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1.
Front Endocrinol (Lausanne) ; 15: 1382066, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38803472

RESUMO

The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is frequent in lung cancer patients. Here, we report a case with persistent hyponatremia, which suggested malignant SIADH and facilitated an early diagnosis of small cell lung cancer (SCLC). A combined radio-chemotherapy led to a partial remission and resolution of SIADH. An early relapse was indicated by reoccurring severe hyponatremia and increased copeptin levels, which were used as surrogate markers for the antidiuretic hormone (ADH). As palliative immunochemotherapy, together with fluid restriction and solute substitution, were unable to control hyponatremia, treatment with the ADH V2-receptor antagonist tolvaptan was initiated. Over time, the dose of tolvaptan needed to be increased, paralleled by a well-documented exponential increase of copeptin levels. In summary and conclusion, this is a rare case of a secondary failure to tolvaptan with unique documentary evidence of increasing copeptin levels. This observation supports the hypothesis that exceedingly high ADH levels may lead to competitive displacement of tolvaptan from the V2 receptor.


Assuntos
Antagonistas dos Receptores de Hormônios Antidiuréticos , Síndrome de Secreção Inadequada de HAD , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Tolvaptan , Humanos , Tolvaptan/uso terapêutico , Síndrome de Secreção Inadequada de HAD/tratamento farmacológico , Síndrome de Secreção Inadequada de HAD/complicações , Carcinoma de Pequenas Células do Pulmão/complicações , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/tratamento farmacológico , Antagonistas dos Receptores de Hormônios Antidiuréticos/uso terapêutico , Masculino , Hiponatremia/tratamento farmacológico , Hiponatremia/etiologia , Idoso , Falha de Tratamento , Pessoa de Meia-Idade
2.
Artigo em Inglês | MEDLINE | ID: mdl-38116790

RESUMO

Summary: Barakat syndrome, also called HDR syndrome, is a rare genetic disorder encompassing hypoparathyroidism (H), sensorineural deafness (D) and renal disease (R). A 64-year-old woman was referred to our endocrinology clinic for a switch in treatment (from dihydrotachysterol to calcitriol). She had progressive sensorineural deafness since the age of 18 and idiopathic hypoparathyroidism diagnosed at age of 36. Her medical history included osteoporosis with hip/spine fractures, nephrolithiasis and a family history of hearing loss, osteoporosis and kidney disease. The patient's clinical presentation indicated Barakat syndrome. Genetic analysis found a GATA3:c.916C>T nonsense variant. Further tests such as audiometry, labs and renal imaging supported the diagnosis. Due to rarity and manifold symptoms, diagnosis can be challenging. Optional GATA3 testing was suggested in 2018, except in cases of isolated sensorineural deafness or renal disease with pertinent family history. In isolated 'H' cases without 'D' and 'R', GATA3 studies are not required, as no haploinsufficiency cases were reported. Given the rise in genetic disorders, physicians should consistently consider rare genetic disorders in patients with suggestive symptoms, even decades after onset. Although diagnosis might not always impact management directly, it aids patients in accepting their condition and has broader family implications. Learning points: There is currently an important increase in genetic and clinical characterization of new orphan diseases and their causative agents. Unbiased re-evaluation for possible genetic disorders is necessary at every consultation. It is essential to recognize the differential diagnosis of idiopathic hypoparathyroidism. The patient's clinical presentation and family history can be important to establish the correct diagnosis. Physicians should not hesitate to search a patient's signs and symptoms online.

3.
Front Pharmacol ; 11: 882, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32595505

RESUMO

We present the case of a kidney transplant patient (Cockroft-Gault estimated creatinine clearance 14 ml/min) who was inadvertently eight-fold overdosed with a single dose of 500 mg intravenous ganciclovir. To prevent the immunosuppressed patient from being exposed to severe risks of prolonged ganciclovir overdosing, including potentially fatal bone marrow suppression and severe neurotoxicity, the patient was treated with hemodiafiltration (HDF) to enhance drug elimination. Since the product label reports a 50% decrease of ganciclovir plasma concentrations after intermittent hemodialysis (HD), two HDF sessions were considered necessary to achieve a ≥75% elimination of the drug by precaution, despite targeted intense HDF prescription. Ganciclovir plasma concentration data were obtained during both HDF sessions and were analyzed retrospectively. Pharmacokinetic analysis revealed that prescribed HDF successfully decreased drug plasma concentrations by ≥90%. This ganciclovir reduction ratio matched the urea reduction ratio achieved (≥92%). Model-based assessment of ganciclovir dialysis clearance (estimated to be 445 ml/min), accounting for its two-compartmental kinetics, was higher than urea dialysis clearance (estimated to be 310 ml/min). This suggests potential relevant accumulation of ganciclovir into blood cells, at least in this patient after overdosing. The amount (fraction) of drug removed by 1st HDF was estimated to 269 mg (93% of total amount of 288 mg eliminated during the 1st HDF session; estimated amount in the body prior to 1st HDF: 380 mg). A literature review was performed to summarize and systematically compare available information on ganciclovir elimination during intermittent renal replacement therapy. In conclusion, the high ganciclovir HDF clearance measured in our patient largely exceeded previously reported elimination during HD, meaning that HDF prescription was highly efficient in the present case, and that a second HDF session might not have been necessary. This finding may be considered to guide renal replacement therapy in the scope of drug overdosing. It may also be evaluated for ganciclovir dose adjustment in patients on chronic HD or HDF with high small solute clearance, since a strong correlation between ganciclovir and urea elimination efficiency was observed.

4.
Front Oncol ; 9: 734, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31475102

RESUMO

Carcinoma showing thymus-like elements (CASTLE) is a rare tumor, most commonly found in the thyroid gland. Here we report a case of CASTLE tumor localized to the parotid gland, recognized in retrospect after a late manifestation of symptomatic pleural carcinomatosis. The original tumor in the parotid gland was treated by surgery followed by radiotherapy. Ten years later, a metastatic disease with recurrent pleural effusions occurred. Pleural carcinomatosis was strongly positive for CD5, CD117, and p63 as was the original tumor of the parotid, which allowed the diagnosis of a CASTLE tumor. Additionally, the pleural tumor expressed high levels of programmed death ligand 1 (PD-L1), and the patient underwent treatment with the monoclonal PD-L1 inhibitor pembrolizumab achieving a partial remission. To the best of our knowledge, this is the first patient with a metastatic CASTLE tumor treated with a PD-L1 inhibitor.

5.
Cell Chem Biol ; 25(2): 175-184.e4, 2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-29249695

RESUMO

Progressive kidney diseases affect approximately 500 million people worldwide. Podocytes are terminally differentiated cells of the kidney filter, the loss of which leads to disease progression and kidney failure. To date, there are no therapies to promote podocyte survival. Drug repurposing may therefore help accelerate the development of cures in an area of tremendous unmet need. In a newly developed high-throughput screening assay of podocyte viability, we identified the BRAFV600E inhibitor GDC-0879 and the adenylate cyclase agonist forskolin as podocyte-survival-promoting compounds. GDC-0879 protects podocytes from injury through paradoxical activation of the MEK/ERK pathway. Forskolin promotes podocyte survival by attenuating protein biosynthesis. Importantly, GDC-0879 and forskolin are shown to promote podocyte survival against an array of cellular stressors. This work reveals new therapeutic targets for much needed podocyte-protective therapies and provides insights into the use of GDC-0879-like molecules for the treatment of progressive kidney diseases.


Assuntos
Indenos/farmacologia , Nefropatias/tratamento farmacológico , Podócitos/efeitos dos fármacos , Pirazóis/farmacologia , Morte Celular/efeitos dos fármacos , Colforsina/química , Colforsina/farmacologia , Humanos , Indenos/química , Nefropatias/metabolismo , Nefropatias/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Podócitos/metabolismo , Podócitos/patologia , Pirazóis/química , Transdução de Sinais/efeitos dos fármacos , Tapsigargina/antagonistas & inibidores , Tapsigargina/farmacologia
6.
Ther Umsch ; 72(3): 149-55, 2015 Mar.
Artigo em Alemão | MEDLINE | ID: mdl-25722307

RESUMO

Diabetic nephropathy is the most common cause of end-stage renal disease and is associated with a high morbidity and mortality. Early diagnosis is important as tight control of albuminuria and hypertension improves the renal prognosis. Similarly, good control of hyperglycemia is critical, but emphasis should be given on individualization of treatment goals. Once the estimated GFR is < 60 ml/min/1.73 m2 the antidiabetic medication needs to be reviewed and a dose reduction of many drugs is necessary. The risk for hypoglycemia is particularly high for the sulfonylureas glibenclamide and glimepiride and they are contraindicated once the GFR is < 60 ml/min/1.73 m2. Because of the increased risk of lactic acidosis, metformin requires a dose adjustment if the GFR is < 60 ml/min/1.73 m2 and the drug should be stopped once the GFR falls < 45 ml/min/1.73 m2. In addition, metformin needs to be paused if acute renal failure is imminent. Inhibitors of the DPP-4 enzyme can be employed with impaired renal function, but their use usually requires dose adjustments. Prescription of GLP-1 receptor agonists is possible with a moderately impaired renal function but they should be discontinued if the GFR falls < 30/min/1.73 m2. From the new class of SGLT2 inhibitors canagliflozin and empagliflozin can be used in an adjusted dose as long as the GFR is > 45 ml/min/1.73 m2.


Assuntos
Nefropatias Diabéticas/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Falência Renal Crônica/tratamento farmacológico , Nefropatias Diabéticas/sangue , Relação Dose-Resposta a Droga , Esquema de Medicação , Taxa de Filtração Glomerular/efeitos dos fármacos , Hemoglobinas Glicadas/metabolismo , Humanos , Falência Renal Crônica/sangue
7.
Artigo em Inglês | MEDLINE | ID: mdl-25386168

RESUMO

Podocyte injury and loss critically contribute to the pathogenesis of proteinuric kidney diseases including diabetic nephropathy. Deregulated lipid metabolism with disturbed free fatty acid (FFA) metabolism is a characteristic of metabolically unhealthy obesity and type 2 diabetes and likely contributes to end-stage kidney disease irrespective of the underlying kidney disease. In the current review, we summarize recent findings related to FFAs and altered renal FFA metabolism with a special focus on podocytes. We will outline the opposing effects of saturated and monounsaturated FFAs and a particular emphasis will be given to the underlying molecular mechanisms involving insulin resistance and endoplasmic reticulum homeostasis. Finally, recent data suggesting a critical role of renal FFA metabolism to adapt to an altered lipid environment will be discussed.

8.
Am J Physiol Renal Physiol ; 306(4): F401-9, 2014 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-24338821

RESUMO

Type 2 diabetes is characterized by dyslipidemia with elevated free fatty acids (FFAs). Loss of podocytes is a hallmark of diabetic nephropathy, and podocytes are susceptible to saturated FFAs, which induce endoplasmic reticulum (ER) stress and podocyte death. Genome-wide association studies indicate that expression of acetyl-CoA carboxylase (ACC) 2, a key enzyme of fatty acid oxidation (FAO), is associated with proteinuria in type 2 diabetes. Here, we show that stimulation of FAO by aminoimidazole-4-carboxamide-1ß-D-ribofuranoside (AICAR) or by adiponectin, activators of the low-energy sensor AMP-activated protein kinase (AMPK), protects from palmitic acid-induced podocyte death. Conversely, inhibition of carnitine palmitoyltransferase (CPT-1), the rate-limiting enzyme of FAO and downstream target of AMPK, augments palmitic acid toxicity and impedes the protective AICAR effect. Etomoxir blocked the AICAR-induced FAO measured with tritium-labeled palmitic acid. The beneficial effect of AICAR was associated with a reduction of ER stress, and it was markedly reduced in ACC-1/-2 double-silenced podocytes. In conclusion, the stimulation of FAO by modulating the AMPK-ACC-CPT-1 pathway may be part of a protective mechanism against saturated FFAs that drive podocyte death. Further studies are needed to investigate the potentially novel therapeutic implications of these findings.


Assuntos
Acetil-CoA Carboxilase/metabolismo , Ácidos Graxos/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Ácido Palmítico/farmacologia , Podócitos/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Aminoimidazol Carboxamida/análogos & derivados , Aminoimidazol Carboxamida/farmacologia , Animais , Carnitina O-Palmitoiltransferase/antagonistas & inibidores , Carnitina O-Palmitoiltransferase/metabolismo , Células Cultivadas , Camundongos , Podócitos/metabolismo , Ribonucleotídeos/farmacologia
9.
Am J Physiol Renal Physiol ; 299(4): F821-9, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20668104

RESUMO

Apoptosis of podocytes is considered critical in the pathogenesis of diabetic nephropathy (DN). Free fatty acids (FFAs) are critically involved in the pathogenesis of diabetes mellitus type 2, in particular the regulation of pancreatic ß cell survival. The objectives of this study were to elucidate the role of palmitic acid, palmitoleic, and oleic acid in the regulation of podocyte cell death and endoplasmic reticulum (ER) stress. We show that palmitic acid increases podocyte cell death, both apoptosis and necrosis of podocytes, in a dose and time-dependent fashion. Palmitic acid induces podocyte ER stress, leading to an unfolded protein response as reflected by the induction of the ER chaperone immunoglobulin heavy chain binding protein (BiP) and proapoptotic C/EBP homologous protein (CHOP) transcription factor. Of note, the monounsaturated palmitoleic and oleic acid can attenuate the palmitic acid-induced upregulation of CHOP, thereby preventing cell death. Similarly, gene silencing of CHOP protects against palmitic acid-induced podocyte apoptosis. Our results offer a rationale for interventional studies aimed at testing whether dietary shifting of the FFA balance toward unsaturated FFAs can delay the progression of DN.


Assuntos
Apoptose/efeitos dos fármacos , Retículo Endoplasmático/efeitos dos fármacos , Ácidos Graxos Monoinsaturados/farmacologia , Ácido Oleico/farmacologia , Ácido Palmítico/farmacologia , Podócitos/efeitos dos fármacos , Estresse Fisiológico/fisiologia , Animais , Caspase 3/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Retículo Endoplasmático/fisiologia , Inativação Gênica , Camundongos , Modelos Animais , Podócitos/citologia , Podócitos/metabolismo , Fator de Transcrição CHOP/genética , Fator de Transcrição CHOP/metabolismo
10.
J Biol Chem ; 278(44): 42906-12, 2003 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-12917409

RESUMO

ATP-binding cassette transporter 1 (ABCA1), the defective transporter in Tangier disease, binds and promotes cellular cholesterol and phospholipid efflux to apolipoprotein I (apoA-I). Based on a high degree of sequence homology between ABCA1 and ABCA7, a transporter of unknown function, we investigated the possibility that ABCA7 might be involved in apolipoprotein binding and lipid efflux. Similarly to cells expressing ABCA1, HEK293 cells overexpressing ABCA7 showed specific binding and cross-linking of lipid-poor apoA-I. ABCA7 expression increased cellular phosphatidylcholine and sphingomyelin efflux to apoA-I in a manner similar to ABCA1 but had no effect on cholesterol efflux. Western analysis showed a high protein level of ABCA7 in mouse spleen, lung, adrenal, and brain but low expression in liver. In contrast to ABCA1, ABCA7 showed moderate basal mRNA and protein levels in macrophages and lymphocytes but no induction by liver X receptor activation. These studies show that ABCA7 has the ability to bind apolipoproteins and promote efflux of cellular phospholipids without cholesterol, and they suggest a possible role of ABCA7 in cellular phospholipid metabolism in peripheral tissues.


Assuntos
Transportadores de Cassetes de Ligação de ATP/fisiologia , Apolipoproteína A-I/metabolismo , Colesterol/metabolismo , Transportadores de Cassetes de Ligação de ATP/metabolismo , Glândulas Suprarrenais/metabolismo , Animais , Transporte Biológico , Western Blotting , Encéfalo/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Linhagem Celular , Células Cultivadas , Proteínas de Ligação a DNA , Eletroforese em Gel de Poliacrilamida , Vetores Genéticos , Humanos , Metabolismo dos Lipídeos , Fígado/metabolismo , Receptores X do Fígado , Pulmão/metabolismo , Linfócitos/metabolismo , Macrófagos/metabolismo , Camundongos , Microscopia Confocal , Receptores Nucleares Órfãos , Peritônio/patologia , Fosfatidilcolinas/metabolismo , Fosfolipídeos/metabolismo , Plasmídeos/metabolismo , Ligação Proteica , RNA Mensageiro/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Esfingomielinas/metabolismo , Baço/metabolismo , Distribuição Tecidual , Transfecção
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