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F L Delmonico

Publications and source records attributed to F L Delmonico.

At least 19 recordsLinked to original sources
PubMed1999

Outcome of transplantation of organs procured from bacteremic donors.

BACKGROUND: Transplantation of organs from donors who are bacteremic is controversial. We examined the outcome of recipients of solid organs from donors with bacteremia and/or fungemia at the time of organ recovery. METHODS: All organ donors from a single organ procurement organization between January 1990 and December 1996 were retrospectively analyzed. We calculated rates of transmission from bacteremic or fungemic donors to their recipients and compared the graft and patient survival rates for recipients of these organs with those for recipients of organs from non-bacteremic donors. RESULTS: There were 95 (5.1%) bacteremic donors from a total of 1775, from whom 212 recipients received organs. Forty-six (48%) of the bacteremic donors had pathogens in their blood. Among the 101 recipients of organs from these, no evidence of transmission could be documented. (0% transmission rate, 95% CI 0-3). The remaining 49 donors had either Staphylococcus epidermidis or other unlikely pathogens recovered from the blood. Examination of the 111 recipients of organs from these donors also found no evidence for transmission (0% transmission rate, 95% CI 0-3). Of the 212 recipients, 193 (91%) received a mean of 3.8+/-2.5 days of antibiotics postoperatively. The 30-day graft and patient survival for recipients of organs from bacteremic donors was not significantly different from recipients of organs from nonbacteremic donors (P = 0.695 for patient survival, and P = 0.310 for graft survival). CONCLUSIONS: Organs transplanted from bacteremic donors do not transmit bacterial infection or result in poorer outcomes. Use of organs from these donors could help increase organ availability.

Adult↗
PubMed1999

Evaluation of pre- and posttransplant donor-specific transfusion/cyclosporine A in non-HLA identical living donor kidney transplant recipients. Cooperative Clinical Trials in Transplantation Research Group.

BACKGROUND: The beneficial effects of donor specific transfusion (DST) have become controversial in the cyclosporine era. This study was performed to evaluate the potential benefits of a new protocol for administering DSTs in the perioperative period. METHODS: Non-HLA identical living donor kidney transplant recipients were randomized prospectively to control or to receive a DST 24 hr before transplant and 7-10 days posttransplant. All patients received similar immunosuppression according to protocol. RESULTS: The protocol had 212 evaluable patients (115 transfused and 97 control). There were no differences in 1- and 2-year graft and patient survival, causes of graft failure, incidence and types of infection, repeat hospitalization, or the ability to withdraw steroids. Immunological hyporesponsiveness (by mixed lymphocyte culture) occurred more frequently in transfused patients (18%) than controls (3%) (P = 0.04). Blood stored for > or =3 days was associated with fewer early rejections than blood stored < or =2 days. Overall, class II antigen mismatches were associated with more rejection episodes than class I antigen mismatches. However, transfused patients, but not control patients, with more class I antigen mismatches were more likely to have rejections. CONCLUSIONS: Administration of DSTs by the method described had no practical influence on patient or graft survival for up to 2 years. However, donor-specific hyporesponsiveness was more common in transfused patients (18 vs. 3%). Longer follow-up will be needed to determine whether DST will be associated with long-term benefit.

Blood Preservation↗
PubMed1999

The clinical usefulness of the renal allograft biopsy in the cyclosporine era: a prospective study.

BACKGROUND: The renal allograft biopsy is generally accepted as the gold standard for clarifying the cause of renal dysfunction. However, the clinical usefulness of this procedure has rarely been studied prospectively, nor have most studies included follow-up of patients to delineate the influence of the biopsy on clinical outcome. In this study, we evaluated prospectively the clinical usefulness of the allograft biopsy in renal transplant recipients receiving cyclosporine (CyA). METHODS: During a 21-month period, 82 biopsies were performed. In 54 instances (47 patients), we outlined a presumed diagnosis and tentative treatment plan before the procedure. After the biopsy, a definitive diagnosis was made and an appropriate patient management approach was instituted. We analyzed the incidence of change in patient management that resulted from histological findings. All patients were followed to monitor their response to treatment and allograft survival. In cases of biopsy-proven acute cellular rejection (ACR) or cyclosporine (CyA) toxicity, clinical and laboratory data from the day of the biopsy were reviewed to determine their diagnostic value. RESULTS: One biopsy specimen was inadequate for definitive interpretation. The biopsy findings resulted in a change in patient management in 22 (41.5%) of the remaining 53 cases (change group). The incidence of altered patient management was 38.7% in biopsy specimens taken in the first month, 55.6% between 1 and 12 months, and 38.5% after 1 year posttransplantation. A change in management was required in 2 of 2 patients with chronic allograft dysfunction, in 44.4% of the 45 patients with acute allograft dysfunction, and in none of the patients with delayed graft function (n=6). Within the first week of treatment 19 of 22 (86.4%) in the change group and 25 of 31 (80.6%) in the no change group had a positive response to therapy. The 1-year allograft survival rate was also similar between the two groups. None of the clinical and laboratory data was useful in distinguishing ACR from CyA toxicity. CONCLUSIONS: Renal allograft biopsy findings alter patient management recommendations in approximately 40% of patients in whom a presumptive diagnosis had been made on the basis of clinical and laboratory findings. Patients who had a change in patient management because of biopsy findings demonstrated a response to therapy and allograft survival similar to those of patients who had no alteration in management plan after the biopsy.

Adult↗
PubMed1999

Evolving trends in liver transplantation: an outcome and charge analysis.

BACKGROUND: Due to the limited supply and increased demand for donor livers, waiting times are progressively lengthening, which may lead to transplantation at more advanced and less cost-effective stages of disease. The purpose of this study was to evaluate the outcomes and hospital charges of liver transplantation during two recent eras to identify areas for providing more cost-effective care. METHODS: A total of 144 primary liver allografts were performed from 1991 to 1996. Patient characteristics, outcome measures, and hospital charges were compared for patients receiving allografts between 1991 and 1993 (group A) versus those receiving grafts between 1994 and 1996 (group B) using unpaired Student t tests for continuous data and chi-squared tests for categorical data. RESULTS: In comparing groups A and B, no significant differences in patient demographics, relative contraindications, or indication for transplantation existed; median waiting time from date of listing until transplant increased from 88 days to 159 days; and a shift in UNOS priority status at time of transplantation occurred, as the percentage of patients requiring inpatient care increased from 58% to 75% (P=0.034). Despite this, patient hospital and 1-year survival significantly improved from 75.0% to 90.3% (P=0.016), and from 68.1% to 88.9% (P=0.002), respectively. Total hospital charges, without correction for inflation, were $174,908+/-16,388 in A and $193,525+/-14,444 in B (P=0.288). The increased charges were associated with longer inpatient length of stay (LOS) before transplant, resulting in increased pretransplant charges from $24,088+/-4134 (A) to $39,490+/-6,196 (B) (P=0.011). Room and service (54%) was the largest pretransplant contributor to charges, while blood products (23%), room and service (21%), organ acquisition (13%), and operating room charges (11%) contributed the most after transplant. CONCLUSIONS: Longer waiting times resulting in transplantation at later stages of disease have occurred, leading to longer pretransplant LOS and its associated charges. Despite more advanced disease, patient survival rates have significantly improved with fewer infection-related deaths. LOS pretransplant, blood products, and operating room services represent potential areas for providing more cost-effective care.

Adolescent↗
PubMed1999

In vivo generation of C4d, Bb, iC3b, and SC5b-9 after OKT3 administration in kidney and lung transplant recipients.

BACKGROUND: OKT3 monoclonal antibody therapy results in an acute clinical syndrome (ACS) associated with the release of tumor necrosis factor and sequestration of neutrophils in the lungs. We have previously shown that inhibition of tumor necrosis factor does not completely eliminate OKT3-ACS, suggesting that other factors also contribute to the ACS. The current studies analyzed complement activation in vivo during the first hour after OKT3 administration. METHODS: Renal (n=4) and lung (n=4) transplant recipients received OKT3 as treatment for rejection and induction therapy, respectively. Complement activation products C4d, Bb, iC3b, and SC5b-9 were measured by ELISA. Hemodynamic parameters were also monitored in the lung transplant recipients. Neutrophil expression of CD11a, CD11b, and CD18 was monitored by flow cytometry. Controls included patients receiving methylprednisolone for rejection (n=4), two adults with adult respiratory distress syndrome who received extracorporeal membrane oxygenation, and normal volunteers (n=5). P values less than 0.05 (*) were considered significant. RESULTS: Increases in the plasma levels of C4d, Bb, iC3b, and SC5b-9 were observed in seven of eight patients after OKT3 administration. Mean values (n=8) at 0, 15, and 60 min (in microg/ml) were as follows-C4d: 1.865, 2.644*, and 2.607*; Bb: 0.245, 0.411, and 0.385; iC3b: 10.881, 17.242*, and 15.145*; and SC5b-9: 0.232, 0.269, and 0.302*. An increase in CD11b and CD18 and a decrease of CD11a on neutrophils in parallel with complement activation was observed. In lung transplant recipients, C3 activation correlated with increases in mean pulmonary and central venous pressures (P<0.05). As compared with extracorporeal membrane oxygenation, which activated classical and alternative pathways, OKT3 predominantly activated complement by the classical pathway. Methylprednisolone pulses did not activate complement. CONCLUSIONS: Complement activation is an early event after OKT3 administration and is associated with the increased expression of adhesion molecules on neutrophils and with pulmonary hemodynamic changes. Effective therapeutic approaches to the control of early monoclonal antibody side effects may require measures that limit complement activation in addition to reducing cytokine activity.

Adult↗
PubMed1999

A new allocation plan for renal transplantation.

BACKGROUND: A novel plan of renal allograft allocation has been conducted by United Network for Organ Sharing Region 1 transplant centers since September 3, 1996, based upon HLA matching, time waiting, and population distance points. The objectives of this plan were to achieve a balance between increasing the opportunity of renal transplantation for those patients listed with long waiting times and promoting local organ donor availability. METHODS: A single list of candidates was formulated for each cadaver donor, assigning a maximum of 8 points for time waiting, a maximum of 8 points for population distance from the donor hospital, and HLA points based upon the degree of B/DR mismatch. Additional points were awarded to a cross-match-negative patient with a panel-reactive antibody of >80%, and to pediatric patients. RESULTS: The total number of kidneys transplanted to patients who had waited >3 years was 100 (46%), and to patients who had waited >2.5-3 years was 29 (13%). However, the total number of kidneys transplanted to patients with the maximum population distance points was only 72 (33%). Thus, although the plan achieved a favorable distribution of kidneys to patients with longer waiting times (nearly 60%), the other, equally important objective of promoting local donor availability was not initially accomplished. Moreover, minor HLA B/DR differences between the donor and the recipient (i.e., not phenotypically matched) were unexpectedly consequential in determining allocation. As a result of these observations, the following adjustments were made in the plan (as of December 3, 1997): a maximum of 10 points for population distance, a maximum of 8 points for time waiting (both by a linear correlation), and the retention of HLA points for 0 B/DR mismatch only. After these interval changes, the percentage of patients receiving a kidney with some population distance points increased from 85% to 96%. Conclusions. We have shown that a heterogeneous region of multiple transplant centers can devise (and modify) an innovative and balanced plan that provides an equitable system of allocation for an ever-increasing number of patients.

Adolescent↗
PubMed1999

Renal thrombotic microangiopathy associated with anticardiolipin antibodies in hepatitis C-positive renal allograft recipients.

Hepatitis C virus (HCV) infection has been associated with de novo or recurrent membranoproliferative glomerulonephritis and acute transplant glomerulopathy in transplanted kidneys. Recently, anticardiolipin antibodies (ACA) have been linked with chronic HCV infection. A few reports have suggested an association between ACA and renal allograft thrombosis. This study examines the clinical and pathologic features of HCV-positive renal allograft recipients at our institution. From 1990 to 1996, 379 kidney transplants were performed. We identified 18 recipients (4.8%) with HCV-positive serology pretransplant. Determination of IgG and IgM ACA was performed by enzyme-linked immunosorbent assay, using pretransplant sera. Among the 18 patients, five patients presented with biopsy-proven de novo renal thrombotic microangiopathy (RTMA), occurring 5 to 120 d (median, 14 d) after transplant. No differences in pretransplant characteristics were observed between patients with (n = 5) or without (n = 13) RTMA. All five patients had a positive ACA test (either IgG or IgM titer > 2 SD above normal), compared with only one of 13 patients without RTMA. The mean value for IgG ACA was significantly higher in the RTMA patients than in patients without RTMA (22.9 +/- 14.1 versus 6.9 +/- 4.9 IgG phospholipid units, P = 0.02); however, there were no significant differences in IgM ACA titers. Rheumatoid factor and complement C4 levels were normal in pretransplant sera of patients with RTMA. Patients with RTMA had their cyclosporine withdrawn (four of five) or the dose was decreased (one of five), and one of five underwent plasmapheresis. Four of five patients died within 5 yr after transplant, compared with no deaths in the other 13 patients. Finally, as a control group, seven HCV-negative renal allograft recipients who presented with RTMA/hemolytic uremic syndrome during the same time period were found to have normal ACA values (IgG or IgM). RTMA associated with ACA in HCV-positive renal allograft recipients may represent a new clinical entity. The occurrence of this syndrome may have deleterious consequences for patient and graft survival.

Adult↗
PubMed1998

Plasma exchange and tacrolimus-mycophenolate rescue for acute humoral rejection in kidney transplantation.

BACKGROUND: Acute renal allograft rejection associated with the development of donor-specific alloantibody (acute humoral rejection, AHR) typically carries a poor prognosis. The best treatment of this condition remains undefined. METHODS: During a 14-month period, 73 renal transplants were performed. During the first postoperative month, five recipients (6.8%) with AHR were identified. The diagnosis was based on: (1) evidence of severe rejection, resistant to steroid and antilymphocyte therapy; (2) typical pathologic features; and (3) demonstration of donor-specific alloantibody (DSA) in recipient's serum at the time of rejection. Pretransplant donor-specific T- and B-cell cross-matches were negative. RESULTS: Plasma exchange (PE, four to seven treatments per patient) significantly decreased circulating DSA to almost pretransplant levels in four of five patients, and improvement in renal function occurred in all patients. One patient had recurrent renal dysfunction in the setting of an increase in circulating DSA. A second series of five PE treatments decreased DSA and reversed the rejection episode. Rescue therapy with tacrolimus (initial mean dose: 0.14+/-0.32 mg/kg/day) and mycophenolate mofetil (2 g/day) was used in five of five and four of five patients, respectively. With a mean follow-up of 19.6+/-5.6 months, patient and allograft survival are 100%. Renal function remains excellent with a mean current serum creatinine of 1.2+/-0.3 mg/dl. (range: 0.9-1.8 mg/dl). CONCLUSIONS: Our findings suggest that a therapeutic approach combining PE and tacrolimus-mycophenolate mofetil rescue has the potential to improve the outcome of AHR.

Acute Disease↗
PubMed1998

De novo collapsing glomerulopathy in renal allografts.

BACKGROUND: Collapsing glomerulopathy is a recently described form of glomerular injury characterized by capillary collapse and visceral epithelial hypercellularity associated with nephrotic range proteinuria and a rapid, progressive decline in renal function. The lesion has rarely been described in allografts. METHODS: We reviewed 892 allograft biopsies from a population of 1079 recipients who received renal transplants between 1978 and 1996. RESULTS: Five cases of de novo collapsing glomerulopathy were identified (0.6% of biopsies; 3.2% since 1993). None occurred before 1993. The patients were 31 to 66 years of age and they presented 6 to 25 months after transplantation. The 24-hr urinary protein ranged from 1.8 to 11.8 g. All patients and donors were negative for the human immunodeficiency virus and had no risk factors for human immunodeficiency virus infection. Diffuse or focal, global or segmental collapse of glomerular capillaries, swelling and hypercellularity of the visceral epithelium, hyaline arteriolosclerosis, and interstitial fibrosis were characteristic histologic features. Two cases had concomitant glomerular immune complex deposits. Progressive decline in allograft function occurred within 2-24 months after diagnosis, culminating in return to dialysis in all patients. CONCLUSION: Collapsing glomerulopathy can arise in renal allografts as a de novo disease. Although its pathogenesis remains to be clarified, it is important to distinguish this lesion in allografts as it can be associated with rapidly progressive graft failure.

Adult↗
PubMed1998

Humanized IgG1 and IgG4 anti-CD4 monoclonal antibodies: effects on lymphocytes in the blood, lymph nodes, and renal allografts in cynomolgus monkeys.

BACKGROUND: Optimizing therapeutic monoclonal antibody (mAb) depends on the incorporation of the necessary effector functions and the development of hypoantigenic "humanized" antibodies by genetic engineering, which then need to be tested in appropriate preclinical trials. METHODS: Constructs of humanized OKT4A containing the complementarity-determining region (CDR) of murine OKT4A and the framework and constant regions of human light (kappa) and heavy chains (IgG1 and IgG4) were prepared and tested in cynomolgus monkeys who received a renal allograft. A prophylactic course of CDR-OKT4A/human (h) IgG1 or CDR-OKT4A/ hIgG4, either as high-dose single bolus (10 mg/kg) or as low-dose multiple infusion (1 mg/kg for 12 days) was given, and the effects on graft survival, immunohistology, circulating cells, and lymph node cells were assessed. RESULTS: The IgG1 isotype induced coating of T cells, modulation of surface CD4 molecules, and profound depletion of CD4+ lymphocytes in peripheral blood, which persisted as long as the animals were followed (up to 7 weeks). The IgG4 isotype induced only cell coating without cell clearance or modulation. In lymph nodes, coating of lymphocytes (approximately 60%) was seen with both isotypes in the earliest sample (6 hr). After 2 days, significant depletion of lymph node CD4 cells was evident, with a decrease in the CD4 to CD8 ratio in the IgG1-treated group; no depletion occurred in the IgG4 group. The emigration of CD4+ cells into the allograft was significantly delayed in the CDR-OKT4A/hIgG1-treated animals when compared with the CDR-OKT4A/hIgG4 group as judged by immunocytochemistry (23.8+/-13.2 days vs. 7.4+/-1.5 days, P<0.001) or interleukin-2-promoted T-cell outgrowth from allograft biopsies (22.2+/-11.0 days vs. 6.3+/-0.5 days, P<0.01). CONCLUSIONS: This study demonstrates that the in vivo effects of CDR-grafted OKT4A are dependent on its isotype. The depleting mAb CDR-OKT4A/hIgG1 significantly delays the entry of CD4+ cells into the graft, inhibiting the early phase of rejection. However, graft rejection occurs when CD4+ cells eventually infiltrate the graft, even in the presence of depressed levels of circulating CD4+ cells. Both isotypes demonstrated therapeutic efficacy: graft survival was prolonged over controls. In the case of CDR-OKT4A/hIgG4, neither lymphocyte depletion, antigenic modulation, nor prevention of infiltration is necessary for a beneficial effect, which indicates that this mAb blocks CD4 function or renders the CD4+ cell less responsive. The lack of depletion is a feature of potential clinical advantage in minimizing the risk of excessive immunosuppression.

Animals↗
PubMed1998

Contribution of native kidney function to total glomerular filtration rate after combined kidney-pancreas transplantation.

BACKGROUND: Combined kidney-pancreas transplantation (CKPT) with its associated euglycemia has been shown to prevent or reduce recurrent diabetic nephropathy in the renal allograft. There has been no evaluation of residual native kidney function after CKPT. The purpose of this study was to determine whether native kidney function may be present in diabetic recipients years after CKPT. METHODS: Between 1986 and 1992, 37 patients with type 1 insulin-dependent diabetes mellitus with renal failure underwent CKPT. In each case, a single native nephrectomy was performed. We studied 16 patients who had continuing renal and pancreas function more than 4 years after CKPT. Fourteen diabetics with a functioning renal allograft but no pancreas function were used as a control group. Simultaneous renal scans (technetium-99m diethylenetriamine pentaacetic acid) of the native and transplanted kidneys were obtained with a dual-head scintillation camera. Total glomerular filtration rate (GFR) was determined from the rate of clearance of the tracer from the extracellular space measured for 2 hr with an ambulatory renal monitor. RESULTS: The study groups had similar pretransplant characteristics. At the time of the study, the mean serum creatinine level was not significantly different in the CKPT and control groups (1.7+/-0.7 vs. 1.5+/-0.3 mg/dl, respectively). In the CKPT and control groups, total GFRs were 70.1+/-33 vs. 72.1+/-16.5 ml/min (NS), allograft GFRs were 63+/-34.2 vs. 70.4+/-16 ml/min (NS), and native kidney GFRs were 7.1+/-7.2 vs. 1.7+/-1.9 ml/min (P < 0.05), respectively. In both groups, there was a significant correlation between total GFR and allograft GFR (P < 0.001), but not between total GFR and native kidney GFR. Significant single native kidney GFR (more than 8 ml/min) was found in 7/16 (44%) patients in the CKPT group, but in none of the controls. CONCLUSIONS: These results suggest that residual native kidney function can be present and contribute moderately to total GFR after CKPT. Euglycemia after CKPT may have a protective role in native kidneys.

Adult↗
PubMed1996

A multicenter trial of FK506 (tacrolimus) therapy in refractory acute renal allograft rejection. A report of the Tacrolimus Kidney Transplantation Rescue Study Group.

A multicenter trial was conducted to evaluate the efficacy and safety of tacrolimus in the treatment of refractory renal allograft rejection. Renal transplant recipients experiencing biopsy-proven recurrent acute allograft rejection were eligible if the current rejection episode was refractory to corticosteroids. A total of 73 patients were enrolled, of whom 59 (81%) had previously received at least one course of antilymphocyte antibody as rejection therapy. One-year follow-up was available in 93% of patients. Median time to tacrolimus rescue therapy was 75 days after transplantation (range, 18-1448 days). Therapeutic responses to tacrolimus included improvement in 78% of patients, stabilization in 11%, and progressive deterioration in 11%. The risk of experiencing progressive deterioration was related to the pretacrolimus serum creatinine level: serum creatinine < or = mg/dl, 3%; 3.1-5 mg/dl, 16% (P < 0.04); > 5 mg/dl, 23% (P < 0.02). Twelve-month (from the time of initiation of tacrolimus therapy) actuarial patient and graft survival rates were 93% and 75%. Graft loss occurred in 19 patients (25%) at a median time of 108 days. Fourteen episodes of recurrent rejection were diagnosed in 10 patients (14%), at a median time of 101 days. Eleven episodes of recurrent rejection were treated (three patients underwent transplant nephrectomy), with resolution achieved in nine patients. Antilymphocyte antibody therapy was not used to treat recurrent rejection. Serum creatinine values improved during tacrolimus therapy: median serum creatinine level before tacrolimus, 3.2 mg/dl; median at 1 year after tacrolimus, 1.8 mg/dl. Twelve infections were documented in 11 patients (15%), including cytomegalovirus infection in three patients (4%). Posttransplant lymphoproliferative disorder was diagnosed in a single patient. Tacrolimus whole blood levels averaged 15.0 +/- 9.9 ng/ml at day 7 of tacrolimus therapy and 9.4 +/- 5.1 ng/ml at 1 year, and were consistent among individual centers. Treatment outcome did not correlate with tacrolimus blood levels. The most commonly observed adverse events were neurological and gastrointestinal. Seventy-four percent of patients received tacrolimus for at least 1 year. Tacrolimus therapy was discontinued in 18% of patients for rejection (11% for progressive, unrelenting rejection, and 7% for recurrent rejection). Tacrolimus therapy was discontinued in 8% of patients due to adverse events. In conclusion, tacrolimus rescue therapy provides (1) prompt, effective reversal of refractory renal allograft rejection, (2) good long-term renal allograft function, (3) a low incidence of recurrent rejection, and (4) an acceptable safety profile in renal allograft recipients experiencing refractory rejection.

Acute Disease↗
PubMed1996

Selective use of veno-venous bypass in orthotopic liver transplantation.

The use of veno-venous bypass (VVB) during the anhepatic phase of orthotopic liver transplantation (OLT) remains controversial. We employ VVB on a selective basis: patients who tolerate intra-operative supra-hepatic IVC test cross-clamping undergo OLT without VVB while patients who, despite maximal volume resuscitation, develop hemodynamic instability during test cross-clamping, undergo OLT with VVB. The records of 150 adult orthotopic liver allograft recipients transplanted at the Massachusetts General Hospital from January 1984 to December 1994 were reviewed to identify any potential adverse affects on peri-operative, 6 months, 1 year outcomes in recipients foregoing VVB during liver transplantation. Thirty-eight patients (25%) underwent OLT without VVB with actuarial survivals of 78.4% and 69% at 6 months and 1 year. 112 patients (75%) underwent OLT with VVB with actuarial survivals at 6 months and 1 year of 73% and 72%. Demographic data, UNOS status, and diagnoses were similar in each group. There were no significant differences in intra-operative PRBC requirements; lengths of hospital stay; retransplantation rates; or 30 day, 6 months and 1 year survivals between these two groups. There was no significant difference in renal function as determined by preoperative, peak post-operative, discharge serum creatinine levels, or number of patients requiring HD between these two groups. There were two major complications (1.8%) possibly resulting from VVB. In conclusion, patients who tolerate IVC test cross-clamping can safely undergo orthotopic liver transplantation without veno-venous bypass. In our experience, there were no significant differences in peri-operative parameters, post-operative renal function, or short-term survival when compared to patients who, due to hemodynamic instability during IVC cross-clamping, underwent OLT with VVB. Given the potential complications associated with VVB, we feel that in those patients who tolerate intra-operative IVC cross-clamping, it is better to proceed without the use of VVB.

Actuarial Analysis↗
PubMed1996

Anti-CD4 monoclonal antibody therapy.

Because they can be selected to target only cells which are crucial for rejection, monoclonal antibodies (mAbs) offer enormous potential for specific manipulation of the immune response. Interest in the clinical potential of anti-CD4 mAbs has been heightened by the demonstration, in experimental models, that such therapy can produce long-term donor-specific non-responsiveness. Early clinical trials using two murine anti-CD4 mAbs (BL4 and mT-151) were discouraging, with over 50% of recipients suffering early rejection episodes. Another murine preparation, OKT4A, was initially found to prolong allograft survival in non-human primates. Limited clinical trials revealed that this mAb was well tolerated, that most recipients produced an antimurine response, and that only 26% of patients suffered rejection episodes during the first 3 post-operative months. Another murine preparation, Max. 16H5, has been reported to reverse late onset acute rejection episodes as effectively as, but more safely than, conventional immunosuppression. More recent interest has focused upon humanized recombinants of these earlier murine anti-CD4 preparations. cMT-412, has been studied in recipients of heart or heart-lung allografts. These patients were observed to have less frequent and markedly delayed rejection episodes, fewer infectious complications, and better overall survival than that observed in an ATG-treated control group. Further studies are thus being undertaken. A CDR grafted IgG4 preparation of OKT4A has also been studied. This molecule (OKTcdr4a) contains only 8% of the parent murine sequence while retaining the binding affinity of OKT4A for the human CD4 antigen. In a pilot trial, biopsy-proven reversible rejection episodes were observed in 2/11 (18%) of renal allograft recipients. There were no allograft failures and no antibody response to the mAb. These and other trials emphasize the intense interest in immunosuppressive regimens incorporating anti-CD4 mAbs as well as the difficulties encountered in defining optimal protocols. Nevertheless, the impressive results observed in rodent and non-human primate models suggest that these agents are likely to play an important role in future immunosuppressive protocols, particularly those designed to induce tolerance.

Animals↗
PubMed1994

CDR-grafted OKT4A monoclonal antibody in cynomolgus renal allograft recipients.

In an attempt to improve therapeutic efficacy and limit antimurine responses to the IgG2a monoclonal antibody OKT4A, humanized complementarity determining region (CDR)-grafted OKT4A mAbs (IgG1 and IgG4 isotypes) were developed from the murine molecule. Preclinical evaluation was undertaken in 12 cynomolgus renal allograft recipients (IgG1, n = 7; IgG4, n = 5). Control animals received either no therapy (n = 2) or OKT3 (n = 2). The mAbs were given as a single 10-mg/kg bolus on the day of transplantation or as multiple 1-mg/kg doses. Mean allograft survival (+/- SEM) was 9 +/- 0.7 days in control animals; 45.2 +/- 6.0 days, P = 0.002 (single dose, n = 5), and 39 +/- 5.0 days, P = 0.053, (multiple doses, n = 2) in IgG1-treated animals; and 35.3 +/- 7.2 days, P = 0.034, (single dose, n = 3) and 15.5 +/- 6.5 days, P = .251 (multiple doses, n = 2) in IgG4-treated animals. Whereas IgG4-treated animals showed coating of peripheral blood CD4+ T cells, significant CD4+ T cell depletion was observed in IgG1-treated animals. These results confirm the retained immunosuppressive efficacy of humanized OKT4A antibodies. In contrast to murine mAbs, the use of these agents would not preclude sequential treatment with mAbs directed against different epitopes. The fact that rejection can occur despite peripheral blood CD4+ cell depletion suggests that indefinite control of allograft rejection in primates may require more intensive therapy than has proved effective in rodent models.

Animals↗