Various desensitization protocols were shown to enable successful living donor kidney transplantation across a positive complement‐dependent cytotoxicity crossmatch (CDCXM). Positive crossmatch ...transplantation, however, is less well established for deceased donor transplantation. We report a cohort of 68 deceased donor renal allograft recipients who, on the basis of broad sensitization (lymphocytotoxic panel reactivity ≥40%), were subjected to a protocol of peritransplant immunoadsorption (IA). Treatment consisted of a single session of immediate pretransplant IA (protein A) followed by posttransplant IA and antilymphocyte antibody therapy. Twenty‐one patients had a positive CDCXM, which could be rendered negative by pretransplant apheresis. Solid phase HLA antibody detection revealed preformed donor‐specific antibodies (DSA) in all 21 CDCXM‐positive and in 30 CDCXM‐negative recipients. At 5 years, overall graft survival, death‐censored graft survival and patient survival were 63%, 76% and 87%, respectively, without any differences between CDCXM‐positive, CDCXM‐negative/DSA‐positive and CDCXM‐negative/DSA‐negative recipients. Furthermore, groups did not differ regarding rates of antibody‐mediated rejection (24% vs. 30% vs. 24%, p = 0.84), cellular rejection (14% vs. 23% vs. 18%, p = 0.7) or allograft function (median 5‐year serum creatinine: 1.3 vs. 1.8 vs. 1.7 mg/dL, p = 0.62). Our results suggest that peritransplant IA is an effective strategy for rapid desensitization in deceased donor transplantation.
This study demonstrates successful transplantation of crossmatch‐positive deceased donor kidney allograft recipients using a protocol of peri‐transplant immunoadsorption for rapid alloantibody depletion immediately before transplant surgery.
Summary
Background
Type I allergies have repeatedly been reported after solid organ transplantation despite T cell‐targeted immunosuppressive therapy. A causal relationship with tacrolimus has been ...proposed.
Objective
The present study directly compared the occurrence of allergic sensitization and disease under tacrolimus‐ vs. cyclosporin A‐based immunosuppressive therapy.
Methods
The prevalences of IgE‐mediated sensitization and allergy were assessed in a cross‐sectional study of kidney‐transplanted adults receiving tacrolimus (n=100) or cyclosporin A (n=100). Methods included a standardized questionnaire, skin prick test and measurement of total and specific IgE against common nutritive and inhalant allergens.
Results
The prevalence of sensitization was significantly higher in the tacrolimus‐ than in the cyclosporin A‐treated group (34%, n=34, vs. 20%, n=20; P=0.026). The rate of clinically relevant allergy in patients receiving tacrolimus was twice that in patients receiving cyclosporin A (15%, n=15, vs. 8%, n=8; P=0.12). No other factor (age, serum drug level, concomitant immunosuppressive medication, time since transplantation, underlying disease) was found to have an influence on sensitization or allergy prevalence (logistic regression).
Conclusion and Clinical Relevance
Our results suggest that post‐transplant immunosuppression with tacrolimus is associated with an increased occurrence of IgE‐mediated sensitization and probably manifestation of allergic disease, which has to be treated specifically despite immunosuppressive therapy.
Cite this as: S. Gruber, K. Tiringer, E. Dehlink, T. Eiwegger, E. Mayer, H. Konstantin, Z. Kikic, A. Graf and Z. Szépfalusi, Clinical & Experimental Allergy, 2011 (41) 1125–1132.
Although diffuse linear C4d deposition in peritubular capillaries (PTCs) is a well-established criterion of alloantibody-mediated kidney transplant rejection, the actual relevance of focal or ...granular C4d deposits or staining outside PTC (glomeruli and arterioles) has yet to be established.
This study was designed to evaluate the diagnostic significance of such nontypical C4d staining patterns. A total of 539 early indication biopsies (329 kidney transplants) were analyzed by immunohistochemistry using a polyclonal anti-C4d antibody.
We found a close interrelationship between diffuse or focal linear C4d deposition in PTC, linear endothelial deposition in glomeruli, and arteriolar C4d. These specific patterns were also related to transplant glomerulitis and recipient presensitization. No such associations, however, were observed for other patterns, such as granular C4d in PTC. Detection of diffuse but not focal linear C4d in PTC was found to be associated with adverse allograft survival (5-year death-censored graft survival: 48% vs. 82%, 89%, or 84% in patients with focal, minimal, or no C4d, respectively; P<0.0001). Univariate analysis also revealed inferior graft survival in recipients with linear C4d in glomeruli (P=0.02). Applying multivariate Cox regression analysis, however, only diffuse linear PTC staining was found to be predictive of graft loss (hazard ratio 3.95 95% confidence interval 1.62-9.60; P=0.002).
There might be a relationship between humoral alloimmunity and distinct less established staining patterns, such as focal linear C4d in PTC, endothelial C4d in glomeruli, or arteriolar C4d. Nevertheless, our results reemphasize the prognostic value of diffuse linear PTC staining.
Recipient presensitization represents a major hurdle to successful renal transplantation. Previous case series have suggested that the proteasome inhibitor bortezomib directly affects the ...alloantibody-secreting plasma cells in rejecting allograft recipients. However, the ability of this agent to desensitize nonimmunosuppressed transplant candidates before transplantation is currently unknown.
In this analysis, two sensitized hemodialysis patients were selected to receive two subsequent bortezomib cycles. Bortezomib was given at 1.3 mg/m(2) on days 1, 4, 8, and 11. Dexamethasone was added to the second cycle to enhance treatment efficiency. Serial immune monitoring included cytotoxic panel reactive antibody testing, Luminex single antigen testing for anti-human leukocyte antigen (HLA) IgG with or without C4d-fixing capability, and ABO antibody detection.
During a half-year follow-up period, cytotoxic panel reactive antibody decreased from 87% to 80% (patient 1) and 37% to 13% (patient 2). Patient 1 showed a 40% reduction in binding intensities of identified Luminex HLA single antigen reactivities and, in parallel, slight reductions in ABO blood group antibody and total immunoglobulin levels. In patient 2, bortezomib did not affect circulating antibody levels in a meaningful way. Both patients showed a more than 50% reduction in the levels of anti-HLA antibody-triggered C4d deposition to Luminex beads.
Our initial experience suggests that, without additional immunosuppressive measures, bortezomib has modest effects on circulating antibodies against HLA or blood group antigens. The reduced levels of antibody-triggered complement fixation, however, imply potential clinical relevance of proteasome inhibition for recipient desensitization.
Hemodialysis immediately before kidney transplant surgery has been suggested to adversely affect early graft function. On the other hand, considering its profound antiinflammatory effects, a ...beneficial impact of regional citrate anticoagulation on the evolution of graft function can be speculated. We sought to assess the clinical impact of preoperative hemodialysis and dialysis anticoagulation in two related randomized trials.
Eligible kidney transplant candidates with a serum potassium less than or equal to 5.0 mEq/L were randomized to receive dialysis or no dialysis before deceased donor transplantation. Patients with a potassium more than 5.0 mEq/L were randomized to receive dialysis with heparin or citrate anticoagulation. The primary endpoint was the estimated glomerular filtration rate (eGFR) at posttransplant day 5.
The first comparison (56 vs. 54 patients) revealed no effect of dialysis on eGFR at day 5 (primary endpoint, 12 interquartile range 5-36 vs. 13 5-37 mL/min/1.73 m2, P=0.98), rates of delayed graft function (22% vs. 27%, P=0.66), cellular rejection (20% vs. 24%, P=0.65), and C4d-positive dysfunction (2% vs. 9%, P=0.11) or 1-year death-censored graft survival (89% vs. 91%, P=0.51). Comparing citrate with heparin anticoagulation (44 vs. 66 patients), no differences in eGFR at day 5 (17 8-31 vs. 14 6-38 ml/min/1.73 m2, P=0.57), delayed graft function (21% vs. 30%, P=0.28), cellular rejection (23% vs. 33%, P=0.29), and graft survival (90% vs. 88%, P=0.44) were found. For citrate anticoagulation, less C4d-positive rejection episodes (P=0.08) and higher 1-year eGFR levels (P=0.03) were observed.
Pretransplant hemodialysis and anticoagulation may not affect early graft function in a meaningful way.
Background. Several studies indicate that interstitial and intracapillary monocytes/macrophages (MO) represent a significant proportion of graft-infiltrating cells in renal allografts and that their ...presence may unfavourably affect clinical outcome. Much less is known about the role of MO in vascular rejection of transplanted kidneys. The aim of our study was to determine the cellular composition of immune cell infiltrates in intimal arteritis and to analyse whether it is associated with features of humoral immunity and impaired graft survival. Methods. In 34 recipients with vascular rejection, we determined the proportion of intimal and interstitial MO and T-cells (expressed as ratio of CD68- and CD3-positive cells) in immunohistochemically double-labelled slides. Results. Intimal arteritis is always composed of T-cells and MO with a median CD68/CD3 ratio of 1.03. In 47% of cases, however, T-cells predominate (CD68/CD3 ratio <1). The median interstitial CD68/CD3 ratio is 0.61, with T-cells dominating in 64% of cases. There is no correlation between the cellular composition of arterial and interstitial infiltrates. The proportion of interstitial and arterial MO has no impact on graft survival, and is, in contrast to previous reports on MO in allograft glomerulitis and capillaritis, not associated with C4d staining. Conclusions. Intimal arteritis in kidney allograft rejection is composed of a mixed infiltrate of MO and T-lymphocytes. In contrast to MO in PTCitis and glomerulitis, the MO in intimal arteritis are not associated with markers of humoral immune response and there are no different allograft outcomes between MO and T-lymphocyte-dominated groups.
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