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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-[beta]-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. Graphical abstract, Author(s): Giulia Anguissola [sup.1] , Dennis Leu [sup.2] , Giacomo D. Simonetti [sup.1] [sup.2] , Barbara Goeggel Simonetti [sup.1] [sup.2] [sup.3] , Sebastiano A. G. Lava [sup.4] [sup.5] , Gregorio [...]

Abstract There is a high frequency of diarrhea and vomiting in childhood. As a consequence the focus of the present review is to recognize the different body fluid compartments, to clinically assess the degree of dehydration, to know how the equilibrium between extracellular fluid and intracellular fluid is maintained, to calculate the effective blood osmolality and discuss both parenteral fluid maintenance and replacement.

Abstract There is a high frequency of diarrhea and vomiting in childhood. As a consequence the focus of the present review is to recognize the different body fluid compartments, to clinically assess the degree of dehydration, to know how the equilibrium between extracellular fluid and intracellular fluid is maintained, to calculate the effective blood osmolality and discuss both parenteral fluid requirments and repair.

Background Kidney diseases are a recognized cause of posterior reversible leukoencephalopathy syndrome, usually abbreviated as PRES. The purpose of this review was to systematically address the association between acute postinfectious glomerulonephritis and PRES. Methods We performed a systematic review of the literature on acute postinfectious glomerulonephritis associated with PRES. The principles recommended by the Economic and Social Research Council guidance on the conduct of narrative synthesis and on the Preferred Reporting Items for Systematic Reviews and Meta-analyses were used. Databases searched included Excerpta Medica, US National Library of Medicine, and Web of Science. Results For the final analysis, we evaluated 47 reports describing 52 cases (32 males and 20 females). Fifty patients were [less than or equal to] 18 years of age. Blood pressure was classified as follows: normal-elevated (n = 3), stage 1 hypertension (n = 3), stage 2 hypertension (n = 5), and severe hypertension (n = 41). Acute kidney injury was classified as stage 1 in 32, stage 2 in 16, and stage 3 in four cases. Neuroimaging studies disclosed a classic posterior PRES pattern in 28 cases, a diffuse PRES pattern in 23 cases, and a brainstem-cerebellum PRES pattern in the remaining case. Antihypertensive drugs were prescribed in all cases and antiepileptic drugs in cases presenting with seizures. A resolution of clinical findings and neuroimaging lesions was documented in all cases with information about follow-up. Conclusions The main factor associated with PRES in acute postinfectious glomerulonephritis is severe hypertension. Prompt clinical suspicion, rapid evaluation, and management of hypertension are crucial. Graphical abstract A higher resolution version of the Graphical abstract is available as Supplementary information, Author(s): Corinne Orlando [sup.1] , Gregorio P. Milani [sup.2] [sup.3] , Giacomo D. Simonetti [sup.4] [sup.5] , Barbara Goeggel Simonetti [sup.4] [sup.5] [sup.6] , Sebastiano A. G. Lava [sup.7] , [...]

Background The kidney is central for maintaining water balance. As a corollary, patients with impaired kidney function are prone to pathological fluid volumes. Total body water (TBW) is distributed between the extracellular (ECW) and intracellular fluid compartments (ICW). In clinical practice, the judgment of hydration status does not allow to distinguish between ECW and ICW. Here, we evaluate the hydration status in children with chronic kidney disease by analyzing TBW, ECW, and ICW. Methods Hydration was quantified using whole-body bioimpedance spectroscopy (BCM) in 128 outpatients (1-25 years, 52 girls). Forty-two were transplanted (TPL), 43 suffered from chronic kidney disease without kidney replacement therapy (CKD), 21 were on peritoneal dialysis (PD), and 22 on hemodialysis (HD). HD patients were investigated before, after, and sequentially during dialysis. Results The ECW and ICW values obtained by BCM were of the same magnitude as those from the literature using isotope dilution. When compared with a healthy control group, TBW was increased in 9 TPL, 9 CKD, 1 PD, and 11 HD patients before but in none after dialysis. The decline of overhydration during dialysis (p < 0.001, n = 22) correlated with the change in body weight (R.sup.2 = 0.62). The kinetics of fluid compartment changes assessed twice in six HD patients revealed a reproducible linear decay of the ECW/ICW ratio due to an increase of ICW and a decrease of ECW. Conclusion BCM quantifies TBW and acute changes of ECW and ICW in children with chronic kidney failure. The clinical utility of measuring TBW, ECW, and ICW should be defined in the future., Author(s): Sandra M. Frey [sup.1] [sup.2] , Bruno Vogt [sup.1] , Giacomo D. Simonetti [sup.3] , Rainer Büscher [sup.4] , Sandra Habbig [sup.5] , Franz Schaefer [sup.6] Author Affiliations: (1) [...]

Over the last several decades, many seminal longitudinal cohort studies have clearly shown that the antecedents to adult disease have their origins in childhood. Hypertension (HTN), which has become increasingly prevalent in childhood, represents one of the most important risk factors for cardiovascular diseases (CVD) such as heart disease and stroke. With the risk of adult HTN much greater when HTN is manifest in childhood, the future burden of CVD worldwide is therefore concerning. In an effort to slow the current trajectory, professional societies have called for more rigorous, evidence-based guideline development to aid primary care providers and subspecialists in improving recognition, diagnosis, evaluation, and treatment of pediatric HTN. In 2016 the European Society of Hypertension and in 2017 the American Academy of Pediatrics published updated guidelines for prevention and management of high blood pressure (BP) in children. While there are many similarities between the two guidelines, important differences exist. These differences, along with the identified knowledge gaps in each, will hopefully spur clinical researchers to action. This review highlights some of these similarities and differences, focusing on several of the more important facets regarding prevalence, prevention, diagnosis, management, and treatment of childhood HTN., Author(s): Tammy M. Brady [sup.1] , Amalia Stefani-Glücksberg [sup.2] , Giacomo D. Simonetti [sup.2] [sup.3] Author Affiliations: (Aff1) 0000 0001 2171 9311, grid.21107.35, Division of Pediatric Nephrology, Johns Hopkins University, [...]

Background D-lactic acidosis is an uncommon and challenging form of metabolic acidosis that may develop in short bowel syndrome. It has been documented exclusively in case reports and small case series. Methods We performed a review of the literature in the National Library of Medicine and Excerpta Medica databases. Results We identified 84 original reports published between 1977 and 2017. D- lactic acidosis was observed in 98 individuals ranging in age from 7 months to 86 years with short bowel syndrome. The clinical presentation included Kussmaul breathing, confusion, slurred speech, and gait disturbances. Furthermore, among 99 consecutive patients with short bowel syndrome, 21 reported having episodes with symptoms consistent with D-lactic acidosis. In addition, D-lactic acid might also contribute to acidosis in diabetes mellitus. Finally, abnormally high D-lactic acid was documented after administration or ingestion of large amounts of propylene glycol, as paraneoplastic phenomenon and perhaps also in a so far poorly characterized inherited inborn error of metabolism. Conclusions In humans with short bowel syndrome (or carbohydrate malabsorption), D-lactic acidosis is likely rather common and under-recognized. This condition should be included in the differential diagnosis of unexplained high-gap metabolic acidosis where the anion causing the acidosis is not known. Furthermore, diabetic acidosis might be caused by accumulation of both ketone bodies and Dlactic acid. Finally, there are endogenous sources of D-lactic acid in subjects with propylene glycol intoxication. Keywords Carbohydrate malabsorption. Diabetes mellitus. Propylene glycol. Short bowel syndrome, Introduction Humans normally produce 20-25 mmol/kg body weight per day of lactic acid [1, 2]. Lactic acid exists as anionic lactate and as unionized lactic acid, and throughout this report [...]

Background Hyperammonemia usually results from an inborn error of metabolism or from an advanced liver disease. Individual case reports suggest that both distal renal tubular acidosis and urinary tract infection may also result in hyperammonemia. Methods A systematic review of the literature on hyperammonemia secondary to distal renal tubular acidosis and urinary tract infection was conducted. Results We identified 39 reports on distal renal tubular acidosis or urinary tract infections in association with hyperammonemia published between 1980 and 2017. Hyperammonemia was detected in 13 children with distal renal tubular acidosis and in one adult patient with distal renal tubular acidosis secondary to primary hyperparathyroidism. In these patients a negative relationship was observed between circulating ammonia and bicarbonate levels (P < 0.05). In 31 patients (19 children, 12 adults), an acute urinary tract infection was complicated by acute hyperammonemia and symptoms and signs of acute neuronal dysfunction, such as an altered level of consciousness, convulsions and asterixis, often associated with signs of brain edema, such as anorexia and vomiting. Urea-splitting bacteria were isolated in 28 of the 31 cases. The urinary tract was anatomically or functionally abnormal in 30 of these patients. Conclusions This study reveals that both altered distal renal tubular acidification and urinary tract infection may be associated with relevant hyperammonemia in both children and adults., Author(s): Caterina M. Clericetti [sup.1] [sup.2] , Gregorio P. Milani [sup.2] [sup.3] , Sebastiano A. G. Lava [sup.4] , Mario G. Bianchetti [sup.1] [sup.5] , Giacomo D. Simonetti [sup.1] [sup.5] [...]

Guidelines on the diagnosis and management of urinary tract infections in childhood do not address the issue of abnormalities in Na.sup.+, K.sup.+, Cl.sup.- and acid-base balance. We have conducted a narrative review of the literature with the aim to describe the underlying mechanisms of these abnormalities and to suggest therapeutic maneuvers. Abnormalities in Na.sup.+, K.sup.+, Cl.sup.- and acid-base balance are common in newborns and infants and uncommon in children of more than 3 years of age. Such abnormalities may result from factitious laboratory results, from signs and symptoms (such as excessive sweating, poor fluid intake, vomiting and passage of loose stools) of the infection itself, from a renal dysfunction, from improper parenteral fluid management or from the prescribed antimicrobials. In addition, two transient renal tubular dysfunctions may occur in infants with infectious renal parenchymal involvement: a reduced capacity to concentrate urine and pseudohypoaldosteronism secondary to renal tubular unresponsiveness to aldosterone that presents with hyponatremia, hyperkalemia and acidosis. In addition to antimicrobials, volume resuscitation with an isotonic solution is required in these children. In secondary pseudohypoaldosteronism, isotonic solutions (such as 0.9 % saline or lactated Ringer) correct not only the volume depletion but also the hyperkalemia and acidosis. In conclusion, our review suggests that in infants with infectious renal parenchymal involvement, non-renal and renal causes concur to cause fluid volume depletion and abnormalities in electrolyte and acid-base balance, most frequently hyponatremia., Author(s): Anna Bertini[sup.1] , Gregorio P. Milani[sup.2] , Giacomo D. Simonetti[sup.1] [sup.3] , Emilio F. Fossali[sup.2] , Pietro B. Fare[sup.4] , Mario G. Bianchetti[sup.1] , Sebastiano A. G. Lava[sup.1] [sup.3] [...]

Sodium is the most abundant extracellular cation and therefore pivotal in determining fluid balance. At the beginning of life, a positive sodium balance is needed to grow. Newborns and preterm infants tend to lose sodium via their kidneys and therefore need adequate sodium intake. Among older children and adults, however, excessive salt intake leads to volume expansion and arterial hypertension. Children who are overweight, born preterm, or small for gestational age and African American children are at increased risk of developing high blood pressure due to a high salt intake because they are more likely to be salt sensitive. In the developed world, salt intake is generally above the recommended intake also among children. Although a positive sodium balance is needed for growth during the first year of life, in older children, a sodium-poor diet seems to have the same cardiovascular protective effects as among adults. This is relevant, since: (1) a blood pressure tracking phenomenon was recognized; (2) the development of taste preferences is important during childhood; and (3) salt intake is often associated with the consumption of sugar-sweetened beverages (predisposing children to weight gain)., Author(s): Sebastiano A. G. Lava[sup.1] [sup.2] [sup.3] , Mario G. Bianchetti[sup.3] , Giacomo D. Simonetti[sup.1] [sup.2] [sup.3] [sup.4] Author Affiliations: (1) Division of Pediatric Nephrology, University Children's Hospital Bern, Bern, [...]

Background Cystic fibrosis per se can sometimes lead to hyponatremia, hypokalemia, hypochloremia or hyperbicarbonatemia. This tendency was first documented 60 years ago and has subsequently been confirmed in single case reports or small case series, most of which were retrospective. However, this issue has not been addressed analytically. We have therefore systematically reviewed and analyzed the available literature on this subject. Methods This was a systematic review of the literature. Results The reports included in this review cover 172 subacute and 90 chronic cases of electrolyte imbalances in patients with cystic fibrosis. The male:female ratio was 1.57. Electrolyte abnormalities were mostly associated with clinically inapparent fluid volume depletion, mainly affected patients aged ≤ 2.5 years, frequently tended to recur and often were found before the diagnosis of cystic fibrosis was established. Subacute presentation often included an history of heat exposure, vomiting, excessive sweating and pulmonary infection. History of chronic presentation, in contrast, was often inconspicuous. The tendency to hypochloremia, hypokalemia and metabolic alkalosis was similar between subacute and chronic patients, with hyponatremia being more pronounced (P < 0.02) in subacute compared to chronic presentations. Subacute cases were treated parenterally; chronic ones were usually managed with oral salt supplementation. Retention of urea and creatinine was documented in 38% of subacute cases. Conclusions The findings of our review suggest that physicians should be aware that electrolyte abnormalities can occur both as a presenting and a recurring feature of cystic fibrosis. Keywords Cystic fibrosis * Hypokalemia * Hyponatremia * Metabolic alkalosis, Introduction Hyponatremia, hypokalemia, hypochloremia or hyperbicarbonatemia are conditions that can be found in cystic fibrosis patients on drug treatment [1, 2]. Hyponatremia and hypokalemia can also be found in cystic [...]

Background Little information is available on ureteral or vesical involvement in Henoch-Schonlein syndrome. To determine the features of this condition we performed a formal analysis of peer-reviewed scientific literature on this topic. Methods The US National Library of Medicine database was used as the data source. All articles published as full-length articles or letters were collected. Reports published in languages other than English, French, German, Italian or Spanish were not considered. Results We analyzed 32 reports describing 35 cases (24 male and 11 female subjects aged between 3.5 and 63, median 7.0 years) with ureteral (n = 30), vesical (n = 4), or both ureteral and vesical involvement (n = 1). The presentation included colicky abdominal pain, macroscopic hematuria (sometimes containing blood clots), urinary tract infection or urinary retention. The diagnosis of ureteral involvement was often fortuitous. Patients with vesical involvement were managed conservatively. However, the majority of those with ureteral involvement were managed surgically. Conclusions Ureteral or vesical involvement is unusual and likely underappreciated in Henoch-Schonlein syndrome. Improved recognition and wider appreciation of this involvement can help to avoid associated morbidity. Management must be individualized for each patient. A multidisciplinary approach may be of value in planning medical treatment, surgical intervention, and follow-up. Keywords Anaphylactoid purpura * Henoch-Schonlein purpura * Systematic review * Ureteritis, Introduction Henoch-Schonlein syndrome is the most common form of childhood vasculitis with an estimated overall annual incidence of 10-20 cases per 100,000 children under 17 years of age [1]. Palpable [...]

Aims: The aim of this study was to systematically review the use of vaptans (nonpeptide vasopressin receptor antagonists) in children. Methods: Through a database search (Web of Science, the National Library of Medicine, Excerpta Medica), we identified case series and case reports and extracted clinical and laboratory data. Results: Twenty‐six articles, published since 2008, reported on 226 patients. Among 115 children with hyponatraemic (n = 63) and oedematous disorders (n = 52), a 48 hour course of tolvaptan with an initial dose of 0.38 ± 0.27 mg/kg was administered in 106 cases, while intravenous conivaptan was reported in nine cases. An increase (P <.02) in urine output was shown in both oedematous (from 3.2 ± 2.0 to 5.3 ± 6.7 mL/kg/day) and hyponatraemic (from 3.0 ± 1.5 to 4.4 ± 2.3 mL/kg/day) patients. In these latter, sodium increased from 125 ± 6 to 133 ± 6 mmol/L (P <.0001). The increase in sodium level correlated with its basal value, but not with the administered vaptan dose. Among 111 children undergoing cardiac surgery, after tolvaptan 0.21 ± 0.01 mg/kg/day, mostly combined with conventional diuretics, an increase in diuresis by 41 ± 4% was seen within 24 hours (P <.0001). Similarly, a single add‐on dose of tolvaptan 0.45 mg/kg allowed a reduced additional intravenous furosemide administration (0.26 ± 0.23 vs 0.62 ± 0.48 mg/kg, P <.005). Side effects were rarely reported, and included excessive thirst and xerostomia in seven, skin rash in one and elevated aminotransferases in one patient(s). Conclusion: Vaptans appear to be safe for oedematous and hyponatraemic disorders also in children. Although they increase diuresis and natraemia, no superiority to traditional diuretics and sodium supplements has been demonstrated. Reported side effects are rare and non‐serious. [ABSTRACT FROM AUTHOR]