated rejection (ABMR), but data in pediatric patients are scarce. Methods We retrospectively analyzed a carefully phenotyped single-center (University Children’s Hospital Heidelberg, Germany) cohort of 62 pediatric kidney transplant r...

Despite ground-breaking advances in allogeneic transplantation, allograft rejection and immunosuppressant-specific complications remain a major challenge. Growing evidence suggests the human gut microbiome to be a potential contributor to transplantation outcome and patient health. After breakthrough findings in hematopoietic stem cell transplantat...

Importance School and daycare closures were enforced as measures to confine the novel coronavirus disease 2019 (COVID-19) pandemic, based on the assumption that young children may play a key role in severe acute respiratory coronavirus 2 (SARS-CoV-2) spread. Given the grave consequences of contact restrictions for children, a better understanding o...

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 literatu...

Background Approximately 20% of antibody-mediated rejection (ABMR) episodes in the absence of donor-specific antibodies against human leucocyte antigens (HLA-DSA) in pediatric and adult kidney transplant recipients are associated with, and presumably caused by, antibodies against the angiotensin type 1 receptor (AT 1 R-Ab). While the role of AT 1 R...

Background Children are recognised as at lower risk of severe COVID-19 compared with adults, but the impact of immunosuppression is yet to be determined. This study aims to describe the clinical course of COVID-19 in children with kidney disease taking immunosuppressive medication and to assess disease severity. Methods Cross-sectional study hoste...

Eine Glomerulonephritis im Kindesalter präsentiert sich in der Regel mit den Symptomen Hämaturie, Proteinurie, peripheren Ödemen und häufig einer arteriellen Hypertonie. Verschiedene Faktoren können eine Glomerulonephritis auslösen, gemeinsam ist allen Formen eine glomeruläre Schädigung durch Entzündung. Die Entzündung beruht in unterschiedlichem A...

Prinzipiell ist bei jeder Form der terminalen Niereninsuffizienz im Kindesalter die Nierentransplantation die Behandlungsmethode der Wahl. In Deutschland erfolgt eine Nierentransplantation bei ca. 120 Kindern und Jugendlichen pro Jahr, entsprechend ca. 5 % der Gesamtzahl an Nierentransplantationen. Bei etwa 16 % der Patienten erfolgt eine präemptiv...

Despite ground‐breaking advances in allogeneic transplantation, allograft rejection and immunosuppressant‐specific complications remain a major challenge in transplant medicine. Growing evidence suggests the human gut microbiome as a potential contributor to transplant outcome and patient health. After breakthrough findings in haematopoietic stem c...

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 th...

Background: Hereditary cystic kidney diseases such as nephronophthisis, polycystic kidney disease and Bardet-Biedl syndrome (BBS) are caused by a dysfunction of primary cilia. Cilia are involved in a variety of cellular functions and perceptions, with one of them being the sense of smell. Hyposmia is a typical feature found in patients with BBS. H...

Adolescent and young adult age is a high‐risk window with an alarmingly increased likelihood of premature kidney graft loss due to immunological rejection. Using the large database of the Collaborative Transplant Study we analyzed whether a more intense and less variable exposure to tacrolimus could counteract this young‐age‐related enhanced immuno...