RESUMEN
BACKGROUND: COVID-19 is associated with increased morbidity and mortality in patients with chronic kidney disease (CKD) stages G4-G5, on dialysis or after kidney transplantation (kidney replacement therapy, KRT). SARS-CoV-2 vaccine trials do not elucidate if SARS-CoV-2 vaccination is effective in these patients. Vaccination against other viruses is known to be less effective in kidney patients. Our objective is to assess the efficacy and safety of various types of SARS-CoV-2 vaccinations in patients with CKD stages G4-G5 or on KRT. METHODS: In this national prospective observational cohort study we will follow patients with CKD stages G4-G5 or on KRT (n = 12,000) after SARS-CoV-2 vaccination according to the Dutch vaccination program. Blood will be drawn for antibody response measurements at day 28 and month 6 after completion of vaccination. Patient characteristics and outcomes will be extracted from registration data and questionnaires during 2 years of follow-up. Results will be compared with a control group of non-vaccinated patients. The level of antibody response to vaccination will be assessed in subgroups to predict protection against COVID-19 breakthrough infection. RESULTS: The primary endpoint is efficacy of SARS-CoV-2 vaccination determined as the incidence of COVID-19 after vaccination. Secondary endpoints are the antibody based immune response at 28 days after vaccination, the durability of this response at 6 months after vaccination, mortality and (serious) adverse events. CONCLUSION: This study will fulfil the lack of knowledge on efficacy and safety of SARS-CoV-2 vaccination in patients with CKD stages G4-G5 or on KRT. TRIAL REGISTRATION: The study protocol has been registered in clinicaltrials.gov ( NCT04841785 ). Current knowledge about this subject COVID-19 has devastating impact on patients with CKD stages G4-G5, on dialysis or after kidney transplantation. Effective SARS-CoV-2 vaccination is very important in these vulnerable patient groups. Recent studies on vaccination in these patient groups are small short-term studies with surrogate endpoints. Contribution of this study Assessment of incidence and course of COVID-19 after various types of SARS-CoV-2 vaccination during a two-year follow-up period in not only patients on dialysis or kidney transplant recipients, but also in patients with CKD stages G4-G5. Quantitative analysis of antibody response after SARS-CoV-2 vaccination and its relationship with incidence and course of COVID-19 in patients with CKD stages G4-G5, on dialysis or after kidney transplantation compared with a control group. Monitoring of (serious) adverse events and development of anti-HLA antibodies. Impact on practice or policy Publication of the study design contributes to harmonization of SARS-CoV-2 vaccine study methodology in kidney patients at high-risk for severe COVID-19. Data on efficacy of SARS-CoV-2 vaccination in patients with CKD will provide guidance for future vaccination policy.
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Vacunas contra la COVID-19 , Trasplante de Riñón , Diálisis Renal , Insuficiencia Renal Crónica/terapia , Vacunas contra la COVID-19/administración & dosificación , Estudios de Cohortes , Humanos , Países Bajos , Estudios Observacionales como Asunto , Estudios Prospectivos , Factores de TiempoRESUMEN
BACKGROUND: Immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is a rare, genetically heterogeneous, autosomal recessive disorder. Patients suffer from recurrent infections caused by reduced levels or absence of serum immunoglobulins. Genetically, 4 subtypes of ICF syndrome have been identified to date: ICF1 (DNMT3B mutations), ICF2 (ZBTB24 mutations), ICF3 (CDCA7 mutations), and ICF4 (HELLS mutations). AIM: To study the mutation spectrum in ICF syndrome. MATERIALS AND METHODS: Genetic studies were performed in peripheral blood lymphocyte DNA from suspected ICF patients and family members. RESULTS: We describe 7 ICF1 patients and 6 novel missense mutations in DNMT3B, affecting highly conserved residues in the catalytic domain. We also describe 5 new ICF2 patients, one of them carrying a homozygous deletion of the complete ZBTB24 locus. In a meta-analysis of all published ICF cases, we observed a gender bias in ICF2 with 79% male patients. DISCUSSION: The biallelic deletion of ZBTB24 provides strong support for the hypothesis that most ICF2 patients suffer from a ZBTB24 loss of function mechanism and confirms that complete absence of ZBTB24 is compatible with human life. This is in contrast to the observed early embryonic lethality in mice lacking functional Zbtb24. The observed gender bias seems to be restricted to ICF2 as it is not observed in the ICF1 cohort. CONCLUSION: Our study expands the mutation spectrum in ICF syndrome and supports that DNMT3B and ZBTB24 are the most common disease genes.
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Centrómero/genética , ADN (Citosina-5-)-Metiltransferasas/genética , Síndromes de Inmunodeficiencia/genética , Proteínas Represoras/genética , Adolescente , Adulto , Animales , Centrómero/patología , Niño , Preescolar , ADN Helicasas/genética , Metilación de ADN/genética , Cara/anomalías , Cara/fisiopatología , Femenino , Predisposición Genética a la Enfermedad , Humanos , Síndromes de Inmunodeficiencia/fisiopatología , Masculino , Ratones , Mutación Missense , Proteínas Nucleares/genética , Sexismo , Adulto Joven , ADN Metiltransferasa 3BRESUMEN
BACKGROUND: Chronic kidney disease (CKD) is associated with increased cardiovascular risk. Here we evaluate whether strict implementation of guidelines aimed at multiple targets with the aid of nurse practitioners (NP) improves management in patients with CKD. METHODS: MASTER PLAN is a randomised controlled clinical trial, performed in nine Dutch hospitals. Patients with CKD (estimated glomerular filtration rate (eGFR) 20-70 ml÷min) were randomised to receive NP support (intervention group (IG)) or physician care (control group (CG)). Patients were followed for a median of five years. Presented data are an interim analysis on risk factor control at two-year follow-up. RESULTS: We included 788 patients (532 M, 256 F), (393 CG, 395 IG), mean (±SD ) age 59 (±13) years, eGFR 38 (±15) ml÷min÷1.73m(2), blood pressure (BP) 138 (±21)÷80 (±11) mmHg. At two years 698 patients (352 IG, 346 CG) could be analysed. IG as compared with CG had lower systolic (133 vs 135 mmHg; p= 0.04) and diastolic BP (77 vs 80 mmHg; p=0.007), LDL cholesterol (2.30 vs 2.45 mmol(-l); p= 0.03), and increased use of ACE inhibitors, statins, aspirin and vitamin D. The intervention had no effect on smoking cessation, body weight, physical activity or sodium excretion. CONCLUSION: In both groups, risk factor management improved. However, changes in BP control, lipid management and medication use were more pronounced in IG than in CG. Lifestyle interventions were not effective. Coaching by NPs thus benefits everyday care of CKD patients. Whether these changes translate into improvement in clinical endpoints remains to be established.
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Fallo Renal Crónico/enfermería , Fallo Renal Crónico/terapia , Enfermeras Practicantes , Calidad de la Atención de Salud , Antihipertensivos/uso terapéutico , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/prevención & control , Femenino , Tasa de Filtración Glomerular , Humanos , Hipolipemiantes/uso terapéutico , Masculino , Persona de Mediana Edad , Países Bajos , Factores de Riesgo , Conducta de Reducción del Riesgo , Cese del Hábito de FumarRESUMEN
BACKGROUND: Blood pressure (BP) is the most important modifiable risk factor for cardiovascular (CV) disease and progression of kidney dysfunction in patients with chronic kidney disease. Despite extensive antihypertensive treatment possibilities, adequate control is notoriously hard to achieve. Several determinants have been identified which affect BP control. In the current analysis we evaluated differences in achieved BP and achievement of the BP goal between hospitals and explored possible explanations. METHODS: At baseline, BP was measured in a supine position with an oscillometric device in 788 patients participating in the MASTER PLAN study. We also retrieved the last measured office BP from the patient records. Additional baseline characteristics were derived from the study database. Univariate and multivariate analyses were performed with general linear modelling using hospital as a random factor. RESULTS: In univariate analysis, hospital was a determinant of the level of systolic and diastolic BP at baseline. Adjustment for patient, kidney disease, treatment or hospital characteristics affected the relation. Yet, in a fully adjusted model, differences between centres persisted with a range of 15 mmHg for systolic BP and 11 mmHg for diastolic BP. CONCLUSION: Despite extensive adjustments, a clinically relevant, statistically significant difference between hospitals was found in standardised BP measurements at baseline of a randomised controlled study. We hypothesise that differences in the approach towards BP control exist at the physician level and that these explain the differences between hospitals.
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Antihipertensivos/uso terapéutico , Hospitales , Hipertensión/tratamiento farmacológico , Fallo Renal Crónico/patología , Presión Sanguínea/efectos de los fármacos , Femenino , Humanos , Modelos Lineales , Masculino , Persona de Mediana Edad , Análisis Multivariante , OscilometríaRESUMEN
Two patients developed nephrotic syndrome and progressive loss of renal function following treatment with i.v. pamidronate. Renal biopsy revealed collapsing focal segmental glomerulosclerosis (FSGS) in both the patients. In one patient, renal function recovered and the nephrotic syndrome disappeared after discontinuation of pamidronate. The second patient became dialysis dependent despite discontinuation of therapy. Nephrotic syndrome due to collapsing FSGS is a serious complication of treatment with bisphosphonates, especially of i.v. pamidronate. Bisphosphonates may also cause renal insufficiency as a result of tubular toxicity. In order to prevent severe nephrotoxicity clinicians should check urinary protein excretion and renal function regularly in patients who receive long-term treatment with i.v. bisphosphonates. In patients with pre-existing renal impairment (estimated GFR below 30 ml/min), bisphosphonates should be used with caution.
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Conservadores de la Densidad Ósea/efectos adversos , Difosfonatos/efectos adversos , Síndrome Nefrótico/inducido químicamente , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/secundario , Anciano , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/secundario , Femenino , Humanos , Hipercalcemia/tratamiento farmacológico , Hiperparatiroidismo Secundario/tratamiento farmacológico , Trasplante de Riñón , Masculino , Síndrome Nefrótico/fisiopatología , Pamidronato , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/patologíaRESUMEN
Renal toxicity of iodinated radiocontrast media (contrastinduced nephropathy; CIN) is a major cause of acute renal failure in hospitalised patients. Magnetic resonance imaging (MRI) is applied as an alternative technique but the use of gadolinium (Gd) containing contrast media carries the risk of nephrogenic systemic fibrosis (NSF), a potentially lethal disorder that occurs especially in patients with renal failure. In this article we give an update of the literature on toxicity of radiocontrast media and on preventive measures. Risk of nephrotoxicity of iodinated contrast media can be reduced by identification of high-risk patients. In these patients pre- and post-hydration with isotonic saline should be applied. When there is insufficient time to prehydrate, a short infusion protocol with sodium bicarbonate is preferable. There is a lack of evidence to support the use of oral or intravenous N-acetylcysteine or iso-osmolar contrast media. In order to prevent NSF , linear gadolinium chelates should not be used in patients with an estimated glomerular filtration rate (eGFR) of less than 30 ml/min. In patients with eGFR between 10 and 30 ml/min the small chance of NSF with cyclic Gd-containing chelates must be balanced against the high risk of developing CIN, and the morbidity and mortality associated with the start of dialysis. In patients without residual renal function, the small chance of developing NSF after macrocyclic Gd-enhanced MRI imaging may tip the balance to the use of iodine containing contrast media.
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Lesión Renal Aguda/inducido químicamente , Medios de Contraste/efectos adversos , Riñón/efectos de los fármacos , Dermopatía Fibrosante Nefrogénica/inducido químicamente , Lesión Renal Aguda/prevención & control , Gadolinio/efectos adversos , Humanos , Compuestos de Yodo/efectos adversos , Dermopatía Fibrosante Nefrogénica/prevención & controlRESUMEN
Annually, 0.5-1 million injections of contrast media containing iodine are administered in the Netherlands. Almost all contrast media nowadays are low-osmolar and nonionic. Nevertheless, the development ofcontrast-induced nephropathy is still a relevant clinical problem. Through an initiative by the Radiological Society of the Netherlands and with aid of the Dutch Institute for Healthcare Improvement (CBO), a guideline was conceived for the intravascular use of iodine-containing contrast media, based on recent scientific literature. The guideline defines the risk factors for contrast-induced nephropathy. One of the major risk factors is an impaired renal function. It is important to measure the glomerular filtration rate (GFR) in patients with a possible impaired kidney function, preferably by using the 'Modification of diet in renal disease' (MDRD)-study formula. The key measures for avoidance of contrast nephropathy are: limiting the amount of contrast agent used and to assure good hydration, by infusion of sodium chloride 0.9% 12-16 ml/kg body weight, both prior to and after contrast infusion. If time is limited, intravenous administration of sodium bicarbonate is an option. The guideline recommends discontinuation of metformin use from the day of contrast injection, if the GFR < 60 ml/min/1.73 m2, and to restart metformin 2 days following contrast infusion providing the GFR has not significantly deteriorated. Only in the case of previous moderate or severe adverse reactions to contrast media, prophylaxis with corticosteroids and antihistamines is recommended. Iodine allergy or an atopic condition is not a contraindication for the use of iodine-containing contrast media, and no prophylaxis is required. No specific measures are indicated in case of hyperthyroidism, acute pancreatitis, or phaeochromocytoma. Injection of contrast media is not contraindicated in case of pregnancy or lactation.
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Medios de Contraste/efectos adversos , Yodo/efectos adversos , Enfermedades Renales/inducido químicamente , Guías de Práctica Clínica como Asunto , Medios de Contraste/administración & dosificación , Medios de Contraste/metabolismo , Tasa de Filtración Glomerular/fisiología , Humanos , Yodo/administración & dosificación , Yodo/metabolismo , Enfermedades Renales/patología , Enfermedades Renales/prevención & control , Soluciones para Rehidratación , Medición de RiesgoRESUMEN
Autologous stem cell transplantation (ASCT) to treat autoimmune diseases (AID) is thought to reset immunological memory directed against autoantigens. This hypothesis can only be studied indirectly because the exact nature of the pathogenetic autoantigens is unknown in most AID. Therefore, 19 children with juvenile idiopathic arthritis (JIA) or systemic lupus erythematodes (SLE) and 10 adults with multiple sclerosis (MS) were vaccinated with the T-cell-dependent neoantigen rabies and the recall antigen tetanus toxoid after, respectively before, bone marrow harvest. Both vaccinations were repeated after ASCT. All except two of the responders mounted a primary antibody response to rabies after revaccination, and 44% of the responders mounted a primary antibody response to tetanus boost after ASCT. These data show that immunological memory to a neoantigen is lost in most patients with AID after immunoablative pretreatment; however, memory to a recall antigen boosted before bone marrow harvest is only lost in part of the patients. Disease progression was arrested in all patients with JIA/SLE except one, but only in a minority of MS patients. Clinical outcome on a per case basis was not associated with the profile of the immune response toward the vaccination antigens after ASCT.
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Trasplante de Células Madre Hematopoyéticas , Inmunidad Innata , Memoria Inmunológica/inmunología , Vacunas Antirrábicas/inmunología , Toxoide Tetánico/inmunología , Adolescente , Adulto , Enfermedades Autoinmunes/terapia , Niño , Preescolar , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Trasplante Autólogo , Resultado del TratamientoAsunto(s)
Acetilcisteína/administración & dosificación , Medios de Contraste/efectos adversos , Soluciones para Rehidratación/uso terapéutico , Insuficiencia Renal/prevención & control , Cloruro de Sodio/uso terapéutico , Acetilcisteína/farmacocinética , Acetilcisteína/uso terapéutico , Disponibilidad Biológica , Relación Dosis-Respuesta a Droga , Humanos , Países Bajos , Insuficiencia Renal/inducido químicamenteRESUMEN
We investigated the humoral (antigen-specific immunoglobulin isotypes, IgG subclasses, and avidity maturation) and cellular (antigen-specific in vitro proliferation) immune response in 18 healthy adult volunteers, following a primary and a single booster vaccination with the T-cell dependent neoantigen rabies administered at a 3-months interval. The IgG antibody titer showed a mean 31-fold increase (range 3-154) 4 weeks after the first vaccination and a memory response was observed after booster vaccination, i.e. high IgG titers, switch from IgM to IgG and IgA and increased antibody avidity. All healthy adults showed a rabies-induced proliferative response with a mean stimulation index of 45 (range 3.5-200) after in vitro stimulation of PBMC obtained at 4 weeks after booster vaccination. The results obtained in this study provide a frame of reference for the interpretation of specific immune responses to the T-cell dependent neoantigen rabies in patients suspected of a primary or secondary immunodeficiency. Humoral and cellular immune responses to the rabies neoantigen provide complementary information on the condition of the immune system of an individual. Five patients diagnosed with a combined immunodeficiency were vaccinated using the same protocol and showed a number of abnormalities, either in the humoral or the cellular immune response to the rabies neoantigen.
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Anticuerpos/inmunología , Vacunas Antirrábicas/inmunología , Linfocitos T/inmunología , Vacunación , Adulto , Anticuerpos/sangre , Formación de Anticuerpos , Humanos , Inmunidad Celular , Esquemas de Inmunización , Persona de Mediana Edad , Linfocitos T/citologíaRESUMEN
Adrenalectomy enhances apoptosis in the rat dentate gyrus and concurrently decreases the field response of dentate cells to perforant path stimulation. Recent data showed that calcium current amplitude is increased 1 day prior to the appearance of apoptotic cells, pointing to calcium as a risk factor for the onset of apoptosis. We here tested if in vivo administration of nimodipine-thus presumably reducing dentate calcium influx through L type calcium channels-prevents the appearance of apoptotic cells and the change in field responses after adrenalectomy. It was found that nimodipine does not largely alter the number of animals with apoptosis nor the average number of apoptotic cells in the tip of the suprapyramidal blade of the dentate gyrus. After nimodipine treatment, field responses in the dentate gyrus of adrenalectomized rats were comparable to responses in adrenally intact rats. However, this was due to a reduction of the field response in slices from adrenally intact rats, rather than a prevention of synaptic impairment in adrenalectomized rats. The data clearly indicates that in vivo nimodipine treatment is insufficient to prevent apoptosis and synaptic impairment after adrenalectomy.
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Apoptosis/fisiología , Canales de Calcio Tipo L/metabolismo , Señalización del Calcio/fisiología , Corticosterona/deficiencia , Giro Dentado/metabolismo , Neuronas/metabolismo , Vía Perforante/fisiología , Animales , Apoptosis/efectos de los fármacos , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo L/efectos de los fármacos , Señalización del Calcio/efectos de los fármacos , Corticosterona/sangre , Giro Dentado/citología , Giro Dentado/efectos de los fármacos , Estimulación Eléctrica , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Excitadores/fisiología , Masculino , Neuronas/citología , Neuronas/efectos de los fármacos , Nimodipina/farmacología , Ratas , Ratas Wistar , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/fisiologíaRESUMEN
PURPOSE: Proteinuria is frequently encountered in patients in the intensive care unit, most likely as a result of renal tubular cell injury. It has been reported that gelatin-derived plasma substitutes contribute to an increase in renal protein excretion. The aim of this study was to investigate the magnitude and the mechanism of the proteinuric effect of Gelofusine, a modified gelatin. MATERIALS AND METHODS: In six healthy male subjects, renal hemodynamics and urinary protein excretion were measured before and after infusion of 330 mL of Gelofusine. RESULTS: Gelofusine had a minor effect on blood pressure, glomerular filtration rate, effective renal plasma flow, and on urinary excretion of immunoglobulin, and albumin. In contrast, there was a major increase in the urinary excretion of the low-molecular-weight proteins beta2-microglobulin (from 0.06 +/- 0.04 to 43.52 +/- 11.75 microg/min; P <.01) and alpha1-microglobulin (from 11 +/- 8 to 72 +/- 24 microg/min; P <.01). The urinary excretion of N-acetyl-beta-D-glucosaminidase (beta-NAG) remained unchanged, suggesting that there was no significant renal tubular cell injury. CONCLUSIONS: When analyzing proteinuria in patients in the intensive care unit it should be considered that Gelofusine increases the urinary excretion of proteins, in particular those of low molecular weight. This effect is most likely due to competitive inhibition of tubular protein reabsorption.
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Gelatina/efectos adversos , Túbulos Renales/fisiopatología , Sustitutos del Plasma/efectos adversos , Proteínas/metabolismo , Proteinuria/inducido químicamente , Succinatos/efectos adversos , Adulto , Hemodinámica , Humanos , Masculino , Peso Molecular , Países Bajos , Proteínas/químicaRESUMEN
We prospectively studied the reconstitution of lymphocyte subpopulations in a group of 22 children, who survived disease-free at least 6 months after allogeneic BMT for a haematological malignancy. Absolute counts of total lymphocytes, B lymphocytes, T lymphocytes, and CD4+ helper T lymphocytes reached the 5th percentile (p5) of age-matched reference values within 6 months after BMT in 15, 17, 7 and 2 patients, respectively. In particular, CD4+ helper T lymphocyte reconstitution was very slow. Unexpectedly, CMV reactivation had a profound positive influence upon the number of CD4+ helper T lymphocytes in the children. In five patients, absolute B lymphocyte counts above the 95th percentile were reached from 6 months after BMT onwards, mimicking normal ontogeny. Unlike normal ontogeny, the percentages of helper T lymphocytes expressing the 'naive' CD45RA isoform were low and those expressing the 'memory' CD45RO isoform were high in the first 3 months after BMT, as described before. Thereafter, the CD45RA:CD45RO ratio slowly normalised. Also, CD7 expression was absent on up to 90% of T lymphocytes in the first months after BMT, and on a steadily decreasing percentage thereafter, as recently described in adults. However, the absolute counts of CD45RO+/CD4+ and CD7-/CD4+ helper T lymphocytes did not change significantly. So, we found no evidence of peripheral expansion of previously primed donor-derived 'memory' T lymphocytes during the follow-up period which spanned 1-18 months after BMT. The absolute counts of 'naive' CD45RA+ helper T lymphocytes did not show a faster increase after BMT than in adults, despite the presumed presence of a non-involuted thymus in children. Bone Marrow Transplantation (2000) 25, 267-275.
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Trasplante de Médula Ósea/métodos , Subgrupos Linfocitarios/citología , Adolescente , Antígenos CD7/sangre , Linfocitos B/citología , Linfocitos B/inmunología , Trasplante de Médula Ósea/efectos adversos , Antígenos CD5/sangre , Linaje de la Célula , Niño , Preescolar , Citomegalovirus/metabolismo , Femenino , Enfermedad Injerto contra Huésped , Neoplasias Hematológicas/terapia , Neoplasias Hematológicas/virología , Humanos , Inmunofenotipificación , Lactante , Antígenos Comunes de Leucocito/biosíntesis , Antígenos Comunes de Leucocito/sangre , Estudios Longitudinales , Recuento de Linfocitos , Masculino , Estudios Prospectivos , Linfocitos T/citología , Linfocitos T/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Trasplante Homólogo/efectos adversos , VirosisRESUMEN
Anti-gliadin antibodies can be found in the serum of patients with overt and subclinical coeliac disease, but also in that of some controls. The aim of the present study was to identify the linear epitopes of the alpha-gliadin molecule to which the humoral response is directed. Therefore, the IgG and IgA antibody reactivity against an overlapping set of synthetic peptides covering the entire sequence of alpha-gliadin was measured in the sera from patients with coeliac disease, from controls with elevated titres of anti-gliadin antibodies and from healthy children using an ELISA technique. The antibodies mainly recognize peptides derived from the N-terminal region of alpha-gliadin, containing the motif QPFXXQXPY. Reactivity was also detected against two other synthetic peptides, which do not contain this motif and represent a sequence encoded further to the C-terminal region of alpha-gliadin. Anti-gliadin antibodies in sera from patients with coeliac disease and from controls recognize the same linear epitopes. Thus, serological investigation of the specificity of these antibodies using a peptide ELISA does not allow discrimination between patients and controls.
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Enfermedad Celíaca/inmunología , Epítopos de Linfocito B/inmunología , Gliadina/inmunología , Péptidos/inmunología , Adolescente , Secuencia de Aminoácidos , Anticuerpos/sangre , Anticuerpos/inmunología , Enfermedad Celíaca/sangre , Niño , Preescolar , Femenino , Humanos , Inmunoglobulina A/inmunología , Inmunoglobulina G/inmunología , Lactante , Masculino , Datos de Secuencia Molecular , Biosíntesis de PéptidosRESUMEN
Pepsinogen A (PGA) isozymogens are low molecular weight proteins that are present in serum and urine. The differences in the molecular structure of PGA-isozymogens involve only 2-4 amino acid substitutions. In a previous study, performed in 13 subjects only, a remarkable difference between the fractional renal clearances of the main PGA-isozymogens (PGA-3, PGA-4 and PGA-5) has been demonstrated. The aim of the present study was to further investigate these differences in fractional clearance between PGA-isozymogens and to determine whether these differences are caused by differences in glomerular sieving. For this purpose the fractional clearances of PGA-isozymogens were measured in 57 subjects. In accordance with the previous study, the median fractional clearance of PGA-5 (13%) was lower than the median fractional clearance of PGA-4 (17%; p < 0.02) and the median fractional clearance of PGA-4 was lower than the median fractional clearance of PGA-3 (26%; p < 0.001). The glomerular sieving coefficients of PGA-isozymogens were measured in 11 subjects during an elective heart catheterization by means of the fractional renal extraction method. No significant difference between the glomerular sieving coefficients of PGA-isozymogens could be demonstrated, being 0.81 for PGA-3, 0.96 for PGA-4 and 0.84 for PGA-5. It is concluded that the differences in renal handling between PGA-isozymogens must be explained by differences in tubular reabsorption. These differences in tubular reabsorption between PGA-isozymogens support the hypothesis that positively charged amino acid residues of proteins are involved in the tubular protein reabsorption.
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Túbulos Renales/metabolismo , Pepsinógenos/metabolismo , Ensayo de Inmunoadsorción Enzimática , Femenino , Tasa de Filtración Glomerular/fisiología , Humanos , Isoenzimas/metabolismo , Masculino , Persona de Mediana Edad , Pepsinógenos/químicaRESUMEN
The kidney is responsible for a considerable part of the clearance of insulin and C-peptide. Two routes are thought to be involved in the renal extraction of insulin and C-peptide from the circulation: (1) glomerular filtration, and (2) uptake by tubular cells from peritubular capillaries. The aim of the present study was to investigate these processes in non-insulin-dependent diabetes mellitus (NIDDM). For this purpose we measured the renal extraction of inulin, insulin, and C-peptide in 12 NIDDM patients and 16 control subjects during elective heart catheterization. In addition, a 24-h urine sample was obtained from all subjects to assess the fractional clearance of the peptides. The total renal extraction of both insulin and C-peptide exceeded the amount that was extracted by filtration, confirming the supposition that both peptides are cleared by an additional mechanism, most probably peritubular uptake. The peritubular uptake of insulin in the NIDDM group was not significantly different from that in the control subjects, whereas the insulin extraction over the legs was significantly lower in NIDDM than in the controls. The peritubular uptake of C-peptide was significantly lower in NIDDM, while the fractional clearance of C-peptide was significantly higher. The latter indicates that the reabsorption of C-peptide from the luminal side of the tubular cell is impaired in diabetes mellitus. It is therefore concluded that urinary C-peptide excretion is not a reliable index for insulin production in NIDDM.(ABSTRACT TRUNCATED AT 250 WORDS)
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Péptido C/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Insulina/metabolismo , Adulto , Anciano , Transporte Biológico Activo , Femenino , Humanos , Riñón/metabolismo , Glomérulos Renales/metabolismo , Túbulos Renales/metabolismo , Masculino , Persona de Mediana EdadRESUMEN
1. alpha 2-Adrenoceptors on platelet membranes and beta 2-adrenoceptors on lymphocytes were studied in 24 patients with primary Raynaud's phenomenon and in 24 age- and sex-matched control subjects. In two subgroups, a standardized mental arithmetic test and a finger-cooling test were performed. 2. Baseline blood pressure, heart rate and forearm blood flow did not differ between the two groups. 3. Baseline skin microcirculation (laser Doppler flux) was decreased in primary Raynaud's phenomenon (19 +/- 15 arbitrary units) compared with control subjects (33 +/- 14 arbitrary units) (P less than 0.01). 4. Baseline plasma noradrenaline concentration (2.00 +/- 1.44 versus 1.16 +/- 0.36 nmol/l) and alpha 2-adrenoceptor density (301 +/- 119 versus 210 +/- 82 fmol/mg) were increased in patients with primary Raynaud's phenomenon in comparison with the control subjects. The alpha 2-adrenoceptor density/beta 2-adrenoceptor density ratio in patients with primary Raynaud's phenomenon was, with a value of 0.37 +/- 0.04, higher than in the control subjects, where a value of 0.25 +/- 0.02 was measured (P less than 0.001). Plasma adrenaline concentration, beta 2-adrenoceptor density and the antagonist affinity to both receptor subtypes did not differ between both groups under baseline conditions. 5. Whereas during the finger-cooling test no differences were seen in the responses of the parameters measured, the mental arithmetic test induced an increase in laser Doppler flux in patients with primary Raynaud's phenomenon and a decrease in the control group.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Células Sanguíneas/química , Enfermedad de Raynaud/sangre , Receptores Adrenérgicos/análisis , Adulto , Plaquetas/química , Membrana Celular/química , Epinefrina/sangre , Femenino , Humanos , Linfocitos/química , Masculino , Microcirculación/fisiología , Norepinefrina/sangre , Enfermedad de Raynaud/fisiopatología , Receptores Adrenérgicos alfa/análisis , Receptores Adrenérgicos beta/análisis , Piel/irrigación sanguínea , Estrés Psicológico/fisiopatologíaRESUMEN
1. The fractional clearances of pepsinogen A (PGA), pepsinogen C (PGC) and the main PGA isozymogens, i.e. PGA-3, PGA-4 and PGA-5, were measured in 13 healthy male volunteers before and during blockade of tubular protein reabsorption by intravenous infusion of either L-arginine hydrochloride (n = 8; 0.5 g h-1 kg-1 body weight) or an equimolar amount of L-lysine hydrochloride (n = 5; 0.44 g h-1 kg-1 body weight). Glomerular filtration rate was measured by a radioisotope method. 2. The fractional baseline clearance of PGC (1 +/- 1%) was lower than that of PGA (20 +/- 10%). In addition, the fractional clearance of the PGA isozymogens appeared to be different: the fractional clearance of PGA-5 (7 +/- 3%) was lower than that of PGA-4 (18 +/- 9%), and the fractional clearance of PGA-4 was lower than that of PGA-3 (30 +/- 10%). These differences in fractional clearance between PGA isozymogens decreased during infusion of both arginine and lysine. 3. Pepsinogens are freely filtered proteins. It can therefore be concluded that the differences in fractional clearance between PGA isozymogens imply differences in tubular reabsorption. This is remarkable as PGA isozymogens are proteins with an almost identical amino acid sequence and electric charge. The disappearance of the differences in tubular reabsorption during arginine and lysine infusion suggests that PGA isozymogens differ in affinity for negatively charged binding sites in the tubular cell membrane. In order to explain the low fractional clearance of PGC compared with that of PGA and the less marked effect of arginine or lysine infusion on the fractional clearance of PGC, an additional PGC-specific binding site has to be postulated.
Asunto(s)
Aminoácidos Diaminos/farmacología , Isoenzimas/metabolismo , Túbulos Renales/metabolismo , Pepsinógenos/metabolismo , Acetilglucosaminidasa/orina , Adulto , Albúminas/metabolismo , Arginina/farmacología , Tasa de Filtración Glomerular/efectos de los fármacos , Humanos , Riñón/irrigación sanguínea , Lisina/farmacología , Masculino , Tasa de Depuración Metabólica/efectos de los fármacos , Persona de Mediana Edad , Flujo Sanguíneo Regional/efectos de los fármacos , Microglobulina beta-2/metabolismoRESUMEN
In 8 healthy male volunteers, urinary excretion (UE) and fractional clearance (FC) of pepsinogen A (PGA), beta 2-microglobulin (beta 2-m) and albumin were measured after 6 days high protein diet (HPD; 2.0 g/kg/day) and compared to values obtained after 6 days low protein diet (LPD; 0.5 g/kg/day). In addition, the effect of an acute protein load (APL; 500 g beef) on these variables were measured. Both chronic and acute protein loading induced a rise in glomerular filtration rate (GFR) of about 10% together with a parallel rise in effective renal plasma flow. UE PGA and FC PGA increased both after HPD (UE PGA 1,707 +/- 1,106 ng/min; FC PGA 23 +/- 12%) as compared to LPD (UE PGA 1,200 +/- 987 ng/min, p less than 0.01; FC PGA 18 +/- 12%, p less than 0.05), and after APL (UE PGA 2,276 +/- 1,389 ng/min; FC PGA 26 +/- 16%) as compared to baseline (UE PGA 1,418 +/- 965 ng/min, p less than 0.02; FC PGA 21 +/- 12%, p less than 0.05). UE and FC of beta 2-m and albumin were not affected by protein loading. As PGA is nearly freely filtered, it is concluded that the increase in fractional PGA clearance reflects a decrease in fractional tubular PGA reabsorption. Our results suggest that an increase in fractional protein clearance after protein loading is not necessarily due to an impaired glomerular permselectivity but represents a decreased fractional tubular reabsorption as a result of a GFR-mediated increase in filtered load without a concomitant increase in tubular reabsorption.