RESUMO
Afro-caribbean patients are more frequently diagnosed than caucasians as having end-stage renal failure (ESRF) from primary hypertension or diabetic nephropathy. We performed a retrospective study to investigate the diagnostic criteria and to validate the causes of primary renal disease in all new cases of afro-caribbean patients with ESRF who commenced RRT at 3 inner city Hospitals (1991-1995). We collected clinical-pathological data using a standard proforma. Three of us validated the diagnoses. We have identified 142 afro-caribbean patients for inclusion in this study:mean age of 52.3 (15.50, 52.3 percent were male. Renal biopsy was performed in 32 percent of the patients. Before the validation ,the working diagnosis (including that submitted to EDTA) had been diabetic nephropathy 35.2 percent; primary hypertension 18.3 percent; "uncertain" cause 15.5 percent and primary glomerulonephritis 11.3 percent. Following the analysis we ascribed the underlying cause of ESRF to be: diabetic nephropathy 38.7percent (18.2 percent biopsy proven);"uncertain" 21.8 percent; primary glomerulonephritis 10.6 percent (100 percent bx proven); secondary glomerulonephritis 10.6 percent (66.6 percent bx proven); primary hypertension 10.6 percent (40 percent bx proven); pyelonephritis 3.5 percent; polycystic kidneys 2.8 percent. Among the "uncertain" (n=31): twenty four (17 percent) were related to long-standing hypertension but could not be proven as primary disease. Among the diabetic ESRF patients (n=55), only 6 had IDDM while 49 had NIDDM. Twenty percent (28/142) of all patients had accelerated hypertension while 95 percent (134/142) had hypertension at some time during their disease. This study shows that in afro-caribbean patients NIDDM is the main cause of ESRF, whilst the evidence of primary hypertension is over-estimated, the diagnosis is often made on inadequate criteria. Nevertheless primary hypertension plays an important role in progression to ESRF. (AU)
Assuntos
Humanos , Insuficiência Renal Crônica/diagnóstico , Negro ou Afro-Americano , Hipertensão , Nefropatias DiabéticasAssuntos
Alopurinol/uso terapêutico , Imunossupressores/uso terapêutico , Transplante de Rim/imunologia , Adulto , Azatioprina/uso terapêutico , Estudos de Casos e Controles , Creatinina/sangue , Ciclosporina/uso terapêutico , Quimioterapia Combinada , Feminino , Seguimentos , Rejeição de Enxerto/epidemiologia , Rejeição de Enxerto/imunologia , Humanos , Transplante de Rim/mortalidade , Contagem de Leucócitos , Masculino , Prednisolona/uso terapêuticoRESUMO
Early rejection can still complicate renal transplantation even with cyclosporin. We added low-dose allopurinol (25 mg on alternative days) to "triple" immunosuppression with cyclosporin, prednisolone, and azathioprine for twelve recipients of cadaver renal grafts. The controls were fifteen patients on triple therapy alone. Only one rejection episode occurred among the allopurinol-treated patients, whereas eleven controls had rejections (seven with more than one episode). Allopurinol may be toxic when combined with azathioprine, yet the bone marrow tolerated the new regimen well. As expected, reduction of the azathioprine dose was necessary in the treated group.
Assuntos
Alopurinol/administração & dosagem , Azatioprina/administração & dosagem , Ciclosporina/administração & dosagem , Transplante de Rim , Prednisolona/administração & dosagem , Quimioterapia Combinada , Feminino , Rejeição de Enxerto , Humanos , Terapia de Imunossupressão/métodos , MasculinoRESUMO
A catabolic route for azathioprine involving methylation by thiopurine methyltransferase has been directly implicated in the drug's immunosuppressive efficacy. Since ethnic differences in thiopurine methyltransferase activity have been reported in a study of Lapps, this study compared the distribution of thiopurine methyltransferase activity in erythrocyte lysates from 134 healthy, randomly selected subjects living in Brazil, comprising 39 blacks (i.e. Afro-Brazilians), 33 white subjects, 30 mixed-race subjects, and 32 Brazilian-residing Japanese subjects. The results demonstrated bimodality of thiopurine methyltransferase activity compatible with genetic polymorphism in the white, black and mixed-race groups, but not in the Japanese, who were homogeneously 'fast methylators' (high thiopurine methyltransferase activity). Thiopurine methyltransferase activity was generally higher in Brazilian males than females, and some individuals in the black and mixed-race groups had very high activity. Azathioprine-immunosuppressed transplant patients with thiopurine methyltransferase activity above 35 pmol/h/mgHb have previously been shown to have significantly poorer outcomes. Using this thiopurine methyltransferase value as the cut-off point between 'poor responders' and 'good responders' to azathioprine, 65% of the Japanese, 59% of the black subjects, and 63% of the mixed-race subjects fell into the 'poor responder' category, compared with only 42% of the white group. Interestingly, this approximately 20% difference in azathioprine response corresponds to the racial differences seen in allograft survival.
Assuntos
Rejeição de Enxerto , Metiltransferases/genética , Metiltransferases/metabolismo , Grupos Raciais , Adulto , Idoso , Eritrócitos/enzimologia , Feminino , Rejeição de Enxerto/enzimologia , Rejeição de Enxerto/genética , Humanos , Masculino , Metilação , Pessoa de Meia-Idade , Fenótipo , Polimorfismo Genético , Grupos Raciais/genética , Transplante HomólogoRESUMO
The immunosuppressive efficacy of azathioprine is related to its rapid metabolism in vivo to 6-mercaptopurine (6MP), with subsequent conversion to thioguanine nucleotides by an anabolic route involving hypoxanthine-guanine phosphoribosyltransferase. Two alternative catabolic routes exist: oxidation to 6-thiouric acid via xanthine oxidase and methylation to 6-methylmercaptopurine via the enzyme thiopurine methyltransferase (TPMT). Catabolism via either route would restrict formation of the active metabolites. We analyzed TPMT activity in erythrocyte lysates of 25 controls, 25 uremic patients on dialysis, and 68 transplanted patients. Median activity was lower in controls (31.0 pmol/hr/mg Hb, range 16.2-43.0) and transplanted patients receiving only cyclosporine and prednisolone (31.7 pmol/hr/mg Hb, range 12.7-43.5) than in the azathioprine treated group, (36.1 pmol/hr/mg Hb, range 16.1-71.3), or the uremic group on dialysis, (35.5 pmol/hr/mg Hb, range 18.6-62.6) suggesting that both azathioprine and uremia induce the enzyme, but CsA does not. Only 3 patients demonstrated total intolerance to azathioprine, 2 of whom had very low TPMT activity (zero and 12.7 pmol/hr/mg Hb). The intolerance of the third patient, despite high TPMT activity, was attributed to concomitant cotrimoxazole therapy. Patients with intermediate activity (15-26 pmol/hr/mg Hb) could tolerate azathioprine well. Of 29 cadaver recipients given only azathioprine plus prednisolone, 24 with a better clinical outcome had a significantly lower activity (33.1 pmol/hr/mg Hb, range 16.1-46.1) than 5 with reduced allograft function (42.5 pmol/hr/mg Hb, range 33.8-51.5). TPMT activity in these 24 patients was also significantly lower than the general group of azathioprine-treated recipients. This inverse association between TPMT activity and allograft function was again found among 30 patients receiving triple therapy (azathioprine, CsA, prednisolone). Self-selection of the best recipients for azathioprine immunosuppression apparently occurred, based on low catabolism of the drug. We conclude that total intolerance to azathioprine is rare and usually appears in patients with very low TPMT activities. Our results also suggest that the wide range of TPMT activity may be an important factor in determining long-term graft survival in azathioprine-treated patients; those with high activity might benefit from doses near the upper limit generally recommended.