Heiko Billing

• MD PhD
• Head of Department at University of Tübingen

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: 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...

Most patients with congenital anomalies of the kidney and urinary tract (CAKUT) remain genetically unexplained. In search of novel genes associated with CAKUT in humans, we applied whole-exome sequencing in a patient with kidney, anorectal, spinal, and brain anomalies, and identified a rare heterozygous missense variant in the DACT1 (dishevelled bi...

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...

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...

A Correction to this paper has been published: https://doi.org/10.1007/s00467-021-05206-5

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...

Background Atypical hemolytic uremic syndrome (aHUS) is a rare, life-threatening microangiopathy, frequently causing kidney failure. Inhibition of the terminal complement complex with eculizumab is the only licensed treatment but mostly requires long-term administration and risks severe side effects. The underlying genetic cause of aHUS is thought...

Context: Children with nephropathic cystinosis (NC) show persistent hypophosphatemia, due to Fanconi syndrome, as well as mineral and bone disorders related to chronic kidney disease (CKD), but systematic analyses are lacking. Objective: To compare biochemical parameters of bone and mineral metabolism between children with NC and controls across...

Background High prevalence of arterial hypertension is known in pediatric renal transplant patients, but how blood pressure (BP) distribution and control differ between age groups and whether sex and age interact and potentially impact BP after transplantation have not been investigated. Methods This retrospective analysis included 336 pediatric r...

Autosomal recessive polycystic kidney disease (ARPKD) is a severe pediatric hepatorenal disorder with pronounced phenotypic variability. A substantial number of patients with early diagnosis reaches adulthood and some patients are not diagnosed until adulthood. Yet, clinical knowledge about adult ARPKD patients is scarce. Here, we describe forty-ni...

Extracorporeal photopheresis (ECP) is a widely used immunomodulatory therapy for the treatment of various T‐cell mediated disorders like cutaneous T‐cell lymphoma (CTCL), graft‐versus‐host disease (GvHD), or systemic sclerosis. Although clinical benefits of ECP are already well described, the underlying mechanism of action of ECP is not fully under...

Objective: To identify prenatal, perinatal, and postnatal risk factors for dialysis within the first year of life in children with autosomal recessive polycystic kidney disease (ARPKD) as a basis for parental counseling after prenatal and perinatal diagnosis. Study design: A dataset comprising 385 patients from the ARegPKD international registry...

Background: Infants with a body weight of less than 10 kg are often not considered to be suitable candidates for renal transplantation (RTx). The objective of this study was to evaluate this arbitrary weight threshold for pediatric RTx. Methods: We conducted a multicenter, retrospective, match-controlled cohort study on infants weighing less tha...

Background: Avoidance of vaccine-preventable infections in paediatric renal allograft recipients is of utmost importance. However, the development and maintenance of protective vaccination titres may be impaired in this patient population owing to their need for immunosuppressive medication. Methods: In the framework of the Cooperative European...

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare, autosomal-recessive mitochondrial disorder caused by TYMP mutations presenting with a multisystemic, often lethal syndrome of progressive leukoencephalopathy, ophthalmoparesis, demyelinating neuropathy, cachexia and gastrointestinal dysmotility. Hemodialysis (HMD) has been sug...

Background and objectives: Genetic heterogeneity and phenotypic variability are major challenges in familial nephronophthisis and related ciliopathies. To date, mutations in 20 different genes (NPHP1 to -20) have been identified causing either isolated kidney disease or complex multiorgan disorders. In this study, we provide a comprehensive and de...

Background: We recently showed that a 3-year growth hormone (GH) treatment improves linear growth in severely short children with X-linked hypophosphatemic rickets (XLH). It is unknown if GH therapy increases adult height in XLH patients. Methods: We carried out a follow-up analysis of a randomized controlled open-label GH study in short prepube...

Background: Because infections constitute a major cause of morbidity and mortality in paediatric renal allograft recipients, avoidance of preventable systemic infections by vaccination before transplantation is of utmost importance. However, data on the completeness of vaccinations and factors associated with incomplete vaccination coverage are sc...

Long-term home parenteral nutrition (LTPN) in children with chronic intestinal failure (CIF) is associated with renal complications such as fluid and electrolyte imbalances, nephrocalcinosis, nephrolithiasis and chronic kidney disease (CKD). The etiology of CIF-associated nephropathy is multifactorial. The aim of this study was to evaluate renal in...

Objectives It is known that transition, as a shift of care, marks a vulnerable phase in the adolescents’ lives with an increased risk for non-adherence and allograft failure. Still, the transition process of adolescents and young adults living with a kidney transplant in Germany is not well defined. The present research aims to assess transition-re...

Numerous pharmacologic compendia exist to guide most medical treatments even in children with renal diseases. However, some basic principles of pharmacology may be needed to achieve optimal dosing of therapeutic agents in our patients. Drugs may affect kidney function, and kidney function may have a major impact on pharmacokinetics, and subsequentl...

Transition from child to adult-oriented care is widely regarded a challenging period for young people with kidney transplants and is associated with a high risk of graft failure. We analyzed the existing transition structures in Germany and Austria using a questionnaire and retrospective data of 119 patients transferred in 2011 to 2012. Most center...

In order to investigate the hypothesis that the mammalian target of rapamycin inhibitor everolimus (EVR) shows anticytomegalovirus (CMV) activity in pediatric patients, we analyzed the impact of EVR-based immunosuppressive therapy on CMV replication and disease in a large cohort (n = 301) of pediatric kidney allograft recipients. The EVR cohort (n...

Background: Cytomegalovirus (CMV) replication and disease, with its associated morbidity and poor transplant outcome, represents a serious threat to transplant recipients. The pediatric kidney transplant population is at a particularly increased risk of CMV infection. Methods: We therefore analyzed CMV epidemiology in a large cohort of pediatric...

Th17 cells infiltrate the kidneys of patients with lupus nephritis (LN) and are critical for the pathogenesis of this disease. In this study, we show that enhanced activity of Stat3 in CD4(+)CD45RA(-)Foxp3(-) and Foxp3(low) effector T cells from children with LN correlates with increased frequencies of IL-17-producing cells within these T cell popu...

Background: The pharmacokinetics (PK) of tacrolimus (TAC) and mycophenolic acid (MPA) are highly variable. An impact of single-nucleotide polymorphisms (SNPs) of the genes coding for enzymes and transporters involved in the PK of TAC and/or MPA is intuitively conceivable. Accordingly, we sought to analyze the influence of different SNPs on TAC and...

Concerns have been raised that mammalian target of rapamycin inhibitors in pediatric transplant recipients might interfere with longitudinal bone growth by inhibition of growth factor signaling and growth plate chondrocyte proliferation. We therefore undertook a prospective nested, case-control study on longitudinal growth over 2 years in steroid-f...

So far, kidney transplantation constitutes the treatment of choice for children and adolescence with end-stage renal disease. Compared to chronic dialysis patients survival and quality of life can be strikingly improved; preemptive living donor transplantation yielding the best results. In Germany 14 centers participate in pediatric renal transplan...

Purpose The aim is to describe the changes in initial findings of kidney ultrasound examinations in cases of hemolytic uremic syndrome (HUS) in children and to evaluate the respective importance of three sonographical parameters: echogenicity, corticomedullary differentiation (CMD), and kidney size. The correlation with laboratory parameters and pr...

Biomarker-based post-transplant immune monitoring for the prediction of impending graft rejection requires validation in specific patient populations. Serum of 28 pediatric renal transplant recipients within the framework of a well-controlled prospective randomized trial was analyzed pre- and post-transplant for soluble CD30 (sCD30), a biomarker re...

Background: The epidemiology and morbidity of Epstein-Barr virus (EBV) infection in pediatric renal transplant recipients have been characterized insufficiently. Methods: In a prospective, multicenter study among 106 pediatric kidney allograft recipients aged 11.4 ± 5.9 years, we investigated the epidemiology of EBV infection and the relationshi...

So far, kidney transplantation constitutes the treatment of choice for children and adolescence with end-stage renal disease. Compared to chronic dialysis patients survival and quality of life can be strikingly improved; preemptive living donor transplantation yielding the best results. In Germany 14 centers participate in pediatric renal transplan...

: Developmental regulation of the pharmacodynamics of cyclosporin A (CsA) has been suggested by in vitro studies. However, these results have not yet been reproduced in the complexity of an in vivo immune system, because reliable biomarkers of CsA effects have not been available. : Gene expression of interleukin-2 (IL-2), interferon (IFN)-γ, and gr...

Chronic antibody-mediated rejection (AMR) is the major cause of late renal allograft loss. There is, however, no established treatment for this condition. We report the results of a prospective pilot study on an antihumoral therapy (AHT) consisting of high-dose intravenous immunoglobulin G (IVIG) and rituximab in 20 paediatric renal transplant reci...

Prinzipiell ist bei jeder Form der terminalen Niereninsuffizienz im Kindes- und Jugendalter die Nierentransplantation die Behandlungsmethode der Wahl. Im Vergleich zur chronischen Dialysetherapie werden v. a. die Überlebenszeit deutlich gesteigert und die Lebensqualität verbessert. Derzeit kann mit einer 5-Jahres-Nierentransplantatüberlebensrate vo...

Billing H, Breil T, Schmidt J, Tönshoff B, Schmitt C, Giese T, Engelmann G. Pharmacodynamic monitoring by residual NFAT-regulated gene expression in stable pediatric liver transplant recipients. Pediatr Transplantation 2012: 16: 187–194. © 2012 John Wiley & Sons A/S. Abstract: Pharmacokinetic monitoring of CNI is unsatisfactory, because at comparab...

Standard therapy for lupus nephritis is based on non-specific immunosuppression. We aimed to identify specific alterations in T cell and cytokine homeostasis and possible associations with disease activity in children with lupus nephritis (LN). The phenotype of circulating T cells from children with LN and healthy controls (HC) was analyzed by flow...

OriginalpublikationStegall MD, Diwana T, Raghavaiaha S et al (2011) Terminal complement inhibition decreases antibody-mediated rejection in sensitized renal transplant recipients. Am J Transplant 11:2405–2413 Hochimmunisierte Nierentransplantatempfänger haben ein erhöhtes Risiko für akute antikörpervermittelte Rejektionen (AMR) in den ersten Wochen...

Endothelial cell injury plays a key role in the pathogenesis of lupus nephritis (LN) and atherosclerosis. The aim of this study was to identify factors involved in the process of endothelial damage in children and adolescents with LN. We evaluated the relationship between plasma vascular endothelial growth factor (VEGF), its soluble receptors sVEGF...

Children with X-linked hypophosphatemic rickets (XLH) are prone to progressive disproportionate stunting despite oral phosphate and vitamin D treatment. Our objective was to analyze the effects of GH treatment on stature and lengths of linear body segments in short children with XLH. A 3-yr randomized controlled open-label GH study in short prepube...

In patients with refractory steroid-sensitive nephrotic syndrome (SSNS), treatment with rituximab has shown encouraging results; however, long-term follow-up data are not available. We performed a retrospective analysis of 37 patients (25 boys) with steroid-dependent nephrotic syndrome who were treated with rituximab (375 mg/m(2) given weekly for o...

Die membranoproliferative Glomerulonephritis (MPGN) ist eine seltene Nierenerkrankung, die klinisch durch Proteinurie bis hin zum nephrotischen Syndrom und Hamaturie bzw. nephritischem Syndrom gekennzeichnet ist. Eine Hypokomplementamie (erniedrigtes C3) legt den Verdacht auf eine Komplementerkrankung nahe. Sowohl angeborene Mutationen in Genen von...

Children with X-linked hypophosphatemic rickets (XLH) are prone to severe stunting. A multicenter mixed-longitudinal study was conducted to assess age-related stature, sitting height, arm and leg length in XLH patients on continuous treatment with phosphate and calcitriol. Mean standard deviation scores (SDS) for all body dimensions were markedly r...

Current treatment regimens for childhood lupus nephritis (LN) are associated with significant side-effects and toxicity in vulnerable phases of growth and development. The paucity of biomarkers particularly in childhood impedes the appropriate clinical management and the development of new therapeutics. We analyzed markers of immune system (BAFF, R...

Billing H, Giese T, Sommerer C, Zeier M, Feneberg R, Meuer S, Tönshoff B. Pharmacodynamic monitoring of cyclosporine A by NFAT‐regulated gene expression and the relationship with infectious complications in pediatric renal transplant recipients. Pediatr Transplantation 2010: 14:844–851. © 2010 John Wiley & Sons A/S. Abstract: Pharmacokinetic monito...

Tubulointerstitial nephritis and uveitis syndrome (TINU) is a specific form of intraocular inflammation (uveitis) combined with kidney disease that was first described in two patients by Dobrin et al. in 1975. Since then, approximately 200 more cases have been published. The cause of the disease is still unknown. A hypersensitivity reaction is susp...

Chronic antibody-mediated rejection (CAMR) of renal allografts has recently been recognized as a defined nosologic entity. The outcome of CAMR is poor; there is no established treatment protocol for this condition. We therefore initiated a pilot study on treatment of CAMR with an antihumoral regimen consisting of high-dose intravenous immunoglobuli...

We report on a 2-year-old boy on automated peritoneal dialysis (PD) with a history of multiple hernias and dialysate leaks who developed pericardial effusion. Magnetic resonance imaging (MRI) demonstrated a peritoneo-pericardial fistula. Dialysis had to be discontinued, since head-down tilt reproducibly induced significant hypotension. In PD patien...

Schimke-immuno-osseous dysplasia (SIOD) is a multisystem disorder with the following consistent clinical features: spondyloepiphyseal dysplasia with disproportional growth deficiency, nephrotic syndrome with focal and segmental glomerulosclerosis, and defective cellular immunity. Transitory ischemic attacks due to vaso-occlusive processes are compl...

Mutations in the NPHS2 gene encoding podocin are associated with steroid-resistant nephrotic syndrome (SRNS) in childhood. Patients usually present with focal segmental glomerulosclerosis (FSGS). It is unclear to what extent SRNS due to NPHS2 mutations predisposes to recurrence of proteinuria/FSGS after renal transplantation (RTx). A 4-year-old gir...

Iron is an essential metabolite for pathogenic bacteria, and the specificity exhibited by bacteria for host-iron chelates may be correlated with host and tissue tropism. The effect of iron restriction on Chlamydia pneumoniae and C. trachomatis was studied by use of the iron-chelating compound deferoxamine. Growth of C. pneumoniae was inhibited much...

In dieser Arbeit wurden der mögliche Einfluss einer Eisenrestriktion auf Chlamydia pneumoniae und Chlamydia trachomatis und die Fragestellung eines Gewebetropismus dieser Chlamydien-Arten untersucht. In unseren versuchen konnte gezeigt werden, dass Eisen für das Wachstum der Chlamydien eine wichtige Rolle spielt. Die unterschiedliche Empfindlichkei...