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PubMed1999

Respiratory and limb muscle function in lung allograft recipients.

Lung transplantation recipients have reduced exercise capacity despite normal resting pulmonary and hemodynamic function. The limiting factor may be contractile dysfunction of skeletal muscle. To test this postulate, we measured limb and respiratory muscle function in nine clinically stable lung allograft recipients (six men and three women, aged 30 to 65 yr, at 5 to 102 mo after transplantation) with reduced exercise capacity. Respiratory muscle strength was tested by measuring maximal inspiratory and expiratory pressure (MIP and MEP, respectively). Ankle dorsiflexor muscle strength was measured during maximal voluntary contraction (MVC). In a subset of six recipients, we also measured contractile properties and fatigue characteristics of the tibialis anterior muscle, using electrical stimulation of the motor point. Data were compared with values from age- and sex-matched control subjects. MIP values of transplant recipients did not differ from control values; however, MEP was blunted by 30% relative to control (p < 0.05), and MVC was decreased by 39% (p < 0.05). The force-frequency relationships and fatigue characteristics of the tibialis anterior were not different between the patient and control groups. We conclude that stable lung allograft recipients experience expiratory and lower limb weakness that may contribute to exercise intolerance.

Adult↗
PubMed1989

Creatinine excretion after renal transplantation.

For alterations in serum creatinine to reflect changes in GFR, urine creatinine excretion must remain constant. Although serum creatinine is often used to monitor chronic changes in allograft GFR, creatinine excretion has not been systematically investigated in renal transplant recipients. In the present study, creatinine excretion was examined in 100 patients who survived at least 12 months with functioning renal allografts. Overall, there was a progressive decline in creatinine excretion from 1420 +/- 410 mg/24 hr at 3 months to 1240 +/- 394 mg/24 hr at last follow-up, 89 +/- 35 months after transplantation (mean +/- SD). The decline in creatinine excretion was greatest in those who subsequently returned to dialysis (-27.4 +/- 20.2%, P less than .05) compared with those who died (-6.9 +/- 24.1%), or survived with functioning allografts (-3.7 +/- 18.1%). Multivariate analysis demonstrated that age, sex, body weight, obesity, diabetes, and cumulative average daily corticosteroid dose (factors that affect muscle mass) all influenced creatinine excretion. However, early post-transplant clinical parameters failed to predict patients who subsequently had declines in creatinine excretion. Thus, it was not possible to predict patients in whom chronic changes in allograft function would be underestimated by changes in serum creatinine. Although clinically relevant functional alterations can be detected by changes in serum creatinine, additional measures of GFR should be used to complement the serum creatinine and monitor chronic changes in allograft function after renal transplantation.

Age Factors↗
PubMed1991

Time-related, cross-sectional and prospective follow-up of pancreatic endocrine function after pancreas allograft transplantation in type 1 (insulin-dependent) diabetic patients.

It has been established that successful pancreas transplantation in Type 1 (insulin-dependent) diabetic patients results in normal but exaggerated phasic glucose-induced insulin secretion, normal intravenous glucose disappearance rates, improved glucose recovery from insulin-induced hypoglycaemia, improved glucagon secretion during insulin-induced hypoglycaemia, but no alterations in pancreatic polypeptide responses to hypoglycaemia. However, previous reports have not segregated the data in terms of the length of time following successful transplantation and very little prospective data collected over time in individual patients has been published. This article reports that in general there are no significant differences in the level of improvement when comparing responses as early as three months post-operatively up to as long as two years post-operatively when examining the data cross-sectionally in patients who have successfully maintained their allografts. Moreover, this remarkable constancy in pancreatic islet function is also seen in a smaller group of patients who have been examined prospectively at various intervals post-operatively. It is concluded that successful pancreas transplantation results in remarkable improvements in Alpha and Beta cell but not PP cell function that are maintained for at least one to two years.

Blood Glucose↗
PubMed1998

Effects of combined radiation and thermal burn injury on the survival of skin allograft and immune function in rats.

OBJECTIVES: To investigate the effects of combined radiation and thermal burn injury on the survival of skin allografts and to analyze the relationship between the prolongation of allograft survival and the changes of immune functions of the thymocytes and splenocytes in rats. METHODS: Wistar rats were irradiated with 3, 4, 5, 6 and 8 Gy of gamma rays. Thirty minutes after radiation, 15% TBSA III-degree burn was inflicted to the rats. Twenty-four hours after the burn injury, allografts were used to cover the burn wounds. In the 8 Gy group, 1 hour before skin grafting, the bone marrow cells (4 x 10(8)) from the same donor were also transplanted. All rats were carefully observed after injury. The rats with single radiation injury of 5 Gy gamma rays, with single burn injury and with combined radiation-burn injury were killed 3, 7, 10, 15 and 30 days after skin grafting for immunological assay and pathological study. RESULTS: All the allografts in the single burn group were rejected in 10 days. In the combined injury groups, the survival rates of the allografts in rats undergoing 3 and 4 Gy radiation were 20% and 30%, respectively. In the combined injury groups undergoing 5, 6 and 8 Gy radiation, the 10-day survival rates of the allografts were 69%, 88% and 100% respectively, and the 30-day survival rates in the three groups were 36%, 42% and 100% separately. The grafted allogenic skin, with normal epithelial cells and good vascularity, healed well with the recipient's skin. Hairs grew well from the allografts 30 days after grafting. Three, 7 and 15 days after allografting, in the single burn group, the proliferative activities of the thymocytes were 90%, 185% and 130% of the preinjury level, and the antibody forming capacities of the splenocytes were 200%, 171% and 300% of the preinjury level, respectively; in the combined injury groups, the proliferative activities were 6%, 99% and 91% of the preinjury level, and the forming capacities were 2%, 36% and 90% of the preinjury level. CONCLUSIONS: The survival rate of allograft in rats undergoing combined radiation and thermal burn injury rises with the increase in radiation dosage. The allograft covering single bun injury is severely rejected by immune reaction. The prolongation of the survival of allograft in combined injury group mainly results from radiation that suppresses immune functions.

Animals↗
PubMedDate not supplied

Biomechanical analysis of patellar tendon allografts as a function of donor age.

We evaluated the biomechanical properties of patellar tendon allografts from donors aged 18 to 55 years. Bone-patellar tendon-bone complexes were harvested from acceptable donors and processed. Fat and soft tissue were removed, and the tendons were sectioned lengthwise leaving the central third. Area measurements were taken, and mechanical testing was performed. Specimens were pulled to failure at a rate of 10% of the initial length per second. The force at failure, tensile stress, modulus of elasticity, and percent elongation were determined for each specimen. There was no significant correlation (P > 0.05) between age and any of the mechanical properties. Load at failure ranged from 2110 to 4650 N, with a mean of 3424 N. Regression analysis showed slightly decreasing tensile stress with increasing age, but the correlation was not significant. It appears that patellar tendon allografts from donors up to age 55 have similar mechanical properties.

Adolescent↗
PubMed2001

Monocytes in the rat: phenotype and function during acute allograft rejection.

Cells of the monocyte/macrophage system originate from the bone marrow, reach the organs via the blood, immigrate through postcapillary venules and further differentiate into organ-specific tissue macrophages. In rats and other species, activated monocytes/macrophages aggravate autoimmune reactions, rejection of non-vascularized allografts and chronic allograft rejection. It is very likely that they also contribute to acute allograft destruction. So far it has been impossible to distinguish the function of monocytes from that of macrophages, because cell phenotypes and their alterations upon activation are ill-defined. We have thus begun to characterize the ex vivo phenotype and function of rat monocytes in the normal state and during renal allograft rejection. Monocytes are recovered from both the central and the marginal blood pool by perfusing either the recipient's circulation or the allograft vasculature. Rat monocytes have a unique surface phenotype. During allograft rejection or after infusion of interferon-gamma they up-regulate class II MHC molecules, CD161 (NKR-P1A), CD62L and CD8, while CD4 and CD43 are down-modulated. Activated perfusate monocytes exert increased in vitro cytotoxicity against tumour targets, which differs from that of NK cells. We speculate that activated monocytes contribute to kidney allograft destruction by directly damaging endothelial cells or by promoting intravascular coagulation.

Animals↗
PubMed2003

Alterations of the immune response with increasing recipient age are associated with reduced long-term organ graft function of rat kidney allografts.

BACKGROUND: Clinically, an increasing number of older recipients are listed for transplantation. We examined recipient age-associated alterations of the immune response and their effects on graft function. METHODS: Three- and 18-month-old Lewis (LEW) rats received kidneys from 3- and 18-month-old Fischer 344 (F344) rats (1.5 mg/kg/d cyclosporine A for 10 days; n=6/group) and were observed for 180 days. In additional groups, double kidney transplantations were performed to determine the impact of nephron mass and recipient age on graft outcome. RESULTS: All young recipients but only 66% of old recipients survived the observation period. Increasing recipient age resulted in a significant decrease in renal allograft function (P<0.001), more advanced morphologic evidence of chronic allograft damage (P<0.001), and greater cellular infiltration (P<0.05) and major histocompatibility complex expression (P<0.01) within grafts. Additional in vitro studies examined age-related changes in the cellular immune response by enzyme-linked immunosorbent assay, fluorescence-activated cell sorter analysis, and alloreactive enzyme-linked immunospot: splenocytes from old LEW rats produced significantly more interleukin (IL)-2 (P<0.0001), IL-4 (P<0.05), interferon (IFN)-gamma (P<0.0001), and tumor necrosis factor-alpha (P<0.05). IFN-gamma-producing memory-type T cells were significantly elevated in older rats (P<0.0001). Moreover, they revealed significantly more alloreactive T cells directed against F344 (146 +/- 64.2 and 512 +/- 277/10(6) T cells; P<0.05). Double renal allografts from young donors into old recipients confirmed an independent effect of recipient age on the acceleration of chronic graft deterioration. CONCLUSIONS: The enhanced cellular immune responsiveness in elderly recipients was associated with advanced chronic graft injury. Clinically, older recipients may need a modified immunosuppression.

Aging↗
PubMed1992

Effect of pregnancy on long-term function of renal allografts.

Pregnancy in renal allograft recipients is associated with hyperfiltration with the potential for glomerular damage and adverse effects on long-term graft prognosis. We have undertaken a case-controlled study of posttransplant follow-up for a mean of 12 years (range, 4 to 23) in 36 female renal allograft recipients, 18 who became pregnant and 18 controls (matched to underlying disease and renal function) who did not. Assessments included plasma creatinine (PCr), glomerular filtration rate (GFR) by infusion clearance of inulin (Cin), mean arterial pressure (MAP), and documentation of antihypertensive therapy. By the end of follow-up, PCr in the pregnancy group (112 +/- 73 mumol/L [1.26 +/- 0.83 mg/dL]) and controls (127 +/- 52 mumol/L [1.44 +/- 0.59 mg/dL]) had increased by 19% and 8%, respectively, and GFR in the pregnancy group (58 +/- 29 mL/min) and controls (56 +/- 32 mL/min) had decreased by 18% and 7%, respectively. Graft loss or chronic rejection occurred in two patients in each group and there was a death in the pregnancy group 9 years after the second of two successful pregnancies. MAP in the pregnancy group (96 +/- 12 mm Hg) had decreased by 1%, and in the controls (101 +/- 9 mm Hg) had increased by 5%. Two patients in the index group and three in the control group commenced antihypertensive therapy during follow-up. There was, therefore, no evidence of an adverse effect of pregnancy in renal allograft recipients on long-term renal function or development of hypertension.

Adult↗
PubMed1996

Echocardiographic characteristics of the cryopreserved allograft aortic valve replacement assessed by intraoperative transoesophageal echocardiography.

Improvements in cryopreservation techniques have made possible excellent long-term results using aortic valve allografts. Few studies, however, have examined the echocardiographic characteristics of allograft aortic valves and postoperative valve function. Aortic allograft function was evaluated in 16 patients by intraoperative transoesophageal echocardiography, postoperative catheterization, and angiography. The mean(s.d.) coaptation zone length of the allograft leaflet was significantly greater (7.3(1.4) mm) than that of the normal aortic valve (3.2(0.8) mm) (P < 0.01). No regurgitation was noted in any patients with coaptation zone length of 7-11 mm (P < 0.01). The increment of the leaflet coaptation zone length did not produce a significant pressure gradient during exercise and appeared to be one of the important mechanisms for the prevention of postoperative aortic regurgitation, because commissural orientations may be distorted in the new aortic position. This finding is consistent with the report that allografts with the largest diameter implantable in the recipient annulus should be selected for use.

Adult↗
PubMed1997

Combination leflunomide and cyclosporine prevents rejection of functional whole limb allografts in the rat.

Whole rear limbs were transplanted from Brown Norway or Lewis rat donors to Lewis rat recipients (n=6 per group). One group of allograft recipients was treated with leflunomide (10 mg/kg/24 hr/orally) and cyclosporine (5 mg/kg24 hr/orally) starting 2 days before to surgery. Treatment continued for 60 days or until graft rejection. Untreated allografts were rejected over 6-8 days. After isograft transplantation, weight bearing began by day 17-25 after surgery. Sensory function was restored by 50 days after surgery. All allografts in the drug-treated group survived the 60-day period; survival in this group was significantly longer (P=0.0001) than the untreated controls. Weight bearing began by day 30, but was incomplete in two rats at 60 days. Peroneal nerve function was present in half the rats at 60 days after surgery. Leflunomide combined with cyclosporine prevented whole limb allograft rejection across a major histocompatibility barrier.

Animals↗
PubMed1990

[Phenotype and function of cells infiltrating rat renal allograft].

Phenotype and function of graft infiltrating cells (GIC) from rat renal allografts were investigated in comparison with those of spleen (SP) cells, peripheral blood mononuclear cells (PBMC), and regional lymph node (LN) cells of the recipient. Relative proportions of all T cell, suppressor/cytotoxic T cell, helper T cell, and antigen-activated cell displayed significant increases in GIC during ongoing rejection assessed by flow cytometry. Cytolytic activity (using 51Cr release assay) of GIC on day 3 was much higher (20.2%) than those of SP (6.0%), PBMC (3.8%), and LN (3.2%) on BN target cells and this activity gradually increased during ongoing rejection up to 53.1% (GIC), on day 6. In vitro production of cytokines (IL-2, IL-3, gamma-IFN, and BSF-2) from these groups of cells were investigated. GIC demonstrated the most remarkable increases of cytokine production from day 3 to day 6. Especially, GIC on day 6 produced higher amount of BSF-2 compared with SP cells, PBMC and LN cells. These results demonstrated that alloactivated Th cells as well as Tc cells accumulated within the allografts and that the subtype of Th cells which produce BSF-2 preferentially assembled to the allograft.

Animals↗
PubMed2001

Impact of febrile infections on the long-term function of kidney allografts.

PURPOSE: We prospectively determined the impact of febrile infectious disease on long-term renal graft function compared with a matched control group. MATERIALS AND METHODS: Included in our study were 39 patients who presented with episodes of febrile infection with body temperature greater than 38C on 2 consecutive occasions, necessitating hospitalization. In addition, 39 controls without febrile infection requiring hospitalization within 2 months were chosen from the complete data pool of all renal transplant recipients followed at our transplant clinic using the matched pair technique. Renal function was estimated by serum creatinine and calculated creatinine clearance. RESULTS: Of the 39 patients with infection 15 had urinary tract infection and 24 had other, mostly bacterial infection, including pneumonia/severe bronchitis in 12, oral/dental infection in 2, gastroenteritis in 2, shunt sepsis in 1, herpes zoster in 1, cytomegalovirus in 1 and other in 5. Mean estimated creatinine clearance plus or minus standard deviation was similar in the infection and control groups at the beginning of the study (51 +/- 22 and 51 +/- 23 ml. per minute, respectively). During the infectious episode mean creatinine clearance significantly decreased to 38 +/- 17 ml. per minute in the infection group. After infection resolved creatinine clearance returned to an almost baseline mean value of 50 +/- 23 ml. per minute. However, after 2 years of followup there was a significant difference in mean creatinine clearance in the infection group versus controls (45 +/- 25 versus 52 +/- 25 ml. per minute, p = 0.022). CONCLUSIONS: To our knowledge we have shown for the first time in a prospective controlled study that febrile infectious episodes correlate with poor long-term renal graft function.

Adult↗
PubMed1988

Improved immediate function of renal allografts with Belzer perfusate.

The characteristics of 254 cadaveric kidneys were evaluated and the incidence of immediate function identified. The Belzer perfusate was used primarily (n = 140) and secondarily (n = 14) in combination with pulsatile machine perfusion. These two groups were compared with a previous group of kidneys machine-perfused with silica gel (cryoprecipitated human plasma). The incidence of immediate function of the group primarily perfused with Belzer perfusate was statistically significantly improved over that of the silica gel. The secondarily perfused Belzer group, "imported" kidneys previously preserved with simple cold storage, had notably longer periods of preservation and higher resistances on the machine. However, 100% of this group functioned immediately. Other findings in this study show that the Belzer perfusate allows for improved parenchymal function posttransplant, as noted by a more rapid clearance of serum creatinine posttransplant. When comparing the immediate function group with those suffering early dysfunction, there is a statistically significant increased resistance on the machine in the latter group. This allows for prediction of immediate function based on perfusion characteristics of the kidney. The Belzer perfusate, composed of metabolic substrates for high-energy phosphate production, improves the incidence of immediate function in machine-perfused kidneys, as well as improved qualitative function posttransplant. It also is effective as a "rescue" mechanism in previously simple cold-stored (ATP-depleted) kidneys.

Adenosine Triphosphate↗
PubMed1997

Long-term function (6 years) of islet allografts in type 1 diabetes.

Eight type 1 diabetic patients, ages 29-41 years, with mean diabetes duration of 23 years (range 18-29 years) received islet transplants from 1 to 5 donors. Seven patients had stable kidney allografts 1-11 years before the islet transplant, and one patient had a simultaneous islet-kidney allograft. Patients' blood glucose control was poor as reflected by the mean +/- SD HbA1c of 9.1 +/- 1.7% before transplant. Of the first three patients, two (1 and 3) achieved insulin independence for 36 and 38 days, respectively. Two recipients rejected their islet grafts within 1 month (2 and 8) and therefore were excluded from analysis. The HbA1c and insulin requirement of the six remaining patients who had persistent islet function for more than 60 days was significantly reduced from 9.3 +/- 1.9 to 6.4 +/- 1.0% (P = 0.002) and from 0.75 +/- 0.15 to 0.35 +/- 0.12 U x kg(-1) x day(-1) (P < 0.001), respectively. The two patients with the longest graft survival (4 and 6) achieved a normalization or near-normalization of their HbA1c levels during 6 years in the absence of severe episodes of hypoglycemia. As demonstrated by a decline in C-peptide response during Sustacal challenge tests over a 6-year period, there was a diminution of islet allograft function over time, despite persistence of normal or near normal HbA1c. We concluded that transplantation of allogeneic islets with an islet mass comparable with whole or segmental pancreas transplants in type 1 diabetic patients can result in long-term islet allograft function; further, we concluded that, in conjunction with small dosages of exogenous insulin, a functioning islet allograft can result in near-normalization of blood glucose levels and significant improvement in HbA1c. The occurrence of severe hypoglycemic episodes observed for patients in the Diabetes Control and Complications Trial was not observed in recipients with functioning islet transplants, despite the continuous need for exogenous insulin therapy to sustain normal HbA1c over the 6-year follow-up. The significant improvement in metabolic control observed for the patients described in this study, and the potential to significantly decrease or halt the progression of diabetic complications, support the continued application of islet allotransplantation as a treatment modality for type 1 diabetic patients.

Adult↗
PubMed1990

Improved results using OKT3 as induction immunosuppression in renal allograft recipients with delayed graft function.

Delayed graft function remains a major problem in cadaveric renal allograft transplantation. We have used 2 different immunosuppressive induction regimens in patients with delayed graft function. The first regimen, used in 40 patients from January 1985 to December 1986, consisted of CsA (8 mg/kg/day, orally within 48 hr of cadaveric renal transplantation regardless of graft function), azathioprine (1.5-2.5 mg/kg/day), and steroids (methylprednisolone 375 mg on day 0, then prednisone tapered to 30 mg/day by day 10 with slow tapering to 7.5-10 mg/day over the first 6 months after transplantation). A second regimen, used from January 1987 to March 1989, employed the same doses of azathioprine and steroids; however, OKT3 (5 mg i.v./day for 7-21 days) was administered in the 34 patients who had delayed graft function. CsA was withheld until ATN resolved. The use of OKT3 as induction immunosuppression in patients with ATN led to a significant increase in 1-year graft survival (80% vs. 55%) while markedly decreasing the incidence of rejection episodes (44% vs. 82%) and the duration of nonfunction (9.4 vs. 14.9 days). There were 5 CMV infections in patients treated with OKT3. Antibodies to OKT3 developed in only 1 of 34 patients treated with OKT3. Five of 7 patients who received a second course of OKT3 successfully reversed the rejection episode. Patient survival (89%) was the same in the 2 groups. The benefit of OKT3 on long-term graft survival appears to stem from elimination of early rejection episodes that may be difficult to diagnose in a poorly functioning allograft. We conclude that OKT3 induction provides superior results over CsA induction at doses given in renal allograft recipients with delayed graft function without a significant increase in morbidity or mortality and permits the reuse of OKT3 for treatment of rejection in most cases.

Antibodies, Anti-Idiotypic↗
PubMed1987

Segmental small intestinal allografts. II. Inadequate function with cyclosporine immunosuppression: evidence of a protein-losing enteropathy.

Terminal ileum was autografted (24 dogs) or allografted (18 dogs) as a 100-cm Thiry-Vella segment, and absorption, motility, and histology were studied. Dogs with allografts were given cyclosporine (CsA) 20 mg/kg/day. At a second operation 5 to 6 weeks after transplantation continuity of the nontransplanted intestine with the Thiry-Vella segment was restored. At a third operation 3 months after autografting, all the non-transplanted small intestine was excised. All technically successful autografts survived indefinitely, and the dogs weights were maintained at 88 +/- 0.6% (mean +/- SE) of preoperative weights by absorption from the autografted intestine. Administration of cyclosporine to dogs with intestinal autografts produced a reversible impairment of intestinal absorption. Dogs with allografts survived 63.3 +/- 15.5 days (mean +/- SE). Death within 9 weeks of transplantation was from peritonitis secondary to graft rejection. Death in long survivors was a consequence of inadequate intestinal absorption. In the first 4 weeks after transplantation absorption and motility of allografted Thiry-Vella segments was comparable to the intestinal autografts but allografts showed evidence of a protein losing enteropathy. Large volumes of high protein-content fluid were lost from the allografted Thiry-Vella segments, and dogs with allografts became hypoalbuminemic.

Animals↗
PubMed1995

Effect of pregnancy on the long-term function of renal allografts: an update.

In 1992 we published a case-controlled study of posttransplant follow-up in 36 renal allograft recipients (Am J Kidney Dis 19:167-172, 1992). Eighteen of these patients became pregnant and comprise the index group; the 18 patients who did not become pregnant were considered controls. By the end of the follow-up period, plasma creatinine in the index group and controls had increased by 19% and 8%, respectively. Graft loss or chronic rejection occurred in one patient in the index group and in two in the control group. As there were no significant differences between the two groups, we concluded that pregnancy was unlikely to have a major effect on long-term graft function and/or survival. Subsequently, a case control study of Finnish women demonstrated graft survival favoring women who never conceived versus those who did (69% v 100%, respectively; P < 0.005) and thus prompted us to extend our posttransplant follow-up by a further 3 years. Data are currently available for 17 index subjects and 17 controls and during the entire follow-up period, graft losses have occurred in one index subject and in four controls. Plasma creatinine at the end of the follow-up period (1.40 +/- 0.52 mg/dL and 1.54 +/- 0.95 mg/dL, respectively) had increased from 3 years earlier by 11% and 7%, respectively, increments across time that were not significant. Although the increase in plasma creatinine was greater in the index subjects compared with the controls, there were no significant differences between the two groups. While our data do not exclude a minor deleterious effect of pregnancy on long-term graft function, we believe that female allograft recipients can be reassured that pregnancy is unlikely to substantially alter long-term graft function.

Adult↗