Enalapril and low protein reverse chronic puromycin aminonucleoside nephropathy

Enalapril and low protein reverse chronic puromycin aminonucleoside nephropathy. The effects of dietary protein and converting enzyme inhibition (CEI) on chronic puromycin aminonucleoside nephropathy (PAN) were studied. PAN was induced with seven SQ injections of puromycin aminonucleoside 20 mg/kg over 10 weeks in male Sprague-Dawley rats. The rats were divided into a 22.5% protein diet group (Gr 1), a 6% protein diet group (Gr 2), and an enalapril-treated group on 22.5% protein diet (Gr 3). Group 4 animals served as age-matched controls. Both diets were isocaloric and had the same phosphorus content. Rats from groups 1, 2, and 4 were sacrificed at 12, 18 and 24 weeks. Five rats of group 3 were sacrificed at 12 weeks, and the others were divided in subgroups 3A (diet changed to 6% protein) and 3B (no changes); half of each subgroup was sacrificed at 18 and 24 weeks, respectively. Group 2 had significantly less proteinuria than group 1 at all times. Group 3 had the same proteinuria as group 1 until 12 weeks and then began to decrease. In group 3A proteinuria decreased to group 2 levels, while in group 3B the decrease was slower but still prominent. Early lesions of focal and segmental glomerular sclerosis/hyalinosis (FSH) were present in groups 1, 2, 3 at 12 weeks (16 ± 1.2%, 15 ± 1.3%, 7 ± 1.3%, respectively, versus 1.3 ± 0.4% in controls), but by 18 weeks a reversal in FSH was seen in groups 2 and 3A/B (3 ± 1.6%, 2 ± 0.4%, and 3 ± 0.9%, respectively, vs. 14 ± 1.5% in group 1). This reversal persisted at 24 weeks (5 ± 2.5%, 3 ± 0.8%, 4 ± 0.8% vs. 18 ± 2.6%). At 24 weeks mean glomerular diameter was significantly less in group 2 compared to group 1, 100.7 ± 2.0 µ versus 112.2 ± 2.7 µ, P = 0.009. In summary, both low protein diet and CEI for 24 weeks reversed both proteinuria and early FSH lesions in chronic PAN after cessation of PA injections

Influence of antigen distribution on the mediation of immunological glomerular injury

Influence of antigen distribution on the mediation of immunological glomerular injury. To determine if the site of immune reaction could influence the mediation and morphological expression of glomerular injury in experimental anti-glomerular basement membrane (anti-GBM) nephritis and membranous nephropathy, we studied the events that followed the in situ reaction of rat antibody with antigen planted in either the GBM (especially the lamina rara interna) or in the subepithelial space (SE). Non-nephritogenic amounts of noncomplement-fixing sheep anti-GBM or anti-tubular brushborder antibody were injected into separate groups of rats to plant sheep IgG in the GBM and SE, respectively. Kidneys containing sheep IgG were then transplanted into naive recipients that were passively immunized with rat anti-sheep IgG. There was marked proteinuria after 2 days (antigen in GBM: 226 ± 50.7; antigen in SE: 69 ± 50.7 mg/24 hr) that was abrogated by prior depletion of complement in both groups (antigen in GBM: 10.2 ± 1.7; antigen in SE: 14.3 ± 8.7 mg/24 hr). When antigen was planted in SE, inflammatory-cell depletion with either anti-neutrophil (PMN) serum or lethal irradiation had no effect on proteinuria. In contrast, anti-PMN abolished proteinuria (12.0 ± 5.6 mg/24 hr) and irradiation reduced it by 60% when antigen was in GBM. Glomeruli of kidneys with antigen in GBM were significantly larger and more hypercellular than those with antigen in SE after transplantation into immunized recipients. Endothelial cell injury and adherence of inflammatory cells to denuded GBM were prominent in the former (antigen in GBM), while glomeruli with antigen in SE showed only subepithelial deposits, adjacent slit-diaphragm displacement, and epithelial cell foot-process effacement. Thus, the reaction of antigen and antibody in glomeruli produced complement-mediated injury which was cell-independent when complex formation occurred on the outer aspect of the GBM but was cell-dependent when the same reagents reacted more proximally to the circulation. We therefore conclude that antigen distribution can critically influence the mediation and morphologic expression of immune glomerular injury and may, in part, account for variations in the clinical and histological manifestations of antibody-induced glomerular disease in humans.Influence de la distribution antigénique sur la médiation des lésions glomérulaires immunologiques. Afin de déterminer si le site de la réaction immune pourrait influencer la médiation et l'expression morphologique des lésions glomérulaires lors d'une néphrite expérimentale anti-membrane basale glomérulaire (anti-GBM) et d'une néphropathie extra-membraneuse, nous avons étudié les événements qui suivaient la réaction in situ d'anticorps de rat avec un antigène fixé soit dans la GBM (surtout dans la lamina rara interna), soit dans l'espace sous-épithélial (SE). Des quantités non nephritogènes d'anticorps anti-GBM, ou anti-bordure en brosse tubulaire de mouton ne fixant pas le complément ont été injectées à différents groupes de rats pour fixer de l'IgG de mouton dans la GBM et le SE, respectivement. Les reins contenant l'IgG de mouton étaient alors transplantés à des receveurs vierges passivement immunisés avec de l'IgG de rat antimouton. Il existait une protéinurie marquée après deux jours (antigène dans la GBM: 226 ± 50,7; antigène dans SE: 69 ± 50,7 mg/24 hrs) qui à été abrogé par une déplétion du complement dans les deux groupes (antigène dans la GBM: 10,2 ± 1,7; antigène dans SE: 14,3 ± 8,7 mg/24 hr). Lorsque l'antigène était fixé dans SE, une déplétion en cellules inflammatoires par du sérum anti-neutrophile (PMN) ou une irradiation léthale n'avaient pas d'effet sur la protéinurie. A l'opposé, anti-PMN supprimait la protéinurie (12,0 ± 5,6 mg/24 hr) et l'irradiation la réduisait de 60% lorsque l'antigène était dans la GBM. Les glomérules de reins ayant l'antigène dans la GBM étaient significativement plus gros et plus hyper-cellulaires que ceux ayant l'antigène dans SE après transplantation chez des receveurs immunisés. Les lésions cellulaires endothéliales et l'adhérence des cellules inflammatoires à des GBM nues étaient prédominantes chez les premiers (antigène dans la GBM) alors que les glomérules ayant l'antigène dans SE présentaient uniquement des dépôts sous-épithéliaux, un déplacement du slit-diaphragme adjacent et un effacement des pédicelles des cellules épithéliales. Ainsi, la réaction d'un antigène et d'un anticorps dans des glomérules a produit des lésions à médiation complémentaire indépentantes des cellules lorsque la formation de complexes survenait dans la partie extérieure de la GBM, mais dépendantes des cellules lorsque les mêmes réactifs interagissaient de façon plus proximale dans la circulation. Nous concluons donc que la distribution antigénique peut influencer de manière critique la médiation et l'expression morphologique des lésions glomérulaires immunes et qu'elle peut, en partie, rendre compte de variations dans les manifestations cliniques et histologiques de glomérulopathies à médiation par anticorps chez l'homme

New-Onset Diabetes after Kidney Transplantation: An Application of 2003 International Guidelines

Background: The 2003 International Consensus Guidelines defined new-onset diabetes after transplantation. This study determined the risk of new-onset diabetes following kidney transplantation using these criteria. Methods: Consecutive nondiabetic patients who received kidney transplantation between August 2001 and March 2003 (recent, n=61) and before August 2001 (earlier, n=61) were retrospectively evaluated. Results: In all, 74% in the recent group and 56% in the earlier group developed diabetes by 1 year posttransplant. Median time to diabetes development was 23 days in the recent vs. 134 days in the earlier group (P=0.0304). Most patients developed diabetes within 60 days after transplantation. Immunosuppression was the strongest correlate of diabetes development; tacrolimus and cyclosporine A treatments were associated with increased risk. The rate of development was also greater when rapamycin was added to tacrolimus, compared to when it was not. The risk was double in African-Americans compared to whites. Age, body mass index, family history of diabetes, and etiology of renal failure did not predict diabetes; however, the mean age of patients was greater than previously reported. Conclusions: The majority of patients are at risk of developing new-onset diabetes within a short time after kidney transplantation. The risk may be due to preexisting risk factors, immunosuppressive agents, or older age. The significance of these findings is not clear, but demands appropriate follow-up studies related to glycemia, end-organ complications, and graft function. It remains to be determined whether the 2003 International Consensus Guidelines are adequate to appropriately diagnose diabetes in the posttransplant time period, with special emphasis on the first 3 months

New-Onset Diabetes after Kidney Transplantation: An Application of 2003 International Guidelines

Background: The 2003 International Consensus Guidelines defined new-onset diabetes after transplantation. This study determined the risk of new-onset diabetes following kidney transplantation using these criteria. Methods: Consecutive nondiabetic patients who received kidney transplantation between August 2001 and March 2003 (recent, n=61) and before August 2001 (earlier, n=61) were retrospectively evaluated. Results: In all, 74% in the recent group and 56% in the earlier group developed diabetes by 1 year posttransplant. Median time to diabetes development was 23 days in the recent vs. 134 days in the earlier group (P=0.0304). Most patients developed diabetes within 60 days after transplantation. Immunosuppression was the strongest correlate of diabetes development; tacrolimus and cyclosporine A treatments were associated with increased risk. The rate of development was also greater when rapamycin was added to tacrolimus, compared to when it was not. The risk was double in African-Americans compared to whites. Age, body mass index, family history of diabetes, and etiology of renal failure did not predict diabetes; however, the mean age of patients was greater than previously reported. Conclusions: The majority of patients are at risk of developing new-onset diabetes within a short time after kidney transplantation. The risk may be due to preexisting risk factors, immunosuppressive agents, or older age. The significance of these findings is not clear, but demands appropriate follow-up studies related to glycemia, end-organ complications, and graft function. It remains to be determined whether the 2003 International Consensus Guidelines are adequate to appropriately diagnose diabetes in the posttransplant time period, with special emphasis on the first 3 months

New-Onset Diabetes after Kidney Transplantation: An Application of 2003 International Guidelines

Background: The 2003 International Consensus Guidelines defined new-onset diabetes after transplantation. This study determined the risk of new-onset diabetes following kidney transplantation using these criteria. Methods: Consecutive nondiabetic patients who received kidney transplantation between August 2001 and March 2003 (recent, n=61) and before August 2001 (earlier, n=61) were retrospectively evaluated. Results: In all, 74% in the recent group and 56% in the earlier group developed diabetes by 1 year posttransplant. Median time to diabetes development was 23 days in the recent vs. 134 days in the earlier group (P=0.0304). Most patients developed diabetes within 60 days after transplantation. Immunosuppression was the strongest correlate of diabetes development; tacrolimus and cyclosporine A treatments were associated with increased risk. The rate of development was also greater when rapamycin was added to tacrolimus, compared to when it was not. The risk was double in African-Americans compared to whites. Age, body mass index, family history of diabetes, and etiology of renal failure did not predict diabetes; however, the mean age of patients was greater than previously reported. Conclusions: The majority of patients are at risk of developing new-onset diabetes within a short time after kidney transplantation. The risk may be due to preexisting risk factors, immunosuppressive agents, or older age. The significance of these findings is not clear, but demands appropriate follow-up studies related to glycemia, end-organ complications, and graft function. It remains to be determined whether the 2003 International Consensus Guidelines are adequate to appropriately diagnose diabetes in the posttransplant time period, with special emphasis on the first 3 months