RESUMEN
Systemic treatment with immune checkpoint inhibitors (ICI) has revolutionized the treatment of hematological and oncological diseases in recent years. The mechanism of action hinges on enhancing the natural ability of the immune system to eliminate malignant cells. The most important substances in this arena include inhibitors of PD1, PD-L1 and CTLA4. As a consequence, the spectrum of treatment-associated adverse reactions is shifting away from classical cytotoxic effects (e.g. pancytopenia and polyneuropathy) towards novel entities of immune-mediated complex diseases. These so-called immune-related adverse events (irAEs) can involve any organ system and mimic known classical autoimmune conditions. Timely recognition of irAEs is the key for rapid initiation of a suitable treatment and is especially challenging in the clinical routine as it requires an intensive interdisciplinary management. Nephrologists are particularly confronted with this kind of problem due to the highly interdisciplinary nature of their work. This article summarizes the broad spectrum of currently known renal and more frequently occuring non-renal forms of irAEs and aims to prime the reader on diagnostic and therapeutic options.
Asunto(s)
Aneurisma Infectado/etiología , Aneurisma de la Aorta/diagnóstico por imagen , Aneurisma de la Aorta/etiología , Empiema Pleural/complicaciones , Infecciones Neumocócicas/etiología , Aneurisma Infectado/diagnóstico por imagen , Empiema Pleural/diagnóstico por imagen , Resultado Fatal , Humanos , Masculino , Persona de Mediana Edad , Infecciones Neumocócicas/diagnóstico por imagen , Radiografía , Insuficiencia Respiratoria/microbiología , Choque/microbiologíaAsunto(s)
Enfermedades del Ciego/etiología , Servicios Médicos de Urgencia/métodos , Enfermedades del Íleon/etiología , Vólvulo Intestinal/etiología , Mesenterio , Enfermedades Peritoneales/complicaciones , Dolor Abdominal/etiología , Enfermedades del Ciego/diagnóstico , Enfermedades del Ciego/patología , Enfermedades del Ciego/cirugía , Femenino , Humanos , Enfermedades del Íleon/diagnóstico , Enfermedades del Íleon/patología , Enfermedades del Íleon/cirugía , Vólvulo Intestinal/diagnóstico , Vólvulo Intestinal/patología , Vólvulo Intestinal/cirugía , Persona de Mediana Edad , Náusea/etiología , Enfermedades Peritoneales/diagnóstico , Enfermedades Peritoneales/patología , Enfermedades Peritoneales/cirugía , Radiografía Abdominal , Anomalía Torsional , Resultado del TratamientoRESUMEN
A 46-year-old female patient with Sjögren's syndrome, hypertension, and stable chronic renal insufficiency (creatinine [CR], 1.9 to 2.1 mg/dL) had a progressive worsening of renal function (CR, 5.0 mg/dL) after 11 months of chloroquine therapy (155 mg/day; cumulative dose of approximately 51 g). Light microscopy revealed nonspecific angionephrosclerosis. Electron microscopy showed accumulations of lamellated myelinoid material and occasionally also of curvilinear bodies, especially in the glomerular podocytes and to a lesser extent in vascular myothelial and endothelial cells. In the tubular system, mainly protein droplets were stored. Activity of alpha-galactosidase A was normal in isolated leukocytes (56 nmol/mg; range, 33.2 to 109 nmol/mg), ruling out Fabry's disease. Clinical, morphological, and biochemical findings were consistent with chloroquine-associated deterioration of renal function that improved considerably after discontinuation of chloroquine treatment. Adverse effects of chloroquine may aggravate preexisting renal disease. Electron microscopy is a worthwhile tool for establishing the correct diagnosis.
Asunto(s)
Cloroquina/efectos adversos , Enfermedad de Fabry , Enfermedades Renales/inducido químicamente , Fosfolípidos/metabolismo , Síndrome de Sjögren/tratamiento farmacológico , Diagnóstico Diferencial , Femenino , Humanos , Hipertensión/complicaciones , Riñón/ultraestructura , Enfermedades Renales/patología , Fallo Renal Crónico/complicaciones , Glomérulos Renales/ultraestructura , Leucocitos/enzimología , Microscopía Electrónica , Persona de Mediana Edad , Nefroesclerosis , Síndrome de Sjögren/complicaciones , Síndrome de Sjögren/diagnóstico , alfa-Galactosidasa/metabolismoRESUMEN
The expression patterns of plasma membrane transporters that specify the epithelial cell type are acquired with ontogeny. To study this process during metanephrogenic mesenchyme-to-epithelium transition, branching ureteric buds with their adjacent mesenchymal blastema (mouse embryonic day E14) were dissected and explanted on a collagen matrix. In culture, induced mesenchymal cells condensed, aggregated, and converted to the comma- and S-shaped body. During in vitro condensation and aggregation, transcription factor Pax-2 protein was downregulated while the epithelial markers E-cadherin and beta-catenin proteins were upregulated. In addition, Wilms' tumor suppressor protein WT-1 was detectable upon condensation and downregulated in the S stage, where expression persisted in the long arm of the S. Patch-clamp, whole cell conductance (G, in nS/10 pF) of pre-epithelial condensed mesenchymal cells (n = 7) was compared with that of tubular proximal S-shaped-body epithelium (n = 6). Both stages expressed E-cadherin and WT-1 mRNA, as demonstrated by single-cell RT-PCR, testifying further to the epithelial as well as the nephrogenic commitment of the recorded cells. Mesenchymal cells exhibited whole cell currents (G = 6.7 +/- 1.3) with reversal potentials (V(rev), in mV) near equilibrium potential for Cl(-) (E(Cl)) (V(rev) = -40 +/- 7) suggestive of a high fractional Cl(-) conductance. Currents of the S-shaped-body cells (G = 4.0 +/- 1.1), in sharp contrast, had a V(rev) at E(K) (V(rev) = -82 +/- 6) indicating a high fractional K(+) conductance. Further, analysis of K(+)-selective whole cell tail currents and single-channel recording revealed a change in K(+) channel expression. Also, Kir6.1 K(+) channel mRNA and protein were downregulated between both stages, whereas K(v)LQT K(+) channel mRNA was abundant throughout. In conclusion, metanephrogenic mesenchyme-to-epithelium transition is accompanied by a profound reorganization of plasma membrane ion channel conductance.
Asunto(s)
Células Epiteliales/citología , Regulación del Desarrollo de la Expresión Génica , Canales Iónicos/metabolismo , Riñón/embriología , Riñón/metabolismo , Mesodermo/citología , Canales de Potasio de Rectificación Interna , Canales de Potasio con Entrada de Voltaje , Transactivadores , Animales , Cadherinas/genética , Cadherinas/metabolismo , Agregación Celular , Diferenciación Celular , Membrana Celular/metabolismo , Células Cultivadas , Proteínas del Citoesqueleto/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Conductividad Eléctrica , Células Epiteliales/metabolismo , Inmunohistoquímica , Canales Iónicos/genética , Canales de Potasio KCNQ , Canal de Potasio KCNQ1 , Riñón/citología , Mesodermo/metabolismo , Ratones , Factor de Transcripción PAX2 , Potasio/metabolismo , Canales de Potasio/genética , Canales de Potasio/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Cloruro de Sodio/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Proteínas WT1 , beta CateninaRESUMEN
Embryonic metanephroi, differentiating into the adult kidney, have come to be a generally accepted model system for organogenesis. Nephrogenesis implies a highly controlled series of morphogenetic and differentiation events that starts with reciprocal inductive interactions between two different primordial tissues and leads, in one of two mainstream processes, to the formation of mesenchymal condensations and aggregates. These go through the intricate process of mesenchyme-to-epithelium transition by which epithelial cell polarization is initiated, and they continue to differentiate into the highly specialized epithelial cell populations of the nephron. Each step along the developmental metanephrogenic pathway is initiated and organized by signaling molecules that are locally secreted polypeptides encoded by different gene families and regulated by transcription factors. Nephrogenesis proceeds from the deep to the outer cortex, and it is directed by a second, entirely different developmental process, the ductal branching of the ureteric bud-derived collecting tubule. Both systems, the nephrogenic (mesenchymal) and the ductogenic (ureteric), undergo a repeat series of inductive signaling that serves to organize the architecture and differentiated cell functions in a cascade of developmental gene programs. The aim of this review is to present a coherent picture of principles and mechanisms in embryonic renal epithelia.
Asunto(s)
Riñón/embriología , Urotelio/embriología , Animales , Diferenciación Celular , Polaridad Celular , Embrión de Mamíferos , Humanos , Riñón/citología , Mesodermo/citología , Mesodermo/fisiología , Morfogénesis , Urotelio/citologíaRESUMEN
Bradykinin (BK)-stimulated colonic Cl- secretion was studied in T84 colonic adenocarcinoma cells by measuring BK (50 nM)-evoked changes in cytosolic free [Ca2+] ([Ca2+]i), membrane conductance and transepithelial ion transport. In T84 cells grown on impermeable supports, BK stimulated a transient increase in [Ca2+]i as assessed by fura-2 ratio imaging. In cell-attached, patch-clamp recordings, BK transiently activated low-conductance K channels. These channels were activated/inactivated reversibly in inside-out patches by switching [Ca2+]i in the bath between 30 nM and 100 nM. Excised channels recorded with 160 mM [K+] in bath and pipette exhibited an inwardly rectifying current/voltage-relation, conductances of 10+/-1 pS and 34+/-4 pS (n=10) at positive and negative voltages, respectively, and a 15-fold lower permeability for Na+ than for K+. The mean open probability of these channels did not depend on voltage but increased with increasing [Ca2+]i with an apparent concentration for a half-maximal response (EC50) of 110 nM, resembling that of hSK4 K+ channels. Application of the reverse transcriptase-polymerase chain reaction technique showed hSK4 messenger ribonucleic acid (mRNA) to be expressed in T84 cells. Macroscopic currents in T84 cells showed a similar dependence on [Ca2+]i. Whole cell conductance (in nS/10pF) increased from 0.5+/-0. 1 (n=6) at 10 nM [Ca2+]i in the pipette solution to 1.5+/-0.2 (n=7) at 100 nM, and to 2.0+/-0.5 (n=7) at 1 microM due to activation of a K+ conductance. In Ussing-chambered T84 monolayers grown on filters, BK did not evoke a short-circuit current (Isc). When, however, the monolayers were pre-stimulated by forskolin (1 microM), BK further enhanced Cl-secretion (DeltaIsc=21+/-5 microA/cm2, n=10) transiently and biphasically. In conclusion, BK enhances cyclic adenosine monophosphate-stimulated Cl- secretion in T84 cells, probably via basolateral, Ca2+-liganded activation of low-conductance hSK4-type K+ channels.
Asunto(s)
Adenocarcinoma/metabolismo , Bradiquinina/farmacología , Cloruros/metabolismo , Neoplasias del Colon/metabolismo , Canales de Potasio Calcio-Activados , Canales de Potasio/metabolismo , Señalización del Calcio/fisiología , Fura-2 , Humanos , Canales de Potasio de Conductancia Intermedia Activados por el Calcio , Potenciales de la Membrana/fisiología , Técnicas de Placa-Clamp , Canales de Potasio/efectos de los fármacos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células Tumorales CultivadasRESUMEN
The NaCl-reabsorbing collecting duct epithelium develops by budding and branching of the embryonic ureter. The expression of Na+ channels during this branching morphogenesis was studied in the outermost branches of rat ureteric buds (UB; embryonic day E15 to postnatal day P6) and in cortical collecting ducts (CCD; days P7-P28) in primary monolayer culture. Expression of both Na+ channel mRNA and of Na+-selective membrane conductance were estimated by quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) and by patch-clamp recording, respectively. UB and CCD uniformly represented a principal-like cell type in culture. Messenger RNA encoding the alpha-ENaC subunit was detected in oligo-dT primed cDNA (5 ng) of embryonic UB cells (E15-17) after 30 PCR cycles. The abundance of alpha-ENaC mRNA, when normalized by reference to beta-actin, was higher by a factor of 2 in postnatal (P1-6) UB and by a factor of 5 in CCD cells (P7-14) compared with the embryonic stage. Highly Na+-selective, low-conductance channels were identified in apical patches from both UB and CCD monolayers, but only CCD cells exhibited macroscopic, amiloride-sensitive Na+ currents in whole-cell patch-clamp recordings. We conclude that alpha-ENaC mRNA and functional Na+ channel protein are expressed already before morphogenesis of the CCD is completed and prior to the onset of epithelial NaCl reabsorption.
Asunto(s)
Expresión Génica , Corteza Renal/embriología , Túbulos Renales Colectores/embriología , Canales de Sodio/genética , Amilorida/farmacología , Animales , Diferenciación Celular , Conductividad Eléctrica , Epitelio/embriología , Epitelio/metabolismo , Edad Gestacional , Corteza Renal/metabolismo , Túbulos Renales Colectores/metabolismo , Microscopía Electrónica de Rastreo , Morfogénesis , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Uréter/embriología , Uréter/metabolismoRESUMEN
The behavior of 24 children, aged 3-6 years, was recorded on video-tape. Simultaneously the ECG was recorded telemetrically. These observations were made during two pre-school educational programs lasting 90 minutes each: "Didactic games" and "Elementary music and movement program". For each child a scale was developed to show the correlation of mean heart-rate and well defined motor-activity. It was evident that the mean heart-rate was higher during the music program than during the didactic program, corresponding to the higher motor-activity. But it was found that in the didactic program the variation of the heart-rate within short intervals was higher due to the more frequent occurrence of respiratory arrhythmias. It was also seen that during the music program the children showed no signs of exertion as they did towards the end of the didactic program. Respiratory arrhythmias were not seen in children who according to the Schellong-test were classified as stable in their cardiovascular system. The arrhythmias occurred mainly when the children showed signs of fatigue.