RESUMO
Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent cause of genetic renal disease and accounts for 6-10% of patients on kidney replacement therapy (KRT). Very few prospective, randomized trials or clinical studies address the diagnosis and management of this relatively frequent disorder. No clinical guidelines are available to date. This is a revised consensus statement from the previous 2014 version, presenting the recommendations of the Spanish Working Group on Inherited Kidney Diseases, which were agreed to following a literature search and discussions. Levels of evidence mostly are C and D according to the Centre for Evidence-Based Medicine (University of Oxford). The recommendations relate to, among other topics, the use of imaging and genetic diagnosis, management of hypertension, pain, cyst infections and bleeding, extra-renal involvement including polycystic liver disease and cranial aneurysms, management of chronic kidney disease (CKD) and KRT and management of children with ADPKD. Recommendations on specific ADPKD therapies are provided as well as the recommendation to assess rapid progression.
Assuntos
Rim Policístico Autossômico Dominante , Criança , Humanos , Consenso , Rim Policístico Autossômico Dominante/diagnóstico , Rim Policístico Autossômico Dominante/genética , Rim Policístico Autossômico Dominante/terapia , Estudos ProspectivosRESUMO
BACKGROUND AND OBJECTIVES: Some studies suggest that the incidence of IgA nephropathy is increasing in older adults, but there is a lack of information about the epidemiology and behavior of the disease in that age group. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this retrospective multicentric study, we analyzed the incidence, forms of presentation, clinical and histologic characteristics, treatments received, and outcomes in a cohort of 151 patients ≥65 years old with biopsy-proven IgA nephropathy diagnosed between 1990 and 2015. The main outcome was a composite end point of kidney replacement therapy or death before kidney replacement therapy. RESULTS: We found a significant increase in the diagnosis of IgA nephropathy over time from six patients in 1990-1995 to 62 in 2011-2015 (P value for trend =0.03). After asymptomatic urinary abnormalities (84 patients; 55%), AKI was the most common form of presentation (61 patients; 40%). Within the latter, 53 (86%) patients presented with hematuria-related AKI (gross hematuria and tubular necrosis associated with erythrocyte casts as the most important lesions in kidney biopsy), and eight patients presented with crescentic IgA nephropathy. Six (4%) patients presented with nephrotic syndrome. Among hematuria-related AKI, 18 (34%) patients were receiving oral anticoagulants, and this proportion rose to 42% among the 34 patients older than 72 years old who presented with hematuria-related AKI. For the whole cohort, survival rates without the composite end point were 74%, 48%, and 26% at 1, 2, and 5 years, respectively. Age, serum creatinine at presentation, and the degree of interstitial fibrosis in kidney biopsy were risk factors significantly associated with the outcome, whereas treatment with renin-angiotensin-aldosterone blockers was associated with a lower risk. Immunosuppressive treatments were not significantly associated with the outcome. CONCLUSIONS: The diagnosis of IgA nephropathy among older adults in Spain has progressively increased in recent years, and anticoagulant therapy may be partially responsible for this trend. Prognosis was poor. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2019_07_16_CJASNPodcast_19_08_.mp3.
Assuntos
Glomerulonefrite por IGA , Adulto , Idoso , Feminino , Glomerulonefrite por IGA/diagnóstico , Glomerulonefrite por IGA/epidemiologia , Glomerulonefrite por IGA/terapia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Patients with chronic kidney disease (CKD) are at high risk for developing cardiovascular events. However, limited evidence is available regarding the use of aspirin in CKD patients to decrease cardiovascular risk and to slow renal disease progression. STUDY DESIGN: Prospective, multicenter, open-label randomized controlled trial. SETTING AND PARTICIPANTS: One hundred eleven patients with estimated glomerular filtration rate (eGFR) 15-60 ml/min/1.73 m2 without previous cardiovascular events. INTERVENTION: Aspirin treatment (100 mg/day) (n = 50) or usual therapy (n = 61). Mean follow-up time was 64.8 ± 16.4 months. OUTCOMES: The primary endpoint was composed of cardiovascular death, acute coronary syndrome (nonfatal MI, coronary revascularization, or unstable angina pectoris), cerebrovascular disease, heart failure, or nonfatal peripheral arterial disease. Secondary endpoints were fatal and nonfatal coronary events, renal events (defined as doubling of serum creatinine, ≥ 50% decrease in eGFR, or renal replacement therapy), and bleeding episodes. RESULTS: During follow-up, 17 and 5 participants suffered from a primary endpoint in the control and aspirin groups, respectively. Aspirin did not significantly reduce primary composite endpoint (HR, 0.396 (0.146-1.076), p = 0.069. Eight patients suffered from a fatal or nonfatal coronary event in the control group compared to no patients in the aspirin group. Aspirin significantly reduced the risk of coronary events (log-rank, 5.997; p = 0.014). Seventeen patients in the control group reached the renal outcome in comparison with 3 patients in the aspirin group. Aspirin treatment decreased renal disease progression in a model adjusted for age, baseline kidney function, and diabetes mellitus (HR, 0.272; 95% CI, 0.077-0.955; p = 0.043) but did not when adjusted for albuminuria. No differences were found in minor bleeding episodes between groups and no major bleeding was registered. LIMITATIONS: Small sample size and open-label trial. CONCLUSIONS: Long-term treatment with low-dose aspirin did not reduce the composite primary endpoint; however, there were reductions in secondary endpoints with fewer coronary events and renal outcomes. ClinicalTrials.gov Identifier: NCT01709994.
Assuntos
Aspirina/uso terapêutico , Fármacos Cardiovasculares/uso terapêutico , Doenças Cardiovasculares/prevenção & controle , Rim/efeitos dos fármacos , Prevenção Primária/métodos , Insuficiência Renal Crônica/tratamento farmacológico , Idoso , Aspirina/efeitos adversos , Fármacos Cardiovasculares/efeitos adversos , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/mortalidade , Progressão da Doença , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Hemorragia/induzido quimicamente , Humanos , Rim/fisiopatologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/mortalidade , Insuficiência Renal Crônica/fisiopatologia , Fatores de Risco , Espanha , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Resolution of inflammation is regulated by endogenous lipid mediators, such as lipoxins and their epimers, including 15-epi-lipoxin A4 (15-epi-LXA4). However, there is no information on 15-epi-LXA4 and its in vivo regulation in chronic kidney disease (CKD) patients. STUDY DESIGN: Open label randomized clinical trial. SETTING AND PARTICIPANTS: 50 participants with chronic kidney disease (CKD) stage 3 and 4 without prior cardiovascular disease (25 in the aspirin group and 25 in the standard group) followed for 46 months. INTERVENTION: Aspirin (100mg/day) or standard treatment. AIM: To analyze the effect of aspirin on plasma 15-epi-LXA4 levels and inflammatory markers in CKD patients. RESULTS: Baseline plasma15-epi-LXA4 levels were lower in diabetic (1.22 ± 0.99ng/ml) than in non-diabetic CKD patients (2.05 ± 1.06ng/ml, p < 0.001) and inversely correlated with glycosylated hemoglobin levels (r = -0.303, p = 0.006). In multivariate analysis, diabetes was associated with lower 15-epi-LXA4 levels, adjusted for age, inflammatory markers and renal function (p = 0.005). In the whole study population, 15-epi-LXA4 levels tended to increase, but not significantly (p = 0.45), after twelve months on aspirin (from mean ± SD 1.84 ± 1.06 to 2.04 ± 0.75ng/ml) and decreased in the standard care group (1.60 ± 1.15 to 1.52 ± 0.68ng/ml, p = 0.04). The aspirin effect on 15-epi-LXA4 levels was more striking in diabetic patients, increasing from 0.94 ± 0.70 to 1.93 ± 0.74ng/ml, p = 0.017. CONCLUSIONS: Diabetic patients with CKD have lower circulating 15-epi-LXA4 levels than non-diabetic CKD patients. Low dose aspirin for 12 months increased 15-epi-LXA4 levels in diabetic patients. Given its anti-inflammatory properties, this increase in 15-epi-LXA4 levels may contribute to the beneficial effects of low dose aspirin.
Assuntos
Aspirina/uso terapêutico , Lipoxinas/sangue , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/tratamento farmacológico , Idoso , Anti-Inflamatórios/uso terapêutico , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Patients with Stage 5 chronic kidney disease who are on hemodialysis (HD) remain in a chronic inflammatory state, characterized by the accumulation of uremic toxins that induce endothelial damage and cardiovascular disease (CVD). Our aim was to examine microvesicles (MVs), monocyte subpopulations, and angiopoietins (Ang) to identify prognostic markers in HD patients with or without diabetes mellitus (DM). A total of 160 prevalent HD patients from 10 centers across Spain were obtained from the Biobank of the Nephrology Renal Network (Madrid, Spain): 80 patients with DM and 80 patients without DM who were matched for clinical and demographic criteria. MVs from plasma and several monocyte subpopulations (CD142+/CD16+, CD14+/CD162+) were analyzed by flow cytometry, and the plasma concentrations of Ang1 and Ang2 were quantified by ELISA. Data on CVD were gathered over the 5.5 yr after these samples were obtained. MV level, monocyte subpopulations (CD14+/CD162+ and CD142+/CD16+), and Ang2-to-Ang1 ratios increased in HD patients with DM compared with non-DM patients. Moreover, MV level above the median (264 MVs/µl) was associated independently with greater mortality. MVs, monocyte subpopulations, and Ang2-to-Ang1 ratio can be used as predictors for CVD. In addition, MV level has a potential predictive value in the prevention of CVD in HD patients. These parameters undergo more extensive changes in patients with DM.
Assuntos
Angiopoietina-1/sangue , Angiopoietina-2/sangue , Micropartículas Derivadas de Células/metabolismo , Nefropatias Diabéticas/sangue , Nefropatias Diabéticas/terapia , Células Endoteliais/metabolismo , Diálise Renal , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/terapia , Idoso , Biomarcadores/sangue , Estudos de Casos e Controles , Micropartículas Derivadas de Células/patologia , Nefropatias Diabéticas/diagnóstico , Nefropatias Diabéticas/mortalidade , Progressão da Doença , Células Endoteliais/patologia , Feminino , Humanos , Mediadores da Inflamação/sangue , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , Valor Preditivo dos Testes , Prevalência , Diálise Renal/efeitos adversos , Diálise Renal/mortalidade , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/mortalidade , Espanha/epidemiologia , Fatores de Tempo , Resultado do TratamentoRESUMO
C3 glomerulonephritis is a clinicopathologic entity defined by the presence of isolated or dominant deposits of C3 on immunofluorescence. To explore the effect of immunosuppression on C3 glomerulonephritis, we studied a series of 60 patients in whom a complete registry of treatments was available over a median follow-up of 47 months. Twenty patients had not received immunosuppressive treatments. In the remaining 40 patients, 22 had been treated with corticosteroids plus mycophenolate mofetil while 18 were treated with other immunosuppressive regimens (corticosteroids alone or corticosteroids plus cyclophosphamide). The number of patients developing end-stage renal disease was significantly lower among treated compared with untreated patients (3 vs. 7 patients, respectively). No patient in the corticosteroids plus mycophenolate mofetil group doubled serum creatinine nor developed end-stage renal disease, as compared with 7 (significant) and 3 (not significant), respectively, in patients treated with other immunosuppressive regimens. Renal survival (100, 80, and 72% at 5 years) and the number of patients achieving clinical remission (86, 50, and 25%) were significantly higher in patients treated with corticosteroids plus mycophenolate mofetil as compared with patients treated with other immunosuppressive regimens and untreated patients, respectively. Thus, immunosuppressive treatments, particularly corticosteroids plus mycophenolate mofetil, can be beneficial in C3 glomerulonephritis.
Assuntos
Complemento C3 , Glomerulonefrite/tratamento farmacológico , Imunossupressores/uso terapêutico , Ácido Micofenólico/análogos & derivados , Adolescente , Corticosteroides/uso terapêutico , Adulto , Idoso , Anti-Inflamatórios/uso terapêutico , Creatinina/sangue , Ciclofosfamida/uso terapêutico , Progressão da Doença , Quimioterapia Combinada , Feminino , Seguimentos , Glomerulonefrite/complicações , Glomerulonefrite/imunologia , Humanos , Falência Renal Crônica/etiologia , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/uso terapêutico , Estudos Retrospectivos , Taxa de Sobrevida , Adulto JovemRESUMO
Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent cause of genetic renal disease and accounts for 6-10% of patients on renal replacement therapy (RRT). Very few prospective, randomized trials or clinical studies address the diagnosis and management of this relatively frequent disorder. No clinical guidelines are available to date. This is a consensus statement presenting the recommendations of the Spanish Working Group on Inherited Kidney Diseases, which were agreed to following a literature search and discussions. Levels of evidence found were C and D according to the Centre for Evidence-Based Medicine (University of Oxford). The recommendations relate to, among other topics, the use of imaging and genetic diagnosis, management of hypertension, pain, cyst infections and bleeding, extra-renal involvement including polycystic liver disease and cranial aneurysms, management of chronic kidney disease (CKD) and RRT and management of children with ADPKD. Recommendations on specific ADPKD therapies are not provided since no drug has regulatory approval for this indication.
Assuntos
Rim Policístico Autossômico Dominante/diagnóstico , Rim Policístico Autossômico Dominante/terapia , Humanos , Terapia de Substituição Renal , EspanhaRESUMO
The association of hepatitis C virus (HCV) infection and glomerulonephritis is well known. However, the relationship between immune-mediated glomerulonephritis and occult HCV, characterized by the presence of HCV-RNA in liver or in peripheral blood mononuclear cells in the absence of serological markers, is unknown. We tested this in 113 anti-HCV-negative patients; 87 with immune-mediated glomerulonephritis and 26 controls with hereditary glomerular nephropathies. All patients were serum HCV-RNA negative by conventional real-time PCR. Significantly, occult HCV-RNA (detectable viral RNA in peripheral blood mononuclear cells or in serum after ultracentrifugation) was found in 34 of 87 patients with immune-mediated glomerulonephritis versus 1 of 26 control patients. The serum creatinine levels were significantly higher in patients with immune-mediated glomerulonephritis with than in those without occult HCV (1.5 versus 1.1 mg/dl, respectively). A multivariate analysis adjusted for gender showed a significantly increased risk of occult HCV in patients with immune-mediated glomerulonephritis versus the controls (odds ratio of 13.29). Progression to end-stage renal disease tended to be faster in patients with immune-mediated glomerulonephritis and occult HCV than in the negative cases. Thus, occult HCV is strongly associated with immune-mediated glomerulonephritis and may have a role in the progression of the disease.
Assuntos
Glomerulonefrite/epidemiologia , Glomerulonefrite/imunologia , Hepacivirus/genética , Anticorpos Anti-Hepatite C/sangue , Hepatite C/epidemiologia , Nefrite Hereditária/epidemiologia , RNA Viral/sangue , Adulto , Idoso , Creatinina/sangue , Feminino , Glomerulonefrite/sangue , Hepacivirus/imunologia , Hepatite C/sangue , Humanos , Leucócitos Mononucleares/virologia , Masculino , Pessoa de Meia-Idade , Nefrite Hereditária/sangue , Prevalência , Estudos Prospectivos , Fatores de RiscoRESUMO
BACKGROUND: Vitamin D has an important regulatory effect on the renin-angiotensin-aldosterone system, playing a central role in the regulation of proteinuria. We therefore studied the antiproteinuric effect of paricalcitol. METHODS: 36 patients with an estimated GFR of 30-90 mL/min/1.73 m² and proteinuria >400 mg/d with a stable dose of ACE inhibitor or ARB for at least 3 months were recruited. Patients received oral paricalcitol 1 µg/day for 12 months. Primary endpoint was decrease in proteinuria from baseline. Secondary endpoints were changes in creatinine, eGFR, serum levels of calcium, phosphorus, iPTH, 25(OH)vitD, C-Reactive Protein and blood presure. RESULTS: Mean proteinuria was 2806 mg/d and fell to 2199 mg/d at month 6 (p<.0001) and 1931.5 mg/d at month 12 (P<.0001). Patients with >3000 mg/d baseline proteinuria (n=12) saw smaller relative reductions in proteinuria (5956.9±2492.6 mg/d to 4220.4±2613 mg/d at 12 months) than patients with <3000 mg/d baseline proteinuria (1371±627.5 mg/d to 821.3±491.5mg/d at 12 months). There were no changes in BP, eGFR and CRP. We observed significant changes in serum levels of calcium, phosphorus, iPTH, 25(OH) vitamin D. CONCLUSION: Our study shows an important reduction in proteinuria with a low dose of oral paricalcitol in CKD, that is particularly robust with baseline proteinuria between 1-3 g/d.
Assuntos
Ergocalciferóis/uso terapêutico , Nefropatias/tratamento farmacológico , Proteinúria/prevenção & controle , Idoso , Idoso de 80 Anos ou mais , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Proteína C-Reativa/análise , Cálcio/sangue , Doença Crônica , Creatinina/sangue , Ergocalciferóis/administração & dosagem , Feminino , Seguimentos , Taxa de Filtração Glomerular/efeitos dos fármacos , Humanos , Nefropatias/sangue , Nefropatias/complicações , Nefropatias/urina , Masculino , Pessoa de Meia-Idade , Hormônio Paratireóideo/sangue , Fósforo/sangue , Proteinúria/etiologia , Resultado do Tratamento , Vitamina D/análogos & derivados , Vitamina D/sangueRESUMO
INTRODUCTION: Continuous erythropoietin receptor activator (C.E.R.A.) effectively enables anemia control in patients with chronic kidney disease, but little information is available in renal transplant recipients. The authors aimed to evaluate the effect of C.E.R.A. under clinical practice conditions on anemia control in renal transplant recipients. METHODS: This was a multicenter, retrospective, observational study carried out in adult renal transplant patients in the immediate posttransplant period and at late posttransplant period receiving C.E.R.A. in clinical practice. Patients' data were retrieved from their medical charts at baseline and months 1, 3, and 6. RESULTS: A total of 318 evaluable patients were enrolled into the study: 32 in the immediate posttransplant period and 286 at late posttransplant period (erythropoiesis-stimulating agent [ESA]-naïve, n = 44; converting from other ESAs, n = 242). Patients in the immediate posttransplant period experienced a significant increase in hemoglobin (Hb) levels from baseline to month 1 (9.9±1.5 g/dL vs. 11.5±1.4 g/dL; P< 0.001). ESA-naïve patients showed increasing mean Hb levels from baseline to month 6 (10.1±0.7 g/dL vs. 11.7±1.0 g/dL; P < 0.001) and 94.7% achieved Hb ≥11 g/dL during the study. In patients converted from other ESAs, the percentage of patients with Hb between 11-13 g/dL was maintained from baseline to month 6 with no significant differences (61.0% vs. 62.4%). Mean monthly doses of C.E.R.A. at baseline were 134.4±56.4 µg, 81.3±28.1 µg, and 93.0±44.2 µg in immediate posttransplant, ESA-naïve, and converted patients, respectively. C.E.R.A. was well tolerated. CONCLUSION: C.E.R.A. enables anemia control in renal transplant recipients, allowing target Hb levels to be achieved and maintained with doses even below those described in the Summary of Product Characteristics.
Assuntos
Anemia/tratamento farmacológico , Anemia/etiologia , Eritropoetina/administração & dosagem , Hemoglobinas/efeitos dos fármacos , Transplante de Rim/efeitos adversos , Polietilenoglicóis/administração & dosagem , Adulto , Anemia/fisiopatologia , Estudos de Coortes , Relação Dose-Resposta a Droga , Esquema de Medicação , Eritropoetina/efeitos adversos , Feminino , Seguimentos , Hemoglobinas/análise , Humanos , Injeções Subcutâneas , Falência Renal Crônica/diagnóstico , Falência Renal Crônica/cirurgia , Transplante de Rim/métodos , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/efeitos adversos , Cuidados Pós-Operatórios/métodos , Estudos Retrospectivos , Medição de Risco , Gestão da Segurança , Índice de Gravidade de Doença , Espanha , Fatores de Tempo , Resultado do TratamentoRESUMO
The long-term outcome of patients with IgA nephropathy who present with normal renal function, microscopic hematuria, and minimal or no proteinuria is not well described. Here, we studied 141 Caucasian patients with biopsy-proven IgA nephropathy who had minor abnormalities at presentation and a median follow-up of 108 months. None of the patients received corticosteroids or immunosuppressants. We reviewed renal biopsies using the Oxford classification criteria. In this sample, 46 (32%) patients had mesangial proliferation, whereas endocapillary proliferation, focal glomerulosclerosis, and tubulointerstitial abnormalities were uncommon. Serum creatinine increases >50% and >100% were observed in five (3.5%) patients and one (0.7%) patient, respectively; no patients developed ESRD. After 10, 15, and 20 years, 96.7%, 91.9%, and 91.9% of patients maintained serum creatinine values less than a 50% increase, respectively. Using Cox proportional hazards regression, the presence of segmental glomerulosclerosis was the only factor that significantly associated with a >50% increase in serum creatinine. Clinical remission occurred in 53 (37.5%) patients after a median of 48 months. Proteinuria>0.5 and >1.0 g/24 h developed in 21 (14.9%) and 6 (4.2%) patients, respectively. Median proteinuria at the end of follow-up was 0.1 g/24 h, with 41 (29.1%) patients having no proteinuria. At presentation, 23 (16.3%) patients were hypertensive compared with 30 (21.3%) patients at the end of follow-up; 59 (41.8%) patients were treated with renin-angiotensin blockers because of hypertension or increasing proteinuria. In summary, the long-term prognosis for Caucasian patients with IgA nephropathy who present with minor urinary abnormalities and normal renal function is excellent.
Assuntos
Glomerulonefrite por IGA/patologia , Glomerulonefrite por IGA/fisiopatologia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Creatinina/sangue , Feminino , Glomerulonefrite por IGA/complicações , Humanos , Rim/patologia , Falência Renal Crônica/etiologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Prognóstico , Proteinúria/etiologia , Adulto JovemRESUMO
Spontaneous remission is a well known characteristic of idiopathic membranous nephropathy, but contemporary studies describing predictors of remission and long-term outcomes are lacking. We conducted a retrospective, multicenter cohort study of 328 patients with nephrotic syndrome resulting from idiopathic membranous nephropathy that initially received conservative therapy. Spontaneous remission occurred in 104 (32%) patients: proteinuria progressively declined after diagnosis until remission of disease at 14.7 +/- 11.4 months. Although spontaneous remission was more frequent with lower levels of baseline proteinuria, it also frequently occurred in patients with massive proteinuria: 26% among those with baseline proteinuria 8 to 12 g/24 h and 22% among those with proteinuria >12 g/24 h. Baseline serum creatinine and proteinuria, treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor antagonists, and a >50% decline of proteinuria from baseline during the first year of follow-up were significant independent predictors for spontaneous remission. Only six patients (5.7%) experienced a relapse of nephrotic syndrome. The incidence of death and ESRD were significantly lower among patients with spontaneous remission. In conclusion, spontaneous remission is common among patients with nephrotic syndrome resulting from membranous nephropathy and carries a favorable long-term outcome with a low incidence of relapse. A decrease in proteinuria >50% from baseline during the first year predicts spontaneous remission.
Assuntos
Glomerulonefrite Membranosa/complicações , Síndrome Nefrótica/etiologia , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Síndrome Nefrótica/terapia , Proteinúria/etiologia , Remissão Espontânea , Estudos RetrospectivosRESUMO
Mutations in the NPHS1 gene cause congenital nephrotic syndrome of the Finnish type presenting before the first 3 months of life. Recently, NPHS1 mutations have also been identified in childhood-onset steroid-resistant nephrotic syndrome and milder courses of disease, but their role in adults with focal segmental glomerulosclerosis remains unknown. Here we developed an in silico scoring matrix to evaluate the pathogenicity of amino-acid substitutions using the biophysical and biochemical difference between wild-type and mutant amino acid, the evolutionary conservation of the amino-acid residue in orthologs, and defined domains, with the addition of contextual information. Mutation analysis was performed in 97 patients from 89 unrelated families, of which 52 presented with steroid-resistant nephrotic syndrome after 18 years of age. Compound heterozygous or homozygous NPHS1 mutations were identified in five familial and seven sporadic cases, including one patient 27 years old at onset of the disease. Substitutions were classified as 'severe' or 'mild' using this in silico approach. Our results suggest an earlier onset of the disease in patients with two 'severe' mutations compared to patients with at least one 'mild' mutation. The finding of mutations in a patient with adult-onset focal segmental glomerulosclerosis indicates that NPHS1 analysis could be considered in patients with later onset of the disease.
Assuntos
Glomerulosclerose Segmentar e Focal/genética , Proteínas de Membrana/genética , Mutação , Adulto , Idade de Início , Substituição de Aminoácidos , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Estudos de Associação Genética , Glomerulosclerose Segmentar e Focal/congênito , Heterozigoto , Homozigoto , Humanos , Lactente , Recém-Nascido , Masculino , Proteínas de Membrana/química , Mutação de Sentido Incorreto , Síndrome Nefrótica/congênito , Síndrome Nefrótica/genética , EspanhaRESUMO
BACKGROUND: Mutations in the TRPC6 gene have been reported in six families with adult-onset (17-57 years) autosomal dominant focal segmental glomerulosclerosis (FSGS). Electrophysiology studies confirmed augmented calcium influx only in three of these six TRPC6 mutations. To date, the role of TRPC6 in childhood and adulthood non-familial forms is unknown. METHODS: TRPC6 mutation analysis was performed by direct sequencing in 130 Spanish patients from 115 unrelated families with FSGS. An in silico scoring matrix was developed to evaluate the pathogenicity of amino acid substitutions, by using the bio-physical and bio-chemical differences between wild-type and mutant amino acid, the evolutionary conservation of the amino acid residue in orthologues, homologues and defined domains, with the addition of contextual information. RESULTS: Three new missense substitutions were identified in two clinically non-familial cases and in one familial case. The analysis by means of this scoring system allowed us to classify these variants as likely pathogenic mutations. One of them was detected in a female patient with unusual clinical features: mesangial proliferative FSGS in childhood (7 years) and partial response to immunosupressive therapy (CsA + MMF). Asymptomatic carriers of this likely mutation were found within her family. CONCLUSIONS: We describe for the first time TRPC6 mutations in children and adults with non-familial FSGS. It seems that TRPC6 is a gene with a very variable penetrance that may contribute to glomerular diseases in a multi-hit setting.
Assuntos
Glomerulosclerose Segmentar e Focal/genética , Canais de Cátion TRPC/genética , Adolescente , Adulto , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Humanos , Lactente , Pessoa de Meia-Idade , Canal de Cátion TRPC6 , Adulto JovemRESUMO
Hypoalbuminemia may be secondary to volume expansion conditions and an independent risk factor for cardiovascular disease. Bioelectrical impedance analysis (BIA) is an accurate, non-invasive method to measure body composition, especially the water compartments in humans. The aim of this cross-sectional study is to evaluate the relationship between serum albumin concentration (SA) and hydration state measured by whole BIA. The study investigated 108 non-selected patients (73 on hemodialysis, 35 on peritoneal dialysis) with a mean age of 61.4 +/- 15.6 years, 42.7% of whom were female. The patients were allotted to groups according to their SA: Group 1, < or = 3.5 g/dL; Group 2, 3.6-4.0 g/dL; and Group 3, >4.0 g/dL. The BIA parameters used included: total body water, intracellular water (ICW), extracellular water (ECW), phase angle (PA), body cell mass (BCM), ICW/ECW ratio and ICW/ECW ratio patients/controls (fluid index). Seventy-five healthy volunteers formed the control group. A strong positive correlation was found between the PA and fluid index (r (2) = 0.993, P < 0.001), as well as between the PA and SA (r = 0.386, P < 0.001), and the ICW/ECW ratio and SA (r = 0.227, P < 0.001). The ECW was negatively correlated with SA (r = -0.330, P < 0.001). Every 0.1 g/dL decrease in SA was associated with a 0.33 L increase in ECW. Group 1 patients had lower reactance (P = 0.006), PA (P < 0.001), BCM (P = 0.012), fluid index (P < 0.001) and ICW/ECW ratio (P = 0.015), and an increased ECW (NS) than groups 2 and 3. We conclude that hypoalbuminemia is also a marker of fluid excess. The SA is associated to the fluid index and the PA allows assessment of the dry weight and its variations in an individualized manner in dialysis patients.
Assuntos
Compartimentos de Líquidos Corporais , Água Corporal , Impedância Elétrica , Hipoalbuminemia/sangue , Diálise Peritoneal , Diálise Renal , Idoso , Biomarcadores , Composição Corporal , Análise por Conglomerados , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Proteinuria is a significant independent determinant of the progression of chronic renal diseases. It induces an increased synthesis of angiotensin II, endothelin and profibrogenic growth factors, such as transforming growth factor-beta (TGF-beta), by mesangial and tubular cells. The antiproteinuric effect of angiotensin-converting enzyme inhibitors (ACEIs) in diabetic and non-diabetic nephropathies predicts long-term renoprotection afforded by these drugs. Angiotensin II receptor antagonists are renoprotective in patients with type 2 diabetes, but studies about their effect in non-diabetic proteinuric nephropathies are very scarce. METHODS: We randomly assigned 97 patients with non-diabetic nephropathies and proteinuria >1.5 g/24 h to treatment with losartan (50 mg daily) or amlodipine (5 mg daily) for 20 weeks. Doses of the study medications were titrated to achieve a target blood pressure <140/90 mmHg in both groups. Primary outcome was the decrease in the level of 24 h proteinuria. Secondary outcomes were changes in the plasma and urinary levels of TGF-beta. RESULTS: The baseline characteristics in both groups were similar. Proteinuria decreased by 32.4% (95% confidence interval -38.4 to -21.8%) after 4 weeks of treatment and by 50.4% (-58.9 to -40.2%) after 20 weeks in the losartan group, whereas no significant proteinuria changes were observed in the amlodipine group (P < 0.001). There was no significant correlation between the level of baseline proteinuria and the proteinuria decrease induced by losartan. Both losartan and amlodipine induced a similar and significant blood pressure reduction. Target blood pressure was achieved with the initial dose of study medication (50 mg daily) in 76% of losartan group patients and in 68% of the amlodipine group patients (5 mg daily). Urinary TGF-beta significantly decreased with losartan (-22.4% of the baseline values after 20 weeks of treatment), whereas it tended to increase with amlodipine (between-group difference P < 0.05). A significant correlation between proteinuria decrease and urinary TGF-beta reduction was found in the losartan group (r = 0.41, P < 0.005). Serum creatinine and serum potassium remained stable during the study in both groups. CONCLUSIONS: Losartan induced a drastic decrease in proteinuria accompanied by a reduction in urinary excretion of TGF-beta in patients with non-diabetic proteinuric renal diseases.
Assuntos
Anlodipino/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Nefropatias/tratamento farmacológico , Losartan/uso terapêutico , Proteinúria/tratamento farmacológico , Adulto , Antagonistas de Receptores de Angiotensina , Bloqueadores dos Canais de Cálcio/uso terapêutico , Diabetes Mellitus , Método Duplo-Cego , Feminino , Humanos , Nefropatias/sangue , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Proteinúria/sangue , Fator de Crescimento Transformador beta/sangue , Resultado do TratamentoRESUMO
BACKGROUND: Blockade of the renin-angiotensin system (RAS) with angiotensin converting enzyme (ACE) inhibitors or with angiotensin II type 1 (AT1) receptor blockers has been shown to reduce proteinuria and to slow down the progression of renal disease in diabetic and non-diabetic primary proteinuric nephropathies. Additionally, this beneficial effect is not dependent on blood pressure control. METHODS: To assess and compare the effects of lisinopril (up to 40 mg/day), candesartan (up to 32 mg/day) and combination therapy (lisinopril up to 20 mg/day plus candesartan up to 16 mg/day) on urinary protein excretion, 45 patients with primary proteinuric nephropathies (urinary protein/creatinine ratio 3.8+/-2.4 g/g) and normal or slightly reduced renal function (CCr 95+/-33 mL/min) were enrolled in a six month multicenter, prospective, open, randomized, active-controlled and parallel-group trial with 1:1:1 allocation. Blood pressure goal was set at or below 125/75 mm Hg for all patients, with additional antihypertensive medication prescribed if required. RESULTS: Renal function, estimated by creatinine clearance, remained stable throughout the study. Hyperkalemia (K>5.5 mmol/L) was detected in 3.1% of all measurements in follow-up, and was more frequent in patients treated with lisinopril alone or lisinopril plus candesartan (P<0.001) than in those on candesartan alone. No other relevant adverse event was recorded. The blood pressure goal (<125/75 mm Hg) was achieved by week 4 in all treatment groups (P<0.005 when compared to baseline), and afterwards the mean systolic and diastolic blood pressure remained below these values until the end of the trial with no statistically significant differences between groups. Urinary protein/creatinine ratio (percentage reduction 95% confidence intervals CI) decreased in patients treated with lisinopril alone to -33% (CI -12-56) to -31% (CI 0-68) and to -50% (CI -9-90), in patients treated with candesartan to -28% (CI -12-45), to -41% (CI -30-52) and to -48% (CI -32-63), in patients treated with the combination of both to -60% (CI -44-77) to -54% (CI -38-69) and to -70% (CI -57-83) at two, three, and six months, respectively. All comparisons with baseline achieved statistical significance and treatment with combination therapy was statistically more effective in proteinuria reduction than treatment with candesartan alone at two and six months (P=0.004 and P=0.023, respectively) and than treatment with lisinopril only at two months (P=0.03). CONCLUSION: Dual blockade of the renin-angiotensin system with ACE inhibitors and AT1 receptor blockers produces a beneficial antiproteinuric effect that could not be explained only by the systemic blood pressure reduction. All treatments were well tolerated.