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Background Encapsulating Peritoneal Sclerosis (EPS) is a rare phenomenon in paediatric patients with kidney failure treated with peritoneal dialysis (PD). This study highlights clinical challenges in the management of EPS, with particular emphasis on peri-operative considerations and surgical technique. Methods Retrospective analysis of all paediatric patients with EPS treated at the Manchester Centre for Transplantation. Results Four patients were included with a median duration of 78 months on PD. All patients had recurrent peritonitis (> 3 episodes), and all had symptoms within three months of a change of dialysis modality from PD to haemodialysis or transplant. In Manchester, care was delivered by a multi-disciplinary team, including surgeons delivering the adult EPS surgical service with a particular focus on nutritional optimisation, sepsis control, and wound management. The surgery involved laparotomy, lavage, and enterolysis of the small bowel + / − stoma formation, depending on intra-abdominal contamination. Two patients had a formal stoma, which were reversed at three and six months, respectively. Two patients underwent primary closure of the abdomen, whereas two patients had re-look procedures at 48 h with secondary closure. One patient had a post-operative wound infection, which was managed medically. One patient’s stoma became detached, leading to an intra-abdominal collection requiring re-laparotomy. The median length of stay was 25 days, and patients were discharged once enteral feeding was established. All patients remained free of recurrence with normal gut function and currently two out of four have functioning transplants. Conclusions This series demonstrates 100% survival and parenteral feed independence following EPS surgery. Post-operative morbidity was common; however, with individualised experience-based decision-making and relevant additional interventions, patients made full recoveries. Health and development post-surgery continued, allowing the potential for transplantation. Graphical abstract A higher resolution version of the Graphical abstract is available as Supplementary information

Background: Catch-up growth after pediatric kidney transplantation (kTx) is usually insufficient to reach normal adult height. We aimed to analyze the effect of pre-transplant recombinant human growth hormone (rhGH) and corticosteroid withdrawal on linear growth in the first year after kidney transplantation and identify factors associated with final height (FH). Methods: Patients who underwent kTx between 1996 and 2018 at below 18 years old in five Belgian and Dutch centers were included. We analyzed the differences between height Z-scores at kTx and 1 year post-transplant (Δ height Z-score) in children with and without corticosteroids at 1 year (CS + /CS −) and with and without rhGH treatment before kTx (rhGH + /rhGH −). Univariable and multivariable linear regression analysis was applied to identify factors associated with height Z-score at 1 year post-kTx, Δ height Z-score, and FH Z-score. Results: A total of 177 patients were included, with median age 9.3 years at kTx. Median height Z-scores pre-kTx and 1 year later in the CS − /rhGH − , CS + /rhGH − , CS − /rhGH + , and CS + /rhGH + groups were − 1.42/ − 0.80, − 0.90/ − 0.62, − 1.35/ − 1.20, and − 1.30/ − 1.60 (p = 0.001). CS use 1 year post-kTx was the only factor associated with Δ height (p = 0.003) on multivariable analysis. CS use at 1 year was the only variable associated with FH (p = 0.014) in children with pre-transplant height Z-score below − 1 (n = 52). Conclusions: Increase in height Z-score in the first year post-kTx was highest in the CS − /rhGH − group and lowest in the CS + /rhGH + group. The use of corticosteroids at 1 year post-kTx is associated with catch-up growth and in children with pre-transplant height Z-score below − 1 also with final height. Graphical abstract: A higher resolution version of the Graphical abstract is available as Supplementary information [Figure not available: see fulltext.].

Given a discrete group $G$, for any integer $r\geqslant0$ we consider the family of all virtually abelian subgroups of $G$ of rank at most $r$. We give an upper bound for the Bredon cohomological dimension of $G$ for this family for a certain class of groups acting on $\mathrm{CAT}(0)$ spaces. This covers the case of Coxeter groups, Right-angled Artin groups, fundamental groups of special cube complexes and graph products of finite groups. Our construction partially answers a question of J.-F. Lafont., Comment: 11 pages

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.

The calcineurin inhibitor tacrolimus, cornerstone of most immunosuppressive regimens, is a drug with a narrow therapeutic window: underexposure can lead to allograft rejection and overexposure can result in an increased incidence of infections, toxicity and malignancies. Tacrolimus is metabolised in the liver and intestine by the cytochrome P450 3A (CYP3A) isoforms CYP3A4 and CYP3A5. This review focusses on the clinical aspects of tacrolimus pharmacodynamics, such as efficacy and toxicity. Factors affecting tacrolimus pharmacokinetics, including pharmacogenetics and the rationale for routine CYP3A5*1/*3 genotyping in prospective paediatric renal transplant recipients, are also reviewed. Therapeutic drug monitoring, including pre-dose concentrations and pharmacokinetic profiles with the available “reference values”, are discussed. Factors contributing to high intra-patient variability in tacrolimus exposure and its impact on clinical outcome are also reviewed. Lastly, suggestions for future research and clinical perspectives are discussed.

We describe a boy who presented with neonatal hypotonia, followed by delayed motor development and growth impairment. Further evaluation revealed rickets caused by proximal renal tubular dysfunction. At age 3, the boy exhibited dysmorphic features and bilateral cataract. Genetic analysis of the OCRL gene showed a novel variant in exon 13: c.1250T>A, p.Val417Asp; in silico and segregation analysis confirmed the variant to be pathogenic, compatible with the diagnosis of the oculocerebrorenal syndrome of Lowe. Lowe syndrome is a rare multisystemic disorder; the diagnostic triad requires involvement of the eye, central nervous system and the proximal renal tubule. Typical clinical features are congenital cataract, glaucoma, hypotonia, mental and behavioral problems, benign skin lesions, platelet dysfunction and dental abnormalities. Phenotypic features early in life may be nonspecific, which is illustrated by this case with a late manifestation of cataract. Because an early diagnosis can lead to better counseling and treatment, we suggest urinary testing for proteinuria as a part of the evaluation of children with unexplained hypotonia.

Given a group $G$ with bounded torsion that acts properly on a systolic complex, we show that every solvable subgroup of $G$ is finitely generated and virtually abelian of rank at most $2$. In particular this gives a new proof of the above theorem for systolic groups. The main tools used in the proof are the Product Decomposition Theorem and the Flat Torus Theorem., 7 pages

We introduce graphical complexes of groups, which can be thought of as a generalisation of Coxeter systems with 1-dimensional nerves. We show that these complexes are strictly developable, and we equip the resulting Basic Construction with three structures of non-positive curvature: piecewise linear CAT(0), C(6) graphical small cancellation, and a systolic one. We then use these structures to establish various properties of the fundamental groups of these complexes, such as biautomaticity and Tits Alternative. We isolate an easily checkable condition implying hyperbolicity of the fundamental groups, and we construct some non-hyperbolic examples. We also briefly discuss a parallel theory of C(4)-T(4) graphical complexes of groups and outline their basic properties., Comment: 24 pages, 3 figures

Given a non-decreasing function $f \colon \mathbb{N} \to \mathbb{N}$ we define a single player game on (infinite) connected graphs that we call fire retaining. If a graph $G$ admits a winning strategy for any initial configuration (initial fire) then we say that $G$ has the $f$-retaining property; in this case if $f$ is a polynomial of degree $d$, we say that $G$ has the polynomial retaining property of degree $d$. We prove that having the polynomial retaining property of degree $d$ is a quasi-isometry invariant in the class of uniformly locally finite connected graphs. Henceforth, the retaining property defines a quasi-isometric invariant of finitely generated groups. We prove that if a finitely generated group $G$ splits over a quasi-isometrically embedded subgroup of polynomial growth of degree $d$, then $G$ has polynomial retaining property of degree $d-1$. Some connections to other work on quasi-isometry invariants of finitely generated groups are discussed and some questions are raised., V2: Version accepted for publication by Geometriae Dedicata

Background: This study aims to investigate the evolution and factors associated with TAC IPV and its impact on patient outcomes in pediatric LT recipients. Methods: This is a retrospective study including 41 children. The TAC IPV was expressed as the coefficient of variation and was calculated for years 1-5 following LT. The number of missed clinic appointments was used as a surrogate marker for therapy adherence. Results: We identified a decrease in the TAC IPV during the first 3 years after LT (P < 0.01). Serum albumin in the first year (P = 0.03), hematocrit (P = 0.02) and total bilirubin (P = 0.04) in the third year, and therapy adherence (P < 0.01) in the fifth year were associated with TAC IPV. High TAC IPV was associated with biopsy-proven acute allograft rejection (P = 0.04) and the need for biopsy during the first year (P = 0.02). There was a borderline association between TAC IPV and donor-specific antibodies (P = 0.08) and CMV viremia (P = 0.07). High TAC IPV was a predictor of need for liver biopsy and AR with an odds ratio of 1.04 (95% CI 1.0-1.1; P = 0.03) and 1.04 (95% CI 1.0-1.1; P = 0.05), respectively. Conclusions: Our results highlight the impact of biological factors on TAC IPV during the early LT follow-up and later also therapy adherence. High TAC IPV may be associated with adverse patient outcomes.

Given a group $G$ acting geometrically on a systolic complex $X$ and a hyperbolic isometry $h \in G$, we study the associated action of $h$ on the systolic boundary $\partial X$. We show that $h$ has a canonical pair of fixed points on the boundary and that it acts trivially on the boundary if and only if it is virtually central. The key tool that we use to study the action of $h$ on $\partial X$ is the notion of a $K$-displacement set of $h$, which generalises the classical minimal displacement set of $h$. We also prove that systolic complexes equipped with a geometric action of a group are almost extendable., 34 pages, 4 figures

Summary Introduction Kidney transplantation (KT) is the gold-standard treatment for end-stage renal disease (ESRD) in children. Robot-assisted kidney transplantation (RAKT) in adults is becoming increasingly common with potentially improved morbidity compared with open KT. The study objective was to evaluate feasibility and outcomes of RAKT in children. Patients & methods An 8-years-old boy with ESRD received a kidney transplant from his mother. Simultaneously in two operation theatres, the boy underwent single-port (GelPOINT®) right laparoscopic nephro-ureterectomy (LNU), and his mother underwent robot-assisted left donor nephrectomy (RADN).Two full surgical teams were operating at the same time. Subsequently, the boy underwent RAKT, introducing the graft through the GelPOINT®. Results Total operative time for LNU, RADN, and RAKT was 180, 140, and 195 min, respectively, with warm, cold, and rewarming ischemia times 1.5, 200, and 47 min, respectively. Blood loss was 300, 20, and 50 cc, respectively. No intraoperative complications were noted. Convalescence of both donor and recipient was uneventful, with good kidney function at 1-year follow-up. Conclusion RAKT in children is technically feasible and safe, resulting in excellent graft function. Concomitant nephrectomy can be done laparoscopically through the single-site GelPOINT®. An experienced RAKT team with the full support of pediatric nephrologists is mandatory.

We study the structure of the commensurator of a virtually abelian subgroup $H$ in $G$, where $G$ acts properly on a $\mathrm{CAT}(0)$ space $X$. When $X$ is a Hadamard manifold and $H$ is semisimple, we show that the commensurator of $H$ coincides with the normalizer of a finite index subgroup of $H$. When $X$ is a $\mathrm{CAT}(0)$ cube complex or a thick Euclidean building and the action of $G$ is cellular, we show that the commensurator of $H$ is an ascending union of normalizers of finite index subgroups of $H$. We explore several special cases where the results can be strengthened and we discuss a few examples showing the necessity of various assumptions. Finally, we present some applications to the constructions of classifying spaces with virtually abelian stabilizers., Comment: 20 pages

Galloway-Mowat syndrome (GAMOS) is a severe autosomal-recessive disease characterized by the combination of early-onset steroid-resistant nephrotic syndrome (SRNS) and microcephaly with brain anomalies. To date, mutations of WDR73 are the only known monogenic cause of GAMOS and in most affected individuals the molecular diagnosis remains elusive. We here identify recessive mutations of OSGEP, TP53RK, TPRKB, or LAGE3, encoding the 4 subunits of the KEOPS complex in 33 individuals of 30 families with GAMOS. CRISPR/Cas9 knockout in zebrafish and mice recapitulates the human phenotype of microcephaly and results in early lethality. Knockdown of OSGEP, TP53RK, or TPRKB inhibits cell proliferation, which human mutations fail to rescue, and knockdown of either gene activates DNA damage response signaling and induces apoptosis. OSGEP and TP53RK molecularly interact and co-localize with the actin-regulating ARP2/3 complex. Furthermore, knockdown of OSGEP and TP53RK induces defects of the actin cytoskeleton and reduces migration rate of human podocytes, an established intermediate phenotype of SRNS. We thus identify 4 novel monogenic causes of GAMOS, describe the first link between KEOPS function and human disease, and delineate potential pathogenic mechanisms.

We determine the large scale geometry of the minimal displacement set of a hyperbolic isometry of a systolic complex. As a consequence, we describe the centraliser of such an isometry in a systolic group. Using these results, we construct a low-dimensional classifying space for the family of virtually cyclic subgroups of a group acting properly on a systolic complex. Its dimension coincides with the topological dimension of the complex if the latter is at least four. We show that graphical small cancellation complexes are classifying spaces for proper actions and that the groups acting on them properly admit three-dimensional classifying spaces with virtually cyclic stabilisers. This is achieved by constructing a systolic complex equivariantly homotopy equivalent to a graphical small cancellation complex. On the way we develop a systematic approach to graphical small cancellation complexes. Finally, we construct low-dimensional models for the family of virtually abelian subgroups for systolic, graphical small cancellation, and some CAT(0) groups., Second version: 60 pages, 16 figures, new proof of Proposition 4.6, minor corrections in proofs in Sections 4 and 6, this version contains more (expository) material than the version accepted by Groups, Geometry and Dynamics

Prytula AA, Bouts AH, Mathot RAA, van Gelder T, Croes LK, Hop W, Cransberg K. Intra-patient variability in tacrolimus trough concentrations and renal function decline in pediatric renal transplant recipients. Abstract: High intra-patient variability in TCL exposure is a risk factor for allograft loss and late acute rejection. We hypothesized that a higher intra-patient variability leads to a faster decline in GFR in pediatric renal transplant patients and that adolescents have a higher intra-patient variability due to poorer adherence. We included 69 children aged 3.5–18 yr who had undergone renal transplantation between April 1996 and May 2009 in two pediatric nephrology centers in the Netherlands. We analyzed TCL trough concentrations over a period of one yr and calculated TCL trough concentrations variability using VC. We investigated the correlation between the TCL trough concentrations variability and the decline in estimated GFR over four yr. The median intra-patient variability in TCL concentrations was 30.1% (range 8.6–77.6) and the mean GFR slope −3.8 mL/min/1.73 m2/yr. The VC correlated neither with the GFR slope, nor with the patients’ age. However, children with late acute rejection had higher VC (p = 0.045). We were unable to provide evidence that a high variability in TCL exposure leads to a faster decline in renal function, although children with late acute rejection have a higher variability in TCL exposure. Adolescents do not have a higher intra-patient variability in TCL trough concentrations than younger children.