Assessment of Causality in Hospitalized Children With AminoglycosideRelated Nephrotoxicity

Objectives: To evaluate the incidence of aminoglycoside-related nephrotoxicity and ascertain drug causality and its risk factors. Methods: This prospective study was conducted from January, 2019 to January, 2021, and recruited 110 consecutively admitted children aged 1 month to 12 years, receiving aminoglycosides for ?4 days. Drug causality was assessed using Liverpool adverse drug reaction causality assessment tool. Results: 42 (38.2%) children developed acute kidney injury (AKI), with 71 (64.5%) having composite nephrotoxicity (AKI and/or tubular-dysfunction). Only 17 (15.5%) had AKI definitively attributable to aminoglycosides. Hypotension [OR 0.016 (95% CI 0.01-0.71), P=0.03], PRISM-III score 20-29% [OR 55.48 (95% CI 3.66-840.53), P=0.004] and post-surgery patients [OR 3.2 (95% CI 1.01-10.1), P=0.047] were independent predictors of AKI. Conclusions: Only a small proportion of children receiving aminoglycosides had AKI definitively attributable to the drug.

Una nueva mutación de la enfermedad de Dent en un niño de 11 años con nefrolitiasis y nefrocalcinosis / A novel mutation of Dent's disease in an 11-year-old male with nephrolithiasis and nephrocalcinosis

La enfermedad de Dent es una tubulopatía recesiva ligada al cromosoma X caracterizada por proteinuria de bajo peso molecular (bpm), hipercalciuria, nefrocalcinosis o nefrolitiasis, disfunción tubular proximal e insuficiencia renal en la adultez. Las mujeres son portadoras y, en general, padecen una forma leve de la enfermedad. La progresión hacia la insuficiencia renal en estadio terminal se da entre los 30 y los 50 años de edad en el 30-80% de los varones afectados. A falta de un tratamiento dirigido al defecto molecular, en la actualidad, los pacientes con enfermedad de Dent reciben tratamientos complementarios orientados a prevenir la nefrolitiasis y la nefrocalcinosis. El caso que presentamos es el de un niño de 11 años con nefrocalcinosis y nefrolitiasis, en quien se detectó una nueva mutación en el gen CLCN5.

Dent's disease is a rare X-linked recessive tubulopathy characterized by low molecular weight (LMW) proteinuria, hypercalciuria, nephrolcalcinosis or nephrolithiasis, proximal tubular dysfunction and renal failure in adulthood. Females are carriers and usually mildly affected. Progression to endstage renal failure are at the 3rd-5th decades of life in 30-80% of affected males. In the absence of therapy targeting for the molecular defect, the current care of patients with Dent's disease is supportive, focusing on the prevention of nephrolithiasis and nephrocalcinosis. We present an 11-year-old child with nephrocalcinosis and nephrolithiasis caused by a new mutation at CLCN5 gene.

Tenofovir-induced renal tubular dysfunction among human immunodeficiency virus patients on antiretroviral therapy in Nigeria: Prospects for early detection of presymptomatic nephrotoxicity

BACKGROUND: Tenofovir disoproxil fumarate (TDF) is relatively safe, although renal toxicity has been reported. In Nigeria, there is insufficient data on renal toxicity among patients on TDF. This study assesses TDF-associated tubular dysfunction among human immunodeficiency virus (HIV) patients at a hospital in Nigeria. METHODS: In this cohort study, 104 adult HIV patients were recruited with a simple random technique from the outpatient clinic. Biochemical indices of renal function were estimated from serum and urine at the 16th and 24th week after an initial assessment at baseline. RESULTS: There were no significant differences in baseline proteinuria or glycosuria between TDF and non-TDF groups. Mean baseline urine and serum parameters did not differ significantly between the two groups (P > 0.05). In the TDF group, all urine parameters differed significantly between baseline and 24th week values (P < 0.001). After 16 weeks, mean urine phosphate and urine uric acid increased significantly (P < 0.05) by 2.97 mg/dL and 50.9 mg/dL, respectively, in the TDF group. The rise in mean urine glucose from baseline to the 24th week was more marked in the TDF than the non-TDF group (0.25 vs. 0.07 mmol/L). Higher mean differences in urine albumin were also recorded in the TDF group from baseline to the 24th week. CONCLUSION: Indicators of tubular dysfunction were markedly higher among patients on the TDF-based treatment regimen. Biomarkers of tubular dysfunction could be useful for detecting pre-symptomatic nephrotoxicity before marked reduction of glomerular filtration rate in HIV patients on TDF.

Síndrome de artrogriposis, disfunción tubular renal y colestasis: causa de colestasis neonatal. A propósito de un caso / Arthrogryposis-renal tubular dysfunction-cholestasis syndrome: a cause of neonatal cholestasis. Case report

El síndrome de artrogriposis, disfunción tubular renal y colestasis es un trastorno fatal infrecuente que compromete múltiples aparatos y sistemas de órganos. Es un trastorno autosómico recesivo hereditario, causado por defectos en los genes VPS33B y VIPAR. Los tres signos primordiales de este síndrome son la artrogriposis, la disfunción tubular renal y la colestasis. Otros compromisos orgánicos a veces asociados con este síndrome son ictiosis, malformación del sistema nervioso central, anomalías trombocíticas, defectos cardíacos congénitos y grave retraso del crecimiento. Las manifestaciones clínicas, la biopsia de un órgano y los análisis de mutaciones pueden ayudar con el diagnóstico, pero no existe un tratamiento curativo; solamente puede instaurarse un tratamiento sintomático. Varios síntomas de esta afección usualmente se manifiestan en el período neonatal: artrogriposis, colestasis neonatal, lesiones cutáneas, entre otros. En general, la supervivencia se prolonga hasta el primer año de vida. Presentamos el caso de una recién nacida con una rápida evolución y desenlace fatal.

Arthrogryposis-renal dysfunction-cholestasis syndrome is a rare lethal disorder that involves multipl organ system. It is inherited autosomal recessive and caused by defects in the VPS33B and VIPAR genes. Three cardinal findings of this syndrome are arthrogryposis, renal tubular dysfunction and cholestasis.The other organ involvements including ichthyosis, central nervous system malformation, platelet anomalies, congenital heart defects and severe failure to thrive are sometimes associated with this syndrome. Clinical findings, organ biopsy and mutational analysis can help for diagnosing but there is no curative treatment except supportive care. Several symptoms of this condition are already usually present in the neonatal period: arthrogryposis, neonatal cholestasis, skin lesions, among others. Usually survival is until the first year of life. We present a newborn whose evolution was rapidly fatal.

Evaluation of urinary N-acetyl-beta-D-glucosaminidase as a marker of early renal damage in patients with type 2 diabetes mellitus / Avaliação da N-acetil-beta-D-glucosaminidase urinária como marcador de dano renal precoce em pacientes com diabetes melito tipo 2

Objective To evaluate the clinical usefulness of urinary N-acetyl-beta-D-glucosaminidase (NAG) excretion for the detection of early tubular damage in type 2 diabetes mellitus (T2DM). Subjects and methods Thirty six patients with T2DM were divided into two groups based on urinary albumin to creatinine ratio (ACR): normoalbuminuria (ACR <30 mg/g; n=19) and microalbuminuria (ACR =30‐300 mg/g; n=17). The following parameters were determined in both groups: urinary NAG and albumin, serum and urine creatinine, fasting plasma glucose and glycated hemoglobin (HbA1c). Results Urinary NAG levels [Units/g creatinine; median (range)] were significantly increased in microalbuminuria group [17.0 (5.9 - 23.3)] compared to normoalbuminuria group [4.4 (1.5 - 9.2)] (P<0.001). No differences between groups were observed in fasting glucose, HbA1c, serum creatinine levels and estimated glomerular filtration rates (eGFR). Urinary NAG positively correlated with ACR (r=0.628; p<0.0001), while no significant association was observed between NAG and glycemia, HbA1c, serum creatinine and eGFR. Conclusions The increase of urinary NAG at the microalbuminuria stage of diabetic nephropathy (DN) suggests that tubular dysfunction is already present in this period. The significant positive association between urinary NAG excretion and ACR indicates the possible clinical application of urinary NAG as a complementary marker for early detection of DN in T2DM. .

Objetivo Avaliar a utilidade clínica da excreção urinária da N-acetil-beta-D-glucosaminidase (NAG) para a detecção de dano tubular precoce no diabetes melito tipo 2 (DM2). Sujeitos e métodos Foram estudados trinta e seis pacientes com DM2 que se dividiram em dois grupos com base na excreção urinária de albumina (EUA): normoalbuminúrico (EUA <30 mg/g de creatinina; n=19) e microalbuminúrico (EUA =30‐300 mg/g de creatinina; n=17). Em ambos os grupos foram determinados os seguintes parâmetros: NAG e albumina urinária, creatinina sérica e urinária, glicemia de jejum e hemoglobina glicada (HbA1c). Resultados Os níveis de NAG urinária [unidades/g de creatinina; mediana (intervalo interquartílico)] foram significativamente maiores no grupo microalbuminúrico [17,0 (5,9 - 23,3)] em comparação com o grupo normoalbuminúrico [4,4 (1,5 - 9,2)] (p<0,001). Não se observaram diferenças significativas entre os dois grupos nos níveis de glicemia de jejum, HbA1c, creatinina sérica e taxa de filtração glomerular estimada (TFGe). A NAG urinária se correlacionou positivamente com o EUA (r=0,628, p<0,0001), não sendo observada associação significativa da NAG com glicemia, HbA1c, creatinina sérica e TFGe. Conclusões O aumento da NAG urinária na fase de microalbuminúria da nefropatia diabética (ND) sugere que a disfunção tubular já está presente nesse período. A associação positiva significativa entre a excreção urinária da NAG e EUA indica a possível aplicação clínica da NAG urinária como marcador complementar para a detecção precoce da ND no DM2. .

The effect of the toxic heavy metal of cadmium on the health of children / 国际儿科学杂志

Cadmium is one of the toxic heavy metals prevalent in the environment.Long-term,even the lowest dose,exposures to this element can damage various organs including the kidney,liver,lung,skeleton,and might elevate the risk of cancer and deformity.The kidney,skeleton and lung are the tissues most affected by chronic cadmium toxicity.The early sign of renal dysfunction,as a main target for chronic cadmium exposure,is tubular dysfunction,and renal failure can be observed in the terminal stage.In recent years,studies about the burden of cadmium in childhood and health damage are gradually increased.Urinary β2-microglobulin,e1-microglobulin and N-acetyl 3-D-glucosamidase have been employed as markers monitoring for the early phase of cadmium exposure and nephrotoxicity.A biomarker named kidney injury molecule-1 aslo has been used for predicting cadmium-induced tubular impairment.It is reported that kidney injury molecule-1 may be more sensitive than traditional biomarkers.

Disfunción tubular renal distal en pacientes pediátricos con diagnóstico de desnutrición grave / Dystal renal tubular dysfunction in seriously undernourished pediatric patients

La acidosis metabólica es mas frecuente en los pacientes desnutridos graves que en los eutróficos. El objetivo del presente estudio fue evaluar la función tubular renal en 30 niños desnutridos graves hospitalizados. La investigación fue de tipo prospectiva, descriptiva de corte transversal, se realizó prueba de sobrecarga con bicarbonato de sodio al 5 por ciento a 30 desnutridos graves: marasmo, kwashiorkor o mixtos, con edades de 6 meses a 5 años, etiología primaria, de ambos sexos, hemodinámicamente estables, con acidosis metabólica, hipercloremia y anión gap urinario positivo. Se determinó la relación calcio/creatinina e índice ácido úrico/creatinina. Se calcularon las frecuencias absolutas, relativas, valores medios y desviación estándar. Los lactantes representaron 80 por ciento de los pacientes. Prevalecieron las formas clínicas kwashiorkor y mixtas de evolución crónica. En 12 (40,0 por ciento) pacientes se observó acidosis tubular renal distal. El valor promedio de la relación calcio/creatinina en menores de 2 años de edad fue de 0,362 ± 0,414 y en los mayores de 2 años de 0,265 ± 0,22. El valor promedio del índice ácido úrico/creatinina fue de 0,57 ± 0,28. La acidosis metabólica presente en los pacientes, de acuerdo a los resultados observados, obedece a una disfunción tubular renal distal. La interpretación de la relación calcio/creatinina e índice ácido úrico/creatinina urinaria resulta difícil, haciéndose necesario aumentar las investigaciones en estos pacientes.

Seriously undernourished patients have a bigger tendency to metabolic acidosis than euthrophic individuals. The objective of the present work was to realize a study of the renal tubular function in 30 severely undernourished children. The investigation was a prospective, descriptive and transversal study. A test of overload with 5 percent sodium bicarbonate was realized to 30 seriously undernourished children whose primari etiology was marasmus, kwashiorkor or with mixed conditions, with ages of 6 months to 5 years, from both sexes, hemodynamically stable, with metabolic acidosis, hiperchloremia and positive urinary anion gap. The relation calcium/creatinine and the index uric acid/creatinine were determined. The absolute and relatives frequencies, average values and standard deviations were calculated. Infants represented 80 percent of the evaluated patients. The clinical forms kwashiorkor and mixed forms, of chronic evolution prevailed. Distal tubular renal acidosis was observed in 12 patients (40 percent) after the test overload with 5 percent bicarbonate. The average values of the relation calcium/creatinine of children < 2 years was 0.362 ± 0.414 and of children > 2 years was 0.265 ± 0.222. The uric acid/creatinine index was 0.57 ± 0.28. Metabolic acidosis is frequent in serious infantile undernourishment, which, according to the results observed, obeys to distal renal tubular dysfunction. The interpretation of the relation calcium/creatinine and the uric acid/creatinine index is difficult, becoming necessary to increase the investigations in these patients.

Proximal tubular dysfunction as an indicator of chronic graft dysfunction

New strategies are being devised to limit the impact of renal sclerosis on graft function. Individualization of immunosuppression, specifically the interruption of calcineurin-inhibitors has been tried in order to promote better graft survival once chronic graft dysfunction has been established. However, the long-term impact of these approaches is still not totally clear. Nevertheless, patients at higher risk for tubular atrophy and interstitial fibrosis (TA/IF) development should be carefully monitored for tubular function as well as glomerular performance. Since tubular-interstitial impairment is an early event in TA/IF pathogenesis and associated with graft function, it seems reasonable that strategies directed at assessing tubular structural integrity and function would yield important functional and prognostic data. The measurement of small proteins in urine such as α-1-microglobulin, N-acetyl-beta-D-glucosaminidase, alpha/pi S-glutathione transferases, β-2 microglobulin, and retinol binding protein is associated with proximal tubular cell dysfunction. Therefore, its straightforward assessment could provide a powerful tool in patient monitoring and ongoing clinical assessment of graft function, ultimately helping to facilitate longer patient and graft survival associated with good graft function.

Antimicrobial-induced Electrolyte and Acid-Base Disturbances

Antimicrobials are one of the most widely prescribed classes of therapeutic agents. Although adverse effects of antimicrobials are generally minimal and reversible, serious sequelae can sometimes remain, such as unusual forms of renal failure, acid base disturbance and electrolyte abnormalities. Many antimicrobials, especially vancomycin or aminoglycosides, are associated with development of acute renal failure caused by acute tubular necrosis, allergic acute interstitial nephritis, or vasculitis. Besides, some antimicrobial agents can cause serious fluid and electrolyte imbalance. To prevent these serious consequences, early recognition and correction of their harmful renal and electrolyte effects are required.

Clinical Characteristics of Arthrogryposis, Renal Tubular Dysfunction, Cholestasis(ARC) Syndrome in Korea

PURPOSE: ARC syndrome refers to an association of arthrogryposis, renal tubular dysfunction, and cholestasis. The VPS33B gene was recently identified as the causative gene. So far, 41 cases of ARC syndrome have been reported worldwide, and it has rarely been reported in Korea. This study was conducted to report the clinical findings of seven ARC syndrome cases in Korean children, focusing especially on renal tubular dysfunction. METHODS: The hospital records of 7 cases diagnosed as ARC syndrome at Severance Hospital between Mar. 1995 and Aug. 2005 were reviewed and analyzed. RESULTS: Of the 7 cases, 4 were boys and 3 were girls. Six patients(85%) were born with normal birth weight at term, and one was born at preterm. All cases presented with cholestasis and severe jaundice. According to the type of arthrogryposis described by Brown et al, type 3 and 4 were found in 2 patients and type 6, 7, and the undistributed type in one patient respectively. Other associated clinical findings were as follows:failure to thrive in 6(85%), lax skin in 5(71%), and gray platelet syndrome in 4(57%). Urine analysis revealed 6 cases(85%) with proteinuria, 3(43%) with hematuria, 5(71%) with glycosuria, 2(29%) with phosphaturia and 2(29%) with calciuria. Serum electrolytes showed 4 cases(57%) with hyponatremia, 3(43%) with hypokalemia, and 1(14%) with creatinine elevation. Renal tubular dysfunctions were diagnosed as renal tubular acidosis in 6 cases(85%), nephrogenic diabetes insipidus in 2(29%), and Fanconi syndrome in 2(29%). During the follow-up period, 2(29%) had no treatment, 5(85%) had continuous supplementation to correct the electrolyte imbalance and acidosis, and 1(14%) had dialysis. Only one patient had a family history of ARC syndrome in a sibling. Four cases(57%) were diagnosed at the mean age of 8.2 months, and one case was lost during follow-up. Ages of the survived 2 cases were 13 and 25 months, respectively. CONCLUSION: The rare disease of ARC syndrome is associated with severe renal dysfunction. However, this study revealed that the renal manifestation of ARC syndrome in Korean children is relatively mild and survival rate is higher than that of previous studies. Contrary to previous reports, this study showed that familial cases are rare and sporadic occurence is possible in Korea. Thus, the diagnosis of this syndrome requires a careful evaluation of the renal function in cases of congenital arthrogryposis, and a mandatory genetic counseling of affected family for prevention of familial occurance.

Urinary ?-microglobulin excretion for detecting tubular dysfunction in adult patients with primary nephrotic syndrome

The research studied urinary beta2-microglobulin excretion to detect tubular dysfunction in 31 patients with primary nephrotic syndrome. The result showed the increased excretion of beta2-microglobulin was observed in 11/31 cases. There were no sighgicant differences of the urinary creatinine excreation and between group of patients with increased urinary beta2-microglobulin excretion and the group without it. This indicated having combine tubular dysfunction in patients with primary nephrotic syndrome. The finding might suggest the use of urinary beta2-microglobulin for detecting the associated tubular disfuntion in such patients

Renal Problems in Wilson Disease

PURPOSE: Wilson disease is a hereditary metabolic disorder characterized by an accumulation of copper in tissues which sometimes results in renal problems. This study was performed to evaluate the prevalences of the renal problems in Wilson disease and related risk factors. METHODS: In 31 patients with Wilson disease, we looked for renal problems by history taking, physical examination and laboratory tests such as urinalysis, BUN, serum creatinine, creatinine clearance, 24-hour urine total protein, serum and urine electrolytes, serum and 24-hour urine calcium, phosphorus, uric acid, beta2-microglobulin(beta2-MG) levels and 24-hour urine N-acetyl-beta-glucosaminidase(NAG) excretion. RESULTS: All of the patients were on penicillamine therapy for 4.3+/-3.4 years. None of them had any renal symptoms or signs at the time of this study except one patient who had a history of intermittent puffy face for 6 months. In the laboratory studies, 21 cases(68%) had one or more renal problems. Sixteen cases(52%) had one or more tubular dysfunctions; individually, hypercalciuria, increased excretion of beta2-MG, decreased TRP, increased excretion of NAG were detected in 29%, 19%, 16%, and 10%, respectively. Microscopic hematurias were detected in 8 cases(26%), creatinine clearances(Ccr) were decreased in 4 cases(13%). Two cases(6%) revealed proteinuria. Hematurias were more frequent within 3 years after beginning penicillamine treatment(P<0.05). Though not proven statistically, tubular dysfunctions and proteinurias showed the same trends. Prevalence of the decreased Ccr did not change with the treatment duration. CONCLUSION: In Wilson disease, covert renal problems are relatively common. Tubular dysfunctions are the most frequently observed abnormalities followed by microscopic hematuria, proteinuria, and decreased creatinine clearance in order. Hematuria is more common within 3 years after beginning penicillamine treatment, which is also probable for tubular dysfunctions and proteinuria.