Differential effects of donor-specific HLA antibodies in living versus deceased donor transplant.

The presence of donor-specific anti-HLA antibodies (DSAs) is associated with increased risk of graft failure after kidney transplant. We hypothesized that DSAs against HLA class I, class II, or both classes indicate a different risk for graft loss between deceased and living donor transplant. In this study, we investigated the impact of pretransplant DSAs, by using single antigen bead assays, on long-term graft survival in 3237 deceased and 1487 living donor kidney transplants with a negative complement-dependent crossmatch. In living donor transplants, we found a limited effect on graft survival of DSAs against class I or II antigens after transplant. Class I and II DSAs combined resulted in decreased 10-year graft survival (84% to 75%). In contrast, after deceased donor transplant, patients with class I or class II DSAs had a 10-year graft survival of 59% and 60%, respectively, both significantly lower than the survival for patients without DSAs (76%). The combination of class I and II DSAs resulted in a 10-year survival of 54% in deceased donor transplants. In conclusion, class I and II DSAs are a clear risk factor for graft loss in deceased donor transplants, while in living donor transplants, class I and II DSAs seem to be associated with an increased risk for graft failure, but this could not be assessed due to their low prevalence.

Female urothelial cell carcinoma in a failed kidney graft of a male recipient.

We present a case of a male kidney transplant patient harbouring two kidney grafts of which one is functional. In the failed graft, he developed urothelial cell carcinoma with cells containing XX-chromosome, and female tumour cells were also found in the bladder. The patient underwent donor nephrectomy, was treated with epirubicin bladder instillations, and immunosuppression was tapered. Less than a year before re-transplantation a CT scan showed no abnormalities of the first graft. Transplantectomy before a second kidney transplantation is debated.

How can we reduce costs of solid-phase multiplex-bead assays used to determine anti-HLA antibodies?

Solid-phase multiplex-bead assays are widely used in transplantation to detect anti-human leukocyte antigen (HLA) antibodies. These assays enable high resolution detection of low levels of HLA antibodies. However, multiplex-bead assays are costly and yield variable measurements that limit the comparison of results between laboratories. In the context of a Dutch national Consortium study we aimed to determine the inter-assay and inter-machine variability of multiplex-bead assays, and we assessed how to reduce the assay reagents costs. Fifteen sera containing a variety of HLA antibodies were used yielding in total 7092 median fluorescence intensities (MFI) values. The inter-assay and inter-machine mean absolute relative differences (MARD) of the screening assay were 12% and 13%, respectively. The single antigen bead (SAB) inter-assay MARD was comparable, but showed a higher lot-to-lot variability. Reduction of screening assay reagents to 50% or 40% of manufacturers' recommendations resulted in MFI values comparable to 100% of the reagents, with an MARD of 12% or 14%, respectively. The MARD of the 50% and 40% SAB assay reagent reductions were 11% and 22%, respectively. From this study, we conclude that the reagents can be reliably reduced at least to 50% of manufacturers' recommendations with virtually no differences in HLA antibody assignments.

The Maastricht Transplant Center: clinical setting and epitope searches in HLA class II molecules: does the structural localization of a polymorphic site contribute to its immunogenicity?

Our understanding of the immunological processes influencing the clinical outcome after kidney transplantation has advanced majorly over the last few decades. However, many factors still restrict graft and patient survival. Within the Maastricht transplant center we have successfully implemented an alternative immunosuppressive regimen involving Tacrolimus monotherapy in order to minimize the adverse effects associated with long-term use of immunosuppressive drugs. This clinical development has an impact on pre-transplant risk stratification which requires that patients are closely monitored immunologically. In this review we will elaborate on our strategy regarding the analysis of epitopes in HLA-DQ and HLA-DP molecules. In this respect we have also looked at the immunodominance of certain epitopes by assessing their structural localization, conformation and physiochemical properties.

Preservation of renal function and cardiovascular risk factors.

An update is given about some factors leading to loss of renal allograft, especially in relation to the use of tacrolimus and cyclosporine. We discuss both immunological, such as suboptimal immunosuppression, acute rejection, and noncompliance, as well as nonimmunological factor's such as hypertension, hyperlipidemia, chronic toxic effects of immunosuppressants, older donors, and delayed graft function.

Metabolic aspects of tacrolimus in renal transplantation. Consequences for the choice of an immunosuppressive regimen and for the management of post-transplant diabetes mellitus.

The occurrence of post-transplant diabetes mellitus (PTDM) is an important complication after renal transplantation associated with an increased risk of chronic transplant dysfunction and of cardiovascular morbidity and mortality. Both tacrolimus and cyclosporine have been associated with PTDM. In the initial studies, PTDM seemed to occur more often in tacrolimus treated patients than in cyclosporine treated patients. The mechanism by which tacrolimus could cause PTDM was unknown and the relative roles of tacrolimus and corticosteroids, which are often prescribed concomitantly with tacrolimus, were unknown. In several studies we used fasting glucose and insulin levels to assess (peripheral) insulin resistance, and intravenous glucose tolerance tests to assess insulin secretion by the pancreatic b-cells in response to a stimulus (glucose load). Thus, we evaluated the mechanism by which tacrolimus causes glucose metabolic disorders, risk factors for glucose metabolic disorders during tacrolimus treatment, the relative roles of corticosteroids and tacrolimus trough levels in glucose metabolic disorders, and also differences in glucose metabolism between patients using tacrolimus versus patients using cyclosporine. Based on the results of these studies and the available literature, the consequences for the choice of a primary immunosuppressive agent and guidelines for the treatment of PTDM during tacrolimus-based immunosuppression are discussed.

Single-center experience with tacrolimus versus cyclosporine-Neoral in renal transplant recipients.

Tacrolimus has proven to be superior to cyclosporine-Sandimmune with regard to the prevention of acute rejections, but data comparing tacrolimus with Neoral are scarce. A total of 128 consecutive renal transplant recipients was studied. The patients were treated with Neoral-based (n = 74) or tacrolimus-based (n = 54) immunosuppressive regimens. Survival analyses (Cox regression analysis) were performed on an intention-to-treat basis. Renal function and cardiovascular risk profile were analyzed by means of a repeated-measures analysis of variance (ANOVA) up to 12 months after transplantation. Immunological features were less favorable in the tacrolimus group. Two-year patient and graft survival were comparable. Acute-rejection-free survival was 82 % in the tacrolimus group versus 40 % in the Neoral group (P < 0.0001). The severity of the rejections (1997 Banff classification) was comparable (P = 0.43). Immunological graft loss (3.7 % vs. 12.2 %, P = 0.02) and conversion because of rejection (0 % vs. 28.4 %, P < 0.001) were less in the tacrolimus group. A higher proportion (68.5 % vs. 14.9 %, P < 0.001) was successfully put on monotherapy. Creatinine clearance, proteinuria, and fractional uric acid clearance were similar. In the tacrolimus group mean blood pressure was comparable, but patients needed less anti-hypertensive drugs (P < 0.001) and, even with fewer patients on lipid-lowering drugs, total cholesterol was lower (5.2 vs. 6.0 mmol/l, P = 0.003). Treatment for post-transplant diabetes mellitus was 18.5 % versus 10.8 % (P = 0.22). In both groups, antidiabetic medication could be withdrawn for most patients. This study indicates that tacrolimus is superior to cyclosporine-Neoral in preventing acute rejection with comparable patient and graft survival rates. Because of a lower need for treatment of hypertension and hypercholesterolemia, the cardiovascular risk profile is more favorable. A considerable proportion of patients can be successfully weaned off co-medication and treated with tacrolimus monotherapy.

Lung and gastric uptake in bone scintigraphy of sarcoidosis.

We report on 99mTc-MDP uptake in lungs and stomach in a patient with hypercalcaemia and renal failure due to elevated 1,25(OH)2vitD3 because of sarcoidosis. Presently, this typical scan pattern has only been described in patients with malignancies, parathyroid adenoma and drug-induced vitamin D intoxication. We offer possible explanations for the findings in our patient.

[Postinfectious tropical malabsorption and the differences from non-tropical sprue (celiac disease)]. / Postinfectieuze tropische malabsorptie en de verschillen met niet-tropische spruw (coeliakie).

The clinical course is described of a 69-year-old patient with a malabsorption syndrome since her stay in Indonesia. Besides chronic diarrhoea and weight loss she suffered from malnutrition and had partial villous atrophy. Coeliac disease was considered in the differential diagnosis but considering the endemic appearance of postinfectious tropical sprue (PTS) in Indonesia and the extreme vitamin B12 deficiency our patient experienced, PTS appeared more likely. A good response to the therapy prescribed for PTS confirmed the diagnosis.

Evaluation of the coagulation/fibrinolysis balance in patients with colorectal cancer.

The coagulation and fibrinolysis profile was evaluated in 40 patients with newly diagnosed untreated colorectal carcinoma (24 males, 16 females; 29 patients without and 11 patients with metastases). Fibrinogen, von Willebrand factor antigen, FVIII:C, thrombin-antithrombin III complex (TAT III), fibrin monomers (FM), plasminogen activator inhibitor-1 (PAI-1) and D-dimers were tested. None of the patients had clinical or laboratory evidence of serious hemorrhage or thrombosis. The results of global routine coagulation tests (aPTT, PT) were not significantly changed. Significant elevations were found for median fibrinogen, von Willebrand factor antigen, FVIII:C, TAT III and D-dimers, compared with a healthy reference group. These results confirm earlier reports of an enhanced level of both coagulation and fibrinolysis markers in carcinoma patients and might be helpful in trying to understand the impact of several relatively new sensitive coagulation and fibrinolysis parameters in colorectal cancer. Moreover the position of the coagulation/fibrinolysis balance might be an explanation for the elevated incidence of thrombotic events in patients with cancer.

Short-term protein restriction in healthy volunteers: effects on renal hemodynamics and renal response to a meat meal.

We have studied the renal hemodynamic effects of short-term protein restriction and short-term protein loading in 12 healthy volunteers, who adhered to a low protein diet (0.6 g/kg/day) for three weeks and then switched to a high protein diet (1.8 g/kg/day) for another three weeks. Baseline glomerular filtration rate (GFR) was not influenced by dietary protein intake. Effective renal plasma flow (ERPF), however, was significantly lower on the low protein diet (491 +/- 23 ml/min; mean +/- SEM) as compared to values on the high protein diet (538 +/- 19 ml/min; p less than 0.01). The increase of GFR after a meat meal (providing 1.8 g protein/kg body weight) was higher on the high protein diet (GFR: +23.6 +/- 5.1 ml/min) than on the low protein diet (GFR: +13.0 +/- 2.4 ml/min; p less than 0.05). We conclude that three weeks of dietary protein restriction do not decrease glomerular filtration rate and do not enhance the renal response to a meat meal. Therefore, it seems doubtful that dietary protein restriction decreases glomerular capillary pressure through vasoconstriction of the afferent glomerular arteriole. Furthermore, measurement of the renal hemodynamic response to an acute protein load seems of doubtful physiological significance.