Juliet S. Melzer

The risk of transmission of hepatitis B from HBsAg(-), HBcAb(+), HBIgM(-) organ donors.

Liver allografts from HBcAb(+), IgM(-), HBsAg(-) donors can transmit HBV to uninfected recipients. We currently no longer accept these livers for transplantation while continuing to accept the kidneys. The purpose of this study is to determine the risk of donor-transmitted HBV infections from HBcAb(+), HBIgM(-), HBsAg(-) organ donors and determine if the risk of donor-transmitted HBV infections and their severity is dependent on the organ being transplanted. This study consists of a retrospective review of the posttransplant course of recipients of HBcAb(+), HBIgM(-), HBsAg(-) donors accepted at UCSF from 6/85 to 12/93. Transmitted HBV infection was defined as one in which the recipient changed from HBsAg(-) prior to transplantation to HBsAg(+) posttransplant, with no other source. There were 25 of 1190 donors who were HBcAb(+), HBIgM(-), HBsAg(-); 1/42 kidney, 3/6 liver, and 0/7 heart HBsAg(-) transplant recipients of organs from these donors became HBsAg(+) after transplantation. This difference in infection rate (liver vs. kidney and heart) is statistically significant. The clinical course of the liver recipients was also more severe. All of the patients who became infected were HBsAb(-) and HBcAb(-) prior to transplant. We conclude that (1) HBV can be transmitted from HBcAb(+), HBIgM(-), HBsAg(-) organ donors, (2) the rate of transmission is highest and severity of infection is worst in the liver recipients; and (3) we will continue to transplant kidneys from these donors, preferably into immunized recipients.

Cytokine and T cell receptor gene expression at the site of allograft rejection

Intragraft cytokine and T cell receptor gene expression was analyzed in rejecting renal allografts by polymerase chain reaction (PCR). Message for IL-1β, IL-6, and TNF-α was detected in nephrectomy tissue with pathological evidence of acute or chronic rejection. Similarly, mRNA for both IL-6 and TNF-α was present in renal biopsies from acute rejecting kidneys. IL-2R, IL-4, and IL-5 mRNA was present in both rejecting and rejected kidney allografts, indicating that these cytokines may play a role in ongoing renal allograft rejection. Conversely, IL-2, IL-7, and IFN-γ message was detected infrequently. In order to address the diversity of T cells in rejecting kidneys, we have analyzed the clonality of the TcR present within the allograft tissue. Rearranged TcR genes were identified in all allografts examined (n=16) indicating the presence of T cells bearing the α/β TcR. We have determined that there is a heterogeneous infiltration of T cells in the rejected allograft with TcR representing x=7.47±2.4 families rearranged in samples obtained from nephrectomies, whereas x=5.33±0.58 families were detected in samples obtained from biopsy tissue. These data indicate that (1) cytokines are produced locally which may contribute to graft cell destruction, (2) the heterogeneity of intragraft T cells during kidney allograft rejection may exist because nonspecific lymphocytes have been recruited to the site by locally produced cytokines or because T cells are responding to multiple epitopes or multiple donor antigens. Detection of intragraft cytokines and TcR may prove useful in elucidating the mechanism of rejection and therefore lead to improved immunosuppression.

The clinical course of IgA-nephropathy and Henoch-Schönlein purpura following renal transplantation.

Recurrence of IgA-nephropathy and Henoch-Schönlein purpura is a common finding after renal transplantation. From 1970 to 1984, 1788 transplants were performed at our center. 13 patients had IgA-nephropathy and 3 patients had Henoch-Schönlein purpura. No patient with Henoch-Schönlein purpura had a proved recurrence. Six patients with IgA-nephropathy had a recurrence of IgA disease in the allograft within 3 to 8 months of transplantation. Three patients with a recurrence have retained their kidneys with stable renal function (follow-up of 1.7-2.7 years). Two of these patients lost their graft from severe rejection. One patient, who received an HLA-identical transplant, lost the graft from recurrent IgA disease associated with crescenteric glomerulonephritis. We found no difference in the prevalence of HLA-B 35 among the IgA patients compared with our total transplant population. IgA patients who received living related transplants had a higher recurrence rate of IgA in their allograft when compared with recipients of cadaveric kidneys (83% vs. 14%). Some caution is recommended in using related donors, especially HLA-identical siblings in patients with renal failure secondary to IgA-nephropathy.

Flow cytometry crossmatching as a predictor of acute rejection in sensitized recipients of cadaveric renal transplants

Flow cytometry crossmatching (FCXM) was developed as a more sensitive assay than the standard complement‐dependent cytotoxicity crossmatch (CDCXM) for the detection of anti‐donor antibodies, that mediate hyperacute rejection and graft loss in the early post‐transplant period in renal transplant recipients. The role of FCXM in predicting long‐term clinical outcome in renal allograft recipients is unclear. This study examines the role of FCXM in predicting long‐term clinical outcome in highly sensitized recipients of cadaveric renal transplants. All patients (n=100) with peak panel reactive antibody (PRA) levels>30%, who received cadaveric renal transplants between 1/1/’90 and 12/31/’95 at our institution, were divided into FCXM+ and FCXM− groups. The incidence of acute rejection was determined for each group during the first yr after transplant. Graft survival rates at 1, 2, and 3 yr, and creatinine levels were also compared between groups. FCXM+ patients experienced a higher incidence of acute rejection during the first yr after transplant (69 vs. 45%), and a higher percentage of FCXM+ patients had more than one episode of acute rejection during the first yr after transplant (34 vs. 8%) when compared to FCXM− patients. There was no statistically significant difference in 1‐, 2‐, or 3‐yr graft survival between FCXM+ and FCXM− patients (76 vs. 83, 62 vs. 80, 62 vs. 72%, respectively). These results suggest that sensitized FCXM+ cadaveric renal transplant recipients have a higher incidence of acute rejection episodes in the first yr after transplant. Given the association of multiple rejection episodes with poor long‐term allograft survival, FCXM may be a useful predictor of long‐term clinical outcome in this sub‐group of renal transplant recipients.

A seven-year experience with donor-specific blood transfusions. Results and considerations for maximum efficacy.

Two hundred thirty-nine transplants have been performed following donor-specific blood transfusions (DSTs) since 1978. Graft and patient survival in 1-and O-haplotype-matched transplants with DST pretreatment is comparable to HLA-identical results through 4 years. Graft survival in 174 consecutive nondiabetic, non-HLA-identical DST recipients shows that the transfusion effect persists for at least 4 years, with graft survival of 88\pm3% at that time, compared with 83\pm4% in the concurrent HLA-identical group. Graft function, as determined by serum creatinine, was the same in both groups. Graft and patient survival in 20 O-haplotype matched pairs with DST pretreatment is 100% at 2 years. Low-dose Imuran coverage during DST administration (n=91) was compared with a concurrent group with no Imuran (n=93). Imuran had its maximum effect in patients undergoing their first transplant and with a pre-DST PRA less than 10% (12% vs. 21% sensitization rate in the no-Imuran group). Imuran did not appear to confer any beneficial effect in primary transplants with high PRAs and in patients undergoing a second or third transplant. The majority of patients formally excluded from transplantation because of a post-DST positive B-warm crossmatch can now be successfully transplanted with the use of flow cytometry analysis to rule out previously undetectable low levels of anti-T-lymphocyte antibodies. Of 62 patients with a positive B-warm crossmatch alone since 1982, 73% had a subsequent negative fluorescence-activated cell sorter (FACS) crossmatch permitting transplantation. Preliminary results of a DST and cyclosporine treatment study are described. In conclusion, a long-term immunologic effect of DST has been confirmed and the indications and considerations for optimum use of the DST protocol have been more clearly defined.

Inability of cyclosporine to completely prevent the recurrence of focal glomerulosclerosis after kidney transplantation

From January 1984 through July 1986, 15 patients with biopsy-proven focal glomerulosclerosis (FGS) underwent kidney transplantation. Following transplantation, all patients were immunosuppressed with cyclosporine and prednisone. There were 8 men and 7 women with a mean age of 33 years (range, 16-47 years). Five patients (33%) had recurrence of FGS. Two patients had received kidneys from HLA identical siblings, and 3 patients were transplanted with cadaveric kidneys. In 4 out of 5 patients, the recurrence of FGS occurred within 3 months of transplantation. Of the 2 graft losses in this group, one was from recurrence of FGS. Ten patients followed for a mean of 25 months did not develop recurrence of FGS. No graft loss occurred in this group. Three patients with end-stage renal disease of unknown etiology were found to have FGS in the renal allograft and were presumed to have recurrence of FGS. All 3 patients developed the nephrotic syndrome following transplantation, and 1 patient has had progressive renal failure. Cyclosporine did not prevent the recurrence or the clinical manifestations of FGS following kidney transplantation. Additional studies are needed to determine if cyclosporine is effective in certain subgroups of patients with FGS.

The beneficial effect of pretransplant blood transfusions in cyclosporine-treated cadaver renal allograft recipients.

212 cyclosporine-treated recipients of mismatched first cadaveric renal allografts are evaluated with respect to the effect of pretransplant random bood transfusions. It is determined that transfusions do not effect patient survival or morbidity. Pretransplant random blood transfusions correlate with significantly improved allograft success. There is also a trend, although not statistically significant, for further improvement of allograft survival with increasing numbers of transfusions. The transfusion effect is not related to the time at which the transfusions are given up to 2 years prior to transplantation. Transfused patients have a higher percent reactive antibody (PRA) than untransfused patients, but this does not cause them to wait for a cadaveric allograft significantly longer than the untransfused patients. Rejections are less severe in transfused patients. Is is concluded that cyclosporine-treated recipients of first cadaveric renal allografts benefit from pretransplant blood transfusions.

Are blood transfusions beneficial in the cyclosporine era

In patients treated with conventional immunosuppression (azathioprine and prednisone) after renal transplantation, there is a beneficial effect of pre-transplant blood transfusions on graft survival; in patients treated with cyclosporine, this effect may be lost. In 66 children who received living-related donor transplants after donor-specific transfusions (DST) and were treated with azathioprine-prednisone in our center, 1- and 5-year graft survival rates were 99% and 77% respectively. These rates were similar to those reported for children who did not receive DST but were treated with cyclosporine in other centers. There were 634 adult and pediatric recipients of cadaver transplants in our center who were treated with cyclosporine and prednisone (non-sequential therapy,n=89) or antilymphoblast globulin, azathioprine preduisone, and cyclosporin (sequential therapy,n=545). When all patients were considered, graft survival rates were higher in transfused than in non-transfused patients at 3–5 years, but in the sequential therapy group, there were no differences in graft survival rates between transfused and non-transfused patients. The results suggest that transfusions do not improve cadaver graft survival in patients receiving optimal cyclosporine therapy and that equally good related donor graft survival can be achieved with DST and conventional immunosuppression or no DST and cyclosporine.

Dramatic improvement in the success rate for renal transplants in diabetic recipients with donor-specific transfusions.

The chance of achieving successful kidney transplants in diabetic patients was previously limited because few of them had optimally-matched (2-haplotype) related donors. Hence, transplants were usually not carried out until renal failure had already occurred. The application of donor-specific transfusions (DSTs) prior to transplantation to poorly matched donor-recipient pairs (1-hap-lotype) has been associated with a high success rate for type-I diabetic recipients in our center. The rate of graft survival for 35 consecutive transplants in this category was 88%, 80%, and 73% at 1, 2, and 5 years, respectively. Furthermore, the rate of patient survival was 94%, 90%, and 90% at 1, 2, and 5 years. These patient and graft survival data were without significant difference when compared with the corresponding data for 142 optimally-matched (2-haplotype) related transplants performed without DSTs for nondiabetic recipients, and also when compared with the corresponding data for 130 poorly matched (1 or 0-haplotype) related transplants involving nondiabetic recipients who were prepared for transplantation with DSTs. These good results with DSTs in diabetic recipients emphasize that earlier transplantation utilizing poorly matched related donors should be seriously considered for diabetic patients even before the onset of renal failure, as long as the transplants are carried out in association with DSTs.

Ureteral Obstructions and Leaks After Renal Transplantation: Outcome of Percutaneous Antegrade Ureteral Stent Placement in 44 Patients

PURPOSE To analyze the outcome of percutaneous antegrade ureteral stent placement for treatment of ureteral stenoses and leaks after renal transplantation. MATERIALS AND METHODS Antegrade pyelography and percutaneous ureteral stent placement were performed in 45 patients with ureteral obstruction (n = 40), leak (n = 3), or both (n = 2). Obstructions were graded as mild, moderate, or complete, and as early (< or = 3 months after transplantation) or late (> 3 months). RESULTS The outcome of stent placement was successful in 25 (57%) patients (average follow-up, 30 months). The ureteroneocystostomy (UNC) was the most common site of obstructions (22 of 41), leaks (four of five), and successful outcomes (16 of 22). Moderate obstructions were most common (29 of 41) and responded best to treatment (17 of 29). Eighteen (69%) of 26 early obstructions and five (33%) of 15 late obstructions were successfully managed percutaneously. All complications (12 of 45 patients) were minor, with infections the most common (n = 7). No mortality or allograft loss was attributable to stent placement. CONCLUSION Ureteral stents are safe and effective for the treatment of obstructions and leaks and are particularly effective for early and UNC obstructions. These stents may also be useful for temporary drainage.