bluuebunny/crossref_metadata_2025 huggingface dataset:
Urinary nitrate excretion is increased in cardiac transplanted patients with acute graft rejection
Authors: Mügge Andreas , Kurucay Semavet , Böger Rainer H. , Bode‐Böger Stefanie M. , Schäfers Hans‐Joachim , Wahlers Thorsten , Frölich Jürgen C. , Lichtlen Paul R.
Published: September 2024

Acute allograft rejection in patients after cardiac transplantation is associated with intense infiltration of inflammatory cells. It has been shown in animal studies that this inflammatory process is accompanied by an induction of nitric oxide synthase (NOS) enzyme within the grafted organ. We sought to test the hypothesis that acute rejection in cardiac transplanted patients is associated with an increased production of nitric oxide. The radical nitric oxide is unstable in blood and oxidized to nitrite and nitrate; nitrate is secreted by the kidneys. Therefore, nitric oxide production was indirectly assessed by measuring urinary nitrate excretion. During a period of 1 yr, 86 consecutive patients after cardiac transplantation underwent one or more right heart biopsies. (total 194) in order to assess for acute graft rejection. At the time of biopsies, urine was collected under sterile conditions. Urinary nitrate excretion was expressed as the ratio of nitrate to creatinine concentration in the urine (μmol/mmol). Urinary nitrate excretion was 99.7±9.2 (mean±SEM) for patients without evidence of rejection, and tended to increase for patients with moderate/severe rejection (128±15.1). In a subgroup of patients who underwent several biopsies and showed different degrees of rejection (7 patients, 48 biopsies), urinary nitrate excretion significantly increased by about 99% during episodes of acute rejection. It is concluded that urinary nitrate excretion appears to be elevated in a subgroup of cardiac transplanted patients during episodes of acute rejection. Results are consistent with the hypothesis that acute graft rejection stimulates the production/release of nitric oxide. Because of a large interand intraindividual variation in urinary nitrate excretion, this parameter appears not to be suitable for diagnosis of acute rejection in cardiac transplanted patients.
Hematopoietic cell transplantation for the induction of allo‐ and xenotolerance
Authors: Sykes M.
Published: September 2024

Durable tolerance can be reliably achieved by inducing engraftment of allogeneic or xenogeneic hematopoietic cells in recipients initially depleted of T lymphocytes. Engraftment of pluripotent hematopoietic stem cells (PPHSC) provides a constant supply of donor antigen to ensure the ongoing central deletion of donor‐reactive T cell clones, resulting in a permanent state of donor‐specific tolerance. Because of the toxicity of myeloablative therapy used to achieve allogeneic PPHSC engraftment, this approach has not yet been applied in humans. However, a non‐myeloablative, relatively non‐toxic conditioning regimen allowing allogeneic or concordant xenogeneic bone marrow engraftment and tolerance induction has recently been developed in a murine model. Host pre‐treatment with depleting doses of anti‐CD4 and anti‐ CD8 mAbs (and in the xenogeneic combination, anti‐Thy 1.2 and anti‐NK 1.1 mAbs), followed by 3 Gy whole body irradiation (WBI) and 7 Gy of thymic irradiation (TI) allows engraftment of allogeneic or xenogeneic rat bone marrow cells with mixed, multilineage lymphohematopoietic chimerism and donor‐specific skin graft tolerance. TI can be omitted from the regimen if additional mAb treatments are given. Engraftment of allogeneic PPHSC is associated with early migration of donor bone marrow‐derived cells to the host thymus, resulting in deletion of developing thymocytes with reactivity to donor antigens. Maintenance of long‐term tolerance is purely due to this deletional mechanism. In the xenogeneic rat‐mouse species combination, mixed chimerism is also associated with deletional T cell tolerance, and also leads to tolerance at the level of B cells that make natural antibodies. In the discordant pig→ mouse species combination, we have found that physiologic preference for host hematopoiesis is a major barrier to achieving donor hematopoietic reconstitution. Pig‐specific hematopoietic cytokines can at least partially overcome this barrier. Furthermore, if normal, immunocompetent mice are thymectomized, then receive T‐ and NK‐cell‐depleting mAbs, and a fetal swine thymus is grafted, murine CD4 T cells recover in the swine thymus, and demonstrate specific tolerance to the xenogeneic swine donor. These T cells appear to be able to recognize antigen in the context of host MHC, and demonstrate immunocompetence. Our studies have demonstrated for the first time. that donor‐specific skin graft tolerance can be induced across a discordant species barrier.
Two cases of Kaposi's sarcoma in renal and liver transplant recipients treated with interferon
Authors: Halmos Orsolya , Inturri Paolo , Galligioni Alessandra , Di Landro Domenico , Rigotti Paolo , Tedeschi Umberto , Graziotto Agnese , Burra Patrizia , Poletti Alessandro , Rossaro Lorenzo
Published: September 2024

We report two cases of Kaposi's sarcoma in recipients of solid organ transplants, presenting (Case 1) 12 months after liver transplantation and (Case 2) 7 months after kidney transplantation. Both patients share the following features: natives from the Mediterranean area (Southern Italy), multiple immunosuppressive regimen, infection with hepatitis B and cytomegalovirus. During the 3 yr of follow‐up after the diagnosis, their immunosuppressive regimen was reduced and they were treated with alpha interferon with remission of the clinical findings. The management of Kaposi's sarcoma in organ transplant recipients remains a controversial issue because of the risks of organ rejection associated with the reduction of immunosuppression and with the use of interferon.
Analysis of ICAM‐1 and HLA‐DR expression on renal allograft aspirates
Authors: Manfro Roberto C. , Gonçalves Luiz F. S. , Rauber Marco , Moura Luis A. R.
Published: September 2024

ICAM‐1 and HLA‐DR expressions were studied on parenchymal cells obtained by aspirative biopsies of renal allografts. Patients were evaluated during 3 months after transplantation. Conventional cytology and immunoperoxidase stainings using anti‐ICAM‐1 and anti‐HLA‐DR antibodies were employed. The value of the total corrected increment was significantly higher (p<0.05) during acute rejection episodes than during acute tubular necrosis or stable renal function. The percentage of HLA‐DR positive cells were higher in rejection than in stable function periods (p<0.05). The percentage of ICAM‐1 positive cells was higher in rejection than in acute tubular necrosis periods (p<0.05). The sensitivities to the diagnosis of rejection were 71.8% (TCI), 68.4% (ICAM‐1) and 55.0% (HLA‐DR). The specificities were 87.3%, 81.3% and 68.4% respectively. Combinations of the tests resulted in increased sensitivity. We concluded that the use of these monoclonal antibodies improves the sensitivity of conventional aspiration cytology to the diagnosis of acute renal rejection.
Prophylactic wound antibiotics for combined kidney and pancreas transplants
Authors: Barone Gary W. , Hudec Wayne A. , Sailors David M. , Ketel Beverley L.
Published: September 2024

For combined kidney and pancreas transplant recipients infectious complications remain a major source of morbidity. With as many antibiotic protocols as transplant centers, the exact type and duration for prophylactic wound antibiotics remains undefined. A retrospective review of our series of 40 combined kidney and pancreas transplants was performed using a single 1 g dose of cefazolin preoperatively along with cefazolin bladder and intra‐abdominal irrigation. Two patients developed superficial wound infections for a rate of 5% (2/37). The deep wound infection rate was 11% (4/37), and all followed either a bladder anastomotic leak or the initial development of transplant pancreatitis. Our overall rate of 16% is very comparable with other series of combined kidney and pancreas transplant recipients. To help eliminate the potential development of superinfections and resistant organisms, a single dose of antibiotics appears to be as effective for wound prophylaxis in these patients when compared to multiple‐antibiotic and multiple‐day regiments. A randomized prospective study of prophylactic antibiotics in combined kidney and pancreas transplants is needed.
Doppler spectrum analysis in the differential diagnosis of renal transplant dysfunction
Authors: Merkus J. W. S. , van Asten W. N. J. C. , Hoitsma A. J. , van't Hof M. A. , Koene R. A. P. , Skotnicki S. H.
Published: September 2024

Cyclosporin A (CyA) nephrotoxicity and rejection of a renal allograft each demands a specific therapy. This study was designed to establish the capability of Doppler spectrum analysis to diagnose either one of these causes during renal dysfunction. Between October 1989 and October 1991 we performed echo‐Doppler examinations in 209 renal transplant recipients on a routine basis during the first three months after transplantation. Echo‐Doppler examinations during periods of renal dysfunction were analyzed. A total of 93 periods of renal dysfunction, retrospectively due to rejection (n=40) or CyA toxicity (n=53), occurred in 70 patients during the study period. A control group consisted of 82 patients with normal functioning grafts. When compared to the control group, the Doppler features (in segmental arteries) of the rejection group showed significant lower frequency shifts [Fmax (Hz) 1637±423 vs. 1436±465; p<0.05; Fdia (Hz) 582±180 vs. 458±225; p<0.05], a shorter deceleration time of the Doppler spectrum [Tdown (ms) 340±100 vs. 276±102; p<0.05], and a higher Resistance Index (RI 0.64±0.08 vs. 0.68±0.13; p<0.05). Doppler spectra during CyA toxicity showed only a significantly longer acceleration time [Tmax (ms) 123±36 vs. 139±40; p<0.05]. The capability of differentiation between the two causes was assessed with ROC analysis of single Doppler features, stepwise regression and canonic discriminant analysis on a set of Doppler features and with manual selection of several features with extreme values. ROC analysis yielded maximum sensitivity and specificity for the diagnosis of rejection using Tdown (sensitivity 65%; specificity 68%). Stepwise regression and canonic discriminant analysis of a set of features rendered a sensitivity and specificity of 73% and 64%, respectively. Explorative selection of extreme Doppler feature values showed that 18 of the 40 grafts with rejection had values that were only seen in 2 cases with CyA toxicity (positive predictive value 90%; sensitivity 45%; specificity 96%). In half of these cases Doppler features preceded the clinical diagnosis of rejection by a median of 4 d. In conclusion, Doppler spectra are influenced by rejection and CyA toxicity in specific ways. The Doppler features, however, do not enable definite differentiation between rejection and CyA toxicity in all cases. Some changes in Doppler spectra are only seen in cases of rejection and thus enable positive identification of grafts with rejection, often carlier than clinical signs indicate rejection. A normal Doppler spectrum does not exclude rejection as the cause of renal dysfunction.
Kaposi's sarcoma‐associated herpesvirus in Kaposi's sarcoma occurring in immunosuppressed renal transplant recipients
Authors: Kedda Mary‐Anne , Margolius Laurence , Kew Michael C. , Swanepoel Charles , Pearson Darren
Published: September 2024

Kaposi's sarcoma‐associated herpesvirus (KSHV) has been implicated in the genesis of Kaposi's sarcoma and other tumors occurring in immunosuppressed individuals. Using amplification by the polymerase chain reaction and nucleotide sequencing of extracted DNA, we have detected the KS330233 sequence of KSHV DNA in Kaposi's sarcoma tissue from 4 immunosuppressed renal transplant recipients. The sequences shared a greater than 98% homology with those described in KSHV DNA from Kaposi's sarcoma in patients with acquired immunodeficiency syndrome. In another 2 renal transplant recipients KSHV DNA could not be detected in scar tissue at the site of previous Kaposi's sarcoma that had resolved after immunosuppression was discontinued and haemodialysis recommenced. These findings support the hypothesis that KSHV may be the infectious agent concerned in the genesis of Kaposi's sarcoma.
Cyclophosphamide in cardiac transplant recipients with frequent rejection: a six‐year retrospective review
Authors: Wagoner L. E. , Taylor D. O. , Olsen S. L. , Bristow M. R. , O'Connell J. B. , Hammond E. H. , Lappe D. L. , Renlund D. G.
Published: September 2024

Allograft rejection remains a major cause of morbidity and mortality. Cyclophosphamide, a nitrogen mustard, is a potent immunosuppressive agent with effects on both T‐ and B‐lymphocytes, and thus may be effective in preventing further cellular and/or humoral rejection in cardiac transplant recipients with recurrent or recalcitrant rejection. We retrospectively reviewed the records of 320 surviving cardiac transplant recipients. Cyclophosphamide was substituted for azathioprine in 28 patients because of frequent allograft rejection. We then reviewed the rejection history of these 28 patients, specifically looking at rejection frequency, type (cellular, vascular or mixed), and treatment. Cyclophosphamide was substituted for azathioprine at an average of 8.4±2.8 months after transplantation. Despite a 56.0% reduction in prednisone dose (p<0.001), at least a threefold reduction in rejection frequency (p<0.001) was observed, while cyclosporine levels were unchanged. Twenty‐eight percent of the patients did not experience even mild rejection after beginning therapy with cyclophosphamide, 55% had 1 or 2 subsequent mild or moderate rejection episodes, and only 17% had more than two subsequent episodes of mild or moderate rejection. Overall, the number of treated rejection episodes decreased from 0.37 episodes per patient month with azathioprine to 0.10 episodes per patient month on therapy with cyclophosphamide. Separating the patients into two groups based on the predominant rejection type (cellular vs. vascular) occurring at the time of cyclophosphamide substitution revealed a similar reduction in cellular and vascular rejection in each respective group. While white blood cell count decreased by 16%, cyclophosphamide was not discontinued in any patient due to leukopenia, and no change was noted in hematocrit, Cyclophosphamide appears to be safe and effective in maintenance immunosuppression and may reduce rejection frequency in some patients with frequently occurring allograft rejection without necessitating the augmentation of either corticosteroids or cyclosporine.
Expanding the donor pool: use of marginal donors for solid organ transplantation
Authors: Alexander J. W. , Zola J. C.
Published: September 2024

Organ transplantation has become a viable treatment for an increasing number of patients suffering from irreversible organ failure. In response to the steeply rising demand for tansplantation, both the number of transplant centers and the number of patients on waiting lists have grown rapidly. Because organ donation has not kept pace with demand, each year a greater number of patients die while awaiting donor organs. (About 9% of all patients on the list in 1993 but not transplanted died. Death rates were highest, 19% and 16% respectively, for patients awaiting hearts and livers.) Among the factors contributing to the organ shortage are cultural and psychological barriers to donation and missed opportunities to request donation. An accompanying diminution in traumatic deaths of potential young donors has made older and other marginal, or higher‐risk, donors the focus of studies on expansion of the donor pool. The studies reviewed herein evaluate donor risk factors such as age, disease (including infection), obesity, cold ischemia time, suboptimal organ function, and nontraumatic causes of death. Overall, broadened criteria for acceptable donor kidneys, hearts, and livers appear to lessen graft survival rates somewhat compared with rates for ideal donor organs. Nonetheless, use of higher‐risk organs allows lifesaving transplants that could not otherwise be performed and results in acceptable prognoses for survival. Further research is needed to identify better tests for evluating donor organs, provide longer‐term follow‐up of recipients of higher‐risk organs, and develop alternative means to fill the donor‐organ shortfall.
Proteinuria in recipients of liver transplants
Authors: Jindal Rahul M. , Hughes Dianna , Sidner Richard A. , Leapman Stephen B. , Pescovitz Mark D. , Milgrom Martin L. , Lumeng Lawrence L. , Filo Ronald S.
Published: September 2024

We investigated the incidence and significance of proteinuria in recipients of liver transplants. The overall incidence of proteinuria was 59.72%. The peak incidence of proteinuria was at 3 months and at the end of 1 yr posttransplant. Proteinuria was higher in those patients who developed posttransplant diabetes mellitus, and those who developed both posttransplant diabetes and posttransplant hyperlipidemia. Patients who received higher total dosage of steroids and CSA had significantly greater proteinuria. Patients who had a Cr Cl greater than 50 ml/min had greater proteinuria posttransplant for the first 6 months, but the trend was reversed later. We did not find any association of proteinuria with age, weight, rejection episodes, or with the etiology of liver failure. Hypertension was a common occurrence in our patients, and therefore its significance in the causation of proteinuria could not be defined.
Cyclosporine bioavailability: dosing implications and impact on clinical outcomes in select transplantation subpopulations*
Authors: First M. Roy , Schroeder Timothy J. , Monaco Anthony P. , Simpson Mary Ann , Curtis John J. , Armenti Vincent T.
Published: September 2024

Reports in the literature indicate that clinical outcomes in select patient subpopulations have been inferior to those in the general transplantation population. Of potential interest in this regard is the finding that lower cyclosporine bioavailability correlates with a higher incidence of acute rejection and graft loss. To gain insights into these issues, we examined data from renal transplant recipients at our own centers and in one large data base. Our experience revealed that cyclosporine bioavailability was markedly lower in patients who developed acute or chronic rejection than in those with stable graft function. An analysis by demographic or clinical factors showed that cyclosporine bioavailability was lower in diabetics and black patients. In one study, diabetics required much higher daily doses of cyclosporine to achieve outcomes comparable to those in non‐diabetics; even then, diabetics attained lower cyclosporine blood levels. Other work found that long‐term graft survival rates were poorer in blacks, even though cyclosporine dosages and blood levels were comparable to those in whites. A case‐controlled study from the pregnancy registry found that cyclosporine dosages were consistently higher in pregnant patients who maintained good graft function than in those who experienced graft dysfunction. These results suggest that the subpopulations examined should receive immunosuppression with higher cyclosporine dosages than those used in the general transplantation population. These subpopulations may also benefit from a cyclosporine formulation that provides better absorption, resulting in more consistent and predictable cyclosporine bioavailability.
Effect of HLA‐DR3 gene expression on cadaveric renal allograft survival in blacks
Authors: Ngcobo T. K. , Becker P. , Modiba M. C. M.
Published: September 2024

The effect of HLA‐DR3 gene expression was studied in black cadaveric renal allograft recipients of organs from the same donor race. From January 1984 to June 1992, 70 patients received cadaveric renal allografts at the Medical University of Southern Africa (MEDUNSA). The average age and F:M ratio was 30 years and 1: 1.2 respectively. HLA‐A, B and DR matching was zero to one in 80%. Actuarial graft survival at yearly intervals in 22 HLA‐DR3 gene expressors was 62, 55, 38, 30 and 24% as compared to 82, 78, 70, 64 and 58% in 48 non‐HLA DR3 gene expressors (Breslow p=0.01 and Mantel‐Cox p=0.05). There was no statistical differences in creatinine values associated with HLADR3 gene expression during the 1st year after transplantation. Renal allografts were lost from rejection in 9 out of 16 HLA‐DR3 gene expressors as compared to 19 out of 29 non‐HLA DR3 gene expressors (Fisher's exact test p=0.8). HLA‐DR3 gene expression is a risk factor for earlier graft loss in black South Africans.
Urethritis/dysuria after simultaneous pancreas‐kidney transplantation
Authors: Ciancio Gaetano , Burke George W. , Nery Jose R. , Coker Donald , Miller Joshua
Published: September 2024

We evaluated the role of conservative treatment for urethritis. and its complications after simultaneous pancreas‐kidney (SPK) transplant. Twenty‐six type I diabetic recipients with end‐stage renal disease underwent SPK transplants with bladder exocrine drainage. Urethritis/ dysuria occurred in 4/26 (16%) of the patients. All cases resolved with conservative treatment that included Foley catheter and/or suprapubic cystostomy. Despite the frequency of this urological complication, none of the patients needed diversion of the exocrine drainage from the bladder to the intestine.
Gingival overgrowth in renal transplant patients administered cyclosporin A in mixture or in capsule form. A longitudinal study
Authors: Wondimu B. , Sandberg J. , Modéer T.
Published: September 2024

Cyclosporin A (CsA)‐induced gingival overgrowth was longitudinally studied in 45 adult renal transplant patients randomly assigned to be administered CSA orally in mixture or in capsule form. After 1 year of CsA therapy, 37% of the mixture and 43% of the capsule patients exhibited gingival overgrowth. In mixture patients gingival overgrowth was present already after 1 month of CSA therapy and, after 12 months, mixture patients exhibited an increased number of sites with gingival overgrowth in the regions of the upper front and lower molars compared to capsule patients. In addition, the relative increase in gingival width of the interdental papillae of the maxillary central incisors and the mandibular first molars, measured buccolingually on stone casts, was also higher in mixture patients than in capsule patients. In a stepwise multiple logistic regression analysis, the use of nifedipine and the total CSA dose administered during the first 6 posttransplant months were the predictors associated with gingival overgrowth. The study suggests that concomitant administration of nifedipine in renal transplant patients should be avoided and a change from the mixture form of CSA to the capsule form should be considered in order to minimize the development of CsA‐induced gingival overgrowth.
Purine metabolism and immunosuppressive effects of mycophenolate mofetil (MMF)
Authors: Allison Anthony C. , Eugui Elsie M.
Published: September 2024

Mycophenolate mofetil (MMF) is a novel immunosuppressive drug that shows promise in preventing the rejection of organ allografts and in the treatment of ongoing rejection. Orally administered MMF is hydrolyzed by esterases in the intestine and blood to release mycophenolic acid (MPA), a potent, selective, noncompetitive inhibitor of the type 2 isoform of inosine monophosphate dehydroxygenase (IMPDH) expressed in activated human T and B lymphocytes. By inhibiting IMPDH, MPA depletes the pool of dGTP required for DNA synthesis. MPA has a more potent cytostatic effect on lymphocytes than on other cell types, and this is the principal mechanism by which immunosuppressive activity is exerted. MPA also depletes pools of GTP in human lymphocytes and monocytes, thereby inhibiting the synthesis of fucoseand mannosecontaining saccharide components of membrane glycoproteins. These are recognized by the family of adhesion molecules termed selectins. By this mechanism, MPA could decrease the recruitment of lymphocytes and monocytes into sites of graft rejection. In addition to preventing allograft rejection, MMF suppresses graft‐versus‐host reactions in lethal and nonlethal murine models. MMF inhibits primary antibody responses more efficiently than secondary responses. MPA inhibits the proliferation of human B lymphocytes transformed by Epstein‐Barr virus and is not mutagenic. Clinically attainable concentrations of MPA suppress the proliferation of human arterial smooth muscle cells. These two properties of MPA may decrease the risk of lymphoma development and proliferative arteriopathy in long‐term recipients of MMF.
Chimerism after organ transplantation: Is there any clinical significance?
Authors: Burlingham William J.
Published: September 2024

Historically, attempts to clinically correlate microchimerism and cytotoxic T lymphocyte (CTL) dysfunction with allograft tolerance (via a “veto effect”) have not been highly successful. We have re‐examined this question by studying the case of JB, a maternal‐renal allograft recipient who did not develop symptoms of acute or chronic rejection after ceasing immmunotherapy of his own volition. A biopsy showed immunologic activity in the allograft that did not progress to full‐scale rejection. A polymerase chain reaction (PCR) assay showed traces of donor‐derived DNA in JB's peripheral blood leukocytes (PBL), which also were shown to display a “split tolerance” toward donor stimulators (MLC+/CTL‐) in vitro. Subsequent experiments in our laboratory conclusively demonstrated that JB's suppressed CTL function was donor‐specific and that small numbers of donor‐derived cells in his PBL could cause the CTL suppression similar to the “veto effect” observed by other researchers. This confirmed the clinical link between microchimerism, CTL dysfunction, and allograft tolerance in a single patient. We propose a testable model for this unusual type of allograft tolerance. The model is based on donorderived predendritic cell lineages that survive in the host and that exert a powerful “veto effect” by interfering with the normal development and function of donor‐specific CD8+ T cells, perhaps even leading to their apoptosis. Additional experiments to test the details of our hypothetical model are under way.
Rescue therapy with mycophenolate mofetil
Authors:   The Mycophenolate Mofetil Renal Refractory Rejection Study Group
Published: September 2024

Research with human transplant recipients has shown that mycophenolate mofetil (MMF) is a powerful and selective immunosuppressant for maintenance therapy following renal transplantation. An additional body of work suggests that it might also be a valuable tool for arresting ongoing rejection episodes. One randomized, open‐label, multicenter study has compared the efficacy and safety of MMF administered with cyclosporine and maintenance corticosteroids versus high‐dose intravenous corticosteroids (IV steroids) and conventional triple therapy, over a 6‐month postenrollment period, for the treatment of refractory acute cellular renal allograft rejection. Treatment with MMF resulted in a 45% reduction in graft loss and death by 6 months postenrollment. (The number of deaths were the same in both treatment groups during the 6‐month postenrollment period.) Treatment with MMF also significantly reduced the risk of experiencing a subsequent biopsy‐proven rejection episode or treatment failure by almost 50%. The number of patients receiving one or more full courses of antilymphocyte therapy for a rejection episode subsequent to enrollment was more than twofold greater in the IV steroid group compared with the MMF group. Overall, and in most of the body systems, more adverse events were reported for patients in the MMF group, but the overall benefit‐risk ratio for MMF supports its use with cyclosporine and maintenance corticosteroids for the treatment of refractory acute cellular renal allograft rejection.
Mycophenolate mofetil (MMF) in heart transplantation: rejection prevention and treatment
Authors: Renlund Dale G. , Gopinathan Santosh K. , Kfoury Abdallah G. , Taylor David O.
Published: September 2024

Mycophenolate mofetil (MMF), the morpholinoethylester of mycophenolic acid, inhibits the de novo pathway for purine synthesis. Evidence suggests that MMF suppresses lymphocyte function more than that of neutrophils, erythrocytes, and other rapidly dividing cell lines that can utilize salvage pathways for purine synthesis. While rigorous efficacy data await the completion of an ongoing, multicenter, prospectively randomized, placebo‐controlled trial, long‐term safety data are, however, available from numerous uncontrolled trials in cardiac transplantation. Dose‐ranging trials in 49 heart recipients suggest that doses ≥4000 mg/d are associated with significant, reversible gastrointestinal toxicity when compared with doses <4000 mg/d (p<0.001). Patients receiving ≥1000 mg/d may have fewer rejection episodes. Even in the long term, changing from azathioprine to MMF is associated with increases in hematocrit (p<0.001), total WBC count (p<0.005), and absolute neutrophil count (p<0.005). Successful use of MMF in refractory cardiac allograft rejection suggests an advantage over azathioprine. MMF is safe and appears to be at least as effective as azathioprine for immunosuppression following heart transplantation.
Mycophenolate mofetil in liver transplantation
Authors: McDiarmid Sue V.
Published: September 2024

Pharmacokinetic studies: Eleven patients undergoing orthotopic liver transplantation (OLT) received mycophenolate mofetil (MMF) orally for prevention of rejection. Additional immunosuppressives used were cyclosporine (CSA) and steroids. Doses ranged from 3.5 to 4.5 g/d. Pharmacokinetic studies were performed between 11 d and 6 months after OLT. The Cmax and Tmax for mycophenolic acid (MPA) were 3.6‐35.2 μg/mL and 0.5‐4 h, respectively, and did not significantly change over 6 months. Oral clearance of MMF (dose of MMF/area under the curve for MPA) between d 11 and d 17 was significantly lower compared with d 21. Biliary diversion did not affect clearance. Rescue therapy: Twenty‐three patients with steroidand OKT3‐resistant acute rejection were converted to MMF (2‐3.5 g/d) at a mean of 20 wk after OLT. Twenty‐one patients responded, 14 with resolution of rejection and 7 with improvement. Sixteen patients remained on the drug. Eight patients had 14 infections, with cytomegalovirus (CMV) being the most common. The most common adverse events were diarrhea (4 patients) and leukopenia (3 patients). Four patients with chronic rejection all failed to improve after conversion to MMF Dose escalation studies ‐ primary therapy: Seventeen patients received 3.5‐5.0 g of MMF per d orally with reduced‐dose CSA and prednisone as primary prophylaxis of rejection after OLT. Target CSA levels were 125‐175 (whole‐blood high‐performance liquid chromatography). Two patients were terminated from the study for possible study drug‐related reasons: pancreatitis in one and unsatisfactory response in the other. Gastrointestinal side effects were the most common (10 patients), including gastritis, esophagitis, and duodenal ulcer. Two patients developed leukopenia and/or pancytopenia. Of 5 culture‐proven infections, 2 were CMV. After 3 months of follow‐up, 7 of 17 patients had no rejection. Of 10 patients with rejection, 7 were treated with pulse steroids and 3 required OKT3. Dual therapy with MMF and steroids: Four patients with rejection and unacceptable toxicity secondary to either CSA or FK‐506 were treated with MMF 2‐4 g/d and 20 mg of prednisone. After 325‐500 d of followup, 3 had resolved their rejection episode and I had recurrent rejection and was restarted on low‐dose CSA. Conclusion: MMF is a promising new immunosuppressive agent for both treatment of established rejection and primary rejection prophylaxis after OLT. More studies are needed to define its role further.
A prospective study of rapid methods of detecting cytomegalovirus in the blood of renal transplant recipients in relation to patient and graft survival
Authors: Eriksson Britt‐Marie , Wirgart Benita Zweygberg , Claesson Kerstin , Tufveson Gunnar , Magnusson Göran , Tötterman Tomas , Grillner Lena
Published: September 2024

Eighty‐five renal transplant recipients were prospectively monitored for CMV infection up to 4 months post‐transplantation by virus isolation from leukocytes, CMV antigen detection (pp65) in peripheral blood leukocytes (PBL), polymerase chain reaction (PCR) of alkaline treated plasma (P‐PCR), PCR of extracted DNA from PBL (L‐PCR) and serology. Additionally univariate and multivariate analyses of risk factors for patient and graft survival up to 4 yr post‐transplantation were performed. The incidence of CMV infection was 78% and of CMV disease 33%. Antigen detection in PBL was positive before or at onset of symptoms in 23/24 (96%) evaluable patients with CMV disease. The corresponding figures for virus isolation were 22/24 (92%), PPCR 21/24 (88%) and for L‐PCR 18/24 (75%). The percentage of negative samples in patients without CMV disease was 89% for the antigen test, 92% for L‐PCR and 83% for virus isolation and P‐PCR. One rapid test (antigen test, P‐PCR or L‐PCR) was positive at a median of 16 d before the onset of symptoms. The antigen test was generally the first rapid test to become positive. CMV disease did not affect graft survival in the multivariate analysis but was associated with decreased patient survival.
Foot problems in the diabetic transplant recipient
Authors: Kalker Alan J. , Pirsch John D. , Heisey Dennis , Sollinger Hans W. , Belzer Folkert O. , Knechtle Stuart J. , D'Alessandro Anthony M.
Published: September 2024

Diabetic transplant recipients are at a high risk for foot pathology leading to amputation. This retrospective study from 1/85 to 2/92 examines the risk of foot complications in a population (n=340) of diabetic renal and combined renal/pancreas transplant recipients. All groups suffered high lower extremity amputation and foot fracture rates. Patients with better circulation and protective sensation intact fared better. Smoking had a profoundly negative effect on the amputation rate as did an amputation prior to the transplant. Patients with pretransplant dialysis were at a higher risk for post‐transplant amputation. Concomitant pancreas transplant did not in general significantly affect the risk of amputation or fracture. Females had almost twice the fracture rate of males.
Long‐term function of vascular access for hemodialysis
Authors: Enzler Markus A. , Rajmon Tomas , Lachat Mario , Largiadèr Felix
Published: September 2024

Objectives

To compare the outcome of autogenous arteriovenous fistulas (AVF) with interposition graft fistulas for hemodialysis access.

Design

Retrospective clinical study.

Setting

Department of Surgery, Zurich University Hospital.

Methods

Primary and secondary patency rates were calculated by life tables. Factors potentially affecting patency were studied by comparison of life tables using the log rank test.

Main results

From 1980 to 1992, 414 patients were operated on for long‐term vascular access. 720 fistulas were created including 429 AVF and 291 interposition grafts (150 bovine xenografts, 69 PTFE grafts, 59 sheep collagen grafts, 10 autologous and 1 homologous vein grafts). Secondary patency rates after 1 and 3 yr were 74/64% in AVF, 56/24% in bovine xenografts, 58/40% in PTFE grafts and 71/45% in sheep collagen grafts. The latter performed not significantly worse than AVF. Primary and secondary patency rates were significantly lower in women.

Conclusions

AVF remains the procedure of choice. Female sex adversely affects patency rates.
Intragraft IL‐4 mRNA expression is associated with down‐regulation of liver graft rejection
Authors: Baan C. C. , Metselaar H. J. , Mol W. M. , Tilanus H. W. , IJzermans J. M. N. , Zondervan P. E. , Schalm S. W. , Niesters H. G. M. , Weimar W.
Published: September 2024

The mechanism underlying spontaneously resolving allograft rejection following clinical liver transplantation is unidentified. In this process, immunoregulatory T helper (Th)‐2 cytokines like IL‐4, often identified with down‐regulation of the Th1‐dependent (IL‐2) cell‐mediated response, might play a significant but unknown role. For this reason, we analyzed mRNA expression by reverse transcriptase‐polymerase chain reaction (RT‐PCR) in 57 biopsies derived from 19 recipients. Specimens included biopsies without evidence of rejection (n=36), biopsies with histological evidence of rejection (n=10) not followed by clinical signs of graft rejection, and biopsies with histological rejection that were accompanied with clinical rejection (n=11), defined by rising serum bilirubin and aspartate amino transaminase (ASAT) levels. Intragraft IL‐4 mRNA expression significantly correlated with spontaneously resolving rejections. In 70% (7/10) of these biopsies, IL‐4 mRNA was detectable, while only 19% (7/36) of the biopsies without signs of rejection (p<0.01; Fisher's exact test) and 18% (2/11) of the rejection biopsies concurrent with graft dysfunction expressed the IL‐4 gene (p=0.03). In contrast, IL‐2 mRNA expression was not detectable in biopsies derived from the spontaneously resolving rejections. None (0/10) of these samples expressed the IL‐2 gene, which was not significantly different from the proportion of biopsies transcribing the IL‐2 gene in the absence of rejection (11%, 4/36). IL‐2 mRNA expression was found more often in biopsies associated with graft dysfunction (36%, 4/11). These results show that IL‐4, in contrast to IL‐2 mRNA expression, is associated with spontaneously resolving liver rejection. This suggests that Th2 cells down‐regulate the Th1‐dependent cell‐mediated immune response after clinical liver transplantation.
The feasibility of HLA matching for lung transplantation
Authors: McGee C. , Fox M. D. , Loyd J. E.
Published: September 2024

The benefits of HLA matching have been clearly demonstrated in renal and cardiac transplantation. Recent studies suggest that HLA matching may be associated with improved survival rates for lung transplantation as well. However, the effect of HLA matching for lung transplantation has not been clearly demonstrated. Despite the possible benefits of HLA compatibility, matching for lung transplantation is based solely on ABO compatibility and lung size. Several factors limit the feasibility of utilizing HLA matching for lung transplantation. Among these factors is the time required to perform HLA typing, to identify appropriate recipients, and to allocate lungs; an additional constraint is the urgent need for transplantation in patients experiencing rapid clinical decline. The obstacles to using prospective HLA matching for lung allocation are significant, and matching lung donors and recipients according to histocompatibility status would require considerable effort. However, with supra‐regional cooperation among transplant centers and procurement agencies, it appears feasible to consider HLA matching for lung transplantation. Given the potential for improved survival, a project should be undertaken to determine the impact of HLA matching on the outcome of lung transplantation.
Type II diabetes after combined kidney and pancreas transplantation for type I diabetes mellitus and end‐stage renal disease
Authors: Jones Jon W. , Mizrahi Solly S. , Bentley Frederick R.
Published: September 2024

We report a case of a patient who developed type II diabetes after receiving a successful combined kidney and pancreas transplant for type I diabetes and end‐stage renal disease. This patient underwent a combined kidney and pancreas transplant and had no evidence of rejection with good function following the transplant for nine months. The patient developed significant post‐transplant obesity with her transplant weight of 80 kg rising to 109 kg. At this level of obesity, the patient developed fasting hyperglycemia of 180 mg/dl with no change in her renal function or her pancreas exocrine function. She developed hyperinsulinemia to this fasting hyperglycemia. The clinical course of this patient demonstrates that rapid weight gain following transplantation can result in type II diabetes.
SEOPF high‐grade match algorithm: the effect of HLA matching with ROP trays in transplanting highly sensitized patients
Authors: Tardif Gilman N. , McCalmon Robert T.
Published: September 2024

The SEOPF high‐grade match (HGM) algorithm for sharing kidneys was designed to increase utilization of kidneys for excellent HLA matches, decrease sharing for poor HLA matches, and improve the chances for highly sensitized patients to receive a kidney transplant through the use of ROP crossmatch trays. All retrieved kidneys from participating centers were offered to the system to be shared for high‐grade HLA matches after six‐antigen match obligations were satisfied with UNOS. Kidneys were shared according to HLA matches in the following priority: 1) 0‐ABDR mismatch six ‐ Antigen Matches. 2) 0‐AB mismatch PRA>40%, ROP tray negative crossmatch. 3) 0‐BDR mismatch PRA>40%, ROP tray negative crossmatch. 4) 0‐BDR mismatch PRA<40%. All patients with PRA's>40% must be repesented on the ROP tray to be considered for a shared kidney. Preliminary ROP tray crossmatch results must have been known for these patients in order to access the system. Here we report results of 126 shared kidneys using the HGM algorithm from January 1994 to September 1995. HLA typing concordance between the initial typing of cadaver donors by the donor center and repeat typing by recipient center was 94.7%. There were six (5.3%) typing discrepancies: HLA‐A, no typing discrepancies; HLA‐B, 2 (1.8%) typing discrepancies; and HLA‐DR, 4 (3.5%) discrepancies. A total of 34 of 126 (27%) kidneys were shared for patients with high grade HLA matches, PRA's >40% and a negative ROP tray. Twenty‐eight of 34 (82.4%) shared kidneys were final crossmatch negative and transplanted into the intended recipient. Six of 34 (17.6%) shared kidneys were transplanted into backup recipients. All six of the intended recipients had positive final crossmatches using enhanced crossmatch procedures, such as antiglobulin and flow cytometry. In conclusion, the HLA concordance rate for shared kidneys within SEOPF was 94.7%. Kidney sharing using the HGM algorithm was very effective in transplanting highly sensitized patients when good HLA matching was combined with a negative ROP tray result.
Utility of DRB1 subtyping: a case report
Authors: Lower F. E. , Jennings C. D. , Phillips G. L. , Thompson J. S.
Published: September 2024

The purpose of presenting this case is to illustrate the importance of high‐resolution DNA Class 2 typing when assignment of MHC antigens is of extreme importance (i.e. bone marrow transplantation); suggest this test as a substitute for the mixed lymphocyte culture (MLC), and provide evidence that DRB1 subtype mismatches may be clinically significant. Initial serological and monoclonal HLA Class 1 and low‐resolution DNA‐SSP Class 2 typing of a potential bone marrow transplant patient and two sisters revealed all to be HLA identical with apparent homozygosity for DRB1*04. High‐resolution DNA‐SSP Class 2 typing was then performed and revealed electrophoretic banding patterns which were not specific for any DRB1*04 subtype. One sister and the patient had identical patterns, while the other sister had a different pattern. Complete HLA Class 1 and high‐resolution DNA‐SSP Class 2 typing of the parents was performed. The mother was found to be heterozygous for Class 1 and Class 2 antigens and possess the DRB1*0404, 0405 subtypes. In contrast, the father was found to be homozygous for Class 1 antigens, heterozygous for Class 2 antigens and possess the DRB1*0404, 0407 subtypes. This led to the initial false assumption of HLA identity for the patient and her two sisters. However, assignment of haplotypes revealed one sister to be HLA identical with the patient and the other sister to be a one‐haplotype five‐antigen match with the patient, mismatching for one DRB1 allele. Bone‐marrow transplantation was performed utilizing the latter sister, which resulted in intractable acute graft vs. host. disease that resulted in the patient's demise.
T10B9 (MEDI‐500) mediated immunosuppression: studies on the mechanism of action
Authors: Brown Stephen A. , Lucas Bruce A. , Waid Thomas H. , McKeown J. Wade , Barve Shirish , Jackson Lisa R. , Thompson John S.
Published: September 2024

The murine IgM anti‐human CD3/TCR mAb T10B9 is an effective agent for the reversal of acute cellular renal allograft rejection which offers several advantages over conventional OKT3 therapy. These include reduced morbidity and a more rapid decrease in serum creatinine levels. In the studies presented here comparing T10B9 and OKT3, soluble T10B9 is shown to be a nonactivating anti‐T cell mAb. Evidence for its lack of activating potential includes in vitro failure to stimulate PBMC proliferation either alone or in the presence of nonmitogenic doses of phorbol ester, failure to induce the expression of early and late activation antigens and failure to induce IFN‐γ, TNF‐α, IL‐6 or IL‐2 release. Analysis of acute renal allograft rejection patient plasma cytokine levels 2 h after the first dose support the hypothesis that T10B9 has reduced immunoactivation activity in vivo. Both TNFa and IFNy patient plasma levels are significantly reduced in T10B9 as compared to OKT3 therapy. However, T10B9 is capable of cellular signaling as demonstrated by its ability to induce apoptosis and IL‐2 release in the human T cell line Sup‐T13. Thus T10B9 retains the potent immunosuppressive activity of OKT3 with reduced immunoactivation.
Effects of azathioprine withdrawal in kidney recipients with stable function two years after transplant
Authors: Goldman Mitchell H. , Davis Brooks , Cruz Edgar , Miller Patricia , Stevens Scott L. , Freeman Michael B. , Tyler John D.
Published: September 2024

To assess the effects of azathioprine withdrawal, renal recipients with grafts >2 yr function (103 study patients) were tapered off azathioprine over a 1‐yr period and compared to 69 patients 2 yr after transplant who were not tapered (controls). Of the 103 study patients, 16 (15%) were living‐donor transplants and 87 were cadaveric. Of the 69 control patients, 9 (13%) were living related transplants and 60 were cadaveric. The mean HLA match for those tapered was 3.3 Ag and 3.1 Ag for those remaining on azathioprine. Two study patients restarted azathioprine on their own. Age, sex, and cause of renal failure in both groups was similar. Of the 101 study patients remaining, 9 (8.8%) returned to dialysis due to biopsy proven chronic rejection. There were no acute rejection episodes. Six of the 69 control patients (8.7%) also returned to dialysis for the same reason. Of the 92 patients who have completed the taper, 85 have been off azathioprine for six or more months. There was not a significant difference between the mean 12‐ and 24‐month creatinine levels of the study patients (1.6 mg%, 1.7 mg%) and those of the controls (1.5 mg%, 1.8 mg%). The mean 12‐ and 24‐month hematocrits of patients tapered (41.3%, 40.8%) were comparable with patients not tapered (42.3%, 42.8%). Of interest. the mean hematocrits of both study and control patients rose from 28.9% and 33.5%, respectively, to 41.3% and 42.3% 1 yr following entry into the study. The mean 12‐ and 24‐month white blood counts of those tapered (8.9, 8.7) did not differ significantly from those continued on azathioprine (8.8, 8.8). In stable renal transplant patients on triple drug immunosuppression for at least 2 yr, azathioprine can be discontinued, in a tapered protocol, without an increased risk of graft loss or compromise of renal function.