Cyclosporine's effect on insulin secretion in patients with kidney transplants

Adverse effects of cyclosporine on glucose metabolism have been reported in patients with kidney transplantation, but steroids were present in all the immunosuppressive schedules evaluated. We have studied endocrine pancreatic function (OGTT measuring plasma insulin [IRI] and c-peptide [CP]) in 3 groups of patients, matched for age and body-mass index, 16-66 months after functioning Ktx. Seven patients were treated with CsA monotherapy (group I), 7 patients with CsA plus prednisone (group II), and 6 patients with azathioprine plus prednisone (group III). Seven healthy subjects formed the control group. OGTT was normal in all patients, except one in group II (impaired glucose tolerance). There were no significant differences between the 4 groups concerning fasting blood glucose and area under the glucose curve, as well as basal insulin levels, peak insulin response to glucose, and area under the insulin curve. Basal CP, peak CP response to glucose, and area under CP curve were lower in CG than in the 3 groups of patients. Basal CP in group II (4.4 +/- 2.2 ng/ml) was higher than in group I (2.8 +/- 0.6 ng/ml, P less than 0.05). Glucose/IRI molar ratio in group II (5.7 +/- 1.4, P greater than 0.05) was lower than in group I (7.3 +/- 1.8) and CG (8.0 +/- 2.1, P less than 0.025). Our results suggest that CsA at normal dosage has no clinically important effect on beta-cell function. The indirect evidence of insulin resistance observed in patients treated with CsA plus prednisone is ascribable to corticosteroid treatment.     

Immunomodulation of kidney and heart transplants by anti-idiotypic antibodies.

To explore the possibility that circulating HLA antigens from the graft and anti-anti-HLA (anti-idiotypic) antibodies influence the long-term survival of renal and cardiac allografts, analysis of 330 renal allograft recipients and 174 recipients of cardiac allografts was conducted. Anti-donor-HLA antibodies (Ab1) present before or after transplantation are associated with graft failure, whereas irrelevant anti-HLA antibodies had no impact on actuarial graft survival. Ab1 may be uncovered by dissociation of immune complexes and depletion of soluble antigens with monoclonal antibody-coated magnetic beads. Of the 421 sera tested from 65 heart recipients, 97 showed Ab1 before depletion and 178 after depletion; similar rise in positive sera was seen in 39 renal transplant recipients. Three distinct patterns of appearance of Ab1 and Ab2 (anti-Ab1 antibody) were recognized. Patients with cyclic variations of Ab1 in association with Ab2 had 100% graft survival, whereas patients with cyclic variations of Ab1 but no detectable Ab2 had 2-year graft survival of 36% for kidneys and 71% for hearts. Presence of Ab1 in all sera after transplantation led to 47% and 56% 2-year renal and heart allograft survival, respectively.     

Acquired cystic disease in chronically rejected renal transplants.

Acquired cystic disease has been documented to complicate most forms of chronic renal damage; it has only infrequently been described in transplanted kidneys. Five patients with noncystic ESRD and chronically rejected transplants in which acquired cystic disease arose are reported. The diagnosis of acquired cystic disease was established in examination of transplant nephrectomies from four patients and a core biopsy from the fifth. The allografts were in place from 44 to 80 months; three patients were treated with hemodialysis before the diagnosis of acquired cystic disease, whereas two received peritoneal dialysis. Three of the four patients evaluated had cysts in the native kidneys. Although papillary hyperplasia of lining epithelium was evident in four specimens, only one kidney was the site of neoplasms in the form of multiple small tubular adenomas. No malignant neoplasms were noted in this study or in the few similar previous ones; however, it is possible that chronically rejected transplanted kidneys may harbor neoplasms with the same malignant potential as those in acquired cystic disease in native kidneys.     

Monoclonal antibodies against osteonectin show conservation of epitopes across species

Summary Several monoclonal antibodies were produced to bovine osteonectin, a major noncollagenous protein in the extracellular matrix of bone, and four were characterized. These antibodies showed different reactivities in Western immunoblots, immunoprecipitation, and indirect immunofluorescence, indicating that they recognize different epitopes on the protein. The data indicate that an epitope recognized by one of the antibodies is masked in interactions of osteonectin within cells and in the extracellular matrix. The high degree of cross-species immunoreactivity observed against bone osteonectin with these monoclonal antibodies indicates that these common epitopes have been conserved during evolution.     

Outcomes of shipped live donor kidney transplants compared with traditional living donor kidney transplants

The disparity between kidney transplant candidates and donors necessitates innovations to increase organ availability. Transporting kidneys allows for living donors and recipients to undergo surgery with a familiar transplant team, city, friends, and family. The effect of shipping kidneys and prolonged cold ischemia time (CIT) with living donor transplantation outcomes is not clearly known. This retrospective matched (age, gender, race, and year of procedure) cohort study compared allograft outcomes for shipped live donor kidney transplants and nonshipped living donor kidney transplants. Fifty‐seven shipped live donor kidneys were transplanted from 31 institutions in 26 cities. The mean shipping distance was 1634 miles (range 123–2811) with mean CIT of 12.1 ± 2.8 h. The incidence of delayed graft function in the shipped cohort was 1.8% (1/57) compared to 0% (0/57) in the nonshipped cohort. The 1‐year allograft survival was 98% in both cohorts. There were no significant differences between the mean serum creatinine values or the rates of serum creatinine decline in the immediate postoperative period even after adjusted for gender and differences in recipient and donor BMI. Despite prolonged CITs, outcomes for shipped live donor kidney transplants were similar when compared to matched nonshipped living donor kidney transplants.     

Renal function in patients with cadaveric kidney transplants treated with tacrolimus or cyclosporine

INTRODUCTION: Renal function predicts graft survival in kidney transplant patients. This study compared the 2-year evolution of renal function in patients treated with cyclosporine or tacrolimus in combination with mycophenolate mofetil (MMF) and prednisone. METHODS: We studied 1558 cadaveric renal transplant recipients from 14 Spanish hospitals between January 2000 and December 2002. Of these, 1168 were treated with tacrolimus and 390 with cyclosporine. The primary efficacy endpoint was long-term renal function. Renal function was measured by serum creatinine and glomerular filtration rate (GFR) by creatinine clearance calculated from the Cockcroft-Gault formula. This report summarizes the 2-year results. RESULTS: At 24 months the tacrolimus group showed significantly better serum creatinine (1.5 +/- 0.7 vs 1.8 +/- 0.8 mg/dL, P < .001) and GFR (60.5 +/- 20.9 mL/min vs 47.9 +/- 10.0, P < .001) than the cyclosporine group. Additionally, recipients with ideal graft donors (23.5 +/- 2.8 vs 24.0 +/- 2.9 years) had a better serum creatinine at 2 years (1.23 +/- 0.2 vs 1.5 +/- 0.4 mg/dL, P < .05). Multivariate analysis showed that tacrolimus was an independent factor associated with better renal function: odds ratio 1.6, 95% confidence interval (1.2 to 2.2), P < .001. CONCLUSIONS: Patients with a renal transplant treated with tacrolimus in combination with MMF and prednisone displayed better renal function at 2 years than those who received cyclosporine.     

Humoral sensitization against rejected grafts: specific antibodies to graft immunogenic amino acid triplets

Humoral sensitization against immunogenic amino acid (aa) triplets expressed on a rejected graft was analyzed in 83 retransplant candidates. All patients had lost a graft with HLA-A,-B mismatches. The alloantibodies were detected by a complement-dependent cytotoxicity (CDC) technique and an ELISA method in parallel; they were classified as HLA graft-specific (GS) and non-GS antibodies. The aa triplet specificity of the antibodies was assessed using the HLAMatchmaker algorithm. HLA class I antibodies were detected in 74 of 78 (94%) cases, including GS reactivity in 55 (74.3%) and non-GS in 72 (97.2%), either alone (n = 19) or in parallel with GS antibodies (n = 53). For all HLA-GS-antibody-reactive patients, we defined the specificity against immunogenic aa triplets on the previous graft. Moreover, antibodies specific to graft aa triplets were observed within the non-GS antibodies among 19 of 19 and 28 of 53 cases, respectively. Therefore, aa triplet-specific antibodies against the rejected graft were present in all 74 cases with HLA class I antibodies. Antibodies against aa triplets expressed on all HLA class I-mismatched graft antigens were present in 73% of cases. The high extent of humoral alloreactivity against a rejected graft supports the decision to avoid repeated exposure to immunogenic aa triplet mismatches on a second graft. An accurate analysis for performed antibodies in these cases may be beneficial to select the most suitable second donor.     

H-Y antibody development associates with acute rejection in female patients with male kidney transplants

BACKGROUND: Human minor histocompatibility antigens (mHA) and clinically relevant immune responses to them have not been well defined in organ transplantation. We hypothesized that women with male kidney transplants would develop antibodies against H-Y, the mHA encoded on the Y-chromosome, in association with graft rejection. METHODS: We tested sera from 118 consecutive transplant recipients with kidney biopsies. Antibodies that specifically recognized the recombinant H-Y antigens RPS4Y1 or DDX3Y were detected by IgG enzyme-linked immunosorbent assay and western blotting. Immunogenic epitopes were further identified using overlapping H-Y antigen peptides for both the H-Y proteins. RESULTS: In the 26 female recipients of male kidneys, H-Y antibody development posttransplant (1) was more frequent (46%) than in other gender combinations (P<0.001), (2) showed strong correlation with acute rejection (P=0.00048), (3) correlated with plasma cell infiltrates in biopsied kidneys (P=0.04), and (4) did not correlate with C4d deposition or donor-specific anti-human leukocyte antigen (HLA) antibodies. Of the two H-Y antigens, RPS4Y1 was more frequently recognized (P=0.005). CONCLUSION: This first demonstration of a strong association between H-Y antibody development and acute rejection in kidney transplant recipients shows that in solid organ allografts, humoral immune responses against well defined mHA have clear clinical correlates, can be easily monitored, and warrant study for possible effects on long-term graft function.     

Anti-HLA antibodies in kidney transplanted patients

Anti-human leukocyte antibodies (HLA) play a central role in graft survival, particularly in kidney transplantation. The presence of preformed donor specific anti-HLA antibodies is always excluded before transplantation by performing crossmatches using current and historic recipient serum samples. Several recent studies have observed a correlation between HLA antibodies and graft rejection. It has been suggested that these antibodies should be monitored routinely after kidney transplant to predict graft failure. Here in report the results of a study of on serum samples from 111 kidney transplant recipients that were monitored for anti-HLA antibodies using flow cytometry. Anti-HLA antibodies were only detected in four pre-immunized patients and showed the same HLA specificity that was present before the transplantation (in two cases against previous graft antigens). Furthermore, only two patients with functioning grafts developed anti-HLA antibodies, at 1 month and 1 year after the transplantation. However, they were not donor specific, but probably related to posttransplant transfusions. In our study, none of the patients who suffered an adverse event during the first year (including two with histologically documented acute rejection) developed anti-HLA antibodies. These results are probably related to the use of mycophenolate mofetil, which may reduce the incidence of HLA antibodies. We cannot exclude the possibility that antibodies produced by some patients may not be detectable because they are attached to the graft.