X-linked hypophosphatemic rickets: a new mutation / Raquitismo hipofosfatêmico ligado ao X: uma nova mutação

Abstract 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.

Resumo O raquitismo fosfopênico pode ser causado por mutações no gene PHEX (ligado ao X do homólogo da endopeptidase que regula o fosfato). Atualmente, mais de 500 mutações no gene PHEX causam raquitismo hipofosfatêmico. Os autores relatam um caso clínico de uma menina de 4 anos com histórico familiar sem relevância, que apresentou falha no crescimento e arqueamento das pernas. Os exames laboratoriais mostraram hipofosfatemia, fosfatase alcalina elevada, cálcio normal, PTH levemente elevado e níveis normais de 25(OH)D e 1,25(OH)D. O estudo radiológico mostrou deformidades ósseas no rádio e no fêmur. O diagnóstico clínico do raquitismo fosfopênico foi realizado e o estudo genético detectou uma provável variante patogênica heterozigótica do gene PHEX: c.767_768del (p.Thr256Serfs*7). Esta variante não foi descrita anteriormente na literatura ou nas bases de dados. O conhecimento sobre novas mutações pode melhorar o desfecho de pacientes. A análise genética pode ajudar a estabelecer uma correlação genótipo-fenótipo.

X-linked hypophosphatemic rickets: a new mutation.

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.

Intensive Blood Pressure Treatment Reduced Stroke Risk in Patients With Albuminuria in the SPRINT Trial.

Background and Purpose- Albuminuria is associated with stroke risk among individuals with diabetes. However, the association of albuminuria with incident stroke among nondiabetic patients is less clear. Methods- We performed a post hoc analysis of the SPRINT (Systolic Blood Pressure Intervention Trial), which examined the effect of higher versus lower intensity blood pressure management on mortality in 8913 participants without diabetes. We fit unadjusted and adjusted Cox proportional hazards models to estimate the association of baseline albuminuria (urinary albumin-to-creatinine ratio ≥30 mg/g versus<30 mg/g) with stroke risk. We also assessed effect modification according to treatment arms. Results- Mean age was 68±9 years, 35% were female, and 30% were black. Median follow-up was 3.2 years, and 19% patients had baseline albuminuria. Incident stroke occurred in 129 individuals during follow-up. Albuminuria was associated with increased stroke risk (unadjusted hazard ratio, 2.24; 95% CI, 1.55-3.23; adjusted hazard ratio 1.73; 95% CI, 1.17-2.56). The association of albuminuria with incident stroke differed according to the randomized treatment arm (P interaction=0.03). In the intensive treatment arm, the association of albuminuria and stroke was nonsignificant (unadjusted hazard ratio, 1.25; 95% CI, 0.69-2.28), whereas, in the standard treatment arm, it was significant (unadjusted hazard ratio, 3.44; 95% CI, 2.11-5.61). Conclusions- In a post hoc analysis of SPRINT, baseline albuminuria (versus not) was associated with a higher risk of incident stroke, but this relationship appeared to be restricted to those in the standard treatment arm. Further studies are required to conclusively determine if reduction of albuminuria in itself is beneficial in reducing stroke risk. Clinical Trial Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT01206062.

Impaired Fasting Glucose and Chronic Kidney Disease, Albuminuria, or Worsening Kidney Function: A Secondary Analysis of SPRINT.

PURPOSE: Diabetes mellitus is a risk factor for the development and progression of chronic kidney disease (CKD). However, the association of prediabetes with adverse kidney outcomes is uncertain. METHODS: We performed a secondary analysis of the Systolic Blood Pressure Intervention Trial (SPRINT), including 9361 participants without diabetes at baseline. We categorized participants according to fasting glucose level as having impaired fasting glucose [≥100 mg/dL (≥5.6 mmol/L)] or normoglycemia [<100 mg/dL (<5.6 mmol/L)]. Unadjusted and adjusted proportional hazards models were fitted to estimate the association of impaired fasting glucose (vs normoglycemia) with a composite outcome of worsening kidney function [≥30% decrease in estimated glomerular filtration rate (eGFR) to <60 mL/min/1.73 m2 in participants without baseline CKD; ≥50% decrease in eGFR or need for long-term dialysis/kidney transplantation in participants with CKD] or incident albuminuria (doubling of urinary albumin/creatinine ratio from <10 mg/g to >10 mg/g). These outcomes were also evaluated separately and according to CKD status at baseline. RESULTS: Participants' mean age was 67.9 ± 9.4 years, 35.5% were female, and 31.4% were black. The median follow-up was 3.3 years, and 41.8% had impaired fasting glucose. Impaired fasting glucose was not associated with higher rates of the composite outcome [hazard ratio (HR): 0.97; 95% CI: 0.8 to 1.16], worsening kidney function (HR: 1.02; 95% CI: 0.75 to 1.37), or albuminuria (HR: 0.98; 95% CI: 0.78 to 1.23). Similarly, there was no association of impaired fasting glucose with outcomes according to baseline CKD status. CONCLUSIONS: Impaired fasting glucose at baseline was not associated with the development of worsening kidney function or albuminuria in participants of SPRINT.

[Prescribing of Non-Steroidal Anti-Inflammatory Drugs to Patients with Diabetes Mellitus in Portugal]. / Prescrição de Anti-Inflamatórios Não Esteroides a Doentes com Diabetes Mellitus em Portugal.

INTRODUCTION: Portugal presents the highest incidence of stage 5 chronic kidney disease in Europe. It is speculated that a high consumption of non-steroidal anti-inflammatory drugs (NSAIDS) may contribute to this high incidence. Our aim was to characterize the prescription of non-steroidal anti-inflammatory drugs to patients with diabetes mellitus in Portugal. MATERIAL AND METHODS: We analyzed the national prescription database in triennium 2015 - 2017. In patients with diabetes mellitus, we evaluated the prescription of non-steroidal anti-inflammatory drugs according to age, gender and region of the patient and specialty of the prescribing physician. We evaluated the prescription of non-steroidal anti-inflammatory drugs in all patients with diabetes mellitus, in patients with presumed renal impairment, and in those with concomitant prescription of angiotensin converting enzyme inhibitors or angiotensin receptor antagonists. RESULTS: We analyzed 23 320 620 prescriptions, corresponding to 610 157 adults, including 104 306 patients with diabetes mellitus. The most prescribed non-steroidal anti-inflammatory drugs were ibuprofen (20.1%), metamizole (14.7%), and diclofenac (11.4%). The prescription of non-steroidal anti-inflammatory drugs was higher in females, in patients aged 51 - 70 years and in the Alentejo region. Non-steroidal anti-inflammatory drugs were prescribed to 70.6% of patients with diabetes mellitus, from which 10.6% were prescribed ≥ 10 packages during the three years. Among patients with diabetes mellitus on angiotensin converting enzyme inhibitors/angiotensin receptor antagonists and with presumed reduction in kidney function, 69.3% were prescribed non-steroidal anti-inflammatory drugs and 11.5% were prescribed ≥ 10 packages during the three years. DISCUSSION: The level of prescribing of non-steroidal anti-inflammatory drugs to patients with diabetes mellitus is high. The concern of reducing non-steroidal anti-inflammatory drugs prescription to patients already on angiotensin converting enzyme inhibitors/angiotensin receptor antagonists and/or decreased renal function does not seem to exist. CONCLUSION: In Portugal, the level of prescribing of non-steroidal anti-inflammatory drugs to patients with diabetes mellitus should be reduced, particularly in the subgroups identified with higher prescription and with higher risk of progression to stage 5 chronic kidney disease.

Introdução: Portugal apresenta a incidência mais elevada de doença renal crónica estádio 5 na Europa. Especula-se que o elevado consumo de anti-inflamatórios não esteroides possa contribuir para esta incidência. O objetivo do presente estudo foi caracterizar a prescrição de anti-inflamatórios não esteroides a doentes com diabetes mellitus em Portugal. Material e Métodos: Na Base de Dados Nacional de Prescrições do Ministério da Saúde, triénio 2015 - 2017, analisámos a prescrição de anti-inflamatórios não esteroides em doentes com diabetes mellitus, de acordo com a idade, género e região do doente e a especialidade do médico prescritor. Avaliámos a prescrição de anti-inflamatórios não esteroides no total de doentes com diabetes mellitus, em doentes com diminuição presumida da função renal e naqueles com prescrição concomitante de inibidores da enzima de conversão da angiotensina ou antagonistas dos recetores da angiotensina. Resultados: Analisámos 23 320 620 prescrições, correspondendo a 610 157 adultos, dos quais 104 306 doentes com diabetes mellitus. Os anti-inflamatórios não esteroides mais prescritos foram ibuprofeno (20,1%), metamizol (14,7%) e diclofenac (11,4%). A prescrição foi mais frequente nas mulheres, nos doentes com 51 - 70 anos e no Alentejo. Foram prescritos anti-inflamatórios não esteroides a 70,6% dos doentes com diabetes mellitus, dos quais 10,6% receberam prescrições de ≥ 10 embalagens durante os três anos. Dos doentes com diabetes mellitus medicados com inibidores da enzima de conversão da angiotensina ou antagonistas dos receptores da angiotensina e com diminuição presumida da taxa de filtração glomerular, 69,3% receberam prescrição de anti-inflamatórios não esteroides e 11,5% receberam ≥ 10 embalagens durante os três anos. Discussão: A prescrição de anti-inflamatórios não esteroides na diabetes mellitus é elevada. Não parece existir uma preocupação na menor utilização de anti-inflamatórios não esteroides em doentes simultaneamente medicados com inibidores da enzima de conversão da angiotensina ou antagonistas dos recetores da angiotensina e/ou com diminuição da função renal. Conclusão: A prescrição de anti-inflamatórios não esteroides em Portugal a doentes com diabetes mellitus deverá ser reduzida, particularmente nos subgrupos identificados com prescrição mais elevada e com maior risco de progressão para doença renal crónica estádio 5.

[Analysis of the Cochrane Review: Pharmacotherapy for Hyperuricemia in Hypertensive Patients. Cochrane Database Syst Rev. 2017;4:CD008652.] / Análise da Revisão Cochrane: Terapêutica Farmacológica da Hiperuricemia em Doentes Hipertensos. Cochrane Database Syst Rev. 2017;4:CD008652.

Arterial hypertension is a public health problem that affects approximately 25% of the world's adult population. The association between hypertension and hyperuricemia has been shown on epidemiological and experimental studies. However, it is unclear whether lowering serum uric acid might lower blood pressure. This Cochrane systematic review - a revised edition of a previously published one - intended as primary objective to evaluate the effect of hypouricemic drugs in patients with primary hypertension or prehypertension. The secondary objectives were to evaluate the efficacy and safety of hypouricemic drugs. A systematic search until February 2016 on controlled, randomized or quasi-randomized trials comparing the effect of hypouricemic drug versus placebo in hypertensive or prehypertensive patients was performed on the following databases: The Cochrane Hypertension Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), Medline, Embase, The World Health Organization International Clinical Trials Registry Platform, e ClinicalTrials.gov. LILACS database up to March 2016 was also searched and the authors of relevant studies were contacted. There were 349 identified papers, 21 were preselected and three randomized clinical trials (211 patients) were included in the qualitative analysis and in the meta-analysis. Two of the trials were conducted exclusively on adolescents. The authors conclude that hypouricemic drugs are not effective in lowering blood pressure in patients with hyperuricemia and primary prehypertension or hypertension. However, this strategy might be more effective in the specific population of adolescents with prehypertension or mild primary hypertension recently diagnosed. Hypouricemic drugs effectively reduce serum uric acid level and withdrawals of therapy due to adverse effects were not superior in the treated group, comparing to placebo; however, one patient withdrew due to a severe cutaneous reaction.

A hipertensão arterial é um problema de saúde pública que afeta cerca de 25% da população adulta mundial. A associação entre hiperuricemia e hipertensão arterial tem sido demonstrada em estudos epidemiológicos e experimentais. No entanto, não é claro se a terapêutica hipouricemiante reduz os valores de pressão arterial. Esta revisão sistemática - uma versão atualizada de outra previamente publicada - teve como objetivo primário avaliar o efeito da terapêutica hipouricemiante nos valores de pressão arterial de doentes com pré-hipertensão ou hipertensão arterial primárias. Os objetivos secundários foram avaliar a eficácia da terapêutica na redução da uricemia e o perfil de segurança. Foram selecionados ensaios clínicos aleatorizados ou quasi-aleatorizados que comparassem o efeito nos valores de pressão arterial da terapêutica hipouricemiante versus placebo, em doentes com hiperuricemia e pré-hipertensão ou hipertensão arterial essencial. Foram pesquisadas as seguintes bases de dados até fevereiro de 2016: The Cochrane Hypertension Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), Medline, Embase, The World Health Organization International Clinical Trials Registry Platform, e ClinicalTrials.gov. Foi também pesquisada a LILACS até março de 2016 e contactados os autores dos estudos considerados relevantes. Dos 349 artigos identificados, foram pré-selecionados 21, tendo sido incluídos três ensaios clínicos aleatorizados (211 doentes) na análise qualitativa e na meta-análise. Dois destes ensaios incluíram exclusivamente adolescentes. Os autores concluem que a terapêutica hipouricemiante não é eficaz na redução da pressão arterial na população de doentes com hiperuricemia e pré-hipertensão ou hipertensão arterial essencial. No entanto, esta estratégia poderá ser mais eficaz na população específica dos adolescentes com pré-hipertensão ou hipertensão arterial ligeira diagnosticada recentemente. A terapêutica hipouricemiante é eficaz na redução do valor sérico de ácido úrico e a suspensão da terapêutica devido a efeitos adversos não foi superior nos grupos tratados comparativamente com placebo (embora um doente a tenha suspendido por reação cutânea grave).

Increased risk for metachronous gastric adenocarcinoma following gastric MALT lymphoma-A US population-based study.

BACKGROUND: Gastric mucosa-associated lymphoid tissue lymphoma (gMALT) and gastric adenocarcinoma (GC) are long-term complications of chronic Helicobacter pylori (HP) gastritis. Treatment of HP infection induces remission in most patients with gMALT. Endoscopic follow-up is not currently endorsed after complete remission. However, the risk of GC in these patients is unclear. OBJECTIVE: The objective of this study is to estimate GC risk in gMALT patients. METHODS: The National Cancer Institute Surveillance, Epidemiology and End Results 13 (SEER) database-Nov 2014 Sub (1992-2012) was used to identify adult patients diagnosed with gMALT between 1992 and 2012. The standardized incidence ratio of second primary GC after a latency period of 12 months was calculated and compared to a reference SEER cohort of identical age, sex and time period. The risk of GC in these patients was also stratified by latency period (five years) and age. RESULTS: We identified 2195 cases of gMALT lymphoma, and 20 (0.91%) of them subsequently developed GC with a relative risk (RR) of 4.32 (95% CI 2.64-6.67) compared to the American population. The median latency time was five years and the risk was maintained afterward (RR 4.92, 95% CI 2.45-8.79). When stratified by age group the risk was highest for the 45-64 group (RR 14.04, 95% CI 5.64-28.93). CONCLUSION: gMALT lymphoma is associated with an increased risk of metachronous gastric adenocarcinoma. The risk is still present after more than five years of follow-up. Further studies may clarify the most adequate follow-up strategy.