RESUMO
RATIONALE & OBJECTIVE: Data supporting the efficacy of preventive pharmacological therapy (PPT) to reduce urolithiasis recurrence are based on clinical trials with composite outcomes that incorporate imaging findings and have uncertain clinical significance. This study evaluated whether the use of PPT leads to fewer symptomatic stone events. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Medicare enrollees with urolithiasis who completed 24-hour urine collections that revealed hypercalciuria, hypocitraturia, low urine pH, or hyperuricosuria. EXPOSURE: PPT (thiazide diuretics for hypercalciuria, alkali for hypocitraturia or low urine pH, or uric acid lowering drugs for hyperuricosuria) categorized as (1) adherent to guideline-concordant PPT, (2) nonadherent to guideline-concordant PPT, or (3) untreated. OUTCOME: Symptomatic stone event occurrence (emergency department [ED] visit or hospitalization for urolithiasis or stone-directed surgery). ANALYTICAL APPROACH: Cox proportional hazards regression. RESULTS: Among 13,942 patients, 31.0% were prescribed PPT. Compared with no treatment, concordant/adherent PPT use was associated with a significantly lower hazard of symptomatic stone events for patients with hypercalciuria (HR, 0.736 [95% CI, 0.593-0.915]) and low urine pH (HR, 0.804 [95% CI, 0.650-0.996]) but not for patients with hypocitraturia or hyperuricosuria. These associations were largely driven by significantly lower rates of ED visits after initiating PPT among the concordant/adherent group versus untreated patients. Patients with hypercalciuria had adjusted 2-year predicted probabilities of a visit of 3.8% [95% CI, 2.5%-5.2%%] and 6.9% [95% CI, 6.0%-7.7%] for the concordant/adherent PPT and no-treatment groups, respectively. Among patients with low urine pH, these probabilities were 4.3% (95% CI, 2.9%-5.7%) and 7.3% (95% CI, 6.5%-8.0%) for the concordant/adherent PPT and no-treatment groups, respectively. LIMITATIONS: Potential bias from the possibility that patients prescribed PPT had more severe disease than untreated patients. CONCLUSIONS: Patients with urolithiasis and hypercalciuria who were adherent to treatment with thiazide diuretics as well as those with low urine pH adherent to prescribed alkali therapy had fewer symptomatic stone events than untreated patients. PLAIN-LANGUAGE SUMMARY: Despite multiple clinical trials demonstrating the efficacy of thiazide diuretics and alkali for secondary prevention of kidney stones, they are infrequently prescribed due in part to a lack of data about their effectiveness in real-world settings. We analyzed medical claims from older adults with kidney stones for whom urine chemistry data were available. We found that patients who took prescribed thiazide diuretics for elevated urine calcium levels or alkali for low urinary pH were less likely to experience symptomatic stone recurrences than untreated patients. This benefit was expressed as lower rates of emergency department visits after initiating therapy. Our findings should inform the prescription of and adherence to treatment with thiazide diuretics and alkali for the prevention of recurrent kidney stones.
Assuntos
Urolitíase , Humanos , Estudos Retrospectivos , Feminino , Masculino , Idoso , Urolitíase/prevenção & controle , Inibidores de Simportadores de Cloreto de Sódio/uso terapêutico , Estudos de Coortes , Prevenção Secundária/métodos , Hipercalciúria/prevenção & controle , Resultado do Tratamento , Estados Unidos/epidemiologia , Idoso de 80 Anos ou mais , MedicareRESUMO
PURPOSE OF REVIEW: Most kidney stones are composed of calcium, and the greatest risk factor for kidney stone formation is hypercalciuria. Patients who form kidney stones often have reduced calcium reabsorption from the proximal tubule, and increasing this reabsorption is a goal of some dietary and pharmacological treatment strategies to prevent kidney stone recurrence. However, until recently, little was known about the molecular mechanism that mediates calcium reabsorption from the proximal tubule. This review summarizes newly uncovered key insights and discusses how they may inform the treatment of kidney stone formers. RECENT FINDINGS: Studies examining claudin-2 and claudin-12 single and double knockout mice, combined with cell culture models, support complementary independent roles for these tight junction proteins in contributing paracellular calcium permeability to the proximal tubule. Moreover, a family with a coding variation in claudin-2 causing hypercalciuria and kidney stones have been reported, and reanalysis of Genome Wide Association Study (GWAS) data demonstrates an association between noncoding variations in CLDN2 and kidney stone formation. SUMMARY: The current work begins to delineate the molecular mechanisms whereby calcium is reabsorbed from the proximal tubule and suggests a role for altered claudin-2 mediated calcium reabsorption in the pathogenesis of hypercalciuria and kidney stone formation.
Assuntos
Cálcio , Hipercalciúria , Cálculos Renais , Cálculos Renais/genética , Cálculos Renais/fisiopatologia , Cálculos Renais/prevenção & controle , Cálculos Renais/terapia , Hipercalciúria/genética , Hipercalciúria/fisiopatologia , Hipercalciúria/prevenção & controle , Hipercalciúria/terapia , Cálcio/metabolismo , Humanos , Animais , Claudina-2/genética , Claudina-2/metabolismo , Claudinas/genética , Claudinas/metabolismo , Estudo de Associação Genômica Ampla , Túbulos Renais Proximais/fisiopatologiaRESUMO
Cetuximab, an inhibitor of the epidermal growth factor receptor that is used widely to treat human cancers including oral squamous cell carcinoma (OSCC), has characteristic side effects of skin rash and hypomagnesemia. However, the mechanisms of and therapeutic agents for skin rashes and hypomagnesemia are still poorly understood. Our gene expression profiling analyses showed that cetuximab activates the p38 MAPK pathways in human skin cells (human keratinocyte cell line [HaCaT]) and inhibits c-Fos-related signals in human embryonic kidney cells (HEK293). We found that while the p38 inhibitor SB203580 inhibited the expression of p38 MAPK targets in HaCaT cells, flavagline reactivated c-Fos-related factors in HEK293 cells. It is noteworthy that, in addition to not interfering with the effect of cetuximab by both compounds, flavagline has additive effect for OSCC growth inhibition in vivo. Collectively, our results indicate that combination of cetuximab and these potential therapeutic agents for cetuximab-related toxicities could be a promising therapeutic strategy for patients with OSCC.
Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Carcinoma de Células Escamosas/tratamento farmacológico , Cetuximab/efeitos adversos , Inibidores do Crescimento/uso terapêutico , Imidazóis/uso terapêutico , Neoplasias Bucais/tratamento farmacológico , Piridinas/uso terapêutico , Animais , Carcinoma de Células Escamosas/complicações , Linhagem Celular Tumoral , Quimioterapia Combinada , Receptores ErbB/antagonistas & inibidores , Exantema/induzido quimicamente , Exantema/genética , Exantema/prevenção & controle , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Redes Reguladoras de Genes , Inibidores do Crescimento/efeitos adversos , Inibidores do Crescimento/antagonistas & inibidores , Células HEK293 , Humanos , Hipercalciúria/induzido quimicamente , Hipercalciúria/genética , Hipercalciúria/prevenção & controle , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Bucais/complicações , Neoplasias Bucais/genética , Nefrocalcinose/induzido quimicamente , Nefrocalcinose/genética , Nefrocalcinose/prevenção & controle , Erros Inatos do Transporte Tubular Renal/induzido quimicamente , Erros Inatos do Transporte Tubular Renal/genética , Erros Inatos do Transporte Tubular Renal/prevenção & controle , Transcriptoma , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The tight junction proteins claudin-10 and -16 are crucial for the paracellular reabsorption of cations along the thick ascending limb of Henle's loop in the kidney. In patients, mutations in CLDN16 cause familial hypomagnesemia with hypercalciuria and nephrocalcinosis, while mutations in CLDN10 impair kidney function. Mice lacking claudin-16 display magnesium and calcium wasting, whereas absence of claudin-10 results in hypermagnesemia and interstitial nephrocalcinosis. In order to study the functional interdependence of claudin-10 and -16 we generated double-deficient mice. These mice had normal serum magnesium and urinary excretion of magnesium and calcium and showed polyuria and sodium retention at the expense of increased renal potassium excretion, but no nephrocalcinosis. Isolated thick ascending limb tubules of double mutants displayed a complete loss of paracellular cation selectivity and functionality. Mice lacking both claudin-10 and -16 in the thick ascending limb recruited downstream compensatory mechanisms and showed hypertrophic distal convoluted tubules with changes in gene expression and phosphorylation of ion transporters in this segment, presumably triggered by the mild decrease in serum potassium. Thus, severe individual phenotypes in claudin-10 and claudin-16 knockout mice are corrected by the additional deletion of the other claudin.
Assuntos
Claudinas/deficiência , Hipercalciúria/prevenção & controle , Túbulos Renais Distais/metabolismo , Alça do Néfron/metabolismo , Deficiência de Magnésio/prevenção & controle , Animais , Cálcio/metabolismo , Claudinas/genética , Modelos Animais de Doenças , Deleção de Genes , Predisposição Genética para Doença , Hipercalciúria/genética , Hipercalciúria/metabolismo , Hipercalciúria/fisiopatologia , Túbulos Renais Distais/patologia , Túbulos Renais Distais/fisiopatologia , Alça do Néfron/patologia , Alça do Néfron/fisiopatologia , Magnésio/metabolismo , Deficiência de Magnésio/genética , Deficiência de Magnésio/metabolismo , Deficiência de Magnésio/fisiopatologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nefrocalcinose/genética , Nefrocalcinose/metabolismo , Nefrocalcinose/fisiopatologia , Nefrocalcinose/prevenção & controle , Fenótipo , Sódio/metabolismoRESUMO
PURPOSE: Kidney stone disease is characterized by a relatively high rate of recurrence. In our study we analyzed the association between relative supersaturation and the risk of stone recurrence. Additionally, we examined the association between the risk of recurrence and changes in relative supersaturation and urinary composition after 1 week of medical treatment. MATERIALS AND METHODS: We performed a post hoc analysis of data from a previously published randomized controlled trial comparing the effect of 2 diets in 120 men with recurrent calcium oxalate stones and hypercalciuria. Baseline and followup 24-hour urine parameters were used to calculate the relative supersaturation of calcium oxalate, calcium phosphate and uric acid using the EQUIL2, JESS and LithoRisk computer programs. Cox models were used to calculate the estimated association between each baseline relative supersaturation, and 1-week changes and the risk of recurrence during followup. RESULTS: During a 5-year followup 35 patients (34%) experienced recurrence. A reduction in calcium oxalate relative supersaturation at 1 week was significantly associated with a lower risk of recurrence using the EQUIL2 calculation (for every 10% reduction from baseline HR 0.92, 95% CI 0.86-1.00, p = 0.044). However, there was no association for relative supersaturation calculated by other methods or for the relative supersaturation of other salts. Changes in the 24-hour urine excretion of citrate, potassium and magnesium were significantly associated with a risk of recurrence. CONCLUSIONS: In recurrent stone formers with hypercalciuria baseline values and changes in the relative supersaturation of calcium oxalate may be associated with the risk of recurrence. Changes in urinary citrate, potassium and magnesium following dietary intervention may also be predictive.
Assuntos
Oxalato de Cálcio/urina , Hipercalciúria/diagnóstico , Cálculos Renais/diagnóstico , Prevenção Secundária/métodos , Adulto , Fosfatos de Cálcio/urina , Ácido Cítrico/urina , Feminino , Seguimentos , Humanos , Hipercalciúria/dietoterapia , Hipercalciúria/prevenção & controle , Hipercalciúria/urina , Cálculos Renais/dietoterapia , Cálculos Renais/prevenção & controle , Cálculos Renais/urina , Magnésio/urina , Masculino , Pessoa de Meia-Idade , Potássio/urina , Valor Preditivo dos Testes , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Recidiva , Medição de Risco/métodos , Fatores de Tempo , Ácido Úrico/urinaRESUMO
Dent disease is a rare X-linked tubulopathy caused by mutations in the endosomal chloride-proton exchanger (ClC-5) resulting in defective receptor-mediated endocytosis and severe proximal tubule dysfunction. Bone marrow transplantation has recently been shown to preserve kidney function in cystinosis, a lysosomal storage disease causing proximal tubule dysfunction. Here we test the effects of bone marrow transplantation in Clcn5Y/- mice, a faithful model for Dent disease. Transplantation of wild-type bone marrow in Clcn5Y/- mice significantly improved proximal tubule dysfunction, with decreased low-molecular-weight proteinuria, glycosuria, calciuria, and polyuria four months after transplantation, compared to Clcn5Y/- mice transplanted with ClC-5 knockout bone marrow. Bone marrow-derived cells engrafted in the interstitium, surrounding proximal tubule cells, which showed a rescue of the apical expression of ClC-5 and megalin receptors. The improvement of proximal tubule dysfunction correlated with Clcn5 gene expression in kidneys of mice transplanted with wild-type bone marrow cells. Coculture of Clcn5Y/- proximal tubule cells with bone marrow-derived cells confirmed rescue of ClC-5 and megalin, resulting in improved endocytosis. Nanotubular extensions between the engrafted bone marrow-derived cells and proximal tubule cells were observed in vivo and in vitro. No rescue was found when the formation of the tunneling nanotubes was prevented by actin depolymerization or when cells were physically separated by transwell inserts. Thus, bone marrow transplantation may rescue the epithelial phenotype due to an inherited endosomal defect. Direct contacts between bone marrow-derived cells and diseased tubular cells play a key role in the rescue mechanism.
Assuntos
Transplante de Medula Óssea , Canais de Cloreto/deficiência , Doença de Dent/cirurgia , Túbulos Renais Proximais/fisiopatologia , Animais , Comunicação Celular , Células Cultivadas , Canais de Cloreto/genética , Técnicas de Cocultura , Doença de Dent/genética , Doença de Dent/metabolismo , Doença de Dent/fisiopatologia , Modelos Animais de Doenças , Endocitose , Predisposição Genética para Doença , Glicosúria/genética , Glicosúria/metabolismo , Glicosúria/fisiopatologia , Glicosúria/prevenção & controle , Hipercalciúria/genética , Hipercalciúria/metabolismo , Hipercalciúria/fisiopatologia , Hipercalciúria/prevenção & controle , Túbulos Renais Proximais/metabolismo , Túbulos Renais Proximais/patologia , Proteína-2 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Poliúria/genética , Poliúria/metabolismo , Poliúria/fisiopatologia , Poliúria/prevenção & controle , Proteinúria/genética , Proteinúria/metabolismo , Proteinúria/fisiopatologia , Proteinúria/prevenção & controle , Recuperação de Função Fisiológica , Quimeras de TransplanteRESUMO
UNLABELLED: The aim of the study was to evaluate bone mineral density (BMD) in the lumbar spine in children with idiopathic hypercalciuria. PATIENTS AND METHODS: The study group included 31 children (14 boys, 17 girls) aged 5 to 17 years (mean age 9.8 ± 4.0 years) with idiopathic hypercalciuria. All children remained on normal calcium diet, without vitamin D and citrate supplementation. We evaluated lumbar spine (L1-L4) BMD (L1-L4 BMD) (expressed as Z-score) and blood serum levels of 25-hydroxyvitamin D3 (250HD3), calcium (Ca), phosphorus (P), alkaline phosphatase (ALP), and intact parathormone (iPTH). We also evaluated 24-hour urinary Ca, P, and sodium (Na) excretion. RESULTS: Reduced L1-L4 BMD Z-score <-1 was found in 25.8% of children, Z-score values from -1 to 1 in 64.5% of children, and Z-score > 1 in 9.7% of children. Reduced 250HD3 level (< 20 ng/mL) was found in 71% of children, levels in the range of 20-30 ng/mL in 22.6% of children, and levels > 30 ng/mL in 6.4% of children. Seven out of 8 children with L1-L4 BMD Z-score <-1 were found to have 250HD3 deficiency (level < 20 ng/mL). Among children with reduced lumbar spine BMD, most were girls at the mean age of 13.8 years. Ca and P levels were normal in all children. We did not find significant differences in 25OHD3, Ca, and P levels in relation to gender and age. We found a positive correlation between L1-L4 BMD Z-score and serum 250HD3 level. Concomitant nephrolithiasis was found in 50% of patients with reduced lumbar spine BMD. CONCLUSIONS: Reduced lumbar spine BMD in patients with idiopathic hypercalciuria seems to be related to vitamin D3 deficiency.
Assuntos
Densidade Óssea , Hipercalciúria/sangue , Hipercalciúria/diagnóstico por imagem , Vértebras Lombares/diagnóstico por imagem , Absorciometria de Fóton , Adolescente , Fosfatase Alcalina/sangue , Biomarcadores/sangue , Calcifediol/sangue , Cálcio/sangue , Criança , Feminino , Humanos , Hipercalciúria/prevenção & controle , Masculino , Hormônio Paratireóideo/sangue , Fósforo/sangue , PolôniaRESUMO
We report about a female patient with severe hypomagnesemia under therapy with proton pump inhibitors (PPI) who presented with a cerebral seizure. Chronic use of PPIs can cause hypomagnesemia. Because of mostly unspecific symptoms which become symptomatic only with severe deficiency, the disease pattern is underdiagnosed. Hypomagnesemia is currently coming increasingly more to the forefront of medical literature.
Assuntos
Apraxias/induzido quimicamente , Tontura/induzido quimicamente , Hipercalciúria/induzido quimicamente , Hipercalciúria/diagnóstico , Nefrocalcinose/induzido quimicamente , Nefrocalcinose/diagnóstico , Inibidores da Bomba de Prótons/efeitos adversos , Erros Inatos do Transporte Tubular Renal/induzido quimicamente , Erros Inatos do Transporte Tubular Renal/diagnóstico , Convulsões/induzido quimicamente , Idoso , Apraxias/prevenção & controle , Diagnóstico Diferencial , Tontura/prevenção & controle , Feminino , Humanos , Hipercalciúria/prevenção & controle , Nefrocalcinose/prevenção & controle , Erros Inatos do Transporte Tubular Renal/prevenção & controle , Convulsões/prevenção & controleRESUMO
Osteoporosis is characterized by a reduction in bone mineral density (BMD) . Reduced BMD has been reported in urolithiasis patients with hypercalciuria, as well as in those with normocalciuria. Bisphosphonates potently inhibit bone resorption and are used in the management of osteoporosis. We show the ability of bisphosphonate to prevent the recurrence of urolithiasis. Bisphosphonate reduced the excretion of urinary calcium and the ion activity product index of calcium phosphate in urolithiasis patients, and prevented urinary stone formation in long-term bed rest test. The results suggest that ALN not only improves osteoporosis but also reduces the risk of calcium stone formation. Bisphosponates are believed to reduce the urinary excretion of calcium by improvement of bone metabolism, and to have a direct effect in the prevention of urolithiasis.
Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Difosfonatos/uso terapêutico , Urolitíase/tratamento farmacológico , Urolitíase/prevenção & controle , Alendronato/farmacologia , Alendronato/uso terapêutico , Animais , Repouso em Cama/efeitos adversos , Conservadores da Densidade Óssea/química , Conservadores da Densidade Óssea/farmacologia , Reabsorção Óssea/prevenção & controle , Osso e Ossos/metabolismo , Fosfatos de Cálcio/metabolismo , Difosfonatos/química , Difosfonatos/farmacologia , Humanos , Hipercalciúria/prevenção & controle , Osteoporose/tratamento farmacológico , Osteoporose/metabolismo , Fatores de Tempo , Urolitíase/etiologia , Urolitíase/metabolismoRESUMO
There is a paucity of data on the use of SGLT2 inhibitors on outcomes in kidney transplant recipients. There may be concern in initiating these agents, especially within the first year post-transplant when renal function is more labile and immunosuppression more intense, due to a presumed high risk of urinary infections and acute kidney injury. This is a retrospective study on 50 kidney transplant recipients, half of whom were started on therapy within the first year of transplant. Over a follow-up period of 6 months, overall patients had a statistically significant improvement in weight by -2.95 kg [SD 3.54, P = <.0001 (CI: 3.53, 1.50)] as well as hypomagnesemia 0.13 [SD 1.73, P = .0004 (CI: 0.06, 0.20)]. Overall insulin usage declined by -3.7 units [SD 22.8, P = .17]. 14% of patients had at least one urinary tract infection although this rate is not different (~20%) than that reported historically in this high-risk population.
Assuntos
Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/cirurgia , Eletrólitos/metabolismo , Transplante de Rim , Inibidores do Transportador 2 de Sódio-Glicose/administração & dosagem , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/prevenção & controle , Adulto , Idoso , Feminino , Seguimentos , Humanos , Hipercalciúria/etiologia , Hipercalciúria/prevenção & controle , Transplante de Rim/efeitos adversos , Masculino , Pessoa de Meia-Idade , Nefrocalcinose/etiologia , Nefrocalcinose/prevenção & controle , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/prevenção & controle , Erros Inatos do Transporte Tubular Renal/etiologia , Erros Inatos do Transporte Tubular Renal/prevenção & controle , Estudos Retrospectivos , Risco , Fatores de Tempo , Resultado do Tratamento , Aumento de PesoRESUMO
Postsurgical hypoparathyroidism is the most common complication of thyroid surgery. Conventional therapy with high-dose calcium and vitamin D can correct hypocalcemia but can increase the risk of hypercalciuria, renal stones, or ectopic calcification. The aim of the present study was to investigate the efficacy of a calcium-sensing receptor antagonist, also called a calcilytic (AXT914), in rat models of postsurgical hypoparathyroidism. Two postsurgical hypoparathyroidism rat models were made by hemi-parathyroidectomy or total parathyroidectomy with autotransplantation in 10-week-old female Wistar rats. AXT914 or vehicle was administered orally for 2 to 3 weeks. Serum PTH, calcium, and phosphorus levels, and the urinary excretion of calcium were measured. Autotransplanted parathyroid tissues were collected and examined histologically. In the hemi-parathyroidectomy model, the oral administration of the calcilytic AXT914 (5 and 10 mg/kg) for 2 weeks increased serum PTH and calcium levels and decreased serum phosphorus levels and urinary calcium excretion. In the total parathyroidectomy with autotransplantation model, the oral administration of AXT914 (10 mg/kg) for 3 weeks increased serum PTH and calcium levels and decreased serum phosphorus levels. The serum PTH and calcium levels increased by AXT914 were maintained for 1 week, even after discontinuation of the drug. In conclusion, AXT914 increased PTH secretion in rat models of postsurgical hypoparathyroidism, thereby correcting abnormal calcium and phosphorus homeostasis. Furthermore, AXT914 improved the functional recovery of autotransplanted parathyroid tissues.
Assuntos
Hipoparatireoidismo/tratamento farmacológico , Complicações Pós-Operatórias/tratamento farmacológico , Quinazolinonas/administração & dosagem , Animais , Terapia Combinada , Modelos Animais de Doenças , Esquema de Medicação , Feminino , Hipercalciúria/etiologia , Hipercalciúria/prevenção & controle , Hipoparatireoidismo/etiologia , Hipoparatireoidismo/patologia , Glândulas Paratireoides/transplante , Paratireoidectomia/efeitos adversos , Paratireoidectomia/métodos , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/patologia , Período Pós-Operatório , Ratos , Ratos Wistar , Terapias em Estudo , Doenças da Glândula Tireoide/cirurgia , Tireoidectomia/efeitos adversos , Transplante AutólogoRESUMO
PURPOSE: Cetuximab and panitumumab are monoclonal antibodies that target the epidermal growth factor receptor (EGFR). Treatment with cetuximab and panitumumab commonly causes hypomagnesemia, and optimal management of this adverse effect remains unclear. Here, we evaluated the optimal magnesium replacement points based on the risk of severe hypomagnesemia in colorectal cancer patients who received cetuximab or panitumumab. METHODS: We retrospectively evaluated 184 patients who received cetuximab or panitumumab for colorectal cancer at Ogaki Municipal Hospital (Ogaki, Japan) between January 2010 and December 2019. Univariate analyses were conducted to evaluate the relationship between patient baseline characteristics and development of hypomagnesemia following cetuximab or panitumumab treatment. Variables that were significantly associated with hypomagnesemia in the univariate analyses as well as previously reported risk factors were entered into a multivariate logistic regression model. RESULTS: The incidence of hypomagnesemia was associated with panitumumab treatment, pre-replenishment serum magnesium concentration, treatment duration, and treatment line. Severe hypomagnesemia post-cetuximab or panitumumab treatment was significantly associated with low baseline magnesium concentrations (< 1.8 mg/dL; odds ratio 18.100, 95% confidence interval 1.570-210.000; p = 0.020) and low serum magnesium concentrations during treatment (< 1.1 mg/dL; odds ratio 93.800, 95% confidence interval 3.510-2510.000; p = 0.007). CONCLUSION: To minimize the risk of severe hypomagnesemia during anti-EGFR treatment, magnesium replenishment should be initiated in patients with pre-replenishment concentrations of < 1.8 mg/dL, preferably before reaching intra-treatment concentrations of < 1.1 mg/dL.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Hipercalciúria/prevenção & controle , Magnésio/administração & dosagem , Recidiva Local de Neoplasia/tratamento farmacológico , Nefrocalcinose/prevenção & controle , Erros Inatos do Transporte Tubular Renal/prevenção & controle , Adulto , Idoso , Idoso de 80 Anos ou mais , Cetuximab/administração & dosagem , Neoplasias Colorretais/patologia , Feminino , Seguimentos , Humanos , Hipercalciúria/induzido quimicamente , Hipercalciúria/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Nefrocalcinose/induzido quimicamente , Nefrocalcinose/patologia , Panitumumabe/administração & dosagem , Prognóstico , Erros Inatos do Transporte Tubular Renal/induzido quimicamente , Erros Inatos do Transporte Tubular Renal/patologia , Estudos RetrospectivosRESUMO
Hypoparathyroidism is the most common complication after total or completion thyroidectomy. It is defined as the presence of hypocalcemia accompanied by low or inappropriately normal parathyroid hormone (PTH) levels. Acute hypocalcemia is a potential lethal complication. Hypocalcemia treatment is based on endovenous or oral calcium supplements as well as oral calcitriol, depending on the severity of the symptoms. The risk of clinical hypocalcemia after bilateral thyroidectomy is considered very low if postoperative intact PTH decrease less than 80% with respect to preoperative levels. These patients could be discharged home without treatment, although this threshold may vary between institutions, and we recommend close surveillance in cases with increased risk (Graves disease, large goiters, reinterventions or evidence of parathyroid gland removal). Long-term treatment objectives are to control the symptoms and to keep serum calcium levels at the lower limit of the normal range, while preserving the calcium phosphate product and avoiding hypercalciuria.
Assuntos
Hipoparatireoidismo/etiologia , Tireoidectomia/efeitos adversos , Calcitriol/uso terapêutico , Cálcio/sangue , Cálcio/uso terapêutico , Doença de Graves/cirurgia , Humanos , Hipercalciúria/prevenção & controle , Hipercalciúria/terapia , Hiperfosfatemia/tratamento farmacológico , Hiperfosfatemia/etiologia , Hipocalcemia/etiologia , Hipoparatireoidismo/tratamento farmacológico , Hipoparatireoidismo/prevenção & controle , Cuidados Intraoperatórios , Glândulas Paratireoides/cirurgia , Glândulas Paratireoides/transplante , Hormônio Paratireóideo/sangue , Cuidados Pós-Operatórios , ReimplanteRESUMO
Hypoparathyroidism is the most common complication after total or completion thyroidectomy. It is defined as the presence of hypocalcemia accompanied by low or inappropriately normal parathyroid hormone (PTH) levels. Acute hypocalcemia is a potential lethal complication. Hypocalcemia treatment is based on endovenous or oral calcium supplements as well as oral calcitriol, depending on the severity of the symptoms. The risk of clinical hypocalcemia after bilateral thyroidectomy is considered very low if postoperative intact PTH decrease less than 80% with respect to preoperative levels. These patients could be discharged home without treatment, although this threshold may vary between institutions, and we recommend close surveillance in cases with increased risk (Graves disease, large goiters, reinterventions or evidence of parathyroid gland removal). Long-term treatment objectives are to control the symptoms and to keep serum calcium levels at the lower limit of the normal range, while preserving the calcium phosphate product and avoiding hypercalciuria.
Assuntos
Hipoparatireoidismo/etiologia , Complicações Pós-Operatórias/etiologia , Tireoidectomia/efeitos adversos , Assistência ao Convalescente/normas , Algoritmos , Calcitriol/uso terapêutico , Cálcio/administração & dosagem , Cálcio/efeitos adversos , Cálcio/uso terapêutico , Gerenciamento Clínico , Bócio/complicações , Bócio/cirurgia , Doença de Graves/complicações , Doença de Graves/cirurgia , Humanos , Hipercalciúria/induzido quimicamente , Hipercalciúria/prevenção & controle , Hipocalcemia/tratamento farmacológico , Hipocalcemia/etiologia , Hipoparatireoidismo/sangue , Hipoparatireoidismo/tratamento farmacológico , Complicações Intraoperatórias , Glândulas Paratireoides/lesões , Hormônio Paratireóideo/sangue , Hormônio Paratireóideo/deficiência , Cuidados Pós-Operatórios/normas , Complicações Pós-Operatórias/tratamento farmacológicoRESUMO
PURPOSE: The urological community has had a vital role in the author's 35 years of research on the medical management of urolithiasis. The goal of this article is to review the progress made from the perspective of collaborating urologists and urological journals in which the findings were reported. MATERIALS AND METHODS: The author's work appeared in 94 articles in urological journals, including 63 in The Journal of Urology, and in 28 other journals with collaborating urologists. Progress on various aspects of medical management of stone disease was reviewed based on these articles. RESULTS: Pathophysiological exploration was performed by elucidating metabolic-dietary etiologies of hypocitraturia, separating hypercalciuria into 3 types, and linking gouty diathesis (uric acid stones) with obesity and insulin resistance. Physicochemical consequences of hypocitraturia were delineated and semi-empirical methods were developed to assess calcium salt saturation. Potassium-rich fruit juices differed from potassium-poor fruit juices and excessive salt intake increased the stone forming risk. Vital to diagnostic separation was a comprehensive analysis of urine for stone risk factors. As an example of selective treatment, potassium citrate was shown to be useful for controlling uric acid stones by urinary alkalinization as well as calcareous stones by hypercitraturia. CONCLUSIONS: During the last 35 years much progress has been made on the pathophysiology of stone formation, crystallization of stone forming salts, diagnostic separation and prevention of stone recurrence. The author's contribution in this effort would not have been possible without the active participation and support of the urological community.
Assuntos
Urolitíase/terapia , Pesquisa Biomédica , Dieta , Humanos , Hipercalciúria/complicações , Hipercalciúria/prevenção & controle , Citrato de Potássio/uso terapêutico , Recidiva , Fatores de Risco , Urolitíase/classificação , Urolitíase/etiologia , Urolitíase/fisiopatologiaRESUMO
In advanced squamous cell carcinoma of the head and neck, concomitant radiotherapy with cisplatin and/or cetuximab is frequently combined with cisplatin-based induction chemotherapy, which can cause severe hypomagnesemia, hypocalcemia, and hypokalemia. The aim of our study was to analyze the effects of magnesium sulfate supplementation on the incidence of hypomagnesemia, hypokalemia, and hypocalcemia during four cycles of TPF (docetaxel, cisplatin, and 5-fluorouracil) induction chemotherapy followed by concomitant radiotherapy (CRT) with cisplatin and cetuximab. Twenty-five patients included in a phase II prospective study received routine magnesium sulfate infusions before each cycle of cisplatin, and additional supplementation based on laboratory findings. During TPF, the incidence of grade 1/2 and grade 3/4 hypomagnesemia was 16% and 4%, respectively; and increased despite magnesium supplementation during CRT to 72% and 8%, respectively. During TPF, a grade 2 and grade 4 hypocalcemia occurred in 8% and 4%, respectively; and during CRT, it reached 36% (grade 1/2). Grade 1 hypokalemia only was observed during TPF (4%) and CRT (8%). The median amounts of supplemented magnesium sulfate during TPF and CRT were 20 mEq and 50 mEq, respectively. It appears that a low incidence of grade 3/4 hypomagnesemia and hypocalcemia in our patients resulted from intensive magnesium supplementation. Thorough measurements of magnesium and calcium during cisplatin-based chemoradiation protocols in patients with head and neck cancer are crucial in preventing the development of grade 3/4 hypomagnesemia and hypocalcemia.
Assuntos
Quimiorradioterapia/efeitos adversos , Hipercalciúria/prevenção & controle , Hipocalcemia/prevenção & controle , Sulfato de Magnésio/uso terapêutico , Nefrocalcinose/prevenção & controle , Erros Inatos do Transporte Tubular Renal/prevenção & controle , Cetuximab/efeitos adversos , Cetuximab/uso terapêutico , Cisplatino/efeitos adversos , Cisplatino/uso terapêutico , Feminino , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Masculino , Estudos ProspectivosRESUMO
Nephrolithiasis is a common urological disease and could be secondary to primary hyperparathyroidism (PHPT). PHPT is traditionally characterised with hypercalcaemia. Recently, a normocalcemic PHPT has been officially recognised at the International Workshops. Regarding this new phenotype, nephrolithiasis is frequently found in studies that evaluate low bone mass. However, until now, no study on aetiology of nephrolithiasis considered normocalcemic PHPT. Hypercalciuria related to PHPT is considered as an important risk factor of stone formation in hypercalcemic PHPT, but the precise relationships between hypercalcemic PHPT and nephrolithiasis and between normocalcemic PHPT and nephrolithiasis remain unclear. In patients with hypercalcemic PHPT, after a surgical cure of PHPT, the renal calcium excretion and stone recurrence rate reduce but remain higher above health controls. This finding implies that abnormalities not caused by PHPT also probably affect stone formation. According to the new guideline, the presence of stones indicates the need for parathyroidectomy in patients with either hypercalcemic or normocalcemic PHPT unless contraindications exist. Patients with contraindications for parathyroidectomy or those who do not want to receive parathyroidectomy should be monitored for signs of disease progression and given of medical management. Moreover, due to decreased but significantly higher frequency of nephrolithiasis above those of healthy controls, patients with nephrolithiasis associated with PHPT after parathyroidectomy still should be motivated to explore strategies to prevent stone occurrence.
Assuntos
Hipercalcemia/etiologia , Hipercalciúria/etiologia , Hiperparatireoidismo Primário/complicações , Nefrolitíase/etiologia , Densidade Óssea , Cálcio/sangue , Cálcio/urina , Progressão da Doença , Humanos , Hipercalcemia/epidemiologia , Hipercalcemia/prevenção & controle , Hipercalcemia/urina , Hipercalciúria/epidemiologia , Hipercalciúria/prevenção & controle , Hipercalciúria/urina , Hiperparatireoidismo Primário/epidemiologia , Hiperparatireoidismo Primário/cirurgia , Hiperparatireoidismo Primário/urina , Nefrolitíase/epidemiologia , Nefrolitíase/prevenção & controle , Nefrolitíase/urina , Paratireoidectomia , RecidivaRESUMO
Hypomagnesemia is one side effect in patients receiving cisplatin. However, there are few reports of cisplatin-induced hypomagnesemia in Japan. We retrospectively investigated the incidence of hypomagnesemia and nephrotoxicity in patients undergoing radiation therapy who were treated with cisplatin alone (dosage: 40 mg/m2, administration interval: 1 week) for cervical cancer. Thirty-two patients undergoing radiation therapy who received cisplatin alone for cervical cancer between January 2012 and May 2016 at Aichi Medical University Hospital were included. We measured patients' serum magnesium and creatinine levels on the day before cisplatin was administered. We utilized the RIFLE criteria (categorized into "risk", "injury", "failure", "loss", and "end-stage kidney disease") to define levels of cisplatin-induced nephrotoxicity, and classified cisplatin-induced nephrotoxicity into "risk" or "injury". Eighteen patients (56.3%) had cisplatin-induced hypomagnesemia, the majority of which occurred after the 4th treatment cycle. The number of patients with moderate renal dysfunction classified as "risk" in the hypomagnesemia group was not significantly higher than in the non-hypomagnesemia group (hypomagnesemia group=27.8%, non-hypomagnesemia group=7.1%; p=0.20). This survey sheds light on the incidence rates of cisplatin-induced hypomagnesemia in patients receiving cisplatin alone. We recommend monitoring the serum magnesium levels during cisplatin administration to prevent hypomagnesemia.
Assuntos
Antineoplásicos/efeitos adversos , Cisplatino/efeitos adversos , Hipercalciúria/induzido quimicamente , Hipercalciúria/epidemiologia , Nefrocalcinose/induzido quimicamente , Nefrocalcinose/epidemiologia , Erros Inatos do Transporte Tubular Renal/induzido quimicamente , Erros Inatos do Transporte Tubular Renal/epidemiologia , Neoplasias do Colo do Útero/tratamento farmacológico , Antineoplásicos/toxicidade , Cisplatino/toxicidade , Terapia Combinada , Feminino , Humanos , Hipercalciúria/prevenção & controle , Incidência , Monitorização Fisiológica , Nefrocalcinose/prevenção & controle , Erros Inatos do Transporte Tubular Renal/prevenção & controle , Estudos Retrospectivos , Neoplasias do Colo do Útero/radioterapiaRESUMO
Over the past 10 years, major progress has been made in the knowledge of urinary lithogenesis, including the potential pathogenetic role of Randall's plaques and renal tubular crystal retention. Urine supersaturation is the driving force of this process and can be induced by some risk factors, including low urine volume, high urinary excretion of calcium oxalate and uric acid and low urinary excretion of citrate. Primary hypercalciuria can be due to intestinal overabsorption renal leak and bone reabsorption of calcium. Prophilaxis is mainly conducted with thiazides and low calcium diet which is indicated only in the intestinal form. Primary hyperoxaluria is treated with pyridoxine and may require in the severe forms simultaneous renal and liver transplantation. Enteric hyperoxaluria is secondary to fatty acids malabsorption and requires diet, oral calcium and cholestiramine. Hyperuricosuria is caused by diet endogenous overproduction, mainly due to enzymatic defects or high renal excretion of uric acid. Urine alkalinization with K or K and Mg citrate can prevent stone formation even in idiopathic uric acid nephrolithiasis, in which a defect of urine acidification is supposed to be the main abnormality, and in hypocitraturic patients. Cystinuria is a rare inherited defect with an intense clinical impact. It can be classified in three forms and urinary stone formation is the role. Increased solubility and conversion of cystine in a more soluble form are the main goals of the prophylaxis which includes K citrate and thiol agents administration. Tiopronin is preferred to D-penicillamine due to its lower side effects.
Assuntos
Cistinúria/prevenção & controle , Hipercalciúria/prevenção & controle , Hiperoxalúria/prevenção & controle , Rim/metabolismo , Nefrolitíase/metabolismo , Nefrolitíase/terapia , Catárticos/uso terapêutico , Ácido Cítrico/uso terapêutico , Cistinúria/complicações , Quimioterapia Combinada , Humanos , Hipercalciúria/complicações , Hiperoxalúria/complicações , Nefrolitíase/dietoterapia , Nefrolitíase/tratamento farmacológico , Nefrolitíase/etiologia , Nefrolitíase/prevenção & controle , Compostos Organometálicos/uso terapêutico , Piridoxina/uso terapêutico , Fatores de Risco , Distribuição por Sexo , Tiazidas/uso terapêutico , Tiopronina/uso terapêutico , Resultado do Tratamento , Complexo Vitamínico B/uso terapêuticoRESUMO
'Biased agonism' refers to the ability of a ligand to selectively recruit different intracellular signaling proteins to elicit distinct phenotypic effects in cells. While conventional G protein-coupled receptor (GPCR) agonism and antagonism can be regarded as modulating the quantity of efficacy, functionally selective or 'biased' ligands qualitatively change the trafficking of information flowing across the plasma membrane. The concept of ligand directed signaling fundamentally raises the potential of pharmacologic agents with novel therapeutic profiles possessing improved therapeutic efficacy or reduced side effects. Currently, there is little experimental evidence that biased ligands offer advantages over conventional agonists/antagonists in vivo. Recent work examining biased agonism at the type I parathyroid hormone receptor (PTH1R) demonstrates that selective activation of G protein-independent arrestin-mediated signaling pathways elicits a physiologic response in bone distinct from that induced by the conventional PTH1R agonist PTH(1-34). While intermittent (daily) administration of PTH(1-34) (teriparitide) is effective in increasing bone formation, PTH(1-34) administration is also associated with increases in bone resorption and a propensity to promote hypercalcemia/hypercalcuria. In contrast, D-Trp12,Tyr34-bPTH(7-34) (PTH-ßarr), an arrestin pathway-selective agonist for the PTH1R, induces anabolic bone formation independent of classic G protein-coupled signaling mechanisms. Unlike PTH(1-34), PTH-ßarr appears to 'uncouple' the anabolic effects of PTH1R activation from its catabolic and calcitropic effects. Such findings offer evidence that arrestin pathway-selective GPCR agonists can elicit potentially beneficial effects in vivo that cannot be achieved using conventional agonist or antagonist ligands.