bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of immunosuppression as a treatment for pre‐sensitization in renal transplant candidates
Authors: Scornik Juan C. , Salomon Daniel R. , III Robert S. Fennell , Howard Richard J. , Pfaff William W.
Published: September 2024

The management of patients with broadly reactive antibodies remains an unsolved problem in renal transplantation. In patients who do not require transfusions, antibody levels may fall spontaneously. However, in some patients sensitization persists and effective treatments for these patients are lacking. Despite previous reports on the use of plasma exchange or selected IgG depletion plus immunosuppression, this therapy has not gained wide acceptance because of its complexity, expense and toxicity. In addition, little information is available on the independent contribution of immunosuppression or plasma exchanges to the reduction of antibody levels. To study these issues we performed plasma exchanges alone, immunosuppression alone, or plasma exchanges plus immunosuppression (prednisone and cyclophosphamide or cyclosporine) in patients with long‐standing sensitization. Plasma exchanges produced an immediate reduction of antibody levels whose magnitude was similar whether or not immunosuppression was given concomitantly. The net antibody reductions induced by plasma exchanges alone, however, were small and short‐lasting. In contrast, immunosuppression had little immediate effect but induced a reduction of antibody levels which was apparent between 2–8 weeks after initiation of a 3‐wk treatment period. These results indicate that a short course of immunosuppression induces a reduction of antibody levels that lasts for several weeks after termination of therapy with no evidence of rebound and suggest that continued therapy might permit successful transplantation.
A safer renal allograft needle biopsy
Authors: Dixon Timothy K. , III James S. Bowman , Sago Alvin L. , Jaffers Gregory
Published: September 2024

Histologic tissue evaluation remains the most accurate method for the assessment of renal allograft dysfunction, even though numerous noninvasive techniques exist. Reliable biopsy techniques have previously consisted of surgical biopsy or Tru‐cut (14 g) needle biopsy. Complications are infrequent but serious complications have prevented widespread use and thus management of acute allograft dysfunction often entails monitoring clinical responses to empiric therapy based on nonspecific findings from noninvasive studies. We performed percutaneous renal allograft biopsies using the Bard Biopty Gun (18 g) needle with ultrasound guidance and compared the results with prior percutaneous Tru‐cut needle biopsies. Using the Biopty technique, 128 allograft biopsies were performed and compared to 121 prior Tru‐cut needle biopsies. The Biopty technique resulted in one (0.8%) major complication, a perinephric hematoma, as compared to 7 (5.8%) major complications, including loss of 2 (1.7%) allografts, with Tru‐cut needle biopsies. The Bard Biopty needle technique offers a method to provide safer renal allograft biopsies that can be repeated at frequent intervals, facilitating accurate assessment of allograft dysfunction.
Successful kidney transplantation in the presence of IgM alloantibodies
Authors: McCalmon Robert T. , Spees Everett K. , Tardif Gilman N. , Kuruvila K. Chakko , Kortz Warren J. , Kam Igal , Karrer Frederick M.
Published: September 2024

The presence of anti‐donor IgM lymphocytotoxic antibodies in transplant recipient sera has been suggested as being clinically insignificant with regard to immediate and/or early graft survival. We have transplanted 20 cadaveric kidneys since June 1988 into recipients whose “extended standard crossmatch” was positive but whose crossmatch was negative after treating the sera with dithiothreitol (DTT). Within this group, 16 recipients received a primary kidney graft and 4 individuals had underlying connective tissue diseases. However, only one of these patients was auto‐crossmatch positive. Nine patients had a percent reactive antibody (pRA) level greater than 50% at the time of transplantation. Fourteen individuals had a positive T‐cell crossmatch, and all 20 had a positive B‐cell crossmatch. Seventeen of the 20 patients transplanted are alive. Four patients demonstrated delayed graft function. One patient died of pneumonia, 1 patient died of infectious complications, and 1 patient developed a coagulopathy and infarcted his kidney and mesenteric blood vessels. One patient had an accelerated humoral rejection which was reversed after plasmapheresis (X7). Fourteen of 20 recipients (70%), 13 of whom are 15 to 27 months posttransplant, are doing well with an average serum creatinine of 1.53 mg/dl. These results indicated that one can successfully transplant a kidney into a recipient whose positive crossmatch was due to IgM alloantibodies.
Liver transplantation and the disliked patient: A clinical and ethical dilemma
Authors: Hans Paul , Gutheil Thomas G.
Published: September 2024

Transplantation as a treatment for liver failure has increased dramatically over the last 20 years. There has been considerable discussion of the ethical, social, and economic dilemmas raised by this procedure, but little has been written about the impact of these problems on hospital personnel engaged in the clinical care of liver transplantation patients. The stress normally felt is accentuated when the patient is someone who is disliked by the staff. A case is described in which problems in caring for the disliked patient were encountered. Reasons for the difficulties are suggested, and proposals made for helping to resolve them.
Analysis of plasma interleukin‐2 receptor (sIL‐2R) and tumor necrosis factor‐alpha (TNF‐α) in renal transplant patients
Authors: Noronha Irene L , Daniel Volker , Möhring Klaus , Opelz Gerhard
Published: September 2024

In an attempt to elucidate the role of soluble interleukin‐2 receptor (sIL‐2R) and tumor necrosis factor‐α (TNF‐α) in renal allograft reaction, we tested plasma samples of 68 renal transplant patients using a sandwich enzyme immunoassay and an immunoradiometric assay. Patients with stable renal function demonstrated increased sIL‐2R levels (946 ±34 vs 361 ± 17 U/ml in healthy controls, mean ±SEM; p<0.0001). During acute rejection episodes the level of sIL‐2R was significantly higher (1987± 147 U/ml; p<0.0001). The highest level was observed during OKT3 treatment (3636±511 U/ml; p<0.0001). Patients with cyclosporine A (CyA) nephrotoxicity presented values similar to those of patients with stable allograft function (757 ±71 U/ml; ns). In 8 patients with viral infections the sIL‐2R plasma levels were also elevated (2651 ±412 U/ml; p<0.0001 compared to stable renal function; ns compared to acute rejection and OKT3 therapy). sIL‐2R was also augmented in uremic patients (1452± 62 U/ml). TNF‐α plasma levels were consistently low or sometimes undetectable in normal individuals, patients with stable renal function, and patients with CyA nephrotoxicity (2 ±0.7, 7± 1.5, 1 ±0.7 pg/ml, respectively). Patients with acute rejection had increased plasma TNF‐α (55± 14 pg/ml; p<0.05), especially after OKT3 therapy (157±24 pg/ml; p < 0.05). Six patients with viral infections had plasma TNF‐α levels similar to those found during acute rejection (49 ±9 pg/ml; ns compared to acute rejection; p<0.05 compared to stable renal function). Pretransplant uremic patients presented elevated plasma TNF‐α (56±9.8 pg/ml: p< 0.0001 compared to stable renal function; ns compared to acute rejection). In a scries of in vitro experiments, sIL‐2R and TNF‐α concentrations were measured in the supernatant of peripheral blood mononuclear cells (PBMC) submitted to in vitro stimuli. Both sIL‐2R and TNF‐α increased progressively with time in the supernatant of PBMC stimulated with Phytohemagglutinin (PHA) or OKT3. We conclude that both sIL‐2R and TNF‐α plasma levels are significantly elevated during acute rejection episodes, viral infections and in uremic patients but not during periods of CyA nephrotoxicity. OKT3 is a potent inducer of sIL‐2R and TNF‐α release, demonstrated both in vivo and in vitro.
Effect of the simultaneous administration of rifampicin and erythromycin on the metabolism of cyclosporine
Authors: Soto J. , Sacristan J. A. , Alsar M. J.
Published: September 2024

The administration of erythromycin plus rifampicin in a cardiac transplant produced a fall in cyclosporine blood concentrations when, in the same patient, 2 weeks previously the administration of erythromycin alone produced an increase in cyclosporine blood concentrations that reached the toxic range. When these two antibiotic are given together with cyclosporine, the inducing effect of rifampicin is greater than the inhibitory effect of erythromycin. Since the maintenance dose of cyclosporine should not be reduced, cyclosporine blood concentration should be routinely monitored to keep it within the therapeutic range.
A randomized trial with two anti‐CMV hyperimmune globulins in the prevention of CMV disease in CMV‐negative renal transplant patients
Authors: Pakkala Seppo , Salmela Kalja , Lautenschlager Irmeli , Hirvonen Marjatta , Ahonen Juhani , Häyry Pekka
Published: September 2024

Cytomegalovirus (CMV) causes marked morbidity in renal transplant patients which may be prevented by passive immunization. We studied the effect of two different hyperimmune globulins in the prevention of CMV disease in seronegative patients receiving renal transplants from seropositive donors. Thirty patients were randomized to receive either anti‐CMV i.v. Ig (pH 4‐pepsin treated), or CytotectR (beta‐propiolactone treated) 1.5 ml/kg on day 1, 1.0 mg/kg on d 14 and 28, 0.5 ml/kg on d 42, 56, 84 and 112 post‐transplantation. As controls, 15 patients transplanted without CMV prophylaxis immediately before (12 patients) and after (3 patients) the randomization period, were included. All patients and controls received same basic immunosuppression and sulfa‐trimethoprime prophylaxis. Of the 30 patients on prophylactic anti‐CMV globulin, 21 (70%) became CMV‐positive and 11 patients (37%) developed virologically confirmed CMV disease. Two additional patients had fever without other signs of CMV disease. Two patients developed interstitial pneumonitis (IPn). Eleven (37%) patients developed acute rejection and had symptomatic CMV disease after transplantation. CMV disease developed earlier in patients treated for rejection with antithymocyte globulin (ATG) than in patients treated with methylprednisolone. In the historical control group, 5 patients (33%) developed CMV disease and 1 of them had pneumonitis. Seven patients (47%) underwent episodes of acute rejection and 3 of them had CMV disease at the same time. There were no opportunistic infections in cither group.
Serum levels of soluble interleukin‐2 receptor, C‐reactive protein, neopterin, myoglobin and light chains of cardiac myosin fail to correlate with the occurrence of rejection in long‐term renal and heart transplant patients
Authors: Volk H. D. , Schüler St. , Czerlinski S. , Reinke P. , Spindler A. , Warnke H. , Josimovic‐Alasevic O. , Porstmann B. , Bürger W. , Diamantstein T. , Hetzer R. , Baehr R. V.
Published: September 2024

Even in the late phase following heart and kidney transplantation (> 1 year post‐Tx) there are still acute interstitial rejections which are generally verified by invasive diagnosis (biopsy). We raised the question whether serum parameters pointing to immunologic activation (neopterin, C‐reactive protein [CRP], soluble interleukin‐2 receptor [sIL‐2R]), which have been described to be diagnostically relevant for an “early” rejection (during the first months post Tx), are also suitable for noninvasive diagnosis of “late” rejections of heart and kidney transplants. In addition, myoglobin and light chains of cardiac myosin (myosin L‐chains), being markers pointing to an ischemically injured myocardium, have been quantified in the serum of heart transplant recipients. 161 heart allograft recipients (13 with moderate to severe rejection, 34 with mild rejection) and 20 kidney allograft recipients (10 with acute rejection) were investigated in this study. In all cases, the diagnosis has been confirmed by the histology of transplant biopsy. More than 300 sera have been investigated. Although about one third of the patients had an increased sIL‐2R level and more than 80% of the heart transplant patients increased myoglobin and myosin L‐chain levels (10% even strongly increased), we were not able to detect a significant relation between the increase in serum parameters and the occurrence and degree of rejection in long‐term transplant patients. We therefore concluded that the serum parameters tested are not suitable for non‐invasive rejection diagnosis in the late phase after transplantation. Long‐term follow‐up studies will show whether increased myoglobin and myosin L‐chain levels in heart transplant recipients might be considered as an early diagnostic marker for coronary artery disease.
Association of kidney graft failure with a positive flow cytometric crossmatch
Authors: Berteli A. J. , Daniel V. , Möhring K. , Staehler G. , Opelz G.
Published: September 2024

We examined the pretransplant sera of 154 cadaver kidney recipients for anti‐donor antibodies against T lymphocytes using the flow cytometry technique. All patients had negative routine lymphocytotoxic crossmatches. 31 of the 154 (20%) patients were positive in the flow cytometric T‐cell crossmatch (FACS‐T‐XM). A positive FACS‐T‐XM was associated with irreversible rejection (p < 0.01 at 14 days, p < 0.001 at 30 d, p < 0.001 at 1 year). The 1‐yr graft survival rate of FACS‐T‐XM‐negative patients was 85% in contrast to 58% for FACS‐T‐XM‐positive patients (p < 0.001). 84% of the irreversible rejections in FACS‐T‐XM‐positive patients occurred within the 1st month after transplantation. These results suggest that a positive FACS‐T‐XM should be considered a contraindication for transplantation. We developed a flow cytometric assay to determine the complement‐fixing capacity of antibodies causing a positive FACS‐T‐XM. Of 14 patients who were examined, 10 had noncomplement‐fixing and 4 complement‐fixing antibodies. All 10 patients with noncomplement‐fixing antibodies experienced acute rejections, which were irreversible in 4. These results demonstrate that noncomplement‐fixing anti‐T cell antibodies, which cannot be detected in the lymphocytotoxic crossmatch assay, are clinically relevant.
Fatal lymphoma in association with OKT3 antibody therapy diagnosed by allograft biopsy
Authors: Murray Brian M. , Venuto Rocco C. , Kohli Romesh K. , Brentjens Johannes R. , Anthone Sidney , Cunningham Eugene E. , Gerbasi Joseph R.
Published: September 2024

We report two renal transplant recipients who died of rapidly fatal lymphoma within 3 months of transplantation. Both presented with fever and deteriorating graft function during the 2nd week of OKT3 therapy for rejection and the removed allograft showed lymphomatous infiltrates. OKT3 may have enhanced in vivo EBV infection in these patients predisposing to lymphomatous transformation. Retrospective review of renal transplants done since July 1986 showed that the incidence of lymphoma in patients receiving OKT3 was 4% and lymphoma has not been seen in patients who did not receive OKT3. Clearly, the risks of OKT3 therapy must be carefully weighed in the aggressively immunosuppressed patient.
Influence of noncompliance on the response to OKT3 in late renal allograft rejection
Authors: Mayes James T. , Jacobs Gretta H. , Moir Ellen J. , Bartucci Marilyn R. , Hricik Donald E. , Schulak James A.
Published: September 2024

OKT3 is an effective therapy for acute renal allograft rejection. However, the efficacy of this drug in treating rejections occurring more than 1 year after transplantation is not well established. Herein we review our use of OKT3 in 29 patients who received OKT3 therapy for rejections occurring more than 1 yr after kidney transplantation. Patients were classified as responders or nonresponders in an attempt to identify clinical or histologic predictors of response. Clinical variables evaluated included the timing of rejection, HLA B‐DR match, race, sex, number of previous rejection episodes, number of transplants, and patient compliance with immunosuppressive drugs. Histopathology was reviewed retrospectively to assess the degree of concomitant chronic rejection. Only noncompliance correlated with response to OKT3 therapy (p < 0.02). Morbidity and mortality was acceptable, with 3 deaths that were unrelated to the OKT3 therapy. Although overall response rate was 67%, 72% of the responding patients obtained 1 yr of subsequent graft function. This experience suggests that OKT3 therapy is effective therapy for late renal rejection episodes, particularly when it is caused by noncompliance.
Importance of bone marrow cell dose in bone marrow transplantation
Authors: Paulin Thomas
Published: September 2024

The importance of the size of the infused marrow cell dose (MCD) was investigated in 274 patients undergoing allogeneic BMT between 1975 and 1990. Among those, 65 had acute myelogenous leukemia (AML), 79 acute lymphoblastic leukemia (ALL), 58 chronic myelogenous leukemia (CML) and 25 severe aplastic anemia (SAA). MCD was analyzed in bivariate and multivariate analysis together with 6 other clinical factors. In multivariate analysis a low MCD was significantly associated with increased incidence of acute graft‐versus‐host disease (GvHD) in all patients (p = 0.005) and in ALL patients (p = 0.02) whereas in CML a high dose was instead correlated to acute GvHD. A low MCD was also correlated to an increased incidence of symptomatic cytomegalovirus (CMV) infection (p = 0.001). A low MCD was also correlated to death in acute GvHD in all patients (p = 0.01) and to a poor survival in all patients (p = 0.04) (AML, p = 0.07).
Mycobacterium tuberculosis after liver transplantation: Management and guidelines for prevention
Authors: Higgins Robert S. D. , Kusne Shimon , Reyes Jorge , Yousem Sam , Gordon Robert , Van Thiel David , Simmons Richard L. , Starzl Thomas
Published: September 2024

During a 9‐year period, from January 1981 to December 1989, 6 mycobacterial infections were diagnosed among 2380 orthotopic liver transplants performed at the University of Pittsburgh. These infectious complications, although rare, were a major source of morbidity and mortality (40%). There were several associated risk factors in these patients, including extensive travel through or birth in endemic areas, severe pretransplant illness, post‐transplant rejection requiring adjunct (i.e., OKT3) immunosuppression, and HIV infection. Five patients had M. tuberculosis (MTB) infections; the 6th patient developed a solitary pulmonary nodule which grew mycobacterium avium intracellulare (MAI). Invasive diagnostic studies were usually necessary to document MTB infection and tissue samples often revealed early granuloma formation. Multiple drug regimens (INH, Rifampin, Ethambutol, and Pyrazinamide) were initiated early in the clinical course and effective therapy was judged by resolution of the clinical illness and/or radiographic resolution. The patient with MAI had no pulmonary or infectious symptoms. He was observed without anti‐tuberculous therapy and the pulmonary nodule decreased in size 3 months after the diagnosis was made. We recommend that all patients have pre‐operative PPD skin tests. Only those patients who fall into high‐risk categories, demonstrating x‐ray evidence of pulmonary disease or those who have a documented recent skin conversion, should receive INH prophylaxis in the peri‐operative period because of the associated risk of INH hepatotoxicity in these patients. MAI infection in asymptomatic patients may be managed with expectant observation. If the patient develops pulmonary symptoms, or the lesion persists, pulmonary nodule resection and antituberculous chemotherapy guided by culture sensitivities may be appropriate.
Correlation of endomyocardial biopsy findings with electrocardiogram voltage in pediatric cardiac allografts
Authors: Nakhleh Raouf E. , III R. Morton Bolman , Shumway Sara , Braunlin Elizabeth
Published: September 2024

Endomyocardial biopsy is said to be the gold standard for the diagnosis of cardiac rejection. In the pediatric age group endomyocardial biopsy is more difficult, and technically may be unsatisfactory. It is therefore desirable to correlate the biopsy finding with non‐invasive studies so that patients may be monitored meaningfully, and endomyocardial biopsy may be used in a more selective manner. Ten pediatric patients (age range 2‐16 years, mean 11.1 yr) underwent endomyocardial biopsy and electrocardiography simultaneously during their post‐transplant course (2‐24 biopsies, mean 14 biopsies). All patients were treated with triple‐drug therapy including cyclosporine, azathioprine and prednisone. Biopsies were classified according to the working formulation of the International Society for Heart Transplantation. The total electrocardiographic voltage (summation of leads 1, 2, 3, V1 and V6) and the limb lead voltage (summation of leads 1, 2, and 3) were calculated. The measurements were then converted into percentage of the highest voltage for each patient, and these values were then compared in the different biopsy groups by analysis of variance. Both the total voltage and the limb lead voltage were significantly lower in the group with grade 3 biopsies versus all other groups (p < 0.0005). At a level of 10% decline in total voltage, changes in EKG voltage had low specificity (87%) and positive predictive value (51%) but high sensitivity (94%) and negative predictive value (99%). We conclude that, although strong correlation is present between rejection and low voltage, a decline in voltage is not specific for rejection. However, lack of change from baseline EKG values is an excellent indicator that rejection is not present. Therefore, the EKG may be used as a screening test for rejection but is not a definitive diagnostic test.
Drug interactions with cyclosporine: Focus on antimicrobial agents
Authors: Chan Gary L. , Sinnott John T. , Emmanuel Patricia J. , Yandle Susan , Weinstein Samuel S.
Published: September 2024

Unique pharmacokinetics and a narrow therapeutic range predispose cyclosporine to interactions with antimicrobial agents. Such interactions may occur through increased or decreased cyclosporine blood levels, or through enhanced nephrotoxicity. Ketoconazole and erythromycin have consistently been associated with elevated cyclosporine levels. While both ketoconazole and erythromycin inhibit hepatic cytochrome P450 enzymes, increased oral absorption of cyclosporine also contributes to the erythromycin‐cyclosporine interaction. Other antimicrobial agents that have been suggested to increase cyclosporine levels include fluconazole, itraconazole, josamycin, posinomycin, pristinamycin, roxithromycin, troleandomycin, norfloxacin and imipenem/cilastatin. On the other hand, coadministration of rifampin consistently results in reduced cyclosporine levels, which have led to allograft rejection in some patients. Nafcillin, intravenous sulphadimidine and imipenem/cilastatin have also been postulated to decrease cyclosporine levels. When these antimicrobial agents are used in conjunction with cyclosporine, cyclosporine levels should be monitored frequently. Aminoglycosides and amphotericin B are known nephrotoxins and have been shown to potentiate cyclosporine‐induced nephrotoxicity. Coadministration of ciprofloxacin or trimethoprim‐sulfamethoxazole with cyclosporine has also been implicated, in several reports, in increased renal damage. These antimicrobial agents should be used with cyclosporine only when therapeutic benefit outweighs the risk of enhanced nephrotoxicity.
Health‐related quality of life outcomes of pancreas transplant recipients
Authors: Gross Cynthia R. , Zehrer Cindy L.
Published: September 2024

The health status and quality of life outcomes of 131 patients who were 1 to 11 years post‐pancreas transplant were studied. Patients were compared based on the current status of their pancreas graft, i.e. whether or not their grafts were successful in maintaining an insulin‐independent state, and according to recipient category (pancreas alone vs kidney and pancreas). For this study, quality of life was defined as patients' perceptions of their well‐being and ability to function in six areas: physical and mental health, social functioning, role (work and home) functioning, overall health perceptions, and physical pain. Patient self‐report questions from the Medical Outcome Study were used to provide a score scaled from 0 to 100, for each area. Health status was assessed by sick days, hospitalizations, and emergency room visits. Patients with a successful pancreas graft (N = 65) reported significantly more positive health perceptions (51.9 vs 28.9), less pain (33.9 vs 45.3), and greater ability to function socially (84.9 vs 71.3) than did patients whose pancreas grafts were not successful. In addition, patients with successful pancreas grafts rated their ability to perform routine activities as nearer to normal on the Karnofsky Index (2.82 vs 3.63) and were more likely to view themselves as healthier since the pancreas transplant than were patients whose pancreas grafts were not successful. These effects persisted after statistical adjustment for recipient category and case‐mix factors of age, sex, education, and length of time since pancreas transplant. While it is possible that a failed pancreas transplant may adversely effect quality of life, the willingness of so many patients to repeat the procedure and patient perceptions of improved health since transplant support the conclusion that much of the reported differences can be attributed to benefits of pancreas transplant.
Candidal peritonitis resulting from vaginal douche in a renal transplant patient
Authors: Mays Spyrie D. , Ozaki Claire , Shaw Byers W. , Taylor Rodney J.
Published: September 2024

Douching‐induced peritonitis has been reported in non‐immunosuppressed patients. We present a case of candida peritonitis caused by excessive vaginal douching in a renal transplant patient. This case highlights this clinical entity and emphasizes the need to caution patients against vaginal douching following transplantation.
OKT3 treatment of acute renal allograft rejection in children
Authors: Pescovitz Mark D. , Breen Nancy , Book Benita K. , Leapman Stephen B. , Milgrom Martin L. , Pollard Stephen G. , Filo Ronald S.
Published: September 2024

Although the monoclonal antibody OKT3 has been shown to be highly effective in the treatment of acute cellular renal allograft rejection in adults, there are only a few reports of its use in children. We have analyzed our experience with OKT3 in pediatric renal transplantation to determine its effectiveness and toxicity. Twenty‐four children (10 female, 14 male, age 1 to 17 years) received an initial course of OKT3 as either primary (n = 15) or rescue (n = 9) treatment of acute cellular rejection of 11 cadaver and 13 living‐related renal transplants. Baseline immunosuppression consisted of azathioprine, steroids, and cyclosporine (CyA). Fourteen patients had the CyA stopped during treatment with OKT3. Seven to 16 doses (11.8 ± 2.5, mean ± S.D.) of OKT3 were given, 5 mg for patients over 30 kg and 2.5 mg for those under 30 kg: 22/24 (92%) of the rejections were reversed: 7/22 (32%) had an early re‐rejection within 2 months (33.2 ± 10.5 days). Antibody to OKT3 (OKT3Ab) following the initial course was detected in 7 of the 22 patients tested. Toxicity included a febrile reaction, an increase in the serum creatinine, two late seizures, and one episode of hypotension. Infections requiring extended or repeat hospitalization within 2 months developed in 12/24 patients following OKT3. Patients who received high‐dose steroids (> 5 mg/kg, 26 ± 8 mg/kg, mean ± S.D.) on the 1st d of OKT3 therapy had a blunted febrile response and a blunted creatinine rise when compared to the low steroid group (< 5 mg/kg, 1 ± 0.5 mg/kg). OKT3 was reused for rejection in 8 patients, 4 of whom had developed OKT3Ab following their first course of OKT3. Half (4/8) responded to the second course with reversal of rejection: 3/4 without OKT3Ab responded but only 1/4 with OKT3Ab responded. OKT3Ab developed in 3/4 who were originally OKT3Ab‐negative; it increased in 3/4 who were positive and decreased in 1. No case of anaphylaxis or severe OKT3 reaction occurred during second course therapy. In summary, OKT3 is highly effective in reversing renal allograft rejection in children. Its use is not complicated by severe toxicity nor by an inordinate frequency of re‐rejection or OKT3Ab development. In children without previous OKT3Ab, a second course of OKT3 is usually effective, and can occasionally be effective with a history of previous OKT3Ab development.
A successful second renal allograft across positive B‐cell crossmatch due to IgG anti‐HLA DR5 antibody
Authors: Panajotopoulos Nicolas , Ianhez Luiz E. , Neumann Jorge , Rosales Claudia , Sabbaga Emil , Kaill Jorge
Published: September 2024

The role of antibodies specific to donor B‐cell antigens in renal transplantation remains to be firmly established. We have used, in a sensitized patient awaiting his second transplant, reduction with dithiothreitol (DTT), platelet absortion and panel reactivity analysis to identify imunoglobulin class and specificity of the antibody causing positive B‐cell crossmatch. The results show that the antibody was an IgG anti‐HLA DR5. The transplant was performed using the recipient's mother, specifically mismatched for DR5, as donor. The graft has excellent function 18 months after transplantation. The experience with this patient raises questions about the clinical significance of anti‐DR antibodies, and of anti‐B cells antibodies in general, in kidney transplantation.
Impact of chronic corticosteroid administration on intraocular pressure in renal transplant recipients
Authors: Perell H. Frederick , Friedman Robert , Burnett Henry W. , Weir Matthew R. , Klassen David K. , Shen Steve Y. , Kittur Dilip
Published: September 2024

Chronic corticosteroid use has been associated with elevation of intraocular pressure. Intraocular pressure was determined in 46 renal transplant recipients who had received chronic corticosteroid therapy (range 45‐5500 days), with a total cumulative dose of 2.3 to 81 grams. No significant positive correlation was observed between intraocular pressure and either total corticosteroid dose or duration of therapy. Contrary to prior data, there was a trend toward lower intraocular pressure with higher total corticosteroid exposure. Although our data did not demonstrate a correlation between steroid dosage and durations and elevations in IOP in this kidney transplant population, individual pressure elevation requiring treatment was recorded, and the physician needs to be aware of the complication of IOP elevations.
Polyclonal and monoclonal posttransplant lymphoproliferative diseases (LPD)
Authors: Hanto Douglas W.
Published: September 2024

The Epstein‐Barr virus (EBV) causes a spectrum of B‐cell lymphoproliferative diseases that are reviewed. There are three groups classified by their clinical presentation, morphologic characteristics, and clonality as determined by staining for heavy‐ and light‐chain surface and cytoplasmic immunoglobulin, cytogenetic analysis, and immunoglobulin gene rearrangement studies. There are benign polyclonal hyperplasias without cytogenetic abnormalities and immunoglobulin gene rearrangements that resemble infectious mononucleosis and respond to acyclovir, oftentimes not requiring decrease in immunosuppression. There are malignant monoclonal lymphomas with clonal cytogenetic abnormalities and with clonal immunoglobulin gene rearrangements in a majority of cells. These patients present with solid tumors that are not dependent on EBV replication for growth and are therefore acyclovir‐resistant, respond poorly to chemotherapy and radiation therapy, and have a high mortality. There are immediate lesions that are morphologically malignant and contain clonal cytogenic abnormalities and immunoglobulin gene rearrangements in a subpopulation of cells, but are predominantly made up of a polyclonal B‐cell proliferation. These patients present with a clinical syndrome resembling infectious mononucleosis as in the first group, respond to acyclovir, but should also have their immunosuppression decreased because of the documented risk of progression from a polyclonal to monoclonal lymphoproliferation. These findings have important implications for the pathogenesis of EBV‐related lymphoproliferative diseases, which are discussed.
Antiviral therapy – An anti‐malignancy strategy for transplant recipients?
Authors: Hibberd Patricia L. , Rubin Robert H.
Published: September 2024

The post‐transplantation lymphoproliferative disorder (PTLD), a well‐recognized complication of immunosuppression, has been linked to the interaction between the Epstein‐Barr virus (EBV) and the exogenous immunosuppressive therapy that is administered to the transplant recipient. Although the specific risk factors for the development of the disorder have not been well characterized, the risk appears to be increased in patients in whom the “net state of immunosuppression” is likely to be the greatest, such as cardiac transplant recipients receiving OKT3 in addition to conventional immunosuppressive regimens, or renal transplant recipients treated with high‐dose cyclosporine. Two potential strategies that may decrease the incidence of PTLD include: 1) reduction of the doses of concomitant immunosuppression during therapy with antibody preparations, such as murine mAb CD3 (OKT3) and anti‐lymphocyte globulin (ALG); and 2) the use of “preemptive” antiviral therapy, with agents such as acyclovir and ganciclovir, during periods of maximal immunosuppression, i.e. during the administration of antibody preparations.
Two distinct patterns of post‐transplantation lymphoproliferative disorder (PTLD): Early and late onset
Authors: Alfrey E. J. , Friedman A. L. , Grossman R. A. , Perloff L. J. , Naji A. , Barker G. F. , Montone K. T. , Tomaszewski J. E. , Chmielewski C. , Holland T. , Zmijewski C. , Dafoe O. C.
Published: September 2024

In our multi‐organ transplant program, we have noted two distinct patterns of PTLD: 1) potentially treatable PTLD appearing in the early post‐transplant period (≤ 90 days); and 2) fatal insidious PTLD of late onset. Between 1965 and 1990, 1662 transplants were performed and 16 patients developed PTLD. PTLD represented 18% of all malignancies during this time interval. Fourteen PTLDs occurred in kidney transplant recipients (KTxp) and 2 in liver transplant recipients (LTxp). Six of the 16 patients with PTLD presented within 90 d of transplantation (mean time 5 weeks) and 10 presented 4 months to 8 years after transplantation (mean time 152 wk). In the early‐onset PTLD group there was a disproportionate number of allografts well‐matched at DR loci. Four of 6 cases of early‐onset PTLD had evidence of recent Epstein‐Barr virus (EBV) infection. Five of these patients had also received OKT3. In the late‐onset group, 4 of 10 patients had received anti‐lymphocyte globulin (ALG). Three of 6 patients with early‐onset PTLD underwent transplant nephrectomy and survived, whereas all patients with late‐onset PTLD expired. Based on this small experience, it appears that early PTLD was associated with DR match, vigorous immunosuppression and EBV infection.
Experience with posttransplant lymphoproliferative disorders in solid organ transplant recipients
Authors: Nalesnik Michael A. , Locker Joseph , Jaffe Ronald , Reyes Jorge , Cooper Mark , Fung John , Starzl Thomas E.
Published: September 2024

Nearly 6000 solid organ transplants have been performed at the University of Pittsburgh since 1981. Posttransplant lymphoproliferative disorders (PTLD) have occurred in 131 patients, at a frequency of 2.2%. The majority of cases manifest within 6 months following allograft, but individual lesions may arise several years thereafter. From 1981 to 1989, cyclosporine‐A (CsA) served as the primary immunosuppressant in this population. In March of 1989, FK506 was introduced for clinical trials. Since that time, 1421 patients have received FK506 either for primary immunosuppression or as rescue therapy. The frequency of PTLD in this subpopulation is 1.5%. PTLD arising under FK506‐containing regimens have clinicopathologic features similar to those arising with CsA immunosuppression. The frequency of PTLD at this point in time is approximately 1% in kidney allograft patients, 2.7% in liver, 3.3% in heart and 3.8% in heart/lung or lung recipients. An understanding of the range of histologic appearance is important for the diagnosis of PTLD, especially when it involves the allograft itself. Immunoglobulin heavy chain gene analysis shows that lesions with no rearrangements or with a rearrangement in only a small proportion of cells are more likely to respond to reduced immunosuppression than are those with clonal rearrangement involving a high proportion of cells. However, this distinction is not absolute, and a trial of reduced immunosuppression appears to be indicated regardless of clonal status.
Incidence of malignancies in renal and cardiac transplant recipients in relation to treatment with biologic agents
Authors: Hardy Mark A. , Benvenisty Alan I. , Cohen David , Barr Marc , Rose Eric , Suciu‐Foca Nicole
Published: September 2024

An 8‐year review was conducted of 1077 transplanted patients at Columbia Presbyterian Medical Center with the specific aim of analyzing the incidence of malignancies in immunosuppressed patients carrying a graft for more than 1 month. The patients studied included 589 renal allograft recipients and 488 cardiac allograft recipients. There was a 3.04% incidence of malignancies following grafting, of which 15 were in the renal and 17 in the cardiac allograft recipients resulting in equal incidence in both groups. Of the 120 renal allograft recipients who were treated with OKT3, 4 were diagnosed as having cancer and only 1 developed lymphoproliferative polyclonal B‐cell disease. More hematopoietic malignancies were found in cardiac allograft recipients (12/488) but only 1 of 56 patients treated with OKT3 developed lymphoma. This study concludes that there is no relationship between the use of OKT3 and development of malignancies in renal or cardiac allograft recipients and that the overall degree of immunosuppression along with the presence of a graft and perhaps viremia relates best to the incidence of lymphoid malignancies.
De novo lymphoma after liver transplantation
Authors: Klintmalm Goran B.
Published: September 2024

A total of 482 liver transplants were performed in 416 consecutive liver transplant recipients between December 1984 and November 1990. The maintenance immunosuppression protocol was based on cyclosporine and prednisolone. Azathioprine was added only after first rejection. Rejections were treated with steroids. OKT3 was then used for rescue therapy, 5 mg q day for 10‐14 d. A total of 8 lymphomas were diagnosed. There were 2 in 164 patients who had not had a rejection. In 43 patients who had received only steroid therapy for rejection 1 lymphoma was found and in 109 patients who had received OKT3 treatment for rejection 5 lymphomas were seen. However, in 6 patients who received 2 courses of anti‐lymphocytic therapy, either consisting of OKT3 twice or OKT3 and anti‐lymphocytic globulin, 4 lymphomas were found (p < 0.000). Two of the 8 patients survived their lymphomas. In these 2 patients all immunosuppression had been immediately discontinued at the diagnosis of lymphoproliferative disorder. They were maintained only on prednisolone, 10 mg q d. Immunosuppression was later gradually reinstituted after immunological reconstitution with disappearance of the lymphomas and the commencement of rejection. It is concluded that post‐transplant lymphoma seems to be related to the amount of immunosuppression given, and more than 1 course of OKT3 for rescue should not be used. In cases of unrelenting rejection unresponsive to OKT3 re‐transplantation should be contemplated or some of the newer immunosuppressants such as FK 506 or RS‐61443.
Diagnosis of hepatic allograft rejection: Role of liver biopsy
Authors: Aran Peter P. , Bissell Michael G. , Whitington Peter F. , Bostwick D. G. , Adamac Thomas , Baker Alfred L.
Published: September 2024

The role of the liver biopsy for establishing a diagnosis of liver allograft rejection was investigated by examining under code 151 liver biopsies from 32 recipients and correlating the results with the clinical diagnosis determined by chart review. One‐hundred‐and‐four biopsies were obtained to evaluate the cause of liver dysfunction and 47 were performed on a weekly protocol basis independent of the clinical status. A diagnosis of “definite histologic rejection” was made if a biopsy contained portal triaditis, bile duct injury, and endotheliales, while biopsies were said to be suspicious for rejection if portal triaditis and bile duct injury were evident. A diagnosis of rejection using clinical and biochemical findings and response to therapy was made in association with 37 biopsies, of which 16 had definite histologic rejection and 13 were suspicious for rejection. Of the 114 biopsies performed in patients without clinical rejection, 71 had histology suspicious for rejection. Thus, biopsy was sensitive for the detection of rejection (78%), but was not very specific (33%). The positive predictive value was low (28%), while the negative predictive value was high (83%). These results indicate that liver biopsy is useful to evaluate graft dysfunction, to exclude rejection, to confirm clinically suspected rejection, and to diagnose other problems that can affect allograft function. Protocol biopsies appear to have little value.
Recurrent Kaposi's sarcoma in a renal transplant recipient: Regression following treatment of cytomegaloviremia with ganciclovir
Authors: Burke George W. , Jordan M. Colin , Simmons Richard L. , Saltzman Robin L. , Quirk Mary R. , Crane R. Thomas , Najarlan John S.
Published: September 2024

Kaposi's sarcoma is a rare tumor occurring with a particularly high frequency in immunosuppressed patients with transplants or the acquired immune deficiency syndrome. There is considerable evidence associating cytomegalovirus (CMV) infection with the occurrence of Kaposi's sarcoma (KS), including the demonstration in hybridization experiments of CMV DNA and RNA in KS. We report an HIV‐negative renal transplant recipient, with a history of KS 20 years previously that was treated successfully with radiation therapy. Nine months following kidney transplantation, the KS recurred and progressed despite marked reduction of immunosuppression. He was treated with ganciclovir after the demonstration of 1) CMV and CMV DNA in blood cultures, and 2) CMV DNA in specimens of KS, but not in normal contiguous skin. The KS lesions subsequently halted, most regressed, and his viremia cleared. The lesions may have regressed spontaneously or secondarily to reduction in immunosuppression. A third more intriguing possibility is that regression of the recurrent KS may have been related to treatment of the CMV‐viremia. If so, this represents further evidence associating CMV with KS. Mechanisms may involve the eradication of CM V as an immunosuppressive agent, infectious agent, and/or oncogene, with subsequent immune enhancement.
Chronic allograft rejection: An update
Authors: Häyry Pekka
Published: September 2024

The etiology of chronic rejection is most probably multifactorial. The common feature in all organ allografts undergoing chronic rejection is persistent perivascular inflammation and a concentric generalized arteriosclerosis affecting all first and second order intramural arteries. A hypothesis is presented that low‐grade damage to endothelium induces the secretion of growth factors which, in turn, are responsible for smooth muscle cell replication and their influx into intima.
Chronic rejection ‐ Definition and correlates
Authors: Matas Arthur J.
Published: September 2024

With current immunosuppressive protocols, the incidence of graft loss to acute rejection has been markedly reduced; however, there has been no change in graft loss to chronic rejection. Recently, attention has been focused on the prevention and management of chronic rejection. Because neither the clinical course nor the biopsy is definitive for the diagnosis of chronic rejection, we believe both should be included in the definition. For kidney transplant recipients, the major risk factor for development of chronic rejection appears to be a previous acute rejection episode. Other risk factors include low‐dose maintenance immunosuppression and previous infection. For extrarenal transplant recipients, CMV and HLA mismatch have been implicated. Noncompliance probably plays a role for all patients. Laboratory studies have suggested that the development of chronic rejection (or lack thereof) may be due to an interplay of immunoregulatory factors. Patients with anti‐HLA antibodies have an increased incidence of late graft loss whereas those with antiidiotypic antibodies or with donor‐specific hyporesponsiveness (in MLC) have improved outcome and less chronic rejection. These findings have led to five testable hypotheses as to the pathogenesis of chronic rejection: I) chronic rejection is inadequately treated acute rejection; 2) chronic rejection can be prevented by maintaining adequate long‐term immunosuppression; 3) preventing or adequately treating infection will prevent chronic rejection; 4) the balance of immunoregulatory factors determines chronic rejection; 5) chronic rejection is the result of noncompliance. Each may play a role in some patients. Clinical and laboratory studies of risk factors and of the influence of intervention are necessary.
A contemporary view of transplantation tolerance: An immunologist's perspective
Authors: Lafferty Kevin J.
Published: September 2024

The unique feature of the immune system is its capacity to distinguish between self and non‐self components. The selectionists have postulated that deletion of clones during development could account for this phenomenon. The Bretscher/Cohn theory of self/non‐self discrimination provided a model whereby self‐reactive clones could be eliminated at any stage of the animal's life. Experimental evidence demonstrates that clonal deletion can occur and is probably dependent on lymphohematopoietic chimerism involving the passage of cells to the thymus. However, tolerance to peripheral tissue antigens that do not have direct access to the thymus is not maintained by deletional tolerance. In this situation an active process negatively regulates the response of the immune system to non lymphoid, tissue‐specific antigens.