Safety of Inulin and Sinistrin: Combining Several Sources for Pharmacovigilance Purposes.

Introduction: Inulin and its analog sinistrin are fructose polymers used in the food and pharmaceutical industries. In 2018, The French National Agency for the Safety of Medicines and Health Products (ANSM) decided to withdraw products containing sinistrin and inulin due to several reports of serious hypersensitivity reactions, including a fatal outcome. Objective: To assess the safety of inulin and sinistrin use in France. Methods: We searched multiple sources to identify adverse reactions (ARs) to inulin or sinistrin: first, classical pharmacovigilance databases including the French Pharmacovigilance (FPVD) and the WHO Database (VigiBase); second, data from a clinical trial, MultiGFR; third, data regarding current use in an hospital. All potential ARs to inulin or sinistrin were analyzed with a focus on hypersensitivity reactions and relationships to batches of sinistrin. Results: From 1991 to 2018, 134 ARs to inulin or sinistrin were registered in the FPVD or VigiBase. Sixty-three cases (47%) were classified as serious, and 129 cases (96%) were hypersensitivity reactions. We found an association between a batch of sinistrin and the occurrence of hypersensitivity reactions. During the MultiGFR clinical trial, 7 patients (7/163 participants) had an Adverse reaction; of these, 4 were hypersensitivity reactions including one case of grade 4 anaphylactic shock. In the hospital, no ARs were observed. In the literature, ARs to inulin and sinistrin are very rarely reported and mostly benign. Conclusion: Most ARs to inulin and sinistrin are hypersensitivity reactions that appear to be associated with sinistrin batches.

Efficacy of intralesional sodium thiosulfate injections for disabling tumoral calcinosis: Two cases.

INTRODUCTION: Tumoral calcinosis (TC) is a difficult-to-treat complication that can occur during several diseases such as dermatomyositis or genetic hyperphosphatemia. It is a painful and disabling condition that can lead to local complications including joint mobility reduction, cutaneous ulceration and superinfection. For the largest lesions, the treatment relies essentially on surgery. Intravenous sodium thiosulfate (STS) is efficient to treat calciphylaxis in patients undergoing hemodialysis. Local injections of STS seem efficient in superficial calcifications. OBJECTIVE: To report the efficacy and safety of intra-lesional injections of STS in tumoral calcinosis. RESULTS: We report two cases of successful intra-lesional injections of STS. A 44-year-old woman, with a history of dermatomyositis, presenting large subcutaneous calcifications in the right elbow, and a 42-year-old man, with a history of familial tumoral calcinosis, presenting large intramuscular calcifications in the right buttock, received weekly intra-lesional of 1-3g STS injections for 12 and 21 months, respectively. In both cases, the treatment relieved pain and greatly reduced the tumoral calcinosis with a very significant functional improvement without specific adverse effects. In case 1, TC size decreased from 28.7*56.0mm at baseline to 21.5*30.6mm at M12 treatment (59% reduction). In case 2, TC reduced from 167.5*204.3mm at baseline to 86.2*85.2mm at M21 treatment (79% reduction). CONCLUSION: Local injection of STS could be a promising therapeutic strategy for large and deep TC lesions and could therefore be an alternative to surgery.

[Nephrolithiasis of adult: From mechanisms to preventive medical treatment]. / Lithiase rénale de l'adulte : des mécanismes au traitement médical préventif.

Nephrolithiasis is a very common (prevalence around 10 to 12% in France) and recurrent disorder. Nephrolithiasis is associated to chronic kidney disease and is responsible for 2 to 3% of cases of end-stage renal disease, mainly if it is associated to nephrocalcinosis or to a monogenic disorder (1.6% of nephrolithiasis in adults, among them 1% of cystinuria). To understand the underlying pathophysiological processes, stone analysis (morphology and using infrared spectrophotometry) as well as minimal biological assessment including urine crystal research are required. The calcic nephrolithiasis is the more frequent subtype (>80%). Its medical treatment relies on simple dietary rules: non-alkaline hyperdiuresis>2 liters/day, calcium intake normalization (1 gram per day divided between the three principal meals), normalization of sodium (6 to 7 grams per day) and protein intake (1g/kg of theoretical body weight/day), and eviction of foods rich in oxalate. In case of persistent hypercalciuria (>0.1mmol/kg of theoretical body weight/day on free diet), a thiazide diuretic can be started while being aware to correct iatrogenic decrease in plasma potassium and urine citrate excretion. Measurement of bone mineral density must systematically be performed in patients with high 24 h-urinary calcium excretion. The medical treatment of uric acid nephrolithiasis relies on alkaline hyperdiuresis (goal of urine pH: 6.2 to 6.8). The use of allopurinol is justified only if urine uric acid is over 4mmol/day. Thanks to a well-managed preventive medical treatment, one can expect to stop the activity of nephrolithiasis in more than 80% of cases, making it one of the most accessible renal pathologies to preventive medical treatment.

Estimated or Measured GFR in Living Kidney Donors Work-up?

The value of estimated glomerular filtration rate (eGFR) in living kidney donors screening is unclear. A recently published web-based application derived from large cohorts, but not living donors, calculates the probability of a measured GFR (mGFR) lower than a determined threshold. Our objectives were to validate the clinical utility of this tool in a cohort of living donors and to test two other strategies based on chronic kidney disease epidemiology collaboration (CKD-EPI) and on MDRD-eGFR. GFR was measured using 51 Cr- ethylene-diamine tetraacetic acid urinary clearance in 311 potential living kidney donors (178 women, mean age 50 ± 11.6 years). The web-based tool was used to predict those with mGFR < 80 mL/min/1.73 m2 . Inputs to the application were sex, age, ethnicity, and plasma creatinine. In our cohort, a web-based probability of mGFR <90 mL/min/1.73 m2 higher than 2% had 100% sensitivity for detection of actual mGFR <80 mL/min/1.73 m2 . The positive predictive value was 0.19. A CKD-EPI-eGFR threshold of 104 mL/min/1.73 m2 and an MDRD-eGFR threshold of 100 mL/min/1.73 m2 had 100% sensitivity to detect donors with actual mGFR <80 mL/min/1.73 m2 . We obtained similar results in an external cohort of 354 living donors. We confirm the usefulness of the web-based application to identify potential donors who should benefit from GFR measurement.

[Primary hyperparathyroidism]. / Hyperparathyroïdie primitive.

For the past 40 years, primary hyperparathyroidism has been recognized as a common endocrine disease which is, most often, "non-symptomatic", without the occurrence of nephrolithiasis or osteitis fibrosa cystica. Our knowledge in the pathophysiology has increased largely and diagnosis of primary hyperparathyroidism is usually easy. The only radical treatment is surgery and the surgical indications have been codified by several consensus conferences. For patients who do not undergo surgery, prolonged medical monitoring is needed.

[Hyperuricemia in sickle cell disease in France]. / Hyperuricémie chez les patients drépanocytaires suivis en France.

PURPOSE: Hyperuricemia has been reported to be a common feature of sickle cell disease occurring between 32 to 41% of the patients, in studies conducted during the 1970's. Since then, this notion has been rarely challenged. The objective of this study was to assess the prevalence of hyperuricemia and gout in adult patients with sickle cell disease in France. METHODS: Between May 2007 and March 2009, serum and urinary urate concentration, creatininemia and hemogram were prospectively assessed in all consecutive sickle cell patients, followed in our sickle cell disease centre. All subjects were in a clinically steady state. Clinical acute gout history was also recorded. RESULTS: Sixty-five patients (mean age 31±10.3 years) were investigated. Mean uric acid serum level was 281.6±74µmol/L. Hyperuricemia was evidenced in six patients only (9.2%) (95% IC: 3.5-19.0). None of the patient had a medical history of acute gout. Patients in the higher serum uric acid tertile concentration had higher serum creatinine level (62.3±17.1µmol/L vs 51.5±12.6µmol/L, P<0.01), lower fractional excretion of urate (4.5% vs 6.8%, P<0.03) and higher reticulocyte count (median 219500/mm(3) vs 144000/mm(3), P=0.08) compared to the other patients. CONCLUSION: Hyperuricemia and gout are not a clinical problem in sickle cell disease in our country. Nevertheless, our findings indicate that kidney function has to be fully explored if serum uric acid level is elevated or significantly deteriorates during follow-up. Serum uric acid level could be an early marker of renal dysfunction in sickle cell disease patients.

[Effect of vitamin D deficiency on cardiovascular risk]. / Influence de la vitamine D sur le risque cardiovasculaire.

Vitamin D deficiency affects almost 50 % of the population worldwide. Besides its classical effects on bone and calcium metabolism, vitamin D displays a wide spectrum of non classical effects. Among these effects, those targeting the cardiovascular system are mostly documented by observational, experimental and small intervention trials that most often evaluated intermediate parameters. The time has now come for large placebo-controlled trials targeting clinical endpoints such as the incidence of major cardiovascular events and mortality.

[Update on vitamin D and evaluation of vitamin D status]. / Actualité sur les effets de la vitamine D et l'évaluation du statut vitaminique D.

Knowledge about vitamin D has greatly improved during the last few years. Vitamin D cannot any more be considered as exclusively necessary to prevent ricket/osteomalacia. Its role in the prevention of some osteoporotic fractures in the elderly (in association with calcium nutrition) is now well demonstrated and many epidemiologic and laboratory data argue for a role in the prevention of several diseases or anomalies (cancer, auto-immune diseases, cardiovascular events, sarcopenia...). A few intervention studies confirming some of these effects also exist. Vitamin D status can easily be assessed by measuring serum 25 hydroxy vitamin D (25OHD) level. However, many experts have claimed that the population-based reference values for 25OHD are too low and that the cut-off value below which vitamin D insufficiency can be present is somewhere between 20 and 40 ng/mL with a clear tendency to target values above 30 ng/mL (75 nmol/L). The main consequences are that vitamin D insufficiency is highly frequent whereas the currently recommended supplementation doses are not sufficient.