Fanconi Syndrome after Ifosfamide Exposure

ntroduction: Ifosfamide is an antineoplastic drug frequently used in the treatment of pediatric malignancies. However it is responsible for nephrotoxicity in up to 30% of patients, which can be manifested from asymptomatic tubulopathy to overt renal failure. We report a case of a patient who developed Fancony syndrome after exposure to ifosfamide. Clinical Case: A two-year-old caucasian boy was diagnosed with stage IV Burkitt lymphoma with hepatic and renal involvement without central nervous system (CNS) invasion. Baseline evaluation showed GFR of 60 mL/min per 1.73 m2 (Shwartz formula, k=0.143). He underwent five cycles of chemotherapy involving cyclophosphamide, vincristine, prednisolone, doxorubicin, methotrexate and cytarabine. The patient was in remission but three months later relapsed with evidence of involvement of the liver and kidneys on CT. Another course of chemotherapy was initiated with ifosfamide, carboplatin, etoposide, rituximab (R-ICE) and intratecal administration of methotrexate and aracitabine. After five cycles of R-ICE, the patient had a bone marrow transplant. According to protocol, busulfan, cyclophosphamide, tacrolimus, methotrexate, fluconazole and acyclovir were administered. No immediate complications were registered. Four months after transplant, the patient showed significant downward growth percentile crossing and urinalysis suggested tubulopathy. Upon nephrologist referral, laboratory investigations showed GFR 60 mL/min per 1.73 m2, metabolic acidosis, hypouricemia, hypokalemia, hypophosphatemia, glycosuria, proteinuria, high FEUa and FEK, and low GFR of phosphorus. Fancony syndrome was diagnosed and adequate supplementation was initiated. After literature review the most probable causing agent was ifosfamide. After adequate treatment patient’s general condition improved with slow percentile recovery. Conclusions: Nephrotoxicity secondary to chemotherapy is a major cause of morbidity in pediatric cancer survivors. Our case represents a rare situation with unspecific clinical signs. Clinicians must be alert to the necessity of close monitoring to identify renal toxicity as early as possible and allow adequate supplementation, which is crucial in preventing side effects.info:eu-repo/semantics/publishedVersio

Laboratory and Field Studies on Herpetosoma Trypanosomes From Portugal

Several small mammals were trapped in the Arrabida region (Portugal) and checked for the presence of trypanosomes which were found in 33 of the 197 (11.1 %) Mus spretus and in 9 of the 29 (31 %) Crocidura russula observed. To our knowledge, this was the first time that trypanosomes were isolated from these mammals species. In the liver of one dead C. russula was observed different parasite forms. The studies of infectivity to experimental rodents, analyses of the DNA buoyant density and the isoenzymatic profiles, show that trypanosomes isolates from M. spretus were identical to Trypanosoma musculi isolates from Mus musculus. However the isolates from C. russula, although related to the isolates from murine rodents, were clearly separated from these and close to Trypanosoma microti. These findings may allow further studies on the detection of their vectors and on the study of trypanosome reproduction.publishersversionpublishe

Hypophosphatemic Rickets: A New Mutation

Introduction: Phosphopenic rickets is characterized by hypophosphatemia with hyperphosphaturia, normal calcemia and normal or mildly elevated PTH. This pathology may be caused by mutations in PHEX gene (phosphate regulating endopeptidase homolog X-linked). We present a clinical report of a girl with phosphopenic rickets, as consequence of a new mutation of PHEX gene. Clinical Case: We present a 4-year-old female, with unremarkable family history, who presented with failure to thrive since the first year of life (height at the 5th centile, and with the age of four below 5th centile). Blood tests showed hypophosphatemia (2.4 mg/dL), elevated alkaline phosphatase (495 U/L), normal calcemia, mildly elevated PTH (97.2 pg/mL; RR <68.3) and normal levels of 25(OH)D and 1.25(OH)D vitamins. The radiological study showed bone deformity of the radius and femur. Diagnosis of hypophosphatemic rickets was made and she was medicated with phosphorus and calcitriol. Currently, the patient has no clinical or radiographic signs of rickets, osseous age is according to real age and there was a considerable increase in growth rate (between 25th and 50th centiles). Renal ultrasound shows incipient signs of nephrocalcinosis since she was 9-year-old. The genetic study detected a heterozigous mutation of the PHEX gene: variant c.767_768del (p.Thr256Serfs*7). This variant is not described in the literature or databases. However, since it introduces a premature stop codon that can produce a truncated protein, this is very likely a pathogenic variant. The parent’s genetic study is still in progress. Conclusions: Presently more than 200 mutations in the PHEX gene have been found to cause hypophosphatemic rickets. We describe a new mutation of this gene. Knowledge about new mutations can improve patient’s outcome.info:eu-repo/semantics/publishedVersio

Influenza B-Associated Atypical Hemolytic Uremic Syndrome

Introduction: Influenza A infections have been described to cause secondary hemolytic uremic syndrome and to trigger atypical hemolytic uremic syndrome (aHUS) in individuals with an underlying genetic complement dysregulation. To date, Influenza B has only been reported to trigger aHUS in 2 patients. In 61% of aHUS cases, mutations are found in H, B and I factors, membrane cofactor protein (MCP), C3 and thrombomodulin. MCP (CD46) mutations account for 10-15% of cases. Clinical Case: A 13-year-old boy was transferred to a terciary pediatric centre with acute renal lesion in the context of HUS. Evidence was found for Influenza B infection and results for other etiologic agents were negative. He was treated with Oseltamivir for 5 days. Etiologic study revealed decreased C ́3 (0,81 g/L), normal C ́4 (0,27 g/L) and all antibodies were negative: anti-Beta2 GP1 IgG / IgM, anti-cardiolipine IgG / IgM, anti-neutrophil-citoplasm-PR3 and MPO. Alternate complement pathway study (AH 50) were 112 % of normal value (reference value >70%) and ADAMTS 13 activity were 0.79 (values above 0.67 may be found in aSHU as well as other microangiopathic trombopathies). Molecular study of complement including 11 genes (CFH, CD46 (MCP), CFI, C3, THBD, CFB,CFHR5, CFHR1 CFHR3, CFHR4, DGKE) found a pathogenic heterozygotic missense variant on CD46 (MCP) gene, c.554A>G, p.Asp185Gly, associated with aHUS. Conclusions: aHUS patients should be screened for all known disease-associated genes. Screening should not be stopped after finding a mutation to avoid missing other genetic susceptibility factors influencing disease phenotype, particularly in patients with MCP or CFI mutations, because they have a higher probability of also carrying mutation in another gene than patients with CFHor C3 mutations. Influenza B is a trigger for aHUS and might be underreported as such. Influenza vaccination may protect patients at risk.info:eu-repo/semantics/publishedVersio

Raquitismo hipofosfatêmico ligado ao X: uma nova mutação

Phosphopenic rickets may be caused by mutations in the PHEX gene (phosphate regulating endopeptidase homolog X-linked). Presently, more than 500 mutations in the PHEX gene have been found to cause hypophosphatemic rickets. The authors report a clinical case of a 4-year-old girl with unremarkable family history, who presented with failure to thrive and bowing of the legs. Laboratory tests showed hypophosphatemia, elevated alkaline phosphatase, normal calcium, mildly elevated PTH and normal levels of 25(OH)D and 1.25(OH)D. The radiological study showed bone deformities of the radius and femur. Clinical diagnosis of phosphopenic rickets was made and the genetic study detected a heterozygous likely pathogenic variant of the PHEX gene: c.767_768del (p.Thr256Serfs*7). This variant was not previously described in the literature or databases. Knowledge about new mutations can improve patient’s outcome. Genetic analysis can help to establish a genotype-phenotype correlation.info:eu-repo/semantics/publishedVersio

The role of ionic vs. non-ionic excipients in APIs-based eutectic systems

Aiming to contribute to drug pre-formulation, new eutectic mixtures were developed. Thymol, coumarin, or quaternary ammonium chlorides as excipients, were combined with the active pharmaceutical ingredients (APIs) acetylsalicylic acid, acetaminophen, ibuprofen, ketoprofen, or lidocaine. Their solid-liquid equilibrium (SLE) binary phase diagrams were measured to study eventual phase separation between the compounds, preventing manufacturing problems, and to study the molecular interactions between the APIs and ionic or non-ionic excipients. The Conductor-like Screening Model for Real Solvents (COSMO-RS) capability to predict the SLE of mixtures containing non-ionic excipients was further evaluated. COSMO-RS gives a good quantitative description of the experimental SLE being a tool with great potential in the screening of eutectic systems containing APIs and non-ionic excipients. While thymol presents strong interactions with the APIs, and consequently negative deviations to thermodynamic ideality, systems containing coumarin follow a quasi-ideal behavior. Regarding the ionic excipients, both choline chloride and the tetraalkylammonium chlorides are unable to establish relevant interactions with the APIs, and no significant negative deviations to ideality are observed. The liquefaction of the APIs here studied is favored by using non-ionic excipients, such as thymol, due to the strong interactions it can establish with the APIs.This work was developed within the scope of the project CICECO Aveiro Institute of Materials, UIDB/50011/2020 & UIDP/50011/2020, and CIMO-Mountain Research Center, UIDB/00690/2020, both financed by national funds through the Portuguese Foundation for Science and Technology/MCTES. L.P.S. acknowledges FCT for her PhD grant (SFRH/BD/135976/2018).info:eu-repo/semantics/publishedVersio

Primary Hyperoxaluria type 1 – Two Case Reports

Primary hyperoxaluria type 1 is a rare autosomal recessive inherited disease, caused by mutations in AGXT gene, with an estimated incidence of 1:100.000 live births per year in Europe. Over 50% present with end stage renal disease at diagnosis. Case reports: The first case is a 14‑year‑old boy, second child to consanguineous parents, with history of recurrent lithiasis and ureteral dilatation starting 5 years before. Urine/stone analysis revealed calcium oxalate monohydrate crystals and markedly elevated urine oxalate excretion. Genetic tests confirmed a mutation in AGXT gene, c.1151T>C, in homozygosity. Two years after, nephrocalcinosis was identified and glomerular filtration rate gradually declined. Oxalate deposition in solid organs was excluded and successful orthotopic liver transplantation was performed, with stabilization of glomerular filtration rate. The second case is a 16‑year‑old girl, with recurrent episodes of renal colic. At diagnosis, she had obstructive hydronephrosis, multiple kidney stones and an estimated glomerular filtration of 42.1mL/min/1.73m2. Metabolic study showed hypocitraturia and hyperoxaluria. With dietetic measures and irregular treatment, urine oxalate excretion remained high but renal function improved. Genetic tests confirmed the presence of two pathologic variants in AGXT gene: c.731T>C and c.1151T>C in compound heterozygous. Conclusions: Recurrent urolithiasis and nephrocalcinosis in children along with family history/consanguinity should raise the suspicion of Primary Hyperoxaluria type 1. Conservative treatment may increase renal survival. Effects of systemic oxalosis must be screened when glomerular filtration rate declines below 30‑50mL/ min/1.73m2, and sequential or combined liver and kidney transplantation should be considered.info:eu-repo/semantics/publishedVersio

P-Sulfonic acid calix[4]arene-functionalized alkyl-bridged organosilica in esterification reactions

Two new p-sulfonic acid calix[4]arene- and p-sulfonic acid calix[6]arene-functionalized organosilica have been synthesized using a sol-gel method and applied as heterogeneous catalysts in esterification reactions. The catalytic performance was evaluated using the esterification of carboxylic acids with ethanol, and good catalytic activity (i.e., 55-88%) was observed under the optimum reaction conditions. This study reports the first promising example of the successful employment of calix[n]arenes as a heterogeneous catalyst for catalytic esterification. The catalyst was easily separated by filtration and reused five times without any significant loss of activity.Fil: De Assis, J. V.. Universidade Federal de Viçosa; BrasilFil: Abranches, P. A. S.. Universidade Federal de Viçosa; BrasilFil: Braga, I. B.. Universidade Federal de Viçosa; BrasilFil: Portilla Zúñiga, Omar Miguel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigación y Desarrollo en Ciencias Aplicadas "Dr. Jorge J. Ronco". Universidad Nacional de la Plata. Facultad de Ciencias Exactas. Centro de Investigación y Desarrollo en Ciencias Aplicadas; ArgentinaFil: Sathicq, Angel Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigación y Desarrollo en Ciencias Aplicadas "Dr. Jorge J. Ronco". Universidad Nacional de la Plata. Facultad de Ciencias Exactas. Centro de Investigación y Desarrollo en Ciencias Aplicadas; ArgentinaFil: Romanelli, Gustavo Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigación y Desarrollo en Ciencias Aplicadas "Dr. Jorge J. Ronco". Universidad Nacional de la Plata. Facultad de Ciencias Exactas. Centro de Investigación y Desarrollo en Ciencias Aplicadas; ArgentinaFil: Sato, A. G.. Universidade Federal de Viçosa; BrasilFil: Fernandes, S. A.. Universidade Federal de Viçosa; Brasi

Nephrolithiasis in a Portuguese Pediatric Population

Introduction and Aims: Nephrolithiasis incidence in children has increased considerably. It is associated with substantial morbidity, recurrence and increased adulthood cardiovascular risk and chronic kidney disease. A thorough investigation is essential, as rare forms of urolithiasis have increased risk of renal failure. We aim to determine the epidemiology and outcomes of a pediatric population with nephrolithiasis presented in a nephrology unit of a tertiary centre. Methods: Retrospective study of the records of all children (<18 years) with nephrolithiasis diagnosis between 2008‑17. Clinical features, etiology, recurrence, treatment, and outcomes were evaluated and compared throughout the study period through two equal periods (2008‑12 versus 2013‑17). Results: We identified 80 cases: isolated nephrolithiasis (86%) and associated with nephrocalcinosis (14%). Mean follow‑up was 36 months (14–120). Median age at presentation was 8.6 years [3 months – 17 years]: 21% < 2 years‑old and 46% ≥ 10 years. The annual ratio of referrals for nephrolithiasis increased on average 1.2% per year [0.3‑11.8%]. Multiple etiological factors were present in 34%. A metabolic abnormality was identified in 54%: hypocitraturia (34%), hypercalcuria (24%), hyperoxaluria (15%), hyperuricosuria (15%) and cystinuria (1%), without age predominance (p=0.2). Urinary tract infection (24%) was the next most significant etiology and was more frequent below 2 years of age (p=0.001) and associated with struvite calculi (p=0.033). Median age at diagnosis was significantly lower in the study’s first half (5 vs 10 years; p=0.019) and an infectious etiology was more frequent (p=0.043). In a logistic‑regression analysis, a family history of nephrolithiasis was associated with a metabolic cause (p<0.01). Sixty‑three percent became stone free and 24% had recurrence. Discussion: Nephrolithiasis new referrals gradually increased throughout the study period. The most common etiology was metabolic, which is usually responsible for nephrolithiasis appearance and its recurrence, emphasizing the need for a complete evaluation.info:eu-repo/semantics/publishedVersio

Ciliopatias – Experiência de uma Unidade de Nefrologia Pediátrica de um Hospital Terciário

Introdução: As ciliopatias constituem um grupo de doenças associadas a mutações genéticas que condicionam alterações na estrutura e função dos cílios. A disfunção ciliar pode manifestar-se com doença renal, degeneração retiniana e anomalias cerebrais. Outras manifestações menos frequentes são a doença fibroquística congénita do fígado, diabetes, obesidade e displasia óssea. Objetivo: Caracterizar os casos de ciliopatias seguidos na Unidade de Nefrologia Pediátrica de um Hospital Terciário, nos últimos 10 anos. Resultados: No período em estudo (Janeiro de 2008 a Dezembro de 2017) foram seguidos na Unidade de Nefrologia Pediátrica 8 doentes com ciliopatias; 62,5 % do sexo feminino, 7 doentes de nacionalidade portuguesa e 1 natural do Paquistão. No momento do diagnóstico 2 doentes tinham função renal normal e 6 doença renal crónica (DRC): 1 DRC estadio III, 1 DRC estadio IV e 4 (50%) DRC estadio V; destes 4 realizaram diálise peritoneal e 1 hemodiálise, sendo 4 já submetidos a transplante renal. Dois doentes têm estudo genético concluído, ambos com mutação no gene NPHP1, um deles com Síndrome de Senior Loken. Um doente apresenta Síndrome de Alström e 1 doente apresenta Síndrome de Joubert. Foram submetidos a biópsia renal 5 doentes, todos com alterações compatíveis com nefronoptisis. Conclusões: As ciliopatias constituem um grupo heterogéneo de doenças, com atingimento renal variável e com possível progressão para insuficiência renal crónica. Muitos casos apenas são diagnosticados em estadios avançados de doença renal, pela indolência da progressão da patologia. Salienta-se a necessidade de um elevado grau de suspeição, nomeadamente quando existe atingimento multissistémico (ocular, neurológico, esquelético ou endocrinológico). Nos casos com atingimento primordial renal, é muito frequente a anemia grave e a poliúria/polidipsia severas, que poderão também constituir orientações para o diagnóstico. Quando há envolvimento renal ligeiro, torna-se essencial manter a vigilância clínica e laboratorial, pelo potencial de evolução para DRC.info:eu-repo/semantics/publishedVersio