bluuebunny/crossref_metadata_2025 huggingface dataset:
FK 506: An update
Authors: Klintmalm Goran B.
Published: September 2024

A metabolite of the fungus Streptomyces tsukubaensis was isolated in 1984. It was given the investigative code name FK 506 and was found to have potent immunosuppressive effects in vitro and vivo. In 1989 the first human trials were begun in Pittsburgh. Based on the positive findings of those trials two large multicenter trials were started, one in the United States and one in Europe. In the U.S. trial the study group was treated with FK 506 and corticosteroids at half the dose of the control group. The control group was treated with cyclosporine, azathioprine and corticosteroids. The protocol design grew out of the observations and concerns raised at the early trial in Pittsburgh. The 1‐year patient survival was 80% in both groups, and the graft survival was 82% in FK 506 and 79% in the control group (NS). However, at the end of the 1st year 32% of the study group had not had any rejections vs 24% of the control group (p<0.002). This was accentuated in the pediatric patients, of whom 58% of the FK 506‐ treated patients were free of rejections vs 28% of the control group at 6 months. The incidence of OKT3 treatment for steroid‐resistant rejection was significantly lower (16%) in the FK 506 group compared to the control group (29%); p=0.0001. The main adverse experiences were renal and neurotoxicity which were more common in the FK 506 patients than in the control group. FK 506 has been used extensively for rescue of treatment‐resistant rejections. Unfortunately, no such trials have been randomized. However, the results as compared with historical controls for rescue treatment (steroids‐OKT3‐steroids) are clearly superior to any other treatment available in the past. FK 506 has been shown to be an effective drug for maintenance immunosuppression as well as for the treatment for unresponsive acute rejections. The side effect profile is very similar to that of cyclosporine, with a nephrotoxicity that seems to be almost identical to that caused by cyclosporine. The concern, however, is the neurotoxicity that is seen. When initiating FK 506 therapy, monitoring the FK 506 levels is imperative to avoid serious toxicity.
Day‐to‐day variability in azathioprine pharmacokinetics in renal transplant recipients
Authors: Ohlman S. , Albertioni F. , Peterson C.
Published: September 2024

The intraindividual and the interindividual variability in the pharmacokinetics of azathioprine (Aza) and its main metabolite 6‐mercaptopurine (6‐MP) were investigated in 10 renal transplant patients on 2 consecutive days, after repeated oral doses of Aza. On the 1st study, the dose‐adjusted Aza AUC (0‐6 h) ranged from 8.4 to 129.1 ngh*ml−1/mg*kg−1. mean 41.4 (±37.6) ngh*ml−1/mg*kg−1. The corresponding values for the dose‐adjusted 6‐MP AUC (0‐6 h) ranged from 37.9 to 172.0 ngh*ml−1/mg*kg−1, mean 91.7 (+ 50.7) ngh*ml−1/mg*kg−1. The absolute percentage intraindividual difference in Aza AUC (0‐6 h) between the two days ranged from 1.2% to 256.6% (mean 64.7%), and for 6‐MP AUC (0‐6 h) from 5.9% to 98.5% (mean 49.8%). However, no statistically significant difference was found when comparing the pharmacokinetics on the 2 study days. The mean half‐life of Aza was 1.7 It and of 6‐MP 1.2 h. Impaired renal function did not seem to affect the pharmacokinetics. No correlation was found between the given dose of Aza and AUC (0‐6 h) for Aza or 6‐MP. A strong correlation was found between the concentrations of Aza and 6‐MP obtained at 2 h after the oral dose and the corresponding AUCs (0‐6 h) (Aza: r = 0.85, p < 0.001. n = 20; 6‐MP: r = 0.9. p < 0.001. n = 20). We conclude that the intraindividual variability in Aza pharmacokinetics is marked, but it is less pronounced than the even larger interpatient variability found in this study and previously described.
Steroid‐related complications in the cyclosporine era
Authors: Fryer J. P. , Granger D. K. , Leventhal J. R. , Gillingham K. , Najarian J. S. , Matas A. J.
Published: September 2024

Steroid withdrawal has potential risks (rejection) and benefits (fewer complications). Most data on steroid‐related complications predates cyclosporine (CsA). We tabulated the incidence of posttransplant complications considered to be steroid‐related in 748 adult kidney transplant recipients (with at least 1 year of follow‐up) on CsA and prednisone. Using logistic regression analysis, we considered the effects of pre‐ and postoperative variables for these complications: cataracts; new‐onset post‐transplant diabetes; bone/joint complications; avascular necrosis; and posttransplant hypertension. Variables included pretransplant steroid therapy; initial steroid dose; prednisone dose at 1 month and 1 year; steroid‐treated rejection episodes; cumulative time on steroids; sex; age; race; pretransplant hypertension; pretransplant diabetes; donor source; non‐steroid treated rejection episodes; other immunosuppressive therapy; cumulative time on dialysis; and previous renal or extrarenal transplants. Cataracts occurred in 21.1%, new‐onset posttransplant diabetes in 7.6%, bone/joint complications in 49.9%, avascular necrosis in 5.5%, and post‐transplant hypertension in 74.9% of recipients. Significant variables for cataract development were prednisone dose at I year (odds ratio [OR] = 1.32; p<0.05), cumulative time on steroids (OR = 1.65; p< 0.001), age > 50 years (OR = 1.85; p< 0.0001), and pretransplant diabetes (OR= 1.63; p<0.0001). For new‐onset posttransplanl diabetes, age >50 years (OR = 1.63; p<0.05) and nonwhite race (OR = 2.12; p< 0.001) were significant, For bone/joint complications, cumulative time on steroids was significant (OR= 1.45; p< 0.001). No factors were significant for avascular necrosis. Significant variables for posttransplant hypertension were pretransplant hypertension, prednisone dose at I month (OR= 1.5; p<0.05), and male sex (OR = 15; p< 0.01). Steroid‐related complications still account for significant morbidity in CSA‐lrcatcd transplant recipients. Risk factors include prednisone dose at I month and 1 year as well as cumulative time on steroids.
Expression of early and late activation markers on peripheral blood T lymphocytes does not reliably reflect immune events in transplanted hearts
Authors: Loertscher Rolf , Forbes R. D. Clarke , Halabi Georges , Lavery Paula , Quinn Timothy
Published: September 2024

Monoclonal antibodies directed against early (receptors for interleukin‐2 and transferrin [IL‐2R, TfR]) and late (PTAI, alpha I integrin VLA‐1) activation antigens were used as probes to monitor cardiac transplant patients for episodes of acute graft rejection. Age‐ and sex‐matched patient control groups con+sisting of 11 patients awaiting cardiac transplantation and 13 kidney transplant recipients with long‐term grafts, respectively, were used to define an upper limit for normal activation antigen expression (mean+ 3 SD) in patients. Expression of all cell markers was significantly higher in both patient control groups than in healthy control individuals. Therefore, the level of activation marker expression in heart patients awaiting transplantation was used as comparison for the patient population under study. Sequential monitoring of 24 heart transplant recipients tailed to demonstrate a significant correlation of increased activation marker expression with clinical events of immune activation. Subsequently 62 consecutive endomyocardial biopsy scores in 36 patients were compared with the expression of IL‐2R,TfR and VLA‐I on peripheral blood T cells. Neither increased cellular infiltration of the endocardium, nor of the myocardium, was associated with increasing proportions of IL‐2R, TfR, or VLA‐I positive T cells. Elevated T‐cell expression of the three markers combined indicated acute graft rejection with a sensitivity, specificity, and overall accuracy of 38'M., 52%, and 43%, respectively. Acute graft rejection in biopsies with associated myofiber damage (biopsy rejection scores 2 and 3A.B) was not associated with a change in the proportion of activated T cells in circulation within the first 6 months after transplantation. In contrast, acute graft rejection later than 6 months after transplantation was associated with a significant decrease of IL‐2R, TfR, and PTAI expressing T cells, possibly due to sequestration of activated T cells within the graft and at other sites. We conclude that incorporation of a patient control population for determination of an accurate range of normal values is absolutely required for valid interpretation of the significance of T‐cell activation marker data in this setting.
Simultaneous pancreas‐kidney versus kidney‐alone transplants in diabetics: Increased risk of early cardiac death and acute rejection following pancreas transplants
Authors: Douzdjian Viken , Abecassis Michael M. , Corry Robert J. , Hunsicker Lawrence G.
Published: September 2024

The decision between a simultaneous pancreas‐kidney (SPK) or kidney‐alone (KA) transplant Tor the treatment of diabetic end‐stage renal disease depends on the risk‐versus‐benefit of each procedure. In this study we compared the mortality, morbidity, graft function and acute rejection after 88 SPK and 65 KA transplants. All acute rejection episodes were biopsy‐proven. Patient survival was higher in the KA group (KA 92%, SPK 83%) at 1 year, but similar in both groups at 5 years (SPK 78%, KA 71%). Whereas myocardial infarction accounted for a similar proportion of deaths in both groups, sepsis and surgical complications were more common causes of death in the SPK group. The majority of cardiovascular deaths occurred early in the SPK group compared to the KA group. Kidney graft survival was similar at l year (SPK 79′%, KA 81%) and 5 years (SPK 66%, KA 59′%). Pancreas graft survival at 1 and 5 years was 75% and 60% respectively. Biopsy‐proven acute rejection occurred more frequently in the SPK group (SPK 63%. KA 46′%). Morbidity was greater in the SPK group and included vascular (SPK 19%, KA 3%), non‐infectious urologic (SPK 23%, KA 3%) and infectious complications (SPK 86%, KA 33%). The majority or complications in the SPK group were related to the pancreas allograft. In summary. SPK transplants were associated with an increased risk of early cardiovascular death, greater morbidity and more frequent biopsy‐proven acute rejection episodes. However, kidney graft survival was not affected by the addition of the pancreas allograft.
Prognostic factors for long‐term survival in leukemic marrow recipients with special emphasis on age and prophylaxis for graftversus‐host disease
Authors: Aschan Johan , Ringdén Olle
Published: September 2024

Long‐term survival of 182 leukemic patients after allogeneic bone marrow transplantation (BMT) was analyzed retrospectively regarding the type of graft‐versus‐host disease (GvHD) prophylaxis and patient age. Monotheraphy with either methotrexate (MTX) (n=59) or cyclosporin (CSA) (n=40) was given to 79 patients less than 30 years of age and to 20 older patients. These patients were compared to those receiving a combination of MTX+CSA (n=55) or T‐cell depletion (TCD) (n = 28) (38 patients ≤30 and 45 >30 years of age). Patient characteristics were similar in the two pairs of groups. The median follow‐up time was between 4.7 and 9.6 years in the different groups. In younger patients, the incidence of grade II‐IV acute GvHD was 38% amongst those treated with MTX or CSA and 14% in the MTX+CSA/TCD group (p=0.008). Forty percent of older patients on monotherapy developed grade II‐IV acute GvHD compared to 26% of those over 30 treated with MTX+CSA/TCD (ns). As a consequence, mortality from GvHD among younger patients was 19% in the monotherapy group and 3% in the MTX+CSA/TCD group (p=0.03) with 37% and 10% (p=0.04) in the older patient groups. The cumulative incidence of chronic GVHD was similar amongst treatments in the younger patients (39% in monotherapy and 39% in MTX+CSA/ TCD), but was significantly lower in the MTX+CSA/TCD group among patients > 30 (55% vs 25%, p=0.05). The actuarial overall survival at 5 years was unchanged in patients ≤30, 49% and 43% in the monotherapy and MTX+CSA/TCD groups, respectively. However, in older patients survival increased from 25% to 46% (p=0.04). An increase in leukemic relapse associated with MTX+CSA/TCD among both younger (26% vs 48%, p=0.05) and older patients (0% vs 46%, p=0.05) influenced the relapse‐free survival, 48% vs 39% (ns) in younger and 25% vs 37% (ns) in older patients. Risk‐factors for survival were dependent on the type of GvHD prophylaxis used. Using monotherapy, in contrast to combination therapy or TCD, multivariate analysis showed that recipient age > 30 years and HLA disparity between donor and recipient were correlated. with poor outcome. In patients receiving MTX+CSA or TCD, a female donor to a male recipient correlated significantly with poor survival, which was not the case with monotherapy. Disease status beyond 1st complete remission (1 CR) or 1st chronic phase (1 CP), grade II‐IV acute GVHD and recipient CMV seropositivity were significant risk‐factors among all patients regardless of the type of GvHD prophylaxis.
Vasculopathy in cyclosporine‐treated renal allografts: Possible protection by diltiazem
Authors: Choy Bo Ying , Walker Rowan G. , Becker Gavin J.
Published: September 2024

Morphometric quantitative analysis of the renal arterioles (arteriole wall thickness and overall vessel size) in renal biopsies from 21 cadaveric renal allograft recipients taken immediately prior to (0 months) and 3 months after transplantation was carried out using a computeraided image analyzer. Patients (n = 10) who received standard therapy (cyclosporine, azathioprine and prednisolone) showed an increase in arteriole wall thickness at 3 months compared to 0 months (p<0.01). Patients (n=11) who received standard therapy and oral diltiazem (60 mg t.d.s.) showed no such change in the arteriole wall thickness between 0 and 3 months. As cyclosporine toxicity and/or chronic vascular rejection are associated with an increase in arteriole wall thickness, the differences observed in this study may imply a protective role for diltiazem on renal arterioles.
Liver transplantation for fulminant hepatic failure in the United States: October 1987 through December 1991
Authors: Detre Katherine , Belle Steven , Beringer Kimberly , Daily O. Patrick
Published: September 2024

Background. Early mortality and retransplantation rates following liver transplantation for fulminant hepatic failure (FHF) are high. We investigated possible reasons for these findings. Methods. Data were obtained from the liver transplantation database of the United Network for Organ Sharing (UNOS) Scientific Registry. Recipient information was limited to waiting time; diagnosis; demographic, laboratory and serologic data; and six UNOS functional status codes. Donor information included demographic characteristics, cause of death, ABO blood type, and serology test results. Comparisons between FHF and non‐FHF were carried out for children and adults separately. The influence of an FHF diagnosis on 1‐year patient and graft survival was examined using the Cox proportinal hazard model. The same model was used to determine independent predictors of outcome following transplantation for FHF. Results. The majority of FHF recipients were on pretransplant life support, had much shorter waiting times, and were less well matched for ABO blood type (especially the children) than their non‐FHF counterparts. Although 1‐ year survival and graft survival were significantly lower, the significance of these differences was eliminated when the initial recipient, donor and matching characteristics between the two groups were controlled in the analysis. For FHF recipients, ABO mismatch and abnormal kidney function were the strongest independent predictors of adverse outcome. Conclusions. The results of this study provide circumstantial evidence that patients with FHF derive as much benefit from liver transplantation as patients with other diagnoses of comparable severity.
Organ procurement in Spain: Impact of transplant coordination
Authors: Matesanz R. , Miranda B. , Felipe C.
Published: September 2024

Organ transplantation is a well‐established treatment for irreversible renal, liver, cardiac, and respiratory failure. However, there is a shortage of organs that remains a serious obstacle to the full development of these therapeutic procedures. Some solutions such as presumed consent laws, the use of organs from living unrelated donors, compensation or payment for organs or xenografting have been proposed. In Spain during the last 3 years a well‐designed program of transplant organization including a network of well‐trained transplant coordinators has been established. In each potential donor hospital there is a transplant coordination team that is responsible for the whole process of organ procurement, from the detection of the donor to the organ grafting or tissue banking. Annual rate of cadaveric donors rose from 14.3 per million population (pmp) in 1989 to 21.7 donors pmp in 1992. Organ retrieval rate increased by 81% during the same period. Renal, liver and cardiac transplants increased by 44%, 175% and 162% respectively. We conclude that this particular approach to the problem has been successful in Spain, overcoming obstacles such as untrained or undertrained requesting staff, unidentified donors, and reluctance to approach grieving families. This kind of approach should be considered initially before resorting to more controversial approaches to the problem of the organ donor shortage.
Morphologic features of chronic rejection in kidney and less commonly transplanted organs
Authors: Sibley Richard K.
Published: September 2024

Chronic rejection is characterized by morphological evidence of destruction of the transplanted organ. The injury to the organ is associated with collagenization of variable degree. The destruction and fibrosis of the organ is probably the result of 1) direct alloimmune cytotoxic injury (i.e., acute and/or ongoing rejection) of the organ tissue, and 2) end‐organ ischemic injury secondary to fibroproliferative endarteritis (i.e.. chronic vascular rejection). The cardinal morphological feature of chronic rejection in all allografts is fibroproliferative endarteritis, which is characterized by widening of the subendothelial space due to a cellular fibrosis which may have an onion‐skin appearance with a PAS or silver stain. Macrophages with foamy cytoplasm and lymphocytes may be present in this fibrotic tissue. The smooth muscle wall may show foci of fibrosis as well, if involved by previous necrotizing rejection. These features are commonly found in needle core biopsies of kidney allografts and may involve the interlobular, arcuate, and interlobar arteries. They are less commonly found in pancreatic needle biopsies, and only rarely in hepatic and pulmonary allograft biopsies, rendering the diagnosis of chronic rejection often difficult to establish. Though the vascular lesions may not be apparent in biopsies, they are typically found in explained organs where larger vessels can be examined. Thus, the diagnosis of chronic rejection may rest upon other and in some instances less specific abnormalities, usually ischemic in origin due to vascular lesions and consequent decreased perfusion of the graft. In the kidney these changes are characterized by strips of cortical atrophy (tubular atrophy, interstitial fibrosis and collapsed glomerular tufts) and infarcts, in the liver by centrolobular ballooning degeneration and canalicular cholestasis, and in the pancreas by chronic pancreatitis and infarcts. In lung allografts, the major and only reliable morphological feature of chronic rejection is bronchiolitis obliterans. Additional features of chronic rejection include onion‐skinning of glomerular capillary walls (chronic transplant glomerulopathy) in the kidney, chronic active hepatitis and paucity of bile ducts in the liver, and destruction of the islets in pancreas allografts.
Lipid overload and proteoglycan expression in chronic rejection of the human transplanted heart
Authors: McManus Bruce M. , Malcom Gray , Kendall Todd J. , Gulizia James M. , Wilson Janet E. , Winters Gayle , Costanzo Maria R. , Thieszen Sheldon , Radio Stanley J.
Published: September 2024

The degree to which transplant arteriopathy in solid organ allografts is an atheromatous process remains somewhat controversial. If atheromata develop as common and integral components of the arteriopathic lesions, then the process may be approached therapeutically in a manner analogous to native atheromatous diseases. Approaches to understanding the arteriopathic process may include not only the modulation of alloimmunity, but also the interruption of “storage” phenomena. We have examined the epicardial coronary arteries of nearly 50 explanted human heart allografts using biochemical, morphological, morphometrical, immunohistochemical, and molecular techniques in an effort to establish the degree, nature, and distribution of lipid accumulation in the vessel walls. Concomitantly, we studied the ascertainment of proteoglycan gene expression, represented by biglycan and decorin messenger RNA, and the localization of proteoglycan proteins in the vessels. The degree of lipid and proteoglycan buildup in both the intima and media of transplanted vessels is striking, and correlated strongly with intimal thickening, crosssectional area reduction of the lumen, cumulative cyclosporine dose, corticosteroid dose, and serum cholesterol levels. Notably, lipid accumulation is not related to implant duration, this being true in an unselected series of “failed” allografts ranging from 4 to 1610 days post‐transplant. The profound lipid accumulation in coronary walls of many grafts begins very early post‐transplant and appears to contribute substantially to intimal thickening. Whether dysregulation of proteoglycan production leads to entrapment of lipids and lipoproteins remains an important and testable hypothesis.
International standardization of criteria for histologic diagnosis of chronic rejection in renal allografts
Authors: Solez Kim
Published: September 2024

An accurate diagnosis of acute rejection in renal allografts can be made histologically by quantitating specific morphologic changes observed on biopsy. The Banff Schema, an internationally standardized system of renal allograft biopsy assessment published in the August 1993 issue of Kidney International (1) has been shown to be highly reproducible and clinically valid for acute rejection. The schema also includes quantitation of the lesions of chronic rejection: fibrous intimal thickening, chronic transplant glomerulopathy, interstitial fibrosis, tubular atrophy. Biopsies that demonstrate these lesions are assigned the noncommittal term “chronic transplant nephropathy,” as other conditions such as cyclosporine toxicity, hypertension, infection, and reflux can generate these lesions as well. In certain clinical settings, some lesions probably are specific for chronic rejection, such as fibrous intimal thickening with fragmentation of the elastic lamina, but because of their extreme focality they are infrequently seen on biopsy. It is possible that chronic rejection involves a specific pattern of scarring and peritubular capillary injury, but these changes have yet to be fully characterized. Late allograft biopsies in ongoing clinical trials of new immunosuppressive agents will help to further define the specific pathologic changes of chronic rejection.
Differences in the procurement of organs and tissues by health care professionals
Authors: Siminoff Laura A. , Arnold Robert , Miller David Scott
Published: September 2024

Background: The act of donating organs is familiar to most health care professionals (HCPs). However, the process of tissue and cornea donation is not nearly as well known. Most studies of the donation process have neglected the issue of tissue and cornea donation. This study offers some preliminary data concerning the differences between organ and tissue and cornea donation processes. As well, this is one of the first studies to report an eligibility rate for tissues among hospital deaths. Methods: During a 5‐month period in 1989, the charts of all patients (n=233) who died in the study hospital were reviewed on a weekly basis. to establish eligibility to donate organs, tissues and corneas. A case series of 50 eligible patients cases was selected for in‐depth interviews. Cases were defined as those patients who were eligible to donate tissues or organs. The patient's attending physician, house officer, and primary nurse were interviewed using an open‐ended interview format. These audiotaped interviews focused on the events surrounding the patient's death, focusing on the issue of donation. We also collected information. concerning HCP knowledge of the medical criteria for donation and their attitudes toward donation. Consent was obtained from all HCPs before beginning the interview process. Results: Of the 233 deaths, 4.3% were eligible to donate organs, 11.2% were eligible to donate tissues, and 18.9% were eligible to donate corneas. On the basis of our interview data we found that all eligible organ donors were identified and their families asked by at least one member of the patient's health care team to consider donation. HCPs were less successful identifying tissue patients: 30 of the 41 tissue donors (73.2%) were identified and only 65.9% of donor families were asked to donate. Rates of consent to donation were lower than might be expected based on public opinion polls. 33.3% of families consented to organ donation while only 29.6% consented to donate tissue and cornea. Conclusion: HCPs performed less efficiently in terms of the procurement process for tissues and corneas as compared to organs. They were also less knowledgeable about the donation criteria for tissues and corneas than organs. They generally exhibited more positive attitudes about corneal donation. More education of HCPs is necessary before we can optimally procure tissues for transplantation.
New medical technologies and clinical practice: A survey of lymphocyte subset monitoring
Authors: Cambrosio Alberto , Guttmann Ronald D. , Keating Peter
Published: September 2024

Background: Since its inception in the early 1980s, lymphocyte subset (LS) monitoring of transplant patients has been a controversial technique. The clinical literature is replete with contradictory claims concerning its usefulness. No systematic information is however available on clinicians' attitudes towards the new technology. Method. We carried out a mail survey of the members of The Transplantation Society concerning the availability, use, value, and critical assessment of LS monitoring. Results. Results show that LS monitoring technology is available in most clinical settings surveyed and is regularly used by about half of the respondents associated with a clinical transplant program. About half of the users obtain diagnostically relevant measurements (T4/T8 ratios), as opposed to measurements related to OKT3 anti‐rejection therapy. While claiming that LS measurement is a useful tool, respondents attribute a low average score to the diagnostic value of the technique; about 2/3 believe that its absence would not affect their clinical judgment. Finally, 25% of the respondents send blood for LS measurements although they do not believe the technique is useful. Conclusions. The results suggest that research instruments which generate clinical interest may develop clinical‐diagnostic routines despite a lack of consensus concerning their usefulness. More importantly, these routines avoid a critical assessment of key notions such as “immune monitoring” which tend to blur the distinction between research and therapy.
Influence of oral felodipine on serum cyclosporine concentrations
Authors: Cohen David J. , Teng Shi‐Nee , Appel Gerald B.
Published: September 2024

Hypertension and nephrotoxicity are frequent in renal transplant patients treated with cyclosporine. Calcium‐channel blockers, because of their vasodilatory effects on the renal afferent arteriole, may be the anti‐hypertensive agents of choice in this population. Unfortunately, many calcium channel blockers inhibit the clearance of cyclosporine, resulting in elevated blood levels, and worsening nephrotoxicity. Thirteen hypertensive renal transplant patients, on stable cyclosporine doses and with stable cyclosporine blood levels, had felodipine added to their antihypertensive regimens. The effect on cyclosporine level was measured. Mean trough serum cyclosporine concentration increased slightly, from 122.8±51.8 ng/ml to 143.1±81.9 ng/ml with chronic felodipine administration (p=NS). Mean systolic and diastolic pressures both fell significantly, by approximately 10 mm Hg (systolic from 161±14 to 152±13 mm Hg; diastolic from 100±6 to 90±7 mm Hg). Serum creatinine remained unchanged. Four patients eventually discontinued felodipine. There was no significant change in their mean trough serum cyclosporine concentration when felodipine was discontinued. Thus, felodipine is an effective anti‐hypertensive medication in cyclosporine‐treated renal transplant recipients, without significant effect on cyclosporine blood levels, or adverse effect on allograft function.
Reticulocyte response to endogenous erythropoietin after renal transplantation
Authors: Serre A. F. , Souweine B. , Evreux O. , Bonhomme J. , Baguet J. C. , Deteix P. M.
Published: September 2024

We determined in a prospective study reticulocyte counts and serum erythropoietin concentrations after renal transplantation in 37 recipients of renal allografts. Erythropoietin decreased in 35 patients out of 37 during surgery. Results concerning reticulocyte counts allowed us to define two groups of patients. Group 1: 33 patients had a reticulocyte peak before d29. Among them the reticulocyte peak followed the first Epo peak in 22 patients (la) and occurred after several Epo peaks in 11 patients (Ib). Patients of groups 1b had a serum creatinine level above 300 μmol/l at the time of the first Epo peak. Group 2: 4 patients with acute tubular necrosis had no reticulocytes peak before d29 despite one or several erythropoietin peaks. Post‐operative erythropoietin reduction was not entirely explained by hemodilution or by per‐operative blood transfusions. The erythropoietin peak appeared to be efficient only when creatinine at the time of the peak was under 200 μmol/l according to the inhibition of erythropoiesis during renal failure.
The relationship between fever and acute rejection or infection following renal transplantation in the cyclosporin era
Authors: Toogood Giles J. , Roake Justin A. , Morris Peter J.
Published: September 2024

In the past, fever has been considered to be an important sign of rejection in renal transplant patients but since the introduction and widespread use of cyclosporin this relationship has become less clear. We have studied the relationship between fever defined as a single temperature reading 38.5°C or recordings ≥38.0°C over 2 consecutive days, and acute rejection or infection in 99 consecutive renal transplants. Within the first 6 months after transplantation 90 acute rejection episodes were recorded in 61 patients and most (83%) were not associated with fever. Forty‐seven episodes of fever were documented in 37 patients and ascribed to acute rejection (15), infection (17), antibody therapy (11) or other causes (4). Fever in the first 16 days was significantly more likely to be due to rejection than to infection (γ2=24.47, p <0.001). Episodes of fever due to infection tended to occur after the 1st month, coincident with the peak incidence of cytomegalovirus (CMV) infection. However, with the exception of CMV disease, fever was not a reliable guide for the presence of infection, including septicemia.
Spontaneous proliferation of peripheral blood lymphocytes as an indicator of intragraft immune activation in liver transplant patients
Authors: Kiuchi Tetsuya , Kato Hironori , Kanaya Seiichiro , Nashan Björn , Schlitt Hans J. , Inamoto Takashi , Ringe Burckhardt , Ozawa Kazue , Pichlmayr Rudolf
Published: September 2024

The presence of activated lymphocytes in the blood of transplant recipients is considered to be a marker of an ongoing immune process. In this study, the clinical utility of spontaneous proliferation (SP) of peripheral blood mononuclear cells (PBMC) as a marker of in vivo activation was evaluated by in vitro [H]thymidine incorporation in 22 patients in the 1st month after liver transplantation. Also immune activation in the graft was monitored by transplant aspiration cytology (TAC‐A). In the study period, there were only 2 mild episodes of clinical acute rejection, where SP of PBMC was 1290 and 1541 cpm (vs. 99 cpm averaged in healthy controls). Though SP of PBMC was also increased in systemic infections, a significant positive correlation was observed between SP of PBMC and TAC‐A score. In all episodes where TAC‐A score was elevated to above 2, SP of PBMC was simultaneously increased to more than 1000 cpm. In 8 patients prophylactically treated with the anti‐interleukin‐2‐ receptor antibody, BT563, SP of PBMC was significantly lower compared to 7 patients treated with antithymocyte globulin. It is suggested that SP can be a reliable parameter of the in vivo activation of lymphocytes, which accompanies immune activation in liver graft, and is potentially useful as a sensitive, although rather non‐specific, and non‐invasive monitoring of intragraft alloresponse.
Cytomegalovirus colitis in a pediatric heart transplant patient
Authors: Etheridge Susan P. , Bolman R. Morton , Braunlin Elizabeth A.
Published: September 2024

Cytomegalovirus colitis is one of the sequelae of cytomegalovirus infection in transplant patients and can be associated with severe consequences. This case details the clinical, radiographic, and laboratory. features of this infection in a child after heart transplantation where early recognition and treatment resulted in complete resolution of the disease.
Long‐term bone loss after renal transplantation: comparison of immunosuppressive regimens
Authors: McIntyre H. David , Menzies Betty , Rigby Russell , Perry‐Keene Donald A. , Hawley Carmel M. , Hardie Ian R.
Published: September 2024

Serial measurements of serum and urine markers of bone mctabolism and of forearm bone density (BMD) by dual photon absorptiometry were performed in 22 patients undergoing renal transplantation in 1986. Patients were randomised to immunosuppression with (1) cyclosporin alone (CsA group, n=10), (2) cyclosporin for 3 months followed by azathioprine‐prednisone (CSA/AzP group, n=3) or (3) long‐term azathioprine‐prednisone (LT AzP group, n=9). As no reduction in bone mineral density (BMD) was noted in the first 6 months, groups 2 and 3 were considered together (AzP group, n=12). Mean±SEM BMD fell by 19±2% at 36 months (n=19, p<0.01), with similar reductions seen in the CSA and AzP groups. At 60 months, BMD of the AzP group was 25±3% below baseline (p<0.01), while the CSA group were only 5±4% below baseline (p=NS vs baseline, p<0.05 vs AzP group). The degree of reduction in BMD over 5 years correlated with total glucocorticoid dose (r=0.63, p<0.05), but not with biochemical markers of bone turnover. Serum alkaline phosphatase fell post‐transplant in patients treated with AzP, but not in the CSA group. These results demonstrate significant loss of forearm bone mineral with long‐term follow‐up after renal transplantation, but suggest that patients treated with cyclosporin monotherapy may be at lower risk of this complication.
Soluble interleukin‐2 receptor (sIL‐2R) levels in renal transplantation: Comparison between clinical and laboratory analysis
Authors: Montagnino Giuseppe , Tarantino Antonio , Grignani Simona , Braga Mario , Ponticelli Claudio
Published: September 2024

Soluble interleukin‐2 receptor levels (sIL‐2R) were retrospectively evaluated in 43 consecutive kidney transplant recipients (22 males, 21 females), from day 0 up to 90 days after transplantation. 11 pts were on CSA only, 13 on CSA+MP and 19 on CSA+MP+Aza. All graft‐worsening episodes were then retrospectively analyzed, either according to clinical criteria only, or taking into account sIL‐2R levels.On clinical grounds, 50 rejections were observed: “a posteriori” 5 turned out to be either infections or non‐immunological worsenings of graft function (prevalence of misdiagnosis in the rejection set: 5/50, 10%). Of the 8 infections, 2 were actually treated as rejections (margin of error: 2/8, 25%). CsA toxicity was correctly diagnosed in 2/4 episodes.The analysis based onsIL‐2R levels increase confirmed the clinical diagnosis in 52/79 cases (66%). The prevalence of misdiagnosis was: 21.2% in rejection, 2/3 in CsA toxicity, while infections were overestimated in 60% of cases. Isolated sIL‐2R level increase was not associated with rejection in 87.5% of cases, while an associated increase of IL‐ 2R and plasma creatinine had a 5% chance of being wrong. SIL‐2R levels increased before any rise in plasma creatinine in late rejections (28±21 days after transplantation), while they increased after the rise of plasma creatinine in early rejections (10±5 days) (p=0.014). In the rejection set, sIL‐2R had a sensitivity of 83.4%, a specificity of 80%, a positive predictive value of 50.2% and a negative predictive value of 95.2%. SIL‐2R determination does not provide superior results to those obtained with clinical tools (p= 0.15). Nevertheless, sIL‐2R may help in predicting rejections occurring later than the 15th post‐transplant day, or in disclosing subclinical episodes of smouldering infection and immunological activation.
Living‐related liver transplantation in adult recipients: A hypothesis
Authors: Habib N. , Tanaka K.
Published: September 2024

Living‐related liver transplantation (LRLT) in pediatric recipients has been successful with 90% 1‐year survival (1, 2). LRLT in adults is yet to succeed. We hypothesize a management strategy based on the donor graft weight‐to‐recipient body weight ratio (GRBWR) and the Redox Tolerance Index (RTI) (3). Favorable recipients (GRBWR above 0.7%) are candidates for left liver orthotopic transplantation. Unfavorable recipients (GRBWR 0.5‐0.7% and RTI above 0.5%) are suitable for left liver auxiliary‐orthotopic transplantation. Compromized recipients (GRBWR below 0.5% or RTI below 0.5%) might be suitable for a left liver auxiliary‐heterotopic transplantation. The above hypothesis remains to be validated.
Hepatic levels of cyclosporine and metabolites in patients after liver transplantation
Authors: Lacerda Marco A. , Bowers Larry D. , Snover Dale C. , Payne William D. , Bloomer Joseph R.
Published: September 2024

Despite the critical role of the liver in the metabolism of cyclosporine, only a few studies have measured hepatic levels (CSA) in patients receiving the drug, and none has directly assayed hepatic levels of the metabolites. In this study we measured CSAH, and its principal metabolites (mono‐OH and di‐OH CSA) by HPLC/mass spectroscopy in 19 liver biopsy specimens collected from 14 patients who had undergone liver transplantation, in order to determine how they correlated with blood levels (CSAB). The hepatic concentrations were also compared with biochemical and histological parameters of cholestasis. A positive correlation was observed between CSAH and CSAB (r=0.47), irrespective of the length of time the patients had received the drug (7 to 1662 days) as defined by the relationship: CSAH,(ng/g wet weight)=6.7×CSAB(ng/ml)+338. Hepatic levels of metabolites exceeded those of the parent compound in 11 biopsy specimens. No correlation was found for CSAH and the metabolites and serum bilirubin or the degree of cholestasis in the liver biopsy specimens. These findings indicate that: (1) CSA is concentrated in liver tissue several‐fold over blood; (2) The hepatic concentration can be estimated from the blood concentration even in the presence of cholestasis; (3) Significant levels of CSA metabolites are found in liver tissue, frequently exceeding the concentration of the parent compound.
Single‐center experience of combined liver and kidney transplantation
Authors: Kliem Volker , Ringe Burkhard , Frei Ulrich , Pichlmayr Rudolf
Published: September 2024

Kidney or liver transplantation (KTx, LTX) today is a standard. therapeutic procedure if one of these organs fails. However, the need for transplantation of both organs may arise with deterioration of organ function. To evaluate the success of combined LTX/KTx we analyzed 20 patients (aged 14‐64) who received a total of 21 LTX and 31 KTX. Simultaneous LTX/KTx was performed in 14 patients, of whom 5 required further replacement of one or the other of the grafted organs. Six patients had sequential transplantation: 3 had LTx prior to the KTx, and 3 KTX prior to LTx. In 12 patients the indication for LTX was end‐stage liver cirrhosis, and of these 8 died after LTx, mostly of infections. In a group of 8 transplant recipients without liver cirrhosis (e.g. polycystic liver), only 1 patient died. Eleven of the 20 grafted patients are still alive now (followup after LTX 14‐120 months). Episodes of liver and kidney rejection occurred in only 30% and 15% of transplanted patients respectively. Only I patient is back on hemodialysis, the others have normal liver and kidney function. Combined LTX/KTx may be successful in appropriate circumstances. However, patients with liver cirrhosis have a very poor prognosis due to their poor overall clinical state at the time of terminal renal failure. In contrast, patients without liver cirrhosis are better candidates, even for simultaneous LTx/KTx. In general, the indication for simultaneous organ transplantation should be considered earlier than for transplantation. involving only one organ.
FK 506 rescue therapy for hepatic allograft rejection: Experience with an aggressive approach
Authors: Woodle E. Steve , Perdrizet George A. , So Samuel K. S. , White Heather M. , Marsh J. Wallis
Published: September 2024

Although initial experiences with FK 506 rescue therapy for acute hepatic allograft rejection have provided promising results, analysis of available data indicates that inferior results are obtained when FK 506 rescue therapy is initiated in the latter stages of rejection. Since its initial availability, we have applied an aggressive approach towards FK 506 rescue therapy based on early conversion and assiduous dosing. We have reviewed our experience with this approach in patients with refractory hepatic allograft rejection to provide an assessment of this approach. Sixteen patients were treated for corticosteroid and OKT3‐resistant acute hepatic allograft rejection. Fourteen patients were treated for cellular rejection and 2 for humorally‐mediated rejection. Median followup was 7.3 months posttransplant and 6.0 months post‐initiation of FK 506 therapy. Median time to first rejection was 8 days and median time to FK 506 therapy was 29 days. Laboratory values at the time of initiation of FK 506 therapy included: mean serum bilirubin, 4.0±3.1 mg/dl and SGPT 136±105 Ul. Prior to FK 506 therapy, patients received an average. of 35.5±19.1 mg/kg of bolus/taper corticosteroids (prednisone equivalent) and 11.25±4.8 days of OKT3 therapy. FK 506 therapy was succesful in reversing all episodes of rejection. Median time to rejection reversal with FK 506 rescue therapy was 23 days (mean±SD, 27.6±16.7 days) in patients with cellular rejection. Time to rejection reversal was 26 and 28 days in the 2 patients with humoral rejection. Patient and graft survival at 6 months were 100%/100%, and 94%94% at 12 months. Graft loss to rejection was not observed. Significant CMV infections occurred in 44% of patients: CMV hepatitis in 5 (31%), CMV pneumonitis in 1 patient (6%), and CMV viremia alone in 1 (6%). The mean time to CMV disease occurred on posttransplant day 29, which corresponded to a median of 5 days of FK 506 therapy, suggesting that CMV disease was more probably the result of intense immunosuppression which was administered prior to FK 506 therapy. These results indicate that an aggressive approach to FK 506 rescue therapy in patients with refractory hepatic allograft rejection: 1) provides high rates of reversal, 2) provides excellent patient and graft‐survival rates in a subset of patients at high risk for allograft loss, 3) appears to provide similar results for cellular and humorally‐mediated hepatic allograft rejection, and 4) allows for effective, simultaneous treatment of CMV disease and rejection. Continued attempts. to reverse OKT3‐resistant hepatic allograft rejection with conventional approaches (corticosteroids, repeat OKT3 therapy, polyclonal antilymphocyte preparations) may no longer be warranted.
Analysis of functional abnormalities uncovered during preoperative evaluation of donor candidates for living‐related liver transplantation
Authors: Morimoto Taisuke , Awane Masaaki , Tanaka Akira , Ikal Iwao , Nakamura Yoshiaki , Yamamoto Yuzo , Takada Yasutsugu , Honda Kazuo , Inamoto Takashi , Uemoto Shinji , Inomata Yukihiro , Tanaka Koichi , Yamaoka Yoshio , Shimahara Yasuyuki , Ozawa Kazue
Published: September 2024

Functional abnormalities of the liver uncovered during preoperative routine evaluation were analyzed in 109 donor candidates for 100 cases of living‐related liver transplantation (LRLT) performed during the period from June, 1990 to May, 1994 at the Second Department of Surgery, Kyoto University Hospital. High serum transaminase (GOT, GPT) levels were noted in 10 (9.2%) cases among 109 candidates, high alkaline phosphatase in 4 (3.7%), hyperbilirubinemia in 3 (2.8%), anemia in 3 and high choline esterase in 3 cases. Positive hepatitis C antibody (HCV) was also noted in I case. Fatty liver was detected in 10 (9.2%) cases, cholecystitis in 2 cases, 1 case each of cyst and calcification in the liver by diagnostic imaging (ultra sonograph and/or computed tomography). These abnormalities of the liver necessitated replacing the initial candidate with the other parent in 9 cases, including 1 case without any functional abnormality whose graft liver was too large to fit the recipient abdominal cavity. There were 14 cases of ABO blood type incompatible combination. Switching the initial candidate due to these abnormalities mentioned above resulted in incompatible combinations in 4 of these 14 cases. Although the advantages of the LRLT are the superior viability of the donor graft and the genetic histocompatibility between recipient and donor, to optimize the advantage of LRLT, all donor candidates should be strongly advised to make every effort preoperatively to improve their physical condition in preparation for the LRLT protocol, since many of these abnormalities are typically reversible.
Lethal acute graft‐versus‐host disease in a liver transplant recipient: Relations with cell migration and chimerism
Authors: Pageaux G. P. , Perrigault P. F. , Fabre J. M. , Portales P. , Souche B. , Dereure O. , Eliaou J. F. , Larrey D. , Domergue J. , Michel H.
Published: September 2024

We report herein the case of a patient who developed fatal acute graft‐versus host disease (GvHD) after liver transplantation (LT). GvHD occurred 18 days after LT and was characterized by skin epidermolysis, diarrhea and leucopenia. Skin biopsy showed epidermal dyskeratosis with epithelial necrosis, a lesion consistent with GvHD. Despite immunosuppressive therapy, the patient died within 24 days. In our observation, GvHD occurred although five HLA compatibilities were identified between the donor and the recipient, an apparently favorable and uncommon situation. This case further supports the qualification that LT may be complicated by GvHD and strongly suggests that minor rather than major histocompatibility antigens are the main target of allogenic interactions of GvHD. The involvement of chimerism in GvHD is controversial and requires further investigation.