RESUMO
Apolipoprotein L1 gene (APOL1) nephropathy variants in African American deceased kidney donors were associated with shorter renal allograft survival in a prior single-center report. APOL1 G1 and G2 variants were genotyped in newly accrued DNA samples from African American deceased donors of kidneys recovered and/or transplanted in Alabama and North Carolina. APOL1 genotypes and allograft outcomes in subsequent transplants from 55 U.S. centers were linked, adjusting for age, sex and race/ethnicity of recipients, HLA match, cold ischemia time, panel reactive antibody levels, and donor type. For 221 transplantations from kidneys recovered in Alabama, there was a statistical trend toward shorter allograft survival in recipients of two-APOL1-nephropathy-variant kidneys (hazard ratio [HR] 2.71; p = 0.06). For all 675 kidneys transplanted from donors at both centers, APOL1 genotype (HR 2.26; p = 0.001) and African American recipient race/ethnicity (HR 1.60; p = 0.03) were associated with allograft failure. Kidneys from African American deceased donors with two APOL1 nephropathy variants reproducibly associate with higher risk for allograft failure after transplantation. These findings warrant consideration of rapidly genotyping deceased African American kidney donors for APOL1 risk variants at organ recovery and incorporation of results into allocation and informed-consent processes.
Assuntos
Apolipoproteínas/genética , Negro ou Afro-Americano/genética , Variação Genética/genética , Rejeição de Enxerto/genética , Nefropatias/cirurgia , Transplante de Rim , Lipoproteínas HDL/genética , Doadores de Tecidos , Adolescente , Adulto , Alabama , Aloenxertos , Apolipoproteína L1 , Feminino , Genótipo , Rejeição de Enxerto/etnologia , Rejeição de Enxerto/mortalidade , Humanos , Nefropatias/mortalidade , Transplante de Rim/mortalidade , Masculino , Pessoa de Meia-Idade , North Carolina , Fatores de Risco , Taxa de Sobrevida , Resultado do Tratamento , Adulto JovemRESUMO
Coding variants in the apolipoprotein L1 gene (APOL1) are strongly associated with nephropathy in African Americans (AAs). The effect of transplanting kidneys from AA donors with two APOL1 nephropathy risk variants is unknown. APOL1 risk variants were genotyped in 106 AA deceased organ donors and graft survival assessed in 136 resultant kidney transplants. Cox-proportional hazard models tested for association between time to graft failure and donor APOL1 genotypes. The mean follow-up was 26.4 ± 21.8 months. Twenty-two of 136 transplanted kidneys (16%) were from donors with two APOL1 nephropathy risk variants. Twenty-five grafts failed; eight (32%) had two APOL1 risk variants. A multivariate model accounting for donor APOL1 genotype, overall African ancestry, expanded criteria donation, recipient age and gender, HLA mismatch, CIT and PRA revealed that graft survival was significantly shorter in donor kidneys with two APOL1 risk variants (hazard ratio [HR] 3.84; p = 0.008) and higher HLA mismatch (HR 1.52; p = 0.03), but not for overall African ancestry excluding APOL1. Kidneys from AA deceased donors harboring two APOL1 risk variants failed more rapidly after renal transplantation than those with zero or one risk variants. If replicated, APOL1 genotyping could improve the donor selection process and maximize long-term renal allograft survival.
Assuntos
Apolipoproteínas/genética , Transplante de Rim/métodos , Lipoproteínas HDL/genética , Insuficiência Renal/etnologia , Insuficiência Renal/terapia , Adulto , Negro ou Afro-Americano , Apolipoproteína L1 , Feminino , Seguimentos , Genótipo , Glomerulosclerose Segmentar e Focal/imunologia , Sobrevivência de Enxerto , Antígenos HLA/imunologia , Humanos , Imunossupressores/uso terapêutico , Rim/patologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Modelos de Riscos Proporcionais , Risco , Doadores de Tecidos , Transplante HomólogoRESUMO
Recurrence of focal segmental glomerulosclerosis (FSGS) with nephrotic syndrome is relatively common after kidney transplantation in young recipients whose predialysis course consists of heavy proteinuria, hypertension and subacute loss of kidney function. The gene(s) mediating this effect remain unknown. We report an unusual circumstance where kidneys recovered from a deceased African American male donor with MYH9-related occult FSGS (risk variants in seven of eight MYH9 E1 haplotype single nucleotide polymorphisms) were transplanted into an African American male child with risk variants in four MYH9 E1 risk variants and a European American female teenager with two MYH9 E1 risk variants. Fulminant nephrotic syndrome rapidly developed in the African American recipient, whereas the European American had an uneventful posttransplant course. The kidney donor lacked significant proteinuria at the time of organ procurement. This scenario suggests that donor-recipient interactions in MYH9, as well as other gene-gene and gene-environment interactions, may lead to recurrent nephrotic syndrome after renal transplantation. The impact of transplanting kidneys from donors with multiple MYH9 risk alleles into recipients with similar genetic background at high risk for recurrent kidney disease needs to be determined.
Assuntos
Transplante de Rim/efeitos adversos , Proteínas Motores Moleculares/genética , Cadeias Pesadas de Miosina/genética , Síndrome Nefrótica/etiologia , Adolescente , Pré-Escolar , Feminino , Genótipo , Haplótipos , Humanos , Masculino , Síndrome Nefrótica/genéticaRESUMO
Flow cytofluorometric analyses of lymphocytes harvested from the mesenteric lymph node (MLN), mucosal epithelium, and lamina propria of C57BL/6 mice demonstrate that expression of alpha/beta or gamma/delta T-cell receptors (TCR) and CD4 or CD8 molecules by T lymphocytes in the intestinal immune system varies depending upon their anatomic location. The MLN contained equivalent numbers of CD4+ and CD8+ T cells, the vast majority of which were alpha/beta TCR positive (alpha/beta TCR+). The lamina propria T cells were predominantly CD4+ and alpha/beta TCR+, while the intestinal intraepithelial lymphocytes consisted of equivalent numbers of alpha/beta and gamma/delta T cells, the majority of which were CD8+. There were no significant changes in these T-cell phenotypic profiles when the mice were antibiotic decontaminated or monoassociated with Escherichia coli. Mice were depleted of CD4+ T cells and/or CD8+ T cells in vivo by intraperitoneal injections of monoclonal antibody GK 1.5 (rat anti-mouse CD4) and/or monoclonal antibody 2.43 (rat anti-mouse CD8). T-cell depletion was confirmed in the MLN, lamina propria, and the intestinal epithelium by flow cytometry. E. coli C25 translocation from the gastrointestinal (GI) tract to the MLN was significantly increased in mice depleted of CD4+ T cells, CD8+ T cells, or both. T-cell-deficient athymic beige/nude mice also exhibited greater levels of E. coli C25 translocation to the MLN than beige/het euthymic littermates. Salmonella typhimurium translocation also was increased following CD4+ and CD8+ T-cell depletion in mice monoassociated with S. typhimurium. Depletion of CD4+ and/or CD8+ T cells also increased the translocation to the MLN of certain indigenous GI flora bacteria. These results confirm that T-cell-mediated immunity is involved in the host defense against bacterial translocation from the GI tract.
Assuntos
Enterobacteriaceae/imunologia , Intestinos/imunologia , Subpopulações de Linfócitos T/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Antígenos CD8/imunologia , Movimento Celular/imunologia , Enterobacteriaceae/patogenicidade , Escherichia coli/imunologia , Escherichia coli/patogenicidade , Feminino , Sistema Imunitário/imunologia , Imunidade Inata , Mucosa Intestinal/imunologia , Intestinos/anatomia & histologia , Linfonodos/citologia , Linfonodos/imunologia , Depleção Linfocítica , Mesentério/citologia , Mesentério/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Salmonella typhimurium/imunologia , Salmonella typhimurium/patogenicidade , Organismos Livres de Patógenos Específicos , Baço/citologia , Baço/imunologia , Virulência/imunologiaRESUMO
Escherichia coli and Proteus mirabilis translocate to different segments of the mesenteric lymph node (MLN) complex at levels reflecting their population levels in the regions of the gastrointestinal tract that provide lymph to these various MLN segments. Salmonella typhimurium, however, translocates to all segments of the MLN complex equally regardless of regional intestinal population levels.
Assuntos
Sistema Digestório/microbiologia , Escherichia coli/fisiologia , Linfonodos/microbiologia , Mesentério/microbiologia , Proteus mirabilis/fisiologia , Animais , Feminino , Camundongos , Camundongos Endogâmicos C57BL , MovimentoRESUMO
Bacterial translocation is defined as the passage of viable bacteria from the gastrointestinal (GI) tract to extraintestinal sites, such as the mesenteric lymph node (MLN), spleen, liver, kidneys, and blood. Previously, we reported that depletion of CD4+ and/or CD8+ T cells promotes bacterial translocation from the GI tract to the MLN. In the present study, CD4+ and/or CD8+ T cells, harvested from donor mice, were adoptively transferred to mice previously depleted of T cells by thymectomy plus intraperitoneal injection of rat anti-mouse T-cell monoclonal antibodies. The adoptively transferred CD4+ and/or CD8+ T cells inhibited the translocation of Escherichia coli from the GI tract. Migration of the adoptively transferred T cells to the spleens and MLNs of the recipient mice was determined by utilizing Thy 1.1+ donor cells adoptively transferred into mice whose cells express the Thy 1.2 marker. These results provide further evidence of the importance of T cells in the host immune defense against bacterial translocation from the GI tract.