RESUMO
BACKGROUND: Thrombotic microangiopathies are complex diseases, requiring early differential diagnosis and targeted intervention. OBJECTIVES: Presentation of clinical phenotype and diagnostic algorithm, discussion of underlying pathophysiology, clinical management and therapy. METHODS: Summary of current knowledge from literature and expert opinion. RESULTS: Our understanding of pathophysiology and therapeutic options have changed substantially in recent years. Early differential diagnosis and targeted therapy are of prognostic relevance. CONCLUSIONS: A better understanding of underlying pathophysiology, increased clinical awareness and novel therapeutic options allow for a better prognosis of patients with thrombotic microangiopathy.
Assuntos
Púrpura Trombocitopênica Trombótica , Microangiopatias Trombóticas , Diagnóstico Diferencial , Humanos , Troca Plasmática , Prognóstico , Púrpura Trombocitopênica Trombótica/diagnóstico , Microangiopatias Trombóticas/diagnósticoRESUMO
Renal sinus fat (RSF) is a perivascular fat compartment located around renal arteries. In this in vitro and in vivo study we hypothesized that the hepatokine fetuin-A may impair renal function in non alcoholic fatty liver disease (NAFLD) by altering inflammatory signalling in RSF. To study effects of the crosstalk between fetuin-A, RSF and kidney, human renal sinus fat cells (RSFC) were isolated and cocultured with human endothelial cells (EC) or podocytes (PO). RSFC caused downregulation of proinflammatory and upregulation of regenerative factors in cocultured EC and PO, indicating a protective influence of RFSC. However, fetuin-A inverted these benign effects of RSFC from an anti- to a proinflammatory status. RSF was quantified by magnetic resonance imaging and liver fat content by 1H-MR spectroscopy in 449 individuals at risk for type 2 diabetes. Impaired renal function was determined via urinary albumin/creatinine-ratio (uACR). RSF did not correlate with uACR in subjects without NAFLD (n = 212, p = 0.94), but correlated positively in subjects with NAFLD (n = 105, p = 0.0005). Estimated glomerular filtration rate (eGRF) was inversely correlated with RSF, suggesting lower eGFR for subjects with higher RSF (r = 0.24, p < 0.0001). In conclusion, our data suggest that in the presence of NAFLD elevated fetuin-A levels may impair renal function by RSF-induced proinflammatory signalling in glomerular cells.
Assuntos
Gordura Intra-Abdominal/fisiologia , Glomérulos Renais/citologia , Glomérulos Renais/metabolismo , Rim/anatomia & histologia , Rim/fisiologia , Artéria Renal/anatomia & histologia , alfa-2-Glicoproteína-HS/metabolismo , Adipócitos/metabolismo , Adulto , Células Cultivadas , Técnicas de Cocultura , Citocinas/metabolismo , Feminino , Expressão Gênica , Humanos , Imuno-Histoquímica , Mediadores da Inflamação/metabolismo , Gordura Intra-Abdominal/diagnóstico por imagem , Rim/diagnóstico por imagem , Macrófagos/metabolismo , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/genética , Artéria Renal/diagnóstico por imagemRESUMO
OBJECTIVE: To evaluate improvement in gastrointestinal (GI) symptoms and health-related quality of life (HRQoL) in liver transplant recipients switched from mycophenolate mofetil (MMF) to enteric-coated mycophenolate sodium (EC-MPS). METHODS: A multicenter, open-label, single-arm study was undertaken in maintenance liver transplant recipients who reported GI complications with MMF therapy. The patients were switched to equimolar doses of EC-MPS at baseline. The primary end point was the change in the Gastrointestinal Symptom Rating Scale (GSRS) total score after 6 to 8 weeks of treatment with EC-MPS. Other key assessments for GI symptoms and HRQoL included the GSRS subscores, the Gastrointestinal Quality of Life Index (GIQLI), the Psychological General Well-Being Index, and the Overall Treatment Effect (OTE). Paired t-test was used to assess the difference in the mean score changes over time. RESULTS: A total of 34 patients were enrolled and switched to equimolar doses of EC-MPS. After 6 to 8 weeks of EC-MPS treatment, mean GSRS total score improved significantly from 2.88 ± 0.66 to 2.10 ± 0.78. Mean improvement in GSRS total score (-0.77 score points; P = .001) exceeded the minimal clinically important difference. Significant improvements were observed in all GSRS subscales (P < .05), GIQLI total scores (P = .001), and GIQLI subscales "GI symptoms" (P < .001) and "physical function" (0.013). Patients who continued EC-MPS reported sustained benefits compared with patients who switched back to MMF after 6 to 8 weeks of treatment with EC-MPS. On the OTE scale, improvement in symptoms was reported in 76.5% and 61.8% of the patients as perceived by the physicians and the patients. Improvement in HRQoL was reported by 41.2% of the patients. No deaths, biopsy proven acute rejections, or graft losses were reported during the study. CONCLUSION: Conversion from MMF to EC-MPS was associated with a significant improvement in GI symptoms and HRQoL in liver transplant recipients.
Assuntos
Gastroenteropatias/induzido quimicamente , Falência Hepática/cirurgia , Transplante de Fígado , Ácido Micofenólico/análogos & derivados , Qualidade de Vida , Adulto , Idoso , Feminino , Gastroenteropatias/complicações , Gastroenteropatias/psicologia , Humanos , Imunossupressores/efeitos adversos , Falência Hepática/complicações , Falência Hepática/psicologia , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/efeitos adversos , Índice de Gravidade de Doença , Inquéritos e Questionários , Comprimidos com Revestimento Entérico , Transplantados , Resultado do TratamentoRESUMO
The feasibility of de novo everolimus without calcineurin inhibitor (CNI) therapy following liver transplantation was assessed in a multicenter, prospective, open-label trial. Liver transplant patients were randomized at 4 weeks to start everolimus and discontinue CNI, or continue their current CNI-based regimen. The primary endpoint was adjusted estimated GFR (eGFR; Cockcroft-Gault) at month 11 post randomization. A 24-month extension phase followed 81/114 (71.1%) of eligible patients to month 35 post randomization. The adjusted mean eGFR benefit from randomization to month 35 was 10.1 mL/min (95% confidence interval [CI] -1.3, 21.5 mL/min, p = 0.082) in favor of CNI-free versus CNI using Cockcroft-Gault, 9.4 mL/min/1.73 m(2) (95% CI -0.4, 18.9, p = 0.053) with Modification of Diet in Renal Disease (four-variable) and 9.5 mL/min/1.73 m(2) (95% CI -1.1, 17.9, p = 0.028) using Nankivell. The difference in favor of the CNI-free regimen increased gradually over time due to a small progressive decline in eGFR in the CNI cohort despite a reduction in CNI exposure. Biopsy-proven acute rejection, graft loss and death were similar between groups. Adverse events led to study drug discontinuation in five CNI-free patients and five CNI patients (12.2% vs. 12.5%, p = 1.000) during the extension phase. Everolimus-based CNI-free immunosuppression is feasible following liver transplantation and patients benefit from sustained preservation of renal function versus patients on CNI for at least 3 years.
Assuntos
Inibidores de Calcineurina , Ciclosporina/administração & dosagem , Rejeição de Enxerto/tratamento farmacológico , Imunossupressores/administração & dosagem , Hepatopatias/cirurgia , Transplante de Fígado , Sirolimo/análogos & derivados , Adolescente , Adulto , Idoso , Ciclosporina/efeitos adversos , Everolimo , Estudos de Viabilidade , Feminino , Seguimentos , Rejeição de Enxerto/etiologia , Sobrevivência de Enxerto/efeitos dos fármacos , Humanos , Imunossupressores/efeitos adversos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Sirolimo/administração & dosagem , Fatores de Tempo , Suspensão de Tratamento , Adulto JovemRESUMO
Eculizumab (anti-C5) has been sporadically reported as an efficient therapy for atypical hemolytic uremic syndrome (aHUS). However, the lack of series precludes any firm conclusion about the optimal use of anti-C5 for preventing or treating aHUS posttransplant aHUS recurrence. We thoroughly studied 22 renal transplant recipients with aHUS who received off-label therapy with anti-C5, including 12 cases, which have not been reported yet. Nine patients, all carrying a complement genetic abnormality associated with a high risk of aHUS recurrence, received prophylactic anti-C5 therapy to prevent posttransplant recurrence. Eight of them had a successful recurrence-free posttransplant course and achieved a satisfactory graft function, while the remaining patient experienced early arterial thrombosis of the graft. Thirteen renal transplant recipients were given anti-C5 for posttransplant aHUS recurrence. A complete reversal of aHUS activity was obtained in all of them. Importantly, the delay of anti-C5 initiation after the onset of the aHUS episode inversely correlated with the degree of renal function improvement. Three patients in whom anti-C5 was subsequently stopped experienced a relapse. Altogether these data suggest that long-term eculizumab is highly effective for preventing and treating posttransplant aHUS recurrence. Our study also indicates that anti-C5 should be promptly started if a recurrence occurs.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Síndrome Hemolítico-Urêmica/tratamento farmacológico , Transplante de Rim/efeitos adversos , Complicações Pós-Operatórias , Prevenção Secundária , Adolescente , Adulto , Síndrome Hemolítico-Urêmica Atípica , Criança , Pré-Escolar , Complemento C5/antagonistas & inibidores , Complemento C5/imunologia , Feminino , Síndrome Hemolítico-Urêmica/etiologia , Humanos , Lactente , Masculino , Prognóstico , Estudos Retrospectivos , Adulto JovemRESUMO
Posttransplant immunosuppression with calcineurin inhibitors (CNIs) is associated with impaired renal function, while mTor inhibitors such as everolimus may provide a renal-sparing alternative. In this randomized 1-year study in patients with liver transplantation (LTx), we sought to assess the effects of everolimus on glomerular filtration rate (GFR) after conversion from CNIs compared to continued CNI treatment. Eligible study patients received basiliximab induction, CNI with/without corticosteroids for 4 weeks post-LTx, and were then randomized (if GFR > 50 mL/min) to continued CNIs (N = 102) or subsequent conversion to EVR (N = 101). Mean calculated GFR 11 months postrandomization (ITT population) revealed no significant difference between treatments using the Cockcroft-Gault formula (-2.9 mL/min in favor of EVR, 95%-CI: [-10.659; 4.814], p = 0.46), whereas use of the MDRD formula showed superiority for EVR (-7.8 mL/min, 95%-CI: [-14.366; -1.191], p = 0.021). Rates of mortality (EVR: 4.2% vs. CNI: 4.1%), biopsy-proven acute rejection (17.7% vs. 15.3%), and efficacy failure (20.8% vs. 20.4%) were similar. Infections, leukocytopenia, hyperlipidemia and treatment discontinuations occurred more frequently in the EVR group. No hepatic artery thrombosis and no excess of wound healing impairment were noted. Conversion from CNI-based to EVR-based immunosuppression proved to be a safe alternative post-LTx that deserves further investigation in terms of nephroprotection.
Assuntos
Inibidores de Calcineurina , Imunossupressores/administração & dosagem , Transplante de Fígado , Sirolimo/análogos & derivados , Adulto , Everolimo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Sirolimo/administração & dosagemRESUMO
BACKGROUND: Evaluation of potential kidney donors requires the assessment of both kidney anatomy and function. In this prospective study, we sought to expand the diagnostic yield of magnetic resonance (MR) by adding functional measurements of glomerular filtration rate (GFR) and split renal function. METHODS: Between 2007 and 2009, all potential kidney donors presenting to our facility underwent a comprehensive single-stop MR study that included an assessment of anatomy, angiography and functional measurements. GFR was measured after a bolus injection of gadobutrol (4 ml, approximately 0.05 mmol/kg) and calculated from the washout of the signal intensity obtained over the liver. Split renal function was calculated from the increase of signal intensity over the renal cortex. Values were compared to renal scintigraphy with (99m)Tc-DTPA from the same day. RESULTS: The MR investigation was successfully performed in 21 participants. The GFR derived from MR (MR-GFR) correlated well (r = 0.84) with the GFR derived from scintigraphy (DTPA-GFR). The mean value of the paired differences was 4 +/- 13 [SD] ml/min/1.73 m(2) and was not significantly different from zero. The ratio between right and left kidney function was similar with both techniques (1.01 +/- 0.17 with MR and 1.06 +/- 0.12 with scintigraphy, P = 0.20). CONCLUSIONS: We demonstrate an MR-based approach to comprehensively evaluate both kidney anatomy and function in a single investigation, thereby facilitating the evaluation of potential kidney donors.
Assuntos
Testes de Função Renal/métodos , Transplante de Rim , Rim/anatomia & histologia , Rim/fisiologia , Doadores Vivos , Imageamento por Ressonância Magnética/métodos , Adulto , Creatinina/metabolismo , Feminino , Taxa de Filtração Glomerular , Humanos , Rim/irrigação sanguínea , Rim/diagnóstico por imagem , Testes de Função Renal/estatística & dados numéricos , Angiografia por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Cintilografia , Compostos Radiofarmacêuticos , Pentetato de Tecnécio Tc 99mRESUMO
Nephrogenic systemic fibrosis (NSF) is a novel disease entity, increasingly diagnosed over the last years in patients with renal functional impairment and chronic kidney disease. Recently, gadolinium-containing MR contrast agents have been causally associated with the development NSF. Herein, we present the case of a dialysis-dependent young patient with systemic lupus erythematodes, who developed disabling cutaneous sclerosis of extremities, abdomen and mammae. Clinical and laboratory investigations revealed no signs of activity of the underlying disease. Histopathological examination of a skin biopsy was consistent with NSF showing profound thickening of tissue septae with mucine deposition and slight fibroblast proliferation without inflammatory reaction. Analysis of the patient's medical history revealed that she had undergone repeated contrast enhanced MR scans, including MR angiographies with high doses of gadopentetate. UV phototherapy was little effective, and not until kidney transplantation two years later with good allograft function, improvement of clinical symptoms was observed. Discussion of this case summarizes the current knowledge of clinical features and pathogeneses of NSF, including the role of gadolinium-containing contrast agents. Evolving clinical implications are summarized in the current Tübingen University Hospital guideline for the use of contrast-enhanced MR scans in patients with impaired renal function.
Assuntos
Gadolínio/efeitos adversos , Falência Renal Crônica/terapia , Escleroderma Sistêmico/diagnóstico , Escleroderma Sistêmico/etiologia , Pele/patologia , Adulto , Meios de Contraste/administração & dosagem , Meios de Contraste/efeitos adversos , Meios de Contraste/química , Feminino , Gadolínio/administração & dosagem , Gadolínio/química , Humanos , Falência Renal Crônica/complicações , Imageamento por Ressonância Magnética , Diálise RenalAssuntos
Abscesso Abdominal/diagnóstico , Falha de Equipamento , Extravasamento de Materiais Terapêuticos e Diagnósticos/diagnóstico , Hérnia Abdominal/diagnóstico , Imageamento por Ressonância Magnética , Diálise Peritoneal Ambulatorial Contínua/efeitos adversos , Peritonite/diagnóstico , Tomografia Computadorizada por Raios X , Calcinose/diagnóstico , Doença Crônica , Diagnóstico Diferencial , Diálise Peritoneal Ambulatorial Contínua/instrumentação , Sensibilidade e EspecificidadeAssuntos
Pressão Sanguínea/fisiologia , Sobrevivência de Enxerto/fisiologia , Transplante de Rim/fisiologia , Complicações Pós-Operatórias/fisiopatologia , Proteinúria/fisiopatologia , Fatores Etários , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Doença Crônica , Seguimentos , Hemoglobinas Glicadas/análise , Rejeição de Enxerto/epidemiologia , Humanos , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Fatores de Tempo , Doadores de Tecidos , Falha de TratamentoRESUMO
Several studies have recently suggested a principal role of adenosine in the pathogenesis of radiocontrast media-induced nephropathy. In the present experiments, we therefore investigated the renal protective effects of 8-(noradamantan-3-yl)-1,3-dipropylxanthine (KW-3902), a potent and selective adenosine A1 receptor antagonist, on radiocontrast media-induced nephropathy in the model of the N-pi-nitro-L-arginine methyl ester (L-NAME) hypertensive, chronic nitric oxide (NO)-depleted rat. Chronic NO depletion was induced by pretreatment with L-NAME, 50 mg/ml, added to drinking water for 8 weeks. Clearance experiments were performed in anesthetized rats and glomerular filtration rate was assessed prior to and following the application of high osmolar radiocontrast media (sodium diatrizoate, 3 ml/kg, i.v.) or an equivalent volume of isoosmolar mannitol to examine the role of hyperosmolarity in radiocontrast media-induced nephropathy. Subgroups received KW-3902 (0.1 mg/kg, i.v.), 20 min prior to radiocontrast media administration. Age-matched, untreated rats served as controls. Radiocontrast media application induced a significant decline in glomerular filtration rate in L-NAME hypertensive animals, whereas no effects were observed in control rats. KW-3902 fully prevented the drop in glomerular filtration rate in response to radiocontrast media in L-NAME hypertensive rats. No renal hemodynamic alterations were observed in mannitol-infused animals. The present experiments demonstrate that the decrease in glomerular filtration rate following radiocontrast media occurred independently of the osmotic load, and that KW-3902 effectively prevented the radiocontrast media-induced deterioration in renal function. KW-3902 may be especially beneficial in patients at high risk for developing acute renal failure following radiocontrast media application or in patients in which extracellular fluid volume expansion is limited by clinical conditions such as congestive heart failure.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Diuréticos/farmacologia , Taxa de Filtração Glomerular/efeitos dos fármacos , Nefrose Lipoide , Óxido Nítrico/deficiência , Antagonistas de Receptores Purinérgicos P1 , Xantinas/farmacologia , Animais , Pressão Sanguínea/fisiologia , Meios de Contraste/efeitos adversos , Diatrizoato/efeitos adversos , Modelos Animais de Doenças , Diuréticos/uso terapêutico , Diuréticos Osmóticos/farmacologia , Inibidores Enzimáticos/farmacologia , Taxa de Filtração Glomerular/fisiologia , Masculino , Manitol/farmacologia , NG-Nitroarginina Metil Éster/farmacologia , Nefrose Lipoide/induzido quimicamente , Nefrose Lipoide/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , Receptores Purinérgicos P1/fisiologia , Sódio/urina , Xantinas/uso terapêuticoAssuntos
Diuréticos/farmacologia , Diuréticos/uso terapêutico , Ascite/tratamento farmacológico , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Hipertensão/tratamento farmacológico , Falência Renal Crônica/tratamento farmacológico , Falência Hepática/tratamento farmacológico , Intoxicação/tratamento farmacológicoRESUMO
The present study was designed to investigate, in human subjects, urinary dopamine excretion under different conditions of sodium and water homeostasis. In a cross-over trial, ten healthy volunteers were subjected to low-salt (LS; dietary salt restriction, sodium chloride (NaCl) intake <5 g per day), normal-salt (NS; normal food ad libitum), and high-salt (HS; normal food plus NaCl 100 mg/kg per day) regimens for 8 days in a randomized order. On day 7, urine was collected for 24 h. The variations in urinary sodium excretion reflected the dietary salt intake (LS: 16.3+/-4.7; NS: 144.1+/-18.2; HS: 221.9+/-12.9 mmol 24 h(-1) 1.73 m(-2)), but were not accompanied by significant changes in urinary dopamine excretion. On day 8, clearance studies showed that an acute oral water load of 1500 ml did not alter glomerular filtration rate or renal plasma flow but significantly increased urinary flow rate without affecting dopamine excretion. Assuming that excreted dopamine is not metabolized or reabsorbed during the tubular passage, both the unchanged urinary dopamine output in spite of 14-fold variations in sodium excretion and its independence of an acute water load argue against the hypothesis that dopamine in the tubular lumen acts as a natriuretic and/or diuretic factor in humans.
Assuntos
Dopamina/urina , Sódio na Dieta/farmacologia , Água/administração & dosagem , Administração Oral , Adulto , Estudos Cross-Over , Diurese/efeitos dos fármacos , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Valores de Referência , Análise de Regressão , Fluxo Plasmático Renal/efeitos dos fármacosRESUMO
To study the possible mechanism of renoprotective effects of adenosine A1-receptor antagonist against radiocontrast media (RCM)-induced nephropathy, we investigated the effects of adenosine A1-receptor antagonist on tubuloglomerular feedback (TGF) activity prior to and following application of RCM in chronic NO-depleted rats. TGF in NO-depleted rats was significantly enhanced compared with that in normal rats. After RCM application, the enhanced TGF was continued. A selective adenosine A1-receptor antagonist, KW-3902 (8-(noradamantan-3-yl)-1,3-dipropylxanthine), inhibited the enhanced TGF. These results suggest that KW-3902 could inhibit TGF in chronic NO-depleted rats. Renoprotective effects by adenosine antagonists could be partly due to an inhibition of TGF via the blockade of the adenosine A1-receptor.
Assuntos
Meios de Contraste/efeitos adversos , Nefropatias/tratamento farmacológico , Glomérulos Renais/fisiopatologia , Túbulos Renais/fisiopatologia , Óxido Nítrico/deficiência , Antagonistas de Receptores Purinérgicos P1 , Xantinas/uso terapêutico , Animais , Doença Crônica , Nefropatias/induzido quimicamente , Nefropatias/fisiopatologia , Masculino , Ratos , Ratos Sprague-Dawley , Xantinas/farmacologiaRESUMO
Renal hemodynamic changes could play a key role in radiocontrast media-induced nephropathy (RCIN), although the pathophysiological mechanisms are unclear. We investigated the role of adenosine in RCIN caused by sodium diatrizoate (Urografin, 3 ml/kg) in nitro-L-Arg methyl ester (L-NAME)-hypertensive rats in different hydration states [eight weeks of L-NAME (50 mg/liter) in drinking water; high or low sodium intake for the last two weeks]. In clearance experiments under thiobutabarbital anesthesia in these previously mentioned animals, glomerular filtration rate (GFR), renal blood flow (RBF), and mean arterial pressure (MAP) were measured in the presence or absence of the adenosine A1-receptor antagonist 8-cyclopropyl-1,3-dipropylxanthine (DPCPX, 100 microg/kg bolus plus 10 microg/kg/hr). DPCPX or pretreatment did not change control hemodynamics. Contrast medium caused GFR and RBF to fall significantly in volume-depleted rats (from 0.29 +/- 0.02 to 0.21 +/- 0.02 ml/min/100 g and 5.4 +/- 0.3 to 4.0 +/- 0.4 ml/min, respectively) without change in MAP. In volume-expanded rats, changes were not significant (0.25 +/- 0.01 to 0.24 +/- 0.02 ml/min/100 g and 5.6 +/- 0.3 to 5.3 +/- 0.4 ml/min, respectively). In the volume-depleted rats, changes were prevented by DPCPX (0.27 +/- 0.02 to 0.24 +/- 0.02 ml/min/100 g and 4.8 +/- 0.1 to 5.0 +/- 0.1 ml/min, respectively). The acute hemodynamic effects elicited by contrast medium in L-NAME hypertensive rats thus can be prevented by volume expansion. Adenosine, via A1-receptors, contributes to the adverse effects of contrast media.
Assuntos
Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/metabolismo , Adenosina/análise , Meios de Contraste/efeitos adversos , Injúria Renal Aguda/tratamento farmacológico , Animais , Pressão Sanguínea , Inibidores Enzimáticos , Espaço Extracelular/química , Hematócrito , Hipertensão Renal/induzido quimicamente , Hipertensão Renal/tratamento farmacológico , Hipertensão Renal/metabolismo , Rim/química , Rim/metabolismo , Masculino , NG-Nitroarginina Metil Éster , Antagonistas de Receptores Purinérgicos P1 , Ratos , Ratos Wistar , Água/metabolismo , Xantinas/farmacologiaRESUMO
Exogenous angiotensin (Ang) 1-7 affects renal function, but the receptor(s) involved in this response remain(s) to be determined. In an in vitro preparation of proximal tubules, Ang 1-7 was shown to act on Ang II AT1 receptors (minor component), but also on a non-AT1, non-AT2 Ang receptor (major component) to inhibit reabsorption. In brain, Ang 1-7 also exerts effects mediated by a non-AT1, non-AT2 binding site; these effects are inhibited, however, by the angiotensin analog [7-D-Ala]-Ang 1-7. Therefore we tested the effect of Ang II AT1-receptor antagonist losartan and [7-D-Ala]-Ang 1-7 on the renal response to exogenous Ang 1-7 in standard renal-clearance experiments in the anesthetized rat. We found that Ang 1-7 (100 pmol/kg/min, i.a.) increased glomerular filtration rate (GFR), urinary flow rate (UV), and urinary sodium excretion (UNaV) without affecting mean arterial blood pressure (MAP) or urinary potassium excretion (UKV), confirming previous reports. Losartan (10 mg/kg, i.v.) blocked the pressor effect of exogenous Ang II (100 pmol/kg/min, i.a.), but did not significantly affect the renal response to Ang 1-7. Conversely, pretreatment with [7-D-Ala]-Ang 1-7 (5 nmol/kg/min) did not affect the pressor effect of Ang II, but abolished the renal response to Ang 1-7. Application of [7-D-Ala]-Ang 1-7 in the absence of exogenous Ang 1-7 did not alter MAP or GFR, but increased UNaV (by 52%). Our data indicate that similar to the response in brain, the renal response to exogenous Ang 1-7 may be mediated predominantly by a distinct non-AT1 binding site, which is sensitive to blockade by [7-D-Ala]-Ang 1-7. Furthermore, ambient endogenous Ang 1-7 acting on this distinct binding site may not contribute significantly to control of MAP or GFR, but exerts an antinatriuretic influence in the anesthetized rat.
Assuntos
Angiotensina II/análogos & derivados , Angiotensina II/antagonistas & inibidores , Rim/efeitos dos fármacos , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/farmacologia , Anestesia , Angiotensina I , Angiotensina II/farmacologia , Animais , Anti-Hipertensivos/farmacologia , Testes de Função Renal , Túbulos Renais Proximais/efeitos dos fármacos , Losartan/farmacologia , Masculino , Ratos , Ratos Sprague-Dawley , Circulação Renal/efeitos dos fármacosRESUMO
BACKGROUND AND OBJECTIVE: In patients with chronic glomerular nephropathy associated arterial hypertension and proteinuria are considered to be cardinal risk factors in the progressive deterioration of renal function. Treatment regimens which reduce proteinuria and hypertension improve prognosis. The effect of the new beta-receptor blockers compared to common ACE-Inhibitors is of special interest. PATIENTS AND METHODS: The studied cohort consisted of 11 patients with CGN, hypertension and proteinuria > 400 mg/24 h. Four drugs were given for 4 weeks, doubly blinded and randomized according to a "Latin-square design": Celiprolol (beta-1-antagonist, beta-2-agonist, 200 mg/d), Atenolol (selective beta-1-antagonist, 50 mg/d), Ramipril (ACE-inhibitor, 2.5 mg/d) and placebo. There was a two-week wash-out phase between each of the four treatment phases. At the end of each treatment phase glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured by inulin and para-amino-hippuric acid (PAH) clearance. Proteinuria was determined in the course of a three-day collection period at the end of each treatment phase. During this period blood pressures were measured with a continuous 24-hour blood pressure monitor. RESULTS: Mean arterial blood pressure (MAP) was significantly reduced, compared with placebo, by all three antihypertensives (108 +/- 9 mm Hg with placebo, 98 +/- 12 mg Hg with atenolol, 101 +/- 11 mm Hg with celiprolol and 98 +/- 8 mm Hg with ramipril; P < 0.01). Celiprolol produced a significant rise In ERPF (322 +/- 109 ml/min with placebo, 391 +/- 110 ml/min with celiprolol: P < 0.05). GFR was slightly, but not significantly, reduced by celiprolol and atenolol. Filtration fraction remained unchanged with atenolol and celiprolol, while it was slightly, but not significantly, reduced with ramipril. Compared with the placebo, all three drugs significantly reduced proteinuria (P < 0.05): 1.8 +/- 1.3 g/24 h with placebo, 1.2 +/- 1.2 g/24 h with atenolol, 1.2 +/- 1.1 g/24 h with celiprolol and 1.4 +/- 1.4 g/24 h with ramipril. CONCLUSION: These data indicate that, in addition to ACE inhibitors, the new generation of beta-receptor blockers in particular, because of their vasodilator action, favourably influence proteinuria and renal blood flow in patients with CGN and arterial hypertension.
Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Anti-Hipertensivos/farmacologia , Glomerulonefrite/fisiopatologia , Proteinúria/tratamento farmacológico , Proteinúria/fisiopatologia , Circulação Renal/efeitos dos fármacos , Adulto , Atenolol/farmacologia , Celiprolol/farmacologia , Doença Crônica , Método Duplo-Cego , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Inulina/sangue , Masculino , Pessoa de Meia-Idade , Proteinúria/etiologia , Ramipril/farmacologia , Fluxo Plasmático Renal Efetivo/efeitos dos fármacos , Resultado do Tratamento , Ácido p-Aminoipúrico/sangueRESUMO
To evaluate therapeutic options for the prevention of radiocontrast media (RCM)-induced nephropathy, a model was developed in which rats received NG-nitro-L-arginine methyl ester (L-NAME) for 10 wk in order to inhibit nitric oxide (NO) synthetase. This study tests the hypothesis that infusion of an adenosine antagonist before RCM application may avoid the vasoconstrictive response in NO-depleted rats. Rats received L-NAME for 10 wk orally (50 mg/L drinking water) to achieve NO depletion. Renal function was determined by [3H]inulin clearance for analysis of the GFR and by flowmetry for assessing renal blood flow (RBF). After a control clearance period (baseline clearance period), the renal response to RCM application (sodium diatrizoate, 2 ml/kg body wt) was measured two times every 30 min starting 30 min after RCM application (clearance periods 1 and 2). L-NAME rats and control rats received two adenosine antagonists. The nonselective adenosine antagonist theophylline was given as an initial bolus of 50 mumol/kg body wt within 10 min, followed by continuous infusion of 100 mumol/kg body wt per h, and the specific adenosine A1-receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) was given as a bolus of 100 micrograms/kg body wt before RCM application. Results were compared with vehicle infusion. In the control group, no significant change of GFR or RBF could be detected after application of RCM with or without prior infusion of DPCPX or theophylline. In L-NAME rats, RBF decreased significantly after RCM application (baseline, 5.6 +/- 0.2 ml/min; first clearance period, 4.6 +/- 0.3 ml/min [P < 0.05]; second clearance period, 4.3 +/- 0.3 [P < 0.01]). GFR was also reduced in L-NAME rats without previous infusion of theophylline or DPCPX (baseline, 0.95 +/- 0.1 ml/min; first clearance period, 0.83 +/- 0.1 ml/min; second clearance period, 0.69 +/- 0.1 ml/min [P = 0.058]). Prior treatment with either theophylline or DPCPX resulted in complete protection against a decline of RBF and GFR induced by RCM in L-NAME rats. Rats with chronic NO blockade showed a significant increase of the renal vasoconstrictive effect of contrast media. Application of L-NAME in rats seems to constitute a suitable animal model to study the pathophysiology of radiocontrast media-induced nephropathy. In this animal model, administration of adenosine antagonists prevented the decline of GFR and RBF.