HIV-associated nephropathy: experimental models.

Since 1984 reports of renal involvement in AIDS patients have been presented in the literature. Different forms of renal disease were noted in the AIDS population including those related to systemic and local renal infections, tubulointerstitial disease, renal involvement by neoplasm and glomerular disease including collapsing glomerulopathy (CG). HIV-associated nephropathy (HIVAN) has been demonstrated to be more severe in the black population. HIVAN is the most common cause of renal failure in HIV-1-seropositive patients. The term HIVAN is reserved for the typical histopathological form of focal and segmental glomerulosclerosis (FSGS) characterized by the findings of coexistent glomerular and severe tubulointerstitial disease. In both humans and the murine model, glomerular lesions include FSGS, glomerular collapse and podocyte hyperplasia. The tubulointerstitial damage as well as the glomerular collapse can also be seen in non-HIV primary collapsing GN, raising the question of common mechanisms to HIV and other non-identified viral agents related to the development of the disease. Although controversial, increasing evidence supports a direct effect of the virus on renal cells either as a result of exposure to viral proteins or direct renal parenchyma infection. The use of a HIV-1 transgenic mouse model has demonstrated a direct etiologic link between HIV-1 expression in kidney and the development of HIVAN with unique viral-host interactions, which depend at the same time on stimulating features of the virus and the individual nature of the host response. The infection of renal cells by HIV-1 could be detected by reverse transcription-polymerase chain reaction (RT-PCR) of gag RNA at a low level. Some studies using an HIV-1 transgenic mouse model have demonstrated that expression of HIV- 1 in the kidney is required for the development of HIVAN. The final common pathway in the development of HIV-associated nephropathy is likely to involve alterations in the patterns of gene expression of renal parenchyma cells by cytokines and growth factors, leading to interstitial fibrosis and enhanced glomerular matrix synthesis. The nature of the host response to viral infection is critical to the development of nephropathy.HLA-linked responses particular to a subset of blacks may explain some of the epidemiologic features of HIVAN. There may also be biological heterogeneity in the strains of HIV-1 that could account for a particular renotropic strain. HIV strains from different parts of the world may vary by as much as 15% at the level of nucleotide sequence. The infectivity of human immunodeficiency virus (HIV-1) in human glomerular cells has been evaluated by exposing homogeneous cultures of human glomerular capillary endothelial, mesangial and epithelial cells to HIV in vitro. The mechanism of access of HIV into glomerular endothelial and mesangial cells is unknown up to now; HIV is generally infectious for cells expressing the CD4 antigen in their cell membrane. Other modes of HIV entry into cells independent of the CD4 receptor are possible through mechanisms involving Fc-receptors or coinfection with other enveloped viruses such as HTLV-l. Our understanding of the pathogenesis of HIVAN has been aided by the development of a transgenic model. The curious fact that only 3 of 8 founded transgenic lines developed nephropathy emphasizes that the expression of viral gene products per se is not sufficient to produce nephropathy. Human renal epithelium does not express CD4 receptors and in vitro attempts to infect glomerular epithelial cells using laboratory strains of HIV-1 have proven fruitless. The striking morphologic and phenotypic similarities between HIVAN and collapsing idiopathic FSGS raise the question whether the altered podocyte gene expression in collapsing idiopathic FSGS may also be due to a viral infection. This hypothesis is further supported by de novo occurrence of collapsing idiopathic FSGS in immunosuppressed renal transplantation patients and by epidemiologic data. In conclusion, there are likely to be common mechanisms in the pathogenesis for collapsing idiopathic glomerulosclerosis and HIVAN. A primary injury of the podocyte leading to dysregulation of the cellular phenotype appears to mediate the glomerular tuft collapse in both conditions. Primary collapsing glomerulopathy recurs post-transplantation, raising the possibility of circulating factors implicated in the pathogenesis of visceral epithelial cell damage in steroid-resistant minimal change disease or recurrent FSGS. Recurrence of CG can occur hours after transplantation, suggesting that the plasma of CG patients contains one or more factors capable of inducing proteinuria due to the damage of the podocyte that results in the increase in glomerular permeability. In a rat model of CG developed by our group, the injection of serum from CG patients resulted in proteinuria, glomerular tuft retraction and podocyte damage at the ultrastructural level (visceral epithelial cell foot-process effacement). No ultrastructural or light microscopy abnormalities were seen in rats injected with serum from non-collapsing FSGS or healthy subjects. Based on the experience of our group, circulating factors play a dominant role in the pathogenesis of idiopathic CG.

被引量：6 发表：1970

Evaluation of two different preconditioning regimens for ABO-incompatible living kidney donor transplantation. A comparison of splenectomy vs. rituximab-treated non-splenectomy preconditioning regimens.

Although splenectomy has been employed in most documented protocols for ABO-incompatible kidney transplantation (ABO-ILKT), its utility is not yet determined. The aim of this study was to evaluate the long-term results of ABO-ILKT with splenectomy, and also compare the outcome of ABO-ILKT with splenectomy versus non-splenectomy. We did a retrospective study of ABO-incompatible living donor kidney transplants at our institution and affiliated hospital between January 2001 and December 2006 (n = 70). All patients were treated with a combination of immunosuppressive drugs, including tacrolimus (FK), mycophenolate mofetil (MMF) and methylprednisolone (MP). Between January 2001 and December 2004, all patients underwent pretransplant double filtration plasmapheresis (DFPP) and splenectomy at the time of transplant (n = 46) (ABO-I-SPX group). Between January 2005 and December 2006, splenectomy was not performed and a protocol that involved pretransplant low-dose injection of rituximab was employed (ABO-I-RIT group). ABO-compatible living kidney transplants (n = 55) performed between January 2001 and December 2004 were employed as a control group (ABO-C group). Patient survival was 100% in all groups. Three-year graft survival was 98.2, 93.5 and 95.8% in the ABO-C, ABO-I-SPX and ABO-I-RIT groups, respectively. Five-year graft survival was 93 and 91.3% in the ABO-C and ABO-I-SPX groups, respectively. Renal allograft function was comparable among the three groups. However, compared to the ABO-I-RIT group, the incidence of acute antibody-mediated rejection (acute AMR) or chronic AMR was significantly higher in the ABO-C and ABO-I-SPX groups. Although long-term outcome of the ABO-I-SPX group was excellent and showed no significant difference compared to the ABO-C group, splenectomy is not essential for successful ABO-ILKT. The rituximab-treated patients showed excellent short-term graft survival and renal function, and the incidence of AMR in the ABO-I-RIT group was significantly reduced compared to the ABO-I-SPX group.

被引量：8 发表：1970

Fluid resuscitation and the septic kidney: the evidence.

被引量：3 发表：2007

Body protein index based on bioelectrical impedance analysis is a useful new marker assessing nutritional status: applications to patients with chronic renal failure on maintenance dialysis.

被引量：5 发表：2007

A simplified approach to understanding urea kinetics in peritoneal dialysis and hemodialysis.

被引量：- 发表：2006