RESUMO
BACKGROUND: Mortality of critically-ill patients with acute kidney injury (AKI) requiring renal replacement therapy (RRT) in an intensive-care setting continues to remain high. There is still uncertainty as to which factors should guide clinical judgement. METHODS: A cohort of 155 patients admitted to an intensive-care unit and necessitating RRT due to AKI were retrospectively analyzed. Demographic and clinical parameters at the time of RRT initiation were retrieved. Multi- and univariate analyses were performed to determine the impact of different risk factors on mortality. RESULTS: The most common causes of AKI were sepsis (39.3%) and cardiac events (32%). The majority of patients were treated by continuous (67.3%), the others by intermittent RRT. After 30 days, 51.0% of patients survived. Nonsurvivors were older (73 vs. 69 years), had a higher APACHEE II score (30.1 ± 5.6 vs. 26.5 ± 7.1), and were more likely to be vasopressor dependent, mechanically ventilated, or treated by continuous RRT. Multivariate analysis revealed that higher age, higher APACHEE II score, and lower serum creatinine at baseline were independent predictors for mortality, whereas histories of diabetes mellitus, arterial hypertension, coronary heart disease, or stroke were not. CONCLUSION: Critically-ill patients with AKI requiring RRT continue to have a high mortality. Age and APACHE II score showed an impact on mortality whereas traditional cardiovascular risk factors did not. Higher BUN and creatinine levels do not have a negative impact on mortality. Our findings support the current practice that RRT initiation should primarily be guided by clinical decision.â©.
Assuntos
Injúria Renal Aguda/mortalidade , Unidades de Terapia Intensiva , Terapia de Substituição Renal , Injúria Renal Aguda/terapia , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de RiscoRESUMO
BACKGROUND: Although citrate dialysate (CiDi) is regarded to be safe, dialysis modalities using higher dialysate volumes, like haemodiafiltration (HDF), may expose patients to higher citrate load and thus increase the risk of complications. We investigated the residual risk of CiDi compared with standard dialysate (StDi) in patients on different dialysis modalities and its effect on dialysis dose. METHODS: In a multicentre randomized crossover study, 92 dialysis patients (HDF post-dilution: n = 44, HDF pre-dilution: n = 26, haemodialysis: n = 25) were treated for 4 weeks with each dialysate (StDi and CiDi). Hypocalcaemia (ionized calcium ≤0.9 mmol/L), alkalosis (pH ≥7.55), post-treatment bicarbonate ≥32 mmol/L, pre-treatment bicarbonate ≥27 mmol/L, intra-dialytic events (IEs) and adverse events (AEs) between dialysis sessions were investigated as primary end points. The secondary objective was dialysis efficacy, i.e. dose and removal ratios of urea, creatinine, phosphate and ß-2-microglobulin. RESULTS: Post-dialysis overcorrection of bicarbonate (>32 mmol/L) was less frequent with CiDi (P = 0.008). Other predefined calcium and acid-base disturbances did not vary. There was no significant difference in IE. However, more patients developed AEs such as fatigue, muscle spasms or pain using CiDi (StDi: 41 versus CiDi: 55 patients, P = 0.02), particularly in the first 2 weeks of exposure. Dialysis efficacy was comparable with both dialysates. CONCLUSIONS: It can be confirmed that CiDi is not associated with the development of severe calcium and acid-base disorders, even when dialysis modalities with higher citrate loads are used. However, a refinement of the CiDi composition to minimize AEs is necessary.
Assuntos
Ácido Cítrico/farmacologia , Soluções para Diálise/farmacologia , Hipercalcemia/prevenção & controle , Falência Renal Crônica/terapia , Diálise Renal/métodos , Adulto , Idoso , Quelantes de Cálcio/farmacologia , Estudos Cross-Over , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
Interleukin-17A (IL-17) promotes inflammatory renal tissue damage in mouse models of crescentic glomerulonephritis, including murine experimental autoimmune anti-myeloperoxidase glomerulonephritis, which most likely depends on IL-17-producing Th17 cells. In human anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis, however, the cellular sources of IL-17 remain to be elucidated. Therefore, we analyzed human kidney biopsies of active necrotizing and crescentic ANCA-associated glomerulonephritis by immunohistochemistry using an IL-17-specific antibody and by immunofluorescent colocalization with cell type markers. We detected numerous IL-17-expressing (IL-17(+)) cells in the glomeruli and in the tubulointerstitium. Unexpectedly, most of these IL-17(+) cells were polymorphonuclear neutrophilic granulocytes, while IL-17(+) T cells and IL-17(+) mast cells were present at significantly lower frequencies. IL-17 was not detected in other infiltrating or resident kidney cells. In those patients who had not received immunosuppressive treatment before biopsy, serum creatinine levels were positively correlated with tubulointerstitial IL-17(+) neutrophils as well as IL-17(+) T cells. Furthermore, we could demonstrate that purified human blood neutrophils expressed IL-17 protein and released it upon stimulation in vitro. In conclusion, these results support a pathogenic role for IL-17 in human ANCA-associated glomerulonephritis. Our data suggest that in the acute stage of the disease neutrophils may act as an important immediate-early innate source of IL-17 and may thereby initiate and promote ongoing renal inflammation. IL-17 may thus be a target for treating acute ANCA-associated glomerulonephritis.
Assuntos
Anticorpos Anticitoplasma de Neutrófilos/metabolismo , Glomerulonefrite/metabolismo , Interleucina-17/metabolismo , Rim/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Anticitoplasma de Neutrófilos/imunologia , Feminino , Glomerulonefrite/imunologia , Humanos , Rim/imunologia , Masculino , Mastócitos/imunologia , Mastócitos/metabolismo , Pessoa de Meia-Idade , Neutrófilos/imunologia , Neutrófilos/metabolismoRESUMO
BACKGROUND: Continuous venovenous haemofiltration (CVVH) in the intensive care setting requires anticoagulation to prevent clotting of the extracorporeal circuit. Several protocols avoiding heparin and using regional citrate anticoagulation have been developed to diminish bleeding risks. However, data from randomized trials comparing citrate anticoagulation with systemic heparinization are very limited. METHODS: One hundred and seventy-four patients on mechanical ventilation, requiring renal replacement therapy for acute renal failure, were included in this prospective randomized multicentre trial comparing regional citrate with systemic heparin. The study was performed at nine different intensive care units at university or academic teaching hospitals. The participants were randomized to either CVVH using regional citrate anticoagulation or CVVH using systemic anticoagulation with unfractionated heparin. The primary outcome was to compare treatment efficacy represented by the patients' acid base status on Day 3 and on each consecutive day. Several parameters of safety and efficacy were analysed as secondary outcomes. RESULTS: Comparison of standard bicarbonate from Day 3 to Day 11 revealed no difference between both treatment modalities. Use of citrate resulted in less systemic anticoagulation, a lower risk of bleeding and a longer haemofilter patency. Episodes of hypercalcaemia, hypocalcaemia and the need for additional bicarbonate infusions occurred more often under citrate. The patients' high mortality was not influenced by the mode of anticoagulation. CONCLUSIONS: Citrate may be used as a regional anticoagulant and the only buffering agent in CVVH with adequate treatment efficacy and safety. However, neither citrate nor heparin anticoagulation should be regarded as a therapeutic standard, since there is no advantage of one of these substances with regard to patient mortality.
Assuntos
Injúria Renal Aguda/terapia , Anticoagulantes/uso terapêutico , Citratos/uso terapêutico , Estado Terminal , Hemofiltração , Heparina/uso terapêutico , Idoso , Bicarbonatos/uso terapêutico , Soluções Tampão , Feminino , Hemorragia/etiologia , Hemorragia/prevenção & controle , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Diálise Renal , Taxa de Sobrevida , Resultado do TratamentoRESUMO
AIM: We evaluated the influence of C-344T polymorphism of the aldosterone synthase gene, associated with aldosterone levels and the development of arterial hypertension, on focal segmental glomerulosclerosis (FSGS). METHODS: We studied 81 patients with primary FSGS followed up for 8.0 ± 12 years. Patients were classified according to their slope of reciprocal serum creatinine into group A (slow progressors, n = 57) and B (fast progressors, n = 24). One hundred healthy volunteers were analysed as controls. The biopsies of n = 50 patients were reviewed and analysed by the same pathologist. C-344T polymorphism was determined by polymerase chain reaction. RESULTS: The allele frequencies differed significantly between patients (C-allele: 0.55, T-allele: 0.45) and controls (C-allele: 0.45, T-allele: 0.55; P < 0.05). Patients carrying the C-allele tended to have a higher percentage of sclerosed glomeruli (41.8 ± 30% vs 31. 2 ± 19% in TT genotype, ns) and tubulointerstitial fibrosis (22.8 ± 18% vs 16.0 ± 5%, ns). The rate of deterioration of renal function was higher in the CC/CT genotypes (-0.216 ± 0.449 dL/mg per year) compared to the TT genotype (-0.030 ± 0.041 dL/mg per year, P = 0.002). Furthermore, 36.4% of the C-allele carriers and none of the patients with the TT genotype belonged to group B (P = 0.005). C-allele carriers also had a worse kidney survival in the Kaplan-Meier analysis (P = 0.027). CONCLUSION: Our results indicate that aldosterone synthase gene C-344T polymorphism not only acts as a risk factor for the development of FSGS, but also may influence its pathologic appearance and could serve as a marker of disease progression.
Assuntos
Citocromo P-450 CYP11B2/genética , Glomerulosclerose Segmentar e Focal/genética , Polimorfismo Genético , Adulto , Progressão da Doença , Feminino , Frequência do Gene , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Genótipo , Glomerulosclerose Segmentar e Focal/epidemiologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , Adulto JovemRESUMO
AIM: In the past years, aldosterone has been identified as an important mediator of renal injury. In this study, we evaluated the influence of C-344T polymorphism of aldosterone synthase gene, associated with serum aldosterone levels and the development of arterial hypertension, on IgA nephropathy (IgAN). METHODS: We studied n = 143 patients with biopsy-proven IgAN followed up for 7.1 ± 6.2 years. Patients were classified according to the slope of reciprocal serum creatinine into group A (slow progressors, n = 93) and group B (fast progressors, n = 50). One hundred healthy volunteers were analyzed as controls. The biopsies of n = 79 patients were reviewed and analyzed by the same pathologist. Aldosterone synthase gene C-344T polymorphism was determined by polymerase chain reaction amplification. RESULTS: The genotype distribution was similar in patients and control subjects [not significant (ns)]. Age, initial renal function, proteinuria, and blood pressure did not differ significantly between patients with different genotypes (ns). The percentage of sclerosed glomeruli tended to be higher among patients carrying the CC/CT genotypes (29.4 ± 26.5% vs. 21.7 ± 25.2% in TT genotype; ns). C-344T polymorphism was associated with the progression of IgAN as shown by the different genotype frequencies in group Α (slow progressors, CC/CT: 60.2%, TT: 39.8%) and group B (fast progressors, CC/CT: 78.0%, TT: 22:0%; p = 0.032). CONCLUSION: Our results indicate that aldosterone synthase gene C-344T polymorphism is a risk factor for accelerated progression in Caucasian patients with IgAN.
Assuntos
Aldosterona/sangue , Citocromo P-450 CYP11B2/genética , Glomerulonefrite por IGA/genética , Hipertensão/etiologia , Adulto , Biópsia , Progressão da Doença , Feminino , Genótipo , Glomerulonefrite por IGA/complicações , Glomerulonefrite por IGA/metabolismo , Glomerulonefrite por IGA/patologia , Humanos , Rim/patologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Adulto JovemRESUMO
BACKGROUND: There are few anecdotal reports of circulating antineutrophil cytoplasmic autoantibodies (ANCAs) in patients with immunoglobulin A (IgA) nephropathy. STUDY DESIGN: Retrospective case series. SETTING & PARTICIPANTS: We studied 8 patients with crescentic IgA nephropathy associated with ANCAs against myeloperoxidase (n = 5) and proteinase 3 (n = 3) followed up for 2.4 +/- 1.7 years. They were compared with 26 patients with IgA nephropathy with > 10% crescentic glomeruli, but negative for ANCAs. OUTCOMES: We analyzed clinical and histologic features of patients and their response to treatment. MEASUREMENTS: Screening for ANCAs was performed using indirect immunofluorescence, and positive results were verified using enzyme-linked immunosorbent assay. RESULTS: All patients with crescentic IgA nephropathy and positive for ANCAs, compared with only one-third of ANCA-negative patients, presented with the clinical syndrome of rapid progressive glomerulonephritis. ANCA-positive patients reached a higher peak serum creatinine level within the first 3 months (4.2 +/- 2.2 vs 2.5 +/- 1.9 mg/dL; estimated glomerular filtration rate, 19.3 +/- 10.2 vs 45.9 +/- 30.1 mL/min/1.73 m(2)). ANCA-positive patients with IgA nephropathy had a higher percentage of crescentic glomeruli (54.3% +/- 18%) compared with ANCA-negative patients with crescentic IgA nephropathy (34.5% +/- 26%). ANCA-positive patients were treated using cyclophosphamide and corticosteroids. Kidney function improved in all these patients: serum creatinine level decreased from the peak of 4.2 +/- 2.2 to 1.7 +/- 0.7 mg/dL at the end of follow up (estimated glomerular filtration rate, 19.3 +/- 10.2 to 44.6 +/- 11.1 mL/min/1.73 m(2)). In contrast, no significant improvement was achieved in ANCA-negative patients. CONCLUSION: Patients with IgA nephropathy, crescents, and positive for ANCAs represent a clinical entity with a diverse more exaggerated clinical and histologic picture. However, disease in these patients responded well to aggressive immunosuppressive therapy.
Assuntos
Anticorpos Anticitoplasma de Neutrófilos/sangue , Glomerulonefrite por IGA/sangue , Adulto , Feminino , Glomerulonefrite por IGA/classificação , Humanos , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
Acute kidney injury (AKI) can be considered as an inflammatory systemic disorder affecting virtually every organ. It has great impact on morbidity and mortality of critically ill patients. DIAGNOSTIC: The use of electronic alerts for detection of AKI combined with the use of standardized kidney care bundles can improve patient outcomes. Currently, it is important to find ways to implement these in everyday clinical practice. PREVENTION/CONSERVATIVE THERAPY: Volume replacement therapy should always be carried out with balanced solutions. The use of 0.9â% NaCl solution should be avoided. In individual cases, patients can also benefit from a colloidal solution in the form of human albumin. Urgently indicated radiographic diagnosis with iodine-containing contrast agent should not be delayed or canceled due to renal impairment. The prophylactic measures in this context are not different from the general recommendations in AKI (achieve euvolemia, avoid nephrotoxins), specific measures do not exist. Indiscriminate hydration of non-hypovolemic patients has no advantages and is associated with an increased risk of cardiac decompensation and AKI. RENAL REPLACEMENT THERAPY: Treatment dose and modality should be adapted to the clinical needs of the patient. The recommended dose of 20â-â25âml/kg/h serves as orientation. Continuous and intermittent therapies should be available. Regional citrate anticoagulation (RCA) can also be safely used for patients with liver damage or lactic acidosis, provided that early signs of citrate accumulation are closely monitored. In the case of lactic acidosis, lactate clearance rather than baseline level of lactate is particularly important for the risk of citrate accumulation.
Assuntos
Injúria Renal Aguda , Cuidados Críticos , Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/fisiopatologia , Injúria Renal Aguda/terapia , Estado Terminal , Humanos , Unidades de Terapia Intensiva , Terapia de Substituição RenalRESUMO
OBJECTIVES: The International Society of Nephrology (ISN) has called for zero deaths by 2025. This survey aimed to determine the preparedness of Southern African Development Community (SADC) countries and Nigeria to heed this call. SETTING: A questionnaire was emailed to facilities, where renal replacement therapy is available; to determine type of services available; quality of care and identify clinicians involved. PARTICIPANTS: Clinicians and administrators involved in the care of patients with acute kidney injury (AKI) completed the questionnaire. RESULTS: Completed questionnaires were received from 12 of the 15 SADC countries and Nigeria, covering 48 service providers. The government provided partial funding for dialysis in 41.7% of services. There was no funding for acute dialysis in two countries. Interdisciplinary teams in 72.9% of hospitals covered the intensive care units (ICUs), which included at least one nephrologist in 75%. Only 77% were able to provide dialysis in ICU. Intermittent haemodialysis was the most common modality available (91.7% of facilities), sustained low-efficiency dialysis in 50%, continuous therapies in 35% and peritoneal dialysis in 33.3%. Almost half (47.9%) of the sites were limited to one mode of dialysis and unable to care for severely ill patients. The clinical status was used to initiate and monitor dialysis, with very few sites having clear written standard operating procedures. CONCLUSION: In the 16 countries surveyed, the majority had limited ability to provide comprehensive dialysis programmes for patients with AKI due to lack of facilities and government funding. Additionally, nephrologists are scarce; modes of dialysis are limited; as is the care for severely ill patients and lack of standard operating procedures. Resources, training and funding need to be made available to create universal coverage of dialysis for AKI. The ISN goal of providing renal replacement therapy to all by 2025 is unlikely to be achieved in SADC and Nigeria.
Assuntos
Injúria Renal Aguda/terapia , Acessibilidade aos Serviços de Saúde/estatística & dados numéricos , Equipe de Assistência ao Paciente/estatística & dados numéricos , Terapia de Substituição Renal/estatística & dados numéricos , África Subsaariana , Terapia de Substituição Renal Contínua/estatística & dados numéricos , Humanos , Unidades de Terapia Intensiva/estatística & dados numéricos , Terapia de Substituição Renal Intermitente/estatística & dados numéricos , Nigéria , Gravidade do Paciente , Diálise Peritoneal/estatística & dados numéricos , Guias de Prática Clínica como Assunto , Terapia de Substituição Renal/economia , Inquéritos e QuestionáriosRESUMO
BACKGROUND: The G-1082A polymorphism of the interleukin-10 (IL-10) gene has been associated with modified gene expression and the progression of primary IgA nephropathy (IgAN). In the present study, we evaluated its influence on recurrent IgAN after renal transplantation. METHODS: We studied 103 patients who suffered from IgAN and underwent renal transplantation, followed up for 5.8 -/+ 3.4 years. A cohort of 206 matched renal allograft recipients with other primary diseases was analyzed as a control group. IL-10 gene G-1082A polymorphism was determined by PCR amplification. RESULTS: Microscopic hematuria and/or proteinuria of more than 500 mg/24 hours occurred in 22 patients (21%). Histological confirmation of IgAN recurrence was obtained in 16 patients. Young recipient age was associated with biopsy-proven IgAN recurrence in the Kaplan-Meier analysis of recurrence-free survival (p=0.05). The presence of IgAN recurrence had no impact on graft survival (not significant [NS]). Furthermore, graft survival was similar in patients with IgAN and patients with other primary diseases (NS). The IL-10 GG genotype was associated with a higher recurrence rate in the Kaplan-Meier analysis of recurrence-free survival (p<0.05). CONCLUSIONS: IgAN recurrence is a common complication, especially in younger renal transplant recipients. IL-10 gene G-1082A polymorphism was associated with an increased recurrence rate.
Assuntos
DNA/genética , Glomerulonefrite por IGA/genética , Interleucina-10/genética , Polimorfismo Genético , Adulto , Alelos , Biópsia , Intervalo Livre de Doença , Ensaio de Imunoadsorção Enzimática , Feminino , Seguimentos , Genótipo , Glomerulonefrite por IGA/sangue , Glomerulonefrite por IGA/cirurgia , Sobrevivência de Enxerto , Humanos , Interleucina-10/sangue , Transplante de Rim/patologia , Masculino , Reação em Cadeia da Polimerase , Recidiva , Estudos Retrospectivos , Fatores de Risco , Fatores de TempoRESUMO
AIM: To study the demographics and outcome of acute kidney injury (AKI) at Groote Schuur Hospital, Cape Town, South Africa. METHODS AND FINDINGS: A prospective observational study of AKI fulfilling the Kidney Disease: Improving Global Outcomes definition, from 8 July 2012 to 8 July 2013. Ethics approval was granted by the University of Cape Town Human Research Ethics Committee. Consent was waived because patient data was de-identified and patient management was not adversely affected by the study. A clerking sheet was used for data collection. Patients were reassessed after 3 months. Main outcomes were renal recovery and 3 month mortality. Descriptive statistics and multivariate logistic regression were carried out for risk factors. Over this period there were 10,750 hospital admissions and 366 patients with AKI giving an incidence of 3.4%. Median age was 44 years (IQR 14-82) and 214 (58.5%) were male, with 152 (41.5%) female. Most, 265 (72.4%), had community acquired AKI. Common underlying comorbidities were hypertension (n = 152, 41.5%), diabetes mellitus (n = 65, 17.8%) Human immunodeficiency virus (HIV) (n = 75, 20.6%), heart disease (n = 58, 16.1%), and chronic kidney disease (n = 37, 10.1%). Renal biopsies were performed in 36 (9.8%) patients. In total, 202 (55.2%) patients were in the intensive care unit, and of the whole study population 204 (55.7%) were dialysed. Those admitted to ICU who required dialysis amounted to 145 (39.6%). The overall 3 month mortality was 38.8%. Among the 145 patients dialysed in ICU, there were 71 deaths (49%) at 3 month follow up. Of the 119 patients with follow up serum creatinine, 95 (79.8%) had full renal recovery, and 4 (3.4%) had end-stage renal disease. On multivariate analysis, mechanical ventilation was associated with 3 month mortality (OR 2.46, p-value 0.019, 95% CI 1.41-4.03). Sepsis had a borderline significant association (OR 1.83, P-value 0.066, 95%CI 1.02-3.27), as did prolonged time to dialysis (OR 1.93, p-value 0.08, 095% CI 0.93-4.03). HIV status did not affect outcome. The main study limitations were the large numbers of patients with AKI stage 3, reflecting the fact that the institution is a tertiary referral centre and that patients with earlier stages of AKI tended not to be referred. Another study limitation was the low number of patients who were available for follow up for 3 month serum creatinine. CONCLUSIONS: The incidence of AKI in the population studied is 3.4% of hospital admissions and carries a high mortality risk, most significant in mechanically ventilated patients. Sepsis and late dialysis initiation may carry a risk of mortality, but HIV infection did not affect outcome. Follow up of patients at least 3 months after an episode of AKI is essential to detect and appropriately manage those with incomplete renal recovery. In this study 36 patients underwent a kidney biopsy, and in many of these the results guided patient management. This study demonstrates finally that it remains imperative that clinicians actively pursue underlying causes of acute decline in renal function, including urine analysis, renal ultrasonography and if indicated and safe, a renal biopsy.
Assuntos
Injúria Renal Aguda/terapia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , África do Sul , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Beta3 integrin subunit is expressed as alpha(IIb)beta3 integrin on platelets and as alpha(v)beta3 integrin on a variety of cells including renal endothelial, mesangial and tubular cells. Leu33/Pro33 polymorphism of beta3 integrin has been associated with altered platelet functions, cardiovascular complications and the incidence of acute rejection episodes in renal transplantation. We investigated its influence on IgA nephropathy (IgAN), focal segmental glomerulosclerosis (FSGS) and membranous glomerulonephritis (MGN). METHODS: We studied 251 patients with biopsy-proven primary glomerulonephritis (IgAN n = 127, FSGS n = 71, MGN n = 53) followed up for 6.3 +/- 5.3 years and 100 control subjects. Patients were classified according to the slope of reciprocal serum creatinine into slow (n = 162) and fast progressors (n = 89). Leu33/Pro33 polymorphism was determined by PCR amplification followed by restriction with the endonuclease Bcnl. RESULTS: The genotype frequencies were similar in patients and controls (n.s.). Initial renal function, proteinuria and blood pressure did not differ significantly between patients with different genotypes (n.s.). The genotype frequencies were similar in slow and fast progressors (n.s.). Furthermore, Leu33/Pro33 polymorphism had no impact on renal survival in the Kaplan-Meier analysis (n.s.). CONCLUSION: Our results indicate that beta3 integrin Leu33/Pro33 polymorphism is not a risk factor or a marker of progression in primary glomerulonephritis.
Assuntos
Glomerulonefrite por IGA/genética , Glomerulonefrite Membranosa/genética , Glomerulosclerose Segmentar e Focal/genética , Integrina beta3/genética , Adulto , Pressão Sanguínea , Estudos de Casos e Controles , Feminino , Genótipo , Glomerulonefrite por IGA/patologia , Glomerulonefrite Membranosa/patologia , Glomerulosclerose Segmentar e Focal/patologia , Humanos , Rim/fisiologia , Falência Renal Crônica/fisiopatologia , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Polimorfismo Genético , Proteinúria , Análise de SobrevidaRESUMO
Renal transplant recipients treated with cyclosporine A (CsA) and FK506 (tacrolimus) develop signs of hypoaldosteronism despite normal plasma aldosterone levels, suggesting a relative resistance of the distal nephron to aldosterone action. To examine the effects of immunosuppressants on human MR (hMR) function, we established the M cell model, renal tubular cells stably transfected with hMR. Upon CsA and FK506 administration, hMR mRNA levels and aldosterone binding in M cells remained unchanged (maximum number of sites, approximately 80 fmol/mg protein; K(d) = approximately 1 nM). Aldosterone-dependent intracellular localization of green fluorescent protein-hMR was not affected by immunosuppressants. A major impact of CsA or FK506 on the multidrug resistance gene product in cellular accumulation of aldosterone was also excluded. In contrast, aldosterone-stimulated hMR transcriptional activity was reduced to 53 +/- 11.2% (P < 0.03) after pretreatment of M cells for 3 d with CsA and to 71 +/- 9.6% (P < 0.05) after pretreatment with FK506. These effects were both time and concentration dependent (IC(50) of CsA, 10(-6) M; IC(50) of FK506, 10(-5) M) and needed at least 2 d to develop. Such an inhibitory effect does not depend on the N-terminal part of hMR, as CsA also reduced transcriptional activity of a 1-453 deletion mutant of hMR. Our results demonstrate that immunosuppressants inhibit hMR transcriptional activity without affecting hMR expression, aldosterone binding properties, and hMR nucleocytoplasmic trafficking. They suggest that ion transport alterations in renal graft recipients are in part induced by impaired hMR function.
Assuntos
Aldosterona/fisiologia , Ciclosporina/farmacologia , Imunossupressores/farmacologia , Transplante de Rim/fisiologia , Antagonistas de Receptores de Mineralocorticoides , Pseudo-Hipoaldosteronismo/induzido quimicamente , Tacrolimo/farmacologia , Transcrição Gênica/efeitos dos fármacos , Aldosterona/metabolismo , Northern Blotting , Depressão Química , Genes MDR/genética , Gliceraldeído-3-Fosfato Desidrogenases/biossíntese , Gliceraldeído-3-Fosfato Desidrogenases/genética , Humanos , Túbulos Renais/citologia , Túbulos Renais/efeitos dos fármacos , Túbulos Renais/metabolismo , Luciferases/genética , Modelos Biológicos , Receptores de Mineralocorticoides/biossíntese , Receptores de Mineralocorticoides/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/efeitos dos fármacos , Esteroides/metabolismo , Frações Subcelulares/metabolismo , Transfecção , beta-Galactosidase/genética , beta-Galactosidase/metabolismoRESUMO
BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha) is a major pro-inflammatory cytokine. Recently, the G-308A polymorphism of the TNF-alpha gene has been associated with modified gene expression and increased TNF-alpha production in the -308A allele. We evaluated its influence on the incidence and clinical course of membranous glomerulonephritis. METHODS: We studied 53 patients with biopsy-proven primary membranous glomerulonephritis followed up for 5.7 +/- 4.9 years. 100 volunteers were analyzed as controls. According to the slope of the curve of reciprocal serum creatinine against time, group A (slow progressors, n = 35) and group B (fast progressors, n = 18) were defined. TNF-alpha G-308A polymorphism was determined by polymerase chain reaction amplification. RESULTS: The frequency of the A-allele (associated with higher TNF-alpha levels) was significantly higher in patients than control subjects (patients: G-allele: 0.66, A-allele: 0.34; controls: G-allele 0.85, A-allele 0.15, p < 0.001). Similarly, the genotype distribution differed significantly between our study and control populations (patients: GG-genotype: 41.5%, GA: 49.1%, AA 9.4%; controls: GG: 71%, GA: 27%, AA 2%, p = 0.001). Age, renal function, proteinuria and blood pressure were similar at the time of renal biopsy between patients with different genotypes (NS). There was also a tendency towards an overpresentation of the A-allele in group B indicating a possible impact on the progression of membranous nephropathy, but a significance was not reached. Furthermore, no impact on renal survival in the Kaplan- Meier analysis was detected (NS). CONCLUSION: Our results suggest that TNF-alpha gene G-308A polymorphism is a risk factor for the development of membranous glomerulonephritis.
Assuntos
Glomerulonefrite Membranosa/genética , Fator de Necrose Tumoral alfa/genética , Adulto , Alelos , Feminino , Humanos , Masculino , Polimorfismo Genético , Fatores de RiscoRESUMO
BACKGROUND: Interleukin-10 (IL-10) is a cytokine with immunosuppressive properties. We evaluated the influence of G-1082A polymorphism in the IL-10 gene promoter, which has been associated with modified IL-10 production, on the two most common forms of primary glomerulonephritis: IgA nephropathy (IgAN) and focal segmental glomerulosclerosis (FSGS). METHODS: We studied Caucasian patients (N= 191) with biopsy-proven glomerulonephritis (IgAN: N= 123, FSGS: N= 68) followed-up for 6.5 +/- 5.5 years. Patients were classified according to the slope of reciprocal serum creatinine (>/= or <-0.1 dL(*)mg(-1) (*)year(-1)) into group A (slow progressors, IgAN: N= 75, FSGS: N= 47) and group B (fast progressors, IgAN: N= 48, FSGS: N= 21). One hundred healthy volunteers were analyzed as control patients. G-1082A polymorphism was determined by polymerase chain reaction (PCR) amplification. RESULTS: The allele frequencies were similar in patients and control group (NS). Initial renal function, proteinuria, and blood pressure did not differ significantly between patients with different genotypes. G-1082A polymorphism was associated with the progression of both IgAN and FSGS: GA/AA genotypes were more frequent in group B (fast progressors) than in group A (slow progressors; P= 0.012 for IgAN, P < 0.05 for FSGS). Patients with the GA/AA genotypes showed a worse outcome in the Kaplan-Meier analysis of renal survival (P < 0.05 for both IgAN and FSGS). The IL-10 polymorphism remained an independent risk factor for progression in multivariate analysis (Cox regression model, P < 0.05 for IgAN and FSGS). CONCLUSION: Our results suggest that IL-10 gene G-1082A polymorphism is an important marker of progression in patients with IgAN and FSGS.
Assuntos
Glomerulonefrite por IGA/fisiopatologia , Glomerulosclerose Segmentar e Focal/fisiopatologia , Interleucina-10/genética , Polimorfismo Genético , Adenina , Adulto , Progressão da Doença , Feminino , Frequência do Gene , Genótipo , Glomerulonefrite por IGA/genética , Glomerulosclerose Segmentar e Focal/genética , Guanina , Humanos , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
BACKGROUND: Recently, polymorphisms of cytokine genes have been associated with modified gene expression and increased cytokine production. We evaluated the influence of TGF-beta(1) gene Arg(25)-->Pro, TNF alpha gene G-308A and IL-6 gene G-174C polymorphisms on the clinical manifestations of focal segmental glomerulosclerosis (FSGS). METHODS: The clinical course of 71 patients with biopsy-proven primary FSGS followed up for 6.0 +/- 4.4 years was studied. Patients were classified according to the slope of reciprocal serum creatinine into slow (n = 49) and fast (n = 22) progressors. One hundred healthy volunteers were analysed as controls. Genetic polymorphisms were determined by PCR amplification. RESULTS: The genotype distribution of the studied polymorphisms was similar in patients and controls (n.s.). Age, initial renal function, proteinuria and blood pressure did not differ significantly between patients with different genotypes (n.s.). The investigated polymorphisms were not associated with the progression of FSGS as shown by the similar genotype frequencies among slow and fast progressors (n.s.) and the renal survival in the Kaplan-Meier analysis (n.s.). CONCLUSION: Our results indicate that TGF-beta(1) gene Arg(25)-->Pro, TNF alpha gene G-308A and IL-6 gene G-174C polymorphisms are not risk factors or markers of progression in focal segmental glomerulosclerosis.