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- Long-term treatment with tenofovir: prevalence of kidney tubular dysfunction and its association with tenofovir plasma concentration. [JOURNAL ARTICLE]
- Antivir Ther 2014 Feb 28.
Monitoring of side effects of long-term HIV treatment has become increasingly important. Tenofovir disoproxil fumarate (TDF), a first-line treatment option, is associated with kidney tubular dysfunction (KTD). Our objective was to further investigate the prevalence and risk factors of KTD, in particular its association with TDF plasma concentration in HIV infected patients treated with TDF for at least one year.An observational cross-sectional single-centre study was conducted. KTD was defined as the presence of at least two of the following criteria: (1) Urinary α1-microglobulin / creatinine ratio > 15mg/10mmol; (2) Fractional excretion (FE) of phosphate > 20% in the presence of hypophosphatemia; (3) FE of uric acid > 10% in the presence of hypouricemia; (4): Glucosuria. Multivariate logistic regression was used to study which variable was associated with KTD.161 HIV patients were included. Abnormalities in tubular function were observed in 101 patients (62.7%), while 17 patients (10.6%) fulfilled the definition of KTD. Urinary α1-microglobulin/creatinine ratio was the most sensitive parameter to detect KTD. Multivariate logistic regression showed TDF plasma concentration to be the only variable associated with KTD. Post-hoc analysis showed a stronger association between the product of TDF plasma concentration and TDF exposure and KTD.Parameters of KTD are frequently observed in patients on long-term TDF-containing combination antiretroviral therapy (cART). KTD is associated with higher TDF plasma concentrations. A stronger association between the product of TDF plasma concentration and TDF exposure with KTD could suggest cumulative toxicity. A causative role for elevated TDF plasma concentration in development of KTD cannot be demonstrated in this cross-sectional analysis. Longitudinal research is needed to investigate the development and clinical relevance of KTD.
- Meglitinide Analogues in Adolescent Patients With HNF1A-MODY (MODY 3). [Journal Article]
- Pediatrics 2014 Mar; 133(3):e775-9.
For pediatric patients with hepatocyte nuclear factor-1A (HNF1A)-maturity-onset diabetes of the young (MODY 3), treatment with sulfonylureas is recommended. In adults with HNF1A-MODY, meglitinide analogues achieve lower postprandial glucose levels and pose a lower risk of delayed hypoglycemia compared with sulfonylureas. This therapy has not yet been reviewed in pediatric patients. We report on meglitinide analogue treatment in 3 adolescents with HNF1A-MODY. Case 1 (14-year-old girl) was diagnosed asymptomatically but had an hemoglobin A1c (HbA1c) level of 7.4%; her father had been recently diagnosed with HNF1A-MODY. With repaglinide, her HbA1c level decreased to 5.5%, with no hypoglycemic episodes. Case 2 (14-year-old boy) was diagnosed incidentally with glucosuria (HbA1c level: 7.0%) and was treated with insulin. After the HNF1A-MODY diagnosis, he was switched to glibenclamide. Due to several hypoglycemic episodes, treatment was changed to nateglinide and his HbA1c level decreased to 6.2% with no further hypoglycemic episodes. Case 3 (11-year-old girl) presented with polyuria and polydipsia (HbA1c level: 10.1%) and was initially treated with insulin. After the HNF1A-MODY diagnosis, treatment was changed to repaglinide. She was obese (BMI: 28.8 kg/m(2); z-score: +2.2), and glucose control with repaglinide alone was insufficient. Therefore, neutral protamine Hagedorn insulin (0.27 U/kg per day) was added. With this combination therapy, her HbA1c level decreased to 8.2%. The use of meglitinides in these 3 adolescent patients was well tolerated and effective. Furthermore, hypoglycemic episodes were rare compared with treatment with insulin or sulfonylureas. We therefore suggest considering meglitinides as the primary oral treatment option for adolescents suffering from HNF1A-MODY.
- Long-term Observation of Osteomalacia Caused by Adefovir-Induced Fanconi's Syndrome. [Journal Article]
- Acta Med Okayama 2014 Feb; 68(1):53-6.
A 64-year-old man suffering polyarthralgia and bone pain was referred to our hospital. Renal dysfunction, hypophosphatemia and increased levels of bone alkaline phosphatase were found. The patient's serum creatinine level had gradually increased after the initiation of adefovir dipivoxil administration for hepatitis B. In agreement with multifocal uptakes of bone scintigraphy, iliac bone biopsy revealed an abnormal increase in osteoid tissues. Reducing the dose of adefovir and initiating the administration of eldecalcitol were effective for reducing proteinuria and glucosuria, and for ameliorating bone pain with an increase in serum phosphate level. This case first showed a clinical course of hypophosphatemic osteomalacia caused by secondary Fanconi's syndrome for 8 years after adefovir administration. Early diagnosis is important for the reversibility of bone damage and for a better renal prognosis.
- Usefulness of Benedict's test for the screening of galactosemia. [JOURNAL ARTICLE]
- Clin Biochem 2014 Feb 12.
Benedict's test for the screening of galactosemia presents a high false-positive rate, which puts into question its usefulness.We evaluated the results of Benedict's test as screening strategy for galactosemia, and the patients' definite diagnosis in our hospital in the last 25years. We also assessed the most prevalent clinical conditions among the false-positive cases.Apart from glycosuria, many non-galactosemic newborns with heart alterations, prematurity, icterus and sepsis usually lead to false-positive results using Benedict's. No false-negative case for Benedict's test was reported in our hospital.A better approach in terms of cost-effectiveness, sensitivity and specificity is needed for an effective screening of galactosemia.
- Genital and urinary tract infections in diabetes: Impact of pharmacologically-induced glucosuria. [REVIEW]
- Diabetes Res Clin Pract 2014 Jan 8.
Predisposition to genital infections and urinary tract infections (UTIs) in type 2 diabetes mellitus (T2DM) results from several factors such as glucosuria, adherence of bacteria to the uroepithelium and immune dysfunction. The tendency to develop these infections could be even higher in patients with T2DM treated with the emerging class of sodium-glucose cotransporter-2 (SGLT2) inhibitors. Studies have shown that pharmacologically-induced glucosuria with SGLT2 inhibitors raises the risk of developing genital infections and, to a relatively lesser extent, UTIs. However, a definitive dose relationship of the incidence of these infections with the SGLT2 doses is not evident in the existing data. Therefore, the precise role of glucosuria as a causative factor for these infections is yet to be fully elucidated.
- Unusual manifestation of crystalline light chain tubulopathy in patient with multiple myeloma: case report and review of the literature. [JOURNAL ARTICLE]
- Ren Fail 2014 Feb 10.
Abstract Multiple myeloma (MM) is the second most common hematological malignancy, with an annual incidence in Europe and the USA of about 4-6 cases per 100,000. Several forms of renal disease are found in the course of MM, including: cast nephropathy, light chain (LC) deposition disease and primary amyloidosis. Less frequent forms include: acute and chronic tubulopathies, neoplastic plasma cell infiltration and interstitial nephritis. In this paper, we discuss a case of 53-year-old male patient with MM who presented with massive proteinuria (24 g/24 h), mild renal insufficiency (eGFR 43 mL/min), and Fanconi-like syndrome (as reflected by normoglycemic glycosuria). In kidney biopsy glomeruli were normal, whereas abundant AFOG-positive deposits were found in the cytoplasm of proximal tubular epithelial cells. These deposits were strongly positive for kappa light chains on immunofluorescence. Electron microscopy revealed electron-dense, intracytoplasmic crystalloid deposits of variable shape (needle-shaped, round and rectangular), and size in the proximal tubular cells. This unusual variant of microscopic renal lesions in the course of MM coupled with coincidence of Fanconi-like and nephrotic syndrome as a clinical manifestation has not been reported to date.
- Prevalence of renal abnormalities in chronic HBV infection: The HARPE study. [JOURNAL ARTICLE]
- Liver Int 2014 Feb 6.
Few data are available on the prevalence of renal abnormalities in chronic hepatitis B virus (HBV)-infected patients. The multicentric cross-sectional HARPE study evaluated the prevalence of kidney disease indicators, in chronic HBV surface antigen carriers patients (HBsAg+) with active or inactive infection.Two hundred and sixty-eight HBsAg+ adult patients, naïve of any oral antihepatitis B virus treatment were prospectively included over 2 years. Data for renal assessment were collected once from patient files. Univariate tests and multiple linear regressions were performed with the SAS software, version 8.02 (SAS, Inc., Cary, NC, USA).Among the 260 patients analysed, 58% were men, the mean age was 42 ± 14 years, 59.6% were inactive carriers whereas 47 patients, mostly active, were about to start an antiviral therapy. Prevalence of proteinuria, haematuria, glycosuria, uninfectious leukocyturia was 38.1%, 20.6%, 3.9% and 9% respectively. According to the international definition, a total of 64.6% of patients were found to have kidney disease. Diabetes, hypertension and dyslipidaemia were observed, respectively, in 4.6%, 9.2% and 38.8% patients. There were no significant differences in these results within the three subgroups.Renal abnormalities are highly prevalent in our population and pre-exist before the initiation of any antihepatitis B virus treatment. This emphasizes the need for: (i) a baseline renal evaluation in all HBs antigen-positive patients; (ii) a regular renal monitoring before and during antihepatitis B virus treatment to diagnose and manage renal impairment and adjust antihepatitis B virus treatment doses to renal function when necessary.
- Mathematical modeling of renal tubular glucose absorption after glucose load. [Journal Article]
- PLoS One 2014; 9(1):e86963.
A partial differential Progressive Tubular Reabsorption (PTR) model, describing renal tubular glucose reabsorption and urinary glucose excretion following a glucose load perturbation, is proposed and fitted to experimental data from five subjects. For each subject the Glomerular Filtration Rate was estimated and both blood and urine glucose were sampled following an Intra-Venous glucose bolus. The PTR model was compared with a model representing the conventional Renal Threshold Hypothesis (RTH). A delay bladder compartment was introduced in both formulations. For the RTH model, the average threshold for glycosuria varied between 9.90±4.50 mmol/L and 10.63±3.64 mmol/L (mean ± Standard Deviation) under different hypotheses; the corresponding average maximal transport rates varied between 0.48±0.45 mmol/min (86.29±81.22 mg/min) and 0.50±0.42 mmol/min (90.62±76.15 mg/min). For the PTR Model, the average maximal transports rates varied between 0.61±0.52 mmol/min (109.57±93.77 mg/min) and 0.83±0.95 mmol/min (150.13±171.85 mg/min). The time spent by glucose inside the tubules before entering the bladder compartment varied between 1.66±0.73 min and 2.45±1.01 min. The PTR model proved much better than RTH at fitting observations, by correctly reproducing the delay of variations of glycosuria with respect to the driving glycemia, and by predicting non-zero urinary glucose elimination at low glycemias. This model is useful when studying both transients and steady-state glucose elimination as well as in assessing drug-related changes in renal glucose excretion.
- Transient Fanconi syndrome in Quarter horses. [Journal Article, Research Support, N.I.H., Extramural]
- Can Vet J 2014 Feb; 55(2):147-51.
Two Quarter horses with weight loss had glucosuria, euglycemia, and a mild metabolic acidosis suggesting a proximal renal tubular defect. Further testing revealed transient generalized aminoaciduria, lactic aciduria, and glucosuria, indicating Fanconi syndrome. Both horses recovered with supportive therapy. This is the first report of acquired Fanconi syndrome in horses.
- Carcinogenicity Risk Assessment Supports the Chronic Safety of Dapagliflozin, an Inhibitor of Sodium-Glucose Co-Transporter 2, in the Treatment of Type 2 Diabetes Mellitus. [JOURNAL ARTICLE]
- Diabetes Ther 2014 Jan 29.
Dapagliflozin is a selective inhibitor of the sodium-glucose co-transporter 2 (SGLT2) that increases urinary glucose excretion to reduce hyperglycemia in the treatment of type 2 diabetes mellitus. A robust carcinogenicity risk assessment was undertaken to assess the chronic safety of dapagliflozin and SGLT2 inhibition.Genotoxicity potential of dapagliflozin and its metabolites was assessed in silico, in vitro, and in vivo. Dapagliflozin was administered daily by oral gavage to mice, rats, and dogs to evaluate carcinogenicity risks, including the potential for tumor promotion. SGLT2(-/-) mice were observed to evaluate the effects of chronic glucosuria. The effects of dapagliflozin and increased glucose levels on a panel of human bladder transitional cell carcinoma (TCC) cell lines were also evaluated in vitro and in an in vivo xenograft model.Dapagliflozin and its metabolites were not genotoxic. In CD-1 mice and Sprague-Dawley rats treated for up to 2 years at ≥100× human clinical exposures, dapagliflozin showed no differences versus controls for tumor incidence, time to onset for background tumors, or urinary bladder proliferative/preneoplastic lesions. No tumors or preneoplastic lesions were observed in dogs over 1 year at >3,000× the clinical exposure of dapagliflozin or in SGLT2(-/-) mice observed over 15 months. Transcription profiling in Zucker diabetic fatty rats showed that 5-week dapagliflozin treatment did not induce tumor promoter-associated or cell proliferation genes. Increasing concentrations of glucose, dapagliflozin, or its primary metabolite, dapagliflozin 3-O-glucuronide, did not affect in vitro TCC proliferation rates and dapagliflozin did not enhance tumor growth in nude mice heterotopically implanted with human bladder TCC cell lines.A multitude of assessments of tumorigenicity risk consistently showed no effects, suggesting that selective SGLT2 inhibition and, specifically, dapagliflozin are predicted to not be associated with increased cancer risk.