Combined liver-kidney transplantation in patients with cirrhosis and renal failure: effect of a positive cross-match and benefits of combined transplantation.

Patients with renal failure after liver transplantation have a particularly poor prognosis. Therefore, in the setting of end-stage renal disease requiring dialysis or severe renal insufficiency that will not improve after liver replacement, combined liver-kidney transplantation (LKT) is the preferred approach. We have adopted a policy of LKT in patients with end-stage liver disease and renal insufficiency undergoing dialysis or with a creatinine clearance less than 35 mL/min and evidence of chronic renal dysfunction. Since 1991, we have performed 208 orthotopic liver transplantations. Fourteen patients (8%) have undergone combined LKT, including 6 patients undergoing hemodialysis. Cytotoxic cross-matches (modified Amos technique and antihuman globulin method) were performed on 13 of 14 patients and were positive in 3 patients. Two patients died less than 4 months after LKT and 12 patients are alive and well. Graft survival censored for patient death was 100% for liver allografts and 93% for renal allografts, with a mean follow-up of 39 +/- 24 months. The most recent serum creatinine level in the patients with the 11 functioning grafts was 1.1 +/- 0.6 mg/dL. Biopsy-proven acute rejection occurred in 50% of simultaneous liver allografts. By contrast, only a single episode (6%) of renal allograft dysfunction was attributable to acute rejection. All rejection episodes occurred in the first 90 days after transplantation and were steroid sensitive. Three of 14 combined procedures were performed in the setting of a positive cytotoxic cross-match. In 2 recent patients, the results were confirmed by positive cross-matches to the donor's T and B cells by flow cytometry. Flow cytometric cross-matches reverted to negative 1 hour after liver transplantation and several hours before the administration of antithymocyte globulin. The cross-matches remained negative on postoperative days 1 and 7. Presently, all 3 patients with a positive cross-match enjoy normal hepatic and renal function at 631, 706, and 2275 days follow-up. Renal scans were performed in 4 LKT recipients not previously undergoing hemodialysis and indicated varying and unpredictable degrees of function in the native and transplanted kidneys. In conclusion, combined LKT can be performed safely and is associated with a low rate of acute rejection, even in the setting of a positive cross-match. Predicting which patients with renal insufficiency will benefit from LKT remains challenging; however, these results suggest that LKT should be encouraged in patients with evidence of irreversible renal insufficiency who require liver transplantation.

Two hundred one consecutive living-donor nephrectomies.

OBJECTIVE: To assess donor morbidity, recipient outcome, and changing trends during the past decade in donor nephrectomy for living-donor kidney transplantation. DESIGN AND SETTING: Retrospective review at an academic tertiary care referral center. PATIENTS: We reviewed 201 consecutive living-donor kidney transplantations performed between January 1988 and June 1997. INTERVENTION: Donor nephrectomy and living-donor kidney transplantation. MAIN OUTCOME MEASURES: Donor surgical complications, correlation of preoperative imaging of donor vascular anatomy and operative findings, and donor lengths of stay in the hospital were analyzed. Recipient delayed graft function and actuarial 1- and 5-year patient and graft survival rates were also analyzed. RESULTS: Major donor postoperative complications were bleeding (0.5%), pneumothorax requiring a chest tube (1%), wound infection (1%), and pneumonia (1%). Minor postoperative complications were asymptomatic pneumothorax resolving spontaneously (10%), urinary retention (6%), and urinary tract infection (0.5%). Preoperative imaging failed to detect small accessory renal arteries in 12% of donors. The mean donor length of stay in the hospital was 5.0 days but decreased from 6.2 to 4.0 days during the study. Twenty donors (10%) were unrelated (ie, spouse or friend). Three (1.5%) cases of delayed graft function occurred. Overall recipient patient survival at 1 and 5 years was 97% and 90%, and graft survival was 95% and 83%, with no difference between related and unrelated living donors. CONCLUSIONS: Living-donor nephrectomy is associated with low surgical morbidity. Recent trends include shortened lengths of stay in the hospital, the use of computed tomographic angiography instead of digital subtraction angiography for preoperative imaging of donor vascular anatomy, and an expanded use of unrelated living donors.

Peripheral vascular disease after kidney-pancreas transplantation in diabetic patients with end-stage renal disease.

OBJECTIVE: To determine the long-term effect of a functioning pancreas transplant on peripheral vasculopathy. DESIGN: We compared the progression of peripheral vascular disease in 39 recipients of successful kidney-pancreas transplants (KPT) with 65 consecutive diabetic patients who received cadaver kidney transplants alone (KTA) during the same period in a nonrandomized, retrospective control study. The mean duration of follow-up was more than 4 years in both groups. SETTING: Academic subspecialty referral practice. PATIENTS: A consecutive sample of all KPT recipients with more than 6 months of pancreas allograft function performed between May 1, 1988, and April 30, 1995. All patients who received cadaver renal transplants for diabetic nephropathy during the same period and who maintained a functioning renal allograft for more than 6 months were included as controls. INTERVENTION: Kidney-pancreas transplantation. MAIN OUTCOME MEASURE: Progression of peripheral vascular complications (PVC) defined as any midfoot or limb amputation (AMP), any ischemic ulceration requiring treatment (ULCER), and lower-extremity bypass surgery or angioplasty (LEBP). Ulcers leading to amputation were considered as single events (AMP only). RESULTS: Thirty-five (90%) of 39 KPT recipients are insulin-free. The KTA recipients had more atherosclerotic risk factors, including a higher incidence of coronary artery disease (P = .008), higher serum cholesterol levels (P = .03), and higher triglyceride levels (P = .04) than KPT recipients. Peripheral vascular complications before transplantation were comparable (P = .94) between groups. After transplantation, there were 35 new PVC (9 AMP, 11 ulcers, and 15 LEBP) in 18 of 39 KPT recipients vs 32 PVC (10 AMP, 8 ulcers, and 14 LEBP) in 20 of 65 KTA recipients (P = .005), indicating that KPT recipients had more PVC than did KTA recipients, despite a functioning pancreas. Seven bypass grafts failed after KPT, resulting in 6 limb amputations. In contrast, only 3 limb amputations were performed in 14 patients undergoing lower-extremity bypass procedures after KTA. CONCLUSIONS: Despite fewer risk factors for peripheral vasculopathy and the presence of insulin independence, KPT recipients had a higher incidence of PVC than a cohort of uremic diabetic patients undergoing KTA during the same period. These data show that a functioning pancreas allograft performed with a renal transplantation not only does not alter the progression of peripheral vascular disease in patients with renal failure secondary to diabetic nephropathy but also may accelerate PVC.

Correlation of clinical outcomes after tacrolimus conversion for resistant kidney rejection or cyclosporine toxicity with pathologic staging by the Banff criteria.

BACKGROUND: Refractory rejection and cyclosporine (CsA)-induced nephropathy remain important causes of renal allograft loss. Previous studies demonstrated that 70-85% of the episodes of refractory acute rejection (AR) occurring in renal allograft recipients on a CsA-based immunosuppressive regimen could be salvaged by conversion to tacrolimus. No data are available regarding the correlation between allograft histology at the time of conversion and the response to tacrolimus. We examined the response to tacrolimus conversion in relation to preconversion biopsies stratified by the Banff criteria. METHODS: Since May 1992, we have converted 22 patients from CsA to tacrolimus as part of a rescue protocol. We report on 18 patients in whom 6-month follow-up was available after conversion for biopsy-proven AR (n=13) or CsA toxicity (n=5). Sixteen patients were recipients of renal allografts, including three second transplants, and two were recipients of kidney-pancreas transplants. All patients with AR were treated with one or more courses of methylprednisolone and OKT3 before conversion. Renal allograft biopsies were interpreted by a transplant pathologist blinded to the clinical history, and graded according to the Banff criteria. Responses to tacrolimus were scored as improved (creatinine returned to within 150% of baseline), stabilized (creatinine rise arrested), or failed (returned to dialysis). RESULTS; Mean follow-up was 17.3+/-8 months. Fourteen of 18 patients (78%) showed improvement or stabilization in renal function as assessed by creatinine at 6 months or 1 year (when available). Of the 13 patients with histological AR, nine (69%) improved, including five of six with borderline AR, two of three with grade I AR, and two of four with grade II AR. Of the four other patients with AR, two stabilized and two failed. Three of five patients with severe clinical rejection requiring dialysis (range 2-16 weeks) recovered renal function after conversion. Of five patients with CsA toxicity, two (40%) improved. Seven of eight patients who were converted to tacrolimus less than 90 days after transplantation improved, compared with only 4 of 10 who were converted more than 90 days after transplantation. No grafts were lost in patients with a creatinine <3.0 mg/dl at the time of conversion versus two of seven grafts lost when the creatinine was 3.1-5.0 mg/dl and two of eight grafts lost when the creatinine was >5.0 mg/dl. CONCLUSION: The majority of steroid and antilymphocyte antibody (OKT3 or ATGAM) unresponsive rejections in patients on CsA-based immunosuppression will improve or stabilize after conversion to tacrolimus. There was no correlation with allograft histology stratified by the Banff criteria and the response to tacrolimus. Although there was a trend toward a poorer response with more severe histological rejection, higher serum creatinine at the time of conversion, and longer time from transplantation to conversion, favorable responses were noted in all groups. This indicates that a trial of conversion is warranted, irrespective of the histological severity of injury.

A single-center experience with six-antigen-matched kidney transplants.

OBJECTIVES: To review our center's experience with the United Network of Organ Sharing six-antigen-matched (6-AgM) kidney program. Specifically, to determine whether recipients of 6-AgM cadaver kidney transplants have less perioperative and short-term (< 1 year) morbidity in comparison with living-related donor (LRD) recipients and a control group of immunologically less well-matched cadaver recipients. DESIGN: A retrospective review of all solitary kidney transplantations performed over a 24-month period, from 1992 to 1993. SETTING: A large urban tertiary care referral center with a long history of renal and extrarenal transplantation. PATIENTS: Adult patients receiving a solitary kidney transplant from either a cadaver or a living donor. MAIN OUTCOME MEASURES: Mortality, morbidity, and patient and graft survival. Other variables measured included rejection episodes, length of stay, readmissions, postoperative complications, waiting time, and delayed postoperative graft function. RESULTS: Recipients of 6-AgM kidney transplants were at higher risk than the control groups of cadaver and LRD recipients, with more retransplantations, higher sensitization, and more with diabetes. There were fewer rejection episodes in the 6-AgM group, and these were more steroid responsive. They had fewer hospital days (22.6 days) in the first year following transplantation, compared with the remaining cadaver group (28 days). The delayed postoperative graft function rate was also significantly lower than that of the cadaver control group. Graft and patient survival were excellent for all groups. Analysis of these factors showed similar results when comparing the LRD and 6-AgM groups and a marked improvement over the cadaver control group. CONCLUSIONS: Identical HLA matching for cadaver recipients provides superior results for graft and patient survival. There is much less perioperative morbidity in comparison with the less well-matched cadaver recipients. The effect of HLA matching is reflected in the perioperative courses of these patients, in addition to the long-term benefits of graft survival. Allograft survival is superior for this select group of cadaver recipients. The 6-AgM recipients behave similarly to LRD recipients in this cohort of patients. Our results would support the continued sharing of 6-AgM kidneys to optimize outcome and best use the limited resources available to the patients undergoing transplantation.

Kidney transplantation in diabetic patients using cyclosporine. Five-year follow-up.

OBJECTIVE: To review our center's experience with kidney transplantation in diabetic recipients; specifically, to compare long-term (5-year) patient and graft survival rates between diabetic and nondiabetic recipients overall and according to donor source using cyclosporine-based immunosuppression. DESIGN: A retrospective review of all kidney transplants performed over the 7-year period from 1987 to 1993. SETTING: A large urban tertiary care referral center with a long history of kidney transplantation and care of the diabetic patient. PATIENTS: All patients receiving a kidney transplant, either alone or simultaneously with a pancreas transplant, were reviewed. MAIN OUTCOME MEASURES: Actuarial patient and graft survival, serum creatinine levels, and causes of late graft loss. RESULTS: There was no significant difference in actuarial 5-year patient or kidney graft survival between diabetic and nondiabetic recipients overall or when analyzed by donor source. There was no significant difference in mean serum creatinine levels at 5 years between diabetic and nondiabetic recipients overall or between diabetic and nondiabetic cadaveric recipients. While chronic rejection was the major cause of late graft loss in nondiabetic recipients, death with a functioning graft, principally due to cardiovascular disease, was the major cause of graft loss in diabetic recipients. CONCLUSIONS: With cyclosporine-based immunosuppression, diabetic kidney transplant recipients have 5-year patient and graft survival rates and allograft function comparable to nondiabetic recipients. Given the high mortality of diabetic patients receiving dialysis, kidney transplantation is the treatment of choice for end-stage diabetic renal disease.

Combined kidney and pancreas transplantation. A 3-year experience.

Between May 1988 and September 1991, we performed 26 simultaneous kidney and pancreas transplants and one pancreas transplant after a kidney transplant. All transplants consisted of bladder drainage via a duodenal segment. Actuarial patient, kidney, and pancreas graft survival rates at 12 months were 96%, 88%, and 85%, respectively, and at 24 months were 96%, 88%, and 81%, respectively, and were not significantly different from those of diabetic recipients of cadaver kidney transplants alone. Excellent long-term glycemic control was obtained as monitored by fasting blood glucose and glycosylated hemoglobin levels and by oral glucose tolerance tests. The mean period of hospitalization and number of hospital admissions in the first year posttransplant were significantly greater for patients who received combined kidney and pancreas transplants than for those who received cadaver kidney transplants alone. Combined kidney and pancreas transplants can be performed with patient and graft survival comparable to those of kidney transplants alone, with excellent long-term glycemic control, but result in increased morbidity in the first postoperative year.

Bioavailability and patient acceptance of cyclosporine soft gelatin capsules in renal allograft recipients.

OBJECTIVE: To evaluate the relative bioavailability and patient acceptance of cyclosporine (CSA) soft gelatin capsule versus oral solution in renal allograft recipients. DESIGN, SETTING, AND PATIENTS: The bioavailability of CSA capsules was compared with that of CSA solution with crossover study design in the outpatient clinic setting. Nine renal allograft recipients with stable renal function participated in this study. METHODS: CSA dose was switched from solution to capsule in each patient for seven days. At steady-state, nine blood samples were obtained over a 12-hour period from each patient on day 7 for CSA solution and on day 14 for CSA capsules. CSA blood samples were analyzed by HPLC and fluorescence polarization immunoassay (FPIA) methods. Time to peak concentration (Tmax), peak concentration (Cmax), and area under the curve (AUC) were calculated on days 7 and 14, and compared using the matched Student's t-test. Patient acceptance was evaluated by patient preference on the questionnaire. RESULTS: For CSA blood concentrations measured by HPLC assay, the Tmax, Cmax, and AUC were 3.4 +/- 1.3 h, 569 +/- 240 nmol/L, and 4659 +/- 2144 h.nmol/L (mean +/- SD), respectively, with solution and 4.2 +/- 2.1 h, 560 +/- 257 nmol/L, and 4765 +/- 1799 h.nmol/L (mean +/- SD), respectively, with capsules. These differences were not significant (p greater than 0.1). The bioavailability was not significantly different between capsules and solutions when it was measured by PFIA assay (p greater than 0.1). The mean (+/- SD) relative bioavailability of capsules compared with solution was 109 +/- 29 percent AUC (0-12 h) measured by HPLC and 111 +/- 27 percent AUC (0-12 h) measured by FPIA. All patients expressed preference for capsules over the solution. CONCLUSIONS: CSA oral soft gelatin capsule is bioequivalent to CSA oral solution and most patients preferred the capsule to the oral solution.

Use of Dacron cuffed silicone catheters as long-term hemodialysis access.

Sixty-five Dacron cuffed, dual lumen, silicone central venous dialysis catheters (Quinton PermCath, Seattle, WA) were inserted in 51 patients as the sole form of permanent access for chronic hemodialysis. Six and 12 month actuarial survival rates of patients for all catheters were 53% and 35%, respectively. When calculations included revisions, 6 and 12 month actuarial catheter survival rates were 61% and 43%, respectively. The major limiting factors in survival using long-term catheters remain infection and thrombosis. Dacron cuffed, dual lumen, central venous, dialysis catheters can provide long-term vascular access for hemodialysis in high risk patients.

Immunologic heterogeneity among potential transplant recipients. Prospects for predicting immune responses to allografts with in vitro tests.

The ability to accurately predict the response of a specific patient to a specific organ allograft has long been a goal of organ transplantation. The role of histocompatibility antigens in determining the acceptance or rejection of an allograft-recipient combination has been thoroughly investigated, but is being reevaluated as improved immunosuppressive agents become available. Early efforts at immunologic monitoring are reviewed in addition to more recent efforts that focus on the cellular and molecular mediators of immunity. The authors' own experience with lymphokine measurements in clinical transplantation is also reviewed, with emphasis on the role of interleukin-2 (IL-2) and its soluble receptor (IL-2R) in various transplant-associated conditions. The authors conclude that information useful in the management of transplant patients may be derived from serial measurements of IL-2 and IL-2R, but that infections, especially CMV, may not be ruled out with certainty by these measurements alone. The available data suggest that study of additional lymphokines such as interferon-gamma (IFN-gamma) and tumor necrosis factor (TNF) may be useful in discriminating rejection from infections in transplant patients.

Sequential interleukin 2 and interleukin 2 receptor levels distinguish rejection from cyclosporine toxicity in liver allograft recipients.

Previous studies of renal transplant recipients have demonstrated that allograft rejection is accompanied by an increase in plasma and urinary levels of interleukin 2 and its soluble receptor before the development of clinical symptoms. After measuring interleukin 2 and interleukin 2 receptor levels in the plasma, bile, and urine of liver transplant recipients, we found that rejection is preceded by elevation of plasma and biliary levels of both substances, that cyclosporine toxicity did not affect either of these levels, and that urinary levels of the substances are unaffected in either condition. Levels of interleukin 2 and interleukin 2 receptors increased in bile earlier than in plasma, and interleukin 2 levels did not overlap among stable patients and those experiencing rejection, whereas levels of interleukin 2 receptors did. Serial measurements of interleukin 2 levels, particularly in the product of the transplanted organ, provide a reliable assessment of the immunologic status of the allograft.