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PubMed1998

Long-term follow up of renal function and histology after renal allograft transplantation in early childhood.

Survival rates, renal function, and histopathology were evaluated in 49 prospectively followed patients transplanted under 5 years of age at our center. Most patients (84%) suffered from congenital nephrosis of the Finnish type. Triple immunosuppression with cyclosporine administered in three daily doses to pre-school children was used. Patient survival 7 years after transplantation was 98% and graft survival 88%. All graft losses were due to post-transplantation nephrosis. The proportion of pathological findings in the follow-up biopsies did not change substantially with time. Five years after transplantation, 47% showed a normal histology and after 7 years this rose to 67%. Mean glomerular filtration rate (GFR) was 68 and 55 ml min per 1.73 m2 5 years and 7 years, respectively, after transplantation. The decline in GFR with time was significant. We conclude that good long-term results can be achieved with individually tailored triple immunosuppression in the youngest age group, even with cadaveric donors.

Child, Preschool↗
PubMed1986

Tc-99m DTPA scans in renal allograft rejection and cyclosporine nephrotoxicity.

Renal allograft dysfunction arising from rejection or cyclosporine (CsA) nephrotoxicity can currently only be distinguished reliably by allograft biopsy. We have assessed Technetium (Tc)-99m diethylamine pentacetic acid (DTPA) scanning in 30 CsA-treated patients with allograft dysfunction. Scintigrams were performed during 20 biopsy-proved episodes of rejection and during 14 episodes of CsA nephrotoxicity. These results were compared with the scintigrams of 15 allografts showing stable function. Quantitative indices expressing allograft perfusion (flow index) and function (uptake index) derived from the DTPA scintigrams showed no significant differences between the groups of patients with rejection, CsA nephrotoxicity, or stable or improving function. Similarly, the flow and uptake indices of individual allografts obtained during periods of stable or improving function and then during episodes of dysfunction due to rejection or CsA nephrotoxicity did not significantly change. We conclude that Tc-99m DTPA scintigrams are of limited value in the management of allograft dysfunction in patients immunosuppressed with CsA.

Cyclosporins↗
PubMed2004

Cyclosporine treatment preserves coronary resistance artery function in rat cardiac allografts.

BACKGROUND: A marked decline in vascular myogenic response occurs during the course of rat cardiac allograft rejection. Two important contributory features are an inducible nitrous oxide synthase (iNOS)-catalyzed, NO-mediated vasodilation and a loss of smooth muscle function. In this study, we examine the effect of cyclosporine immunosuppressive therapy on the alleviation of arterial dysfunction of coronary resistance arteries in allografts using pressure myography. METHODS: Rats receiving heterotopic abdominal cardiac transplantation were treated with cyclosporine (5 mg/kg), Cremophore or distilled water. Coronary septal arteries (internal diameter 200 microm) were dissected from isograft (Lewis to Lewis) and allograft (Fisher to Lewis) rat hearts at Day 21 post-transplantation and mounted on a pressure myograph. Pressure-induced vasoconstriction was measured before and after iNOS inhibition with aminoguanidine (AG; 100 micromol/liter). Both endothelium-based (ACh-induced) and endothelium-independent (sodium nitroprusside-induced) vasorelaxation were also recorded in each group. RESULTS: Pressure-induced myogenic contraction was reduced in allograft coronary arteries at Day 21 post-transplantation compared with matched isografts (p < 0.05). AG potentiated myogenic tone in allograft arteries, but had no effect on untreated Day 21 isograft vessels, indicating the presence of iNOS-based relaxation only in allograft vessels. Depolarization-induced vasoconstriction was lower in allograft compared with isograft arteries (p < 0.05). Cyclosporine therapy also improved depolarization-induced constriction in allograft vessels compared with untreated groups (p < 0.05). Furthermore, cyclosporine therapy preserved endothelium-based and endothelium-independent vasorelaxation in allograft arteries at Day 21 post-transplantation. CONCLUSIONS: Cyclosporine immunosuppressive therapy has a significant effect on the alleviation of early endothelial and smooth muscle dysfunction in coronary allograft arteries.

Animals↗
PubMed1981

Altered immunoregulatory function in long-term renal allograft recipients.

In order to determine immunoregulatory lymphocyte subsets in patients with long surviving renal allografts, a study utilising functionally characterised monoclonal antibodies with analysis by flow cytometry using a Fluorescence Activated Cell Sorter was carried out. Cells from 35 patients with allograft survival from one to 15 years were analysed with monoclonal antibodies for the following markers: inducer-helper, cytotoxic-suppressor, monocytes, Ia, IgG and IgM. Control groups consisted of long-term dialysis patients and a group of normal individuals. The results show a strikingly significant difference between the long-term allograft recipients and the control population in terms of the inversion of the normal inducer-helper to cytotoxic-suppressor ratio. Additionally, there were significant differences in the number of Ia+ cells in long-term transplant patients and dialysis patients compared with normals. No impressive differences were found in the numbers of Ig bearing cells. Thus the long-term allograft state is a clear example of an overabundance of cellular suppression and may explain many of the general phenomena seen in surviving recipients.

Cytotoxicity, Immunologic↗
PubMed2002

Janus kinase 3 inhibitor WHI-P131/JANEX-1 prevents graft-versus-host disease but spares the graft-versus-leukemia function of the bone marrow allografts in a murine bone marrow transplantation model.

The purpose of the present study was to evaluate the effects of graft-versus-host disease (GVHD) prophylaxis with the Janus kinase 3 (JAK3) inhibitor WHI-P131/JANEX-1 on the graft-versus-leukemic (GVL) function of marrow allografts in mice undergoing bone marrow transplantation (BMT) after being challenged with an otherwise invariably fatal dose of BCL-1 leukemia cells. GVHD prophylaxis using WHI-P131 markedly improved the survival outcome after BMT. The probability of survival at 30 days after BMT was 11% +/- 6% for vehicle-treated recipients (median survival time, 25 days) versus 63% +/- 12% for recipients treated with WHI-P131 (median survival time, 36 days; P <.0001). Because WHI-P131 is devoid of antileukemic activity against BCL-1 leukemia cells, this marked improvement in survival outcome was due to reduced incidence of GVHD-associated fatalities combined with sustained GVL function of the allografts in the WHI-P131 group. Notably, adoptive transfer experiments demonstrated that the spleens of WHI-P131-treated allograft recipients contained less than 0.001% BCL-1 cells. Notably, GVHD prophylaxis with WHI-P131 plus methotrexate resulted in 100% survival of mice receiving allotransplants challenged with an otherwise invariably fatal dose of BCL-1 leukemia. Taken together, our results provide strong experimental evidence that GVHD prophylaxis using WHI-P131 does not impair the GVL function of the allografts and consequently contributes to an improved post-BMT survival outcome of the recipient mice.

Animals↗
PubMed1989

Impaired liver function in stable renal allograft recipients.

Hepatic failure as a cause of death is increased in stable renal allograft recipients when compared with patients on dialysis. In order to assess the magnitude and the natural history of the hepatic functional derangement, the kinetics of xenobiotics which are metabolized by cytosolic (galactose) or microsomal (prednisolone, cyclosporine A) enzymes were determined in 28 consecutive stable kidney transplant patients 1 month and 1 year after transplantation. Renal transplant patients had a decreased mean (+/- S.D.) galactose elimination capacity at 1 month (6.26 +/- 0.94 mg per min x kg) and at 1 year (5.93 +/- 0.96 mg per min x kg), when compared with a different group of 28 healthy control subjects (7.52 +/- 0.78 mg per min x kg, p less than 0.001) and a decreased total body clearance of prednisolone at 1 month (2.13 +/- 0.34 ml per min x kg vs. 2.71 +/- 0.43 ml per min x kg in controls, p less than 0.001), which further decreased over the following year to 1.76 +/- 0.32 ml per min x kg (p less than 0.001). The clearance of cyclosporine A declined significantly during the first year of successful transplantation (5.9 +/- 2.1 ml per min x kg vs. 4.9 +/- 1.2 ml per min x kg, p less than 0.05). In conclusion, a substantial proportion of stable renal transplant recipients have decreased cytosolic and microsomal liver functions despite the absence of clinical and laboratory evidence of significant liver disease.

Cyclosporins↗
PubMed2005

Early cyclosporine withdrawal from a sirolimus-based regimen results in better renal allograft survival and renal function at 48 months after transplantation.

We report the 48-month results of a trial testing whether withdrawal of cyclosporine (CsA) from a sirolimus (SRL)-CsA-steroid (ST) regimen would impact renal allograft survival. Eligible patients receiving SRL-CsA-ST from transplantation were randomly assigned at 3 months to remain on triple therapy (SRL-CsA-ST, n = 215) or to have CsA withdrawn and SRL trough concentrations increased (SRL-ST, n = 215). SRL-ST therapy resulted in significantly better graft survival, either when including death with a functioning graft as an event (84.2% vs. 91.5%, P = 0.024) or when censoring it (90.6% vs. 96.1%, P = 0.026). Calculated glomerular filtration rate (43.8 vs. 58.3 ml/min, P < 0.001) and mean arterial blood pressure (101.3 vs. 97.1 mmHg, P = 0.047) were also improved with SRL-ST. Differences in the incidences of biopsy-proven acute rejection after randomization (6.5% vs. 10.2%, SRL-CsA-ST versus SRL-ST, respectively) and mortality (7.9% vs. 4.7%) were not significant. SRL-CsA-ST-treated patients had significantly higher incidences of adverse events generally associated with CsA, whereas those in the SRL-ST group experienced greater frequencies of events commonly related to higher trough levels of SRL. In conclusion, early withdrawal of CsA from a SRL-CsA-ST regimen rapidly improves renal function and ultimately results in better graft survival.

Adrenal Cortex Hormones↗
PubMed2005

Functional recovery of rat hind-limb allografts.

Few papers have assessed the long-term functional recovery of animal limb allografts. In this study, the functional recovery of rat limb allografts was serially and quantitatively investigated for a period of 1 year. The donor's hind limb was orthotopically transplanted into the recipient. Fifteen recipients with allografts were treated with FK506. Functional recovery of the grafted limb was assessed serially by cutaneous reaction test, walking track analysis, and electrophysiologic evaluation. Sensibility improved to a similar extent in both isografts and allografts, and the recovery rate at 1 year was 68 percent, compared to the normal side. Sciatic function index significantly improved to - 70 points after 1 year. The amplitude recorded from the gastrocnemius muscle significantly improved, and the ratio compared to the normal side was 43 percent. Limb isografts and allografts treated with FK506 showed no significant differences in functional recovery. The data can be used as a reference standard for future investigations.

Animals↗
PubMedDate not supplied

Analysis of myocardial function in orthotopic cardiac allografts after prolonged storage in UW solution.

The need for a better organ preservative solution in heart transplantation is clear. At the same time, newer techniques in the assessment of cardiac function in the laboratory have made accurate load-independent quantification of myocardial preservation possible. Therefore a study was undertaken to evaluate left ventricular function in transplanted hearts after 14 hours of preservation in the intracellular lactobionate solution. Nine dogs were instrumented with ultrasonic dimension transducers, to measure left ventricular epicardial volume, and with micromanometers, to measure left ventricular pressure. Left ventricular wall volumes were determined from epicardial echocardiograms. To define the extent of organ injury resulting from the transplant procedure and cardiopulmonary bypass alone, four other animals were instrumented in a similar fashion, and left ventricular function was assessed after standard cardioplegic arrest and transplantation. The transplant procedures were performed with a warm ischemic period of 0.75 +/- 0.2 hours. In all experiments, data were collected before graft harvest and 1 hour after separation from cardiopulmonary bypass. Standard cardioplegic arrest and 2.4 +/- 0.1 hours of ischemia resulted in a decrease in left ventricular ejection fraction from 0.43 +/- 0.04 to 0.27 +/- 0.1 (37%) (p less than 0.01), a decrease in the slope of the stroke work/end-diastolic volume relationship from 15.4 +/- 7.9 to 7.9 +/- 2.0 erg X 10(4) (49%; p less than 0.01), and a decrease in the myocardial power output from 19.7 +/- 10.9 to 5.9 +/- 1.9 (70%; p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗
PubMed1974

Histopathology of one-stage bilateral lung allografts.

Morphological features of modified and unmodified bilateral lung allografts were studied in 87 dogs. Immunosuppressive treatment consisted of various combinations of azathioprine, methotrexate, prednisolone, methylprednisolone and antilymphocyte serum. The classic acute rejection was observed in the unmodified dogs, which died between 4 and 9 days. Progression of the lesion was confined to a certain stage in these lung allografts charged with providing total pulmonary function, so that hemorrhagic necrosis was never encountered. Immunosuppressive drugs decrease the speed and intensity of classic rejection, and increase the complications of respiratory infection in the protracted course. Of 14 dogs surviving more than 14 days, 4 died of chronic rejection at 72, 84, 177, and 396 days after transplantation. Death of the remaining animals was attributed to acute rejection (3 dogs); severe anemia (3 dogs); pulmonary infection and sepsis (3 dogs); and arterial thromboembolism (1 dog). In these long-functioning lung allografts, the alveolar lining cells were frequently replaced by very atypical cells presumed to be type 2 pneumocytes. The bronchus was occluded by mucus plugs, and the alveolar surface was covered with hyaline membrane, or obliterated by organized fibrocellular precipitate. The alveolar walls and perivascular area were thickened by fibrosis. Obliterative intimal thickening of pulmonary arteries was not observed. Although the immunologic and non-immunologic mechanisms responsible for the development of these lesions are difficult to separate, these cumulative changes apparently accompany the deterioration of the vital function of the graft until ultimate death.

Animals↗
PubMed2000

Neuromuscular paralysis as a pharmacodynamic probe to assess organ function during liver transplantation.

Potential for assessing liver function during liver transplantation surgery by monitoring muscle paralysis from nondepolarizing neuromuscular blockers that are hepatically cleared is critically assessed. Rocuronium is strongly favored as a promising pharmacodynamic probe for predicting allograft liver function because it is predominantly eliminated via the liver and its putative metabolites are not active. Prolongation of recovery from rocuronium paralysis is closely correlated with allograft liver function postoperatively. Vecuronium, pancuronium, and perhaps pipecuronium may also prove to be useful probes, but the two former blockers have active metabolites. Further prospective studies are necessary with more precise measurement of neuromuscular function to confirm the predictive value of this method. Alterations in neuromuscular blocker plasma concentrations that are correlated with changes in liver function and either the dose required or the intensity or duration of paralysis needs to be demonstrated for this technique to be clinically useful.

Androstanols↗
PubMedDate not supplied

Comparison of early postoperative function of liver and renal allografts with radionuclide imaging.

OBJECTIVES: Radionuclide imaging is a valuable tool during the early posttransplantation period for evaluating the functional status of renal and liver allografts. The aim of this study was to compare the early postoperative function of renal and liver allografts with serial radionuclide imaging. METHODS: Twenty-two renal and 22 liver allograft recipients were evaluated with serial radionuclide imaging. All grafts were from living related donors. For renal scintigraphy, recipients were injected with Tc-99m DTPA, and imaging was performed on postoperative days 3 and 7. Liver allograft recipients were evaluated with Tc-99m mebrofenin hepatobiliary scintigraphy within the first postoperative week and as required thereafter. The following parameters were computed for each scintigraphy: uptake, time to excretion of the radiopharmaceutical (T(ex)), and retention of radioactivity at the end of the study. RESULTS: Among 22 renal transplant recipients, 19 (86%) had normal uptake and T(ex) values on day 7 posttransplantation. Nine (41%) renal grafts exhibited retention. Among 22 liver transplant recipients, 7 (32%) had normal findings on the first hepatobiliary scan. All except eight liver grafts (64%) had a delay in T(ex), and 15 (68%) had parenchymal retention on the first scan, with improvement of function observed on serial scintigraphies obtained during follow-up. Decreases in uptake were seen less frequently and correlated with a prolonged postoperative hospital stay. CONCLUSION: Renal transplant recipients are more likely than liver allograft recipients to have a normal scintigraphy in the early posttransplantation period. Retention of radioactivity at the end of the study was the most frequently observed abnormality for both renal and liver allografts. Most liver transplant recipients exhibited a delay in excretion, and parenchymal retention, of radioactivity on the first evaluation, with subsequent improvement on follow-up serial scintigraphy studies.

Humans↗
PubMed1976

Effect of organ culture on the survival of thyroid allografts in mice.

Mouse thyroid can be maintained in organ culture for 4 weeks. Uncultured BALB/c thyroid is rejected 10-15 days after transplantation under the kidney capsule of H-2 disparate recipients (C57BL, CBA). Organ culture of thyroid tissue prior to transplantation prolongs allograft survival. This prolongation of graft survival increases with increasing time in culture and 80-90% of BALB/c thyroids maintained in culture for 26 days survive in allogeneic CBA recipients for a 60- to 70-day test period. These allografts show normal function as measured by 125I uptake, and show no histological evidence of chronic rejection. Cultured allografts can be rejected if the host's immune system is stimulated with viable leukocytes of donor origin. Host animals carrying a functioning allograft are not tolerant of donor tissues and will reject a second uncultured allograft from the same donor strain.

Animals↗
PubMed1998

Morphological findings in non-episode biopsies of kidney transplant allografts treated with FK506 or cyclosporine.

We conducted an analysis of biopsy specimens of non-episode renal allografts from patients treated with tacrolimus (FK506) or cyclosporine (CsA) to evaluate chronic drug-induced nephropathy in stable allografts. A total of 38 biopsy specimens from stable functioning renal allografts were examined. The patients had been treated with FK506 (n = 16) or CsA (n = 18) as main immunosuppressant for 0.3 to 7.4 years. Of the 38 biopsy specimens, 15 showed mild drug-induced arteriolopathy (hyalinosis or insudative change of arterioles and small arteries) with striped-form interstitial fibrosis, 10 showed minimum interstitial cellular infiltration (borderline rejection), 2 showed IgA nephropathy, 4 showed evidence of chronic rejection (transplant nephropathy) and 12 showed no abnormal findings. Of 34 renal allograft biopsy specimens with stable function, 22 (65%) showed pathological evidence of drug-induced nephropathy. There were no significant qualitative or quantitative differences between FK506- and CsA-associated nephropathy.

Biopsy↗
PubMed1996

Delayed-type hypersensitivity-like mechanisms dominate late acute rejection episodes in renal allograft recipients.

Episodes of acute rejection (aRx) may occur in functional renal allografts even at a very late stage post-Tx. Histopathology in early and late aRx looks quite similar--however, there is a slower deterioration of graft function in late aRx, suggesting that pathogenetic immune mechanisms are different. In order to investigate this phenomenon we studied the gene expression pattern (IL-1beta, 2, 4, 8, 10, IFNgamma, TNFalpha, GrnA, IL-2R p55/p75) in PBMC and core biopsies from long-term renal allograft recipients with histologically proven late aRx and compared it with transplant and non-transplant controls using a semiquantitative RT-PCR technique. PBMC and graft-infiltrating cells of patients with late aRx showed an upregulation, especially of IFN-gamma, IL-4, IL-10, and TNFalpha transcripts. While IL-2 mRNA was only detected in PBMC of two patients with late aRx who were not on cyclosporine, upregulation of intragraft IL-2 mRNA allowed the best discrimination between aRx and the other groups (sensitivity: 83%, specificity: 93%). In contrast to several reports on early Rx we did not notice an elevation of granzyme A transcripts in comparison with the controls, suggesting that cell-mediated inflammatory processes (CD4+ T cell-mediated DTH) dominate the late aRx, while early aRx is characterized by the additional involvement of cytotoxic T cell response. This may explain the distinct clinical course. Additionally, in a pilot study we successfully treated late aRx in 10/12 patients with the anti-CD 4 mAb, 16H5. Our encouraging therapeutic results underline the pathogenetic role of CD4+ T cells and support our hypothesis on DTH-like mechanisms in late aRx.

Cytokines↗
PubMed1984

Non-renin dependent hypertension in renal allograft rejections. A structural and functional analysis.

A 25-year-old recipient of a cadaveric renal allograft underwent three acute rejection episodes within the first 40 days after transplant, the final episode necessitating nephrectomy. The saralasin acetate infusion test and plasma renin activity (as measured by radioimmunoassay of angiotensin I) were used as functional tests of the renin-angiotensin axis. Biopsy specimens of the allograft one hour after implantation and sections of the nephrectomy specimen were fixed and stained with hematoxylin-eosin for structural analysis. On three separate dates, during the final rejection episode, saralasin acetate infusion of up to 20 micrograms/kg/min failed to lower BP significantly. The final two trials were preceded by furosemide administration the previous day to reduce fluid volume. Plasma renin activity was low on all three dates. On nephrectomy, the allograft was noted grossly to be infarcted. Histologic examination revealed cortical necrosis, markedly narrowed or occluded intrarenal vessels, and extremely narrowed large vessels within the renal pelvis. The allograft renal artery was thickened and narrowed. From our structural and functional analysis we conclude that (1) hypertension, in this case, was probably volume dependent and was clearly renin independent; and (2) the low renin levels are explainable on the basis of extensive vascular occlusion producing renal infarction and resulting in a kidney incapable of producing significant amounts of renin (autonephrectomy).

Adult↗