Proteasome inhibitor-based therapy for antibody-mediated rejection

The development of donor-specific anti-human leukocyte antigen antibodies (DSAs) following renal transplantation significantly reduces long-term renal graft function and survival. The traditional therapies for antibody-mediated rejection (AMR) have provided inconsistent results and transient effects that may be due to a failure to deplete mature antibody-producing plasma cells. Proteasome inhibition (PI) is a novel AMR therapy that deletes plasma cells. Initial reports of PI-based AMR treatment in refractory rejection demonstrated the ability of bortezomib to deplete plasma cells producing DSA, reduce DSA levels, provide histological improvement or resolution, and improve renal allograft function. These results have subsequently been confirmed in a multicenter collaborative study. PI has also been shown to provide effective primary AMR therapy in case reports. Recent studies have demonstrated that PI therapy results in differential responses in early and late post-transplant AMR. Additional randomized studies are evaluating the role of PI in transplant induction, acute AMR, and chronic rejection in renal transplantation. An important theoretical advantage of PI-based regimens is derived from several potential strategies for achievement of synergy

Alemtuzumab preconditioning with tacrolimus monotherapy - The impact of serial monitoring for donor-specific antibody

BACKGROUND. Antibody preconditioning with tacrolimus monotherapy has allowed many renal allograft recipients to be maintained on spaced weaning. METHODS. Of 279 renal allograft recipients transplanted between March 2003 and December 2004, 222 (80%) had spaced weaning (i.e., reduction of tacrolimus monotherapy dosing to every other day, three times a week, twice a week, or once a week) attempted. Routine monitoring for donor-specific antibody (DSA) was begun in September 2004. Mean follow-up is 34±6.5 months after transplantation and 26±8.1 months after the initiation of spaced weaning. RESULTS. One hundred and twenty-two (44%) patients remained on spaced weaning. One- and 2-year actual patient/graft survival was 99%/99%, and 97%/96%. Fifty-six (20%) patients experienced acute rejection after initiation of spaced weaning. One- and 2-year actual patient/graft survival was 100%/98%, and 94%/78%. Forty-two (15%) patients with stable renal function had spaced weaning stopped because of the development of DSA, which disappeared in 17 (40%). One- and 2-year actual patient and graft survival was 100% and 100%. CONCLUSION. Adult renal transplant recipients who are able to be maintained on spaced weaning have excellent outcomes. Patients with stable renal function who have reversal of weaning because of the development of DSA also have excellent outcomes. Routine monitoring for DSA may allow patients to avoid late rejection after spaced weaning. © 2008 Lippincott Williams & Wilkins, Inc

Early outcomes in human lung transplantation with Thymoglobulin or Campath-1H for recipient pretreatment followed by posttransplant tacrolimus near-monotherapy

Objectives: Acute and chronic rejection remain unresolved problems after lung transplantation, despite heavy multidrug immunosuppression. In turn, the strong immunosuppression has been responsible for mortality and pervasive morbidity. It also has been postulated to interdict potential mechanisms of alloengraftment. Methods: In 48 lung recipients we applied 2 therapeutic principles: (1) recipient pretreatment with antilymphoid antibody preparations (Thymoglobulin [SangStat, Fremont, Calif] or Campath [alemtuzumab; manufactured by ILEX Pharmaceuticals, LP, San Antonio, Tex; distributed by Berlex Laboratories, Richmond, Calif]) and (2) minimal posttransplant immunosuppression with tacrolimus monotherapy or near-monotherapy. Our principal analysis was of the events during the critical first 6 posttransplant months of highest immunologic and infectious disease risk. Results were compared with those of 28 historical lung recipients treated with daclizumab induction and triple immunosuppression (tacrolimus-prednisone-azathioprine). Results: Recipient pretreatment with both antilymphoid preparations allowed the use of postoperative tacrolimus monotherapy with prevention or control of acute rejection. Freedom from rejection was significantly greater with Campath than with Thymoglobulin (P = .03) or daclizumab (P = .05). After lymphoid depletion with Thymoglobulin or Campath, patient and graft survival at 6 months was 90% or greater. Patient and graft survival after 9 to 24 months is 84.2% in the Thymoglobulin cohort, and after 10 to 12 months, it is 90% in the Campath cohort. There has been a subjective improvement in quality of life relative to our historical experience. Conclusion: Our results suggest that improvements in lung transplantation can be accomplished by altering the timing, dosage, and approach to immunosuppression in ways that might allow natural mechanisms of alloengraftment and diminish the magnitude of required maintenance immunosuppression. Copyright © 2005 by The American Association for Thoracic Surgery

The significance of renal C4d staining in patients with BK viruria, viremia, and nephropathy.

Peritubular capillary C4d staining in allograft kidney is an important criterion for antibody-mediated rejection. Whether BK virus infection can result in complement activation is not known. We studied 113 renal allograft biopsies from 52 recipients with a history of BK virus activation. The samples were classified into four groups according to the concurrent detection of BK virus DNA in urine, plasma, and/or biopsy: BK-negative (n=37), viruria (n=53), viremia (n=7), and nephropathy (n=16) groups. The histological semiquantitative peritubular capillary C4d scores in the viremia (0.3+/-0.8) and BK nephropathy (0.6+/-0.9) groups were lower than those in the BK-negative group (1.2+/-1.1, P=0.05 and P=0.06, respectively) and the viruria group (1.2+/-1.1, P=0.04 and P=0.06, respectively). Diffuse or focal peritubular capillary C4d staining was present in 9/76 (12%) and 14/76 (19%) of all samples with concurrent BK virus reactivation (viruria, viremia, and nephropathy). The diagnosis of antibody-mediated rejection could be established in 7/9 (78%) and 5/14 (36%) of these samples, respectively. Diffuse tubular basement membrane C4d staining was restricted to BK nephropathy cases (4/16, 25%). Semiquantitative tubular basement membrane C4d scores were higher in BK nephropathy (1.2+/-1.3) compared with BK-negative (0.05+/-0.3, P=0.017) and viruria (0.0+/-0.0, P=0.008) groups. Bowman\u27s capsule C4d staining was more frequent in BK nephropathy (5/16) compared with the aforementioned groups (2/36 (P=0.023) and 4/51 (P=0.03), respectively). Within the BK nephropathy group, samples with tubular basement membrane stain had more infected tubular epithelial cells (12.1+/-7.6% vs 4.4+/-5.0%, P=0.03) and a trend toward higher interstitial inflammation scores. In conclusion, peritubular capillary C4d staining remains a valid marker for the diagnosis of antibody-mediated rejection in the presence of concurrent BK virus infection. A subset of biopsies with BK nephropathy shows tubular basement membrane C4d staining, which correlates with marked viral cytopathic effect

Retransplant candidates have donor-specific antibodies that react with structurally defined HLA-DR,DQ,DP epitopes

Diplomski rad predstavlja proračun dizalice topline voda-voda za grijanje i hlađenje stambene zgrade na otoku Krku. Stambeni prostor je korisne površine 328 m2 kojeg čine prizemlje i dva kata. Dizalica topline radi u monovalentnom načinu rada s podzemnom vodom kao izvorom energije. Ogrjevno/rashladna tijela po prostorijama korištena u ovom KGH sustavu su ventilokonvektori. Toplinsko opterećenje stambene zgrade određuje se prema postupku iz norme HRN EN 12831. Pri proračunu projektnih toplinskih gubitaka zgrade promatraju se transmisijski i ventilacijski toplinski gubici. Ukupni toplinski gubici zgrade zimi iznose 12,5 kW. Toplinsko opterećenje zgrade ljeti računa se prema normi VDI 2078, a podijeljeni su na unutrašnje i vanjske toplinske dobitke. Ukupni toplinski dobici ljeti iznose 10,8 kW. Potrebna toplinska energija za grijanje određuju se prema normi HRN EN ISO 13790. Proračun prema normi HRN EN ISO 13790 provodi se tako da se cijela zgrada tretira kao jedna zona. Ukupna godišnja toplinska energija za grijanje zgrade iznosi 12884 kWh što iznosi 39,28 kWh/m2 godišnje te se time zgrada svrstava u B energetski razred. Temperaturni režim grijanja je 47/42 °C pa je prema tome odabrana temperatura kondenzacije od 50 °C. Za izvor topline u obliku podzemne vode koja je na konstantnoj temperaturi od 13 °C odabrana je temperatura isparavanja od 4 °C. Kao radna tvar za krug dizalice topline odabrana je prirodna radna tvar R290 (propan), ponajviše zbog malog utjecaja na okoliš. Učinak isparivača je izračunat i iznosi 9,8 kW. Površina izmjene topline pločastog isparivača iznosi 1,26 m2, a pločastog kondenzatora 1,11 m2. Provedena je energetsko-ekonomska analiza dizalice topline voda-voda koja ukazuje na izrazito visoke investicijske troškove sustava dizalice topline. Naime, uz duplo manje troškove pogona u odnosu na konvencionalne sustave cijena investicije je tolika da će dizalica topline voda-voda tek nakon 20 godina rada biti isplativa. Ipak, ekološka analiza je pokazala nešto bolju sliku o dizalicama topline koje u odnosu na konvencionalne sustave grijanja imaju nekoliko puta manju emisiju CO2.Master thesis represents the calculation of the heat pump water-water for heating and cooling of residential building on the island of Krk. Usable area of this building is 328 m2 which consists of three floors. Heat pump works in mono mode with ground water as a source of energy. Heating/cooling units on the premises used in this HVAC system are fan coils. The heat load of the residential building is determined according to the procedure of the standard EN 12831. When calculating projected heat losses of the building, transmission and ventilation heat losses are observed. The total heat loss of the building in winter is 12,5 kW. The heat load of the building in summer is calculated according to VDI 2078. The heat load is divided into internal and external heat sources. The total heat gain in summer is 10,8 kW. Energy use for heating is determined according to EN ISO 13790. Calculation according to ISO 13790 is carried out so that the whole building is treated as one zone. Total annual energy use for heating the building is 12884 kWh, which is 39,28 kWh/m2 per year, thereby building is classified as B energy class. The temperature mode of heating is 47/42 °C and accordingly to that condensation temperature is 50 °C. For the heat source in the form of ground water which is at a constant temperature of 13 °C selected vaporization temperature is 4 °C. Natural refrigerant R290 (propane) is chosen for the heat pump, mainly due to the low environmental impact. Evaporator power is calculated to 9,8 kW. Heat transfer surface of the plate evaporator is 1,26 m2 and 1,11 m2 of the plate condenser. Conducted energy-economic analysis of the heat pump water-water points out an extremely high investment costs of the system. In fact, with half the operating costs compared to conventional heating systems, investment is such that after 20 years of operation heat pump water-water will be profitable. However, environmental analysis showed a slightly better picture of the heat pumps, which in comparison to conventional heating systems have several times less CO2 emissions

Clinical significance of the distribution of C4d deposits in different anatomic compartments of the allograft kidney.

Diffuse C4d deposition in peritubular capillaries is a well-recognized marker of antibody-mediated rejection. The significance of staining patterns that are focal or affect non-peritubular capillary compartments is less well defined. Paired frozen section and paraffin-embedded tissue stains were performed in 52 kidney allograft biopsies, and correlated with clinicopathologic parameters. Diffuse peritubular capillary C4d deposits were more often seen in frozen sections (22/52, 43% frozen tissue vs 10/52, 19% paraffin-embedded tissue), whereas focal staining was observed more frequently within paraffin sections (13/52, 25% paraffin-embedded tissue vs 7/52, 14% frozen tissue). In biopsies taken from patients with a history of donor-specific antibodies, diffuse, focal and negative peritubular capillary C4d staining patterns were seen in 11/14 (79%), 1/14 (7%) and 2/14 (14%) of frozen biopsies vs 5/14 (36%), 6/14 (43%) and 3/14 (21%) of paraffin-embedded biopsies. Transplant glomerulopathy score in paraffin-embedded biopsies was higher in specimens with vs without glomerular basement membrane C4d staining (1.5+/-0.8 vs 1.0+/-0.6, P=0.03). Tubular basement membrane staining was present in 4% paraffin-embedded and 48% frozen specimens independent of tubular atrophy. Arteriolar hyalinosis score in paraffin-embedded specimens was higher in biopsies with vs those without arteriolar C4d deposits (1.3+/-0.9 vs 0.9+/-0.8, P=0.04). Arterial staining was unrelated to the degree of intimal thickening. In conclusion, peritubular capillary deposits correlate well with circulating donor-specific antibody. For paraffin-embedded tissue, combining the results of focal and diffuse staining allows a diagnostic sensitivity comparable to diffuse staining in frozen tissue. Finally, C4d deposits preferentially in lesions of chronic transplant glomerulopathy and arteriolar hyalinosis