Outcomes Following ABO-Incompatible Kidney Transplantation Performed After Desensitization by Nonantigen-Specific Immunoadsorption.

BACKGROUND: For desensitization of ABO-incompatible kidney transplant recipients we recently proposed nonantigen-specific immunoadsorption (IA) and rituximab. METHODS: We now compared clinical outcomes of 34 ABO-incompatible living-donor kidney recipients who were transplanted using this protocol with that of 68 matched ABO-compatible patients. In addition, we analyzed efficacy and cost of nonantigen-specific as compared to blood group antigen-specific IA. RESULTS: Before desensitization, the median isoagglutinin titer of 34 ABO-incompatible patients was 1:64 (Coombs technique). Patients received a median of 7 preoperative IA treatments. Twenty-four patients had a median of 2 additional plasmapheresis treatments to reach the preoperative target isoagglutinin titer of 1:8 or less. After a median postoperative follow-up of 22 months, overall graft survival in the ABO-incompatible group was not significantly different from that in ABO-compatible patients (log-rank P = 0.20), whereas patient survival tended to be lower (log-rank P = 0.05). The incidence of rejection episodes was 15% in both groups. The ABO-incompatible kidney recipients had a higher incidence of BK virus replication (P = 0.04) and nephropathy (P = 0.01) and showed more often colonization with multidrug resistant bacteria (P = 0.02). In comparison to blood group antigen-specific IA, nonantigen-specific IA showed equal efficacy but was associated with reduction in cost. CONCLUSIONS: Clinical outcomes of ABO-incompatible patients desensitized with a nonantigen-specific IA device and rituximab do not differ from that of matched ABO-compatible patients although a trend toward reduced patient survival was noted. Special attention must be paid to the higher incidence of BK virus infection in recipients of ABO-incompatible grafts.

Generation of suppressive blood cells for control of allograft rejection.

Our previous studies in rats showed that incubation of monocytic dendritic cells (DCs) with the chemotherapeutic drug mitomycin C (MMC) renders the cells immunosuppressive. Donor-derived MMC-DCs injected into the recipient prior to transplantation prolonged heart allograft survival. Although the generation of DCs is labour-intensive and time-consuming, peripheral blood mononuclear cells (PBMCs) can be easily harvested. In the present study, we analyse under which conditions DCs can be replaced by PBMCs and examine their mode of action. When injected into rats, MMC-incubated donor PBMCs (MICs) strongly prolonged heart allograft survival. Removal of monocytes from PBMCs completely abrogated their suppressive effect, indicating that monocytes are the active cell population. Suppression of rejection was donor-specific. The injected MICs migrated into peripheral lymphoid organs and led to an increased number of regulatory T-cells (Tregs) expressing cluster of differentiation (CD) markers CD4 and CD25 and forkhead box protein 3 (FoxP3). Tolerance could be transferred to syngeneic recipients with blood or spleen cells. Depletion of Tregs from tolerogenic cells abrogated their suppressive effect, arguing for mediation of immunosuppression by CD4⁺CD25⁺FoxP3⁺ Tregs. Donor-derived MICs also prolonged kidney allograft survival in pigs. MICs generated from donor monocytes were applied for the first time in humans in a patient suffering from therapy-resistant rejection of a haploidentical stem cell transplant. We describe, in the present paper, a simple method for in vitro generation of suppressor blood cells for potential use in clinical organ transplantation. Although the case report does not allow us to draw any conclusion about their therapeutic effectiveness, it shows that MICs can be easily generated and applied in humans.

Cellular infiltrates and NFκB subunit c-Rel signaling in kidney allografts of patients with clinical operational tolerance.

BACKGROUND: Nuclear factor kappa B (NFκB) plays a potential role in tolerance by orchestrating onset and resolution of inflammation and regulatory T cell differentiation through subunit c-Rel. We characterized cellular infiltrates and expression of NFκB1, c-Rel and its upstream regulators phosphatidylinositol 3-kinase/RAC-alpha serine/threonine kinase, in allograft biopsies from patients with spontaneous clinical operational tolerance (COT). METHODS: Paraffin-fixed kidney allograft biopsies from 40 patients with COT (n=4), interstitial rejection (IR; n=12), borderline changes (BC; n=12), and long-term allograft function without rejection (NR; n=12) were used in the study. Cellular infiltrates and immunohistochemical expression of key proteins of the NFκB pathway were evaluated in the cortical tubulointerstitium and in cellular infiltrates using digital image analysis software. Results were given as mean±SEM. RESULTS: Biopsies from patients with COT exhibited a comparable amount of cellular infiltrate to IR, BC, and NR (COT, 191±81; IR, 291±62; BC, 178±45; and NR, 210±42 cells/mm) but a significantly higher proportion of forkhead box P3-positive cells (COT, 11%±1.7%; IR, 3.5%±0.70%; BC, 3.4%±0.57%; and NR, 3.7%±0.78% of infiltrating cells; P=0.02). c-Rel expression in cellular infiltrates was significantly elevated in IR, BC, and NR when analyzing the number of positive cells per mm (P=0.02) and positive cells per infiltrating cells (P=0.04). In contrast, tubular PI3K and c-Rel expression were significantly higher in IR and BC but not in NR compared with COT (P=0.03 and P=0.006, respectively). With RAC-alpha serine-threonine kinase, similar tendencies were observed (P=0.2). CONCLUSIONS: Allografts from COT patients show significant cellular infiltrates but a distinct expression of proteins involved in the NFκB pathway and a higher proportion of forkhead box P3-positive cells.

Effect of paricalcitol and calcitriol on aortic wall remodeling in uninephrectomized ApoE knockout mice.

Despite an only minor reduction in the glomerular filtration rate, uninephrectomy (UNX) markedly accelerates the rate of growth of atherosclerotic plaques in ApoE-/- mice. It has been suggested that vitamin D receptor (VDR) activation exerts an antiproliferative effect on vascular smooth muscle cells, but the side effects may limit its use. To assess a potentially different spectrum of actions, we compared the effects of paricalcitol and calcitriol on remodeling and calcification of the aortic wall in sham-operated and UNX ApoE-/- mice on a diet with normal cholesterol content. Sham-operated and UNX mice were randomly allotted to treatment with solvent, calcitriol (0.03 µg/kg) or paricalcitol (0.1 µg/kg) 5 times/wk intraperitoneally for 10 wk. Semithin (0.6 µm) sections of the aorta were analyzed by 1) morphometry, 2) immunohistochemistry, and 3) Western blotting of key proteins involved in vascular calcification and growth. Compared with sham-operated animals (5.6 ± 0.24), the wall-to-lumen ratio (x100) of the aorta was significantly higher in solvent- and calcitriol-treated UNX animals (6.64 ± 0.27 and 7.17 ± 0.81, respectively, P < 0.05), but not in paricalcitol-treated UNX (6.1 5 ± 0.32). Similar differences were seen with respect to maximal plaque height. Expression of transforming growth factor (TGF)-ß1 in aortic intima/plaque was also significantly higher in UNX solvent and UNX calcitriol compared with sham-operated and UNX paricalcitol animals. Treatment with both paricalcitol and calcitriol caused significant elevation of VDR expression in the aorta. While at the dose employed paricalcitol significantly reduced TGF-ß expression in plaques, calcitriol in contrast caused significant vascular calcification and elevated expression of related proteins (BMP2, RANKL, and Runx2).

In renal transplants with delayed graft function chemokines and chemokine receptor expression predict long-term allograft function.

BACKGROUND: Chronic loss of renal allograft function is associated with interstitial fibrosis and tubular atrophy (IF/TA). Independent of the underlying reason, one initial step in the development of fibrosis is chemokine-driven invasion of leukocytes from the blood vessels into the allograft. We studied the role of chemokines in kidney allografts with delayed graft function and the subsequent long-term outcome of renal function and fibrosis. METHODS: We examined repetitive biopsies of 30 patients without signs of acute rejection but with initially delayed graft function for IF/TA. In addition, we examined the expression of chemokine receptor (CCR)-1 and CCR2 on invaded leukocytes and macrophages and the corresponding ligands regulated upon activation, normal t-cell expressed, and secreted (RANTES) and monocyte chemotactic protein-1 on residential kidney cells. RESULTS: The initial expression of CCR1 positive invading cells and RANTES in glomerular cells correlated with the allograft function 12 months after transplantation and at last follow-up. The expression was independent of donor characteristics such as age, gender, infectious state, cause of death, or use of vasopressive agents. Furthermore, it did not correlate with the duration of cold ischemia time. Among the patients with the most progressive loss of allograft function follow-up biopsy specimen did not reveal any signs of rejection but showed increased CCR1 and RANTES expression in the interstitium suggesting ongoing inflammation and fibrosis. CONCLUSION: An early expression of RANTES in renal allografts with delayed graft function with consecutive invasion of CCR1 positive cells seems to promote ongoing IF/TA and to worse renal allograft outcome.

Clinical profile, predictors of mortality, and treatment of patients after myocardial infarction, in an academic medical center hospital.

OBJECTIVE: To evaluate clinical profiles, predictors of 30-day mortality, and the adherence to international recommendations for the treatment of myocardial infarction in an academic medical center hospital. METHODS: We retrospectively studied 172 patients with acute myocardial infarction, admitted in the intensive care unit from January 1992 to December 1997. RESULTS: Most patients were male (68%), white (97%), and over 60 years old (59%). The main risk factor for coronary atherosclerotic disease was systemic blood hypertension (63%). Among all the variables studied, reperfusion therapy, smoking, hypertension, cardiogenic shock, and age were the predictors of 30-day mortality. Most commonly used medications were: acetylsalicylic acid (71%), nitrates (61%), diuretics (51%), angiotensin-converting enzyme inhibitors (46%), thrombolytic therapy (39%), and beta-blockers (35%). CONCLUSION: The absence of reperfusion therapy, smoking status, hypertension, cardiogenic shock, and advanced age are predictors of 30-day mortality in patients with acute myocardial infarction. In addition, some medications that are undoubtedly beneficial have been under-used after acute myocardial infarction.

Perfil clínico, preditores de mortalidade e tratamento de pacientes após infarto agudo do miocárdio, em Hospital Terciário Universitário / Clinical profile, predictors of mortality, and treatment of patients after myocardial infarction, in an Academic Medical Center Hospital

OBJECTIVE: To evaluate clinical profiles, predictors of 30-day mortality, and the adherence to international recommendations for the treatment of myocardial infarction in an academic medical center hospital. METHODS: We retrospectively studied 172 patients with acute myocardial infarction, admitted in the intensive care unit from January 1992 to December 1997. RESULTS: Most patients were male (68 percent), white (97 percent), and over 60 years old (59 percent). The main risk factor for coronary atherosclerotic disease was systemic blood hypertension (63 percent). Among all the variables studied, reperfusion therapy, smoking, hypertension, cardiogenic shock, and age were the predictors of 30-day mortality. Most commonly used medications were: acetylsalicylic acid (71 percent), nitrates (61 percent), diuretics (51 percent), angiotensin-converting enzyme inhibitors (46 percent), thrombolytic therapy (39 percent), and beta-blockers (35 percent). CONCLUSION: The absence of reperfusion therapy, smoking status, hypertension, cardiogenic shock, and advanced age are predictors of 30-day mortality in patients with acute myocardial infarction. In addition, some medications that are undoubtedly beneficial have been under-used after acute myocardial infarction