Early Switch From Tacrolimus to Everolimus After Liver Transplantation: Outcomes at 2 Years.

The observational CERTITUDE study follows liver transplant patients who completed the SIMCER trial. SIMCER randomized patients at month 1 after transplant to everolimus (EVR) with stepwise tacrolimus (TAC) withdrawal or to standard TAC, both with basiliximab induction and mycophenolic acid ± steroids. After completing SIMCER at 6 months after transplant, 65 EVR-treated patients and 78 TAC-treated patients entered CERTITUDE. At month 24 after transplant, 34/65 (52.3%) EVR-treated patients remained calcineurin inhibitor (CNI) free. Mean estimated glomerular filtration rate (eGFR) was significantly higher with EVR versus TAC during months 3-12. At month 24, eGFR values were 83.6 versus 75.3 mL/minute/1.73 m2 , respectively (P = 0.90) and adjusted mean change in eGFR from randomization was -8.0 versus -13.5 mL/minute/1.73 m2 (P = 0.15). At month 24, 45.9%, 31.1%, and 23.0% of EVR-treated patients had chronic kidney disease stages 1, 2, and 3, respectively, versus 25.7%, 45.7%, and 28.6% of TAC-treated patients (P = 0.05). Treated biopsy-proven acute rejection affected 4 EVR-treated patients and 2 TAC patients during months 6-24. Adverse events led to study discontinuation in 15.4% and 7.7% of EVR-treated and TAC-treated patients, respectively. Grade 3 or 4 hematological events were rare in both groups. A CNI-free EVR-based maintenance regimen appears feasible in approximately half of liver transplant patients. It preserves renal function effectively with good efficacy without compromising safety or hematological tolerance.

The burden of chronic urticaria: French baseline data from the international real-life AWARE study.

BACKGROUND: The AWARE study is an ongoing international study of patients with chronic urticaria refractory to H1-antihistamines. The aim of this study is to evaluate the burden of disease and the use of healthcare resources in real-life conditions. OBJECTIVES: To analyse the baseline data of French patients included in the AWARE study. MATERIALS & METHODS: AWARE is a prospective, non-interventional, international study that includes adult patients who have had chronic urticaria, refractory to at least one H1-antihistamine, for at least two months. RESULTS: Ninety-four patients (mean age: 47.9 years; 71.3% women) with chronic urticaria (50.0% spontaneous only, 9.6% inducible only, and 40.4% both) were included in French centres. The median duration from diagnosis was three years and angioedema was present in 31.5% of patients for the past six months. In 63.8% of cases, the patients received at least one treatment for urticaria (H1-antihistamine for 66.0%). Chronic urticaria was poorly controlled (UCT score <12) in 88.9% of patients and quality of life was severely impaired (mean DLQI score: 8.6). The use of healthcare resources was significant with frequent visits to general practitioners (80.8% of patients; mean: 8.1 visits). However, more than half of patients had not previously consulted a dermatologist. CONCLUSION: These baseline data of French patients in the AWARE study show that patients suffering from chronic urticaria, refractory to H1-antihistamines for a median of three years, are insufficiently treated and that their quality of life is impaired. Despite the significant use of healthcare resources, access to specialised consultations remains insufficient.

Characterization of a splice-site mutation in the tumor suppressor gene FLCN associated with renal cancer.

BACKGROUND: Renal cell carcinoma is among the most prevalent malignancies. It is generally sporadic. However, genetic studies of rare familial forms have led to the identification of mutations in causative genes such as VHL and FLCN. Mutations in the FLCN gene are the cause of Birt-Hogg-Dubé syndrome, a rare tumor syndrome which is characterized by the combination of renal cell carcinoma, pneumothorax and skin tumors. METHODS: Using Sanger sequencing we identify a heterozygous splice-site mutation in FLCN in lymphocyte DNA of a patient suffering from renal cell carcinoma. Furthermore, both tumor DNA and DNA from a metastasis are analyzed regarding this mutation. The pathogenic effect of the sequence alteration is confirmed by minigene assays and the biochemical consequences on the protein are examined using TALEN-mediated transgenesis in cultured cells. RESULTS: Here we describe an FLCN mutation in a 55-year-old patient who presented himself with progressive weight loss, bilateral kidney cysts and renal tumors. He and members of his family had a history of recurrent pneumothorax during the last few decades. Histology after tumor nephrectomy showed a mixed kidney cancer consisting of elements of a chromophobe renal cell carcinoma and dedifferentiated small cell carcinoma component. Subsequent FLCN sequencing identified an intronic c.1177-5_-3delCTC alteration that most likely affected the correct splicing of exon 11 of the FLCN gene. We demonstrate skipping of exon 11 to be the consequence of this mutation leading to a shift in the reading frame and the insertion of a premature stop codon. Interestingly, the truncated protein was still expressed both in cell culture and in tumor tissue, though it was strongly destabilized and its subcellular localization differed from wild-type FLCN. Both, altered protein stability and subcellular localization could be partly reversed by blocking proteasomal and lysosomal degradation. CONCLUSIONS: Identification of disease-causing mutations in BHD syndrome requires the analysis of intronic sequences. However, biochemical validation of the consecutive alterations of the resulting protein is especially important in these cases. Functional characterization of the disease-causing mutations in BHD syndrome may guide further research for the development of novel diagnostic and therapeutic strategies.

The kidney stone and increased water intake trial in steel workers: results from a pilot study.

Preventing dehydration in subjects at risk may provide a means of primary prevention of kidney stones. The purpose of this pilot study was to assess the hydration status of an at-risk group of steel plant workers based on end-of-shift ('post-shift') spot urine osmolality and 24-h urinary stone risk parameters. 100 volunteers were recruited from Gerdau Midlothian steel mill in Texas on 11/14/14 and 12/5/14. Clinical data were recorded and post-shift spot urine sample was used to measure urine osmolality. Participants were invited to submit a 24-h urine sample within 4 weeks of enrollment. The mean age was 41 years and 95 % were men. The majority of subjects were white (75 %), followed by 10 % Hispanic and 9 % black. The mean body mass index was 30.1 kg/m2 and overall 16 % had a past history of stone disease. Mean post-shift urine spot osmolality was 704.5 mOsm (169-1165 mOsm) and was >800 and >700 mOsm in 39 and 57 %, respectively. Among 59 24-h urines samples, the mean volume was 1.89 ± 0.92 l/day, with 56 % < 2 L and 17 % < 1 L. Elevated levels of urinary analytes were found in 29 % of subjects for calcium (>250 mg/TV), 39 % for uric acid (>700 mg/TV), 25 % for oxalate (>45 mg/TV) and 50 % for sodium (>200 meq/TV). The prevalence of stone disease in this population of steel workers was higher than the published prevalence of stone disease in the general population. A significant number of workers had concentrated post-shift and 24-h urines and elevated levels of urinary analytes.

Contribution of Water from Food and Fluids to Total Water Intake: Analysis of a French and UK Population Surveys.

Little has been published on the contribution of food moisture (FM) to total water intake (TWI); therefore, the European Food Safety Authority assumed FM to contribute 20%-30% to TWI. The aim of the present analysis was to estimate and compare TWI, the percentage of water from FM and from fluids in population samples of France and UK. Data from 2 national nutrition surveys (Enquête Comportements et Consommations Alimentaires en France (CCAF) 2013 and the National Diet and Nutrition Survey (NDNS) 2008/2009-2011/2012) were analyzed for TWI and the contribution of water from FM and fluids. Children and adults TWI were significantly lower in France than in the UK. The contribution of water from foods was lower in the UK than in France (27% vs. 36%). As TWI increased, the proportion of water from fluids increased, suggesting that low drinkers did not compensate by increasing intake of water-rich foods. In addition, 80%-90% of the variance in TWI was explained by differences in water intake from fluids. More data on the contribution of FM to TWI is needed to develop more robust dietary recommendations on TWI and guidance on fluid intake for the general public.

Loss of the Birt-Hogg-Dubé gene product folliculin induces longevity in a hypoxia-inducible factor-dependent manner.

Signaling through the hypoxia-inducible factor hif-1 controls longevity, metabolism, and stress resistance in Caenorhabditis elegans. Hypoxia-inducible factor (HIF) protein levels are regulated through an evolutionarily conserved ubiquitin ligase complex. Mutations in the VHL gene, encoding a core component of this complex, cause a multitumor syndrome and renal cell carcinoma in humans. In the nematode, deficiency in vhl-1 promotes longevity mediated through HIF-1 stabilization. However, this longevity assurance pathway is not yet understood. Here, we identify folliculin (FLCN) as a novel interactor of the hif-1/vhl-1 longevity pathway. FLCN mutations cause Birt-Hogg-Dubé syndrome in humans, another tumor syndrome with renal tumorigenesis reminiscent of the VHL disease. Loss of the C. elegans ortholog of FLCN F22D3.2 significantly increased lifespan and enhanced stress resistance in a hif-1-dependent manner. F22D3.2, vhl-1, and hif-1 control longevity by a mechanism distinct from insulin-like signaling. Daf-16 deficiency did not abrogate the increase in lifespan mediated by flcn-1. These findings define FLCN as a player in HIF-dependent longevity signaling and connect organismal aging, stress resistance, and regulation of longevity with the formation of renal cell carcinoma.