Minimization of immunosuppressive therapy and immunological monitoring of kidney transplant recipients with long-term allograft survival.

Incidence of cardiovascular complications, cancers and chronic allograft nephropathy (CAN) suggests reduction of immunosuppressive dosages. Some studies analyzed the effects of minimization of immunosuppression until the avoidance of immunosuppressive drugs. However minimization seems to be related to a higher incidence of acute rejection. Induction of tolerance after transplantation and use of immunological tests that could monitor the immune reactivity are required. The aim of this study is to evaluate immunological state in a group of recipients after deceased and living donor kidney transplantation and to minimize immunosuppressive therapy monitoring simultaneously clinical and immunological parameters. We analyzed 41 patients, 38 from deceased donors and 3 from living donor kidney transplantation. All patients were treated with triple immunosuppressive therapy: cyclosporine or sirolimus or tacrolimus, mycophenolate mofetil and steroids. In all recipients the presence of CD8+CD28- T suppressor cells (Ts) was analyzed. Patients were divided in 2 groups, according to the presence of Ts. In patients with Ts, (Group A, n=19), mycophenolate mofetil (MMF) was progressively reduced and then stopped. Steroids were subsequently reduced and then interrupted, maintaining an immunosuppressive therapy with low doses of calcineurin inhibitors (CNI) or sirolimus (SIR). 22 patients were without presence of Ts: we enrolled for the study only patient acute rejection free, without proteinuria and with creatinine levels stable (Group B, n=19). In these patients, MMF was reduced and then stopped, while steroids were decreased to 5 mg at alternate days, maintaining CNI or SIR at medium therapeutic dosages (minimized therapy). Patient and graft overall survival in Group A and in Group B were respectively at 100% and 94.7%. Incidence of acute rejection was respectively at 0% in group A and 15.7% in Group B. Presence of episodes of acute rejection in Group B confirms risk of later minimization of steroids and the relevance of the analysis of recipient immunological reactivity before modification of immunosuppressive therapy. A careful evaluation of recipient immune reactivity with the presence of T regulatory cells can allow adequate and personalized immunosuppressive regimens, without high risks of acute rejection.

Plasmapheresis, Photopheresis, and Endovenous Immunoglobulin in Acute Antibody-mediated Rejection in Kidney Transplantation.

INTRODUCTION: Acute antibody-mediated rejection (AAMR) is the subject of much research. It is diagnosed by C4d staining at biopsy and circulating donor-specific antibodies (DSA). The combination of intensive plasmapheresis and intravenous immunoglobulin (IVIG) has been recognized as an effective treatment for AAMR. We report our single-center experience on AAMR treatment. MATERIALS AND METHODS: We treated 23 transplanted patients (group A) with protein-A immunoadsorption (IA) and 7 patients (group B) with double-filtration plasmapheresis. All patients were treated with IVIG (400 mg/kg/d). Basic immunosuppression included cyclosporine, steroids, azathioprine, and antilymphocyte globulin or monoclonal antibodies (OKT3). A subgroup of 3 patients (3/7; group B1) was treated with photopheresis. RESULTS: In both groups, the mean number of extracorporeal procedures was 7.3 ± 4.5 and 5.5, respectively; the mean duration of treatment was 12.3 ± 10.2 and 14.5 days, respectively. In group A, we observed negative cross-matching in 96% after mean of 18 days; 1 patient died from sepsis, and 6 lost their grafts. In group B, negative circulating DSA were observed in all patients after a mean of 25 days, and 1 patient lost their allograft. CONCLUSIONS: In our observation, the 2 extracorporeal procedures had similar effects in terms of graft survival, DSA removal, and cross-match negativity (group A 74% vs 86%; 95.6% vs 100%). IA was faster for DSA removal. In our opinion, the higher costs of IA suggests its use just in high-risk cases, such as in hyperimmune or sensitized patients. Further studies are necessary to improve our knowledge.

Enhanced production of interferon-gamma by T lymphocytes cloned from rejected kidney grafts.

Seventy-seven T cell clones were generated from cell blasts infiltrating rejected kidney allografts. All clones, either CD4 or CD8, displayed cytolytic activity evaluated by lectin-dependent cell-mediated cytotoxicity (LDCC) and natural killer activities. Furthermore, both types of clones were able to produce IFN-gamma following PHA stimulation. These data suggest that the graft infiltrate is characterized by T cell clones with cytolytic potential responsible for the killing of graft cells. The production of IFN-gamma, enhancing the class II MHC expression, may amplify the recipient immune response.

Detection of T suppressor cells in patients with organ allografts.

Specific immunosuppression of host's immune response to donor HLA antigens has been a major goal to clinical transplantation. Recent evidence has been accumulating to show that a distinct population of T cells expressing the CD8(+) CD28(-) phenotype display suppressor function and inhibit Th activation and proliferation by modulating the APC function. To assess the presence of Ts in transplant recipient's circulation, we have developed a flow cytometry method that measures the expression of costimulatory molecules on donor APC exposed to recipient Th and Ts. Our results demonstrate that quantitation of the capacity of CD8(+) CD28(-) T cells from patient circulation to suppress the activation of costimulatory molecules (CD80, CD86) on donor APC offers a reliable tool for monitoring specific immunosuppression against the graft in solid organ transplantation.

Mechanism of liver allograft rejection: the indirect recognition pathway.

Transplant rejection is mediated by the direct and indirect pathways. To explore the role of the indirect recognition pathway in the rejection of liver allografts, T cells obtained from peripheral blood were expanded in medium containing IL-2 and tested in LDA for reactivity to synthetic peptides corresponding to the hypervariable regions of the mismatched HLA-DR antigen(s) of the donor. Serial investigations of 17 recipients showed that T-cell reactivity to donor HLA-DR peptides was strongly associated with acute rejection episodes. In recipients carrying a graft that was mismatched by two HLA-DR alleles, a single donor antigen was targeted during primary rejection, although allopeptide reactivity against the second HLA-DR antigen was observed during subsequent episodes of acute rejection. The finding that allopeptide reactivity occurs early following transplantation and is predictive of rejection is consistent with the notion that processing of donor alloantigens by recipient APCs activates the indirect T-cell recognition pathway that plays a major role in initiating and amplifying allograft rejection.

Survival in kidney transplantation from living donors: a single-center experience.

BACKGROUND: Transplantation from living donors, in Italy, is still not accepted, in particular those from unrelated donors. The aim of this paper was to present the experience of one transplant center. MATERIALS AND METHODS: Since 1982, 608 transplants were performed from living donors using cyclosporine as the main component of immunosuppressive therapy. Among those, 402 transplants were from related living donors (338 one haplotype pairs and 25 zero haplotypes pairs) and 206 from unrelated living donors (171 spouses and 35 emotionally related subjects). RESULTS: Graft survival at 1, 5, and 10 years showed no statistically meaningful difference between the two groups. A group of 19 transplants performed in predialytic phase patients was compared with a contemporaneous group of 167 transplants performed in patients who were already receiving dialysis. These two groups did not show any statistically meaningful difference in graft survival at 1, 5, or 10 years. DISCUSSION AND CONCLUSIONS: We think that transplants from living donors, whether related or unrelated, must always be proposed as a therapeutic option for end-stage renal disease patients, since they show an higher graft survival than that from cadaveric donors, independent of the compatibility between donor and recipient and independent of the degree of relationship of the pair. Transplantation from living donors definitely is a complementary, not substitutive, program to that from cadaveric donors, which should always be encouraged with awareness campaigns among the population and targeted programs for healthy personnel.

Immunoadsorption with protein A in humoral rejection of kidney transplants.

The presence of alloantibodies may play a role in accelerated or acute humoral rejection. Different therapeutic strategies based on a removal of anti donor antibodies and prevention of their resynthesis have been used in the management of transplant rejection episodes. Immunoadsorption with staphylococcal protein A, a method to selectively remove immunoglobulin G, may represent a new treatment to reverse humoral rejection in kidney transplantation. From 1991 to January 1996, such a method was used in 23 patients in whom an acute humoral rejection developed over a mean period of 14.1 +/- 9.5 days after operation. Twenty-two patients had been transplanted from living donors and one from a cadaveric donor. The ages ranged from 23 to 58 years (mean, 34 +/- 10 years). All transplants were performed according to a negative direct crossmatch. Basic immunosuppression included cyclosporine, steroids, azathioprine, and antilymphocyte globulin or monoclonal antibodies (OKT3). Rejection was diagnosed on the basis of hematochemical tests, Doppler ultrasonography, and kidney biopsy. Only steroid and monoclonal and polyclonal antibody resistant rejections with > 165% positive direct crossmatches against the donor were treated with Protein A immunoabsorption. The procedure used is based on the treatment of 2-3 plasma volumes for the first 2 days and then every other day until a negative crossmatch is obtained, together with improvement in clinical status (mean treatments, 7.3 +/- 4.5 [range, 4-23]; mean duration of treatment, 12.3 +/- 10.2 days [range, 3-44]). From the start of treatment, azathioprine is replaced by cyclophosphamide at a dose of 1-2 mg/kg/day. During treatment, a remarkable fall in immunoglobulin G levels is achieved on the first day, whereas immunoglobulin M titers remain constant, with a slight decrease in serum albumin. Immediately after treatment, a negative crossmatch was found in 22 (95.6%) of 23 patients. In six patients (26%), graft function did not recover, and one patient (4.3%) died. Preliminary results show that immunoabsorption with staphylococcal protein A may be an effective support in the treatment of humoral acute rejection, particularly when it is performed as soon as an early diagnosis of humoral rejection is made. In fact, such treatment has a highly selective adsorption, allows treatment of large volumes of plasma, and can achieve a rapid decrease in the titer of circulating immunoglobulins.

[Long-term follow up of patients surgically treated for pyelo-ureteral disease by the Anderson-Hynes technique]. / Follow-up a distanza dei pazienti operati di malattia del giunto pielo-ureterale (GPU) secondo Anderson-Hynes.

A series of 48 patients with hydronephrosis (mean age 31 yrs.) underwent on Anderson-Hynes pyeloplasty. Assessment was carried out in 30 pts. after a mean observation time of 90 months, with a minimum 5 years follow-up. Clinical examination, laboratory investigations, renal ultrasonography, urography and renal scan were performed pre-operatively and at follow-up. There was one patient with evidence of stenosis in the ureteropelvic junction; one patient developed urinary leakage post-operatively and required surgical correction. All patients had symptoms pre-operatively and no one had symptoms post-operatively. Four patients had calcolosis associated, postoperatively all pts. were stone free; four years later one patient developed litiasis. We observed that the results of surgical intervention in hydronephrosis are excellent especially in patients aged less than 30 years.

[The evolution of immunosuppression in clinical kidney transplantation: the experience of 700 cases]. / Evoluzione dell'immunosoppressione nel trapianto clinico di rene: esperienza su 700 casi.

Kidney transplantation was first introduced in Italy in 1966 by the II Surgical Pathology of the University of Rome giving a great contribution to the development of the transplant surgery in this country. The authors report their 25-year experience analyzing the results obtained in more than 700 kidney allografts. A progressive refinement in the surgical transplant technique both from cadaver and live as well as clinical trials on new immunosuppressive protocols characterized their work.

Multimodal therapy with combined plasmapheresis, photoapheresis, and intravenous immunoglobulin for acute antibody-mediated renal transplant rejection: a 2-year follow-up.

BACKGROUND: Recently, the role of antibodies has been documented in the development of acute rejection episodes. Antibody-mediated acute rejection (AMAR) may develop at any time after transplantation, with an incidence of almost 7%. Several therapeutic approaches have been proposed in the past decades. However, no data exist regarding combined plasma treatment (PT) and extracorporeal photopheresis (ECP). The aim of this study was to report an initial single-center experience of combined PT and ECP with high-dose intravenous immunoglobulin (IVIg) for the treatment of AMAR. METHODS: Three patients were treated with this approach. RESULTS: In 2 cases, we observed immediate restoration of graft function, and in 1 case, in which we interrupted the protocol owing to lack of patient consent, the graft was lost. No organ infections were reported during the therapy period. The rationale for use of ECP is related to the presence of mixed antibody and cell-mediated mechanisms in acute rejection episodes. ECP inhibits specific pathogenic T cells. CONCLUSION: Our approach seemed to give good results in terms of graft survival and safety.