Triple-drug Immunosuppressive Therapy Research Articles

Experience of outpatient follow-up of heart transplant recipients at Shumakov center

Heart transplantation (HT) is considered the optimal therapy for end-stage heart failure. In recent years, the number of operations performed has been growing, which has led to a rise in the number of heart transplant recipients requiring outpatient follow-up.Objective: to evaluate the effectiveness of the model of dual personalized follow-up of heart transplant recipients in the consultative and diagnostic department of Shumakov National Medical Research Center of Transplantology and Artificial Organs.Materials and methods. The study included 1,436 patients under outpatient follow-up from January 2008 to December 2022. Recipient data, results of laboratory and instrumental examination methods, nature and frequency of complications at different follow-up periods were analyzed.Results: At the time of discharge from the hospital, 98.7% of patients had received triple-drug immunosuppressive therapy; 6 months later, methylprednisolone was discontinued in 72.2% of recipients. Mean tacrolimus level during the 1-year follow-up was 8.7 ± 2.7 ng/mL; in the period from 1 to 5 years of followup, the mean was 5.1 ± 2.4 ng/mL. At year 1 after transplantation, 23 (1.7%) recipients had been converted to everolimus; by the end of year 5 of follow-up, the number had increased to 8.6%. The most frequently detected complications during outpatient follow-up were: hypertension (48.65%), post-transplant diabetes mellitus (7.24%), nephropathy (35.97%), and malignant neoplasms (4.2%). Recipient survival, excluding in-hospital mortality, was 96.5%; and 88.0% at year 1 and 5 of follow-up, respectively.Conclusion: The dual personalized approach model for outpatient follow-up and treatment of heart transplant recipients will improve recipient survival and quality of life in the long-term post-HT period.

Biomarkers for Clinical Response of Extracorporeal Photopheresis

Biomarkers for Clinical Response of Extracorporeal Photopheresis

Heart Transplantation for Giant Cell Myocarditis: A Case Series

BackgroundGiant cell myocarditis (GCM) has a poor prognosis without heart transplant, but post-transplant survival is unknown. PurposeTo describe the post-transplant survival of patients with GCM at a large transplant center. MethodsSeven patients underwent heart transplant for histologically confirmed GCM of the explanted heart. The median age was 59 years, and 43% (3 of 7) were female. All patients had cardiogenic shock, multiorgan failure, elevated troponin, and recurrent ventricular tachycardia, and some required mechanical circulatory support. All patients received rabbit antithymocyte globulin (rATG) in the perioperative period at a dose of 1.5 mg/kg daily for 1 to 5 days and 4 received intravenous immunoglobulin 1 g/kg daily for 2 days after rATG. All patients had early initiation of tacrolimus by first to third postoperative day depending on renal function, early mycophenolate, and high dose steroid. All were maintained using tacrolimus, mycophenolate, and prednisone. ResultsOne patient had asymptomatic recurrence of GCM at 3 months, managed by up-titration of tacrolimus, and had asymptomatic 2R cellular rejection at 4 months, managed with steroid bolus. No patient had high-grade rejection. One patient died at 267 days, possibly of GCM. Six of 7 (86%) remain alive at a median of 842 days (2.3 years) post transplant. ConclusionsPatients with GCM have excellent post-transplant survival with use of rATG and triple drug immunosuppressive therapy; however, some patients remain at risk for GCM recurrence after transplant, which may respond to augmented immunosuppression.

The Immune Response to Eastern Equine Encephalitis Virus Acquired Through Organ Transplantation.

The human immune response to eastern equine encephalitis virus (EEEV) infection is poorly characterized due to the rarity of infection. We examined the humoral and cellular immune response to EEEV acquired from an infected donor via liver transplantation. Both binding and highly neutralizing antibodies to EEEV as well as a robust EEEV-specific IgG memory B cell response were generated. Despite triple-drug immunosuppressive therapy, a virus-specific CD4+ T cell response, predominated by interferon-γ production, was generated. T cell epitopes on the E2 envelope protein were identified by interferon-γ ELISpot. Although these results are from a single person who acquired EEEV by a non-traditional mechanism, to our knowledge this work represents the first analysis of the human cellular immune response to EEEV.

Arrhythmogenic right ventricular cardiomyopathy in recipients on heart transplant waiting list

Aim. To determine the clinical features of arrhythmogenic right ventricular dysplasia (ARVD) in recipients on heart transplant waiting list (WL) and after a heart transplantation (HTx).Material and methods. From January 2010 to December 2018, we included 192 recipients in heart transplant waiting list (HTx WL) on behalf of Almazov National Medical Research Center. ARVD was diagnosed in 4 subjects (F Marcus et al. criteria, 2010). All 4 patients (female, mean age 46,5 years-old (16-54-year-old)) underwent HTx. Prior to HTx, arrhythmias (atrial fibrillation, atrial flutter) were diagnosed in 3 recipients. In patient №2, pacemaker in VVI mode was implanted due to sick sinus syndrome (SSS) and tachycardia-bradycardia syndrome and others underwent ICD implantation.Results. Survival after HTx was 30,9 (3,9-46,2) months. All recipients were treated with triple-drug immunosuppressive therapy (calcineurin inhibitors, mycophenolic acid, steroids) and induction with Basiliximab. All patients experienced high sensitivity to immunosuppressive therapy (agranulocytosis), and therefore a colony-stimulating factor was administered to all of them. After immunosuppression reduction (Tacrolimus plus Methylprednisolone) agranulocytosis did not recur.Conclusion. ARVD is a rare disease in the structure of end-stage heart failure in recipients in HTx WL. An examination of this pathology is necessary to manage patients on-time with surgical treatment (ICD, HTx). According to our results, causal variants in desmosome genes were determined in 1 from 4 patients and simultaneous presence of two unique genetic variants in the RKR2 gene were found in one. A special feature of post-HTx management was the development of agranulocytosis, which once again underlines the need for a personalized approach to the selection of the immunosuppressive therapy.

Abstract 19328: Clinical Predictors of Renal Failure in Heart Transplant Patients Following Initiation of Calcineurin Inhibitor Free Regimen

Purpose: Calcineurin inhibitor (CNI) therapy has been the cornerstone of standard triple-drug immunosuppressive therapy that has significantly improved outcomes after heart transplantation (HTx). However, CNI-induced nephrotoxicity remains a significant cause of morbidity and mortality. Renal-sparing protocols (RSP) using CNI-free regimens have improved renal function in some patients (pts). The clinical variables associated with development of renal failure despite RSP initiation are unknown. We therefore evaluated HTx pts on RSP for possible risk factors associated with renal failure. Methods: Of 1,424 HTx pts between 1/1994 to 1/2011, 61 were identified who underwent RSP. Creatinine values were obtained at time of RSP initiation and ≥3 months post-RSP. The CKD-EPI Cr Equation (2009) was used to estimate GFR. We assessed pts for type of CNI, prednisone use, ACE-inhibitor/ARB use, calcium-channel blocker use, sex, race, hypertension, diabetes mellitus, obesity, and hypercholesterolemia. A logistic regression model was used to determine if there was an association between the clinical variables measured and stage IV renal failure (estimated GFR <30 mL/kg/m2). Results: 40 patients (66%) developed renal failure at an average of 14.4 ± 12.8 months after initiating RSP. Pts with an estimated GFR <30 mL/kg/ m2 at time of RSP initiation had a 5.4-fold (1.69-17.26, p=0.004) higher risk of developing renal failure. By multivariate logistic regression, this relationship remained significant after controlling for potential confounders in the relationship between RSP and renal failure, with a 8.9-fold (1.64-48.4; p=0.01) risk of renal failure in pts with an estimated GFR <30 mL/kg/ m2 at time of RSP initiation. The other clinical variables tested did not significantly affect outcome (Table). Conclusions: RSP does not appear to be effective in pts with advanced renal disease. RSP should be considered in pts with CNI nephrotoxicity at an earlier stage of the disease.

De NovoDonor-Specific HLA Antibody Development and PeripheralCD4+CD25highCells in Kidney Transplant Recipients: A Place for Interaction?

The aim of this study was to determine whether the abundance of regulatory T cells (Tregs) (CD4+CD25high) affects the de novo development of anti-HLA donor-specific antibodies (DSAs) in kidney transplant recipients (KTRs). Methods. Unsensitized (PRA ≤ 10%, no DSA) adult primary KTRs who received a living (83%) or deceased (17%) KT in our Institution during 2004/2005 were included. DSA testing was performed monthly, and Tregs were quantified by flow cytometry every 3 months, during the 1st year after KT. All patients received triple drug immunosuppressive therapy (CNI + MMF or AZA + PDN); 83% received anti-CD25. Results. 53 KTRs were included; 32% developed DSA during the 1st year after KT. Significantly lower 7-year graft survival was observed in those who developed DSA. No difference was observed in Treg numbers up to 9 months after KT, between DSA positive and negative. However, at 12 months after KT, DSA-negative patients had significantly higher numbers of Treg. Conclusions. Early development of DSA was not associated to variations in Treg abundance. The differences in Treg numbers observed at the late time point may reflect better immune acceptance of the graft and may be associated to long-term effects. Additional inhibitory mechanisms participating earlier in DSA development after KT deserve to be sought.

Benefit of immune monitoring in heart transplant patients using ATP production in activated lymphocytes

Balancing immunosuppression to prevent rejection while minimizing infection or drug toxicity risk is a major challenge in heart transplantation. Therapeutic drug monitoring alone is inadequate to measure the immune response. An immune monitoring (IM) assay (ImmuKnow; Cylex, Columbia, MD) performed on peripheral blood measures adenosine triphosphatase (ATP) release from activated lymphocytes and may predict the immune state. Therefore, we sought to determine the utility of IM in heart transplant recipients. Between November 2005 and July 2008, 296 heart transplant recipients had a total of 864 IM assays performed at 2 weeks to 10 years post-transplant and were correlated with infection and rejection events that occurred within 1 month after IM testing. All patients received standard triple-drug immunosuppressive therapy with tacrolimus, mycophenolate mofetil and corticosteroids, without induction therapy. There were 38 infectious episodes and 8 rejection episodes. The average IM score was significantly lower during infection than steady state (187 vs 280 ng ATP/ml, p < 0.001). The average IM score was not significantly different during rejection when compared with steady state (327 vs 280 ng ATP/ml, p = 0.35). Interestingly, 3 of 8 rejection episodes were antibody-mediated rejections and had hemodynamic compromise and, for these, the mean IM score was significantly higher than for steady-state patients (491 vs 280 ng ATP/ml, p < 0.001). The non-invasive IM test appears to predict infectious risk in heart transplant patients. The association between high IM scores and rejection risk is inconclusive due to the small number of rejection episodes. Further studies with larger sample sizes for rejection episodes are required.

Triple drug Therapy for the Prevention of Early Acute Renal Allograft Rejection in Dogs

A triple drug therapy with emulsified cyclosporine, mycophenolate mofetil and predonisolone was used for 90 days for the prevention of acute rejection in six renal transplanted beagles. Five dogs survived for 90 days, but one dog died suddenly from unknown reason with a functioning graft 9 days after transplantation. Allografts of three of the five survived dogs showed no evidence of acute rejection based on Banff'07 histopathological classification. The other two dogs showed acute allograft rejection on histopathological evaluation and urinary tract infection at the end of the study. None of the dogs showed adverse effects such as hepatotoxicity and myelosuppression. At necropsy, abnormal cystic dilatation of the crypts with secretory accumulation was found in the duodenum mucosa in all dogs survived for 90 days. With further research, this triple drug immunosuppressive therapy could become a potential alternative of the classical immunosuppressive protocol (cyclosporine, azathiopurine and predonisolone) for the prevention of acute allograft rejection in dogs.

Pregnancy after liver transplantation: Four-year follow-up of the first case in mainland China

The safety and feasibility of pregnancy following liver transplantation (LT) have been accredited in a series of LT center. The first case in mainland China is reported. The follow-up data of a 22-year-old pregnant patient with end-stage liver disease undergone orthotopic liver transplantation were analyzed retrospectively. After surgery, the patient was uneventfully recovered and became pregnant 33 mo after LT. The patient was closely monitored and treated with a standard and individualized triple-drug immunosuppressive therapy throughout her pregnancy. Caesarean section was performed in March 18, 2004, and a health live-born infant was delivered. After the delivery, a 4-year follow-up period indicated that the patient was satisfactory with her condition and her baby was healthy. Our case shows that a successful pregnancy following LT is possible and safe in women with end-stage liver diseases under close monitoring. Three factors including mother, baby, and transplanted liver function must be considered for the safety of high-risk pregnancies.

Skin lesions in adult liver transplant recipients: a study of 100 consecutive patients

The surgical advances made in the area of organ transplantation along with the use of more efficacious immunosuppression have meant an increase in patient survival. This longer-living transplant population has started to exhibit cutaneous problems, some of which lead to an increased mortality while others lead to a decline in the quality of life. The primary objective was to determine the different types of cutaneous lesions encountered in the adult liver transplant population. Secondary objectives were to determine the impact, if any, of the duration of transplant, the type of immunosuppression involved and the degree of sun exposure and skin phototype, on the skin cancers encountered in this transplanted population. Two dermatologists examined 100 consecutive liver transplant recipients (LTRs) attending the transplant outpatient department. Skin examination included the face and whole body and lesions found were categorized into the following groups: cutaneous malignancies, squamoproliferative lesions, cutaneous infections and others that did not fall into any of these categories. The reasons for organ transplantation were numerous. The mean age at transplantation was 42.5 years. The average time since transplantation was 5.5 (range 0.75-16 years). Four patients developed skin cancers; among them there were a total of seven skin cancers (one squamous cell carcinoma, six basal cell carcinomas). Fungal infections accounted for 19% of all cutaneous infections seen, viral infections 2% and bacterial infections 5%. Triple-drug immunosuppressive therapy (ciclosporin A, azathioprine and prednisolone) was used in 35% of LTR patients, while dual therapy (tacrolimus and prednisolone) was used in 48% and monotherapy (tacrolimus) was used in 17% of LTRs. Immunosuppressive therapy is believed to be one of the most important risk factors in the development of skin cancer in solid organ transplant recipients. The relatively low prevalence of skin cancer in our liver transplant population may in part be explained by the relatively high percentage of recipients on dual and monotherapy (48% and 17% respectively), and the shorter duration of therapy. Our study suggests that although LTRs are at higher risk of developing nonmelanoma skin cancer than the general population, the risk is comparable with other solid organ transplant recipients.

Results of Clinical Renal Transplantation in 15 Dogs Using Triple Drug Immunosuppressive Therapy

To evaluate outcome of renal transplantation in dogs administered cyclosporine, azathioprine, and prednisolone immunosuppression. Prospective clinical study. Fifteen dogs with chronic renal failure. Nine dogs died within 1 month of surgery; 5 died from complications associated with generalized thromboembolism. Three dogs survived for 6-25 months. Three dogs alive at the time of this report have survived 22-48 months; however, all 3 dogs have had bacterial infections that responded to antibiotic therapy. There was no biochemical evidence of acute allograft rejection in any dog. Perioperative use of enoxaparin may have prevented thromboembolism in 5 dogs. Triple drug immunosuppressive therapy used in this study prevented acute renal allograft rejection in 6 dogs that survived >4 weeks; however, immunosuppression was excessive, resulting in an unacceptable frequency of infection and other drug-related complications. Perioperative anticoagulation therapy seem to be warranted. Survival time and quality of life for this group of dogs was poor; however, there was no evidence of acute rejection in the dogs surviving >4 weeks. This protocol should only be used if the degree of immunosuppression is reduced, and early evidence of allograft rejection is monitored by renal biopsy or markers of lymphocyte activation.

Pharmacokinetics and pharmacodynamics of pravastatin in pediatric and adolescent cardiac transplant recipients on a regimen of triple immunosuppression.

In adults, pravastatin reduces the development and progression of transplant vasculopathy, the main long-term risk after cardiac transplantation. The pharmacokinetics of pravastatin is not known in children taking calcineurin inhibitors. Our aim was to determine the single-dose pharmacokinetics and short-term safety of pravastatin in children undergoing regular triple-drug immunosuppressive therapy after cardiac transplantation. Nineteen pediatric cardiac transplant recipients (aged 4.4 to 18.9 years) receiving triple immunosuppression therapy consisting of methylprednisolone (19 patients), cyclosporine (INN, cyclosporin) (17 patients) or tacrolimus (2 patients), and azathioprine (18 patients) or mycophenolate mofetil (1 patient) ingested a single 10-mg dose of pravastatin, and plasma pravastatin concentrations were measured up to 24 hours. Subsequently, the patients took 10 mg pravastatin orally once daily for 8 weeks. The lipid-lowering effect and the safety of pravastatin therapy were studied. The mean peak plasma concentration (C(max)) of pravastatin was 122.2 +/- 88.2 ng/mL (range, 11.4-305.0 ng/mL), and the area under the plasma concentration-time curve of pravastatin from 0 to 10 hours [AUC(0-10)] was 264.1 +/- 192.4 ng.h/mL (range, 30.8-701.6 ng.h/mL). These C(max) and AUC(0-10) values are nearly 10-fold higher than the corresponding values reported in hypercholesterolemic children in the absence of immunosuppressive therapy. The time of peak concentration (t(max)) of pravastatin was 1.1 +/- 0.4 hours (range, 0.5-2 hours), and the mean elimination half-life (t(1/2)) was 1.2 +/- 0.3 hours (range, 0.7-2.2 hours); these parameters were similar to those in the hypercholesterolemic children. By 8 weeks of treatment, the concentration of serum total cholesterol decreased by 13% (P =.005), low-density lipoprotein cholesterol by 27% (P <.0001), and triglycerides by 6% (not significant, P =.28); the concentration of high-density lipoprotein cholesterol increased by 7% (not significant, P =.30). No clinically significant increases in serum ALT, creatine kinase, or creatinine levels were observed. The plasma concentrations of pravastatin in pediatric cardiac recipients receiving triple immunosuppressive medication are nearly 10-fold higher than in hypercholesterolemic children after the same pravastatin dose. However, the short-term therapy of pravastatin was well tolerated and effective in lowering serum cholesterol levels in cardiac recipients.

Successful islet auto- and allotransplantation in diabetic pigs.

Because of its anatomical and physiological similarities to humans, the pig appears to be a suitable large animal model for preclinical studies of islet transplantation. The aim of this study was to investigate islet auto- and allotransplantation in a pig model with diabetes induced by total pancreatectomy. Porcine islets were isolated by a continuous digestion-filtration device at 32 degrees C and purified by a discontinuous iso-osmolar Ficoll-sodium-diatrizoate gradient on a Cobe 2991. The purified islets were autografted into the liver or the renal subcapsular space. The liver appears to be a more suitable site for the islet grafts than the renal subcapsular space, and the minimal amount of islets for reversal of diabetes is >5 microl/kg of body weight. Persistent normoglycemia (fasting blood glucose level: 72.4+/-44.38 mg/dl) with a normal insulin secretion response to glucose stimulation was successfully achieved in five of six diabetic pigs by implanting a sufficient islet mass into the liver. Triple-drug immunosuppressive therapy with cyclosporine, azathioprine, and prednisolone did not prevent porcine islet allografts from experiencing early failure. However, the addition of 15-deoxyspergualin to the triple-drug immunosuppressive regimen significantly prolonged the function of the islet allografts. When antithymocyte globulin was added to the above-mentioned immunosuppressive drug regimen, the normoglycemic period was prolonged to more than 1 month (fasting blood glucose level: 75.4+/-17 mg/dl). We conclude that autotransplantation with a sufficient islet mass can induce normoglycemia with a normal insulin secretion response to glucose stimulation in pancreatectomized diabetic pigs and that allotransplantation can be successfully achieved when 15-deoxyspergualin and antithymocyte globulin are combined with the triple-drug immunosuppression described above. However, this immunosuppressive protocol results in a high rate of infectious complications.

GLUCOSE INTOLERANCE AFTER RENAL TRANSPLANTATION DEPENDS UPON PREDNISOLONE DOSE AND RECIPIENT AGE1

Retrospective studies on the prevalence of posttransplant diabetes mellitus (PTDM) in patients on triple-drug immunosuppressive therapy have shown great dispersity, while the incidence of posttransplant impaired glucose tolerance (IGT) is unknown. The aim of our study was to prospectively examine the incidence of posttransplant glucose intolerance and to assess potential risk factors. Glucose intolerance was prospectively examined in 173 consecutive kidney transplant recipients by oral glucose tolerance tests (n=167) or the diagnosis of manifest diabetes mellitus (n=6) at 10 weeks after transplant. We found a high incidence of PTDM (18%) and IGT (31%). Univariate analysis revealed that age, family history of diabetes, HLA-B27 phenotype, DR mismatch, rejection, actual prednisolone dose, total methylprednisolone dose, total steroid dose, cytomegalovirus (CMV) infection, and the use of furosemide were associated with PTDM. Age, prednisolone dose, CMV infection, and the use of beta-blockers were associated with IGT. Gender, body mass index, donor source, and cyclosporine level did not influence glucose tolerance. Prednisolone dose, age, family history of diabetes, CMV infection, and HLA-B27 phenotype were independent predictors of PTDM with the use of multiple stepwise logistic regression analysis. Age, prednisolone dose, and the use of a beta-blocker were associated with IGT in the multivariate model. Both univariate and multivariate linear regression analysis revealed a significant relationship between the 2-hr serum glucose and prednisolone dose. The risk of developing PTDM was 5% per 0.01 mg/kg/day of increase in prednisolone dose. Increased prednisolone dose and older age are strongly associated with the development of posttransplant glucose intolerance.

In vivo immunoadsorption of antipig antibodies in baboons using a specific Gal(alpha)1-3Gal column.

The major role of anti-alphaGal antibodies in the hyperacute rejection of pig organs by humans and baboons has been clearly demonstrated. Spacered alpha-galactose disaccharide (Gal(alpha1)-3Gal) hapten was produced by chemical synthesis and covalently attached to a flexible, hydrophilic polymer (PAA), which in turn was covalently coupled to macroporous glass beads, forming an immunoadsorbent that is mechanically and chemically stable and can be sterilized. The extracorporeal immunoadsorption (EIA) of anti-alphaGal antibodies using this column has been investigated in vivo in 3 baboons. In Baboon 1 (which had hyperacutely rejected a pig heart transplant 4 months previously, was not splenectomized, and did not receive any pharmacologic immunosuppression) the levels of anti-alphaGal antibody and antipig IgM and IgG, as well as serum cytotoxicity, fell significantly after each of 3 EIAs but were not eliminated. Serum cytotoxicity, antipig immunoglobulin and anti-alphaGal antibody rose steeply within 24 hr of the final EIA, suggesting that the return of cytotoxicity was associated with anti-alphaGa1 antibody. In Baboons 2 and 3 (which were immunologically naive and splenectomized, and received triple drug immunosuppressive therapy) serum cytotoxicity was totally eliminated and anti-alphaGal antibody and antipig IgM and IgG levels were greatly reduced by courses of EIA. In Baboon 2, cytotoxicity and all antibody levels remained negligible for approximately one week after the final (fourth) daily EIA. In Baboon 3, cytotoxicity and antibody levels were maintained low by intermittent EIA (over a period of 13 days) for almost 3 weeks, although antipig IgM began to rebound 4 days after the final EIA. We conclude that, in an immunosuppressed, splenectomized baboon, repeated EIA using a specific alphaGal disaccharide column will reduce antipig and anti-alphaGal antibody levels and serum cytotoxicity significantly for several days. This reduction in cytotoxicity will almost certainly be sufficient to delay the hyperacute rejection of a transplanted pig organ, but further studies are required to investigate whether it will be sufficient to allow accommodation to develop.

Successful Renal Transplantation in a Patient with Large Granular Lymphocytic Leukemia with Natural Killer Cell Proliferation

A patient with advancing renal failure attributed to focal segmental glomerulosclerosis was found to have marked NK (CD56+) cell expansion and large granular lymphocytic leukemia. Subsequent living-related renal transplantation was accomplished with two early bouts of acute cellular rejection requiring therapy with methylprednisolone and monoclonal antibody OKT3. Chronic triple drug immunosuppressive therapy has substantially reduced the marked NK (CD56+) proliferation. The renal transplantation remains successful after 15 months despite persistent but reduced numbers of circulating NK cells, the potential role of which in the pathogenesis of the underlying nephropathy or the cellular rejection process remains speculative.

Theophylline Modulates Erythrocytosis after Renal Transplantation

Erythrocytosis occurs in 10-15% of renal transplant recipients and there is evidence that the production of erythropoietin is modulated by adenosine. We prospectively evaluated the effects of theophylline, a nonselective adenosine antagonist, in 8 patients with erythrocytosis after renal transplantation. All patients were given triple-drug immunosuppressive therapy with methylprednisolone (8 mg/daily), azathioprine (2 mg/kg b.w. daily) and cyclosporin A (4 mg/kg b.w. daily). After an 8-week course of theophylline treatment (Theodur 300 mg x 2 daily), the mean serum erythropoietin levels were significantly reduced (from 61 mIU/ml before to 16.5 mIU/ml after treatment, p < 0.05). Also the hematocrit was reduced from 0.58 before to 0.50 after treatment (p < 0.05). The previous requirement of monthly phlebotomy was eliminated in all transplant recipients. The above effects were reproducible when the patients were rechallenged with theophylline after a recovery period. It is suggested that theophylline modulates the production of erythropoietin as well as the hematocrit levels in patients with erythrocytosis after renal transplantation and may be useful in the treatment of this condition.

Comparison of the effectiveness of lovastatin therapy for hypercholesterolemia after heart transplantation between patients with and without pretransplant atherosclerotic coronary artery disease

With the aim of assessing the effectiveness and safety of lovastatin in patients with hypercholesterolemia after heart transplantation, as well as the potential differences in the lipid-lowering effect of lovastatin between patients with or without pretransplant coronary artery disease (CAD), we studied 63 heart transplant patients who had serum total cholesterol >250 mg/dl in spite of dietary therapy. Mean age of subjects was 47 ± 2 years. Triple-drug immunosuppressive therapy consisted of cyclosporine, azathioprine, and steroids. Thirty-nine patients (62%) had pretransplant CAD and 24 (38%) did not. Pretreatment serum lipid levels were: total cholesterol, 302 ± 32 mg/dl; low-density lipoprotein (LDL) cholesterol, 201 ± 35 mg/dl; high-density lipoprotein (HDL) cholesterol, 60 ± 19 mg/dl; triglycerides, 205 ± 86 mg/dl; and total/HDL cholesterol ratio, 5.4 ± 1.6. Patients received 10 to 40 mg/day of lovastatin (mean dose 17 ± 6) for 13 ± 4 months. There were no serious adverse events. At 3 months, lovastatin decreased total cholesterol by 15% (p < 0.001), LDL cholesterol by 21% (p < 0.001), triglycerides by 17% (p < 0.05), and total/HDL cholesterol ratio by 17% (p < 0.001), and increased HDL cholesterol by 3% (NS). Although lovastatin was effective in both patients with pretransplant CAD and non-CAD, analysis of its effect in each subgroup (CAD and non-CAD) revealed that its lipid-lowering effect was higher for non-CAD patients (−20% vs −12% for total cholesterol, and −27% vs −17% for LDL cholesterol, both p < 0.01). Thus, lovastatin was useful and safe for the treatment of hypercholesterolemia after heart transplantation, although it was more effective in patients without pretransplant CAD.