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PubMed1991

Fate of frozen intercalary allograft at one year after implantation with adjuvant chemotherapy treatment. A case report.

The proximal humerus of a 21-year-old man was reconstructed with a frozen allograft combined with a Neer shoulder prosthesis. At graft retrieval one year later, the proximal end of the allograft had revascularized with some osteogenic activity, but distally neither vascular ingrowth nor osteogenic activity was seen. Allografts should not be used unsupported because of their potential weakness with time. Intramedullary stems should be used to support functional allografts which primarily facilitate soft-tissue reattachment.

Adult↗

PubMed1994

Risk factors predicting chronic rejection of renal allografts.

Chronic rejection is clinically defined as a gradual but progressive impairment of renal allograft function in the absence of other specific causes. The risk factors predisposing to chronic rejection are incompletely known. In this prospective single-center project, logistic regression analysis was used to study the long-term outcome of 94 consecutive first renal allografts in relation to 10 potential risk factors. Whether serum lipid levels, histopathological changes or the mode of immunosuppressive therapy had a predictive value for chronic rejection was of special interest. The risk factors for renal allograft outcome were determined 2 years after the transplantation, when graft function was still normal, and the results were evaluated 2 years later. Occurrence of acute rejections, cold ischemia time, the high-density lipoprotein cholesterol level, and the high-density lipoprotein and total cholesterol ratio were not significant predictors of graft outcome. In a univariate analysis, triglyceride, total cholesterol, and low-density lipoprotein cholesterol level, and donor age were significantly related to graft outcome. In a logistic regression analysis, triple immunosuppressive therapy was better than any double-drug regimen in preventing the deterioration of renal allografts. Incipient histological changes in graft biopsy, quantitated as the "chronic allograft damage index," was the most important single predictor of chronic rejection. The effect of both the histological changes and low-density lipoprotein cholesterol on adverse graft outcome was level dependent.

Adult↗

PubMed1991

Atrial natriuretic factor does not improve the outcome of cadaveric renal transplantation.

Atrial natriuretic factor (ANF) ameliorates renal damage in animal models of acute ischemic renal failure. Consequently, ANF could blunt acute tubular necrosis related to ischemia that occurs frequently in cadaveric renal transplants. Ten pairs of cadaveric kidneys were transplanted into 20 recipients. Paired recipients received either alpha-human ANF (hANF) or vehicle alone in a prospective, double-blind protocol. Upon revascularization of the allograft, either hANF or vehicle was administered intravenously as a 50-micrograms bolus, followed by a 4-h infusion (0.1 microgram/kg/min). Glomerular filtration rate ([125I]iothalamate clearance) was measured between 4 and 7 days posttransplant and again between 14 and 21 days posttransplant. Serum creatinine was measured daily when patients were in the hospital, then twice weekly as patients were examined in the outpatient clinic. Between the groups, there was no significant difference in age of the recipients or donors, cold ischemia time, or histocompatibility leukocyte antigen match. Infusion of hANF had no adverse effects. When subjects receiving hANF were compared with those treated with vehicle alone, there were no significant differences in serum creatinine or glomerular filtration rate. Three hANF and four vehicle recipients required dialysis postoperatively. At 1 month posttransplant, 19 of 20 patients had functioning allografts; an allograft from one hANF recipient never functioned. It was concluded that hANF, when given by the protocol of this study, had no beneficial effect on the outcome of cadaveric renal transplantation in humans.

Acute Kidney Injury↗

PubMed1989

Fc-receptor for mouse IgG1 (Fc gamma RII) and antibody-mediated cell clearance in patients treated with Leu2a antibody.

A pilot study was performed to explore the clinical potential of Leu2a antibody in reversing acute renal allograft rejection. Anti-Leu2a, a murine IgG1 monoclonal antibody (mIgG1 mAb), is specific for the CD8 molecule that is expressed in high density on class I reactive T cells. Of the 6 recipients treated with anti-Leu2a, two responded with a complete reversal of rejection with long-term allograft function maintained for over a year. In two other recipients, acute rejection was initially reversed, but later rejection episodes resulted in allograft failure at 2-3 months posttreatment. Rejection in the two other recipients showed no response to Leu2a mAb treatment. Specific depletion of peripheral blood CD8+ cells occurred in four of the six recipients. Even in this small series, it was evident that cell clearance was neither necessary nor sufficient for reversal of rejection. However, a complete correspondence between cell clearance and the ability of the recipients' mononuclear cells to undergo mitogenic response to the mIgG1 anti-CD3 (Leu4) mAb in vitro was noted. Binding of IgG1 mAb to the Fc-receptor (Fc gamma RII/CD32) expressed on blood monocytes is known to be essential for the T cell mitogenic response to soluble mIgG1 CD3 mAb in vitro. Our data suggest that binding to Fc gamma RII may be an essential step in the process of mIgG1 Leu2a mAb-mediated cell clearance in vivo.

Animals↗

PubMed1997

Expression of an allogeneic MHC DRB transgene, through retroviral transduction of bone marrow, induces specific reduction of alloreactivity.

BACKGROUND: Transfer of MHC class II genes, through allogeneic bone marrow (BM) transplantation, induced long-lasting acceptance of renal allografts in miniature swine. To adapt this approach to the clinic, we have now examined whether somatic transfer of allogeneic class II DR genes, into otherwise autologous bone marrow cells (BMC), can provide the matching required for inducing immune tolerance. METHODS: Autologous BMC were transduced ex vivo with recombinant retroviruses for allogeneic DRB followed by BM transplantation. The recipients were then challenged with kidney allografts solely matched to the DRB transgene. RESULTS: Five miniature swine received autologous BMC conditioned with growth factors and transduced with recombinant retrovirus vectors containing allogeneic (n=4) or syngeneic (n=1) class II DRB genes and a drug-resistance marker. Expression of retrovirus-derived products in BM-derived cells was demonstrated by the detection of drug-resistant colony-forming progenitors and the presence of DRB retrovirus transcripts in peripheral cells. Analysis of selective mixed lymphocyte reaction responses to DR or DQ antigens indicated decreased reactivity toward the transduced DR gene product. Among all of the animals receiving fully mismatched kidney allografts, but with DRB matched to the transduced DRB, the one with the highest gene transduction rate showed stable allograft function and essentially normal renal histology for 2.5 years. A control animal, which received a syngeneic DRB gene, rejected its kidney allograft in 120 days after an earlier rejection crisis. CONCLUSIONS: These studies demonstrate that allogeneic MHC gene transfer into BM provides a new strategy for inducing tolerance across MHC barriers.

Animals↗

PubMed2004

Tubular chimerism occurs regularly in renal allografts and is not correlated to outcome.

Recent studies have demonstrated an integration of recipient-derived progenitor cells into solid allografts with differentiation into parenchymal cells. Whether or to what extent this phenomenon influences allograft outcome has still to be elucidated. To detect epithelial chimerism tubular cells were harvested from sequential renal allograft biopsy samples by laser microdissection in 36 patients. Recipient-derived cells were detected by short-tandem repeat-based genotyping. In cases with gender-mismatched transplantation, chimerism was semiquantitatively evaluated by in situ hybridization for the Y-chromosome. Findings were correlated to different pathomechanisms of epithelial injury as well as to morphologic and clinical outcome. Epithelial chimerism was detectable as early as 8 d after transplantation and lasted for 8 yr. A total of 88% of the patients showed an epithelial chimerism; 72% had a stable chimerism in sequential biopsy samples. Evaluation of Y-chromosome by in situ hybridization revealed low percentages of chimerical tubular epithelial cells (2.4% to 6.6%). No correlation to morphology was found. Chimerism was detectable in inconspicuous protocol biopsy samples, cases of drug toxicity, and rejected allografts with and without chronic changes. No correlation was found to allograft function. Epithelial microchimerism is an early and persistent phenomenon after renal transplantation. There is no correlation to morphologic or functional outcome. Probably recipient-derived stem cells contribute in a minor fashion to tissue homeostasis, and cell turnover in renal allografts is predominantly enabled by donor cell renewal.

Biopsy↗

PubMed1976

The response of the juxtaglomerular apparatus to stimuli effecting renin or erythropoietin release in canine renal allografts.

The functioning canine renal allograft produces plasma renin activity (PRA) and erythropoietin (ESF) activity and can maintain normal blood pressure and normal erythropoiesis. Moreover, in response to various provocative stimuli it can: (i) increase plasma renin activity in response to low sodium intake; (ii) suppress PRA in response to high sodium intake; (iii) produce increased serum erythropoietin in response to hypoxia. The granulation activity of the juxtaglomerular apparatus correlates best with the degree of graft rejection and with the PRA in groups manipulated by changing sodium balance. This is not the case with hypoxia. Thus, the juxtaglomerular apparatus, even in the presence of vascular changes seen with the severe degree of rejection in renal allografts, can respond to stimuli that can regulate renin release. Renin production by the transplanted kidney can be dissociated from ESF secretion. Blood pressure changes in the present model were not directly associated with increased PRA or juxtaglomerular apparatus activity. In such conditions hypertension can exist in the presence of suppressed PRA and without hypergranulation of the apparatus. The majority of correlations of this study thus establish a close association of the degree of juxtaglomerular index activity with PRA levels, rather than ESF.

Animals↗

PubMed1995

Chronic renal allograft rejection and clinical trial design.

Both the choice of endpoints and the selection of patients will be critical study design features in randomized controlled trials needed to test the effectiveness of treatments for chronic renal allograft rejection. We examined the feasibility of carrying out clinical trials with different endpoints and patient inclusion criteria by analyzing data from a population of 627 cadaveric kidney transplant recipients who survived with a functioning allograft for at least six months. Among those who lost grafts to chronic rejection, decreases in renal function of 30% and 60% preceded graft loss by a median of only 1.1 and 0.7 years, respectively, suggesting that little would be gained in a clinical trial that used a predetermined reduction in renal function as a surrogate endpoint. Less clear is whether histologic changes could be used as a surrogate endpoint. At present, graft loss to chronic rejection and graft failure from any cause are the most reliable endpoints. Unfortunately, large numbers of patients are needed to demonstrate clinically relevant therapeutic effects on these endpoints. Limiting enrollment to patients who are at high risk for developing chronic rejection, by selecting patients who already have a decline in renal function, for example, may reduce the number of patients needed in a clinical trial. On the other hand, selecting patients with disease that is too advanced may diminish the effectiveness of therapy. In any case, it is impossible to accurately determine the number of patients needed for a definitive clinical trial without preliminary data demonstrating the expected magnitude of the treatment effect. Thus, well-designed pilot studies are needed to measure possible treatment effects before conducting large-scale clinical trials for chronic renal allograft rejection.

Clinical Trials as Topic↗

PubMed1991

Disseminated histoplasmosis in a renal transplant patient: a cause of renal failure several years following transplantation.

A 49-year-old man developed disseminated histoplasmosis 6 1/2 years after transplantation. The organism was initially present in the urine and in a tongue lesion. Treatment with itraconazole was instituted. However, there was further dissemination of the disease and worsening of renal function. Allograft biopsy showed extensive involvement with the organism. Amphotericin B was started, resulting in a rapid resolution of the disease. However, renal function deteriorated, leading to permanent hemodialysis.

Biopsy↗

PubMed1981

Renal transplantation in systemic lupus erythematosus.

3 patients with chronic renal failure due to lupus nephritis received kidney allografts from cadaver donors. Serological activity was present in 2 patients at the time of transplantation, and continued unabated despite intensive immunosuppressive therapy. Their allograft failed at 5 and 7 months after transplantation. Anti-DNA antibody in the allograft was found in 1 patient. The 3rd patient, with no serological activity at the time of transplantation, remained serologically negative, and her allograft functioned for 18 months. The persistence of serological activity in 1 patient, and the recovery of anti-DNA antibody from her allograft provide proof for the recurrence of lupus nephritis in the allograft.

Adult↗

PubMed1999

Donor bone marrow and transplantation tolerance: historical perspectives, molecular mechanisms and future directions (review).

The induction of transplantation tolerance, defined as the indefinite existence of an intact, functioning allograft, has been a goal of transplantation immunologists for decades because of the morbid effects of immunosuppressive drugs required to maintain graft function. One promising method of tolerance induction involves the peritransplant administration of cytoablative drugs followed by administration of a low dose of donor bone marrow cells. A subpopulation of donor bone marrow cells bearing the CD8 accessory molecule cause the functional deletion of graft reactive T cells via a CD95 dependent mechanism that also involves the cytokine TGFbeta. This interaction is bi-directional in which the bone marrow cell deletes the graft reactive T cell that recognizes it. Therefore, only T cells that recognize the donor antigens are deleted, leaving the immune response to other antigens intact. This protocol has been successfully used in rodents and an outbred large animal model. Clinical trials of donor bone marrow administration are now underway and initially indicate that administration of donor bone marrow is clinically safe.

Animals↗

PubMed1995

Postischemic injury, delayed function and Na+/K(+)-ATPase distribution in the transplanted kidney.

We evaluated the postischemic renal injury in 22 patients undergoing renal transplantation. Renal tissue obtained 45 to 60 minutes after reperfusion of the allograft was stained with specific antibodies against the delta subunit of Na+/K(+)-ATPase, fodrin and ankyrin. The distribution of each cytoskeletal protein was analyzed by laser confocal microscopy. Subsequent allograft function was assessed on two occasions, 1 to 3 and 36 hours post-reperfusion, respectively. Recipients were divided into two groups: those who achieved a normal GFR on post-transplant day 3 (group 1, N = 12) and those with persistent hypofiltration (group 2, N = 10). Patients of both groups exhibited impaired sodium reabsorption and isosthenuria one to three hours postoperatively, but these abnormalities persisted on day 3 only in group 2 subjects with persistent hypofiltration. Abnormalities of Na+/K(+)-ATPase, ankyrin and fodrin were confined to proximal tubule cells and were marked only in the subjects of group 2. They consisted of redistribution of each cytoskeletal protein from the basolateral membrane to the cytoplasm. We conclude that postischemic injury to a renal allograft results in a loss of polarity of proximal tubule cells. We propose that ensuing impairment of proximal sodium reabsorption could activate tubuloglomerular feedback, thereby contributing to the protracted hypofiltration that characterizes this form of postischemic, acute renal failure.

Adolescent↗

PubMed1991

Renal transplantation into ileal conduits: results and long-term follow-up.

From 1977 through 1990, 708 renal transplants were performed at our institution. Eight of these allografts (1.1%) were placed into recipients who required ileal conduits. This report describes the long-term follow-up of these patients. Five out of 8 patients currently have functioning allografts 29 to 102 months after transplantation (with a mean allograft survival of 50 months). Construction of an ileal conduit in patients without bladders or in those who have non-functioning bladders is a straightforward approach with minimal increased morbidity and good long-term results.

Adult↗

PubMed1994

Further studies of veto activity in rhesus monkey bone marrow in relation to allograft tolerance and chimerism.

Infusing the DR-/dim fraction of bone marrow cells (BMC) from an allogeneic kidney donor into rabbit antithymocyte globulin-treated transplant recipients delivers a tolerogenic signal, leading to functional allograft tolerance in rhesus monkeys without additional drug therapy. Our updated results in an expanded series show a median 131-day graft survival of recipients given DR-/dim donor BMC with a 23% 1-year survival (P < 0.00001 vs. rabbit antithymocyte globulin controls). Removing DRbright cells from donor BMC appeared to have a significant effect (P < 0.05). We have further investigated the tolerogenic mechanism within the experimental framework of the veto hypothesis in this preclinical model. In limiting dilution assays, we demonstrated the donor specificity of clonal inactivation of CTL precursors (CTLp) after in vitro or in vivo exposure to DR-/dim donor BMC, confirming specific tolerance. Additionally, in vitro studies confirmed the allogeneic specificity of CTLp inactivation in 3-cell MLR assays; minimal bystander effects were seen on normal CTLp responses to third party stimulator cells, while CTLp responses to the BMC donor's cells were abrogated in the same cultures. BMC mediating the veto effect were found to be resistant to L-leucyl-L-leucine methyl ester (Leu-leu-OMe), which excluded BMC-mediated cytotoxicity by NK or lymphokine-activated killer cells, CTL, or activated macrophages. In contrast, veto activity was abolished if the BMC were pretreated with either high dose UV-B light irradiation, mitomycin, or gamma-irradiation, indicating that BMC contained a UV-B-sensitive precursor of the veto effector, and that a proliferative step separated the two. Irradiation of DR-/dim donor BMC or administration of cyclophosphamide after infusion of nonirradiated BMC prevented the tolerogenic effect. Only recipients given nonirradiated DR-/dim donor BMC demonstrated PBL chimerism, which associated with functional deletion of antidonor CTLp and duration of graft survival. The Leu-leu-OMe resistance and the other properties of the allogeneic monkey CD3- CD2+ CD8+ BMC subpopulation that exhibits tolerance-promoting activity in vitro and in vivo lead us to postulate that a donor BMC-derived precursor population, possibly a dendritic cell population, may induce allogeneic unresponsiveness in this model.

Animals↗

PubMed2002

Treatment of recurrent allograft dysfunction with intravenous hematin after liver transplantation for erythropoietic protoporphyria.

Erythropoietic protoporphyria (EPP) is a rare inherited disorder of the heme biosynthetic pathway in which toxic levels of protoporphyrins often precipitate in the liver, leading to cirrhosis, liver failure, and the need for liver transplantation (OLT). Because the underlying enzyme defect in EPP is bone marrow derived, the risk for recurrent EPP allograft dysfunction is high. Although plasmapheresis may ameliorate acute allograft disease, strategies to maintain disease remission are needed. A 59-year-old man who underwent OLT for hepatic EPP experienced increased bilirubin and aminotransferases on postoperative day 700. Allograft biopsy demonstrated recurrent EPP. He was managed initially with plasmapheresis, hypertransfusion, and infusions of i.v. hematin. After normalization of liver tests, the hematin infusions have been given intermittently, are well tolerated, and associated with normal allograft function for nearly 2 years. This is the first case of the use of hematin given post-OLT to help achieve and maintain remission of allograft EPP disease.

Biopsy↗

PubMed2002

A case of acute antidonor antibody-mediated humoral rejection after renal transplantation with specific consideration of serial graft biopsy histology.

A 61-year-old-woman with end-stage renal disease caused by IgA nephropathy received living unrelated kidney transplantation from her husband in February 2001. Pre-transplant donor-specific T- and B-cell cross-match was negative. Immunosuppressive treatment consisted of tacrolimus (TAC), mycophenolate mofetil (MMF), methylprednisolone (MP) and antilymphocyte globulin (ALG). The kidney functioned immediately after kidney transplantation. On post-operative day 9, the level of serum creatinine (S-Cr) rose from 1.1 to 1.5 mg/dL. The allograft biopsy specimen taken on the day revealed moderate accumulations of polymorphonuclear leucocytes in peritubular capillaries (PTCs), dilatation of PTCs and transplant glomerulitis, moderate to severe. Immunofluorescent study of a frozen section of the allograft biopsy specimen showed a strong, diffusely distributed endothelial staining pattern in PTCs for the stable complement split product C4d. Post-transplant donor-specific T- and B-cell cross-matches performed on post-operative day 13 were positive. From the allograft biopsy and the positive post-transplant donor-specific T- and B-cell cross-matching, acute humoral rejection (AHR) associated with the development of antidonor antibodies (ADA) was diagnosed. Plasma exchange (PE) treatment was initiated on day 11. After a total of 13 treatments of PE, donor-specific T- and B-cell cross-matches became negative and the biopsy performed on day 72 revealed mild transplant glomerulopathy without accumulation of polymorphonuclear leucocytes in PTCs or a C4d staining pattern in PTCs of immunofluorescence. The allograft functioned well and the creatinine level was 1.1 mg/dL 7 months post-transplant. This was a case of AHR after renal transplantation associated with the development of ADA, which was triggered by spousal-donor antigens. The presence of widespread C4d deposition in PTCs in renal allograft biopsies played a role in the diagnosis of AHR and the diagnosis was confirmed by positive donor-specific T- and B-cell cross-matches at the time of rejection, which were negative at pre-transplantation. Several treatments of PE were effective for resolving AHR in this case and the effect of PE in the treatment of AHR could be assessed by the degree of peritubular capillaritis (PTCitis) and C4d deposits in PTCs.

Antibodies↗

PubMed1990

Cyclosporine-induced changes in glomerular filtration rate and urea excretion.

PURPOSE: Cyclosporine is the mainstay of many immunosuppressant protocols, but confers a significant risk of nephrotoxicity. We sought to clarify the effects of cyclosporine on renal function in renal transplant recipients after induction of mild intravascular volume depletion. PATIENTS AND METHODS: Two groups of renal transplant patients with normal allograft function at least 6 months after transplantation whose immunosuppressive regimens differed only by the presence or absence of cyclosporine usage were enrolled in a 10-day in-hospital protocol. After a 3-day control period, intravascular volume depletion was produced by dietary restriction of sodium chloride for 4 days and the administration of furosemide. Creatinine and urea clearances, true glomerular filtration rate (GFR) (by radioisotope technique), and the fractional excretion of sodium were measured. The patients were subsequently given a high amount of sodium chloride by intravenous infusion (3.8 mEq/kg body weight/day) for 3 days and the studies were repeated. RESULTS: Ten patients treated with azathioprine and prednisone (azathioprine-treated) and nine patients treated with cyclosporine, azathioprine, and prednisone (cyclosporine-treated) were enrolled. The two groups developed a similar degree of intravascular volume depletion; blood pressure did not change and urine flow rates did not differ between the groups throughout the protocol. The cyclosporine-treated patients showed significant decreases in GFR, creatinine clearance, and urea clearance, and increases in blood urea nitrogen (BUN) and percent urea reabsorption after intravascular volume depletion; these findings resolved after challenge with the sodium chloride load. In contrast, the azathioprine-treated patients' BUN, urea clearance, GFR, and creatinine clearance did not significantly change throughout the protocol. The decrease in the fractional excretion of sodium after intravascular volume depletion was significantly greater in the cyclosporine-treated patients. CONCLUSION: Cyclosporine predisposes to acute reversible nephrotoxicity by compromising the renal compensatory mechanisms. Proximal tubular function, as manifested by urea and sodium reabsorption, remains intact.

Adult↗

PubMed1999

Tuberculosis isolated to the renal allograft.

Immunosuppressed patients after renal transplantation are at increased risk of developing infective complications, including tuberculosis. We describe four renal transplant patients who presented with tuberculosis isolated to the renal allograft. The three patients with adequate follow-up presented with a febrile illness 12-26 months after the transplant. The mycobacterial infection was found in the graft nephrectomy specimen in three patients. One patient with renal allograft dysfunction had a percutaneous biopsy that showed tuberculosis. The latter patient recovered renal allograft function after anti-tuberculous therapy. None of the patients had evidence of tuberculosis elsewhere. We conclude that tuberculosis isolated to the renal allograft, especially in an endemic area, may be the cause of renal dysfunction, and appropriate therapy could lead to salvage of the graft.

Adult↗