FP342SCREENING FOR KIDNEY DISEASE IN PREGNANCY: MODELLING AND COST EFFECTIVE OF A CONTROL POLICY

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Positron Emission Tomography Can Support the Diagnosis of Dialysis-Related Amyloidosis

Background: The improvements in dialysis have not eliminated long-term problems, including dialysis-related amyloidosis (DRA), caused by Beta-2 microglobulin deposition. Several types of scintigraphy have been tested to detect DRA, none entered the clinical practice. Aim of the study was to assess the potential of PET-FDG scan in the diagnosis of DRA. Methods: Forty-six dialysis patients with at least one PET scan (72 scans) were selected out 162 patients treated in 2016–2018. Subjective global assessment (SGA), malnutrition inflammation score (A), Charlson Comorbidity Index (CCI), were assessed at time of scan; 218 age-matched cases with normal kidney function were selected as controls. PET scans were read in duplicate. Carpal tunnel syndrome was considered a proxy for DRA. A composite “amyloid score” score considered each dialysis year = 1 point; carpal tunnel-DRA = 5 points per site. Logistic regression, ROC curves and a prediction model were built. Results: The prevalence of positive PET was 43.5% in dialysis, 5% in controls (p < 0.0001). PET was positive in 14/15 (93.3%) scans in patients with carpal tunnel. PET sensitivity for detecting DRA was 95% (specificity 64%). Carpal tunnel was related to dialysis vintage and MIS. A positive PET scan was significantly associated with dialysis vintage, MIS and amyloid score. A prediction model to explain PET positivity combined clinical score and MIS, allowing for an AUC of 0.906 (CI: 0.813–0.962; p < 0.001). Conclusions: PET-FDG may identify DRA, and may be useful in detecting cases in which inflammation favours B2M deposition. This finding, needing large-scale confirmation, could open new perspectives in the study of DRA

Phosphate binders as a cause of hypothyroidism in dialysis patients: practical indications from a review of the literature

Abstract Background Although fatigue is common in dialysis patients, polypharmacy is seldom listed among its causes. In this report, we describe a dialysis patient who developed severe fatigue due to pharmacological interaction between two commonly prescribed drugs, phosphate binders and levothyroxine. Case Presentation A 65-year old woman, on dialysis for 17 years, complained of fatigue (weight 54 Kg, height 1.55 m, BMI: 23 Kg/m2; malnutrition inflammation index: 10; Charlson index 9). She had been treated with lithium for about 20 years. A heavy smoker, she was obese and diabetic when young, but stopped treatment after weight loss. She had undergone thyroidectomy for papillary carcinoma, left hemicolectomy for colon adenocarcinoma, left quadrantectomy followed by radiotherapy for ductal mammary adenocarcinoma, subtotal parathyroidectomy for tertiary hyperparathyroidism. At the time of this report, she was on thrice-weekly hemodiafiltration (Daugirdas 2 Kt/V: 1.6–1.8). Her recent treatment included spironolactone, amlodipine, perindopril, valproate, lamotrigine, levothyroxine, vitamin D, calcium carbonate, sodium polystyrene and sevelamer. After she questioned her doctor about whether her fatigue might be the result of a drug interaction, levothyroxine interference was identified (TSH, previously normal, increased to 13.07 mU/L, after increasing sevelamer dose, and normalized after change of drug schedule). Literature review: only 5 relevant papers on levothyroxine and phosphate binders on dialysis were found on Pubmed and EMBASE (out of 351 titles retrieved). Information was therefore inferred from studies in normal volunteers or in other diseases. Discussion and conclusions Our case differs from other reports on lower TSH at diagnosis, underlining the need for awareness of the importance of early diagnosis. Integrating the scant literature on dialysis patients with data available in the general population, some working conclusions can be reached: while all phosphate binders potentially interfere with levothyroxine absorption, interference seems to be highest for sevelamer; interference is limited but not excluded by increasing the intervals between drugs; morning fast is usually indicated but, when clashing with the timing of other drugs, a bedtime dose and liquid preparations may be indicated. In the absence of an agreed control schedule, our case supports close monitoring of TSH (1–3 months if unstable, twice-yearly in stable patients)

Looking beyond Entecavir to discover Gitelman Syndrome in a 50 year-old man

Potassium (K+) is essential for cells functions and alterations of the normal plasmatic levels can be life-threatening. The kidney is crucial in maintaining K+ homeostasis, mainly by regulating its secretion in the urine. Hypokalemia is influenced by acid-base status and can be associated to both metabolic alkalosis or acidosis. In adults, drug-induced hypokalemia is the most common form, however, genetically undiagnosed conditions should always be investigated

Design, synthesis and biological evaluation of novel TRβ selective agonists sustained by ADME-toxicity analysis

Although triiodothyronine (T3) induces several beneficial effects on lipid metabolism, its use is hampered by toxic side-effects, such as tachycardia, arrhythmia, heart failure, bone and muscle catabolism and mood disturbances. Since the α isoform of thyroid hormone receptors (TRs) is the main cause of T3-related harmful effects, several efforts have been made to develop selective agonists of the β isoform that could induce some beneficial effects (i.e. lowering triglyceride and cholesterol levels reducing obesity and improving metabolic syndrome), while overcoming most of the adverse T3-dependent side effects. Herein, we describe the drug discovery process sustained by ADME-Toxicity analysis that led us to identify novel agonists with selectivity for the isoform TRβ and an acceptable off-target and absorption, distribution metabolism, excretion and toxicity (ADME-Tox) profile. Within the small series of compounds synthesized, derivatives 1 and 3, emerge from this analysis as "potentially safe" to be engaged in preclinical studies. In in vitro investigation proved that both compounds were able to reduce lipid accumulation in HepG2 and promote lipolysis with comparable effects to those elicited by T3, used as reference drug. Moreover, a preliminary in vivo study confirmed the apparent lack of toxicity, thus suggesting compounds 1 and 3 as new potential TRβ-selective thyromimetics

A case series of adult patients affected by EAST/SeSAME syndrome suggests more severe disease in subjects bearing KCNJ10 truncating mutations

EAST/SeSAME syndrome is a rare disease affecting the Central Nervous System (CNS), inner ear, and kidney. The syndrome is due to loss-of-function mutations in the KCNJ10 gene encoding the inward-rectifying potassium channel Kir4.1. EAST/SeSAME syndrome is mainly diagnosed during childhood with a tonic-clonic seizure being the usual first symptom. Due to a limited number of patients and recent identification of the disease, few data are available on the clinical progress of this disease in adulthood. In particular, neurologic and nephrological outcomes have not been reported. We present a case series of 4 adult patients harbouring homozygous missense mutation p.Ala167Val and homozygous frameshift mutations p.Asn232Glnfs*14 and p.Gly275Valfs*7. Effects of these mutations were predicted by in silico modelling and bioinformatic tools. Patients with truncating mutations were associated with more severe outcomes, both in tubulopathy severity and neurological symptomatology. Conversely, either missense or truncating mutations were correlated with similar severity of epilepsy, with a long free-of-event period up to 20 years old. No eGFR decline was documented. Modelling predicted that truncating mutations lead to complete Kir4.1 dysfunction. Finally, all patients had a mild increase in urinary protein excretion. Our study indicates that the prognosis of patients suffering from EAST/SeSAME syndrome is related to the severity of the mutation causing the disease. As predicted by in silico modelling, truncating mutations of KCNJ10 are associated with more severe disease, with recurrence of symptomatic hypokalemia and more severe neurological phenotype. The type of mutation should be considered for the therapy tailored to patients' phenotype

Towards Pervasive and Trustworthy Artificial Intelligence: How standards can put a great technology at the service of humankind

With the printing industry sparing no efforts publishing books on Artificial Intelligence (AI), why should there be another that, in its title and subtitle, combines the overused words AI and trustworthy, with the alien words standards and pervasive? The answer is that the book describes a solution that covers all the elements of the title: to effectively combine the AI and trustworthy words, but also to make AI pervasive. How? By developing standards for AI-based data coding. Many industries needed standards to run their business and used to have high respect for them. The MP3 standard put users in control of the content they wanted to enjoy, and the television – and now the video – experiences have little to do with how users approached audio-visual content some 30 years ago. At that time, the media industry was loath to invest in open standards. The successful MPEG standards development model, however, changed its attitude. Similarly, the AI industry has been slow in developing AI-based data coding standards making proprietary solutions their preferred route. This book provides the full description of mission, achievements and plans of the Moving Picture, Audio and Data Coding by Artificial Intelligence (MPAI) standards developing organisation. It describes how MPAI develops standards that can also be used, how standards can make AI pervasive and promote innovation, how MPAI gives users the means to make informed decisions about how to choose a standard implementation having the required level of trustworthiness. MPAI is a unique adventure open to those who want to make the MPAI vision real