Early and late humoral rejection: a clinicopathologic entity in two times.

Humoral rejection is an important cause of early and late graft loss. The late variant is difficult to diagnose and treat. There is a close correlation between sclerosing nephropathy and anti-HLA antibodies. We analyzed 113 renal allograft recipients between August 2004 and April 2007. Acute humoral rejection was defined as acute graft dysfunction in presence of donor-specific antibodies (DSA) detected by flow panel reactive antibodies (PRA) and/or C4d positive pericapilary tubules (PTC) detected histopathologically by immunofluorescent or immunoperoxidase at less than 3 months postransplantation. Late humoral rejection was defined as dysfunction occurring after 3 months postransplantation with histopathologic glomerulopathy or vasculopathy and positive C4d PTC. We included all patients who were diagnosed with early or late graft dysfunction and underwent biopsy, all of which were examined for C4d. Four patients had acute humoral rejection treated with IVIG or plasmapheresis. The patient and graft survivals were 100% and serum creatinine averaged 1.7 mg/dL. Three recipients experienced late humoral rejection at 3 to 10 years posttransplantation All received high-dose IVIG; one also was treated with thymoglobulin. Immunosuppression was switched to tacrolimus, mycophenolate mofetil, and steroids. Only one patient recovered renal function; the others returned to dialysis. Among seven patients only one had an actual PRA (>20%) and three showed 10% to 20%. However, six had a positive historical PRA of 10% to 50%. In conclusion, Recognition of acute humoral rejection has contributed to graft rescue by controlling alloantibody production through new specific immunosuppressive therapies in contrast with the clinical response to acute therapy, treatment of a chronic entity has shown poor outcomes, probably because antibody mediated chronic graft damage is already present when the late diagnosis is established by biopsy.

Antihypertensive drug treatment in chronic renal allograft rejection in the rat. Effect on structure and function.

To gain insight into the contribution of immunologic and hemodynamic factors in the progressive demise of structure and function in chronic renal allograft dysfunction, we studied the histological changes, the immunostainable glomerular anionic sites, and glomerular capillary hydrostatic pressures of rat renal allografts with chronic rejection. Recipient animals were left untreated, received 8 weeks of treatment with the immunosuppressive drug cyclosporine, or received antihypertensive drugs consisting of the combination of reserpine, hydralazine and hydrochlorothiazide, the angiotensin-converting enzyme inhibitor cilazapril, or the angiotensin II receptor blocker L-158,809. Grafts in untreated recipients developed chronic interstitial inflammation, as well as vascular and glomerular lesions consistent with chronic rejection. These lesions were associated with immunohistochemical loss of the negatively charged heparan sulfate proteoglycan side chain. All treatment regimens decreased the systemic and glomerular capillary pressures and were associated with no loss of function, decreased proteinuria, and a tendency to improved graft function. Cyclosporine prevented all histological manifestations of rejection, and antihypertensive drugs decreased the extent of glomerular mesangiolysis and glomerulosclerosis; L-158,809 and cilazapril also inhibited graft atherosclerosis and tubular atrophy. We conclude that chronic rejection is primarily an immune-mediated process, but hemodynamic and angiotensin II-mediated effects may play a pivotal role in the expression of immune-mediated lesions.

Inhibition of radiation-enhanced expression of integrin and metastatic potential in B16 melanoma cells by a lipoxygenase inhibitor.

Low-dose gamma radiation stimulates expression of phenotypic characteristics in B16 melanoma cells which regulate metastatic potential. A transient increase in the expression of an integrin receptor (alpha IIb beta 3) was observed after exposure of B16 melanoma cells to 0.25 to 2.0 Gy of gamma radiation. This increased receptor expression resulted in enhanced adhesion of tumor cells to fibronectin in vitro and increased experimentally induced metastasis in vivo. In this report, we determined a role for the 12-lipoxygenase metabolite, 12-HETE, in radiation-enhanced metastasis. A significant increase in biosynthesis of 12-HETE in B16 melanoma cells was detected < 5 min after exposure to 0.5 Gy gamma radiation. We then determined that radiation-enhanced expression of alpha IIb beta 3 integrin and adhesion of B16 melanoma cells to fibronectin in vitro and metastasis in vivo were reduced by treatment of the cells with the lipoxygenase inhibitor NDGA prior to irradiation. These findings suggest that low-dose radiation, at levels comparable to those used in fractionated or hyper-fractionated radiotherapy, increases the metastatic potential of surviving tumor cells via a rapid and transient alteration in lipoxygenase metabolism of arachidonic acid and surface expression of an integrin receptor.

Glomerular capillary pressures in long-surviving rat renal allografts.

Many renal transplants undergo gradual deterioration in structure and function in the months or years after transplantation. The processes that underlie this progressive decline have not been defined, and may include immunological and nonimmunological mechanisms. The present experiments were designed to investigate the glomerular capillary hydrostatic pressure in long-surviving rat renal transplants with or without chronic rejection. Stop-flow glomerular pressures were measured in F344 renal allografts with chronic rejection, syngeneic F344 grafts, and long-surviving syngeneic and allogeneic LEW grafts without chronic rejection; control measurements were done in nontransplanted intact animals or after subtotal renal ablation. Renal ablation or transplantation resulted in increased glomerular pressure in F344 but not LEW kidneys; the glomerular pressure in syngeneic F344 grafts was not different from that in allogeneic F344 grafts. There was no correlation between the mean arterial pressure and the glomerular capillary pressure. Our data suggest that the glomerular capillary pressure is determined by local intrarenal factors. The glomerular capillary pressure in allotransplanted kidneys resembles that of the donor kidney after subtotal renal ablation. The importance of increased glomerular pressure in the progressive decline of graft function of chronic rejection remains to be established.