Primary Graft Survival Research Articles

Prope tolerance with alemtuzumab

We have proposed that the mechanisms of alloengraftment and variable acquired tolerance can be facilitated by minimum posttransplant immunosuppression. It was further suggested that the efficacy of minimalistic treatment could be enhanced by preoperative recipient conditioning with an antilymphoid antibody preparation. A total of 76 adults (38 hepatitis C virus [HCV], 38 HCV) were infused with 30 mg alemtuzumab before primary cadaveric liver transplantation and maintained afterward on daily monotherapy unless breakthrough rejection mandated additional agents. In stable patients, the intervals between tacrolimus doses were lengthened (“spaced weaning”) after approximately 4 months. Eighty-four contemporaneous nonlymphoid-depleted liver recipients (58 HCV, 26 HCV) were treated with conventional postoperative immunosuppression. The overall incidence of rejection was similar with the two strategies of immunosuppression. With follow-ups of 14 to 22 months, patient and primary graft survival in HCV cases are 97% and 90%, respectively, with alemtuzumab depletion plus minimal immunosuppression versus 71% and 70%, respectively, under conventional immunosuppression. In HCV recipients, current patient and graft survival in the alemtuzumab-pretreated group are 71% and 70% versus 65% and 54%, respectively, under conventional treatment. With both strategies of immunosuppression, the adverse effect of preexisting HCV on survival parameters and graft function already was significant at the 1-year milestone, but its extent was not evident until the second year. With or without HCV, 62% of the 64 surviving lymphoid-depleted patients are on spaced immunosuppression, and four patients receive no immunosuppression. Lymphoid depletion with alemtuzumab and minimalistic maintenance immunosuppression is a practical strategy of liver transplantation in HCV recipients but not HCV recipients. Transplantation. 2004 Oct 15;78(7):966–71. Background We combined alemtuzumab (Campath-1H, Berlex Laboratories, Montville, NJ) and tacrolimus (Tac) immunosuppression for intestinal and multivisceral transplantation. Materials and methods: A total of 21 adult patients received 24 grafts: 14 intestinal, nine multivisceral, and one liver-intestinal graft. Alemtuzumab was administered perioperatively in four doses with low-dose Tac (levels 10–15 ng/dL) and no maintenance steroids. Tac was substituted with sirolimus in case of Tac-related complications. Suspected or mild rejections were treated with steroids. Moderate rejections were treated with steroids or OKT3. Severe rejections were treated with OKT3. Results Of the 16 patients that were followed up for an average of 9 months, 12 are alive with functioning grafts. Two patients experienced severe rejection, three experienced moderate rejection episodes, and seven experienced mild acute rejection episodes. Four patients never developed acute rejection. Infectious complications included a cytomegalovirus enteritis and four fungal infections (related to central venous access). Conclusions The combination of alemtuzumab and Tac therapy without steroid use seems to efficiently prevent acute rejection in a significant number of patients without causing frequent opportunistic infections. Transplantation. 2003 May 15;75(9):1512–7.

Use of alemtuzumab and tacrolimus monotherapy for cadaveric liver transplantation: with particular reference to hepatitis C virus.

We have proposed that the mechanisms of alloengraftment and variable acquired tolerance can be facilitated by minimum posttransplant immunosuppression. It was further suggested that the efficacy of minimalistic treatment could be enhanced by preoperative recipient conditioning with an antilymphoid antibody preparation. A total of 76 adults (38 hepatitis C virus [HCV], 38 HCV) were infused with 30 mg alemtuzumab before primary cadaveric liver transplantation and maintained afterward on daily monotherapy unless breakthrough rejection mandated additional agents. In stable patients, the intervals between tacrolimus doses were lengthened ("spaced weaning") after approximately 4 months. Eighty-four contemporaneous nonlymphoid-depleted liver recipients (58 HCV, 26 HCV) were treated with conventional postoperative immunosuppression. The overall incidence of rejection was similar with the two strategies of immunosuppression. With follow-ups of 14 to 22 months, patient and primary graft survival in HCV cases are 97% and 90%, respectively, with alemtuzumab depletion plus minimal immunosuppression versus 71% and 70%, respectively, under conventional immunosuppression. In HCV recipients, current patient and graft survival in the alemtuzumab-pretreated group are 71% and 70% versus 65% and 54%, respectively, under conventional treatment. With both strategies of immunosuppression, the adverse effect of preexisting HCV on survival parameters and graft function already was significant at the 1-year milestone, but its extent was not evident until the second year. With or without HCV, 62% of the 64 surviving lymphoid-depleted patients are on spaced immunosuppression, and four patients receive no immunosuppression. Lymphoid depletion with alemtuzumab and minimalistic maintenance immunosuppression is a practical strategy of liver transplantation in HCV recipients but not HCV recipients.

WHAT IS THE COURSE OF PATIENTS UNDERGOING ANTI-VIRAL THERAPY FOR RECURRENT HEPATITIS C VIRUS LIVER DISEASE?

Purpose: Chronic hepatitis C virus (HCV) liver disease is the commonest indication for orthotopiclivertransplantation(OLT) in the USA. Allograft reinfection is universal, and recurrent HCV liver disease seemingly inevitable. Anti-viral therapy (AVT; interferon alpha and/or ribavirin) is being used post-OLT, but outcomes are uncertain. Reports of acute and/or ductopenic allograft rejection during AVT for recurrent HCV liver disease have led to concern about the appropriateness of such treatment. We sought to determine the proportion of patients who developed acute and/or ductopenic allograft rejection whilst undergoing AVT for recurrent HCV liver disease; and the impact this had on graft and patient survival. Methods: We identified all patients who underwent OLT at our institution for chronic HCV liver disease between 1/1991 and 5/2004, and to whom AVT was prescribed for histologic recurrent HCV liver disease. Patients who developed acute and/or ductopenic allograft rejection whilst receiving AVT were compared to those patients who did not, with respect to age at OLT, gender, race, viral genotype, primary calcineurin inhibitor (CI) therapy, graft survival, and death. Results: One hundred-seventeen patients underwent OLT for chronic HCV liver disease during the study period. Forty-nine patients(39 men) received AVT for histologic recurrent HCV liver disease. Seven patients (four men; five white, one AA, one Asian; median age 52 years{range 40–61); five infected with genotype 1, and two not known) developed acute and/or ductopenic allograft rejection during AVT. Primary CI therapy comprised cy-closporine(2) and tacrolimus(5). Cholestatic liver test abnormalities developed a median of 4 months(range 3–7) after starting AVT (pegylated interferon and ribavirin), and in each case this development was associated with HCV RNA elimination from serum(4), or almost total clearance thereof(3). Three patients died of complications of profound cholestasis. None of the other 42 patients developed acute and/or ductopenic rejection in the course of AVT: 12 achieved SVR, and 18 obtained measurable liver test improvement. Conclusions: Aggressive anti-HCV therapy post-OLT led to SVR in 32.6% of patients; however, this was associated with rejection in 14.3% of patients. Given the apparent trade-off of SVR for rejection, attention to immunosup-pression during AVT is mandatory. Randomized controlled trials are needed in large cohorts to ascertain whether AVT leads to improved outcomes.

IS RECURRENT CHRONIC HEPATITIS C VIRUS LIVER DISEASE AFTER ORTHOTOPIC LIVER TRANSPLANTATION INEVITABLE?

Purpose: Chronic hepatitis C virus (HCV) liver disease is the commonest indication for orthotopic liver transplantation (OLT) in the USA. Important recurrent chronic liver disease is very common, but there appears to be a small number of patients who do not exhibit evidence of recurrent HCV liver disease, in some cases years after OLT. We hypothesized that certain clinico-epidemiologic factors might play a role in this phenomenon, and performed a case-control study to try and identify those factors important in the development of recurrent HCV liver disease. Methods: We identified all patients who underwent OLT for chronic HCV liver disease at our institution between 1/1991 and 5/2004, including those whose serum aminotransferase concentrations remained normal in follow-up. Control subjects transplanted during the same year for HCV liver disease were matched to cases. Specific variables were evaluated: age, gender, race, viral genotype, primary calcineurin inhibitor (PCI), anti-viral therapy, graft survival, and death. Results: 117 patients underwent OLT for chronic HCV liver disease during the study period. Seven white subjects with no evidence of recurrent HCV liver disease were identified. All were white, six were male, their median OLT age was 46 years (range 44–59), and median follow-up was 64 months. Four were infected with genotype 1, one with genotype 3, and the genotype was not known in two subjects. PCI therapy comprised CyA (5), and tacrolimus (2). One patient died nine years after OLT, of a non-liver related illness. 28 control patients were identified (matched 4:1 with cases, by year of OLT), of whom 23 were white, four were black and one was Asian; seven were women. Their median OLT age was 46 years (range 16–65). Viral genotypes were as follows: 1 (seventeen); 2 (three); 3 (two); 4 (one), and five were unknown. PCI comprised CyA (17), and tacrolimus (11). All controls demonstrated histologic evidence of recurrent chronic HCV liver disease a median of 10 months (range 1–95) post OLT. 18 received anti-viral therapy, resulting in four SVRs. Four patients died; two underwent re-OLT for recurrent HCV liver disease. Conclusions: Subjects without evidence of recurrent chronic HCV liver disease had better graft function, and overall survival than those with evidence of recurrent HCV liver disease. However, there were no clinical features that distinguished between the two patient groups. More study is required to understand why a small subgroup of patients fails to develop recurrent chronic HCV liver disease after OLT.

Immune Regulation and Graft Survival in Kidney Transplant Recipients Are Both Enhanced by Human Leukocyte Antigen Matching

We hypothesized that donor/recipient sharing of the human leukocyte antigen (HLA) involved in allopeptide presentation to the T regulatory cell increases the incidence of immune regulation, thus contributing to long-term graft survival. Peripheral blood mononuclear cells (PBMC) were obtained from 40 living related donor (LRD) and 31 cadaver renal transplant recipients. The trans vivo delayed type hypersensitivity (DTH) assay was used to assign patients to regulator, nonregulator, and sensitized categories. In a large cohort (n = 1934 patients), primary graft survival and rejection episodes were analyzed using a log rank test for comparison with the DTH results. The highest incidence of regulated anti-donor DTH was observed in the LRD HLA-identical group (6/6; 100%) followed by the LRD HLA 1 haplotype matched group (18/27; 67%). Within the cadaver population, two DR-matched recipients had a higher frequency of regulated anti-donor DTH (6/11; 55%) than 1 & 0 DR-matched recipients (3/18; 17%). In a multivariate model, matching for HLA-DR alone, or for DR plus DQ was significantly (p = 0.045, p = 0.041) correlated with DTH regulation. The better HLA-matched groups showed the highest incidence of DTH regulation and, in a larger retrospective analysis, displayed better graft survival and freedom from acute rejection (p < 0.0001). HLA matching, and HLA-DR matching in particular, correlates with the incidence of immune regulation after kidney transplantation.

Isolated intestinal transplantation: proof of clinical efficacy.

Isolated intestinal transplantation has been limited by poor patient and graft survival. If high survival could be achieved and if parenteral nutrition-associated liver disease were reversible, this procedure could be more widely applied, with early liver dysfunction indicating the need for transplant evaluation. Twenty-six patients who had failed parenteral nutrition received 28 isolated intestinal transplants. We analyzed patient and graft survival, the effect of sirolimus on the severity and frequency of rejection, and the reversibility of liver dysfunction after transplant. Three-year actuarial patient and primary graft survival were 88% and 71%, respectively. Two patients underwent successful retransplants. Twenty-two patients are alive at a mean of 21+/-15 (median 18; range 3-51) months. Actuarial survival with freedom from parenteral support is 81% at 3 years (21 of 26 patients). Actuarial freedom from parenteral support among survivors is 95.5% at 3 years (21 of 22 patients). Early rejection was less frequent with sirolimus (34% vs. 70% without sirolimus) (P=0.007). Moderate and severe rejection was less frequent with sirolimus (1/11 episodes vs. 9/17 episodes without sirolimus) (P=0.05). No grafts were lost after introduction of sirolimus. In all four patients with advanced liver dysfunction, fibrosis and cholestasis regressed within 1 year. High patient survival and parenteral nutrition-free survival can be achieved after isolated intestinal transplantation. Sirolimus treatment has eliminated graft loss. Parenteral nutrition-associated liver disease is reversible with intestinal transplantation. Refractory liver dysfunction in patients receiving parenteral nutrition should prompt consideration for isolated intestinal transplantation.

Penetrating keratoplasty in young children with congenital hereditary endothelial dystrophy.

To report the visual results and success rate of penetrating keratoplasty (PKP) in a series of young children with congenital hereditary endothelial dystrophy (CHED). This is a retrospective study on twenty-four eyes of 15 patients (seven male and eight female) operated on for CHED. Children less than 12 years of age at the time of surgery who were followed for at least 6 months were recalled. Characteristics of the patients, indications for PKP, final visual outcome, and graft clarity were evaluated. The following tests were employed: McNemmar test for evaluating visual results, Kaplan-Meyer analysis for determination of graft survival, and Mann-Whitney U test for evaluating the relationship between visual outcome and age at PKP. Patients' age at diagnosis and at initial PKP was 6.5 +/- 3.6 and 8.1 +/- 2.5 years, respectively. Follow-up period was 35.5 +/- 36.2 months. Visual acuity could be evaluated by Snellen chart in 19 eyes. Preoperative visual acuity was less than 20/80 in all of these. Postoperatively, visual acuity was less than 20/80 in nine eyes (47.4%) (P < 0.002). Visual acuity improved in 18 (94.7%) of 19 eyes. There was no relationship between age at initial PKP and final visual outcome (P = 0.35). At the last examination (24 grafts), 19 were clear (79.1%), two were hazy (8.3%), and three were opaque (12.5%). Allograft rejection was seen in 10 eyes (43.4%), seven of which were endothelial. Excluding one case of trauma, all graft failures resulted from endothelial rejection. The probability of primary graft survival was 88% at 3 years and 74% at 5 years. Regarding the difficulties in pediatric keratoplasty and the absence of a relationship between postoperative visual outcome and age at keratoplasty, a conservative approach and careful risk-benefit ratio evaluation are recommended in patients with CHED.

Predictors of arteriovenous graft patency after radiologic intervention in hemodialysis patients

Arteriovenous grafts in hemodialysis patients are prone to recurrent stenosis and thrombosis, requiring frequentradiologic and surgical interventions to optimize their long-term patency. Little is known about the factors that determine graft outcome after a radiologic intervention. The present study examined the clinical and radiologic predictors of intervention-free graft survival after elective angioplasty or thrombectomy. A prospective computerized database was used to determine the outcomes subsequent to all graft angioplasties (n = 330) and thrombectomies (n = 326) performed at the University of Alabama at Birmingham between April 1, 1996, and June 30, 1999. Primary graft survival rates after angioplasty and thrombectomy were 86% versus 43% at 1 month, 71 % versus 30% at 3 months, 51% versus 19% at 6 months, and 28% versus 8% at 12 months, respectively. The median intervention-free graft survival time was substantially longer after angioplasty than thrombectomy (6.7 versus 0.6 months; P < 0.001). The superior outcome of angioplasty over thrombectomy was observed even for the subset of procedures with no residual stenosis (median survival, 6.9 versus 2.5 months; P < 0.001). The median graft survival was inversely related to the magnitude of residual stenosis for both elective angioplasty and thrombectomy. Median intervention-free graft survival after angioplasty was inversely related to the postangioplasty intragraft to systemic systolic pressure ratio (7.6, 6.9, and 5.6 months for ratios <0.4, 0.4 to 0.6, and >0.6, respectively; P < 0.001). Intervention-free graft survival after angioplasty or thrombectomy was not affected by graft location (forearm versus upper arm), number of stenotic sites, or presence of diabetes. In conclusion, graft survival is substantially longer after elective angioplasty than thrombectomy, even when the radiologic appearance after the procedure suggests complete resolution of the stenotic lesion. Moreover, the risk for requiring a subsequent graft intervention can be predicted from two simple radiologic measurements: grade of stenosis and intragraft to systemic systolic blood pressure ratio. These parameters may help determine the frequency of monitoring for recurrent stenosis in a given graft.

Natural history of arteriovenous grafts in hemodialysis patients

Most hemodialysis patients in the United States have an arteriovenous graft as their vascular access. Grafts have a relatively short life span and are prone to recurrent stenosis and thrombosis, requiring multiple salvage procedures to maintain their patency. There is little information in the literature regarding the clinical factors that determine graft survival and complications. We evaluated prospectively the outcomes of 256 grafts placed at a single institution during a 2-year period. A salvage procedure to maintain graft patency (thrombectomy, angioplasty, or surgical revision) was required in 29% of the grafts at 3 months, 52% at 6 months, 77% at 12 months, and 96% at 24 months. Thus, primary graft survival (time from graft placement to the first intervention) was only 23% at 1 year and 4% at 2 years. Primary graft survival was significantly less among patients with hypoalbuminemia compared with patients with a normal serum albumin level (P = 0.003). Secondary graft survival (time from graft placement to permanent graft failure) was 65% at 1 year and 51% at 2 years. Neither primary nor secondary graft survival was significantly correlated with patient age, sex, diabetic status, body mass index, or graft site. A mean of 1.22 interventions per graft-year were required to maintain access patency, including 0.51 thrombectomies, 0.54 angioplasties, and 0.17 surgical revisions. In conclusion, hypoalbuminemia is a strong predictor of the requirement for an early graft intervention. Patients with hypoalbuminemia may require a heightened index of suspicion in monitoring their grafts for evidence of stenosis.

Cardiac Allografts from IL-4 Knockout Recipients: Assessment of Transplant Arteriosclerosis and Peripheral Tolerance

To study the role of IL-4 in tolerance induction and transplant arteriosclerosis, BALB/c hearts were transplanted into C57BL/6J wild-type or IL-4 knockout (IL-4(-/-)) recipients. A 30-day course of anti-CD4/8 mAb was used to induce long term graft survival. Primary graft survival was 50% (5 of 10) in IL-4(-/-) recipients comparable to 63% (5 of 8) in wild-type recipients. Mice with allografts surviving >80 days were tested for tolerance by challenge with a second donor or third party (CBA) heart. Secondary donor-strain heart grafts survived >30 days, but showed histologic evidence of ongoing alloimmune response. Third party hearts rejected rapidly. Although immunostaining and 32P RT-PCR assays showed no differences in the mononuclear cell infiltration and T cell activation between IL-4(-/-) and wild-type tolerant recipients, some monokines (IL-12, TNF-alpha, and allograft inflammatory factor-1) were up-regulated in grafts from IL-4(-/-) recipients. Computer-assisted analysis of elastin-stained vessels revealed that the severity of vascular thickening (percentage of luminal occlusion, mean +/- SD, n = 329) was similar in grafts from IL-4(-/-) (63.7 +/- 16.9%) and wild-type (69.5 +/- 17.6%) recipients. Thus, IL-4 deficiency did not alter primary or secondary graft survival, infiltration, or vascular thickening. The selective alterations in monokine expression suggests that alternative pathways are activated and may compensate in IL-4(-/-) mice.

ISOLATED INTESTINAL TRANSPLANTATION (ISBTx) IN CHILDREN: A REAPPRAISAL

Purpose: A clinical trial of intestinal transplantation (Itx) under tacrolimus and prednisone immunosuppression was initiated in June 1990 in children with irreversible intestinal failure and dependent on total parental nutrition (TPN). Methods: 16 patients (9 F, 7M) with a mean age of 7.8 years (range 1.2-16.8) received 17 isolated intestinal allografts. Four patients also received bone marrow infusion, and four received colon. Indications for Itx included: gastroschisis (n=3), volvulus (n=7), intestinal atresia (n=2), chronic intestinal pseudoobstruction (n=1). Hirschsprung's disease (n=1), microvillus inclusion disease (n=1), and trauma (n=1). Recipients with allograft enteroctomy were censored at the time of discharge. Follow-up ranged between 3 mo to 5.8 yrs. Results: Currently 12 (75%) of 16 patients are alive and 12/17 (71%) graft are functioning. Actuarial survival rates at 1, 3 and 5 years was 92% for patient, and 73%, 61% and 61% for primary graft survival respectively. All surviving patients who retained their graft have been liberated from TPN. Recently, 1 recipient was hospitalized with pancreatitis. Immunologic complications have included: intestinal allograft rejection (n=16), PTLD (n=4), CMV (n=5) and GVHD (n=2). OKT3 was used in 12 cases. Five graft losses occurred at 27,54,119,332 and 774 days postransplant, all as a result of untreatable rejection, 2 of them in the setting of PTLD. There were 4 graft removal, one patient was retransplanted after a rest period of 11 months and currently is alive after more than two years of follow-up. The three remaining patients were not retransplanted and died 94, 459 and 496 days post-graft removal of TPN related complications. Conclusion: ISBTx is a valid therapeutic option for patients with intestinal failure dependent on TPN. ISBTx leads to higher patient and graft survival compared with combined liver-small bowel transplantation. Survivors of graft enterectomy succumbe to the natural history of intestinal failure and TPN related complications. Retransplantation is feasible after graft enterectomy, after a rest period. Patients with intestinal failure should be transplanted prior to the end stage complications of TPN.

Identification of high- and low-risk second kidney grafts.

The purpose of this study was to identify recipients who are at low or high risk of early cadaveric regraft failure by segregating results of the flow cytometric crossmatch (FCXM) test with previous graft survival time (PGST). Early immunologic kidney regraft failure was analyzed in 103 multicenter recipients by cross-stratifying FCXM negative/positive status with < or =3- and >3-month PGST. T cell and B cell cytotoxicity crossmatches were negative. All were tested retrospectively in the T cell FCXM and 60 of the 103 were also tested in the B cell FCXM. A positive T and B cell FCXM was defined as a mean channel shift of > or = 9 (256 channel log scale) or > or = 40 (1024 channel log scale) for pretransplant crossmatch serum above negative control serum. Recipients received triple immunosuppression therapy and limited-use antilymphocyte induction therapy. Early cadaveric regraft losses were biopsied. Comparably good rates of second kidney graft survival at 3 years were found among three ow risk subsets: 78% for 18 FCXM-positive patients with PGST >3 months, 78% for 49 FCXM-negative patients with PGST >3 months, and 84% for 19 FCXM-negative patients with PGST < or =3 months. in contrast, 53% 3-month and 44% 3-year regraft survival rates occurred in 17 high-risk FCXM-positive recipients with a PGST < or =3 months. The odds ratio for increased relative risk of early second graft loss was 4.5 (confidence interval: 1.32-1.67) for the high-risk versus low-risk subsets (P = 0.009). Within the high-risk subset, 56% (5 of 9) of those who were FCXM T negative B positive experienced early regraft loss. A positive B cell FCXM has an adverse clinical impact only for high-risk regraft recipients. Pretransplant panel reactive antibody levels, pregnancy, number of blood transfusions between grafts, repeat donor HLA mismatches, and regraft recipient HLA mismatches did not correlate with early regraft loss. We conclude that kidney regraft survival rates in low-risk recipients (PGST >3 months/FCXM negative or positive [T and/or B cell] and PGST < or = 3 months/FCXM negative) approach primary graft survival rates and justify retransplantation, but the rate in high-risk regraft candidates (PGST < or =3 months/FCXM positive T and/or B cell) suggests that retransplantation should be performed only with a negative FCXM.

Liver transplantation for Wilson's disease

Background/Aims: As has been the case with other metabolic diseases of the liver in the last decade, orthotopic liver transplantation has been applied to the treatment of Wilson's disease with increasing frequency. The experience at the University of Pittsburg with orthotopic liver transplantation for Wilson's disease is reported. Methods: Between February 1981 and December 1991, 51 orthotopic liver transplants were performed on 39 patients (16 pediatric, 23 adults) with Wilson's disease. Twenty-two patients were transplanted because of a presentation co-existent with fulminant hepatic failure. Seventeen presented with chronic advanced liver disease with (n=9) or without (n=8) associated neurologic dysfunction. Results: The rate of primary graft survival (n-39) was 73% and patient survival was 79.4%. No patient mortality occurred beyond 3 weeks post-orthotopic liver transplantation. Survival was better for those with a chronic advanced liver disease presentation (90%) than it was for those with a fulminant hepatic failure (73%) presentation, but the difference was not statistically significant. Conclusions: 1) Currently, orthotopic liver transplantation is the treatment of choice for Wilson's disease presenting as fulminant hepatic hepatic failure; 2) orthotopic liver transplantation should be considered for patients with Wilson's disease with advanced, chronic liver disease for whom no other therapy is possible; 3) orthotopic liver transplantation only partially corrects the underlying metabolic defect of patients with Wilson's disease and converts the copper kinetics from that characteristic of an individual affected with a homozygous disease to that of an individual who is an obligate heterozygote, thereby effecting a phenotypic cure.

The Management of Corneal Perforations Associated with Rheumatoid Arthritis: An Analysis of 32 Eyes

Sterile corneal ulceration is a rare complication of rheumatoid arthritis and may lead to corneal perforation. Surgical management for visual restoration frequently is unsuccessful. The authors analyze the factors that may determine the failure of corneal surgery in perforations associated with rheumatoid arthritis. The management of 29 patients with rheumatoid arthritis with corneal perforations requiring surgical intervention was reviewed. The corneal lesions were classified either as necrotizing keratitis (n = 20) or as ulcers secondary to surface disease (n = 12), depending on the most evident primary pathology. The outcome of different methods for primary repair (i.e., application of tissue adhesive, lamellar graft, or penetrating keratoplasty) and graft survival in penetrating keratoplasties were analyzed. Fifty-seven corneal procedures were performed in 32 eyes. Primary repair was successful (i.e., no further corneal surgery within 6 months was required) in five eyes (25%) with necrotizing keratitis and in eight eyes (67%) with perforations secondary to surface disease. The application of tissue adhesive, when planned as long-term treatment, was unsuccessful in all five eyes. Immunosuppression significantly improved the survival of first penetrating grafts (42% graft survival after 1 year versus 11% without immunosuppression, P = 0.02). Of 25 graft failures, 20 (80%) were caused by recurrent melts up to 6 months after penetrating keratoplasty. Ocular surface infection was responsible for failure in six of ten grafts after that time. Complications of corneal surgery in rheumatoid corneal perforations are frequent. The type of surgical procedure, the predominant pathogenic mechanism, and the perioperative immune status influence the outcome. The control of corneal melting and the prevention of surface infection are critical for graft survival.

Intermediate-Term Outcome of Renal Retransplants in the Cyclosporine Era

To determine the influence of selected parameters on intermediate-term outcome of renal retransplants, univariate and multiple regression analyses were performed on all 100 consecutive cyclosporine treated retransplants performed between 1984 and 1990 (mean follow up, 4.6 +/- 2.3 years). Actual 1 year and actuarial 5 year graft survivals were higher in living compared with cadaver donor transplants (84% and 79% vs 69% and 56%, respectively; p < 0.05). Among cadaver donor transplant recipients, allografts with immediate early function had better 1 and 5 year graft survivals when compared with those with delayed function (81% and 62% vs 59% and 38%, respectively; p < 0.05). Recipients with acute rejection had inferior 1 year and 5 year graft survivals when compared with rejection free patients (65% and 35% vs 80% and 57%, respectively; p < 0.05). Graft survival time of primary transplants was also a significant predictor of retransplant outcome with 1 and 5 year graft survivals of 50% and 36%, respectively, in patients in whom primary grafts survived less than 3 months, compared with 75% and 58% in those in whom grafts survived longer than 3 months (p < 0.05). Recipient age, race, renal disease, and levels of panel reactive antibodies had no effect on intermediate-term outcome. In a multiple regression analysis, delayed graft function, acute rejection, and primary graft survival time less than 3 months correlated inversely with long-term survival of retransplants (multiple r = 0.65). A total of 39 grafts were lost due to rejection (22), sepsis (6), graft nonfunction (5), death with a functioning graft (4), noncompliance (1), and recurrent renal disease (1).(ABSTRACT TRUNCATED AT 250 WORDS)

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.

RENAL TRANSPLANTATION DESPITE A POSITIVE ANTIGLOBULIN CROSSMATCH WITH AND WITHOUT PROPHYLACTIC OKT3

The antiglobulin crossmatch (AGXM) is a sensitive technique employed by many transplant centers to enhance detection of preformed antibody to donor antigens that may cause hyperacute rejection. However, positive AGXM may detect irrelevant or very low titers of anti-HLA antibody precluding transplantation in suitable recipients. To investigate the significance of a positive AGXM, cadaveric renal transplantation was carried out despite a weakly positive AGXM (defined as cell killing above background but not greater than 20%) in 48 recipients. In an initial group (n = 10), maintained on triple therapy (cyclosporine, azathioprine, and prednisone), accelerated acute rejection occurred in 4 recipients and 3 grafts were lost. A subsequent group (n = 38) was treated with a prophylactic course of OKT3 then triple therapy. There were no episodes of accelerated acute rejection (P less than 0.01) although clinical hyperacute rejection claimed one graft and the incidence of delayed graft function was high (75%). The prophylactic OKT3 group had a reduced incidence of acute rejection (0.5 versus 1.0) per recipient and the onset of first episodes was delayed (mean onset: 13 versus 35 days after transplantation). One year actuarial primary graft survival was 88% in the prophylactic OKT3 group as compared with only 50% in the initial group. The outcome in the positive AGXM group was similar to a concurrent group (n = 32) with a negative AGXM and immediate graft function. On the other hand, the subset of positive AGXM regraft recipients treated with prophylactic OKT3 fared poorly, with a 36% (4/11) incidence of primary nonfunction. In summary, a positive AGXM, as defined in this report, is not a contraindication to primary renal transplantation--in fact, the use of the AGXM will identify recipients that would benefit from prophylactic OKT3.

Improved cadaveric renal transplant outcome in children

We analyzed the results of 165 pediatric cadaver renal transplants performed at the University of California at Los Angeles to identify the factors which are linked to improved allograft survival. Both univariate life-table analysis and the Cox proportional hazard model were used. The use of a sequential immunosuppressive regimen (P less than 0.001) and kidneys from donors of more than 6 years of age (P less than 0.001) were found to be the factors having the most influence on primary graft survival. The sequential regimen was the only factor favorably influencing retransplants. With sequential therapy 1- and 2-year actuarial graft survival rates were 94% and 91% in primary transplants, and 82% and 70% in retransplants. Medication noncompliance exerted a large negative effect on transplant outcome. Of 70 recipients who had been on cyclosporine for at least 6 months, 50% evidenced noncompliance. Sixty-four percent of adolescents were noncompliant. Thirteen percent of the recipients lost their graft because of noncompliance. We conclude that good results can be obtained with cadaver renal transplants in children with a sequential immunosuppressive regimen and the use of kidneys from adolescent and adult donors. Noncompliance is a great barrier to long-term success in pediatric transplantation.

Dialysis and renal transplantation in children: Long term and recent experience

The outcome of 38 children with endstage renal failure who entered a dialysis and renal transplant programme over a period of 16 years is reported. The initial care was given in an adult programme but in 1985 this was changed to a comprehensive and specifically paediatric programme. Patient survival was 97, 86 and 80% at 1, 5 and 10 years respectively. Thirty-four of the patients spent a mean period of 19 months (range 1-160 months) on dialysis with the preferred form of dialytic therapy being continuous ambulatory peritoneal dialysis. Primary cadaveric graft survival was 72 and 42% at 1 and 3 years respectively; although since 1985 1 year graft survival has risen to 90%. The major long term problems have been growth failure and poor social development. Eighty-seven per cent of children have been able to continue normal schooling, and of the 18 who have left school 14 (78%) are employed or undertaking tertiary education. Thus dialysis and transplantation has allowed not only excellent patient survival but also the achievement of satisfactory educational standards and subsequent employment for the majority of patients.

CAUSES OF GRAFT LOSS BEYOND TWO YEARS IN THE CYCLOSPORINE ERA

While CsA has improved renal-allograft survival rates in the first 2 years compared with Aza, Terasaki's multicenter study (1) failed to show any difference in long-term graft survival in CsA-Pred versus Aza-Pred-treated recipients. The present study examines the long-term graft-survival rates at a single center using CsA immunosuppression and seeks to discern the causes of 58 graft losses among 343 patients with functioning grafts beyond 2 years posttransplantation. The 6-year primary and cadaveric actuarial graft survival at this institution is 59% with a graft half-life of 10 years, which is better than the 40% and 7.7 years, respectively, reported by Terasaki (1) for primary cadaveric recipients on Aza-Pred. It is also better than the 41%, 6-year survival and 5.5-year half-life for primary cadaveric recipients treated with CsA-Pred as reported in the multicenter study. (1) Less experience with the use of CsA may explain the latter comparison. Primary LRD grafts at this institution (2/3 haploidentical) have a 6-year actuarial survival of 77% and a half-life very closely approximating that of HLA-identical LRD grafts under Aza (23.4 years). These results demonstrate that CsA mitigates the effects of HLA incompatibility to reduce graft survival. The most common cause of graft loss beyond 2 years was chronic rejection (36.2%) followed by noncompliance (27.6%). Patient deaths resulted in 13 of the 58 graft losses; most of the deaths were related to cardiovascular diseases. Only 3 patients died from causes that could be attributed to CsA immunosuppression; 2 from sepsis and 1 from viral hepatitis. Acute rejection caused 8.6% of the graft losses on continuous CsA therapy. When immunologic risk factors were analyzed, the entire graft-loss group had a significantly higher proportion of retransplant patients than the graft-survival group (P less than 0.005), suggesting that prior transplantation imposes a higher risk for graft loss not only acutely but long term as well. However, retransplanted patients were significantly less likely to lose their grafts because of noncompliance (P less than 0.005). Male patients were found to be significantly more noncompliant.