Differential expression of cytokines, growth factors, and α-smooth muscle actin in renal allograft biopsies (original) (raw)
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Transplantation, 1998
A significant percentage of biopsies from stable, well-functioning renal allografts have histologic findings consistent with acute rejection or borderline rejection. The implication of this finding is not yet fully understood. We analyzed immune-activation gene transcripts in stable protocol biopsies to determine the extent of immunologic activity of graft-infiltrating cells in this setting. Histologic classification of the biopsies was based on the Banff criteria. To emphasize that the tissue samples were procured from grafts with no clinical evidence of impaired function, we interjected the term "subclinical" into the Banff terminology. This produced three histologic categories: normal, borderline subclinical rejection, and acute subclinical rejection. We used competitive template polymerase chain reaction techniques to quantify transcript amounts for the constant region of the T-cell receptor beta chain; the cytokines, tumor necrosis factor alpha, interleukin (IL)-1beta, transforming growth factor beta, interferon gamma, IL-2, IL-4, IL-10, and IL-15; and the cytotoxic T lymphocyte effector molecules, granzyme B, perforin, and Fas ligand. We found that histologically normal biopsies were typically devoid of gene transcripts or had very low amounts. Conversely, biopsies with acute subclinical rejection by histologic examination had heightened amounts of transcripts for many of the genes assayed. Borderline subclinical rejection samples showed an intermediate amount of expression. These results demonstrate that histologic features of rejection are often accompanied by enhanced expression of pro-inflammatory gene transcripts, despite the absence of clinically overt graft dysfunction. As this state of subclinical rejection could prove detrimental to long-term graft function, a role for surveillance biopsies of stable grafts with intent to treat subclinical rejection should be considered.
2010
9. Kazama JJ, Gejyo F, Shigematsu T et al. Role of circulating fibroblast growth factor 23 in the development of secondary hyperparathyroidism. Ther Apher Dial 2005; 9: 328-330 10. Gutierrez OM, Mannstadt M, Isakova T et al. Fibroblast growth factor 23 and mortality among patients undergoing hemodialysis. N Engl J Med 2008; 359: 584-592 11. Kolek OI, Hines ER, Jones MD et al. 1alpha, 25-Dihydroxyvitamin D3 upregulates FGF23 gene expression in bone: the final link in a renal-gastrointestinal-skeletal axis that controls phosphate transport. Am J Physiol Gastrointest Liver Physiol 2005; 289: G1036-G1042 12. Yu X, Sabbagh Y, Davis SI et al. Genetic dissection of phosphateand vitamin D-mediated regulation of circulating Fgf23 concentrations. Bone 2005; 36: 971-977 13. Nishida Y, Taketani Y, Yamanaka-Okumura H et al. Acute effect of oral phosphate loading on serum fibroblast growth factor 23 levels in healthy men. Kidney Int 2006; 70: 2141-2147 14. Takeda E, Yamamoto H, Nashiki K et al. Inorganic phosphate homeostasis and the role of dietary phosphorus. J Cell Mol Med 2004; 8: 191-200 15. Burnett SM, Gunawardene SC, Bringhurst FR et al. Regulation of C-terminal and intact FGF-23 by dietary phosphate in men and women. J Bone Miner Res 2006; 21: 1187-1196 16. Wadstrom J. Hand-assisted retroperitoneoscopic live donor nephrectomy: experience from the first 75 consecutive cases. Transplantation 2005; 80: 1060-1066 17. Khosravi A, Cutler CM, Kelly MH et al. Determination of the elimination half-life of fibroblast growth factor-23.
Transplantation
A significant percentage of biopsies from stable, well-functioning renal allografts have histologic findings consistent with acute rejection or borderline rejection. The implication of this finding is not yet fully understood. We analyzed immune-activation gene transcripts in stable protocol biopsies to determine the extent of immunologic activity of graft-infiltrating cells in this setting. Histologic classification of the biopsies was based on the Banff criteria. To emphasize that the tissue samples were procured from grafts with no clinical evidence of impaired function, we interjected the term "subclinical" into the Banff terminology. This produced three histologic categories: normal, borderline subclinical rejection, and acute subclinical rejection. We used competitive template polymerase chain reaction techniques to quantify transcript amounts for the constant region of the T-cell receptor beta chain; the cytokines, tumor necrosis factor alpha, interleukin (IL)-1beta...
Chronic rejection of rat renal allograft
Transplant International, 1992
Chronic allograft rejection is both a clinical and a histopathological diagnosis. Until recently, the histological definition of chronic renal allograft rejection was based on clinical diagnostic biopsies, where the evidence was partially obscured by recurrence of the original renal disease, and/or by administration of immunosuppressive drugs. In this communication, we present an experimental rat model for chronic renal allograft rejection, devoid of recurrence of the original disease. By comparing allografts to similarly immunosuppressed syngeneic transplants, we define which histological features should be attributed to chronic rejection and which to cyclosporin nephrotoxicity. Rat renal transplants were performed from DA (Ag-B4, RT1 avx) to WF strain (Ag-B2, RT1 u) or, for control, to DA strain, and immunosuppressed for 2 or 3 weeks with cyclosporin using a variety of different dosages. The animals were monitored weekly for serum creatinine levels and for blood cyclosporin concentrations, and core needle biopsies were performed on the grafts at regular intervals. At 3 months post-transplantation the animals were sacrificed and a complete histopathological evaluation was performed. Thirty-one histological variables were scored blindly by two investigators and separately for the graft interstitium, glomeruli, tubuli, and the graft vasculature. The following histological alterations were significantly more prominent in allografts than in similarly immunosuppressed syngeneic transplants: the intensity of interstitial inflammation, particularly the degree of pyroninophilia within the inflammatory cell population; the extent of glomerular mesangial matrix increase, basement membrane thickening, and glomerular sclerosis; the increase in the vascular intimal thickness affecting in particular the first and second order branches of the renal artery; and the obliteration of the graft vasculature. These alterations were considered as being primarily due to chronic rejection. In contrast, the extent of interstitial fibrosis and the extent of tubular changes, including tubular epithelial vacuolation, epithelial atrophy, and tu-Offprint requests to." E Hfiyry bular basement membrane changes, were not significantly different in the allografts as compared to the syngeneic controls. These alterations were attributed primarily to cyclosporin nephrotoxicity. Serial monitoring of the grafts by needle biopsies clarified the sequence of events in the development of the chronic alterations in the transplant. The first event, as expected, was tubulointerstitial pyroninophilic inflammation, resembling that of acute episodes of rejection. This was significantly stronger and appeared earlier in allografts immunosuppressed for 2 rather than for 3 weeks. Vascular alterations developed next. The last to develop were the glomerular lesions.
Transplantation, 1999
Background. Chronic rejection (CR) remains idiopathic, difficult to prospectively identify, and once detected, unresponsive to increased immunosuppression. We hypothesized that clinically stable human renal allografts have ongoing evidence of injury and immune activity, and that this correlates with the worsening of allograft function characteristic of CR. Methods. The allografts of 40 stable renal allograft recipients were biopsied 2-3 years after transplantation. Biopsies were processed for histology and RNA extraction. RNA was evaluated by semi-quantitative RT-polymerase chain reaction for CD3␥ mRNA (a marker of T cell receptor turnover), and mRNA from cytokine genes previously shown to be transcribed during acute rejection: tumor necrosis factor-␣, interferon-␥, interleukin-(IL) 1, IL-2, IL-4, IL-6, and IL-8. Clinical parameters including urine protein and glomerular filtration rate were measured the day of biopsy. Findings were then compared with clinical outcome to establish associations between subclinical inflammation and graft dysfunction. Allograft function was measured again 2 years after biopsy and correlated with findings at the time of biopsy. Results. Cytokine transcripts and histological evidence of injury were detected in more than two-thirds of stable grafts. The degree of the lymphocytic infiltrate correlated with the degree of proteinuria (P)430.0؍ and histological fibrosis (P.)500.0؍ Similarly, the degree of intragraft CD3␥ transcription correlated with increasing proteinuria (P.)340.0؍ IL-6 and IL-8 transcripts were also correlated with evidence of graft injury. After 2 years, those biopsies originally found to have evidence of fibrosis, tubular atrophy, or CD3␥ transcription had worsening graft function as determined by creatinine and glomerular filtration rate. Conclusions. These data demonstrate that significant injury and immune activity can be detected in patients who are stable on clinical grounds. Undetec-ted subclinical graft injury may be a cause of chronic allograft rejection.