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PubMed1999

Clinically stable human renal allografts contain histological and RNA-based findings that correlate with deteriorating graft function.

BACKGROUND: Chronic rejection (CR) remains idiopathic, difficult to prospectively identify, and once detected, unresponsive to increased immunosuppression. We hypothesized that clinically stable human renal allografts have ongoing evidence of injury and immune activity, and that this correlates with the worsening of allograft function characteristic of CR. METHODS: The allografts of 40 stable renal allograft recipients were biopsied 2-3 years after transplantation. Biopsies were processed for histology and RNA extraction. RNA was evaluated by semi-quantitative RT-polymerase chain reaction for CD3y mRNA (a marker of T cell receptor turnover), and mRNA from cytokine genes previously shown to be transcribed during acute rejection: tumor necrosis factor-alpha, interferon-gamma, interleukin- (IL) 1beta, IL-2, IL-4, IL-6, and IL-8. Clinical parameters including urine protein and glomerular filtration rate were measured the day of biopsy. Findings were then compared with clinical outcome to establish associations between subclinical inflammation and graft dysfunction. Allograft function was measured again 2 years after biopsy and correlated with findings at the time of biopsy. RESULTS: Cytokine transcripts and histological evidence of injury were detected in more than two-thirds of stable grafts. The degree of the lymphocytic infiltrate correlated with the degree of proteinuria (P=0.034) and histological fibrosis (P=0.005). Similarly, the degree of intragraft CD3y transcription correlated with increasing proteinuria (P=0.043). IL-6 and IL-8 transcripts were also correlated with evidence of graft injury. After 2 years, those biopsies originally found to have evidence of fibrosis, tubular atrophy, or CD3gamma transcription had worsening graft function as determined by creatinine and glomerular filtration rate. CONCLUSIONS: These data demonstrate that significant injury and immune activity can be detected in patients who are stable on clinical grounds. Undetected subclinical graft injury may be a cause of chronic allograft rejection.

Biomarkers↗
PubMed1986

Structure and function of orthotopic small bowel allografts in rats treated with cyclosporine.

Previous studies of small bowel transplantation using a variety of animal models and immunosuppressive regimens have failed to demonstrate consistently prolonged survival of bowel allografts capable of maintaining a normal nutritional state. In the present study, total orthotopic small bowel transplantation was performed in inbred rat strains to determine the structure and function of intestinal allografts using cyclosporine for immunosuppression. Without cyclosporine, Lewis-Brown Norway and Brown Norway allografts were quickly rejected by Lewis recipients, resulting in host death. A 15 mg/kg dose of cyclosporine given intramuscularly immediately after operation and for 6 successive days thereafter achieved prolonged but not uniformly indefinite animal and graft survival with clinical courses and pathologic findings consistent with chronic rejection. With continuation of cyclosporine every other day until day 28, all Lewis recipients of Brown Norway allografts were alive and well 8 months after transplantation. Weight gain, maltose absorption, and multiple nutritional indices in these animals were not significantly different from those of either age-matched normal Lewis rats or recipients of Lewis isografts. Full-thickness biopsy specimens of these allografts showed no evidence of graft rejection. These results demonstrate that indefinite survival of intestinal allografts with preservation of their structure and function sufficient to allow normal growth and weight gain can be achieved with cyclosporine therapy. This success in the rat model of orthotopic small bowel transplantation suggests that clinical small-bowel transplantation may become possible using cyclosporine.

Animals↗
PubMed2003

[The effect of cryopreservation on the structural and functional properties of human vascular allografts].

OBJECTIVES: To assess the effet of cryopreservation on the structural and functional properties of venous and arterial human allografts. MATERIALS AND METHODS: Segments of arteries and veins harvested from multiorgan donors were divided into 3 groups: fresh-control tested for 24 hours after harvesting, frozen directly at -80 degrees C and frozen gradually (progressive freezing technique) and preserved in liquid nitrogen at -196 degrees C degree. The 2 cryopreserved groups of segments were allowed in two different cryoprotectant solutions (M1 and M2) containing both dimethyl sulphoxide (10%), RPMI 1640 for the first and M 199 for the second. Rapid thawing was done at regular intervals over 4 months and the allografts were processed for biomechanical, ultrastructural, morphological and immunohistochemical analysis. RESULTS: Cell damage was less intense in the specimens conserved in M1 solution and by progressive freezing technique especially for smooth muscle cells and endothelial cells which remained preserved until 12 weeks. CONCLUSION: Cryopreservation in both the solutions employed induce changes in the morphology of arterial wall. Better results were obtained with RPMI 1640 associated with progressive freezing.

Arteries↗
PubMed1980

Results of renal transplantation in children.

From 1968 to 1978, 66 renal transplants were performed on 58 pediatric patients with end stage renal failure. With a mean followup of 6 years 46 patients (79.3 per cent) are alive and 35 (60.3 per cent) currently have a functioning renal allograft. Live donor allografts yielded fewer surgical complications and better long-term functional survival rates than cadaver allografts. Patient rehabilitation following a successful renal transplant was excellent. However, despite resumption of growth in most cases normal linear growth was achieved rarely. Renal transplantation provides the best long-term solution to the problem of end stage renal disease in children.

Adolescent↗
PubMed1991

Does pancreas transplantation influence the course of diabetic retinopathy?

Between March 1983 and December 1989 a total of 57 pancreas transplants were performed in 54 patients, of whom 49 also received a kidney for end-stage diabetic nephropathy. Of the surviving 44 patients, 39 had regular pre-operative and post-operative ophthalmological examinations. Diabetic retinopathy was classified according to the original "Early treatment diabetic retinopathy study" (ETDRS) protocol. At the time of this analysis a total of 25 patients had a functioning pancreas transplant and 23 of them also a functioning renal allograft after a mean observation time of 43.2 months (Group 1). They were all free of exogenous insulin, HbA1c being 6.2% (5.1-6.9%; normal value 4.2-5.9%). Fourteen patients in Group 2 lost their pancreas transplant during the first four years. Six of them still have a functioning renal allograft, four patients regularly undergo hemodialysis. Mean HbA1c is 7.5% (5.7-9.2%). Before transplantation, grade of retinopathy according the ETDRS protocol was 6.7 (2-10) in group 1 patients and 7.9 (3-10) in group 2. In group 1 patients stabilisation of retinopathy was observed in 33 eyes (73.3%) and clear improvement achieved in 4 eyes (8.8%). Detoriation occurred in 8 eyes (17.7%) only. In group 2, 14 eyes (54%) remained stable, whereas progression of the disease continued in 12 eyes (46%). From these results it is concluded that the course of diabetic retinopathy is positively influenced by successful pancreas transplantation.

Adult↗
PubMed1998

Functional integration of striatal allografts in a primate model of Huntington's disease.

Huntington's disease is an autosomal dominant, inherited disorder that results in progressive degeneration of the basal ganglia (especially the neostriatal caudate nucleus and putamen) and other forebrain structures and is associated with a clinical profile of movement, cognitive and psychiatric impairments for which there is at present no effective therapy. Neuropathological, neurochemical and behavioral features of the disease can all be reproduced in experimental animals by local injection of excitotoxic or metabolic toxins into the neostriatum. All these features of the disease can be alleviated, at least in rats, by transplantation of embryonic striatal tissue into the degenerated striatum, which was the basis for commencing the first clinical trials of striatal transplantation in Huntington's patients. However, although rat striatal xenografts may temporarily reduce apomorphine-induced dyskinesias in monkeys, there has been no demonstration that allograft techniques that work well in rats translate effectively to the much larger differentiated striatum of primates. Here we demonstrate good survival, differentiation and integration of striatal allografts in the primate neostriatum, and recovery in a test of skilled motor performance. Long-term graft survival in primates indicates probable success for clinical transplants in Huntington's disease; in addition, our data suggest that graft placement has a direct influence on the pattern and extent of functional recovery.

Animals↗
PubMed1993

Renal allograft rejection: expression and function of VCAM-1 on tubular epithelial cells.

The interaction between vascular cell adhesion molecule-1 (VCAM-1) and very late antigen-4 (VLA-4) is known to play an important role in stabilizing the adhesion of lymphocytes to endothelial cells. Such cellular adhesion is crucial to many immunological processes including lymphocyte-mediated cell lysis. In this study the expression of VCAM-1 on renal tubular epithelial cells is demonstrated on biopsy sections recovered during acute renal allograft rejection. Experiments performed using epithelial cells cultured from renal tubules show that VCAM-1 is up-regulated by addition of the inflammatory cytokines tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma). Combination of TNF-alpha and IFN-gamma synergized to induce high levels of VCAM-1 expression. Further experiments demonstrated that the cytokines produced by activated lymphocytes in mixed leucocyte culture also up-regulate expression of VCAM-1. Assays of the adhesion of lymphoid cells to cultured renal epithelial cells showed that cytokine pretreatment of the renal cells enhanced the binding of lymphoid cells. The proportion of bound lymphoid cells was significantly reduced by addition of an antibody capable of blocking the interaction of VCAM-1 with VLA-4. This result indicated that the VCAM-1 induced on renal epithelial cells by inflammatory cytokines is functionally capable of binding VLA-4, thereby enhancing the adhesion of potentially graft-damaging lymphoid cells.

Cell Adhesion↗
PubMed1986

Renal transplantation in end stage renal disease patients with existing urinary diversion.

From 1971 to 1984 renal transplantation was performed in 20 patients with end stage renal disease who presented with an existing form of urinary diversion. These patients were evaluated with a cystometrogram, voiding cystourethrogram and cystoscopy. In some cases bladder function was studied further by cycling through a suprapubically placed catheter. The bladder was considered unstable in 13 patients and undiversion was done at transplantation. The period of prior diversion ranged from 3 to 20 years (mean 12.7 years). There were no surgical complications postoperatively and normal bladder function returned in all patients. Currently, 8 patients have a functioning renal allograft 16 months to 9 years after transplantation (mean 4.2 years). Seven patients were considered to have a nonusable bladder owing to severe neurogenic disease or refractory contracture. In these patients transplantation was done into a pre-fashioned intestinal conduit (5) or cutaneous ureterostomy (2). Currently, 4 patients have a functioning renal allograft 16 months to 6.2 years after transplantation (mean 3.8 years). Transplantation candidates who present with an existing form of urinary diversion should be evaluated carefully, since many will have a usable bladder. Regardless of whether the bladder is usable, transplantation can be performed safely with no increased surgical or immunological risk.

Adult↗
PubMed2004

Histological findings in "incidental" intraoperative pancreas allograft biopsies.

Thirty intraoperative needle core biopsies of well-functioning pancreas allografts were performed from 2 days to 7 years posttransplantation (mean 15.4 months). Most samples (83.3%) lacked significant inflammation or fibrosis. The five patients who showed features of ongoing low-grade acute rejection experienced premature graft losses due to chronic rejection. There were no complications related to the intraoperative biopsy itself.

Adult↗
PubMed2004

Methenamine silver staining quantitative digital histochemistry in chronic allograft nephropathy.

Renal function and final outcome of renal allografts have been correlated with irreversible damage. This study describes a quantitative histochemical method relying on periodic acid methenamine silver (PAMS) staining of all renal compartments. Among 60 renal allograft biopsies from 43 patients, 15 biopsies showing pure chronic allograft nephropathy were selected to determine PAMS-stained area percentage (SAP), using image analysis with quantitative histochemistry. Of the 15 cases, 9 (60%) were grade I and 6 (40%) were grade II chronic allograft nephropathy (CAN). The mean serum creatinine (sCr) value was 1.86 +/- 0.47 for allograft biopsies. The mean (+/-SD) SAP for the implantation biopsies was 10.58 +/- 1.87%, and for allograft biopsies 25.26 +/- 9.67 (P <<.000). The serum creatinine (sCr) values for grade I versus II CAN were 1.63 +/- 0.24 versus 2.20 +/- 0.54 mg/dL, respectively (P=.019), and SAP values were 18.97 +/- 0.24 versus 34.7 +/- 5.89 (P=.003). There was a strong positive correlation between sCr values and SAP (P=.005; r=0.64). These findings show the PAMS approach to be a useful alternative method for reflecting damage in more than one compartment of the renal tissue. Also, the method can discriminated implantation and allograft biopsies as well as grade I and II CAN cases. The series is small for a multivariate analysis of the value of SAP measurements in PAMS-stained sections as a prognosticator, but the data support its use.

Biopsy↗
PubMed1999

Functional failure of fascia lata allografts.

OBJECTIVES: Fascia lata allografts are commonly used in urogynecologic procedures. Functional failure of several grafts has occurred, and such failure has been recognized as a materials problem in 12 patients. STUDY DESIGN: Twelve patients with failure of an initial urogynecologic procedure performed with irradiated and freeze-dried donor fascia lata grafts underwent reoperation. Portions of the implanted fascia lata grafts could be retrieved in 7 cases. Graft specimens underwent histologic processing followed by hematoxylin and eosin staining. RESULTS: Histopathologic analyses of the retrieved material demonstrated several ongoing processes in the failed grafts. A few grafts showed areas of ideal remodeling. Most grafts, however, showed areas of disorganized remodeling and areas of graft degeneration. Evidence of immune reaction to the graft was observed in some cases. CONCLUSION: The high materials failure rate associated with the use of irradiated and freeze-dried donor fascia lata grafts suggests that such tissue should not be used for urogynecologic procedures.

Fascia Lata↗
PubMed1973

Human polyomavirus infection in renal allograft recipients.

Cytological and virological studies on 74 patients with functioning renal allografts were undertaken to detect polyomavirus infection of the renal tract. Ten patients (13.5%) were excreting polyomavirus. Virus particles were seen in the electron microscope in urine samples from eight patients. B.K. polyomavirus was isolated from four patients. Infection with a different polyomavirus was probable in one patient. Virus isolation was most readily achieved when large numbers of intact virus particles were seen in the urine. Patients who were excreting large amounts of polyomavirus shed numerous inclusion-bearing cells which could be detected by cytology. A serological study showed that the prevalence of B.K. antibody was similar to that found in the general population and 38% of this series of transplant patients had evidence of active infection with B.K. virus.

Adolescent↗
PubMedDate not supplied

Anterior cruciate ligament allograft transplantation. Long-term function, histology, revascularization, and operative technique.

In recent years much effort has been devoted to finding a satisfactory replacement for the injured ACL. None of the reconstruction techniques used in the past can be considered ideal because of their inability to duplicate the complex geometry, structure, and function of the ligament. Current advances in allograft transplantation and cryopreservation have led us to design and implement an experimental model for testing the feasibility of cryopreserved ACL allotransplantation. Groups of dogs were used to evaluate the effect of cryopreservation on ligament strength and to compare the relative performance of both autograft and allograft ACL transplants up to 18 months after implantation. The ligaments were examined mechanically, histologically, and microangiographically. The cryopreservation process and duration of storage had no effect on the biomechanical or structural properties of the ligament. The mechanical integrity of the allografts was similar to that of the autografts, with both achieving nearly 90% of control ligament strength by 36 weeks. Revascularization approached normal by 24 weeks in both autograft and allograft. No evidence of structural degradation or immunological reaction was seen. Based on these results, we believe that a cryopreserved ACL allograft can provide the ideal material for ACL reconstruction. We have outlined a surgical technique for harvesting and implanting this graft clinically.

Animals↗
PubMed2000

Prediction of pregnancy outcome in subgroups of women with renal disease.

BACKGROUND: The preconception and intraconception parameters that are relevant to outcome in women with underlying renal disease remain controversial. SUBJECTS, MATERIALS AND METHODS: We analyzed the types and frequencies of short- and long-term (2 years after delivery) maternal and neonatal complications in 38 patients with primary renal disease (46 pregnancies), 24 IDDM patients with diabetic nephropathy (24 pregnancies), and 27 patients with a functioning renal allograft (42 pregnancies), most of them with mild renal insufficiency. Logistic regression models were formulated to predict successful outcome. RESULTS: Successful pregnancy outcome (live, healthy infant without severe handicap 2 years after delivery) was observed in 98% of the patients with primary renal disease, 96% of the IDDM patients with diabetic nephropathy, and 89% of the patients with a functioning renal allograft. Factors found to be significantly predictive of successful outcome were absence of preexisting hypertension in all groups, in addition to low preconception serum uric acid level in the primary renal disease patients, and long interval from transplantation to conception and use of a low dose ofprednisone in the renal transplant patients. CONCLUSION: Most women with different subtypes of renal disease have a successful pregnancy outcome with proper prenatal care. Worse pregnancy outcome was observed in women with moderate or severe renal failure. Fitted logistic models may provide useful guidelines for counseling women with preexisting renal disease about their prospects for a successful pregnancy in terms of immediate and long-term maternal and neonatal outcome.

Adult↗
PubMed1999

Long-term survival and function of intrahepatic islet allografts in rhesus monkeys treated with humanized anti-CD154.

Reported effects of anti-CD154 treatment on autoimmunity, alloreactivity, and inflammatory events mediated by macrophages and endothelial cells indicated that it might be an ideal agent for the prevention of intrahepatic islet allograft failure. This hypothesis was tested in MHC-mismatched rhesus monkeys. Transplantation of an adequate number of viable islets resulted in engraftment and insulin independence in six of six recipients treated with anti-CD154 (hu5c8) induction plus monthly maintenance therapy (post-operative day >125, >246, >266, >405, >419, >476). Anti-CD154 (hu5c8) displayed no inhibitory effect on islet cell function. For monkeys followed for >100 days, continued improvement in graft function, as determined by first phase insulin release in response to intravenous glucose, was observed after the first 100 days post-transplant. No evidence of toxicity or infectious complications has been observed. All recipients treated with anti-CD154 became specifically nonresponsive to donor cells in mixed lymphocyte reactions. Furthermore, three monkeys are now off therapy (>113, >67, and >54 days off anti-CD154), with continued insulin independence and donor-specific mixed lymphocyte reaction hyporeactivity. In striking contrast to all previously tested strategies, transplantation of an adequate number of functional islets under the cover of anti-CD154 (hu5c8) monotherapy consistently allows for allogeneic islet engraftment and long-term insulin independence in this highly relevant preclinical model.

Animals↗
PubMed2006

Influence of parathyroidectomy on blood pressure and function of the transplanted kidney in patients with tertiary hyperparathyroidism.

BACKGROUND: Tertiary hyperparathyroidism is one of the causes of bone demineralisation, nephrolithiasis and a potential risk factor influencing blood pressure and excretory graft function in patients after kidney transplantation (Tx). The aim of the study is to analyse the influence of parathyroidectomy (PTx) on graft function and blood pressure control in these patients. METHODS: 392 subsequent patients after kidney Tx were included into this analysis. Records of 84 patients (21.4%) with elevated plasma calcium concentration (> 2.6 mmol/l) during observation were reviewed. In 39 patients (9.9%) calcaemia remained elevated for over 1 year after kidney Tx. Eleven patients (2.81%) were referred for PTx. In 2 cases PTx were performed within the first 6 months, while the 9 others undergone surgery between 16 and 36 months after Tx. We have evaluated the influence of PTx on renal allograft excretory function, blood pressure and the number of antihypertensive drugs in kidney transplant patients. RESULTS: In 7 out of 11 patients the indication for PTx was renal osteodystrophy, while in other cases the indication was the asymptomatic hypercalcaemia. Shortly after surgery normalisation of calcaemia was observed in all cases. However the creatinine clearance did not changed shortly after PTx (64 +/- 12 vs. 63 +/- 16 ml/min), and a slight deterioration of transplanted kidney excretory function was observed in 2 patients. 12 months after PTx deterioration of GFR (5320 ml/min) of borderline significance was found. All patients before PTx suffered from arterial hypertension, ten of them were receiving antihypertensive drugs (average 1.6 medicine per patient). Two weeks after PTx a transient decline of both systolic and diastolic blood pressures (-13 +/- 14 mmHg; p = 0.02 and -46 mmHg; p = 0.06, respectively) was observed. However there was a negative correlation between initial plasma calcium concentration and decline of diastolic blood pressure (R = -0.884; p = 0.0003). Six and twelve months after PTx blood pressure values were at the same magnitude as before PTx. CONCLUSIONS: (1) Parathyroidectomy and normalisation of calcaemia did not influence significantly the excretory allograft kidney function. (2) Patients benefit from PTx only with the transient improvement of their blood pressure control.

Adult↗