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PubMed1999

Histological factors of 1-h biopsy influencing the delayed renal function and outcome in cadaveric renal allografts.

The morphological characteristics of a kidney biopsy specimen taken 1 h after reperfusion of blood into the graft (1-h biopsy) during a cadaveric transplant operation were studied. The aim of the 1-h biopsy is to evaluate the pre-transplant risk factors for the delayed graft function, assess the renal function of the graft, and predict long-term graft survival. The total number of 1-h biopsies was 113, consisting of 86 male and 27 female donors. The mean age of the donors is 39.5 +/- 17.3 yr. Arteriosclerosis (AS) and tubulo-interstitial injury (TI) were both estimated using a semi-quantitative scale. AS score was graded into four categories, according to the severity of the thickening of interlobular artery: 0: none, 1: mild, 2: moderate and 3: severe. No biopsy revealed severe AS of grade 3. The TI score was graded from 0 to 5, according to the morphological injury: 0: none, 1-2 non-specific tubulo-interstitial injury (NSTI), and 3-5 compatible with acute tubular necrosis (ATN) in terms of pathological diagnosis. The mean ages of donors showing as AS of score 0, 1, and 2 were 30.6 +/- 14.6, 49.7 +/- 13.5, and 56.9 +/- 6.30, respectively. The mean donor age of the AS 1 group and AS 2 group was significantly lower than for the AS 0 group. The lowest serum creatinine values after operation (best Cr) of recipients with AS scores of 0, 1, and 2 were 1.31 +/- 0.45, 1.60 +/- 0.70, and 1.84 +/- 0.71 mg/dL, respectively; the best Cr of AS scores of 1 and 2 was significantly higher than in the AS score 0 group. The mean creatinine level at the final point of the AS 0 group was significantly lower than in the combined AS 1 and AS 2 group (serum creatinine 1.44 +/- 1.03 vs 1.87 +/- 1.53 mg/dL: p < 0.01). The duration of severe hypotension less than 50 mmHg or 80 mmHg was significantly shorter in the NSTI group than in the ATN group (less than 50 mmHg was 29.7 +/- 124 vs 72.5 +/- 174, less than 80 mmHg 105 +/- 234 vs 193 +/- 261 min: p < 0.01). The post-operative (po) day expressing diuresis in excess of 1000 mL of urine per d was 8.28 +/- 17.5 and 13.7 +/- 23.3 (p < 0.01) in the NSTI and ATN group, respectively. The po-d of the last hemodialysis and the po-d showing serum creatinine less than 2.0 mg/dL in NSTI and ATN group was 7.74 +/- 17.4 and 13.3 +/- 23.2 (p < 0.01), and 25.0 +/- 30.5 and 38.0 +/- 35.2 (p < 0.01), respectively. We concluded that 1-h renal biopsy is useful for assessing the outcome of renal allograft. AS of a donor kidney is one of the most important risk factors for both short and long-term outcome of the graft. The TI score was useful to predict the outcome of delayed graft function.

Adult↗
PubMedDate not supplied

Limb-sparing surgery in a dog with osteosarcoma of the proximal femur.

OBJECTIVE: To report successful limb-sparing surgery in a dog with a proximal femoral osteosarcoma (OSA) using a composite allograft-prosthetic technique. STUDY DESIGN: Case report. ANIMAL: Client-owned dog. METHODS: A stage IIB OSA of the proximal aspect of the femur was resected in accordance with oncologic and limb-sparing principles. The osseous defect was reconstructed with a proximal femoral allograft and cemented, long-stemmed femoral prosthesis. Soft tissue reconstruction was achieved by suturing host tendons to their respective allogeneic tendons on the allograft. Coxofemoral joint function was preserved using standard total hip arthroplasty techniques. RESULTS: Limb-sparing surgery of the proximal aspect of the femur using a composite allograft-prosthetic technique resulted in excellent limb function. Postoperative complications included aseptic loosening of the femoral composite graft and allograft nonunion, which required revision, traumatic implant luxation, and local tumor recurrence. Limb function was excellent after surgical stabilization of the allograft nonunion but deteriorated after implant luxation 270 days postlimb-sparing surgery. Pulmonary and skeletal metastases were diagnosed and local tumor recurrence suspected 596 and 650 days postoperatively, respectively. The dog was euthanatized 688 days after limb-sparing surgery as a result of progressive local and metastatic disease. CONCLUSIONS AND CLINICAL RELEVANCE: Limb-sparing surgery for dogs with primary bone tumors of the proximal aspect of the femur is feasible with good functional results.

Animals↗
PubMed1985

Functional role of thromboxane production by acutely rejecting renal allografts in rats.

We investigated the role of thromboxane in mediating the reduction in renal function and renal blood flow characteristic of acute renal allograft rejection. We transplanted kidneys from Lewis rats to Brown-Norway recipients. By the third day after transplantation, histologic changes that were consistent with cellular rejection occurred in the kidney. These changes were associated with a moderate reduction in renal function. By day 6, histologic changes of rejection were advanced and included interstitial and perivascular infiltration by mononuclear cells. The clearances of inulin and para-aminohippuric acid were also markedly reduced. As renal function deteriorated, thromboxane B2 (TXB2) production by ex vivo perfused renal allografts increased progressively from 2 to 6 d after transplantation. However, prostaglandin (PG) E2 and 6-keto PGF1 alpha production remained essentially unchanged. There was a significant inverse correlation between the in vivo clearance of inulin and the log of ex vivo TXB2 production. Infusion of the thromboxane synthetase inhibitor UK-37248-01 into the renal artery of 3-d allografts significantly decreased urinary TXB2 excretion and significantly increased renal blood flow (RBF) and glomerular filtration rate (GFR). Although renal function improved significantly after the acute administration of UK-37248-01, GFR and RBF did not exceed 33 and 58% of native control values, respectively. In other animals, daily treatment with cyclophosphamide improved the clearances of inulin and para-aminohippuric acid and reduced thromboxane production by 6-d renal allografts. These studies demonstrate that histologic evidence of rejection is associated with increased renal thromboxane production. Inhibition of thromboxane synthetase improves renal function in 3-d allografts. Cytotoxic therapy improves renal function, reduces mononuclear cell infiltration, and decreases allograft thromboxane production. Thus, the potent vasoconstrictor thromboxane A2 may play a role in the impairment of renal function and renal blood flow during acute allograft rejection.

Animals↗
PubMed1988

Renal scans in pregnant transplant patients.

This study demonstrates the normal technetium-99m diethylenetriaminepentaacetic acid ([99mTc]DTPA) renal scan in pregnant patients with transplanted kidneys. Five pregnant renal transplant patients had seven [99mTc]DTPA renal studies to assess allograft perfusion and function. All scans showed the uteroplacental complex. The bladder was always compressed and distorted. The transplanted kidney was frequently rotated to a more vertical position. In all patients allograft flow and function were maintained. There was calyceal retention on all studies and ureteral retention activity in three of five patients. Using the MIRD formalism, the total radiation absorbed dose to the fetus was calculated to be 271 mrad. This radiation exposure is well within NRCP limits for the fetus of radiation workers and an acceptable low risk in the management of these high risk obstetric patients.

Female↗
PubMed1996

Hyperinflation of canine lung allografts during storage increases reperfusion pulmonary edema.

The optimal state of inflation for lung allografts during preservation is not known. We previously showed that hyperinflation of canine lung allografts during storage improved posttransplant graft function as measured during 10 minutes of contralateral pulmonary artery occlusion. However, we have also shown that hyperinflation during storage increases pulmonary capillary permeability. It is possible that short-term total cardiac perfusion through the transplanted left lung (for assessment) may not adequately reproduce the clinical situation. The purpose of this study was to assess the effects of hyperinflation during storage in a canine left single-lung transplantation model in which all perfusion was continuously directed to the graft after implantation. Twenty canine left single-lung transplants were done. The lungs of donor animals were ventilated at a tidal volume of 750 ml and an inspired oxygen fraction of 100%. Donor lungs were flushed with modified Euro-Collins solution and the trachea occluded at end inspiration. For donors in groups I and III, the trachea was sealed at that postinflation volume. In groups II and IV, 200 cc of air was withdrawn from the endotracheal tube under positive pressure and the trachea sealed at the lower tidal volume. Lungs were then extracted and stored at 1 degree C for 12 hours. After the preservation period, left lung transplants were performed. After implantation in all groups, the right pulmonary artery was ligated. In groups I and II, the right bronchus was ligated and in groups III and IV the right bronchus was kept open. Subsequent allograft gas exchange and hemodynamics were assessed during a 6-hour period of reperfusion. After assessment, both lungs were excised, wet/dry lung weight ratio was calculated, and histologic examination was done. During the 6-hour assessment, lungs stored in a state of hyperinflation (groups I and III) showed rapid deterioration of gas exchange. At the final assessment, arterial oxygen tension and alveolar-arterial oxygen gradient of groups I and III were significantly worse than those of groups II and IV (group I versus group II: arterial oxygen tension 87.5 +/- 15.0 versus 373.8 +/- 65.5 mm Hg, alveolar-arterial oxygen gradient 564.4 +/- 13.2 versus 298.6 +/- 69.3 mm Hg, p < 0.05; group III versus group IV: arterial oxygen tension 245.4 +/- 33.0 versus 543.6 +/- 41.8 mm Hg, alveolar-arterial oxygen gradient 392.5 +/- 35.6 versus 120.5 +/- 34.7 mm Hg, p < 0.01). We conclude that donor lung hyperinflation during storage does not provide better posttransplant allograft function when perfusion is limited only to the allograft.

Animals↗
PubMed2000

Altered intragraft immune responses and improved renal function in MHC class II-deficient mouse kidney allografts.

BACKGROUND: During renal allograft rejection, expression of MHC class II antigens is up-regulated on the parenchymal cells of the kidney. This up-regulation of MHC class II proteins may stimulate the intragraft alloimmune response by promoting their recognition by recipient CD4+ T cells. In previous studies, absence of donor MHC class II antigens did not affect skin graft survival, but resulted in prolonged survival of cardiac allografts. METHODS: To further explore the role of MHC class II antigens in kidney graft rejection, we performed vascularized kidney transplants using donor kidneys from A(beta)b-deficient mice that lack MHC class II expression. RESULTS: At 4 weeks after transplant, GFR was substantially depressed in control allografts (2.18+/-0.46 ml/min/kg) compared to nonrejecting isografts (7.98+/-1.62 ml/min/kg; P<0.01), but significantly higher in class II- allografts (4.38+/-0.60 ml/min/kg; P<0.05). Despite the improvement in renal function, class II- allograft demonstrated histologic features of acute rejection, not unlike control allografts. However, morphometric analysis at 1 week after transplantation demonstrated significantly fewer CD4+ T cells infiltrating class II- allografts (12.8+/-1.2 cells/mm2) compared to controls (25.5+/-2.6 cells/mm2; P=0.0007). Finally, the intragraft profile of cytokines was altered in class II- allografts, with significantly reduced expression of Th2 cytokine mRNA compared to controls. CONCLUSIONS: These results support a role of MHC class II antigens in the kidney regulating immune cells within the graft. Further, effector pathways triggered by class II antigens promote renal injury during rejection.

Animals↗
PubMed2005

Azithromycin reverses airflow obstruction in established bronchiolitis obliterans syndrome.

INTRODUCTION: A recent pilot study noted clinical benefit of macrolide therapy in the management of six lung transplant recipients with bronchiolitis obliterans syndrome (BOS), a condition previously regarded as irreversible. OBJECTIVE: To examine the effect of low-dose macrolides on lung function in lung allograft recipients with established BOS and to assess whether this benefit is sustained. METHODS: We retrospectively evaluated the effect of azithromycin (250 mg alternate days) on clinical status and lung function in 20 allograft recipients with established BOS, confirmed by decline in FEV(1) or FEF(25-75); consistent high-resolution computed tomography findings; and exclusion of acute rejection, infection, or anastomatic complications. Azithromycin was introduced at mean 82 months after transplantation. BOS staging at initiation of treatment was BOS 3 (10), BOS 2 (2), BOS 1 (6), and BOS0-p (2). All patients were on maintenance immunosuppression comprising cell-cycle inhibitor, oral corticosteroids, and calcineurin inhibitor. RESULTS: There was a significant increase in FEV(1) of median 110 ml (range, -70 to 730 ml) between baseline and 3 months of azithromycin therapy (p = 0.002). This improvement was sustained beyond 3 months in the majority of patients, who had initially benefited from azithromycin (up to 11 months follow up). CONCLUSIONS: This case series confirms the benefit of azithromycin in not only halting, but reversing the declining lung function seen in patients with BOS. This benefit appears to be maintained over time. Low-dose macrolides offer a new and exciting therapeutic strategy for the treatment of progressive BOS, and further clinical and translational mechanistic studies are required.

Adult↗
PubMed1986

The effects of delayed function on recipients of cadaver renal allografts. A study of 158 patients randomized to cyclosporine or ALG-azathioprine.

We randomized 158 recipients of cadaver renal allografts to cyclosporine-prednisone (83) or antilymphocyte globulin-azathioprine-prednisone (75) to evaluate: the effects of immunosuppression and pretransplant risk factors on the incidence of delayed graft function, the effects of immunosuppression on the resolution of delayed graft function, and the effects of delayed graft function and pretransplanted risk factors on patient and graft survival. Cyclosporine did not increase the incidence of delayed graft function, compared with ALG-azathioprine-treated patients (33% versus 27%, P = 0.550) but doubled the mean (+/- SD) duration of oliguria (11.8 +/- 11.0 versus 5.9 +/- 3.2 days, P = 0.002) and the number of required dialyses (6.6 +/- 7.6 versus 3.2 +/- 1.3, P = 0.031). Retransplanted patients had a higher incidence of delayed graft function that recipients of primary grafts in both the cyclosporine (82% versus 25%, P = 0.001) and ALG-azathioprine (55% versus 22%, P = 0.025) treatment groups. The presence of delayed function reduced one-year graft survival from 89% in all patients without delayed function to 72% (P = 0.011) in all patients with delayed function. Cyclosporine-treated patients had a slightly, but not significantly better one-year graft survival rate than ALG-azathioprine treated patients both with (73% versus 68%, P = 0.750) and without (92% versus 82%, P = 0.069) delayed graft function. A preservation time longer than 24 hr did not increase the incidence of delayed graft function in cyclosporine-treated patients (34% versus 32%, P = 0.811) or ALG-azathioprine-treated patients (27% versus 27%, P = 0.902). Cyclosporine-treated patients given kidneys with greater than 24 hr of preservation time had reduced graft survival only when delayed graft function occurred (67% versus 92%, P = 0.009). In conclusion, (1) cyclosporine did not increase the incidence of delayed graft function over ALG-azathioprine treatment; (2) cyclosporine did significantly slow recovery of kidneys with delayed function; (3) delayed graft function correlated with poorer graft survival rate in both treatment groups; but (4) prolonged preservation time did not increase the incidence of delayed graft function or reduce graft survival.

Actuarial Analysis↗
PubMed1992

Novel immunohistochemical markers of human renal allograft dysfunction--antithrombin III, Thy-1, urokinase, and alpha-smooth muscle actin.

We have studied the expression of alpha-smooth muscle actin (alpha sm-1) by mesangial cells, and the expression of Thy-1 glycoprotein, antithrombin III (ATIII), and urokinase by tubular epithelial cells in normal kidneys and dysfunctional renal allografts. Kidney biopsies were studied immunocytochemically for changes in each of these markers and the findings were classified into two groups and compared with creatinine plasma levels at the time the biopsies were taken. In dysfunctional grafts, mesangial alpha sm-1 and tubular epithelial Thy-1 reactivities were greatly diminished, and urokinase and ATIII were missing from proximal renal tubular epithelial cells. Urokinase, which was absent from normal renal glomeruli, appeared in glomeruli of some dysfunctional allografts. The possible usefulness of these markers in patient evaluations was supported by our finding that the distribution of vinculin, fibronectin, myosin, actin B4, desmin, glomerular HLA-DR, and the tubular expression of CD15 remained unchanged. These data prompt us to suggest that the immunocytochemical localization and evaluation of alpha sm-1, Thy-1, ATIII, and urokinase in kidney allografts may be useful adjuncts in the assessment of function in renal allografts.

Actins↗
PubMed2002

[Causes of late renal transplant dysfunction].

Renal transplantation is now established as the therapy of choice for end-stage renal failure. The causes of renal allograft loss have changed with the introduction of new immunosuppressive agents. In the pioneer era of transplantation most renal allografts were lost during the first year after transplantation due to acute rejection episodes. Nowadays, chronic allograft nephropathy became the leading cause of graft loss. The causes of chronic allograft nephropathy can be divided into alloantigen-dependent and alloantigen-independent factors. Acute rejection episodes and histoincompatibility have a significant influence on late graft function. Although alloantigen-related injury is of major importance, alloantigen-independent factors also play a significant role in the progression of chronic allograft nephropathy. Prolonged ischemia time leads to induction of inflammation, resulting in fibrotic scarring or proliferation of mesenchymal cells. Donor related factors such as donor brain death, age, nephron number and gender have a definite impact on late allograft function. Posttransplant complications such as hypertension, metabolic factors and viral infections contribute to accelerated deterioration of the functional units of the kidney. Immunosuppressive agents such as cyclosporine and tacrolimus may cause vasoconstriction and decreased glomerular filtration rate. Moreover, non-compliance is one of the most important risk factor for chronic allograft loss. Regardless of the cause of the initial injury the pathophysiology of chronic allograft nephropathy seems to be the same. All these factors can induce endothelial injury, which leads to increased expression of cytokines and growth factors resulting in proliferative processes, remodelling and scarring of the graft. This paper reviews current knowledge about risk factors and their effect on long-term renal allograft function.

Fibrosis↗
PubMed1981

Recurrence of antiglomerular basement membrane glomerulonephritis in sheep renal allografts.

Renal autografts and allografts were placed in the necks of nephrectomized sheep. Some of the sheep which received allografts had been previously injected with human glomerular basement membrane to induce an autoimmune antiglomerular basement membrane glomerulonephritis. All previously diseased and normal recipient animals were treated wtih azathioprine and prednisone from the day before transplantation. The autografts and immunosuppressed allografts in normal recipients functioned similarly for the first 6 d, but subsequently the allografts deteriorated. Allografts in untreated recipients functioned for less than 3 d. Most (90%) of the allografts in previously diseased sheep developed heavy proteinuria and haematuria immediately after transplantation and their renal function remained low. These grafts showed severe glomerular lesions by the third day, and by 8 d more than 50% of the glomeruli contained crescents. At corresponding intervals the glomeruli of autografts and allografts in normal recipients showed only minor changes. These results demonstrate that antiglomerular basement antibodies circulating in the host at the time of transplantation are a significant threat to the survival of renal allografts.

Animals↗
PubMed1984

Rapid in vivo multiple organ cooling prior to harvesting.

The need for extrarenal as well as renal grafts for transplantation surpasses the number of available donated organs. It is important, therefore, to utilize maximally available donors so that organs from cadaveric sources are not wasted. This experimental study tested a new method for multiple organ harvesting that used a technique for rapid in vivo organ cooling by nonpulsatile pump perfusion prior to harvesting. Kidneys, livers, hearts, and pancreases were obtained from ten mongrel dog donors. Kidneys and livers were transplanted into unrelated canine recipients as heterotopic and orthotopic allografts, respectively. Satisfactory function (serum creatinine 1.4 mg/dl) was obtained in all 20 of the renal transplants in the immediate postoperative period. Hepatic allografts also demonstrated satisfactory function with nine of ten liver transplant recipients surviving past the first 24-hour critical period. In addition, biopsies obtained from the simultaneously harvested hearts and pancreases showed normal histology. In summary, this technique provides more consistent cooling of donor organs prior to procurement and therefore effectively reduces warm ischemia and associated compromise of viability during multiple organ harvesting procedures. Clinical application of these techniques would undoubtedly lead to improved quality and an increased supply of usable organs from cadaveric donors.

Animals↗
PubMed1998

Hepatocellular defence against acidosis is preserved after cold storage.

BACKGROUND: Primary non-function of liver allografts is related to preservation time, during which hypoxia leads to intracellular accumulation of acid. Preservation-induced failure of hepatocellular pH regulation may play a role in the pathogenesis of primary graft non-function. METHODS: Using cultured/suspended rat hepatocytes and fluorimetric determination of intracellular pH, we determined whether preservation in University of Wisconsin solution (4 degrees C) impairs hepatocellular defence mechanisms against acidosis. RESULTS: In non-preserved, 24-h-preserved and 48-h-preserved hepatocytes acidified to pH 6.7-6.8, initial Na+/H+ antiport-mediated H+ fluxes averaged 12 +/- 5, 9 +/- 5 and 12 +/- 5 nmol microL-1 min-1 and initial Na+/HCO3- symport-mediated HCO3- fluxes 7 +/- 2, 7 +/- 3 and 6 +/- 2 nmol microL-1 min respectively (P = NS). Preservation did not affect the inverse relationship between Na+/H+ antiport activity and intracellular pH. Thus, hepatocellular defence against intracellular acidosis is maintained during up to 48 h in University of Wisconsin solution. CONCLUSION: Altered pHi homeostasis is unlikely to play a role in the pathogenesis of primary non-function of liver allografts.

Acidosis↗
PubMed1987

Specific tolerance to canine renal allografts following treatment with fractionated bone marrow and antilymphocyte serum.

These results suggest (1) that ALS + BM fractions can be used to promote tolerance in long-term graft survivors; (2) that the presence of apparent BM cells of donor origin in the allograft in normally functioning kidneys may be related to the mechanism of allograft prolongation, and (3) that some promise of possible specific long-term immunosuppression exists clinically.

Animals↗
PubMed1994

Long-term results of renal transplantation into the valve bladder.

Between 1970 and 1990 renal transplantation was performed in 16 patients with a history of posterior urethral valves. While 10 patients had undergone supravesical urinary diversion before the development of end stage renal disease, all but 1 transplant were drained to the unaugmented native bladder. The 2 and 5-year graft survival rates were 70% and 59%, respectively. Of the 15 surviving patients 11 have allografts that are functioning at a mean of 86 months after transplantation with a mean serum creatinine of 2.0 mg./dl. Urological complications occurred in 19% of the transplants. No detrimental effect of the valve bladder on long-term allograft survival or function was apparent. With appropriate treatment of vesical dysfunction, these patients can be expected to have graft function comparable to the general transplant population despite use of the unaugmented native bladder.

Adolescent↗
PubMed1986

Functional characterization of infiltrating T lymphocytes in human hepatic allografts.

We have employed recently developed techniques in T-cell culturing to study the nature and function of infiltrating hepatic allograft T cells. Using the rationale that intragraft T cells are activated during cell mediated damage to the allograft, we were able to show that these cells would propagate and remain functionally active in the presence of the T-cell growth factor, IL-2. In several instances, phenotypic analysis of cells grown in this manner was very similar to that found within the graft. Both proliferative and cytotoxic responses could be detected from the cultured cell lines. The majority of the proliferative responses were donor-directed and immunogenetic analysis could define donor-directed HLA reactivity, to either class I or class II antigens, or both. Monoclonal anti-HLA antibodies inhibition profiles verified the apparent HLA reactivity. In a smaller percentage of cases, only IL-2 responsiveness could be detected, and no HLA reactivity could be determined. Cytotoxicity could be detected against both class I and class II antigens, however, those cells which demonstrated a greater magnitude of donor-directed cytotoxicity appeared to be directed against class I antigens. A significant correlation between donor-directed proliferation of biopsy cultured lymphocytes and cellular rejection was found. This model appears to be useful in delineating functions of the intragraft T-cell population during rejection.

Adolescent↗
PubMed1983

Successful renal transplantation in hyperoxaluria. A report of two cases.

Two patients with documented primary hyperoxaluria have received renal allografts with successful function for 10 years and 25 months. The patient in case 1 required a ureterolithotomy 6 years post-transplantation to remove a renal calculus of calcium oxalate. This case illustrates that despite recurrence of oxalate stones in the allograft, satisfactory renal function can be maintained by careful follow-up and appropriate interventions. Factors that may be important in successful graft function include the occurrence of acute rejection episodes, avoidance of ischemic graft damage, trials of pyridoxine therapy to decrease oxalate excretion, and frequent evaluation with appropriate interventions as necessary. Renal transplantation is a suitable and possibly the preferred form of therapy of end stage renal disease in patients with primary hyperoxaluria.

Adult↗

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