Kidney tubular injury induced by valproic acid: systematic literature review.

BACKGROUND: Valproic acid is prescribed for epilepsy and as prophylaxis for bipolar disorder and migraine headaches. It has also been implicated as a cause of a kidney tubular injury. METHODS: We undertook a review of the literature to characterize the biochemical and histopathological features of the overt kidney tubular injury and to evaluate the possible existence of a pauci-symptomatic injury. The pre-registered review (CRD42022360357) was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology. Searches were conducted in Excerpta Medica, the National Library of Medicine, and Web of Science. The gray literature was also considered. RESULTS: For the final analysis, we retained 36 articles: 28 case reports documented 48 individuals with epilepsy on valproic acid for 7 months or more and presenting with features consistent with an overt kidney tubular injury. The following disturbances were noted: hypophosphatemia (N = 46), normoglycemic glycosuria (N = 46), total proteinuria (N = 45), metabolic acidosis (N = 36), hypouricemia (N = 27), tubular proteinuria (N = 27), hypokalemia (N = 23), and hypocalcemia (N = 8). A biopsy, obtained in six cases, disclosed altered proximal tubular cells with giant and dysmorphic mitochondria. Eight case series addressed the existence of a pauci- or even asymptomatic kidney injury. In the reported 285 subjects on valproic acid for 7 months or more, an isolated tubular proteinuria, mostly N-acetyl-ß-glucosaminidase, was often noted. CONCLUSIONS: Valproic acid may induce an overt kidney tubular injury, which is associated with a proximal tubular mitochondrial toxicity. Treatment for 7 months or more is often associated with a pauci- or oligosymptomatic kidney tubular injury. A higher resolution version of the Graphical abstract is available as Supplementary information.

Seasonal variability of the vitamin D effect on physical fitness in adolescents.

Studies investigating the relationship between vitamin D and physical fitness in youth have provided inconsistent findings. Recent evidence indicates that the expression of receptors and vitamin D-modulated genes in young subjects has a seasonal profile. Therefore, we investigated the role of vitamin D on physical fitness across seasons in a total of 977 male adolescents. Anthropometrics, lifestyle, dietary habits, biochemical profiles and physical fitness were studied. Multiple linear regression models, including pairwise interaction terms involving total 25-OH-vitamin D, were fitted. The interacting effect of season and total 25-OH-vitamin D had a significant influence on physical fitness performance (spring and total 25-OH-vitamin D: ß 0.19, SE 0.07, p = 0.007; summer and total 25-OH-vitamin D: ß 0.10, SE 0.06, p = 0.11; autumn and total 25-OH-vitamin D: ß 0.18, SE 0.07, p = 0.01), whereas the main effect of total 25-OH-vitamin D alone was not significant (p = 0.30). Body fat percentage, recreational physical activity level, time spent per day gaming/TV-watching, smoking, and hemoglobin levels were also related to the physical fitness performance score. Future studies should further explore the role of seasonal-dependent effects of vitamin D on health.

Trimethoprim-associated electrolyte and acid-base abnormalities.

INTRODUCTION: The antimicrobial trimethoprim is structurally related to potassium-sparing diuretics and may consequently lead to derangements in electrolyte and acid-base balance. Since no report so far analyzed the literature documenting individual cases with electrolyte and acid-base derangements induced by trimethoprim, a systematic review was carried out. EVIDENCE ACQUISITION: We retained 53 reports documenting 68 cases (42 males and 26 females 23 to 96 years of age) of electrolyte or acid-base derangements occurring on trimethoprim for about 5 days. EVIDENCE SYNTHESIS: One hundred five electrolyte imbalances were detected in the 68 patients: hyperkalemia (>5.0 mmol/L) in 62 (91%), hyponatremia (<135 mmol/L) in 29 (43%) and metabolic acidosis (pH<7.38 and bicarbonate <19 mmol/L) in 14 (21%) cases. Following possible predisposing factors for electrolyte and acid-base abnormalities were found in 54 (79%) patients: high-dose trimethoprim, comedication with drugs that have been associated with electrolyte and acid-base derangements, preexisting kidney disease, age ≥80 years and diabetes mellitus. CONCLUSIONS: High-dose trimethoprim, comedicated with drugs that have been associated with electrolyte and acid-base derangements, poor kidney function, age ≥80 years and diabetes mellitus predispose to trimethoprim-associated electrolyte and acid-base abnormalities. Clinicians must recognize patients at risk, possibly avoid drug combinations that may worsen the problem and monitor the laboratory values.

Dietary Chloride Deficiency Syndrome: Pathophysiology, History, and Systematic Literature Review.

Metabolic alkalosis may develop as a consequence of urinary chloride (and sodium) wasting, excessive loss of salt in the sweat, or intestinal chloride wasting, among other causes. There is also a likely underrecognized association between poor salt intake and the mentioned electrolyte and acid-base abnormality. In patients with excessive loss of salt in the sweat or poor salt intake, the maintenance of metabolic alkalosis is crucially modulated by the chloride-bicarbonate exchanger pendrin located on the renal tubular membrane of type B intercalated cells. In the late 1970s, recommendations were made to decrease the salt content of foods as part of an effort to minimize the tendency towards systemic hypertension. Hence, the baby food industry decided to remove added salt from formula milk. Some weeks later, approximately 200 infants (fed exclusively with formula milks with a chloride content of only 2-4 mmol/L), were admitted with failure to thrive, constipation, food refusal, muscular weakness, and delayed psychomotor development. The laboratory work-up disclosed metabolic alkalosis, hypokalemia, hypochloremia, and a reduced urinary chloride excretion. In all cases, both the clinical and the laboratory features remitted in ≤7 days when the infants were fed on formula milk with a normal chloride content. Since 1982, 13 further publications reported additional cases of dietary chloride depletion. It is therefore concluded that the dietary intake of chloride, which was previously considered a "mendicant" ion, plays a crucial role in acid-base and salt balance.

Prescription of vitamin D among Swiss pediatricians.

The traditional recommendation that Swiss children receive vitamin D during the first year of life was recently extended to the second and third year of life and during winter for older children. The aim of the study was to identify how Swiss pediatricians prescribe vitamin D. Between December 2016 and March 2017, 795 (52%) of 1530 invited Swiss board-certified pediatricians answered a closed-ended questionnaire. Respondents routinely prescribe vitamin D supplements in infants ≤ 1 year of age, but infrequently in children ≥ 3 years of age. Only a minority of them prescribe vitamin D in children with conditions that predispose to poor vitamin D status. Oily vitamin D preparations are the most popular and are usually prescribed in a once-a-day regimen. In situations like intake of drugs interfering with vitamin D metabolism, intestinal malabsorption, and diabetes mellitus, Swiss pediatricians often seek the advice of a subspecialist. In cases with clinical suspicion of poor vitamin D status, the diagnosis is confirmed by the determination of 25-hydroxyvitamin D.Conclusion: Few pediatricians prescribe a vitamin D supplementation in children ≥ 3 years of age. Collaboration between policymakers and health care professionals is required to fill the gap between guidelines and clinical practice. What is Known: • In Switzerland, vitamin D supplementation is recommended during the first, second, and third year of life as well as during winter for older children. • Both alcoholic and oily preparations are currently available. What is New: • Swiss pediatricians routinely prescribe vitamin D in infants ≤ 1 year of age, but infrequently in children ≥ 3 years of age. • Oily vitamin D preparations are the most popular and are usually prescribed in a once-a-day regimen.

Magnesium in cystic fibrosis--Systematic review of the literature.

BACKGROUND: The metabolism of sodium, potassium, and chloride and the acid-base balance are sometimes altered in cystic fibrosis. Textbooks and reviews only marginally address the homeostasis of magnesium in cystic fibrosis. METHODS: We performed a search of the Medical Subject Headings terms (cystic fibrosis OR mucoviscidosis) AND (magnesium OR hypomagnes[a]emia) in the US National Library of Medicine and Excerpta Medica databases. RESULTS: We identified 25 reports dealing with magnesium and cystic fibrosis. The results of the review may be summarized as follows. First, hypomagnesemia affects more than half of the cystic fibrosis patients with advanced disease; second, magnesemia, which is normally age-independent, relevantly decreases with age in cystic fibrosis; third, aminoglycoside antimicrobials frequently induce both acute and chronic renal magnesium-wasting; fourth, sweat magnesium concentration was normal in cystic fibrosis patients; fifth, limited data suggest the existence of an impaired intestinal magnesium balance. Finally, stimulating observations suggest that magnesium supplements might achieve an improvement in respiratory muscle strength and mucolytic activity of both recombinant and endogenous deoxyribonuclease. CONCLUSIONS: The first comprehensive review of the literature confirms that, despite being one of the most prevalent minerals in the body, the importance of magnesium in cystic fibrosis is largely overlooked. In these patients, hypomagnesemia should be sought once a year. Furthermore, the potential of supplementation with this cation deserves more attention.

Symptomatic management of fever by Swiss board-certified pediatricians: results from a cross-sectional, Web-based survey.

BACKGROUND: Symptomatic management is often all that is recommended in children with fever. To date, only 2 nationwide surveys of pediatricians regarding their attitudes toward fever have been published. OBJECTIVE: The aim of this study was to describe the management of children with fever by pediatricians in Switzerland. METHODS: For this survey, an initial close-ended questionnaire was tested and subsequently corrected. Between June 2010 and March 2011, an invitation was sent via electronic mail containing a link to the final version of the questionnaire. The survey was not commercially sponsored. RESULTS: The questionnaire was sent to 900 pediatricians, of whom 322 (36%) responded. A total of 96% of respondents identified ≥38.5°C as the rectal temperature threshold for fever treatment, and 64% indicated that they prescribe antipyretics for the treatment of general discomfort. A total of 95% of respondents indicated that they prescribe paracetamol (acetaminophen) as the first choice of antipyretic drug, and 91% indicated that they often prescribe ibuprofen as well. An alternating regimen of 2 drugs and physical antipyresis were indicated as common practice by 77% and 65% of pediatricians, respectively. Homeopathic remedies are rarely prescribed (<10% of respondents). The most commonly prescribed routes of administration in children aged 18 months, 5 years, and 10 years were rectal (78%), oral (87%), and oral (99%), respectively. Ninety-two percent of respondents indicated that they believe that an exaggerated fear of fever is common among parents, but 81% stated that they do not lower the temperature threshold for initiating pharmacologic treatment exclusively to calm parents. Most respondents (95%) indicated a belief that it is possible to educate families about the fear of fever. CONCLUSIONS: Based on the findings from the present survey, antipyretics are often prescribed to treat the general discomfort that accompanies fever. Nonetheless, a gap exists between available evidence and clinical practice. Guidelines should take this fact into account.

Demographics of blood pressure and hypertension in children on renal replacement therapy in Europe.

Hypertension is a well-known complication in children on renal replacement therapy and an important risk factor for cardiovascular disease in later life. In order to define the prevalence of and risk factors for hypertension among children, we enrolled 3337 pediatric patients from 15 countries in the ESPN/ERA-EDTA Registry of whom 464 were on hemodialysis, 851 on peritoneal dialysis, and 2023 had received a renal allograft. Hypertension was defined as either systolic or diastolic blood pressures in the 95th percentile or greater for age, height, and gender or use of antihypertensive medication. Analyses were adjusted for age, gender, duration, and modality of renal replacement therapy. In 10 countries in which information on the use of antihypertensive medication was available, hypertension was present in over two-thirds of hemodialysis, peritoneal dialysis, or transplant patients. Blood pressure values above the 95th percentile were significantly more prevalent in very young patients (under 3 years) compared to 13- to 17-year olds (odds ratio 2.47), during the first year compared to over 5 years of renal replacement therapy (odds ratio 1.80), and in patients on hemodialysis compared to transplant recipients or those on peritoneal dialysis (odds ratios of 2.48 and 1.59, respectively). Over time, mean blood pressures decreased in both hemodialysis and transplant patients, but not in peritoneal dialysis patients. Hence, our findings highlight the extent of the problem of hypertension in children with end-stage renal disease in Europe.

Preference for formulations containing calcium and vitamin D(3) in childhood: a randomized-sequence, open-label trial.

BACKGROUND: Children who experience adverse reactions to cow's milk or who have diseases predisposing them to low bone mass are often prescribed a supplementation of calcium and vitamin D(3), but adherence can be poor. Age-specific preferences for different formulations may exist and at least partially explain poor compliance. OBJECTIVE: The aim of this study was to compare the preference of Swiss children at risk for low bone mass for either a single-serving sachet or a suspension containing calcium and vitamin D(3). METHODS: Two different commercial formulations containing calcium and vitamin D(3), either as a lemon-flavored single-serving sachet or as a banana-flavored commercial suspension, were tested for preference by means of a 5-point facial hedonic scale in children aged 4 to 7 and 8 to 11 years. A concealed random allocation procedure was used. The investigator asking about preference was blinded to the sequence. RESULTS: A total of 40 Swiss children (13 boys and 7 girls aged 4-7 years; 11 boys and 9 girls aged 811 years) were assessed in this study. Low bone mass risks included adverse reactions to cow's milk (n = 25); cerebral palsy (4), juvenile idiopathic arthritis (4), cystic fibrosis (3), inflammatory bowel diseases (2), anorexia nervosa (1), and osteogenesis imperfecta (1). Two children (10%) aged 4 to 7 years were not able to express their preference. Twelve of the remaining 18 children (67%) aged 4 to 7 years preferred the suspension, 5 (28%) did not express a clear preference, and 1 (5%) preferred the sachet (P < 0.002). In children aged 8 to 11 years, 15 (75%) preferred the sachet, 4 (20%) did not express a clear preference, and 1 (5%) preferred the suspension (P < 0.001). The results were not significantly different between boys and girls or between children initially presented the suspension and those initially presented the sachet. CONCLUSIONS: In this small study, significantly more Swiss children aged 4 to 7 years who were prescribed a supplementation of calcium and vitamin D(3) preferred a banana-flavored suspension compared with those who preferred a lemon-flavored single-serving sachet. However, significantly more children aged 8 to 11 years prescribed the same supplementation preferred the single-serving sachet compared with the suspension.