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PubMed1995

Mixed allogeneic chimerism achieved by lethal and nonlethal conditioning approaches induces donor-specific tolerance to simultaneous islet allografts.

We previously reported that donor-specific, but not third party, skin allografts were permanently accepted if mixed allogeneic (B10+BR-->B10) reconstitution and skin graft placement were performed sequentially or simultaneously in lethally conditioned (950 cGy) recipients. The purpose of the present study was to examine whether a similar outcome would occur if islets were placed coincident with the time of bone marrow infusion and to establish the minimum dose of cytoreduction sufficient to achieve chimerism and tolerance for simultaneous islet allografts. B10 (H-2b) mice were rendered diabetic using streptozotocin. After sustained hyperglycemia (> 300 mg/dl), diabetic B10 mice were irradiated (950 cGy) and reconstituted with 5 x 10(6) T cell-depleted (TCD) B10 + 15 x 10(6) TCD B10.BR bone marrow cells. Islet allografts genetically matched or disparate to the bone marrow donor were placed under the renal capsule within 24 hr following infusion of bone marrow cells. All donor-specific B10.BR mouse (H-2k) islet allografts were permanently accepted (n = 8; MST > or = 173 days), while 7 of 9 MHC-disparate third-party BALB/c mouse (H-2d) islet grafts were rejected. The other 2 allografts remained functional over 200 days posttransplantation. We recently established a nonlethal conditioning strategy to achieve multilineage mixed chimerism. We applied this model to examine whether simultaneous islet grafts matched to the donor would be permanently accepted if the donor was incompletely myeloablated. Diabetes was induced in B10 mouse recipients. Animals with hyperglycemia were conditioned with 500 cGy of TBI followed by an infusion of 15 x 10(6) untreated B10.BR bone marrow cells. A simultaneous islet allograft matched or MHC-disparate to the bone marrow donor was performed the same day. Two days following bone marrow transplantation, a single dose of cyclophosphamide (200 mg/kg) was injected via the intraperitoneal route. Islet allografts matched to the bone marrow donor were significantly prolonged (n = 9; MST > or 226 days) and showed no evidence for chronic rejection, while MHC-disparate grafts were rejected (n = 5; MST = 34 days). Animals that received islet grafts but no bone marrow also rejected their grafts with a similar time course. These data suggest that permanent donor-specific tolerance to islet allografts placed coincident with bone marrow transplantation can be achieved after lethal as well as incompletely myeloablative conditioning.

Animals↗

PubMed2002

Immunopathogenesis of accelerated allograft rejection in sensitized recipients: humoral and nonhumoral mechanisms.

INTRODUCTION: Accelerated rejection (AccR) in sensitized recipients (second-set rejection) is considered a classic humorally mediated form of allograft rejection, although additional effector mechanisms may be involved. METHODS: We developed a model of AccR in which C57BL6 mice are sensitized by BALB/c skin grafts, followed 10 days later by transplantation of BALB/c hearts. We undertook analysis of various humoral and cellular components in this model using knockout or monoclonal antibody-treated allograft recipients. RESULTS: Sensitized mice rejected cardiac allografts in 34+/-7 hr. AccR was accompanied by endothelial deposition of immunoglobulins, complement, and fibrin, but also by dense expression of multiple chemokines and a mixed polymorphonuclear and mononuclear cellular infiltrate. Whereas neutrophil or complement depletion had no significant effect on the tempo of AccR, surprisingly B cell-deficient recipients still underwent AccR (41+/-7 hr) in conjunction with T cell and macrophage recruitment. In contrast, T cell-deficient (nude) mice maintained functioning cardiac allografts for >720 hr despite prior skin engraftment. CONCLUSIONS: AccR in sensitized experimental recipients involves multiple effector pathways. Although most previous studies have emphasized the key role of humoral pathways in mediating AccR, our data indicate that T cell-dependent mechanisms can also promote AccR, alone or in conjunction with humoral responses.

Animals↗

PubMed2006

Histologic and clinical findings in living donor allografts with long-term stable function.

BACKGROUND/AIMS: Protocol biopsy is an important strategy which assesses the histological changes that can occur in the renal allograft and adversely affect its outcome. We aimed to evaluate histological changes in long-term living donor transplants. METHODS: Elective biopsies were done for 120 live donor renal transplant recipients with well-functioning grafts and no rejection history at least 1 year or more after transplant. All patients had serum creatinine levels <2 mg/dl. The histopathological findings using the chronic allograft damage index score were correlated with different clinical and immunological parameters. RESULTS: Chronic tubulointerstitial fibrosis was the most prevalent finding (85% of cases), mostly of mild degree. Normal biopsies were reported in only 7.5% of cases, whereas chronic cyclosporine nephrotoxicity was detected in 5.8% of biopsies. Posttransplant hypertension was significantly correlated with glomerulosclerosis, and posttransplant diabetes with glomerulosclerosis, mesangial matrix increase, tubular atrophy and interstitial fibrosis. The main risk factors associated with a high chronic allograft damage index score were DR mismatching, posttransplant diabetes and time of biopsy. All histopathological changes increased with advancing donor age and declining graft function. CONCLUSION: Elective biopsies showed that histopathological findings do exist even with stable renal function that may pave the way for predicting long-term graft outcome.

Adult↗

PubMed1976

Progressive muscular dystrophy. Functional improvement after a renal allograft.

From his first years a child showed signs of a primary and rapidly developing muscular dystrophy. The diagnosis was established by an increased serum CK level and by electromyography and muscle biopsies. Afterwards this child developed a severe renal deficiency which needed binephrectomy and the graft of a normal kidney. During the few months just after the graft, the disability increased and the patient could not stand upright by himself. Later on, he gradually became able to walk on his own and without bracing. He could climb stairs and stand up from the floor. The CK activity returned to normal. At present, 4 years after the graft (the patient is 16 years), the improvement of his functional abilities is constant, although the CK activity has increased again. In this article we give evidence that this patient suffers from a primary muscular dystrophy. We discuss the type of dystrophy concerned. We believe that it is the graft of a normal kidney which was responsible for the improvement observed, and not the physiotherapy or the drugs administered after the graft.

Adolescent↗

PubMed1977

The maximal tubular reabsorption of phosphate in relation to serum parathyroid hormone.

The relation between the renal handling of phosphate and the serum concentration of immunoreactive parathyroid hormone (i-PTH) was investigated in 15 patients with a very wide range of i-PTH, glomerular filtration rate (GFR), maximal tubular reabsorption of phosphate (TmP) and TmP/GFR-ratio. The latter was used as an index of the renal handling of phosphate. Seven patients had well functioning kidney allografts (GFR 43.1-64.9 ml/min), while 8 had varying degrees of chronic nephropathy (GFR 2.3-26.7 ml/min). The TmP, i-PTH, 51Cr EDTA clearance, the extracellular volume and serum concentrations of calcium and standard bicarbonate were estimated. An inverse significant correlation was demonstrated between TmP/GFR and i-PTH (p less than 0.001), while none of the other investigated factors correlated thyroid hormone has a key role in the regulation of the tubular handling of phosphate in patients with impaired renal function.

Adult↗

PubMed1993

An alternative approach to the semi-quantitative assessment of the transplanted renal artery velocity sonogram.

There are theoretical problems with the use of resistance based indices, i.e. pulsatility index (PI) or resistive index (RI) as stand alone measures in the renal allograft. PI and RI are heart rate dependent and input pressure dependent for autoregulating organs. A new non-invasive index, termed Pz, has been proposed. Pz may be thought of as the arterial back pressure generated by the kidney representing the pressure which needs to be overcome in perfusing the glomeruli. On a theoretical basis Pz can be shown to be independent of heart rate and resistance and to allow for variations in mean systemic blood pressure. In an initial study, a group of 53 well functioning renal allografts demonstrated a significant reduction in the coefficient of variance for Pz (12.8%) when compared to PI (25.4%). A second study on recently transplanted allografts indicated that acute tubular necrosis could not be separated from rejection on the basis of Pz. Pz did however consistently perform better than PI in terms of reduced variability within pathological groups. We conclude that Pz is more useful than PI in this application.

Blood Flow Velocity↗

PubMed1977

Acute renal failure as a complication of hypertonic saline abortion in a kidney allograft recipient.

Acute renal failure following abortion by intra-amniotic hypertonic saline administration has been described only occasionally. This report concerns a patient with end-stage renal failure who was successfully treated with a kidney allograft and developed reversible acute renal failure following the termination of her pregnancy by intra-amniotic infusion of saline. We suspect that the combination of hemoglobinuria and low grade intravascular coagulation might have been a contributing factor in the development of renal insufficiency in this patient. To our knowledge this modality of abortion has not been used previously in pregnant women with transplanted kidneys. From our experience with one patient it seems wise to express a word of caution on the use of this technique in patients with a functioning kidney allograft.

Abortion, Legal↗

PubMed1981

Clinical considerations of renal allograft pathology.

Eleven out of 31 cases of living renal allografts lost their graft functions. Causes of graft loss were acute rejection in eight cases chronic rejection in one, graft rupture in one, and death due to meningitis with good graft function in one case. Five renal allografts and two biopsy specimens obtained after acute irreversible rejection and one renal allograft due to acute tubular necrosis an rupture were reviewed. We evaluated the correlation between these findings and the irreversibility of renal graft functions. All removed allografts and biopsies demonstrated interstitial edema and cell infiltration. Vascular pathology due to acute irreversible rejection revealed a high level of severity with fibrinoid necrosis and luminal obliteration. These findings suggested that graftectomy and cessation of immunosuppressants were indicated.

Graft Rejection↗

PubMedDate not supplied

Posttransplant lymphoproliferative disorder of the lung in a renal transplant recipient treated successfully with surgery.

Posttransplant lymphoproliferative disorders (PTLDs) are a heterogeneous group of lymphoid diseases that occur after solid organ and bone marrow transplantation. Lung-located PTLD has been reported in recipients of the heart, cord blood stem cells, lungs, and bone marrow transplants, but only four cases were reported previously after kidney transplantation. Thoracic location of PTLD must be regarded as an especially dangerous complication. The pathogenesis, and clinical and histological features of PTLD remain poorly defined but predisposing risk factors are becoming better understood. Namely, Epstein-Barr virus (EBV) and immunosuppressive agents appear to be such risk factors. There has been marginal success in treating PTLD using a number of treatment modalities, including combination chemotherapy with anti-CD20 or high-dose chemotherapy with stem cell rescue. We report a renal allograft recipient transplanted in March 2000, diagnosed with EBV-associated and lung-located PTLD. His initial immunosuppression consisted of tacrolimus, azathioprine, and steroids. Azathioprine was withdrawn in September 2001. In November 2001 a high-resolution computed tomography scan revealed two round masses in the right lung. The patient underwent right thoracotomy and resection of the lower and middle lobe. The diagnosis of PTLD was settled by intraoperative histopathological evaluation. The postoperative histological assessment confirmed the diagnosis and revealed positive staining for EBV. The patient remained in complete remission for 3 years with a well-functioning renal allograft, with current serum creatinine of 1.2 mg%. This case illustrates that the treatment of lung-located PTLD may be successful, but it depends on a combination of prompt diagnosis, reduction of immunosuppression, and of course surgery.

Aged↗

PubMed1994

The outcome of neurovascularized allogeneic muscle transplantation under immunosuppression with cyclosporine.

A model of neurovascularized rectus femoris muscle transplantation was established using inbred rats, and histologic and electrophysiologic investigations were carried out with respect to: 1) whether allogeneic muscle grafts could be established during low-dose, continuous, cyclosporine administration; 2) whether functional restoration of the grafted muscle was possible; and 3) whether immunologic tolerance could be induced by administering a 6-week, low-dose, continuous course of cyclosporine. In the animals continuously administered cyclosporine, no rejection was observed until 12 weeks after surgery; the grafts were completely viable; and M waves could be induced by stimulation of the femoral nerve motor branch. In the animals administered cyclosporine for 6 weeks, rejection was observed 7 weeks after surgery (1 week after discontinuation of immunosuppression), and the grafts became completely necrotic after 10 weeks. These findings suggest that neurovascularized muscle allografts show functional recovery similar to autografts under continuous, low-dose administration of cyclosporine, but that rejection occurs early, and immunologic tolerance does not develop, if the administration is discontinued.

Animals↗

PubMed1995

Sarcomas in organ allograft recipients.

In a review of 8724 de novo malignancies that occurred in 8191 organ allograft recipients sarcomas were 7.4% of cancers. Kaposi's sarcoma (KS) made up 5.7%, and other sarcomas (OS) 1.7% a much higher proportion than in the general population. KS was most common in Arab, black, Italian, Jewish, or Greek patients. In 60% of patients with KS the lesions were confined to the skin and/or oropharynx while 40% involved internal organs and/or lymph nodes. Complete remissions following various treatments occurred in 53% of the former group and 27% of the latter. In both groups 32% and 60% of remissions, respectively, occurred when the only treatment was reduction or cessation of immunosuppressive therapy. However, this treatment caused impaired function or allograft loss from rejection in 22 of 34 kidney recipients. Recurrent KS occurred in 5% of patients in remission when immunosuppressive therapy was resumed. Nine of 114 patients (8%) tested for human immunodeficiency virus were positive. Most OS arose in internal organs or soft tissues. The major types were fibrous histiocytoma (20 patients), leiomyosarcoma (15), fibrosarcoma (12), rhabdomyosarcoma (9), hemangiosarcoma (8), undifferentiated sarcoma (7) and mesothelioma (6). Several unusual features were noted. Remarkably, 10 of 105 (10%) sarcomas occurred adjacent to or in a renal (6) or hepatic (4) allograft. Leiomyosarcomas are rare in children, yet 5 of 15 (33%) occurred in pediatric patients. Three hemangiosarcomas occurred in forearms at sites of arteriovenous fistulas used for pretransplant hemodialysis access. One leiomyosarcoma and one fibrosarcoma occurred in previously irradiated areas. One patient with mesothelioma had a history of asbestos exposure and two others had possible exposure.

Humans↗

PubMed1995

An analytical review of growth hormone studies in children after renal transplantation.

With steady improvement in 1- and 5-year patient and graft survivals in the last decade, rehabilitation of the child is the major focus of the transplant physician. The notion that the elimination of the uremic milieu should enable children to grow has not been born out over time, and growth retardation continues to be a serious morbidity in many children despite a well-functioning renal allograft. In children with chronic renal failure prior to renal transplantation, recombinant human growth hormone (rhGH) has been recently shown in controlled trials to improve growth. The use of rhGH in children after renal transplantation is controversial, since uncontrolled studies have questioned its safety. Acute rejection and graft loss have been reported in children after the initiation of rhGH. This study analyzes the data regarding the safety and efficacy of rhGH in children after renal transplantation as presented in seven current published reports. The demographic characteristics of the patients, the dose and duration of rhGH therapy, the "growth" rates of the patients before and after rhGH therapy, renal function before and after rhGH therapy, and other possible complications are reviewed. Based on this analysis, suggestions for future studies are made.

Child↗

PubMed2000

A case of relapse of C-ANCA-associated glomerulonephritis in post-transplant patients.

We experienced a case of relapse of proteinase 3-specific antineutrophil cytoplasmic autoantibody (C-ANCA)-associated rapid progressive glomerulonephritis (RPGN) in a patient after renal transplantation. A 19-yr-old man, who underwent a living donor kidney transplantation, presented a rapid renal function deterioration along with a sign of infection. Initially he was treated as acute rejection, but renal function did not improve. Renal biopsy revealed crescentic glomerulonephritis, and C-ANCA titer was 12 EU/mL, resulting in the diagnosis of C-ANCA-associated RPGN. He was treated with three consecutive methylprednisolone pulses twice in addition to the basal immunosuppressive medications (cyclosporine A and mizoribine), then his renal function improved to normal. Bearing the possibility of recurrence of glomerulonephritis in mind, we re-evaluated the nature and disease course of renal failure of original kidney. He experienced a rapid deterioration of renal function in 1992, and eventually CAPD was started in 1992. His serum in 1992 revealed high titer of C-ANCA (24 EU/mL), and renal biopsy performed in 1992 showed a crescentic glomerulonephritis. Taken together, we diagnosed this event as a relapse of C-ANCA-associated GN. Lessons from our experience are: 1) steroid pulse and high-dose corticosteroid therapy may be useful for the treatment of relapse of C-ANCA-associated GN patients after renal transplantation; 2) the possibility of a relapse of C-ANCA-associated GN following renal transplantation has to be kept in mind, especially when infection precedes the deterioration of allograft kidney function.

Adult↗

PubMed2006

Anti-HLA antibodies after cryopreserved allograft valve implantation does not predict valve dysfunction at three-year follow up.

BACKGROUND AND AIM OF THE STUDY: As the cause of allograft heart valve degeneration is poorly understood, the study aim was to investigate the host antibody response to allograft valve implantation. METHODS: Sera were obtained from 92 recipients of allograft heart valves (61 pulmonary, 31 aortic). Sera were tested for anti-HLA class I antibodies by ELISA and complement-dependent cytotoxicity (CDC) methods, and anti-HLA class II antibodies by ELISA. Specificities of recipient anti-HLA class I antibodies were defined by standard CDC testing against a panel of T lymphocytes from 80 blood donors. Donor valve HLA typing was performed on stored donor DNA samples using molecular methods. The presence of donor-specific anti-HLA class I antibodies was hence defined in recipient sera. The presence of anti-HLA antibodies and donor-specific anti-HLA class I antibodies were correlated with function of allograft valves at the most recent echocardiographic follow up. RESULTS: At a mean of 3.0 years (range: 0.3-5.4 years) after allograft implantation, 96% (87/92) and 82% (75/92) of patients were positive for anti-HLA class I and II antibodies, respectively, by ELISA testing. Some 68% (61/90) of patients were positive for anti-HLA class I antibody (PRA > 5%) by CDC testing. PRA levels decreased with greater postoperative interval (r = -0.31, p = 0.003). In 68 recipients where donor HLA type was defined, 54% (37/68) of patients had antibodies specific to at least one donor HLA class I antigen. In 87 patients with a recent echocardiographic examination available for analysis (at a mean of 3.5 +/- 1.6 years postoperatively), there was no association between valve dysfunction and antibody status. CONCLUSION: Anti-HLA class I and II antibodies were detected by ELISA methods in most patients after allograft implantation extending to 5.4 years. The clinical significance of these findings is unclear, as no correlation was found between the prevalence of anti-HLA antibody and echocardiographic parameters of valve dysfunction at a mean of 3.5 years follow up.

Adolescent↗

PubMed1987

Function of transplanted human pancreatic allografts after preservation in cold storage for 6 to 26 hours.

Preservation of cadaveric pancreas allografts has been a difficult problem in clinical pancreas transplantation; most institutions use Collins solution and limit preservation time to less than 6 hr. Longer preservation times have been used at the University of Minnesota. Between August 1983, and December 1985, 47 human cadaveric pancreas grafts were transplanted into Type I diabetic recipients after cold storage at 4 degrees C in a modified, hyperosmolar silica-gel filtered plasma (SGFP), a solution previously found to allow dog pancreas grafts to be successfully preserved for up to 48 hr. Ten grafts were preserved for 2-5 hr (group 1); 20 for 6-11 hr (group 2; 17 for 12-26 hr (group 3). Graft function and late outcome were compared between these groups and another group of 7 cadaveric grafts (group 4), which were transplanted immediately and without any preservation. Analysis of exocrine pancreatic function early after transplantation showed a maximum mean serum amylase (IU/L) of 557, 440, 429, and 307 in groups 1, 2, 3, and 4, respectively. Primary preservation failure rates of 0, 5%, 5.8%, and 0%, and endocrine graft function rates at 1 month of 80%, 80%, 76%, and 86% were obtained for groups 1, 2, 3, and 4, respectively (P = NS). Only patients who were insulin-independent were counted as having functioning grafts. Detailed functional studies at 1 month showed that mean plasma glucose levels during 24-hr metabolic profiles were in the normal range in 71%, 68%, 72%, and 50%, while oral glucose tolerance test results were within the normal range in 38%, 81%, 76%, and 66% of groups 1, 2, 3, and 4, respectively (P = NS). At 1 year, patient survival rates were 57%, 88%, 75%, and 100% (P = NS), and the graft functional survival rates were 0, 25%, 33%, and 29% (P = NS) in the respective groups. Five patients in group 2, and 6 in group 3 have currently functioning grafts at 4 to 37 months after transplantation. We conclude that cadaver pancreas grafts can be safely preserved for 12-24 hr in modified SGFP solution, thus making the sharing of these organs between different centers practical and the transplant operation less of an emergency procedure.

Adult↗

PubMed1976

Renal handling of phosphate in relation to serum parathyroid hormone levels.

The relation between the renal handling of phosphate, expressed as the maximal tubular reabsorption of phosphate (TmP)/glomerular filtration rate (GFR) index, and the serum concentration of immunoreactive parathyroid hormone (i-PTH) has been ivestigated in 15 patients with a very wide range of GFR, TmP/GFR and i-PTH. Seven patients had well functioning kidney allografts, with GFR ranging from 43.1 to 64.9 ml/min, while eight had varying degrees of chronic nephropathy, with GFR ranging from 26.7 to 2.3 ml/min. The TmP, the i-PTH concentration, the 51Cr EDTA clearance, the extracellular volume and the serum concentrations of calcium and standard bicarbonate were estimated during conditions where tubular reabsorption of phosphate was maximal. An inverse significant correlation was demonstrated between TmP/GFR and i-PTH (p less than 0.001), while none of the other investigated factors correlated to the TmP/GFR index. It is therefore concluded that the parathyroid hormone has a key role in the regulation of the tubular handling of phosphate in patients with impaired renal function.

Adult↗

PubMed1989

Post-transplant hypertension in the rat: effects of captopril and native nephrectomy.

In patients with well-functioning renal allografts, the presence of diseased native kidneys appears to be a common cause of elevated blood pressure. We evaluated the role of native kidneys in post-transplant hypertension using a rat model in which the confounding variables of rejection and immunosuppression could be eliminated. To produce disease in native kidneys. PVG rats were subjected to 5/6 nephrectomy. Four weeks following renal ablation, these hypertensive animals were transplanted with kidneys from syngeneic PVG donors. Four weeks later, the effects of captopril and native nephrectomy on blood pressure and renal hemodynamics were examined. Animals with remnant native kidneys which received non-rejecting renal isografts had sustained hypertension, elevated plasma renin levels and reduced transplant function. In these animals, administration of captopril reduced systemic blood pressure. Despite the reduction in blood pressure, PAH clearance by the transplanted kidney increased markedly while GFR rose modestly. Removal of the remnant native kidney also acutely lowered blood pressure. However, compared to captopril, native nephrectomy produced a more marked increase in GFR without significantly affecting renal blood flow. In this model of post-transplant hypertension in the rat, elevated blood pressure and reduced isograft function are mediated by the diseased native kidney, in part through the effects of angiotensin II. These data suggest that ACE inhibitors and native nephrectomy may have beneficial hemodynamic effects in patients with post-transplant hypertension caused by native kidneys.

Aminohippuric Acids↗

PubMed2002

Long-term outcome of focal segmental glomerulosclerosis after Japanese pediatric renal transplantation.

Focal segmental glomerulosclerosis (FSGS) is known to recur in some patients after renal transplantation. Over a prolonged period, we followed 13 pediatric patients with FSGS who had undergone transplantation from living-related donors, analyzing risk factors for recurrent disease. Native nephrectomies were performed bilaterally in all patients at least 1 month prior to transplantation. Immunosuppressive therapy consisted of cyclosporine (CyA), mizoribine, prednisone, and antilymphocytic globulin or deoxyspergualin. We examined age at onset, time in months between diagnosis and end-stage disease (dialysis or transplantation), the duration of dialysis, age at transplantation, time since nephrectomy, doses of immunosuppressive agents, and HLA mismatch. Five patients (42.8%) developed recurrent disease in the graft; all showed proteinuria within 24 h of transplantation. However, all allografts have functioned well for 34-156 months following transplantation despite the recurrences, although 1 of these patients now shows proteinuria. The remaining 8 patients have had no recurrence for 104.6+/-30.4 months (mean+/-SD). The serum level of creatinine in patients with recurrence and without recurrence was 1.1+/-0.42 mg/dl and 0.98+/-0.29 mg/dl, respectively. The interval from diagnosis to initiation of dialysis was significantly shorter in patients with recurrence than those without recurrence ( P<0.05), but no other variables differed between these two groups. No recurrence of FSGS was observed in the protocol biopsy at 100 days after transplantation. We believe that CyA and native nephrectomy may limit or reverse progression of recurrent FSGS in renal allografts of Japanese pediatric patients, although this is a limited study.

Adolescent↗