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- Transient renal dysfunction with reversible splenial lesion. [Journal Article]
- Pediatr Int 2014 Oct; 56(5):e68-71.
We report the case of a 6-month-old boy with transient renal dysfunction who had an intensified signal in the splenium of the corpus callosum on magnetic resonance imaging. He presented to hospital with fever and sudden disturbance of consciousness. Cerebrospinal fluid analysis did not show pleocytosis. The mild consciousness disturbance disappeared after 30 min, but the splenial signal persisted even after 8 days. Further, renal glucosuria, increased excretion of select amino acids, and abnormal fractional excretion of electrolytes were observed, indicating renal tubular dysfunction. The abnormal urinary findings spontaneously resolved by day 9 of hospitalization. The splenial lesion took 21 days to normalize. There were no signs of neurological complications 2 months later. This case suggests the possibility of renal involvement in splenial lesions.
- Common mutation causes cystinosis in the majority of black South African patients. [JOURNAL ARTICLE]
- Pediatr Nephrol 2014 Oct 18.
The mutations responsible for cystinosis in South African patients are currently unknown. A pertinent question is whether they are similar to those described elsewhere in the world.Children who were being managed for cystinosis in the Western Cape Province of South Africa between 2002 and 2013 were studied. All underwent molecular analysis to detect sequence variations in the cystinosis gene.This cohort study included 20 patients, 13 of whom were Xhosa-speaking black South Africans and seven were Cape Coloureds (mixed race); none were Caucasian. All had nephropathic infantile-type cystinosis with evidence of proximal tubulopathy, with glycosuria and renal phosphate wasting. Diagnosis was confirmed in 19 cases by demonstrating an elevated cystine concentration in leukocytes. Molecular analysis of the cystinosin gene revealed that 19 patients had a G > A mutation in intron 11 (CTNS-c.971-12G > A p.D324AfsX44) which caused an out-of-frame 10-bp insertion. Of these 19 patients, 16 were homozygous for this mutation, which was the most frequent mutation identified in the alleles of the black South African and Cape Coloured patients (96 and 71 %, respectively).We recommend that black South African and Cape Coloured patients presenting with cystinosis be tested for CTNS-c.971-12G > A in the first instance, with the possibility of prenatal testing being offered to at-risk families.
- Long-term assessment of glucosuria in captive okapi (Okapia johnstoni) after a dietary change. [Journal Article]
- J Zoo Wildl Med 2014 Sep; 45(3):632-4.
Glucosuria in okapis (Okapia johnstoni) was first documented in 1980, yet the etiology remains unclear. In August 2006, an attempt to lower glucosuria in captive okapi by diet modification (omitting all fruit and adding unmolassed beet pulp) was started at the Antwerp Zoo. To study the possible relationship between glucosuria and diet, stress, and/or pregnancy, four okapis were monitored over a period of 4.5 yr. One animal, born in 2006, became glucosuric near the age of three. Three okapis were adults at the start of the study and had been glucosuric for more than 5 yr. The glucose/creatinine urinary ratio values of these four glucosuric animals did not change considerably over time despite dietary changes. Stress did not appear to influence glucosuria in these okapi. Urinary ratio decreased during the second half of pregnancy in two females. In conclusion, the diet change did not reduce glucosuria, but pregnancy appeared to lower urinary glucose in okapis.
- [Executive summary of the recommendations on the evaluation and management of renal disease in human immunodeficiency virus-infected patients.] [JOURNAL ARTICLE]
- Enferm Infecc Microbiol Clin 2014 Oct 7.
The aim of this article is to update the 2010 recommendations on the evaluation and management of renal disease in human immunodeficiency virus (HIV)-infected patients. Renal function should be monitored in all HIV-infected patients. The basic renal work-up should include measurements of serum creatinine, estimated glomerular filtration rate by CKD-EPI, urine protein-to-creatinine ratio, and urinary sediment. Tubular function tests should include determination of serum phosphate levels and urine dipstick for glycosuria. In the absence of abnormal values, renal screening should be performed annually. In patients treated with tenofovir, or with risk factors for chronic kidney disease (CKD), more frequent renal screening is recommended. In order to prevent disease progression, potentially nephrotoxic antiretroviral drugs are not recommended in patients with CKD or risk factors for CKD. The document provides indications for renal biopsy and advises on the optimal time for referral of a patient to the nephrologist. The indicat6ions for and evaluation and management of dialysis and renal transplantation are also addressed.
- Low body weight and tenofovir use are risk factors for renal dysfunction in Vietnamese HIV-infected patients. A prospective 18-month observation study. [JOURNAL ARTICLE]
- J Infect Chemother 2014 Oct 6.
The use of tenofovir has been rapidly increasing in Vietnam. Several studies identified low body weight as a risk factor for tenofovir-induced nephrotoxicity. However, little is known about the impact of tenofovir on renal function in HIV-infected Vietnamese with generally low weight.An observational single-center cohort of adult HIV-infected patients on antiretroviral therapy at National Hospital of Tropical Diseases, Hanoi. Patients on tenofovir or with creatinine clearance ≤60 ml/min at baseline were excluded. The incidence of renal dysfunction was compared between patients who switched to tenofovir and those who did not. Renal dysfunction was defined as 25% decline of creatinine clearance from baseline. Time to renal dysfunction was analyzed by the Kaplan-Meier method between the two groups. The Cox hazard model was used to determine risk factors for renal dysfunction in uni- and multivariate analyses.Of 556 patients enrolled in this study, 403 were non-tenofovir group while 153 were the tenofovir-switched group. Renal dysfunction occurred at a higher rate in the tenofovir-switched group (92.5 per 1000 person-years) than the non-tenofovir group (47.8 per 1000 person-years)(p = 0.023, Log-rank test). Multivariate analysis confirmed that tenofovir use, low body weight and glucosuria were significant risk factors for renal dysfunction (hazard ratio = 1.980; 95% confidential interval, 1.094-3.582, HR = 1.057; 95%CI, 1.016-1.098, HR = 5.202; 95%CI, 1.245-21.738, respectively).Tenofovir use, low body weight and glucosuria were significant risk factors for renal dysfunction. We suggest close monitoring of renal function in patients with these risk factors even in resource-limited setting.
- Activation of Protein Kinase C-α and Src Kinase Increases Urea Transporter A1 α-2, 6 Sialylation. [JOURNAL ARTICLE]
- J Am Soc Nephrol 2014 Oct 9.
The urea transporter A1 (UT-A1) is a glycosylated protein with two glycoforms: 117 and 97 kD. In diabetes, the increased abundance of the heavily glycosylated 117-kD UT-A1 corresponds to an increase of kidney tubule urea permeability. We previously reported that diabetes not only causes an increase of UT-A1 protein abundance but also, results in UT-A1 glycan changes, including an increase of sialic acid content. Because activation of the diacylglycerol (DAG)-protein kinase C (PKC) pathway is elevated in diabetes and PKC-α regulates UT-A1 urea transport activity, we explored the role of PKC in UT-A1 glycan sialylation. We found that activation of PKC specifically promotes UT-A1 glycan sialylation in both UT-A1-MDCK cells and rat kidney inner medullary collecting duct suspensions, and inhibition of PKC activity blocks high glucose-induced UT-A1 sialylation. Overexpression of PKC-α promoted UT-A1 sialylation and membrane surface expression. Conversely, PKC-α-deficient mice had significantly less sialylated UT-A1 compared with wild-type mice. Furthermore, the effect of PKC-α-induced UT-A1 sialylation was mainly mediated by Src kinase but not Raf-1 kinase. Functionally, increased UT-A1 sialylation corresponded with enhanced urea transport activity. Thus, our results reveal a novel mechanism by which PKC regulates UT-A1 function by increasing glycan sialylation through Src kinase pathways, which may have an important role in preventing the osmotic diuresis caused by glucosuria under diabetic conditions.
- [Severe hypernatremia due to sea water ingestion in a child.] [JOURNAL ARTICLE]
- Arch Pediatr 2014 Oct 1.
Drowning in sea water is an unusual cause of severe hypernatremia. We report the case of a 3.5-year-old boy who died 11h after drowning in sea water, with a serum sodium level of 178mmoL/L. In this case, hypernatremia was aggravated by diarrhea and hyperglycemia with glycosuria. Usually, correction of acute hypernatremia must be quick and early, aiming at a reduction of serum sodium concentration of up to 1-2mmoL per liter per hour.
- Tempol, a Superoxide Dismutase Mimetic Agent, Ameliorates Cisplatin-Induced Nephrotoxicity through Alleviation of Mitochondrial Dysfunction in Mice. [Journal Article]
- PLoS One 2014; 9(10):e108889.
Mitochondrial dysfunction is a crucial mechanism by which cisplatin, a potent chemotherapeutic agent, causes nephrotoxicity where mitochondrial electron transport complexes are shifted mostly toward imbalanced reactive oxygen species versus energy production. In the present study, the protective role of tempol, a membrane-permeable superoxide dismutase mimetic agent, was evaluated on mitochondrial dysfunction and the subsequent damage induced by cisplatin nephrotoxicity in mice.Nephrotoxicity was assessed 72 h after a single i.p. injection of cisplatin (25 mg/kg) with or without oral administration of tempol (100 mg/kg/day). Serum creatinine and urea as well as glucosuria and proteinuria were evaluated. Both kidneys were isolated for estimation of oxidative stress markers, adenosine triphosphate (ATP) content and caspase-3 activity. Moreover, mitochondrial oxidative phosphorylation capacity, complexes I-IV activities and mitochondrial nitric oxide synthase (mNOS) protein expression were measured along with histological examinations of renal tubular damage and mitochondrial ultrastructural changes. Tempol was effective against cisplatin-induced elevation of serum creatinine and urea as well as glucosuria and proteinuria. Moreover, pretreatment with tempol notably inhibited cisplatin-induced oxidative stress and disruption of mitochondrial function by restoring mitochondrial oxidative phosphorylation, complexes I and III activities, mNOS protein expression and ATP content. Tempol also provided significant protection against apoptosis, tubular damage and mitochondrial ultrastructural changes. Interestingly, tempol did not interfere with the cytotoxic effect of cisplatin against the growth of solid Ehrlich carcinoma.This study highlights the potential role of tempol in inhibiting cisplatin-induced nephrotoxicity without affecting its antitumor activity via amelioration of oxidative stress and mitochondrial dysfunction.
- Exploring the Potential of the SGLT2 Inhibitor Dapagliflozin in Type 1 Diabetes: A Randomized, Double-Blind, Placebo-Controlled Pilot Study. [JOURNAL ARTICLE]
- Diabetes Care 2014 Sep 30.
Insulin adjustments to maintain glycemic control in individuals with type 1 diabetes often lead to wide glucose fluctuations, hypoglycemia, and increased body weight. Dapagliflozin, an insulin-independent sodium-glucose cotransporter 2 (SGLT2) inhibitor, increases glucosuria and reduces hyperglycemia in individuals with type 2 diabetes.A 2-week, dose-ranging, randomized, double-blind, placebo-controlled proof-of-concept study randomly assigned 70 adults with type 1 diabetes (HbA1c 7-10%), who were receiving treatment with stable doses of insulin, to one of four dapagliflozin doses (1, 2.5, 5, or 10 mg) or placebo. The insulin dose was not proactively reduced at randomization but could be adjusted for safety reasons. The primary objective was to assess short-term safety; secondary objectives included pharmacokinetic, pharmacodynamic, and efficacy parameters.Sixty-two patients (88.6%) completed the study. Any hypoglycemia was common across all treatments (60.0-92.3%); one major event of hypoglycemia occurred with dapagliflozin 10 mg. No diabetic ketoacidosis occurred. Pharmacokinetic parameters were similar to those observed in patients with type 2 diabetes. Glucosuria increased by 88 g/24 h (95% CI 55-121) with administration of dapagliflozin 10 mg and decreased by -21.5 g/24 h (95% CI -53.9 to 11.0) with administration of placebo. Changes from baseline with administration of dapagliflozin 10 mg by day 7 were as follows: -2.29 mmol/L (95% CI -3.71 to -0.87 [-41.3 mg/dL; 95% CI -66.9 to -15.7]) for 24-h daily average blood glucose levels; -3.77 mmol/L (95% CI -6.09 to -1.45 [-63.1 mg/dL; 95% CI -111.5 to -14.8]) for mean amplitude of glycemic excursion; and -16.2% (95% CI -29.4 to -0.5) for mean percentage change in total daily insulin dose. Corresponding changes with placebo were as follows: -1.13 mmol/L (95% CI -3.63 to 1.37), -0.45 mmol/L (95% CI -4.98 to 4.08), and 1.7% (95% CI -22.8 to 33.9), respectively. However, for every efficacy parameter, the 95% CIs for all dapagliflozin doses overlapped those for placebo.This exploratory study of dapagliflozin in adults with type 1 diabetes demonstrated acceptable short-term tolerability, and expected pharmacokinetic profiles and increases in urinary glucose excretion. Within the dapagliflozin groups, dose-related reductions in 24-h glucose levels, glycemic variability, and insulin dose were suggested, which provide hope that SGLT2 inhibition may prove in larger randomized controlled trials to be efficacious in reducing hyperglycemia in type 1 diabetes.
- Clinical and molecular characterization of maturity onset-diabetes of the young caused by hepatocyte nuclear factor-4 alpha mutation: red flags for prediction of the diagnosis. [Journal Article]
- Ann Saudi Med 2014 May-Jun; 34(3):217-21.
The prevalence of maturity-onset diabetes of the young (MODY) in Saudi population remains unknown, and data on molecular etiology of this condition is limited. Therefore, the present study was undertaken to elucidate clinical and molecular characteristics of a Saudi family with MODY 1.This is a case series study conducted at Saad Specialist Hospital in Alkhobar, Saudi Arabia.A 12-year-old female presented to us with symptoms suggestive of diabetes. Investigations revealed hyperglycemia, glycosuria, and ketonuria without acidosis. Pancreatic antibodies were negative. She responded well to subcutaneous insulin. Her family history revealed that 2 of her siblings were diagnosed with type 1 diabetes (T1DM), while her father and mother had type 2 diabetes (T2DM). In view of this strong family history, the possibility of monogenic diabetes was raised, and the 2 genes consistent with this phe.notype, hepatocyte nuclear factor-1 alpha (HNF1a) and hepatocyte nuclear factor-4 alpha (HNF4a), were studied. Accordingly, genomic DNA was isolated from peripheral blood lymphocytes of the 8 members of this family, polymerase chain reaction was carried out, and sequencing of the whole HNF4a and HNF1a genes was done.DNA study of the proband revealed a heterozygous substitution in intron 1 (IVS1b C > T-5)(c.50-5C > T) of the HNF1a gene. This mutation was identified in other 5 members of the family.This study alerts physicians to suspect MODY in patients who have a strongly positive family history of diabetes over a few generations with negative pancreatic antibodies and absence of ketoacidosis and obesity.