Evaluation of vascular lesions using circulating endothelial cells in renal transplant patients

To investigate the correlation between circulating endothelial cells (CECs) and vascular lesions in renal allografts. Sixty-two renal transplant patients were divided into four groups according to biopsy data. CECs were isolated from peripheral blood with anti-CD136-coated immunomagnetic Dynabeads and counted by microscopy during biopsy. CEC numbers were compared in each group, as well as the correlation between CECs and C4d and vascular changes in different groups. CECs counts were higher in the acute rejection (AR) with endarteritis group than in the normal group (p < 0.01), acute tubular necrosis (ATN) group (p < 0.01) and chronic allograft nephropathy (CAN) group (p < 0.01), there were no difference among ATN, normal and CAN) group (p = 0.587). There was no difference among the normal group without hyaline, normal group with hyaline and CAN with hyaline group. An increasing CECs count was related to C4d-positive AR (p = 0.008; κ score = 0.519) and infiltration of inflammatory cells (p = 0.002, κ score = 0.573) in proximal tubule cells (PTCs). The CECs count decreased after intensive therapy in five patients (p = 0.001) (read more).

Conclusion

Elevation of the CEC count in blood was related to endarteritis. Elevation of CEC count was related to C4d deposition and infiltration of inflammatory cells in PTCs.

Evaluation of vascular lesions using circulating endothelial cells in renal transplant patients

To investigate the correlation between circulating endothelial cells (CECs) and vascular lesions in renal allografts.  Sixty-two renal transplant patients were divided into four groups according to biopsy data. CECs were isolated from peripheral blood with anti-CD136-coated immunomagnetic Dynabeads and counted by microscopy during biopsy. CEC numbers were compared in each group, as well as the correlation between CECs and C4d and vascular changes in different groups. CECs counts were higher in the acute rejection (AR) with endarteritis group than in the normal group (p < 0.01), acute tubular necrosis (ATN) group (p < 0.01) and chronic allograft nephropathy (CAN) group (p < 0.01), there were no difference among ATN, normal and CAN) group (p = 0.587). There was no difference among the normal group without hyaline, normal group with hyaline and CAN with hyaline group. An increasing CECs count was related to C4d-positive AR (p = 0.008; κ score = 0.519) and infiltration of inflammatory cells (p = 0.002, κ score = 0.573) in proximal tubule cells (PTCs). The CECs count decreased after intensive therapy in five patients (p = 0.001) (read more).

Conclusion

Elevation of the CEC count in blood was related to endarteritis. Elevation of CEC count was related to C4d deposition and infiltration of inflammatory cells in PTCs.

Predicting renal graft failure by sCD30 levels and de novo HLA antibodies at 1year post-transplantation.

HLA antibodies and sCD30 levels were detected in the serum sampled from 620 renal graft recipients at 1year post-transplantation, which were followed up for 5years. Six-year graft and patient survivals were 81.6% and 91.0%. HLA antibodies were detected in 45 recipients (7.3%), of whom there were 14 cases with class I antibodies, 26 cases with class II, and 5 cases with both class I and II. Much more graft loss was record in recipients with HLA antibodies than those without antibodies (60% vs. 15.1%, p<0.001). Significantly higher sCD30 levels were recorded in recipients suffering graft loss than the others (73.9±48.8 U/mL vs. 37.3±14.6 U/mL, p<0.001). Compared with those with high sCD30 levels, recipients with low sCD30 levels (<50 U/mL) had much better 6-year graft survival (92.4% vs. 46.6%, p<0.001). Further statistical analysis showed that detrimental effect of de novo HLA antibodies and high sCD30 on graft survival was not only independent but also additive. Therefore, post-transplantation monitoring of HLA antibodies and sCD30 levels is necessary and recipients with elevated sCD30 level and/or de novo HLA antibody should be paid more attention in order to achieve better graft survival (read more)

Expansion of Polyreactive B Cells Cross-Reactive to HLA and Self in the Blood of a Patient with Kidney Graft Rejection

Antibody rejection is often accompanied by nondonor HLA specific antibodies (NDSA) and self-reactive antibodies that develop alongside donor-specific antibodies (DSA). To determine the source of these antibodies, we immortalized 107 B-cell clones from a kidney transplant recipient with humoral rejection. Two of these clones reacted to HLA class I or MICA. Both clones were also reactive to self-antigens and a lysate of a kidney cell line, hence revealing a pattern of polyreactivity. Monoclonality was verified by the identification of a single rearranged immunoglobulin heavy chain variable region (VH) sequence for each clone. By tracking their unique CDR3 sequence, we found that one such polyreactive clone was highly expanded in the patient blood, representing ∼0.2% of circulating B cells. The VH sequence of this clone showed evidence of somatic mutations that were consistent with its memory phenotype and its expansion. Lastly, the reactivity of the expanded polyreactive B-cell clone was found in the patient serum at time of rejection. In conclusion, we provide here proof of principle at the clonal level that human antibodies can cross-react to HLA and self. Our findings strongly suggest that polyreactive antibodies contribute to DSA, NDSA as well as autoantibodies, in transplant recipients (read more).

Low median fluorescence intensity could be a nonsafety concept of immunologic risk evaluation in patients with shared molecular eplets in kidney transplantation.

Human leukocyte antigen (HLA) antibodies are usually “epitope” and not “antigen” specific. This work presents an interesting case concerning Luminex median fluorescence intensity (MFI) levels in antibodies considered low risk (<1,000), but producing humoral rejection. These low-titer antibodies could play an important role in transplantation. A 42-year-old woman was retransplanted with a deceased donor with negative complement-dependent cytotoxicity cross-matching. Our patient was pretransplant (PrT) sensitized to HLA antigens (single antigens (SA) = 31%) for 1 previous transplant. Thus, the formerly detected sensitized antigens were A32, A30, A31, cross-reacting group 5C, and DQ3 with a MFImax ≈ 4,127. In the posttransplantation period (PTP), the patient exhibited important instability in renal function and we detected an increased SA percentage (61%) with MFImax = 15,029 (A*32) with other antigens (detected with a low PrT MFI [<1,000]) as anti-A*03 (MFImax = 13,301) and anti-A*11 (MFImax = 13,714) specificities. Anti-A*03 was a donor-specific antibody (DSA). Renal biopsy was compatible with humoral rejection. The patient was pulsed with methylprednisolone, plasmapheresis, and intravenous immunoglobulin without improvement. Thus, we added anti-CD20 and the initial clinical response was highly favorable. Biopsies resulted in suggestive rejection reversion. MFI A*03 DSA decreased to 6,908 and later to MFImax = 5,505. After a 6-month PTP, the patient is well with MFImax = 3,124. It was possible to define exactly the potential immunizing epitope eplets whose recognition determined the specific antibody production. A*32:01, A*30:01, A*31:01 (detected PrT), A*11:01, and A*03:01 (detected PTP) alleles have several shared eplets (62QE, 70AQS, and 76VGT), with 62QE being the only eplet present on all alleles. In conclusion, low MFI levels in antibodies considered low risk could be important in posttransplant humoral rejection, although the patient's renal function can be restored. Thus, specific shared eplets should always be investigated with respect to previous transplant mismatches (read more)

Predictive value of the Luminex single antigen panel for detecting flow cytometry cross-match positivity.

Anti-human leukocyte antigen (HLA) antibodies are a major cause of allograft loss. Solid-phase immunoassays, notably Luminex technology, have lately begun to replace traditional techniques for detecting these antibodies. This platform, however, carries some restrictions in the type of antibodies it detects. For this reason, results using these new technologies must be correlated with results using traditional techniques that have proven clinical significance. We have correlated flow cytometry cross-match (FCXM) outcomes with results from Luminex assays. Serum samples from patients awaiting transplantation who had known anti-HLA antibodies as detected by Luminex were incubated with lymphocytes expressing (a) 1 of the HLA antigens detected by the sera or (b) several of them. Of the 169 T-cell FCXMs we performed, in 92 cases the target cell expressed only 1 of the HLA antigens detected by the serum. The results obtained correlated well with Luminex data (r = 0.84). A cutoff mean fluorescence intensity value of 6,500 for the Luminex single antigen assay yielded a sensitivity of 85% and specificity of 82% for detecting a positive FCXM. In the other 77 cases, the target cell expressed 2 or more of the HLA antigens detected by the serum. In this situation, the same cutoff proved a useful tool for differentiating negative from positive FCXMs (read more)

Comparative pharmacokinetic study of two mycophenolate mofetil formulations in stable kidney transplant recipients

We compared steady-state pharmacokinetics of mycophenolate mofetil (MMF) – Myfenax^® (Teva) and CellCept^® (Roche) – in stable kidney transplant recipients (KTRs). This was an international, multi-centre, randomized, open-label, two-treatment, two-sequence crossover study with a 3-month follow-up. We included KTRs at least 12 months post-transplantation with stable renal graft function for at least 3 months. The maintenance treatment consisted of MMF in combination with tacrolimus with or without steroids. At the end of the two treatment periods, 6-h or 12-h PK studies of mycophenolic acid (MPA) were performed. A total of 43 patients (mean age: 50.7 ± 13.5 years; 19 females, 24 males) were randomized. Estimates of test to reference ratios (90% CIs) were 0.959 (0.899; 1.023) h*μg/ml for AUC_(0–tau) and 0.873 (0.787; 0.968) μg/ml for C_max. Estimates for AUC_(0–6h) were 0.923 (0.865; 0.984) h*μg/ml and 0.985 (0.877; 1.106) μg/ml for C_min. Thus, AUC_(0–tau), AUC_(0–6h), and C_min of MPA were within the predefined margins. C_max was somewhat outside of these margins in this set of patients. The numbers and types of adverse events were not different between the two treatments. The steady-state pharmacokinetics of MPA as well as adverse events are comparable for Myfenax^® and CellCept^® in tacrolimus-treated stable KTRs. (EudraCT-No.: 2009-010562-31; ClinicalTrials.Gov number: NCT00991510) (read more)

Recurrence from primary and secondary glomerulopathy after renal transplant

Glomerulonephritis is the primary cause of end-stage renal failure in 30–50% of kidney transplant recipients and recurrence of the initial disease is an important determinant of long-term graft outcome after transplantation. Although renal transplantation remains the best treatment option for patients with end stage renal diseases in most cases, diagnosis and management of recurrences of glomerulopathies are critical for the optimization and improvement of long-term kidney transplant graft survival and provide a unique opportunity to explore the pathogenesis of native kidney disease. This review aims to update knowledge for a large panel of recurrent primary and secondary glomerulonephritis after kidney transplantation, excluding diabetic nephropathy including primary focal and segmental glomerulosclerosis, membranous nephropathy, IgA nephropathy, membranoproliferative glomerulonephritis, lupus, vasculitis but also less usual secondary nephropathy related to sarcoidosis, AA and AL amyloidosis, monoclonal immunoglobulin deposition disease, and fibrillary glomerulonephritis (read more).

Leflunomide for cytomegalovirus: bench to bedside

Cytomegalovirus (CMV) remains a major cause of morbidity and mortality among transplant recipients, frequently engaging the clinician in a struggle to balance graft preservation with control of CMV disease. Leflunomide has been shown to have immunosuppressive activity in experimental allograft models together with antiviral activity inhibiting CMV both in vitro and in vivo. Data are emerging about its potential role in ganciclovir-sensitive and -resistant CMV, primarily by virtue of a unique mechanism inhibiting virion assembly, as opposed to inhibition of viral DNA synthesis by current agents. This review aims to put in perspective, the knowledge acquired in the last decade or so on leflunomide for CMV. Evidence suggests that it might have activity against human CMV with good oral bioavailability and, more importantly in the resource-poor setting, is economical. Although the data presented here are not from randomized trials, several relevant observations have been made that could influence future, more structured assessments of the drug. An immune suppressive compound with antiviral features and experimental activity in chronic rejection is an attractive combination for organ transplantation, and it appears that leflunomide may just fit that niche (read more).

L-index as a novel index to evaluate both the intensity and duration of lymphopenia after allogeneic hematopoietic stem cell transplantation

We retrospectively investigated L-index, which evaluates both the intensity and duration of lymphopenia after allogeneic hematopoietic stem cell transplantation (HSCT) (n = 50). L-index was defined as the area over the lymphocyte curve during lymphopenia (absolute lymphocyte count < 700/μL). We calculated the L-index from the start of conditioning to day 30 – L-index(30) – and to day 100 – L-index(100) – after HSCT. Multivariate analysis revealed that human leukocyte antigen mismatched donor, female gender, and non-lymphoid disease were significantly associated with high L-index(30). Grade III–IV acute graft-versus-host disease, alemtuzumab-containing regimen, and non-lymphoid disease were identified as independent significant factors for high L-index(100). Cytomegalovirus (CMV) antigenemia was detected > 3 cells/2 slides by C10/11 method in 30 patients (CMV-AG ≥ 3 group) and was not detected in 20 patients (CMV-AG < 3 group). Although no significant difference was seen in absolute lymphocyte count on day 30 between the 2 groups, the L-index(30) was significantly higher in the CMV-AG ≥ 3 group than in the CMV-AG < 3 group (P = 0.050). L-index(30) was identified as an independent factor on CMV reactivation in multivariate analysis, when it was treated as a dichotomous variable with a cut-off value of 22,318, determined by receiver operating characteristic curve analysis. In conclusion, both the intensity and duration of lymphopenia in early phase after HSCT evaluated on the basis of L-index(30) showed significant association with CMV reactivation (read more).

The time interval between kidney and pancreas transplantation and the clinical outcomes of pancreas after kidney transplantation

Pancreas after kidney (PAK) transplantation is one of the accepted pancreas transplant modalities. We studied the impact of time interval between kidney and pancreas transplantation on the outcomes of PAK transplantation. Using OPTN/SRTR data, we included 1853 PAK transplants performed between 1996 and 2005 with follow-up until November 1, 2008. Kaplan–Meier survival and multivariate Cox regression analyses were performed using the time interval between kidney and pancreas transplantation either as a categorical (less than one yr, between one and less than three yr, and greater than or equal to three yr) or as a continuous variable (months) to assess kidney graft and patient survival. Patients who received a pancreas transplant three yr or later after kidney transplantation had higher risk of death-censored kidney graft loss (HR 1.56, 95% CI 1.04, 2.32, p = 0.03). Each month beyond three yr between kidney and pancreas transplantation incurred 1% higher risk of subsequent death-censored kidney graft loss (HR 1.01, 95% CI 1.001, 1.02, p = 0.03). In conclusion, time interval between pancreas and kidney transplantation is an independent risk factor of kidney graft loss following pancreas transplantation. Shortening the time interval between pancreas and kidney transplantation to less than three yr may reduce the risk of kidney graft loss in qualified PAK transplant candidates (read more).

Potent Induction Immunotherapy Promotes Long-Term Insulin Independence After Islet Transplantation in Type 1 Diabetes

The seemingly inexorable decline in insulin independence after islet transplant alone (ITA) has raised concern about its clinical utility. We hypothesized that induction immunosuppression therapy determines durability of insulin independence. We analyzed the proportion of insulin-independent patients following final islet infusion in four groups of ITA recipients according to induction immunotherapy: University of Minnesota recipients given FcR nonbinding anti-CD3 antibody alone or T-cell depleting antibodies (TCDAb) and TNF-α inhibition (TNF-α-i) (group 1; n = 29); recipients reported to the Collaborative Islet Transplant Registry (CITR) given TCDAb+TNF-α-i (group 2; n = 20); CITR recipients given TCDAb without TNF-α-i (group 3; n = 43); and CITR recipients given IL-2 receptor antibodies (IL-2RAb) alone (group 4; n = 177). Results were compared with outcomes in pancreas transplant alone (PTA) recipients reported to the Scientific Registry of Transplant Recipients (group 5; n = 677). The 5-year insulin independence rates in group 1 (50%) and group 2 (50%) were comparable to outcomes in PTA (group 5: 52%; p>>0.05) but significantly higher than in group 3 (0%; p = 0.001) and group 4 (20%; p = 0.02). Induction immunosuppression was significantly associated with 5-year insulin independence (p = 0.03), regardless of maintenance immunosuppression or other factors. These findings support potential for long-term insulin independence after ITA using potent induction therapy, with anti-CD3 Ab or TCDAb+TNF-α-i (read more).

Long-Term (5 Years) Efficacy and Safety of Pancreas Transplantation Alone in Type 1 Diabetic Patients

Background. Although combined pancreas and kidney transplantation is an established procedure for the treatment of type 1 diabetes (T1D) in patients with end-stage renal disease, the role of pancreas transplant alone (PTA) in the therapy of T1D subjects with preserved kidney function is still matter of debate.
Methods. We report our single-center experience of PTA in 71 consecutive T1D patients all with a posttransplant follow-up of 5 years. Patient and pancreas (normoglycemia in the absence of any antidiabetic therapy) survivals were determined, and several clinical parameters (including risk factors for cardiovascular diseases) were assessed. Cardiac evaluation and Doppler echocardiographic examination were also performed, and renal function and proteinuria were evaluated.
Results. Actual patient and pancreas survivals at 5 years were 98.6% and 73.2%, respectively. Relaparotomy was needed in 18.3% of cases. Restoration of endogenous insulin secretion was accompanied by sustained normalization of fasting plasma glucose concentrations and HbA1c levels as well as significant improvement of total cholesterol, low-density lipoprotein-cholesterol, and blood pressure. An improvement of left ventricular ejection fraction was also observed. Proteinuria (24 hours) decreased significantly after transplantation. One patient developed end-stage renal disease. In the 51 patients with sustained pancreas graft function, kidney function (serum creatinine and glomerular filtration rate) decreased over time with a slower decline in recipients with pretransplant glomerular filtration rate less than 90 mL/min.
Conclusions. PTA was an effective and reasonably safe procedure in this single-center cohort of T1D patients (read more).

Estimating the risks of acquiring a kidney abroad: a meta-analysis of complications following participation in transplant tourism

A meta-analysis of odds ratios comparing the risks of participating in transplant tourism by acquiring a kidney abroad to the risks associated with domestic kidney transplant was undertaken. Comparison across 12 medical outcomes indicates transplant tourists are significantly more likely to contract cytomegalovirus, hepatitis B, HIV, post-transplantation diabetes mellitus, and wound infection than those receiving domestic kidney transplant. Results also indicate that domestic kidney transplant recipients experience significantly higher one-yr patient- and graft-survival rates. Analyses are supplemented by independent comparisons of outcomes and provide practitioners with weighted estimates of the proportion of transplant recipients experiencing 15 medical outcomes. Practitioners are encouraged to caution patients of the medical risks associated with transplant tourism. Despite the illegal and unethical nature of transplant tourism, additional efforts are indicated to eliminate the organ trade and to educate wait-listed patients about the risks of transplant tourism (read more).

CD28-Specific Immunomodulating Antibodies: What Can Be Learned From Experimental Models?

Tolerance induction to alloantigens remains a major challenge in transplant immunology. Progress in the last decade of our understanding of T-cell activation has led to the development of new immunotherapeutic strategies to replace conventional immunosuppression which inhibits the immune system in a nonspecific way. In particular, positive and negative costimulatory molecules of the CD28 family have been consistently demonstrated to be critical for the development of productive immune responses as well as the establishment and maintenance of peripheral tolerance. However, recent discoveries of novel costimulatory interactions confer a novel dimension to the immunoregulatory interactions within the B7:CD28 family and compels a revised view within a “quintet” of costimulatory molecules: CD28/B7/CTLA-4/PD-L1/ICOSL. Complexity introduced in this more detailed costimulatory pathway has important implications in therapeutic interventions against human immunological diseases and, especially, highlight the fundamental differences in selectively targeting CD28 molecules instead of B7 counterparts. In this review, we discuss these differences and emphasize different CD28-specific immunomodulating strategies evaluated in experimental models of transplantation and autoimmune diseases (read more).

A Need for Biomarkers of Operational Tolerance in Liver and Kidney Transplantation

Both kidney and particularly liver recipients can occasionally discontinue all immunosuppressive drugs without undergoing rejection. These patients, who maintain stable graft function off immunosuppressive drugs without clinically significant detrimental immune responses and/or immune deficits, are conventionally termed operationally tolerant and offer a unique paradigm of tolerance in humans. The immune characterization of operationally tolerant transplant recipients has recently received substantial attention. Operationally tolerant patients might exhibit a signature of tolerance that could potentially be useful to select recipients amenable to drug minimization or withdrawal. Furthermore, elucidation of the molecular pathways associated with the operational tolerance phenotype could provide novel targets for therapy. Particular emphasis has been placed on the use of blood samples and high-throughput transcriptional profiling techniques. In liver transplantation, natural killer related transcripts seem to be the most robust markers of operational tolerance, whereas enrichment in B cell-related gene expression markers has been consistently found in blood samples from operationally tolerant kidney recipients, suggesting that different mechanisms operate in the two situations. In this minireview, we summarize the main achievements of recently published reports focused on the identification of transcriptional markers of operational tolerance, we highlight their mechanistic and clinical implications and describe their methodological limitations (read more).

HLA-DQA2 and HLA-DQB2 Genes Are Specifically Expressed in Human Langerhans Cells and Encode a New HLA Class II Molecule [MOLECULAR AND STRUCTURAL IMMUNOLOGY]

The precise role of human epidermal Langerhans cells (LCs) in immune response is highly controversial. While studying the gene expression profile of these cells, we were intrigued to identify the HLA-DQB2 gene as potentially expressed in LCs. Despite a strong evolutionary conservation of their sequences, the concomitant expression of the poorly polymorphic HLA-DQA2/HLA-DQB2 genes, paralogous to the HLA-DQA1/HLA-DQB1 genes, has never been detected in any cell type. We confirmed by RT-PCR that the HLA-DQA2 and -DQB2 genes are both expressed in LCs, but not in monocyte-derived dendritic cells, or in blood CD1c⁺ or plasmacytoid dendritic cells. The presence of the HLA-DQβ2 chain in LCs could be demonstrated by Western blotting, whereas immunofluorescence revealed its localization in early endosomes. As in the case of other HLA class II molecules, the HLA-DQα2 and -DQβ2 chains formed heterodimers that had to associate with the invariant chain to reach endosomal compartments. HLA-DQα2/β2 heterodimers were expressed at the cell surface, where they could mediate staphylococcal superantigen stimulation of T cells. Interestingly, HLA-DQα2 and HLA-DQβ1 chains formed mixed heterodimers which efficiently left the endoplasmic reticulum. These observations strongly suggest that the poorly polymorphic HLA-DQA2 and -DQB2 genes should be considered to be of immunological importance. The HLA-DQα2/β2 molecules could influence the complexity of the repertoire of Ags presented by LCs (read more).

Three-year outcome of isolated glomerulitis on 3-month protocol biopsies of donor HLA antibody negative patients

Transplant glomerulitis (TG) can lead to the diagnosis of acute humoral rejection when associated with C4d. Recent data have shown that, in patients with donor-specific antibodies, TG is a sign of humoral rejection, even in the absence of C4d. However, the clinical significance of isolated TG, i.e. TG without C4d deposition or morphological evidence of rejection, has not been specifically studied in protocol biopsies of recipients without donor-specific antibodies. We compared 20 isolated TG-patients with 44 selected recipients without TG or any rejection-associated change. The two groups had similar baseline characteristics. After a 3 year follow-up, renal function, acute rejection rate, and development of HLA antibodies were not significantly different between the two groups. Isolated TG had no deleterious consequences on the 3 year graft outcome. Eleven patients of the glomerulitis-group had another allograft biopsy during follow-up: glomerular lesions returned to normal in six patients whereas the persistence of glomerulitis or features consistent with chronic transplant glomerulopathy were noticed in the remaining five patients. Four of these five patients had pretransplant non-donor specific HLA antibodies. In conclusion, although isolated TG had no impact on allograft function at 3 year, histological outcome could be related to patient sensitization (read more).

Islet Cell Transplantation in Type 1 Diabetes: An Analysis of Efficacy Outcomes and Considerations for Trial Designs

To estimate treatment effect size and other parameters required for planning the designs and analyses of future phase 3 islet transplant trials, we analyzed key clinical and laboratory outcomes of 347 allogeneic islet transplant recipients, using data from the Collaborative Islet Transplant Registry (CITR). At 1 year, approximately 59% of all transplant recipients were free of severe hypoglycemic events and maintained hemoglobin A1c (HbA1c) level of ≤6.5%. The Kaplan–Meier (KM) survival analyses showed that 69%, 54% and 44% of these 1-year responders maintained this composite endpoint at 2, 3 and 4 years, respectively. Ninety-one percent of all recipients were free of severe hypoglycemic episodes at 1 year. Furthermore, the KM survival estimates showed that 91%, 85% and 80% of these subjects maintained this clinical benefit at 2, 3 and 4 years, respectively. These results can be very useful in developing framework for study designs, sample size estimates, and statistical analysis plans for future pivotal trials of islet cell transplantation in type 1 diabetes (read more).

Protocols for uncontrolled donation after circulatory death

Organ shortages have led some countries, including Spain, France, and the USA, to start programmes of uncontrolled donation after circulatory death. In these protocols, donors are people who have had unexpected out-of-hospital cardiac arrest. After ordinary life support attempts (30 min of advanced cardiopulmonary resuscitation [CPR]) by an emergency medical service are judged futile, patients are transported to the hospital with continuing mechanical chest compression and other interventions to preserve the organs, and declared dead at the hospital after a no-touch period of asystole (usually 5 min) (read more).

C4d Deposition and Multilayering of Peritubular Capillary Basement Membrane in Posttransplantation Membranous Nephropathy Indicate Its Association With Antibody-Mediated Injury

Abstract: Membranous nephropathy (MN) may develop as recurrence or de novo after transplantation. Recently, autoimmune or alloimmune responses to unspecified glomerular antigens have been considered as a pathogenetic mechanism. To explore the relationship between antibody-mediated injury and posttransplantation MN, we tested C4d positivity using polyclonal antibody in renal allograft biopsy samples diagnosed as posttransplantation MN. A total of 19 cases (16 males and 3 females), including 2 recurrent and 7 de novo forms, were the subject of the study. On light microscopy, stage II was the most common (n = 9). In addition to glomerular capillary immunoglobulin (Ig)G deposits, all but 2 cases having only sclerotic glomeruli were C4d-positive in glomerular capillary walls. Twelve cases were also positive in cortical peritubular capillaries (PTCs): diffuse in 8 cases and focal in 4 cases. Two of 3 cases associated with acute rejection and 3 of 4 cases associated with chronic rejection were PTC C4d-positive. The frequency of C4d positivity in PTCs was significantly higher than that of posttransplantation IgA nephropathy (P = .028). In conclusion, a higher frequency of PTC C4d positivity suggests an involvement of chronic antibody-mediated injury in the evolution of posttransplantation MN (read more)