C. Troppmann

Delayed Graft Function, Acute Rejection, And Outcome After Cadaver Renal Transplantation: A Multivariate Analysis

The impact of delayed graft function on outcome after cadaver renal transplantation has been controversial, but most authors fail to control their analyses for the presence or absence of rejection. We studied 457 adult recipients of primary cadaver allografts at a single institution during the cyclosporine era. All patients received sequential immunosuppression. The incidence of delayed graft function (defined as dialysis being required during the first week after transplant) was 23%. There was a significant association between delayed graft function and cold ischemia time > 24 hr (P = 0.0001) and between delayed graft function and the occurrence of at least one biopsy-proven rejection episode (P = 0.004). Actuarial graft survival was not significantly different when comparing delayed graft function versus no delayed graft function for patients without rejection (P = 0.02). However, it was significantly worse for patients with both delayed graft function and rejection versus those with delayed graft function but no rejection (P = 0.005), as well as for grafts preserved > 24 hr versus < or = 24 hr (P = 0.007). By multivariate analysis, delayed graft function per se was not a significant risk factor for decreased graft survival for patients without rejection (P = 0.42). In contrast, rejection significantly decreased graft survival for grafts with immediate function (relative risk = 2.3, P = 0.0002), particularly in combination with delayed graft function (relative risk = 4.2, P < 0.0001). While cold ischemia time > 24 hr was also a significant risk factor (relative risk = 1.9, P = 0.02), other variables (preservation mode, 0 HLA Ag mismatch, age at transplantation, gender, diabetic status, and panel-reactive antibody at transplantation) had no impact on graft survival. Patient survival was significantly affected by the combination of delayed graft function and rejection (relative risk = 3.1, P < 0.0001), age at transplantation > 50 years (relative risk = 2.6, P < 0.0001), and diabetes (relative risk = 1.8, P = 0.006). Further studies are necessary to elucidate the mechanisms linking delayed graft function and rejection, which, in combination, lead to poor allograft outcome.

Surgical complications requiring early relaparotomy after pancreas transplantation: a multivariate risk factor and economic impact analysis of the cyclosporine era.

OBJECTIVES To study significant surgical complications requiring early (< or = 3 months posttransplant) relaparotomy (relap) after pancreas transplants, and to develop clinically relevant surgical and peritransplant decision-making guidelines for preventing and managing such complications. SUMMARY BACKGROUND DATA Pancreas grafts are still associated with the highest surgical complication rate of all routinely transplanted solid organs. However, the impact of surgical complications on morbidity, hospital costs, and graft and patient survival rates has not been analyzed in detail to date. METHODS We retrospectively studied surgical complications requiring relap in 441 consecutive cadaver, bladder-drained pancreas transplants (54% simultaneous pancreas and kidney [SPK]; 22% pancreas after kidney [PAK]; 24% pancreas transplant alone [PTA]; 37% retransplant). Outcome and hospital charges were analyzed separately for recipients with versus without reoperation. RESULTS The overall relap rate was 32% (SPK, 36%; PAK, 25%; PTA, 16%; p = 0.04). The most common causes were intraabdominal infection and graft pancreatitis (38%), pancreas graft thrombosis (27%), and anastomotic leak (15%). Perioperative relap mortality was 9%; transplant pancreatectomy was necessary in 57% of all recipients with one or more relaps. The pancreas graft was lost in 80% of recipients with versus 41% without relap (p < 0.0001). Patient survival rates were significantly lower (p < 0.05) for recipients with versus without relap. By multivariate analysis, significant risk factors for graft loss included older donor age (SPK, PAK), retransplant (PAK), relap for infection (SPK, PAK), and relap for leak or bleeding (PAK). For death, risk factors included older recipient age (SPK, PAK),retransplant (SPK, PAK), relap for thrombosis (PAK), relap for infection or leak (SPK), and relap for bleeding (PTA). CONCLUSIONS Posttransplant surgical complications requiring relap were frequent, resulted in a high rate of pancreas (SPK, PAK, PTA) and kidney (SPK, PAK) graft loss, and had a major economic impact (p = 0.0001). Complications were associated with substantial perioperative mortality and decreased patient survival rates. The focus must therefore shift from graft salvage to preservation of the recipients life once a pancreas graft-related complication requiring relap occurs. Thus, the threshold for pancreatectomy should be low. In this context, acceptance of older donors and recipients must be reconsidered.

Delayed graft function in the absence of rejection has no long-term impact. A study of cadaver kidney recipients with good function at 1 year after transplantation

We previously reported that delayed graft function (DGF) in the absence of biopsy-proven acute rejection (Rej) had no effect on outcome of primary cadaver kidney transplantation (TX). By contrast, DGF in combination with Rej strongly predicted poor long-term graft survival. We asked whether this poor long-term outcome was due to early graft loss associated with DGF, or to an ongoing process leading to late graft loss. To answer this question, we studied a subset of 298 cadaver kidney transplant recipients who had not suffered early graft loss and had a serum creatinine level < or = 2.0 mg/dl at 1 year after TX. The incidence of DGF (defined by dialysis during the first week after TX) in this subset was 19%. DGF was associated with cold ischemia time >24 hr (P = 0.0003) and Rej (P = 0.06). For grafts with versus without DGF, the incidence of late acute Rej (>1 year after TX) was similar. Actuarial graft survival was similar for Rej-free recipients with versus without DGF (P = 0.9) and was worse for those with Rej and no DGF (P < 0.02). Importantly, however, in our recipients who all had a serum creatinine level < or = 2.0 mg/dl at 1 year after TX, the worst long-term outcome was noted in the subgroup with both DGF and Rej (P < 0.0001). By multivariate analysis, DGF was also only a risk factor in combination with Rej (P = 0.002, relative risk = 3.7), while a 0-antigen HLA mismatch had no impact. Patient survival decreased for recipients with both DGF and Rej by univariate (P = 0.009) and multivariate (P = 0.02, relative risk = 2.9) analyses. We conclude that DGF without Rej has no impact on long-term survival. However, our data for recipients with both DGF and Rej suggest that a chronic ongoing process leads to late graft failure. Further research is necessary to identify the exact pathophysiology of this process, which appears to be, at least in part, HLA antigen independent.

The surgical risk of pancreas transplantation in the cyclosporine era: an overview

BACKGROUND Pancreas transplants are still associated with the highest surgical complication rate of all routinely performed solid organ transplants. To date, the impact of serious surgical complications in the cyclosporine era on perioperative patient morbidity, graft and patient survival, and hospital costs has not been analyzed in detail. STUDY DESIGN We retrospectively studied surgical complications after 445 consecutive pancreas transplants (45% simultaneous pancreas-kidney [SPK], 24% pancreas after kidney [PAK], and 31% pancreas transplant alone [PTA]). Of these, 80% were primary transplants, 20% were retransplants. Cadaver donors were used in 92%, living related donors in 8%. To develop guidelines for their prevention and management, we studied the impact of significant surgical complications (intra-abdominal infections, vascular graft thrombosis, and anastomotic leak) requiring relaparotomy on graft and patient survival. RESULTS Relaparotomy was required after 32% of all pancreas transplants (SPK: 36%, PAK: 25%, PTA: 16% [p = 0.04]). Perioperative mortality was 9%. Graft and patient survival rates were significantly lower for recipients with (versus without) relaparotomy. The most common procedures were drainage of intra-abdominal abscess with graft necrosectomy (50% of all relaparotomies) and transplant pancreatectomy (34%). The most common causes of relaparotomy were intra-abdominal infection, vascular graft thrombosis, and anastomotic leak. Intra-abdominal infection occurred in 20% (SPK: 18%, PAK: 24%, PTA: 20% [p = NS]). The rate was significantly higher for living related donor (42%) versus cadaver donor (18%) recipients and for those with enteric-drained (39%) versus bladder-drained (18%) transplants. Graft and patient survival rates were significantly lower for recipients with (versus without) intra-abdominal infection. Outcome was better after bacterial (versus fungal) infections. For SPK recipients, those not on dialysis before the transplant had significantly higher graft survival than those on dialysis. Vascular graft thrombosis occurred in 12% of all recipients. The rate was significantly higher for PAK (21%) than for PTA (10%) and SPK (9%) recipients. It was significantly lower for recipients of grafts with donor iliac Y-graft reconstruction (versus all other types of arterial reconstruction) and with right-sided (versus left-sided) graft placement. Of note, patient survival was not different for recipients with versus without vascular graft thrombosis. The incidence of anastomotic or duodenal stump leaks was 10%; of these recipients, 70% required relaparotomy. Patient and graft survival rates were no different for recipients with versus without leaks. CONCLUSIONS Serious surgical complications occurred in 35% of pancreas recipients and had a significant impact on patient and graft survival. Based on multivariate risk factor analyses, we recommend the following: donors over 45 years and those dying of cerebrocardiovascular disease should not be used; recipients over 45 years and those with a history of cardiac disease should be considered for a kidney transplant alone (KTA); surgical technique for graft procurement, preparation, and implantation should be meticulous; right-sided implantation and arterial Y-graft reconstruction should be performed when possible, since they had the highest success rates; when complications require relaparotomy, the focus must switch from graft salvage to life preservation; and the threshold for pancreatectomy should be low. Diagnosis should be timely, and treatment and relaparotomy expeditious. These cornerstones of success should help decrease the risk of surgical complications and mortality after pancreas transplants.

Short- and long-term outcomes of kidney transplants with multiple renal arteries

ObjectiveThe authors determined whether the use of kidney allografts with multiple renal arteries adversely affects post-transplant graft and patient outcome or increases the incidence of vascular and urologic complications. BackgroundKidney grafts with multiple renal arteries have been associated with an increased incidence of early vascular and urologic complications. Kidney transplants with single versus multiple renal arteries have not been compared in regard to long-term graft and patient outcome or post-transplant incidence of hypertension, acute tubular necrosis, rejection, and late vascular and urologic complications. MethodsWe analyzed 998 adult kidney transplants done from December 1, 1985 through June 30, 1993, in which only the recipients external or internal iliac artery was used for anastomosis. We divided the study population into 3 groups: Group A—1 renal artery, 1 arterial anastomosis (n = 835), Group B—>1 renal artery, 1 arterial anastomosis (n = 112), Group C—>1 renal artery, >1 arterial anastomosis (n = 51). We compared the incidence of post-transplant hypertension, acute tubular necrosis, acute rejection, and vascular and urologic complications; mean creatinine levels at 1, 3, and 5 years post-transplant; and patient and graft survival. Univariate and multivariate analyses were done to identify risk factors for vascular complications. ResultsWe found no significant differences among the three groups for the following variables: post-transplant hypertension, acute tubular necrosis, acute rejection, creatinine levels, early vascular and urologic complications, and graft and patient survival. In kidneys with single arteries, the presence (vs. absence) of an aortic patch and the type of the arterial anastomosis (end-to-end to the hypogastric vs. end-to-side to the external iliac artery) did not have an impact on the incidence of early or late vascular complications. In kidneys with multiple arteries, only the rate of late renal artery stenosis was higher, the rate of early vascular and urologic complications was not different. Our multivariate analysis identified acute tubular necrosis as a risk factor for renal artery and vein thrombosis; graft placement on the left side for arterial thrombosis; and preservation time ≥ 24 hours and multiple renal arteries for renal artery stenosis.

Delayed endocrine pancreas graft function after simultaneous pancreas-kidney transplantation. Incidence, risk factors, and impact on long-term outcome.

BACKGROUND The incidence of delayed endocrine pancreas graft function and its impact on long-term outcome after simultaneous pancreas-kidney transplantation are unknown. METHODS We studied 54 technically successful adult type I insulin-dependent diabetic recipients of cadaver, whole organ, bladder-drained simultaneous pancreas-kidney transplants (mean age, 37.6 years; 65% male, 35% female; 9% pancreas retransplants; 63% on chronic pretransplant dialysis; mean duration of diabetes, 25.1 years). Insulin was administered during the first 2 weeks after transplantation, as needed, to keep blood glucose < 150 mg/dl. Delayed endocrine pancreas graft function was defined as total, cumulative insulin requirement of > 30 U between day 5 and day 10, and/or > 15 U between day 11 and 15. Quadruple immunosuppression was used for all recipients. RESULTS The incidence of delayed endocrine pancreas graft function was 69%. By univariate analysis, delayed endocrine graft function was associated with pretransplant recipient weight > 80 kg (P = 0.04), donor age > 45 years (P = 0.02), and cardiocerebrovascular (P = 0.06) and nontraumatic causes of donor death (P = 0.02). The incidence of acute pancreas rejection episodes was similar for recipients without and with delayed endocrine pancreas graft function. Pancreas graft survival at 1 and 3 years was 94% and 82% without versus 76% and 59% with delayed endocrine graft function (P = 0.03). CONCLUSIONS Increased pancreas graft failure after delayed endocrine function was a consequence of insufficient functional reserve (e.g., older donors) rather than increased immunogenicity. Pretransplant reduction of recipient weight and careful donor selection are therefore crucial in order to decrease the incidence of delayed endocrine pancreas graft function and its negative impact on long-term outcome.

Correlation between cystoscopic biopsy results and hypoamylasuria in bladder-drained pancreas transplants.

BACKGROUND Urinary amylase (UA) remains the most common biochemical parameter to detect rejection in bladder-drained pancreas allografts. With the development of the cystoscopic transduodenal pancreas transplant biopsy technique, tissue samples of the pancreas graft are now frequently obtained. A definitive correlative analysis between UA activity and biopsy results has not been done in the three different pancreas transplant categories (simultaneous pancreas-kidney, pancreas transplant alone, and pancreas after kidney). METHODS We studied 66 pancreaticoduodenal biopsy specimens obtained for hypoamylasuria. Rejection was defined as a greater than 25% decrease from stable posttransplantation baseline on two consecutive measurements at least 12 hours apart. To perform biopsies we used our newly developed 14- and 16-gauge core-cut needles (50 cm long). Biopsy specimens were considered positive if either pancreatic or duodenal rejection was found. To assess the quality of UA activity we studied 13 biopsy specimens from patients with stable UA levels; these 13 specimens were negative for rejection. RESULTS Acute rejection was diagnosed in 36 biopsy specimens (55%). The mean decrease in UA levels was 67% +/- 8% (range, 28% to 99%) for the positive biopsy results, and 57% +/- 16% (range, 22% to 92%) for the negative biopsy results (p = 0.147). Within 1 month, UA levels returned to baseline in 19% of our patients with positive biopsy results versus 97% with negative results; postbiopsy 1-year graft survival was 64% versus 97% (p < or = 0.05). In assessing the test quality of our biopsy specimens (including 13 obtained for reasons other than hypoamylasuria), we found a sensitivity of 100% (stable UA levels mean no rejection) and a specificity of 30%. The predictive value of a positive test was 53%; of a negative test it was 100%. By performing biopsies we avoided antirejection treatment in 47% of the patients studied. We found no biopsy-related complications. CONCLUSIONS Stable UA levels reliably rule out rejection; a decrease is a marker for acute rejection but is unspecific. Performing biopsy is currently the only way to reliably diagnose rejection in solitary pancreas recipients (pancreas transplant alone and pancreas after kidney) and in simultaneous pancreas-kidney recipients with isolated hypoamylasuria. The procedure is safe and should always be attempted to avoid unnecessary rejection treatment.

Risk factors for second renal allografts immunosuppressed with cyclosporine

Second renal allograft survival rates are lower than those of primary allografts. For recipients immunosuppressed with azathioprine, prednisone, and Minnesota ALG (conventional immunosuppression), risk factors associated with decreased second graft survival have been identified: age greater than 40, cadaver donor, less than 6 months between primary graft loss and retransplantation, duration of primary graft function (6 months or 1 year, depending on the study), high peak panel-reactive antibody, number of human leukocyte antigen mismatches, and delayed graft function. In this study, we used a multivariate analysis to identify risk factors associated with decreased second graft survival in patients who did or did not receive cyclosporine. Results were compared with primary graft survival rates. Risk factors for patients receiving conventional immunosuppression were: (a) primary graft loss caused by rejection greater than or equal to 6 months (P = 0.01 vs. either rejection less than 6 months or nonimmunologic loss); (b) cadaver donor (P = 0.005 vs. living related); and (c) interval between primary graft loss and retransplantation of greater than or equal to 6 months (P = 0.05 vs. less than 6 months). For CsA, risk factors that most decreased second graft survival were: (a) primary graft loss caused by rejection less than 6 months (P = 0.11 vs. nonimmunologic loss); (b) conventional immunosuppression for the primary graft (P = 0.08 vs. CsA immunosuppression); and (c) a peak PRA of greater than or equal to 21 (P = 0.14 vs. peak PRA of 1-20). For second graft recipients immunosuppressed with CsA, primary graft loss to either rejection greater than 6 months posttransplant or nonimmunologic causes was not a risk factor for second graft survival. These data extend the recent reports of other investigators by identifying risk factors for retransplant recipients treated with CsA and by demonstrating that subgroups of patients in the retransplant population can be retransplanted without additional risk (i.e., their second graft survival rates are similar to primary graft survival rates). This may become more important if, in the future, organ distribution is based on graft survival data. If so, our data would support retransplantation in patients who are immunosuppressed with CsA, especially those who lost their primary graft to either rejection greater than or equal to 6 months posttransplant or nonimmunologic causes; who receive living related grafts; and who have a peak PRA of 1-20.

A prospective study of FK506 versus CsA and pig ATG in a porcine model of small bowel transplantation

Rejection remains a major barrier to successful bowel transplantation, and immunosuppressive protocols are far from standardized. In 88 nonrelated outbred pigs, we compared the effects of two immunosuppressive regimens--one with FK506, the other with cyclosporine (CsA) and pig antithymocyte globulin (ATG)--on incidence and severity of rejection in the early, critical posttransplant period. Group A (n = 14) was nonimmunosuppressed (controls). Group B (n = 17) received pig ATG (10 mg/kg/day x 10 days), CsA (3 mg/kg/day), prednisolone (2 mg/kg/day), and azathioprine (2.5 mg/kg/day); prednisolone and azathioprine were each reduced by 50% at 8 and 15 days posttransplant. Trough CsA whole-blood concentrations were > or = 400 ng/ml for the first 7 days, > or = 200 ng/ml thereafter. Group C (n = 13) received FK506 (0.2 mg/kg/day) and prednisolone (2 mg/kg/day); prednisolone was reduced by 50% at 8 and 15 days. FK506 whole-blood concentrations were > or = 20 ng/ml. All immunosuppression in groups B and C was given intravenously. We performed orthotopic small bowel transplants with systemic venous drainage. Recipient bowel was resected distal to the second portion of the duodenum and proximal to the rectum at transplant; bowel continuity was restored by duodenojejunostomy; ileostomy was created distally to allow access for daily biopsies. We graded interstitial and vascular rejection separately, according to a scoring system (no, mild, moderate, and severe rejection). Rejection-free graft survivals at 7, 14, and 21 days posttransplant were 38%, 19%, and 0% in group A; 93%, 93%, and 62% in group B; and 100%, 91%, and 82% in group C (P < 0.001). Comparing rejection in the immunosuppressed groups, group C (FK506) had a stronger tendency toward rejection than group B (CsA-ATG); significant differences between groups B and C were, however, noted only on individual days posttransplant, not over time. The death rate due to irreversible rejection was not significantly different in groups B and C (P = 0.8), but was significantly better in both of these immunosuppressed groups than in group A (P < 0.001). Pig survival was significantly longer in group C than in B (P = 0.001) due to a lower infection rate in group C. Posttransplant serum interleukin 2 and 7 levels did not correlate with rejection grades. Graft-versus-host reaction was noted only in the skin in 29% of group A, 73% of group B, and 77% of group C pigs; liver and native bowel were not involved.(ABSTRACT TRUNCATED AT 400 WORDS)

Cystoscopic biopsies in pancreaticoduodenal transplantation: Are duodenal biopsies indicative of pancreas dysfunction?

Tissue diagnosis of pancreas graft dysfunction is desirable. Bladder-drained pancreaticoduodenal transplants allow tissue diagnosis by cystoscopic biopsy procedures of the pancreas and duodenum. To assess the diagnostic utility of duodenal biopsies, we reviewed all cystoscopically obtained pancreas and duodenal biopsy tissues at our institution (July 1, 1989 through September 30, 1993). Adequate tissue for histologic examination was obtained from 75 biopsies in 58 recipients. Indications for cystoscopic biopsies were relative hypoamylasuria in 85%, hematuria in 6%, hyperamylasemia in 3%, and other causes in 6%. Duodenal specimens were available from 52 biopsies (25 with, and 27 without, concurrent pancreas biopsies). Of the 27 duodenal biopsies alone, 3 were diagnostic of rejection, 15 had features consistent with rejection, 6 were normal, 1 showed fibrosis, 1 showed necrosis, and 1 was ulcerated. Thus, two-thirds of the duodenal biopsies alone yielded clinically relevant information resulting in antirejection treatment. In 25 of the duodenal biopsies, pancreas tissue was also available (11 simultaneous pancreas-kidney, 9 pancreas transplant alone, and 5 pancreas after kidney recipients). Findings in both organs completely agreed in 9 (36%) of the biopsies. In 7 (28%), rejection was suggested or diagnosed in both organs, although the organs were discrepant with regard to the presence of vascular rejection (6 pancreas, 1 duodenum). In 2 (11%), minor nonrejection discrepant findings were present. Therefore, in 18 of 25 (72%) pancreas-duodenal biopsies, treatment would not have been different if only one graft had been biopsied. But in the other 7 (28%), treatment would have been different if only the organ with negative findings had been biopsied. In 6 cases (4 duodenal, 2 pancreas), rejection was seen in one organ but not the other. In 1 case, cyto-megalovirus (CMV) inclusions were present in the duodenum, but the pancreas was normal. We conclude that (1) the duodenum and pancreas can reject inde-