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Clinical kidney transplants, 1988.

1. The one-year graft survival rate of cadaver donor transplants has increased from about 40% in 1965 to almost 80% in 1988. Much of the improvement lies in the reduction of the one-month failure rates, which went down from one quarter in 1965 to 10% in 1988. 2. Kidneys that failed to function in the first month occurred in 5% of first graft patients without cytotoxins and increased to 9% if cytotoxins to more than 50% of the random panel were present. The non-function rate was 9% in regrafted patients without antibodies and double (18%) in those with a PRA of less than 50%. 3. Some indication that the harmful antibodies can be detected by flow cytometry is provided by the fact that low graft survival rates resulted when transplants were done across a positive flow cytometry crossmatch in sensitized patients and in second graft recipients. In non-sensitized patients and in first graft patients, flow cytometry crossmatches against T cells were of no value. 4. The difference between first grafts, second grafts and transplants into sensitized patients disappeared when the grafts that did not function at one month were removed. 5. Cold ischemia time up to 36 hours had no effect on 1-3-year survival rates. Cold ischemia had relatively little effect even on delayed function in first transplants. However, in regrafts and in grafts into patients with preformed cytotoxins, increasing cold ischemia resulted in an increased incidence of delayed function.(ABSTRACT TRUNCATED AT 250 WORDS)

Graft Survival↗

Delayed implantation of nigral grafts improves survival of dopamine neurones and rate of functional recovery.

In order to test the hypothesis that poor survival of dopaminergic neurones in nigral transplants may be due, at least in part, to acute toxic changes in the host striatum within the first hour after injury, we experimentally evaluated the consequences of imposing a brief delay (20 min, 1 or 3 h) between positioning the injection cannula and extruding the graft tissue. A delay of as little as 1 h resulted in a three-fold increase in survival of dopamine neurones in the grafts and a more rapid abolition of amphetamine-induced rotational asymmetry in the host animals. These results suggest that acute but rapidly resolving changes in the host striatal environment induced by the implantation procedure itself can have a significantly deleterious effect on the survival of embryonic nigral grafts.

Amphetamine↗

Transplantation of kidneys from expanded criteria donors.

BACKGROUND: The critical shortage of organs for transplantation has resulted in a controversial expansion of the criteria used to define a suitable cadaveric organ donor. The shortage of kidneys has a particularly hard impact on those patients on the waiting list who have uncommon major histocompatibility antigens or who are highly immunized. METHODS: To determine outcomes between patients receiving grafts from expanded criteria donors (ECDs) and others, a retrospective review of 105 consecutive kidney transplantations performed at a single institution during a 3 1/2 year period was conducted. A total of 44 (41.9%) patients received kidneys from ECDs, 45 (42.9%) from conventional cadaveric donors, and 16 (15.2%) from live donors. All patients were treated by the same physicians and received either triple or quadruple sequential immunosuppressive therapy. In general, high risk recipients did not receive kidneys from ECDs. RESULTS: Actuarial graft survival, incidence of delayed function, length of stay, and hospital charges were not significantly different between the ECD and conventional cadaveric donor groups of recipients. A higher incidence of urinary complications occurred in the ECD group (p=0.03). This incidence was noted primarily in the recipients of kidneys from donors 5 years of age or younger. However, no allografts were lost as a result of urinary complications. ECD kidneys that were imported from outside the local catchment area accounted for approximately 25% of all cadaveric transplantations performed. CONCLUSIONS: With appropriate selection of organs from ECDs, acceptable results can be obtained. ECD organs can serve to partially alleviate the extreme organ shortage. These organs should be procured and made available to those centers willing to use them.

Adult↗

Early and late recipient graft function and donor outcome after laparoscopic vs open adult live donor nephrectomy for pediatric renal transplantation.

BACKGROUND: Laparoscopically procured live donor kidney grafts are increasingly transplanted into pediatric recipients. The safety and efficacy of this changed surgical practice are unknown. HYPOTHESIS: Outcomes of laparoscopic vs open donor grafts in recipients 18 years and younger are equivalent. DESIGN AND SETTING: Retrospective review at an academic tertiary care referral center. PATIENTS: Eleven consecutive pediatric recipients of laparoscopically procured kidneys between April 1, 1997, and December 31, 2001, were pair matched for age with 11 recipients of openly procured kidneys between December 1, 1991, and March 31, 1997; the 22 adult donors were also studied. MAIN OUTCOME MEASURES: Recipients: surgical complications, graft function and survival. Donors: perioperative morbidity and length of hospital stay. RESULTS: Twenty (91%) of 22 kidneys were donated by a parent of the recipient. In recipients of laparoscopically procured grafts, we observed significantly lower creatinine clearances and higher creatinine levels on days 1, 4, and 6, but by 1 month, graft function was similar in both groups. No significant differences in surgical complications, delayed function, acute and chronic rejection, and graft survival rates were found. No laparoscopic or open donor required blood transfusion, reoperation, or hospital readmission. One laparoscopic donor (9%) was converted to open nephrectomy. For laparoscopic vs open donors, median operative time was longer (difference, 67 min; P =.08), but median postoperative length of stay was significantly shorter (3 vs 5 days; P =.02). CONCLUSIONS: Laparoscopic live donor nephrectomy has no adverse impact on pediatric recipient outcomes. For donors, the laparoscopic operation is safe and the hospital stay is shortened. These results support the continued use of laparoscopically procured live donor kidneys in pediatric renal transplantation.

Adolescent↗

[Kidney transplantation using living donors over age 65].

Efforts to increase the donor pool of available organs have resulted in some unconventional kidney transplantation procedures. One of these is the use of elderly donors for both living and cadaver kidney transplantations. The aim of this study was to review our experience with kidney transplants from living elderly donors. During a period of 10 years, 70 living renal transplantations were performed. In 32 transplants the age of the donor was above 65 years (mean 69 +/- 4 years, range: 65 to 81 years) and in 10 of these 32 transplants the age of the donor was over 70 years. The survival rate was compared with that of 38 transplants from younger donors (mean age 51 +/- 6 years, range: 24 to 59 years). The time to cold and warm ischemia, the preservation procedure and time to anastomosis of blood vessels were comparable in both groups of donors. Immunosuppression included a sequential quadruple protocol, using thymoglobulin (ATG), prednisolone (PRED), azathioprin (AZA) and cyclosporin A (CsA), which replaced ATG/PRED after day seven. A triple drug maintenance therapy (AZA, PRED, CsA) was used in all recipients. Kaplan-Meier survival curves at 1, 3 and 5 years showed that graft survival was 88%, 79% and 64% respectively for grafts from the advanced age donor group and 92%, 82% and 68% respectively for grafts from the younger donor group. The difference was slightly statistically significant (p < 0.05). Functioning of the graft was delayed in six patients who had received grafts from elderly donors and in one patient who had received a graft from a young donor. Despite worse results in transplantation with grafts from elderly donors, we consider this population as an important source of kidneys, which might help solve the present organ shortage, especially in our region.

Adult↗

Gamma delta TCR+ hybridomas derived from mice preimmunized via the portal vein adoptively transfer increased skin allograft survival in vivo.

C57BL/6 mice receiving pretransplant immunization with C3H.SW spleen cells via the portal vein, but not the vena cava, show Ag-specific delayed rejection of allogeneic C3H.SW skin grafts. This delayed rejection is not seen if preimmunization is performed in gamma delta TCR knockout (C57BL/6-Tcrdtm1Mom) mice. gamma delta TCR+ and alpha beta TCR+ hybridoma cells were prepared from Peyer's patch cells harvested from C57BL/6 mice 4 days following portal venous immunization with 100 x 10(6) irradiated C3H.SW spleen cells and skin grafting with C3H.SW tail skin. After recloning, these hybridoma cells were tested for cytokine production in vitro following restimulation with irradiated C3H.SW spleen cells and for their ability to delay rejection of C3H.SW skin grafts after adoptive transfer to C57BL/6 mice. Delayed graft rejection was a function of cells that showed preferential production of IL-10, not IFN-gamma, in vitro, independent of the source (vena cava or portal vein immunized mice) or the TCR phenotype of the hybridoma. Simultaneous infusion of anti-IL-10 mAb abolished this graft prolongation effect of transferred gamma delta TCR+ hybridomas. Hybridoma cells producing IL-10 on restimulation could polarize cytokine production from freshly stimulated mesenteric lymph node away from production of IL-2 and IFN-gamma, and toward IL-4, IL-10, and TGF-beta production. This immunoregulation by hybridoma cells in vivo and in vitro was observed even for third party Ag-stimulated mice/cells as long as the hybridoma cells themselves received stimulation with their specific Ag.

Adoptive Transfer↗

Delayed grafting of BDNF and NT-3 producing fibroblasts into the injured spinal cord stimulates sprouting, partially rescues axotomized red nucleus neurons from loss and atrophy, and provides limited regeneration.

Ex vivo gene therapy, utilizing modified fibroblasts that deliver BDNF or NT-3 to the acutely injured spinal cord, has been shown to elicit regeneration and recovery of function in the adult rat. Delayed grafting into the injured spinal cord is of great clinical interest as a model for treatment of chronic injury but may pose additional obstacles that are not present after acute injury, such as the need to remove an established scar, increased retrograde cell loss and/or atrophy, and diminished capacity for regeneration by neurons which may be doubly injured. The purpose of the present study was to determine if delayed grafting of neurotrophin secreting fibroblasts would have anatomical effects similar to those seen in acute grafting models. We grafted a mixture of BDNF and NT-3 producing fibroblasts or control fibroblasts into a complete unilateral cervical hemisection after a 6-week delay. Fourteen weeks after delayed grafting we found that both the neurotrophin secreting fibroblasts and control fibroblasts survived, but that only the neurotrophin secreting grafts provided a permissive environment for host axon growth, as indicated by immunostaining for RT-97, a marker for axonal neurofilaments, GAP-43, a marker for elongating axons, CGRP, a marker for dorsal root axons, and 5-HT, a marker for raphe spinal axons, within the graft. Anterograde tracing of the uninjured vestibulospinal tract showed growth into neurotrophin producing transplants but not into control grafts, while anterograde tracing of the axotomized rubrospinal tract showed a small number of regenerating axons within the genetically modified grafts, but none in control grafts. The neurotrophin expressing grafts, but not the control grafts, significantly reduced retrograde degeneration and atrophy in the injured red nucleus. Grafts of BDNF + NT-3 expressing fibroblasts delayed 6 weeks after injury therefore elicit growth from intact segmental and descending spinal tracts, stimulate modest regenerative growth by rubrospinal axons, and partially rescue axotomized supraspinal neurons and protect them from atrophy. The regeneration of rubrospinal axons into delayed transplants was much less than has been observed when similar transplants were placed acutely into a lateral funiculus or, after a 4-week delay, into a hemisection lesion. This suggests that the regenerative capacity of chronically injured red nucleus neurons was markedly diminished. The increased GAP43 reactivity in the corticospinal tracts ipsilaterally and contralaterally to the combination grafts suggests that these axons remain responsive to the neurotrophins, that the neurotrophins may stimulate both regenerative and sprouting responses, and that the grafted cells continue to secrete the neurotrophins.

Animals↗

Excellent results with calcineurin inhibitor-free initial immunosuppression in old recipients of old kidneys.

The ever increasing demand for donor organs has forced transplant surgeons to liberalize selection criteria. To avoid initial nephrotoxicity to kidneys from donors over 65 years of age, immunosuppression was begun with an IL-2 receptor antibody, mycophenolate mofetil, and steroids in a total of 38 recipients over 65 years. Calcineurin inhibitors (CI) were added after sufficient graft function was reached. After a mean cold ischemia time of 14:01 hours and a delayed function rate of 31%, patient survival, graft survival, and serum creatinine were 97.4%, 94.7%, and 1.5 mg/dL at 1 and 92.1%, 92.1%, and 1.7 mg/dL at 2 years, respectively. Thus, excellent results can be achieved in old recipients of old donor kidneys with CI-free initial immunosuppression.

Adrenal Cortex Hormones↗

Microchimerism does not induce tolerance after in utero transplantation and may lead to the development of alloreactivity.

In utero transplantation is a new technology that may provide non-toxic treatment for congenital disorders. However, a decade of research on in utero transplantation has demonstrated a low degree of chimerism and tolerance in small and large animal models as well as in human beings. We hypothesized that if large numbers of purified stem cells/progenitors were injected, a higher degree of tolerance would be induced. We have performed a 2-year experiment designed to study chimerism and tolerance after in utero transplantation with large numbers of cytokine-recruited C-kit+ cells. Chimerism in the blood and tissues was tested through the lifespan of the animals, and in vitro immunologic assays were performed at the end of life. C-kit+ cells obtained from the peripheral blood of C57BL/6 mice were injected intraperitoneally into 12- to 13-day-old Balb/c murine fetuses. The injected populations contained 5% to 20% of Sca-1+ and 1% to 5% of CD3+ cells. Twenty-three percent of mice that received transplants showed circulating donor cells in the blood, and 7% to 14% showed donor cells in the tissues. The percent of donor cells in the blood and tissues was low (<0.01%). Timing of injection or cell dose did not affect chimerism or tolerance. Fifty percent (13 of 26) showed accelerated skin graft rejection and 5 of 26 (19%) had prolonged acceptance as compared with control mice not receiving transplants in utero. All mice that rejected skin grafts showed significantly increased natural killer function as compared with the mice with delayed graft acceptance. Fifty percent of tested recipient mice showed reactivity against donor cells in the cytotoxicity assay, which could be related to the prenatal sensitization. We conclude that microchimerism does not lead to the induction of a high degree tolerance after in utero transplantation and instead may lead to the development of alloreactivity to donor cells.

Animals↗

[Traumatic lesions of the deep branch of the radial nerve].

PURPOSE OF THE STUDY: We report a retrospective study of 21 patients treated for an injury of the deep branch of the radial nerve. The aim of this study was to precise the indication and to evaluate the results of nerve surgery and tendon transfer. MATERIAL: 21 patients, mean age 32, with complete divided lesion of the nerve due to open injury were included. 5 cases with fresh discision of the deep branch of the radial nerve were treated in emergency by suture repair. 16 cases were old lesions. 6 of them had initially severe associated lesions involving skin, forearm muscles or radius. In this case, the treatment of the nerve lesion was delayed after the treatment of the associated lesions. 10 were simple lesions of the nerve who were initially misknowned (6 cases) or caused by a surgical procedure at the proximal forearm (4 cases). METHODS: 4 patients had tendon transfers, due to a very old lesion for one of them and a severe muscle involvement for the 3 others. Twelve nerve graft repairs were performed. Their were 8 troncular grafts and 4 fascicular grafts because the lesion was in the posterior forearm at the level of the terminating branches of the nerve. They required a mean length of 5.8 cm and an average of 3 to 4 cables for nerve graft. RESULTS: The mean follow up was 25 months. Results were appreciated on the recovery of 5 functions (supination, fingers extension, thumb abduction, thumb retropulsion, wrist postero-ulnar extension). Primitive nerve repairs had full recovery in all cases. Tendon transfers had good results. The 12 nerve grafts had 2 excellent results, 8 good results, 1 fair and 1 poor result. These 2 last cases required secondary tendon transfers. DISCUSSION: Traumatic lesions of the deep branch of the radial nerve are often misknowned and often iatrogenic. Nerve surgery provides better functional results than tendon transfers. Nerve grafts in delayed nerve repairs are possible even if the lesion is distal. They give excellent or good functional recovery in most cases after a delay of 7 months. Tendon transfers are indicated if nerve surgery fails or in case of large forearm muscle defect, old patient, and when the delay after the injury is superior to 12 months.

Adult↗

Improved outcome of cadaveric renal transplantation due to calcium channel blockers.

Calcium channel blockers (CCB) administered to recipients of cadaveric renal transplants have been shown to improve graft function, decrease the incidence of delayed function, prevent acute cyclosporine toxicity, and lessen the number of rejection episodes in the first several weeks posttransplant. In order to determine whether CCB provide a similar long-term benefit, a retrospective analysis of 83 first cadaveric renal transplants performed in 1987 and 1988 was performed. The clinical course of 17 patients who were discharged and maintained on CCB therapy for 1 year was compared with that of 24 patients who never received CCB during the same 1-year period. The remaining 42 patients were excluded for failing to meet these inclusion criteria. The two groups were similar with respect to age, sex, cold ischemia time, degree of sensitization, HLA matching, DR matching, and DR mismatching. The no CCB group did receive a significantly greater number of pretransplant transfusions. In the 1 year of follow-up, graft loss in the CCB group was less than in the no CCB group (1/17, 5.9% vs. 6/24, 25%). There was a striking decrease in the percentage of first rejection episodes in the CCB group as compared with no CCB therapy (35% vs. 83%, P less than 0.005). In addition, a similar decrease in second rejection episodes was found in the CCB group (18% vs. 33%, P less than 0.05). The two groups also were compared with respect to graft function. Despite similar serum creatinine levels at 1 month (CCB 1.8 mg% vs. no CCB 2.2 mg%, P = 0.37) and 1 year (CCB 1.7 mg% vs. no CCB 2.4 mg%, P = 0.19), the CCB group had a significantly higher glomerular filtration rate at 1 month (53.9 vs. 38.7, P less than 0.05) and 1 year (57.0 vs. 35.0, P less than 0.001) as measured by clearance of radiolabeled iothalamate. These results suggest that the short-term improvements noted in both graft function and rejection episodes with CCB are maintained for the first year posttransplant. More importantly, CCB use results in improved 1-year graft survival.

Adult↗

Incubation of cultured skin substitutes in reduced humidity promotes cornification in vitro and stable engraftment in athymic mice.

Cultured skin substitutes have been used successfully for adjunctive treatment of excised burns and chronic skin wounds. However, limitations inherent to all models of cultured skin include deficient barrier function in vitro, and delayed keratinization after grafting in comparison to native skin autografts. Experimental conditions for incubation of skin substitutes were tested to stimulate barrier development before grafting, and measure responses in function and stability after grafting. Cultured skin substitutes consisted of human keratinocytes and fibroblasts attached to collagen-glycosaminoglycan biopolymer substrates. Parallel cultured skin substitutes were incubated at the air-liquid interface in ambient (48-61%) or saturated (79-91%) relative humidity, and grafted to athymic mice on culture day 14. Additional cultured skin substitutes were incubated in the experimental conditions for a total of 28 days. Cadaveric human skin and acellular biopolymer substrates served as controls. Epidermal barrier was evaluated as the change in surface hydration by surface electrical capacitance with the NOVA Dermal Phase Meter. Cultured skin substitutes and cadaveric skin incubated in ambient humidity had lower baseline surface electrical capacitance and less change in surface electrical capacitance than parallel samples incubated in saturated humidity at all time points in vitro. Data from healing cultured skin substitutes at 2, 4, 8 and 12 weeks after grafting showed an earlier return to hydration levels comparable to native human skin, and more stable engraftment for skin substitutes from ambient humidity. The data indicate that cultured skin substitutes in ambient humidity have lower surface electrical capacitance and greater stability in vitro, and that they reform epidermal barrier more rapidly after grafting than cultured skin substitutes in saturated humidity. These results suggest that restoration of functional epidermis by cultured skin substitutes is stimulated by incubation in reduced humidity in vitro.

Animals↗

European best practice guidelines for renal transplantation. Section IV: Long-term management of the transplant recipient. IV.3.1 Long-term immunosuppression. Late steroid or cyclosporine withdrawal.

GUIDELINES: A. In order to reduce or avoid long-term serious adverse effects of corticosteroids, such as bone fractures, diabetes mellitus, arterial hypertension, osteoporosis and eye complications, steroid withdrawal should be considered. B. Steroid withdrawal is safe only in a proportion of graft recipients and is recommended only in low-risk patients. The efficacy of the remaining immunosuppression should be considered. C. After steroid withdrawal, graft function has to be monitored very carefully because of the risk of a delayed but continuous loss of function due to chronic graft dysfunction. In the case of functional deterioration or dysfunction, steroids should be re-administered. D. Cyclosporine withdrawal might be considered in order to ameliorate nephrotoxicity, arterial hypertension, lipid disorders and hypertrichosis. This can be carried out with no significant long-term risk of progressive graft loss. The efficacy of the remaining immunosuppression should be considered. After cyclosporine withdrawal, careful monitoring for acute rejection is recommended.

Adrenal Cortex Hormones↗

Sural nerve grafting for lower extremity nerve injuries.

Fourteen consecutive patients who had sural nerve grafts to reconstruct the sciatic or peroneal nerve were retrospectively evaluated to determine the functional return of reinnervation. A standardized functional evaluation to assess motor and sensory return of the injured compared with the contralateral side was employed as a means of normalizing the data. The dorsiflexion and plantar flexion strength were quantitatively measured to determine the recovery of muscle strength, and recorded as a percentage of the strength of the contralateral extremity as well as by assigning a motor grade. Sensory recovery was evaluated by sensory grade, two-point discrimination, and response to Semmes-Weinstein monofilaments. The average age of these 14 patients was 20 years (range 8-63 years). All but one of the patients regained protective sensation and five patients regained useful motor function. Four of the five patients regaining useful function were pediatric patients. Improved functional outcome was correlated to the nerve injured, patient age, mechanism of injury, length of graft, and the delay to grafting. The return of lower extremity function, obviating the need for bracing, can occur in children but is a rare occurrence in the adult patient although protective sensation is routinely gained and disabling paresthesias from neuromas are avoided.

Adolescent↗

Role of 99mTc-labeled DISIDA scan in the assessment of marginal liver grafts after orthotopic transplantation.

Accurate prognostic indicators are lacking for livers with early marginal graft function, making the decision to re-transplant a difficult one. Therefore, we studied 99mTc-labeled DISIDA scanning as a predictor of recovery of marginal grafts. Records of 28 liver transplant recipients with prolonged periods of marginal graft function after liver transplantation were analyzed. Twelve of 28 (Group I) had delayed PNF and were re-transplanted within 3-8 days (mean 5.3) of surgery. The remaining 16 (Group II) recovered slowly, with normal graft function at 1 month. All patients received DISIDA scans 2 to 5 d after surgery. Clearance of tracer from the blood pool was slower in Group I patients (77S +/- 241 sec) than in Group II (260 +/- 38 sec; p < 0.01). Qualitative differences in the pattern of parenchymal uptake were also noted. Homogenous uptake, consistent with cholestasis, was seen in 15/16 (94%) Group II patients, with improved uptake after 7-35 d. In contrast, 11/12 Group I patients had non-homogenous uptake, consistent with multiple liver infarctions. This pattern correlated with higher peak SGOT in Group I (4358 +/- 658 U/dl vs 1636 +/- 127 U/dl p < 0.01), and PT (20 +/- 0.7 sec vs. 16.5 +/- 0.36 sec; p < 0.01). In summary, delays in DISIDA tracer clearance from blood, and non-homogenous hepatic uptake correlate with elevated liver function tests and with delayed PNF. Homogenous uptake correlates with graft recovery. DISIDA scans may, therefore, be useful in predicting recovery of marginal grafted livers.

Adult↗

Chemokines: directing leukocyte infiltration into allografts.

Chemokines have been shown to play a critical role in the recruitment of leukocytes to transplanted organs. Animal models and clinical studies have demonstrated predictable temporal and spatial correlations between chemokine production and leukocyte infiltration into allografts. Antagonism of chemokines or chemokine receptors has been shown to delay leukocyte infiltration and prolong graft function, demonstrating an important role for chemokines in allograft rejection.

Animals↗

Graft irradiation abrogates graft-versus-host disease in combined pancreas-spleen transplantation.

A model of combined pancreas-spleen transplantation (PST) was studied in LBN F1 recipients of Lewis grafts in order to evaluate the efficacy of pretransplant graft irradiation in preventing lethal graft-versus-host disease (GVHD). Recipients of unmodified PST uniformly developed severe GVHD and died (MST = 16.7 +/- 3.8 days). Whole body donor irradiation with either 500 or 250 rad prevented lethal GVHD. Similarly, ex vivo graft irradiation with either 1000 or 500 rad also resulted in normal weight gain, graft function, and host survival for the 6-week study period. Conversely, delay of graft irradiation until 3 days after transplantation failed to prevent this complication (MST = 15.8 +/- 3.7 days). Recipients of irradiated grafts displayed glucose tolerance tests that were identical to those in the control group indicating that the doses of radiation employed in these experiments were not deleterious to islet function. Irradiated spleen grafts appeared histologically normal at 6 weeks after transplantation. Cells derived from these grafts failed to stimulate lymph node enlargement in a popliteal lymph node assay for GVHD, suggesting that these spleens may have become repopulated with host cells. These experiments confirm that PST has the potential to cause lethal GVHD and suggest that pretransplant graft irradiation may be used to prevent its occurrence.

Animals↗