Consensus recommendations for the assessment and management of idiopathic intracranial hypertension in children and young people.

BACKGROUND: Idiopathic intracranial hypertension (IIH) is a potentially disabling condition. There is a lack of evidence and national guidance on how to diagnose and treat paediatric IIH, leading to variation in clinical practice. We conducted a national Delphi consensus via the Children's Headache Network to propose a best-practice diagnostic and therapeutic pathway. METHODS: The Delphi process was selected as the most appropriate methodology for examining current opinion among experts in the UK. 104 questions were considered by 66 healthcare professionals, addressing important aspects of IIH care: assessment, diagnosis, treatment, follow-up and surveillance. General paediatricians, paediatric neurologists, ophthalmologists, opticians, neuroradiologists and neurosurgeons with a clinical interest or experience in IIH, were invited to take part. RESULTS: The Delphi process consisted of three rounds comprising 104 questions (round 1, 67; round 2, 24; round 3 (ophthalmological), 13) and was completed between March 2019 and August 2021. There were 54 and 65 responders in the first and second rounds, respectively. The Delphi was endorsed by the Royal College of Ophthalmologists, which engaged 59 ophthalmologists for round 3. CONCLUSIONS: This UK-based Delphi consensus process reached agreement for the management of paediatric IIH and has been endorsed by the Children's Headache Network and more broadly, the British Paediatric Neurology Association. It provides a basis for a pragmatic clinical approach. The recommendations will help to improve clinical care while minimising under and over diagnosis.

P2X7 receptor knockout does not alter renal function or prevent angiotensin II-induced kidney injury in F344 rats.

P2X7 receptors mediate immune and endothelial cell responses to extracellular ATP. Acute pharmacological blockade increases renal blood flow and filtration rate, suggesting that receptor activation promotes tonic vasoconstriction. P2X7 expression is increased in kidney disease and blockade/knockout is renoprotective. We generated a P2X7 knockout rat on F344 background, hypothesising enhanced renal blood flow and protection from angiotensin-II-induced renal injury. CRISPR/Cas9 introduced an early stop codon into exon 2 of P2rx7, abolishing P2X7 protein in kidney and reducing P2rx7 mRNA abundance by ~ 60% in bone-marrow derived macrophages. The M1 polarisation response to lipopolysaccharide was unaffected but P2X7 receptor knockout suppressed ATP-induced IL-1ß release. In male knockout rats, acetylcholine-induced dilation of the renal artery ex vivo was diminished but not the response to nitroprusside. Renal function in male and female knockout rats was not different from wild-type. Finally, in male rats infused with angiotensin-II for 6 weeks, P2X7 knockout did not reduce albuminuria, tubular injury, renal macrophage accrual, and renal perivascular fibrosis. Contrary to our hypothesis, global P2X7 knockout had no impact on in vivo renal hemodynamics. Our study does not indicate a major role for P2X7 receptor activation in renal vascular injury.

Immune checkpoint activity regulates polycystic kidney disease progression.

Innate and adaptive immune cells modulate the severity of autosomal dominant polycystic kidney disease (ADPKD), a common kidney disease with inadequate treatment options. ADPKD has parallels with cancer, in which immune checkpoint inhibitors have been shown to reactivate CD8+ T cells and slow tumor growth. We have previously shown that in PKD, CD8+ T cell loss worsens disease. This study used orthologous early-onset and adult-onset ADPKD models (Pkd1 p.R3277C) to evaluate the role of immune checkpoints in PKD. Flow cytometry of kidney cells showed increased levels of programmed cell death protein 1 (PD-1)/cytotoxic T lymphocyte associated protein 4 (CTLA-4) on T cells and programmed cell death ligand 1 (PD-L1)/CD80 on macrophages and epithelial cells in Pkd1RC/RC mice versus WT, paralleling disease severity. PD-L1/CD80 was also upregulated in ADPKD human cells and patient kidney tissue versus controls. Genetic PD-L1 loss or treatment with an anti-PD-1 antibody did not impact PKD severity in early-onset or adult-onset ADPKD models. However, treatment with anti-PD-1 plus anti-CTLA-4, blocking 2 immune checkpoints, improved PKD outcomes in adult-onset ADPKD mice; neither monotherapy altered PKD severity. Combination therapy resulted in increased kidney CD8+ T cell numbers/activation and decreased kidney regulatory T cell numbers correlative with PKD severity. Together, our data suggest that immune checkpoint activation is an important feature of and potential novel therapeutic target in ADPKD.

Sodium-glucose cotransporter 2 inhibition does not improve the acute pressure natriuresis response in rats with type 1 diabetes.

NEW FINDINGS: What is the central question of this study? Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce cardiovascular risk in patients with both diabetic and non-diabetic kidney disease: can SGLT2 inhibition improve renal pressure natriuresis (PN), an important mechanism for long-term blood pressure control, which is impaired in type 1 diabetes mellitus (T1DM)? What is the main finding and its importance? The SGLT2 inhibitor dapagliflozin did not enhance the acute in vivo PN response in either healthy or T1DM Sprague-Dawley rats. The data suggest that the mechanism underpinning the clinical benefits of SGLT2 inhibitors on health is unlikely to be due to an enhanced natriuretic response to increased blood pressure. ABSTRACT: Type 1 diabetes mellitus (T1DM) leads to serious complications including premature cardiovascular and kidney disease. Hypertension contributes importantly to these adverse outcomes. The renal pressure natriuresis (PN) response, a key regulator of blood pressure (BP), is impaired in rats with T1DM as tubular sodium reabsorption fails to down-regulate with increasing BP. We hypothesised that sodium-glucose cotransporter 2 (SGLT2) inhibitors, which reduce cardiovascular risk in kidney disease, would augment the PN response in T1DM rats. Non-diabetic or T1DM (35-50 mg/kg streptozotocin i.p.) adult male Sprague-Dawley rats were anaesthetised (thiopental 50 mg/kg i.p.) and randomised to receive either dapagliflozin (1 mg/kg i.v.) or vehicle. Baseline sodium excretion was measured and then BP was increased by sequential arterial ligations to induce the PN response. In non-diabetic animals, the natriuretic and diuretic responses to increasing BP were not augmented by dapagliflozin. Dapagliflozin induced glycosuria, but this was not influenced by BP. In T1DM rats the PN response was impaired. Dapagliflozin again increased urinary glucose excretion but did not enhance PN. Inhibition of SGLT2 does not enhance the PN response in rats, either with or without T1DM. SGLT2 makes only a minor contribution to tubular sodium reabsorption and does not contribute to the impaired PN response in T1DM.

The tryptophan-metabolizing enzyme indoleamine 2,3-dioxygenase 1 regulates polycystic kidney disease progression.

Autosomal dominant polycystic kidney disease (ADPKD), the most common monogenic nephropathy, is characterized by phenotypic variability that exceeds genic effects. Dysregulated metabolism and immune cell function are key disease modifiers. The tryptophan metabolites, kynurenines, produced through indoleamine 2,3-dioxygenase 1 (IDO1), are known immunomodulators. Here, we study the role of tryptophan metabolism in PKD using an orthologous disease model (C57BL/6J Pkd1RC/RC). We found elevated kynurenine and IDO1 levels in Pkd1RC/RC kidneys versus wild type. Further, IDO1 levels were increased in ADPKD cell lines. Genetic Ido1 loss in Pkd1RC/RC animals resulted in reduced PKD severity, as measured by cystic index and percentage kidney weight normalized to body weight. Consistent with an immunomodulatory role of kynurenines, Pkd1RC/RC;Ido1-/- mice presented with significant changes in the cystic immune microenvironment (CME) versus controls. Kidney macrophage numbers decreased and CD8+ T cell numbers increased, both known PKD modulators. Also, pharmacological IDO1 inhibition in Pkd1RC/RC mice and kidney-specific Pkd2-knockout mice with rapidly progressive PKD resulted in less severe PKD versus controls, with changes in the CME similar to those in the genetic model. Our data suggest that tryptophan metabolism is dysregulated in ADPKD and that its inhibition results in changes to the CME and slows disease progression, making IDO1 a therapeutic target for ADPKD.

Impact of facial angiofibromas in tuberous sclerosis complex and reported efficacy of available treatments.

Tuberous Sclerosis Complex (TSC) is a genetic condition which leads to a loss of inhibition of cellular growth. Facial angiofibromas (FAs) are hamartomatous growths associated with TSC that appear as multiple small, erythematous papules on the skin of the face and may resemble more severe forms of acne vulgaris. FAs have been reported in up to 74.5% of pediatric TSC patients, rising to up to 88% in adults >30 years old. They have not been closely studied, potentially overshadowed by other, systemic features of TSC. To investigate the impact of FAs, a common clinical feature for patients with TSC, we performed a non-interventional study in the form of a survey, completed by people living with TSC and FAs, or their caregiver as a proxy, if necessary. Patients were recruited via patient organizations in the UK and Germany. Data was received from 108 families in the UK (44 patients, 64 caregivers) and 127 families in Germany (50 patients, 64 caregivers). Exclusion criteria were those outside of 6-89 years, those without FAs, or those enrolled in a clinical trial. Where caregivers reported on behalf of an individual unable to consent, they were required to be adults (>18 years). Patient experience in the design of the survey was considered from practical and logistical perspectives with survey questions assessing multiple aspects relating to FAs including age of onset, perceived severity, treatments, perceived efficacy of treatments and perceived psychosocial impacts of the FAs. The psychosocial impacts of FAs for the individuals as well as for caregivers were explored in terms of social, occupational and leisure activities. Results of the survey demonstrated that for those with TSC-related moderate or severe FAs, there is an impact on quality of life and psychosocial impacts in the form of anxiety and depression. This finding was also noted by caregivers of TSC individuals in these categories. The treatment most frequently received to improve FAs, topical rapamycin/sirolimus, was found to be successful in the majority of those who received it.

International Consensus Recommendations for the Assessment and Management of Individuals With CDKL5 Deficiency Disorder.

CDKL5 Deficiency Disorder (CDD) is a rare, X-linked dominant condition that causes a developmental and epileptic encephalopathy (DEE). The incidence is between ~ 1:40,000 and 1:60,000 live births. Pathogenic variants in CDKL5 lead to seizures from infancy and severe neurodevelopmental delay. During infancy and childhood, individuals with CDD suffer impairments affecting cognitive, motor, visual, sleep, gastrointestinal and other functions. Here we present the recommendations of international healthcare professionals, experienced in CDD management, to address the multisystem and holistic needs of these individuals. Using a Delphi method, an anonymous survey was administered electronically to an international and multidisciplinary panel of expert clinicians and researchers. To provide summary recommendations, consensus was set, a priori, as >70% agreement for responses. In the absence of large, population-based studies to provide definitive evidence for treatment, we propose recommendations for clinical management, influenced by this proposed threshold for consensus. We believe these recommendations will help standardize, guide and improve the medical care received by individuals with CDD.

Management of Enteritis Associated With Tricohepatoenteric Syndrome due to SKIV2L Mutation Using the Combination of JAK1/2 Inhibition and Azathioprine.

Tricohepatoenteric syndrome is a rare genetic disorder caused by mutations in SKIV2L or TTC37. An upregulation of type 1 interferon signaling is associated with the SKIV2L variation. Introduction of Baricitinib as a JAK1/ 2 kinase inhibitor alongside traditional immunosuppressive agents successfully reduced the symptoms of enteritis by blocking the inflammogenic effects of type 1 interferonopathy in a case of tricohepatoenteric syndrome diagnosed in a 5-year-old boy.

Inflammatory Myositis Secondary to Anti-Retroviral Therapy in a Child; Case Report and Review of the Literature.

Here, we describe a five year old girl with congenital HIV who had a six-week onset of rapidly deteriorating mobility and progressive proximal muscle weakness, associated with a raised Creatine Kinase (CK) level of 4330 U/L [25-200 U/L], subsequently diagnosed with an inflammatory myositis. Potential causes were investigated by paediatric neurology and immunology teams. Her viral load had been undetectable over the preceding two years, excluding a primary HIV myositis. While MRI scanning did not show evidence of definite myositis, a muscle biopsy showed evidence of an inflammatory process, comprising a moderate endomysial, perimysial and perivascular mononuclear (CD8 + T cell) infiltrate with increased MHC expression. No particular features of dermatomyositis or immune-mediated necrotising myopathy were identified and there were no features of an inclusion body myositis.Given the absence of active HIV infection, the role of anti-retroviral medications was considered. She had had a recent switch in medication, from twice daily Raltegravir (an Integrase Strand Transfer Inhibitor, INSTI) to once daily Dolutegravir (an INSTI) while continuing on an established daily protocol of Abacavir and Lamivudine (Nucleoside Reverse Transcriptase Inhibitors). Changing the Dolutegravir back to Raltegravir, in combination with continuing Lamivudine and Abacavir for two months made no difference to her weakness or CK levels. Moreover, this drug regimen had been well-tolerated over the preceding 19 month period. Changing the anti-retroviral regime completely to a single drug class (Protease Inhibitors) of Ritonavir and Darunavir, resulted in a dramatic improvement in her symptomatology. Within ten days she regained the ability to stand and walk, with a reduction in her CK from 1700 U/L at time of switch to 403 U/L [25-200]. This case highlights the potential risk of developing inflammatory myositis from anti-retrovirals even 19 months into treatment.

Purinergic signalling in the kidney: In physiology and disease.

Historically, the control of renal vascular and tubular function has, for the most part, concentrated on neural and endocrine regulation. However, in addition to these extrinsic factors, it is now appreciated that several complex humoral control systems exist within the kidney that can act in an autocrine and/or paracrine fashion. These paracrine systems complement neuroendocrine regulation by dynamically fine-tuning renal vascular and tubular function to buffer rapid changes in nephron perfusion and flow rate of tubular fluid. One of the most pervasive is the extracellular nucleotide/P2 receptor system, which is central to many of the intrinsic regulatory feedback loops within the kidney such as renal haemodynamic autoregulation and tubuloglomerular feedback (TGF). Although physiological actions of extracellular adenine nucleotides were reported almost 100 years ago, the conceptual framework for purinergic regulation of renal function owes much to the work of Geoffrey Burnstock. In this review, we reflect on our >20-year collaboration with Professor Burnstock and highlight the research that is still unlocking the potential of the renal purinergic system to understand and treat kidney disease.

Prospective study of bacteremia rate after elective band ligation and sclerotherapy with cyanoacrylate for esophageal varices in patients with advanced liver disease.

CONTEXT: Band ligation (BL) is the most appropriate endoscopic treatment for acute bleeding or prophylaxis of esophageal variceal bleeding. Sclerotherapy with N-butyl-2-cyanoacrylate (CY) can be an alternative for patients with advanced liver disease. Bacteremia is an infrequent complication after BL while the bacteremia rate following treatment with CY for esophageal varices remains unknown. OBJECTIVES: To evaluate and compare the incidence of transient bacteremia between cirrhotic patients submitted to diagnostic endoscopy, CY and BL for treatment of esophageal varices. METHODS: A prospective study comprising the period from 2004 to 2007 was conducted at Hospital of Universidade Federal de São Paulo, UNIFESP, SP, Brazil. Cirrhotic patients with advanced liver disease (Child-Pugh B or C) were enrolled. The patients were divided into two groups according treatment: BL Group (patients undergoing band ligation, n = 20) and CY Group (patients receiving cyanoacrylate injection for esophageal variceal, n = 18). Cirrhotic patients with no esophageal varices or without indication for endoscopic treatment were recruited as control (diagnostic group n = 20). Bacteremia was evaluated by blood culture at baseline and 30 minutes after the procedure. RESULTS: After 137 scheduled endoscopic procedures, none of the 58 patients had fever or any sign suggestive of infection. All baseline cultures were negative. No positive cultures were observed after CY or in the control group - diagnostic endoscopy. Three (4.6 %) positive cultures were found out of the 65 sessions of band ligation (P = 0.187). Two of these samples were positive for coagulase-negative staphylococcus, which could be regarded as a contaminant. The isolated microorganism in the other case was Klebsiella oxytoca. The patient in this case presented no evidence of immunodeficiency except liver disease. CONCLUSIONS: There was no significant difference in bacteremia rate between these three groups. BL or CY injection for non-bleeding esophageal varices may be considered as low-risk procedures regarding bacteremia even when performed on patients with advanced liver disease.

Prospective study of bacteremia rate after elective band ligation and sclerotherapy with cyanoacrylate for esophageal varices in patients with advanced liver disease / Estudo de bacteriemia relacionada à ligadura elástica versus injeção de cianocrilato para varizes esofágicas em pacientes com doença hepática avançada

CONTEXT: Band ligation (BL) is the most appropriate endoscopic treatment for acute bleeding or prophylaxis of esophageal variceal bleeding. Sclerotherapy with N-butyl-2-cyanoacrylate (CY) can be an alternative for patients with advanced liver disease. Bacteremia is an infrequent complication after BL while the bacteremia rate following treatment with CY for esophageal varices remains unknown. OBJECTIVES: To evaluate and compare the incidence of transient bacteremia between cirrhotic patients submitted to diagnostic endoscopy, CY and BL for treatment of esophageal varices. METHODS: A prospective study comprising the period from 2004 to 2007 was conducted at Hospital of Universidade Federal de São Paulo, UNIFESP, SP, Brazil. Cirrhotic patients with advanced liver disease (Child-Pugh B or C) were enrolled. The patients were divided into two groups according treatment: BL Group (patients undergoing band ligation, n = 20) and CY Group (patients receiving cyanoacrylate injection for esophageal variceal, n = 18). Cirrhotic patients with no esophageal varices or without indication for endoscopic treatment were recruited as control (diagnostic group n = 20). Bacteremia was evaluated by blood culture at baseline and 30 minutes after the procedure. RESULTS: After 137 scheduled endoscopic procedures, none of the 58 patients had fever or any sign suggestive of infection. All baseline cultures were negative. No positive cultures were observed after CY or in the control group - diagnostic endoscopy. Three (4.6 percent) positive cultures were found out of the 65 sessions of band ligation (P = 0.187). Two of these samples were positive for coagulase-negative staphylococcus, which could be regarded as a contaminant. The isolated microorganism in the other case was Klebsiella oxytoca. The patient in this case presented no evidence of immunodeficiency except liver disease. CONCLUSIONS: There was no significant difference in bacteremia rate between these three groups. BL or CY injection for non-bleeding esophageal varices may be considered as low-risk procedures regarding bacteremia even when performed on patients with advanced liver disease.

CONTEXTO: A ligadura elástica é considerada o melhor tratamento endoscópico para o sangramento agudo por varizes esofágicas ou para profilaxia do sangramento varicoso, sendo a escleroterapia com N-2-butil-cianoacrilato uma alternativa para os pacientes com doença hepática avançada e distúrbio de coagulação. Bacteriemia é uma complicação rara associada à ligadura elástica, por outro lado, a incidência de bacteriemia relacionada com o uso de N-2-butil-cianoacrilato permanece desconhecida. OBJETIVOS: Avaliar e comparar a incidência de bacteriemia transitória entre os pacientes cirróticos submetidos a endoscopia digestiva alta diagnóstica, escleroterapia com N-2-butil-cianoacrilato ou ligadura elástica para tratamento das varizes esofágicas. MÉTODOS: Estudo prospectivo realizado entre 2004 e 2007 foi conduzido no Hospital da Universidade Federal de São Paulo, UNIFESP, Brasil. Cirróticos com doença hepática avançada (Child B ou C) foram incluídos. Os pacientes foram divididos em dois grupos de acordo com o tratamento: grupo ligadura elástica (pacientes submetidos a ligadura elástica, n = 20) e grupo N-2-butil-cianoacrilato (pacientes submetidos a injeção de N-2-butil-cianoacrilato, n = 18). Cirróticos sem varizes esofágicas ou com varizes esofágicas sem indicação de tratamento endoscópico foram recrutados como controles (grupo endoscopia diagnóstica, n = 20). Bacteriemia foi avaliada por hemocultura basal e 30 minutos após o procedimento. RESULTADOS: Dos 137 procedimentos endoscópicos realizados, nenhum dos 58 pacientes apresentou febre ou qualquer sinal sugestivo de infecção. Todas as hemoculturas de base foram negativas. Nenhuma cultura positiva foi observada após o uso de N-2-butil-cianoacrilato ou no grupo controle. Três (4,6 por cento) culturas positivas foram encontradas após as 65 sessões de ligadura elástica (P = 0,187). Duas dessas foram positivas para Staphylococcus coagulase-negativo, provavelmente relacionadas à contaminação. O microorganismo isolado no terceiro caso foi Klebsiella oxytoca. Nesse caso, o paciente apresentava a própria doença hepática como única situação relacionada à imunodeficiência. CONCLUSÕES: Não houve diferença significante na incidência de bacteriemia entre os três grupos de pacientes. Ligadura elástica ou injeção de N-2-butil-cianoacrilato para profilaxia do sangramento varicoso podem ser considerados procedimentos de baixo risco quanto ao surgimento de bacteriemia, mesmo em pacientes com doença hepática avançada.