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Biomedical subjects

D E Sutherland

Publications and source records attributed to D E Sutherland.

At least 109 records · Page 6Linked to original sources
PubMed1997

Risk factors for prolonged hospitalization after kidney transplants.

A major variable in the cost of kidney transplants is the length of initial hospitalization. Using multivariate analysis, we studied risk factors for hospital stay > 10 d post-transplant. Between 1 January 1985 and 31 August 1995 a total of 1588 patients underwent first or second kidney transplants at the University of Minnesota. Antibody was used for 1 wk in cadaver donor recipients and for 2 wk in pediatric recipients (resulting in a long stay for all pediatric recipients). Adult living related donor recipients were immunosuppressed with triple therapy. Donor risk factors studied were age (< 15, 15-50, > 50 yr) and,- for cadaver recipients, preservation time (< 12, 12-18, 18-24, 24-30, > 30 h) and cause of death (trauma, cerebrovascular accident, or cardiac). Recipient risk factors studied were age (< 18, 18-55, > 55 yr); sex; transplant number; antigen mismatch; peak PRA; PRA at transplant (< 11, 11-50, > 50); diabetic status; pretransplant dialysis (vs. pre-emptive transplant); pretransplant cardiac, peripheral vascular, or respiratory disease; and delayed graft function (DGF) (dialysis in the first week vs. no dialysis). Risk factors were analyzed separately for living donor and cadaver donor recipients. For cadaver donor recipients, DGF was the major risk factor (p < 0.0001); others were age 55 yr (p = 0.03) and diabetes (p = 0.02). For living donor recipients, DGF was also a risk factor (p = 0.003); others were diabetes (p = 0.01), retransplant (p = 0.006), PRA at transplant > 50 (p < 0.0001), age > 55 yr (p = 0.02), pretransplant respiratory disease (p = 0.005), and pretransplant dialysis (p = 0.005). Because DGF was the major risk factor for a prolonged stay, we then studied risk factors for DGF using multivariate analysis. For cadaver donor recipients, risk factors were recipient weight > 90 kg (p = 0.004), preservation time 24 h (p = 0.03), PRA at transplant > 50 (p = 0.03), and donor age < 15 or > 50 yr (p = 0.002). For living donor recipients, risk factors were recipient age < 18 yr (p = 0.01), donor age > 50 yr (p = 0.03), female sex (p = 0.05), pretransplant respiratory disease (p = 0.1), pretransplant peripheral vascular disease (p = 0.05), and recipient weight > 90 kg (p = 0.1). From our data, a profile emerged of recipients likely to have a longer hospital stay. Important variables, either simultaneous with or related to DGF, include donor and recipient age, diabetes, pretransplant recipient weight, PRA at transplant, preservation time, and pretransplant respiratory or peripheral vascular disease.

Adolescent↗
PubMed1997

Effect of initial slow graft function on renal allograft rejection and survival.

Cadaver renal allografts with immediate excellent function have good long-term outcomes, while grafts with delayed function have been associated with an increased incidence of acute rejection (AR) and subsequent poor long-term graft survival. There is, however, an intermediate group with initial slow function whose outcome is not well defined. This group was examined by reviewing 510 patients that received primary cadaver transplants between 1/85 and 8/95. Recipients were grouped by initial function into: 1) those with immediate graft function (IGF), defined by serum creatinine (Cr) level < 3 mg/dl on post-operative day (POD) 5 (n = 237); 2) those with slow graft function (SGF), defined by serum Cr > 3 mg/dl on POD 5 but no need for dialysis (n = 160); and 3) those with delayed graft function (DGF), defined by the need for dialysis in the first week post-transplant (n = 113). Five-year graft survivals were determined for each group by Kaplan-Meier methods and compared by a generalized Wilcoxon test. The incidence of AR in the first 6 months was significantly higher in those with SGF (40%) vs. those with IGF (30%) (p < 0.05); both groups had a lower incidence than those with DGF (47%) (p < 0.05). In the absence of AR, 5-yr graft survival was similar between the 3 groups, 94%, 97% and 92% for IGF, SGF and DGF respectively. In the presence of AR, 5-yr graft survival was significantly reduced in all groups, but most notably in those with SGF (51%) or DGF (53%), as compared to those with IGF (80%), (p < 0.001). We conclude that recipients with SGF, but no AR, have excellent outcomes, comparable to those with IGF. However, there is an increased incidence of early AR associated with SGF. In recipients with SGF or DGF, AR has a more profound detrimental effect on long-term graft survival than in the IGF group. Thus, recipients with SGF are at increased risk for AR with resultant poor long-term graft survival, and may need modified immunosuppressive protocols.

Adult↗
PubMed1997

Pancreas transplants for United States (US) and non-US cases as reported to the International Pancreas Transplant Registry (IPTR) and to the United Network for Organ Sharing (UNOS).

As of November 1997 more than 9,800 pancreas transplants had been reported to the IPTR, including more than 7,400 US and more than 2,400 non-US cases. Cases reported since the inception of UNOS in 1987 (more than 6,800 in the US and more than 2,000 from outside the US) were analyzed, with emphasis on 1994-97 cases. In the US, for all 1994-97 SPK transplants (n = 2,585), one-year patient, pancreas and kidney graft survival rates were 94%, 82% and 90%, respectively; for all PAK cases (n = 230), patient and graft survival rates at one year were 95% and 71%; and for all PTA cases (n = 117), patient and graft survival rates at one year were 93% and 62%, respectively. The 1994-97 pancreas survival rates in all categories were significantly higher than in previous eras. Analysis of bladder versus enteric drainage (BD vs ED) was made only for 1994-97 SPK cases since there were too few solitary ED cases for a comparison. One-year pancreas survival rates (all causes of failure included) were 83% for BD (n = 1,995) versus 80% for ED (n = 456) cases (p = NS). However, nearly 20% of SPK BD grafts had been converted to ED by 2 years. The pancreas retransplant success rates have also significantly increased over time. For 1994-97 pancreas retransplants (n = 92), the one-year graft survival rate was 72%. The technical failure (TF) rate for pancreas transplants has declined over time. For 1994-96 BD cases, the TF rate was 8% in SPK (n = 1,995), 13% in PAK (n = 174) and 11% in PTA (n = 90) cases. For SPK ED cases (n = 456) the TF rate was 11% (p = 0.06 vs SPK BD). The most common cause of technical loss was graft thrombosis, 5.5% for SPK, 10.2% for PAK and 6.7% for PTA. The TF rates were significantly higher in grafts from older (> 45 yrs) donors and donors who died from cardiovascular disease. The immunological graft loss rate has also significantly declined in all categories. For 1994-97, technically successful (TS) cases (DWFG censored), the rejection loss rate at one year was 2% in the SPK (n = 2,234), 9% in the PAK (n = 154), and 16% in the PTA (n = 78) categories. Cox multivariate analyses were done in each recipient category to assess for factors that influence risks of pancreas graft loss. Increasing donor age was a risk factor in all categories. HLA mismatching was important only in the solitary (PAK and PTA) categories. FK506 use was associated with a positive effect in all categories, as was MMF in the SPK category.

Graft Survival↗
PubMed1996

Kidney transplant recipients who die with functioning grafts: serum creatinine level and cause of death.

How to analyze death with function (DWF) in transplant survival statistics has become an important issue. DWF is a predominant cause of late graft loss. We recognize that some deaths may be related to the transplant. However, considering DWF as a graft loss may obscure some analyses. An additional consideration is whether patients who "die with function" actually had good kidney function or whether their death was related to or hastened by impaired function. To answer this question, we studied the serum creatinine level and cause of death for kidney recipients who died with function. Between January 1, 1985, and December 31, 1994, we did 1932 kidney transplants for 1806 recipients. Of these, 220 died with function. For the 220, we assessed the time posttransplant that death occurred, the serum creatinine level before the terminal event, and the cause of death. The most common causes of death were infection (22%), myocardial infarction (17%), and sudden death (15%). Mean serum creatinine levels were less than 2 mg/100 ml at 1 year before and at the time of death for the vast majority of these recipients. Our findings demonstrate that kidney recipients who die with function have good renal function--additional support for presenting graft survival data both with and without death censored.

Cause of Death↗
PubMed1996

Nitric oxide mediates early dysfunction of rat and mouse islets after transplantation.

Evidence presented in this paper indicates that nitric oxide (NO), generated by a nonspecific "wound"-type of inflammation, is an important mediator of the early dysfunction of transplanted islets in rodents. Although allogeneic islets stimulate NO production to a greater degree than syngeneic islets, the amounts of NO produced after either are significantly elevated above baseline. Inhibition of NO production by N(G)-monomethyl-L-arginine (NMA), markedly decreases the time needed to restore euglycemia after intraportal transplantation of syngeneic islets in diabetic rats. The dose of NMA used was not observably toxic, with no significant changes in blood pressure, hepatic artery blood flow, serum hepatic enzyme levels, or in weight compared with control animals. In rat recipients of intraportal syngeneic transplants, evidence that NO is produced at the site of implantation includes (1) an early and transient increase in posttransplant hepatic vein nitrate levels (pretransplant, 90 microM; 24 hr, 230 microM; 48 hr, 250 microM; 72 hr, 170 microM; and 96 hr, 140 microM), (2) concurrent appearance of inducible NO synthase mRNA in liver extracts, and (3) immunohistochemical localization of inducible NO synthase within the transplanted islets. Suppression of NO production or inhibition of NO activity is a potential strategy to increase the early function and engraftment transplanted islets in the clinical setting.

Animals↗
PubMed1996

Improved islet isolation from rat pancreas using 35% bovine serum albumin in combination with Dextran gradient separation.

We have developed a gradient separation technique in which albumin-coated (35% BSA) rat islets are isolated in Dextran (BSA/D). Versus Dextran alone (DA), BSA/D increases mean islet yield from 850 +/- 115 to 1222 +/- 210 islets/donor (mean +/- SD, P=.001). With numbers of donors held constant, the time to euglycemia was significantly shorter in syngenic recipients of BSA/D than DA islets (5.7 +/- 4.8 versus 14.2 +/- 5.6 days, P=.02). However, when the number of islets were held constant, differences in time to cure were not statistically significantly different (P>.19): with 1200 islets, 3.8 +/- 2.8 (DSA/D) versus 9.2 +/- 8.2 (DA) days; with 750 islets, 18.3 +/- 5.8 (BSA/D) versus 18.0 +/- 4.5 (DA) days. In all groups, posttransplant day 1 glucose was lowest with the BSA/D technique. Thus BSA/D isolation gives a higher yield with at least equal viability. We recommend the BSA/D technique for its efficiency and economy.

Animals↗
PubMed1996

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.

Adult↗
PubMed1996

Simultaneous kidney and segmental pancreas transplants from living related donors - the first two successful cases.

Simultaneous pancreas and kidney transplants (SPKs) from cadaver donors have become a widely accepted treatment option for insulin-dependent (Type I diabetic) patients with end-stage nephropathy. However, for technically successful transplants, long-term success is better with living donors (LDs). Sequential kidney and pancreas transplants from LDs have been done, but until now SPKs from LDs have not been attempted. We report here 2 successful SPKs from LDs. Both recipients received a right kidney and distal pancreas: the first (a 28-year-old woman, diabetic since age 7) from her 54-year-old mother; the second (a 46-year-old man, diabetic since age 31) from his 44-year-old sister. Six months posttransplant both recipients have function of both grafts (serum creatinine < or = to 1.5 mg/dl; serum C-peptide normal range, fasting and stimulated). Thus, SPKs from LDs are technically feasible and could be an alternative to segmental transplants or cadaver SPKs for selected type I diabetic patients with end-stage nephropathy.

Adult↗
PubMed1996

Employment patterns after successful kidney transplantation.

We studied 822 kidney transplant recipients followed 1-9 years to determine the dynamics of their entering and leaving the work force. Multivariate analysis revealed that not being diabetic and that being employed pretransplant were associated with a higher rate of posttransplant employment. Some recipients in all pretransplant employment categories, including those receiving disability benefits pretransplant, returned to full-time work posttransplant. The most rapid return to work was in those who had been working full-time or attending school pretransplant. After returning to work, a higher percentage of diabetic recipients stopped working; of those who stopped working, 50% received disability benefits. In contrast, nondiabetic recipients who stopped working full-time were more likely to be retired or working part-time; only 22% received disability benefits.

Adult↗
PubMed1996

A multicenter analysis of the first experience with FK506 for induction and rescue therapy after pancreas transplantation.

Between May 1, 1993 and April 5, 1995, 154 pancreas allograft recipients at 9 institutions were given FK506 posttransplant. Three groups were studied: (1) recipients given FK506 initially for induction and maintenance therapy (n = 82), (2) recipients switched to FK506 for antirejection or rescue therapy (n = 61), and (3) recipients converted to FK506 for other reasons (n = 11). Of 82 patients in the induction group, 7 (9%) had simultaneous bone marrow (BM) and pancreas-kidney (SPK-BM) transplants, 54 (66%) had SPK transplants without BM, 14 (17%) had pancreas transplants alone (PTA), and 7 (9%) had pancreas after previous kidney transplants (PAK). All but 1 recipient was given quadruple immunosuppression (anti-T cell agents plus azathioprine and prednisone) for induction. The median FK506 starting dose was 4 mg/day p.o.; the median average FK506 blood level, 12 ng/ml. The most common side effects were neurotoxicity (16%), nephrotoxicity (13%), and gastrointestinal toxicity (9%). New-onset diabetes mellitus requiring permanent insulin therapy did not occur. Of 61 transplants in the rescue group, 44 (72%) were SPK, 11 (18%) PTA, and 6 (10%) PAK. All but 3 (95%) of the recipients had been on cyclosporine-azathioprine-prednisone triple immunosuppression before substitution of FK506 for cyclosporine; 46% of the recipients had one, and 54% > or = 2, rejection episodes preconversion. The most common side effects were nephrotoxicity (25%), neurotoxicity (23%), and gastrointestinal toxicity (21%). Two recipients were reconverted to cyclosporine because of transient hyperglycemia, and one recipient is on insulin. In the induction group, patient survival at 6 months was 90% for SPK, 100% for PTA, and 100% for PAK. According to a matched-pair analysis, pancreas graft survival for SPK recipients at 6 months was 87% for FK506 versus 70% for cyclosporine recipients (P = 0.04); for PTA recipients, 84% versus 66% (P = n.s.); and for PAK recipients, 80% versus 14% (P = 0.11). When technical failures and death with functioning grafts were censored, pancreas graft survival remained significantly better in the FK506 group. The incidence of first reversible rejection episodes by 6 months in FK506 recipients was 35% for SPK, 40% for PTA, and 20% for PAK. Of 75 pancreas grafts, 64 are currently functioning; in 5 recipients the pancreas failed (1 from rejection); 6 recipients died with a functioning pancreas graft. There were 3 posttransplant lymphomas (all EBV-positive); 2 recipients died and 1 is alive after subtotal colectomy and transplant pancreatectomy. In the antirejection rescue group, patient survival rates at 6 months were 91% for SPK, 100% for PTA, and 80% for PAK (P = n.s.). Pancreas graft survival rates at 6 months were 90% for SPK, 72% for PTA, and 40% for PAK. The incidence of first reversible rejection episodes after conversion to FK506 at 6 months was 44% in SPK, 54% in PTA, and 50% in PAK. Of 61 pancreas grafts, 51 are currently functioning; in 7 recipients the pancreas failed (5 from rejection); 3 recipients died with a functioning graft. There were no posttransplant lymphomas in the rescue group. This multicenter survey shows that FK506 in pancreas transplantation is associated with (1) a low rate of graft loss from rejection when used for induction therapy, (2) a high rate of graft salvage when used for rescue or rejection therapy, and (3) a very low rate of new-onset insulin-dependent diabetes mellitus. These encouraging results are tarnished by 3 posttransplant lymphomas in the induction group; a possible explanation is overimmunosuppression, but further (randomized) studies are necessary to analyze the long-term risk-benefit ratio of FK506 after pancreas transplantation.

Adolescent↗
PubMed1996

Long-term peritoneal dialysis before transplantation and intra-abdominal infection after simultaneous pancreas-kidney transplantations.

OBJECTIVE: To investigate whether long-term peritoneal dialysis before transplantation entails a higher risk than hemodialysis for intra-abdominal infection after bladder-drained simultaneous pancreas-kidney transplantations. DESIGN: Large single-center case-control study. SETTING: A large university hospital (referral center). PATIENTS: In all, 189 bladder-drained simultaneous pancreas-kidney transplantations were done from January 1, 1986, to December 31, 1994: before transplantations were performed, 32 recipients (17%) were undergoing peritoneal dialysis, 71 recipients (38%) were undergoing hemodialysis, and 86 recipients (46) were not undergoing dialysis. MAIN OUTCOME MEASURES: The intra-abdominal infection rate after transplantation and the rate of graft loss due to infection. RESULTS: Intra-abdominal infections developed in 33 recipients (18%) after transplantation. Graft and patient survival rates were significantly lower for recipients with vs without an infection (P < .001 for both). Both the dialysis mode and dialysis dependence did not affect the infection rate: of the 33 recipients with an infection, 7 (21%) were undergoing peritoneal dialysis, 15 (46%) were undergoing hemodialysis, and 11 (33%) were not undergoing dialysis before transplantation (P = .3). The rate of graft loss due to infection was not significantly different for recipients who were undergoing peritoneal dialysis vs hemodialysis (P = .1). However, it was higher for recipients who were undergoing dialysis (peritoneal dialysis and hemodialysis) vs those patients who were not undergoing dialysis (P = .04). CONCLUSIONS: Candidates for simultaneous pancreas-kidney transplantation should undergo the transplantation preemptively (ie, before they become dependent on dialysis) because the rate of graft loss due to infection was higher for recipients who were undergoing dialysis (irrespective of the dialysis mode). If dialysis cannot be avoided, the choice of peritoneal dialysis vs hemodialysis can be individualized, since these dialysis modes do not have significantly different rates of infection or of graft loss due to infection.

Adult↗
PubMed1996

Pancreas graft loss caused by intra-abdominal infection. A risk factor for a subsequent pancreas retransplantation.

OBJECTIVE: To investigate whether previous pancreas graft loss caused by intra-abdominal infection is a risk factor for a subsequent pancreas retransplantation. DESIGN: Retrospective case-series analysis. SETTING: Large university hospital. PATIENTS: Of 97 pancreatic retransplantations (July 1, 1985 to June 30, 1994), 13 (13%) were performed after previous pancreas grafts had been lost because of intra-abdominal infection. MAIN OUTCOME MEASURES: Cause of retransplant graft loss; patient survival. RESULTS: Of 13 cases of pancreatic retransplantations performed after previous grafts had been lost because of intra-abdominal infection, 12 (92%) were again complicated by intra-abdominal infection. Of these 12 retransplantation infections, 10 were caused by the same microbial species that had caused failure of the previous graft 1 to 5 years earlier (8 required graft pancreatectomy [mortality rate, 25%], and 2 were successfully treated) and 2 were caused by different microbial species (both required graft pancreatectomy [mortality rate, 0%]). In 1 of the 13 retransplantations, prophylactic antimicrobial treatment was directed at the microbial species that had caused failure of the previous graft; no recurrent intra-abdominal infection developed. CONCLUSIONS: Intra-abdominal infection after a previous pancreas transplantation is a risk factor for recurrence of infection by the same microbial species after a subsequent retransplantation. For the selected patients who are considered for retransplantation in spite of their previous graft loss caused by intra-abdominal infection, periretransplantation antimicrobial prophylaxis should include a prolonged course of an agent directed against the previously identified microbial species.

Abdomen↗
PubMed1996

Neuropathy and mortality in diabetes: influence of pancreas transplantation.

We collected information on patient status and cause of death for 545 insulin-dependent diabetic subjects who had cardiorespiratory reflex and nerve conduction tests performed to determine if presence and severity of autonomic and somatic neuropathy is associated with mortality and if a functioning pancreas transplantation (PTx) influences mortality. Follow-up was 12-138 months. Abnormal cardiorespiratory reflexes were present in 417 patients and there was abnormal nerve conduction in 392 patients. Mortality rates for patients with abnormal tests were higher (P < 0.0001) than for patients with normal tests. A total neuropathy score that included cardiorespiratory and nerve conduction test scores predicted survival better than separate scores. Patients with moderate neuropathy, but not those with severe neuropathy, who retained a functioning PTx, had longer survival times than patients whose PTx failed in the first 3 months. Considering only patients transplanted after 1985, those with moderate neuropathy who retained a functioning PTx had even longer survival times than nontransplanted patients.

Adult↗
PubMed1996

Use of FK 506 in pancreas transplantation.

Until recently, FK 506 was used only for rescue therapy after pancreas transplantation. We report our initial experience with FK 506 for 67 pancreas recipients (treated between 1 May 1993 and 30 April 1995). Of these recipients, 49 (73%) received FK 506 for induction and maintenance therapy, 12 (18%) for rescue or antirejection therapy, and 6 (9%) for reasons other than rescue or antirejection therapy. In our induction and maintenance therapy group, 32 recipients (65%) underwent a simultaneous pancreas-kidney transplant (SPK), 8 (16%) a pancreas transplant alone (PTA), and 9 (19%) a pancreas after previous kidney transplant (PAK). Quadruple immunosuppression was used for induction; the median FK 506 starting dose was 4 mg/day p.o. and target levels were 10-20 ng/ml. The most common side effects were nephrotoxicity (16%) and neurotoxicity (14%); transient episodes of hyperglycemia were also noted (12%), in particular in the presence of concurrent rejection and infection episodes. A matched-pair analysis was done to compare graft outcome with FK 506 versus cyclosporin A (CsA). For SPK recipients, pancreas graft survival at 6 months was 79% with FK 506 versus 65% with CsA (P = 0.04), for PTA, 100% versus 63% (P > 0.35), and for PAK, 88% versus 33% (P > 0.01). Pancreas graft loss due to rejection at 6 months posttransplant was lower with FK 506 versus CsA. Two FK 506 recipients died from B-cell lymphomas (Epstein-Barr virus positive) at 6 and 7 months posttransplant. In our rescue or anti-rejection group, 5 recipients underwent SPK, 3 PTA, and 4 PAK. The mean average FK 506 dose was 10 mg/day p.o. and the mean average FK 506 blood level was 11 ng/ml. The most common side effects were nephrotoxicity (33%) and neurotoxicity (16%). Two recipients developed hyperglycemic episodes, of whom 1 has remained on insulin with good exocrine pancreas graft function. Graft survival at 6 months after conversion was 75% for SPK, 67% for PTA, and 50% for PAK. Only one graft was lost due to chronic rejection. Our single-center experience shows that FK 506 after pancreas transplantation is associated with: (1) a low rate of graft loss due to rejection when used for induction, in particular for solitary pancreas transplants, (2) a high rate of graft salvage when used for rescue, (3) a 1% rate of new-onset insulin-dependent diabetes mellitus, and (4) a 3% rate of posttransplant lymphoma. Further studies are necessary to analyze the long-term impact of FK 506 on pancreas transplant outcome.

Adult↗
PubMed1996

Allograft tolerance by intrathymic donor splenocyte transfer: an age-dependent, species-specific phenomenon?

Protocols that allow allograft survival without immunosuppression remain the ultimate goal in transplantation. Intrathymic injection of donor splenocytes into a transiently immunosuppressed recipient has induced tolerance to a variety of subsequently transplanted allografts in rats. The purpose of this study was to determine if recipient age is critical to intrathymic tolerance in light of age-dependent thymic changes, and if this protocol can be extended to an outbred, large animal model. Prepubertal and postpubertal Wistar-Furth rats underwent intrathymic injection of splenocytes from Lewis rats and antilymphocyte serum (ALS) intraperitoneally. On day 21, a heterotopic Lewis heart was transplanted, with graft survival evaluated by cardiac palpation. Graft tolerance (> 100 days) occurred in four out of five (80%) of the prepubertal rats compared to two out of six (33%) postpubertal rats. Tolerance was not demonstrated in rats receiving intrathymic injection of buffer only. In puppies, groups 1 and 2 underwent splenectomy with intrathymic injection of allo splenocytes. Control puppies (group 3) received intrathymic auto splenocytes. Groups 1 and 3 were given antilymphocyte gamma globulin (ALG) on days 7 to 0 with respect to the intrathymic injection. Group 2 did not receive ALG, but instead received cyclosporin A (CSA) on days 0-2. On day 21, all puppies underwent bilateral nephrectomy and single renal transplantation. No additional immunosuppression was given. Tolerance (creatinine < 7 mg/dl for 100 days) was not obtained by any dog in all three groups. There was no difference in graft survival between control and experimental dogs, with the longest surviving graft seen in a control dog (26 days). Our results suggest that thymic change during maturation may alter the ability to induce tolerance by intrathymic injection of donor cells in rats, and that the protocol is not easily adapted to large animals.

Age Factors↗
PubMed1996

Total lymphoid irradiation, without intrathymic injection of donor cells, induces indefinite acceptance of heart but not islet or skin allografts in rats.

Allograft tolerance occurs in rodents given a dose of antilymphocyte serum (ALS) and intrathymic injection (ITI) of donor splenocytes (SC) 1-3 weeks prior to transplant (TX). The purpose of our study was to test total lymphoid irradiation (TLI) as an alternative to ALS in ITI tolerance induction to heart, islet, and skin allografts. Prepubertal Wistar Furth rats were recipients. ITI of donor (Lewis) SC was done at the end of the TLI course. Rats received either a heterotopic heart, a skin graft, or 2300 islets (diabetic recipients) intraportally from Lewis donors. TLI (without ITI) in a dose of 200 rads/day for 5 consecutive days, followed by TX in 3 weeks resulted in indefinite acceptance of heart (but not islet or skin) grafts in 60% of the recipients. These data indicate that TLI by a dose schedule of 200 rads/day for 5 days should be tested for clinical relevance in large animal recipients of immediately vascularized grafts.

Animals↗