Kidney transplantation graft rejection

It is often difficult to differentiate ARF from acute rejection in the kidney transplant recipient, as both conditions may present with similar symptoms and physical examination findings. However, fever and graft tenderness are more likely to occur with rejection while neurotoxicity is more likely to occur with cyclosporine or tacrolimus toxicity. Kidney biopsy is often needed to confirm the diagnosis of rejection.42... 

Organ transplants The safety and efficacy of peginterferon alfa-2b alone or in combination with ribavirin capsules for the treatment of hepatitis C in patients who have received liver or other organ transplants have not been studied. Preliminary data indicate that interferon alpha therapy may be associated with an increased rate of kidney graft rejection. Liver graft rejection also has been reported, but a causal... 

Muromonab is a mouse monoclonal antibody against the CD3 receptor of T-lymphocytes. Its activity is based on inhibition of interactions between antigen-presenting cells and T-cells. By preventing antigen presentation it suppresses T-cell activation and proliferation. The indication for muromonab is the treatment of acute graft rejection after kidney, liver and hart transplantations. Its adverse effects consist of those symptoms that are initiated by the release of cytokines and lymphokines as a result of the reaction of muromonab with CD3 positive T-lymphocytes. These symptoms may vary from a mild flu-like syndrome to serious cardiac, pulmonale and neurological reactions. 

The drugs like azathioprine and cyclosporine A are used chiefly to prevent transplant rejection and in the treatment of autoimmune diseases. They are used to prevent graft rejection after kidney, liver, lung, pancreas transplant or bone marrow transplantation. 

Prophylaxis of graft rejection in kidney, liver, and heart allogeneic transplantation... 

Muromonoab-CD3 is used for the treatment of acute organ transplant rejection. It is effective in preventing graft rejection after kidney, heart or liver transplantation. Muromonoab-CD3 is effective in patients who after acute cardiac or liver allograft rejection do not respond to steroid therapy. It is administered intravenously and with a dose of 5 mg/day, a general concentration range of 400-1500 ng/ml can be achieved. A serum concentration of 600-1150 ng/ml in renal transplant patients produces desirable immunosuppressive effects. The levels of CD3 expression, their production and antibodies to the drug determine its rate of clearance. In the absence of antibodies to muromonoab-CD3, its half-life is about 18 h. 

Antibodies to passenger B lymphocytes can pose problems after transplantation. When kidneys from a rhesus-negative cadaveric donor, whose serum contained anti-Rho (D), were transplanted into two rhesus-positive patients, anti-Rho (D) was detected in their serum and on their erythrocytes 3.5 weeks after transplantation (40). One patient had hemolysis. The antibodies persisted for nearly 6 months, despite graft rejection and nephrectomy in one case. These antibodies presumably arose from passenger B lymphocytes in the grafts from the rhesus-immunized donor. 

Interactions of transfusion with transplantation can occur (200). Blood transfusions, and especially donor-specific transfusions, given before kidney transplantation have beneficial effects on graft survival the mechanism for this is not known (201-203). By contrast, pre-transplant transfusions in bone marrow recipients with aplastic anemia cause major complications, and can be responsible for graft rejection and marrow transplantation failure (204). 

The effect of ketoconazole in ciclosporin-treated kidney transplant recipients has been the subject of a prospective randomized study (37). In 51 ketoconazole-treated patients and 49 controls there was a similar frequency of acute rejection episodes. However, in the control group, rejection episodes were more recurrent, with a poorer response to treatment. Acute ciclosporin nephrotoxicity was more common in the ketoconazole group, but this was encountered more at induction and rapidly reversed on further reduction of the dose of ciclosporin. Chronic graft dysfunction was significantly less in... 

There are numerous case reports where patients on a calcineurin inhibitor, such as cyclosporine or tacrolimus, began taking St. John s wort and developed significant reductions in plasma concentrations of the drugs (74-81). Both cyclosporine and tacrolimus are metabolized by the CYP3A4 enzyme system, and cyclosporine is also a substrate of Pgp (74,81). There are reports of acute graft rejections caused by low cyclosporine or tacrolimus serum concentrations in heart, liver, and kidney transplant recipients who were taking St. John s wort (75,76). 

Joseph Murray in Boston performed the first successful transplant in 1954 when he performed a donor transplant from one twin to the other. In 1959 Dameshek and Schwartz used 6-mercaptopurine (6-MP) in place of irradiation to precondition patients for bone marrow transplantation. Caine developed this work with the introduction of a safer derivative of 6-MP called azathioprine (AZA). By 1963, maintenance AZA and corticosteroids became the standard regimen for kidney transplantation. Kidney transplant or graft survival with these treatment protocols was approximately 40% at 12 months. In the late 1970s to early 1980s cyclosporin A (Cy A) was introduced and has been the mainstay immunosuppressive regimen in combination with AZA and corticosteroids. Cy A-based protocols led to fewer episodes of acute rejection and improved graft survival at 12... 

Clinical experience following kidney transplantation suggests that primary prophylaxis with tacrolimus results in 1-year graft and patient survival rates that are equivalent to those achieved with Cy A therapy, although with lower rates of acute rejection episodes.Five-year follow-up data suggest improved graft survival with tacrolimus compared with Cy A. Nephrotoxicity, hypertension, and posttransplant diabetes mellitus may occur and v/ere reported commonly in the early studies. ... 

Fig. 5. A nonlinear map (NLM) of 33 human urine samples from patients after kidney transplantation based on the levels of six urinary metabolic descriptors. The diamonds correspond to patients showing good kidney graft function after transplantation, the squares are from patients showing cyclosporin nephrotoxicity and the circles are from patients with kidney rejection.

MMF also has demonstrated efficacy in the treatment of acute rejection. Kidney transplant recipients converted to MMF after the first acute rej ection episode had fewer subsequent rejections compared with those who continued with azathioprine after rejection treatment. The change in therapy was associated with no increase in adverse effects or malignancies and a trend toward better graft function and survival. ... 

Goldman, M., J.L. Van Laethem, D. Abramowicz, L. De Pauw, P. Kinnaert and P. Vereerstraeten. Evolution of renal function during treatment of kidney graft rejection with OKT3 monoclonal antibody. Transplantation 1990 50(1) 158-159. 

A multicenter randomized comparative trial of tacrolimus in combination with azathioprine or mycofenolate mofetU (MMF) versus cyclosporin (microemulsion) with MMF after cadaveric kidney transplantation demonstrated that all regimens yielded similar acute rejection and graft survival rates at 1 year. The tacrolimus-MMF regimen was associated with the lowest rate of steroid-resistant rejection requiring antilymphocyte therapy. In addition, the tacrolimus-treated patients had lower incidence of hyperlipidemia, a side effect of particular concern in these patients [60]. 

A study in 39 kidney transplant patients taking ciclosporin at a mean dose of 158 mg daily found that the ciclosporin dose needed to be increased by between 150 to 525 mg daily (an average dose of469 mg daily) when rifampicin 450 to 600 mg daily was taken as part of a regimen for tuberculosis. An increased incidence of acute rejection occurred during treatment with ciclosporin and rifampicin and 16 patients had kidney graft failure and needed to go back on haemodialysis because of this interaction. ... 

A 39-year-old man taking ciclosporin, whose second kidney transplant functioned subnormally, and who required treatment for hypertension with atenolol and minoxidil, developed ankle oedema, which was resistant to furosemide, despite doses of up to 750 mg daily. When metolazone 2.5 mg daily was added for 2 weeks his serum creatinine levels more than doubled, from 193 to 449 micromol/L. When metolazone was stopped the creatinine levels fell again. Ciclosporin serum levels were unchanged and neither graft rejection nor hypovolaemia occurred. ... 

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