Immunosuppression after organ transplantation is an acknowledged risk factor for skin cancer and lymphoma. We examined whether there was also an excess of leukemia in patients after transplantation and whether this might be related to a particular immunosuppressive treatment. Data from more than 170 000 patients indicated that organ transplantation is associated with a significantly increased risk for acute myeloid leukemia (AML). AML was more frequent after heart transplantation and lung transplantation than after kidney transplantation and was associated with immunosuppression by azathioprine, a thiopurine prodrug. Cellular resistance to thiopurines is associated with DNA mismatch repair (MMR) deficiency. We demonstrate that thiopurine treatment of human cells in vitro selects variants with defective MMR. Consistent with a similar selection in patient bone marrow, in 7 of 7 patients, transplantrelated AML/myelodysplastic syndrome (MDS) exhibited the microsatellite instability (MSI) that is diagnostic for defective MMR. Because MSI occurs infrequently in de novo AML, we conclude that the selec- IntroductionThe immunosuppression required to prevent the rejection of a transplanted organ is associated with an increased risk for cancer. Skin carcinoma, non-Hodgkin lymphoma, and other cancers are more frequent among transplant recipients. 1-3 Part of the increased cancer risk reflects immunosuppression and is paralleled by a high incidence of malignancies in HIV-immunocompromised patients (for reviews see Penn 1 and Mueller 4 ). Long-term treatment with drugs may also be a risk factor for cancer. The ability of therapeutic drugs to inflict DNA damage may contribute to the increasing incidence of therapy-related malignancy, particularly therapyrelated acute myeloid leukemia/myelodysplastic syndrome (tAML/ MDS) (for a review, see Leone et al 5 ).Azathioprine is a thiopurine prodrug that is related to 6-mercaptopurine and 6-thioguanine (6-TG). 6 Azathioprine is widely used as an immunosuppressant in recipients of organ transplant, often in conjunction with cyclosporin A and steroids. Although the mechanism of action of the thiopurines is not completely understood despite more than 3 decades of clinical use, the cell's DNA mismatch repair (MMR) system is known to be an important cofactor. It is widely accepted that the formation of thiopurine nucleotides and the eventual incorporation of 6-TG into DNA underlie the cytotoxicity and therapeutic effect of thiopurines (for a review, see McLeod et al 7 ). Although substituting DNA with 6-TG is not, in itself, particularly detrimental, nonenzymatic methylation of DNA 6-TG generates DNA lesions. 8 The rare DNA 6-thiomethylguanine (6-meTG) bases are then processed by MMR. 9 MMR-dependent processing is linked to apoptosis, and inactivation of repair provides an escape from thiopurine-induced cell death. Thus, MMR-deficient cells can tolerate 6-meTG in their DNA, and their resistance to killing by 6-TG is well documented. MMR performs similar lethal processing on the structurall...

The outcome of simultaneous pancreas-kidney (SPK) transplantation in type 1 diabetes has dramatically improved in recent years because of optimized surgical techniques and new immunosuppressive drug regimens. Normoglycemia is followed by stabilization or even regression of diabetic lesions, i.e., of heart and kidneys. However, these effects are only visible after more than five yr of normoglycemia (achieved by a functioning allograft). This is also a likely explanation for the conflicting results of studies that investigated patient or kidney graft survival in SPK transplantation compared to kidney transplantation alone. Most studies had too short follow-up periods, i.e., less than five yr, to compare effectively different transplant strategies in patients with type 1 diabetes and therefore failed to discover a survival benefit in favor of simultaneously transplanted patients. Recent data now indicate that, with a longer follow-up, there is an increasing survival benefit for simultaneously transplanted patients compared to patients who received a single kidney transplant. This is paralleled by the comparison of simultaneously transplanted patients to patients who received a single kidney transplant from a living donor. A survival benefit for the combined procedure was here visible after 10 yr of follow-up. We give a short overview on SPK transplantation, with a focus on the effects of this procedure on diabetic complications as well as patient and kidney graft survival.

This negative result is surprising, given the importance of this receptor in modulating antibody effector function.

In hematopoietic stem cell transplantation (HSCT), disparities between recipients and donors for minor histocompatibility antigens (mHags) have been shown to be related to graft-versus-host disease (GVHD) and graftversus-leukemia (GVL) effects. We investigated the effect of mHag mismatches on kidney allograft survival.

Renin-angiotensin system blockade retards the progression of diabetic and non-diabetic chronic kidney disease of the native kidneys. Though most patients suffer from a significant renal insufficiency (chronic kidney disease stage III) and a concomitant heart disease after renal transplantation, there is up to now no evidence supporting the use of inhibitors of the renin-angiotensin system in these patients. We wish to summarize the available evidence on the use of inhibitors of the renin-angiotensin system after renal transplantation. We specifically discuss potential beneficial as well as adverse effects of a renin-angiotensin system blockade. In addition, we review their influence on morphologic and biochemical markers as well as on renal function, graft and patient survival after renal transplantation.