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PubMedDate not supplied

Individualization of immunosuppressive therapy. II. Sirolimus as a less nephrotoxic alternative to calcineurin inhibitors.

The nephrotoxic effects of chronic administration of calcineurin inhibitors have created a demand for a potent immunosuppressive drug free of this side effect. Sirolimus (SRL) clearly displays fewer and a lesser degree of adverse effects on renal function by itself. However, in combination with calcineurin antagonists, it tends to augment the nephrotoxicity due, at least in part, to a pharmacokinetic interaction. The use of SRL for de novo immunosuppression (even with adjunctive mycophenolate mofetil) is probably not sufficient to avert alloimmune reactions. A useful combination with SRL can be achieved by reducing calcineurin inhibitor exposure by 80% for immediately functioning kidneys or by delaying its inception until renal graft recovery. SRL proffers additional benefits as an inhibitor of endothelial and smooth muscle cell proliferation, serving as the foundation of chronic immunosuppressive therapy.

Cyclosporine↗
PubMed1983

Localization of major histocompatibility complex (HLA-ABC and DR) antigens in 46 kidneys. Differences in HLA-DR staining of tubules among kidneys.

Biopsies from 46 kidneys that were subsequently transplanted were examined with monoclonal antibodies and the peroxidase-antiperoxidase technique to localize HLA-ABC and DR antigens. There was no variation in the expression of HLA-ABC which was present on all cells of the renal parenchyma. HLA-DR was found consistently on the endothelium of glomeruli and of intertubular capillaries but was only weakly expressed, or not expressed at all, on the endothelium of large vessels. The mesangium of glomeruli also stained for HLA-DR. But there was a striking variation in the expression of HLA-DR by proximal renal tubular cells in the 46 kidneys. HLA-DR was absent from tubules in 11 of 46 kidneys (23%) and probably absent or very weakly expressed in a further 8 kidneys (17%). The expression of HLA-DR in tubular epithelium was not related to the donor's age, sex, blood group, or ischemia times. However, the frequency of HLA-DR3 increased (55%) in donors of kidneys with tubular DR-negative kidneys, as compared with a frequency of 15% in donors of tubular DR-positive kidneys. Although this difference was not significant after a correction for the number of comparisons made, it suggests a genetic influence on the expression of tubular DR. The survival of tubular DR-negative kidneys was better at 1 year than that of tubular DR-positive kidneys (70% vs. 57%--not significant), and tubular DR-positive grafts may have had a higher rate of delayed function when transplanted in cases with a donor-specific positive B cell crossmatch. There was no obvious variation in the number of dendritic cells stained with antibodies to HLA-DR and the leukocyte common antigen despite prior administration of high doses of steroids to some donors before nephrectomy.

Adolescent↗
PubMed2005

Combined use of the JAK3 inhibitor CP-690,550 with mycophenolate mofetil to prevent kidney allograft rejection in nonhuman primates.

BACKGROUND: Immunosuppression via Janus kinase (JAK) 3 inhibition affords significant prolongation of allograft survival. We investigated the effects of an immunosuppressive regimen combining the JAK3 inhibitor CP-690,550 with mycophenolate mofetil (MMF) in nonhuman primates (NHPs). METHODS: Life-supporting kidney transplantations were performed between ABO-compatible, MLR-mismatched NHPs. Animals were treated orally twice a day with CP-690,550 and MMF (n=8) or MMF alone (n=2) and were euthanized at day 90 or earlier due to allograft rejection. RESULTS: Mean survival time (+/-SEM) in animals treated with MMF alone (23+/-1 days) was significantly extended in animals that concurrently received CP-690,550 (59.5+/-9.8 days, P=0.02). Combination animals exposed to higher levels of CP-690,550 had a significantly better survival (75.2+/-8.7 days) than animals that received less CP-690,550 (33.3+/-12.6 days, P=0.02). Three combination therapy animals were euthanized at day 90 with a subnormal renal function and early-stage acute graft rejection. Rejection, delayed by treatment, ultimately developed in other animals. Anemia and gastrointestinal intolerance was seen in combination therapy animals that otherwise did not show evidence of viral or bacterial infection besides signs consistent with subclinical pyelonephritis (n=3). One incidental lymphosarcoma was noted. CONCLUSIONS: Addition of CP-690,550 to MMF significantly improved allograft survival. The observed side effects appear amenable to improvements upon alteration of dosing strategies. Efficacy of this combination regimen suggests that it could become the backbone of calcineurin inhibitor-free regimens.

Animals↗
PubMed2001

Long-term ovarian function evaluation after autografting by implantation with fresh and frozen-thawed human ovarian tissue.

The transplantation of ovarian tissue has recently been the focus of intense investigation with the aim of avoiding premature ovarian failure mainly in patients receiving chemotherapy or radiotherapy for malignant disease. Here, we present an evaluation of the long-term function of both fresh (patients 1, 2, and 3) and cryopreserved (patient 4) ovarian autografts in four premenopausal patients aged 46-49 yr who underwent heterotopic ovarian transplantation and were followed over a 1-yr period without receiving gonadotropins to stimulate follicular growth. In patients 1 and 2, approximately 1 cm(3) ovarian cortical autograft was placed sc in the inner aspect of the arm, whereas and in patients 3 and 4 minced ovarian tissue was placed into a muscle pocket in the abdominal wall. In patients 1, 2, and 4 the ovarian hormone secretion (as suggested by sequential estradiol and FSH serum measurements) was reestablished 3-4 months after autotransplantation, and graft function was not improved by immediate rather than delayed heterotopic ovarian autografting. Despite a reestablished ovarian function, a 2- to 7-fold increase in peripheral FSH concentration was evidenced. The cases reported here suggest that hormonal protection can be restored after fresh or cryopreserved heterotopic ovarian transplantation in women, albeit for only a short reproductive span.

Chorionic Gonadotropin↗
PubMed1992

Opiates and immune function. Consequences on infectious diseases with special reference to AIDS.

There is an increasingly body of evidence, obtained both in vitro and in vivo, showing that exogenous opioids have a variety of effects on cells of the immune system. The consequence is that opiates at pharmacological concentrations suppress cell-mediated immunity, as reflected by depressed T-dependent antibody production by B lymphocytes, altered T lymphocyte functions such as proliferation, delayed-type hypersensitivity, graft-versus-host responses and decreased cytotoxic NK cell activity. The macrophage/monocyte oxidative burst and phagocytosis are also impaired, effects probably mediated by various opioid receptor types as they are blocked or reversed by naloxone, an opioid antagonist. Other possible mechanisms of interaction remain to be elucidated: exogenous opioids can act on neurons of the central nervous system, thereby activating the neuroendocrine system with a subsequent increase in serum glucocorticoid levels. Another potential link between the central nervous system and lymphoid tissue is the sympathetic nervous system, via which opioid-induced activation could result in noradrenergic inhibition of the immune system. The clinical consequences of these suppressive effects on the immune system are seen in the striking increase in the incidence of infections in intravenous opioid addicts. The advent of AIDS and the identification of intravenous drug abusers as a critical risk group have propelled interest in this area. Data obtained both in vitro and in vivo with various experimental models shows that morphine increases susceptibility to bacterial and viral infections, the latter effect possibly being related to a depressive effect of opioids on gamma-interferon levels. The dosage and time of administration strongly influence the results: it appears that chronic opioid treatment in vivo induces a state of immune tolerance, with normal resistance to viral infections, whereas short or single administration has a detrimental effect. In the former context, other factors such as a morphine-induced increase in CD4+ cell numbers may tend to enhance the infectivity of HIV-infected subjects.

AIDS-Related Opportunistic Infections↗
PubMed1995

The fate of renal allografts functioning for a minimum of 20 years (level 5A)--indefinite success or beginning of the end? A proposed classification of long-term allograft survivals.

Fifty-five renal allografts (44 from living-related and 11 from cadaver donors) that have functioned for at least 20 years (mean 22.9 +/- 2.3, range 20.1 to 30.7 years) were evaluated in three groups based on renal function: group I (n = 26), with a GFR of > or = 60 ml/min/1.73 m2 or serum creatinine < or = 1.4 mg/dl and no proteinuria; group II (n = 9), with a GFR of > or = 60 ml/min/1.73 m2 or serum creatinine < or = 1.4 mg/dl but > 150 mg proteinuria/24 hr; and group III (n = 20), with a GFR < 60 ml/min/1.73 m2 and/or serum creatinine > 1.4 mg/dL with or without proteinuria. Allograft factors, including acute rejection (AR) in 62% (34/55) and delayed function (DF) in 55% (6/11) of the cadaver grafts, did not preclude 20-year success and the prospect of continued survival since they were not significantly more frequent in group I, II, or III. However, AR was confined to a limited period within the first three months posttransplant in 18/18 recipients in groups I and II but only in 7/16 of group III (P = 0.0002). In groups I and II AR was treated with IVMP in 14/18 cases and only 6/16 in group III (P = 0.035). Donor age < or = 50 years and recipient age < or = 40 years each occurred in 87% (48/55) of these transplants. One- or two-HLA haplotype matching was present in 98% (43/44) of living related transplants. Major risks to the recipient were coronary artery disease (11 cases and 3 deaths), malignancy (18 cases and 1 death), and severe infection and hepatitis (35 cases and 3 deaths, 2 of whom also had coronary artery disease). Hypertension occurred in 25 recipients and diabetes mellitus in 12. Potential open-end success was compromised by renal dysfunction in groups II and III, but appeared possible in 12 of the 26 patients in group I. There is no apparent "safe-haven" point of time for immunosuppressed renal allograft recipients, who remain at increased risk for eventual renal allograft dysfunction, as well as cardiovascular, neoplastic, infectious, and metabolic diseases. In order to clarify and standardize the words "long-term," a simple classification of long-term allograft survivals is proposed.

Adolescent↗
PubMed1976

Reconstruction after mandibulectomy for cancer.

Reconstruction after mandbulectomy for cancer presents a major problem in head and neck surgery. This study reports the experiences with a planned staged method of reconstruction that aims at both cosmetic and functional rehabilitation and that is based on a close cooperation between surgeon and prosthodontist. Stabilization of the remaining mandibular fragments by means of intermaxillary fixation at the time the tumor is resected, delayed bone grafting, and preprosthetic surgery to allow the use of a functional denture are the high points of the method. The results in 58 patients are discussed.

Alveoloplasty↗
PubMedDate not supplied

Treatment of fourth-degree hand burns.

Fourth-degree hand burns are rare but devastating injuries. They cannot be grafted readily but often require flaps and amputation, and impairment is significant. We report our 10-year experience (1981 to 1990) with deep hand burns to characterize our treatment and outcome. A total of 25 patients (35 hands) were treated. Eight local flaps, nine distant flaps, and two free-tissue transfers were performed. Eleven hands were treated with K-wire immobilization and grafting. Thirty-three amputations were done. Postburn function was evaluated in 25 salvaged hands. Eleven hands had good outcomes, whereas seven had moderate sequelae and seven were severely affected. Patients who were treated with flap coverage of exposed tendons and joints had better functional outcomes than those treated with delayed closure with immobilization and grafting. The excellent outcomes in the flap coverage group justifies the added commitment of technical and therapeutic resources that this treatment requires.

Adult↗
PubMed1993

A comparison of duplex Doppler ultrasonography and intrarenal manometry in the diagnosis of acute renal transplant rejection.

Renal transplant rejection is frequently difficult to differentiate from other causes of renal dysfunction. This study examined the use of duplex Doppler ultrasound and intrarenal manometry in a consecutive series of 73 patients who underwent renal transplantation. Altogether 327 duplex scans were analyzed and, for each, a resistive index (RI) was calculated. A raised RI predicted rejection in patients with grafts that functioned immediately, but not in those that had delayed function. A rise in intrarenal pressure ( greater than or equal to 40 mmHg) indicated the presence of rejection in both groups. However, neither test had a sensitivity of more than 71% and this was not improved by combining the results of the two tests for each patient. Although both tests have a place in transplantation, renal biopsies may still be required to confirm rejection.

Adolescent↗
PubMed1999

[Endoscopic therapy of ischemia-type biliary lesions in patients following orthotopic liver transplantation].

Ischemic-type biliary lesions (ITBL) mainly induce stenoses in liver transplants causing cholestasis thus endangering the allograft. ERC enables distinction of ITBL from other differential diagnosis. From 1988 to 1998, 1,026 liver transplantations had been carried out at our clinic. 2.4% (25 out of 1,026) of liver transplanted patients were afflicted from ITBL. 60% (15 out of 25) of patients were endoscopically treated by means of sphincterotomy and balloon dilation. Furthermore, some patients needed extraction of calculi (n = 3), bile duct sequester (n = 6) or stenting (n = 4), respectively. Three patients suffered from ITBL type 1 (= only extrahepatic lesions) and five other patients were afflicted from ITBL type 2 (= circumscript intrahepatic lesions). 90% of those patients revealed long-term benefit from endoscopic therapy (follow-up to seven years). Another 15 patients elicited ITBL type 3 (= multiple intra- and extrahepatic lesions). Therefrom, nine patients had to be retransplanted directly while eight others were assigned to endoscopic treatment. Follow-up investigations revealed that retransplantation could be avoided in 50% of ITBL patients by means of endoscopic therapy for at least three years. In contrast, only 27% of ITBL patients could survive for more than three years without endoscopic therapy. Endoscopic success depends on localization and severity of ITBL complications in the biliary tract of the liver allograft. Therefore, benefit of endoscopic therapy depends on proper diagnosis as early as possible guiding further therapeutic strategy. Conclusively, endoscopic success enables maintenance of liver function in ITBL afflicted liver grafts and avoids or at least, delays retransplantation.

Bile Ducts↗
PubMed1983

Delayed skin grafting.

The use of skin grafts on granulating wounds is an established practice. Delaying the application of a full- or split-thickness skin graft may be an advantageous alternative method of surgical reconstruction in selected cases. Partial healing by secondary intention is useful for filling in deeper defects and usually produces a wound that is much smaller and of more normal contour than the original defect. Contraction of the graft bed is markedly influenced by location, tissue laxity, surface tension lines, motion, and wound geometry. Proper wound care, correct surgical preparation of the defect, and timing of the graft procedure are all important considerations in maximizing the overall result. Through-and-through defects and wounds produced over areas with little underlying support (eyelids and lip) often need flap reconstruction or immediate grafting to prevent undesirable functional and cosmetic results. By combining delayed healing and conventional reconstructive techniques, major tissue loss can often be restored while minimizing patient morbidity.

Humans↗
PubMedDate not supplied

Renal allograft outcome in the cyclosporine era: comparison between intermediate-term failure and long-term survival.

A single center experience of 160 cyclosporine-treated renal allografts that survived longer than 1 year was reviewed in an attempt to analyze the contribution of selected parameters to long-term survival. Sixty-one grafts were lost between 1 and 5 years, with the remaining functioning for longer than 5 years. Parameters with a significant influence on long-term survival included both quality of early graft function, with 13% of long-term survivors having delayed function, compared to 52% among the short-term survival group, and the incidence of acute rejection in the first year posttransplant (31% in long-term survivors compared to 63% in the short-term survival group). A marker for long-term survival (greater than 5 years) was a lower serum creatinine at 1 year (1.9 +/- 0.1 mg/dl, compared with 2.6 +/- 0.2 mg/dl in the short-term survival group). Recipient race, original renal disease, number of transplants and/or transfusions, panel reactive antibodies, and human leukocyte antigens matching did not appear to influence long-term outcome.

Adult↗
PubMed1983

Restoration of full mass in nerve-intact muscle grafts after delayed reinnervation.

A rat muscle freely grafted with the motor nerve intact becomes restored to full mass and contractile function, in contrast to the reduced weight of a standard free graft. By crushing the nerve to a nerve-intact graft and delaying reinnervation, full mass is still restored. One can conclude that earlier reinnervation is not the reason for the success of nerve-intact grafts, but that it is rather due to reinnervation along preserved Schwann cell channels.

Animals↗
PubMed1999

[Evaluation of factors affecting early and late outcome of 225 kidney transplantations].

The aim of this study was to evaluate some chosen factors affecting early and late outcome of 225 renal transplantations performed in the Department of General and Transplantation Surgery of the Pomeranian Medical Academy in Szczecin from 1985 to 1995. Analysed groups were elected from this number in a way as to be comparable and their demographic data were discussed. Factors taken into consideration were: the impact of transplantation team experience, operator, graft perfusion method, preservation solution, multiple renal arteries, uretheral stent, multiorgan harvesting and donor sex. The early outcome was estimated as: immediate function, delayed function and nonfunction. The late outcome was: 3 months, 1 year and 3 years graft and patient survival. Analysed groups were compared as far as an incidence of following surgical postoperative complications: urological, vascular, septic, graft rupture, bleeding, fluid collections and other surgical complications, is concerned. The data base was statistically elaborated using t-Student and Chi 2 test taking as statistically significant p less than 0.05. Results show that the impact of transplantation team experience was an important factor (Tab. 1, 2, 3). The comparison of three following groups of transplantations (75 cases each) elucidates that after learning period came a stabilisation period, in which the outcome is close to that achieved in other Polish transplantation centers. While investigating the factor of operator two groups of transplantations performed by seniors and one "learning group" were compared and no statistically significant difference was found. This is probably because each transplantation done by learning surgeon was assisted by one of above seniors. The perfusion method impact was investigated comparing two small groups (in situ and ex situ perfusion) and no benefit of any was proved. The difference between outcomes of groups in which UW or Eurocollins was used, was statistically significant as far as three years graft survival is concerned. In UW group it was 55.9%, whereas in Eurocollins group it was 29.4%. The probable explanation is that the possibility of longer cold ischemia time, given by UW solution, implicates more time to find better suited recipient for particular graft. The impact of multiple renal arteries on the outcome of transplantation was analysed by comparing group of 105 grafts with one artery and 25 multiple arterias grafts. The immediate function occurred in 92% of group with multiple and 62.9% of group with one artery. The difference was statistically significant. The factor of indwelling uretheral stent was investigated comparing the group of 94 transplantations where it was used and the group of 35 transplantations without it. There was no difference as far as urological complications are concerned. Multiorgan harvesting plays a very important role facing serious organ shortage in all developed countries. The comparison of 37 multiorgan and 95 kidney harvestings showed no negative implications of the first one for the outcome of renal transplantations. Evaluation of donor sex factor did not show any essential differences while comparing group of 162 grafts taken from male and the group of 63 grafts taken from female donors. Following conclusions were established after discussion of above results: the most important factor was the impact of transplantation team experience; preservation by UW solution caused better late outcome of treatment; there was no negative influence of transplanting grafts with multiple arteries; the impact of operator, donor sex, perfusion method, multiorgan donation and use of uretheral stent was not proved.

Evaluation Studies as Topic↗
PubMed2001

Absence of CSF-1-dependent macrophages does not improve function of transplanted islets of Langerhans.

A role of macrophage-mediated inflammatory events in early islet graft loss is increasingly acknowledged. Osteopetrotic mice (op/op) have a complete absence of CSF-1, and thus of most tissue macrophages. We have investigated whether the absence of CSF-1-dependent macrophages in the graft itself or at the transplant site could decrease the delay to function of a syngeneic marginal islet mass. Islets transplanted into op/op or control recipients reversed diabetes in 59 days vs. 10 days (p = 0.28, NS). Islets isolated from op/op or control mice reversed diabetes in 11 days vs. 10 days. IL-1 and TNF-alpha release by cultured islets was markedly decreased for op/op islets compared with control islets (IL-1: 0 vs. 4.2 pg/ml, p = 0.07; TNF-alpha: 67 vs. 311 pg/ml, p = 0.002). In contrast, IL-6 release by op/op islets was significantly increased (11.1 vs. 4.3 ng/ml, p = 0.006). CSF-1-dependent tissue macrophages may not be critical in the inflammatory insult to islet transplants. Alternate patterns of intraislet release of deleterious proinflammatory cytokines may exist.

Animals↗
PubMed2006

CD34(+)-selected stem cell boost for delayed or insufficient engraftment after allogeneic stem cell transplantation.

BACKGROUND: Poor graft function without rejection may occur after stem cell transplantation (SCT). CD34(+) stem cell boost (SCB) can restore marrow function but may induce or exacerbate GvHD. We therefore investigated the feasibility and efficacy of CD34(+)-selected SCB in some patients with poor graft function. We present the results for eight patients (median age 46 years) transplanted initially for myelofibrosis, acute leukemia, myeloma and NHL. Six patients had received HLA-matched and two mismatched grafts (PB, BM; n=5, 3). After a median of 128 days post-transplant, the median leukocyte and platelet counts were, respectively, 2.05/nL and 18/nL. None had achieved platelet counts >50/nL even though donor chimerism was >95% in seven recipients. METHODS: Positive selection of CD34(+) stem cells was performed on a CliniMACS device, observing GMP and achieving a median of 98.5% purity. The patients received a median of 1.7 x 10(6)/kg CD34(+) cells and 2.5 x 10(3)/kg CD3(+) T lymphocytes. RESULTS: Hemograms at days +30, +60 and +90, respectively, showed steadily increasing median leukocyte (2.55, 3.15 and 4.20/nL) and platelet (29, 39 and 95/nL) counts. After a median follow-up of 144 days, five patients remained alive. No patient had developed acute or chronic GvHD. One patient died of leukemic relapse and two others of systemic mycosis. DISCUSSION: These preliminary results point to the possibility of safely improving graft function using CD34(+) positively selected stem cells without necessarily increasing the incidence of GvHD in patients with poor graft function post-SCT. Experience with more patients and longer follow-up should clarify the optimal role for this procedure.

Adolescent↗
PubMed1978

[In vivo determination of local tissue pO2 in renal cortex in kidney transplantation].

From measurement of local tissue PO2 in human kidney grafts after restoration of renal circulation, a correlation between initial microcirculation and kidney function can be drawn. PO2-histograms of kidney grafts with sufficient function are normal, whereas PO2-histograms of kidneys with delayed onset of function (congruent to 3 weeks) show distinct disturbances of microcirculation. These preliminary results suggest that measuring local tissue PO2 in transplanted kidneys may be of value for the prognosis of the graft.

Humans↗
PubMed2002

Experimental models of small intestinal transplantation in rats: orthotopic versus heterotopic model.

Two kinds of surgical models of small intestinal transplantation (SITx) in rats, namely heterotopic (HIT) and orthotopic transplantion (OIT), have been reviewed. In OIT, the small intestine of the recipient is removed and the transplanted intestine replaces it in continuity. On the other hand, in the HIT model, the small intestinal grafts are rendered dysfunctional without alimentary tract continuity. Histological evidence showed that acute rejection appeared earlier in HIT as compared to OIT. Hyperplasia and hypertrophy of the muscularis externa produced in the chronic rejection process were more pronounced in HIT allografts. The HIT grafts showed severe mucosal atrophy due to the lack of intraluminal trophic factors, because oral feedings can stimulate tropic hormones for mucosal growth, and provide nutrients for enterocytes. Intestinal permeability was consistently higher after HIT than after OIT. The HIT grafts demonstrated less contractility and less response to chemical stimulation than did OIT grafts. The OIT models are advantageous in studies of intraluminal nutrients, and intestinal secretions in these models might modulate the intestinal immune status and possibly delay rejection. The superior intestinal barrier function and the delayed onset of rejection in OIT rats suggest that nutrients and other factors in the succus entericus are important for the maintenance of intestinal graft function.

Animals↗