Primary Immunosuppressive Therapy Research Articles

An investigation of the primary immunosuppressive therapy's influence on kidney transplant survival at one month after transplantation

Immunosuppressive therapy is complex and challenging to do correctly due to on-target and off-target side effects. However, it is vital to successful allotransplantation. In this article, we analyzed the critical classes of immunosuppressants used in renal transplantation, highlighting the mechanisms of action and typical clinical applications used to develop predictive models for the diagnosis of various diseases, including the prediction of survival after kidney transplantation. In patients, the authors used a dataset with two immunosuppressants (tacrolimus and cyclosporin). The primary task was investigating critical risk factors associated with early transplant rejection. For this, the censored Kaplan-Meier survival estimation method was used. Our study shows a pairwise correlation between taking and not using a particular immunosuppressant. Therefore, the correct choice of immunosuppressive drugs is necessary to improve the prognosis of transplant survival.

MO957: Breakthrough Infections Following Mrna Sars-Cov-2 Vaccination in Kidney Transplant Recipients

Abstract BACKGROUND AND AIMS The clinical effectiveness of COVID-19 vaccination in kidney transplant (KT) recipients is lower than in the general population. However, the evidence reported is limited so far. Our purpose is to analyze the characteristics and outcomes of a large series of KT with COVID-19 breakthrough infection and compare them with unvaccinated patients. As a secondary objective, we analyzed the evolution according to the type of mRNA vaccine administered. METHOD From April to October 2021, KT recipients with COVID-19, included in the Spanish Society of Nephrology COVID-19 Registry, were analyzed. Data regarding vaccination status and type of vaccine were collected and outcomes of unvaccinated patients were compared with fully vaccinated patients. Univariable and multivariable Cox proportional hazard regression analyses were assessed for independent risk factors of COVID-19-related death. To avoid bias as much as possible, a sensitivity analysis was done exclusively in hospitalized patients. RESULTS During the period of the study, 481 KT recipients with COVID-19 were included in the registry: 351 fully vaccinated and 130 unvaccinated. Age, gender, KT vintage, diabetes as primary kidney disease, induction and maintenance immunosuppression and anti-COVID therapy were similar between both groups. Clinical picture was similar between fully vaccinated and unvaccinated patients: 10% versus 15.4% remained asymptomatic (P = 0.100), 56.7% versus 58.5% developed pneumonia (P = 0.720) and 66.1% versus 63.8% were hospitalized (P = 0.640), respectively. Survival analysis showed no differences between groups: 21.7% of fully vaccinated patients and 20.8% of unvaccinated died (P = 0.776). In multivariable analysis, age (HR: 1.05, CI 95% 1.03–1.08, P < 0.001) and pneumonia (HR: 14.16, CI: 95% 5.02–39.88, P < 0.001) were independent risk factors for death, while vaccination status was not related to mortality. These results remained similar when we analyzed exclusively hospitalized patients (death rate in fully vaccinated patients 31.9% versus 31.3% in unvaccinated patients, P = 0.840). Regarding the type of mRNA vaccine, 213 patients were vaccinated with the mRNA-1273 vaccine (Moderna) and 161 with the BNT162b2 (Pfizer-BioNTech), showing no differences in any of baseline and treatment-related variables analyzed. Patients vaccinated with the mRNA-1273 vaccine showed a significantly lower mortality than those who received BNT162b2 (16.4% versus 28.8%, P = 0.002), maintaining this difference in the multivariable analysis (reference mRNA-1273 vaccine: HR: 0.52, CI: 95% 0.31–0.85, P = 0.010). CONCLUSION COVID-19 severity in KT patients has remained high and has not improved despite receiving two doses of an mRNA vaccine. The mRNA-1273 vaccine has shown higher clinical effectiveness than BNT162b2 in KT recipients with breakthrough infection, so it could be considered as the first option in these patients.

Steven-Johnson Syndrome associated with anti-tuberculosis drugs: a case reports

Introduction: Steven-Johnson syndrome (SJS) is an acute reaction to the skin and mucous membranes that is characterised by damage and flaking of the skin, accompanied by pain and can cause death. Treatment with anti-TB drugs sometimes results in side effects including SJS  as one of the skin rash reaction and liver dysfunction. Steven-Johnson syndrome incidence and mortality due to anti-TB is quite rate and here we present a case with SJS and some other drugs side effect symptoms who passed away on the ninth day of treatment. Case description: A 53-year-old woman admitted to our emergency department with dyspnea, fatigue, erosion on oral mucosa, and erythema appears in the whole body accompanied by itch since two weeks ago, she also has yellowish sclera. She is in ongoing therapy of anti-tuberculosis drugs. History of hepatitis B, on admission there was marked elevation of leukocyte and liver function test (AST and ALT). Systemic corticosteroid was given as characterised therapy with topical steroid and antibiotics regimen for maculopapular rash.Conclusion: SJS is an emergency requiring high attention and intensive care evaluation with administration of intravenous systemic steroids as primary immunosuppressive therapy.

Maintenance Immunosuppression in Solid Organ Transplantation: Integrating Novel Pharmacodynamic Biomarkers to Inform Calcineurin Inhibitor Dose Selection.

Calcineurin inhibitors, the primary immunosuppressive therapy used to preventalloreactivity of transplanted organs, have a narrow therapeutic index. Currently, treatment is individualized based on clinical assessment of the risk of rejection or toxicity guided by trough concentration monitoring. Advances in immune monitoring have identified potential markers that may have value in understanding calcineurin inhibitor pharmacodynamics. Integration of these markers has the potential to complement therapeutic drug monitoring. Existing pharmacokinetic-pharmacodynamic (PK-PD) data is largely limited to correlation between the biomarker and trough concentrations at single time points. Immune related gene expression currently has the most evidence supporting PK-PD integration. Novel biomarker-based approaches to pharmacodynamic monitoring including development of enhanced PK-PD models are proposed to realize the full clinical benefit.

Prevalence and risk factors of post-kidney transplant hyperparathyroidism: a single-center study

Objective:to assess the prevalence of hyperparathyroidism (HPT) and the factors affecting its development in kidney transplant recipients.Materials and methods. The single-center observational cohort study included 97 kidney transplant recipients – 40 men, 57 women, age 50 ± 9 years. Inclusion criteria: more than 12 months of post-transplant period, 3 months of stable renal transplant function. Non-inclusion criterion: therapy with vitamin D, with its alternatives or with cinacalcet. Dialysis ranged from 0 to 132 months (median 18); 46% of patients had pre-operative secondary HPT. A comprehensive laboratory study included evaluation of serum concentrations of parathyroid hormone (PTH), 25-OH vitamin D, calcium, phosphorus, magnesium, total alkaline phosphatase (ALP) activity, albumin, creatinine and daily proteinuria. At the dialysis stage, the target PTH range of 130–585 pg/ ml was used, in the post-transplant period – ≤130 pg/ml. Glomerular filtration rate (eGFR) was calculated using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) formula.Results.Patients were divided into two groups based on PTH threshold level (130 pg/ml): the first with HPT (PTH >130 pg/ml, median 203), the second without HPT (PTH ≤130 pg/ml, median 101). Both groups were comparable in terms of gender, age, primary renal disease, dialysis modality, post-transplant follow-up, and immunosuppressive therapy regimen. In group 1 and group 2 recipients, dialysis therapy, pre-transplant median PTH level, incidence of reoperation and incidence of immediate renal graft function were 30 (14; 50) and 14 (6; 28) months (p = 0.004), 681 (538; 858) and 310 (182; 556) pg/ml (p < 0.001), 17% and 2% (p = 0.028), 51% and 80% (p = 0.005), respectively. At the time of the study, 72% of group 1 recipients had eGFR <60 ml/min, versus 36% of group 2 (p >< 0.001). Among HPT biochemical parameters, there were differences for ionized serum calcium (1.32 ± 0.07 versus 1.29 ± 0.04 mmol/l, p = 0.017) and ALP activity (113 ± 61 versus 75 ± 19 u/l, p = 0.021). Serum vitamin D in both groups reduced in equal measures – 14 ± 4 and 15 ± 6 ng/ml.Conclusion.Persistent HPT in the long-term post-transplant period reaches 48.5%. Risk factors for its development included dialysis for more than 18 months, pre-operative secondary HPT, repeated kidney transplantation, delayed graft function, and eGFR <60 ml/min.

THE IMPACT OF SIROLIMUS-RELATED PROTEINURIA ON PROGRESSION OF CARDIAC ALLOGRAFT VASCULOPATHY AND OUTCOMES AMONG HEART TRANSPLANT RECIPIENTS

We have previously described the use of sirolimus (SRL) as primary immunosuppression therapy following heart transplantation (HT). The advantages of this approach include attenuation of cardiac allograft vasculopathy (CAV), improvement in glomerular filtration rate (GFR) and a decrease in rates of

Incidence and Outcome in Aplastic Anemia Diagnosed 2000-2011 - a Nationwide Swedish Registry Study

Introduction: Aplastic anemia (AA) is a rare life-threatening disease but since the introduction of immunosuppressive therapy (IST) and allogeneic stem cell transplantation (alloHCT), the outcome in selected patient cohorts has improved considerably with a 5-year overall survival of 70-80 %. However, there is a lack of contemporary population-based data on the incidence and survival of AA.Aims: To determine incidence, treatment and survival in AA patients (pts) diagnosed in Sweden during 2000-2011.Patients and Methods: In a retrospective study, the Swedish National Patient Registry was utilized to identify pts diagnosed with AA. After careful revision of each patient's chart, 257 cases proved to fulfill the diagnostic Camitta criteria. Incidence and confidence intervals were calculated according to Rothmann, rates and proportions with Pearson's chi-square test, survival statistics using the Kaplan-Meier and log-rank method and the relative survival analysis used the Ederer II method.Results: The overall incidence of AA was 2.35 (95% CI 2.06-2.64) cases per million inhabitants per year. A biphasic age distribution was seen; one peak in pts aged 15-20 (CI 2.87; 1.72-4.03), and one in pts >60 years (4.36; CI 3.55-5.18). Median age at diagnosis was 60 (2-92) years (yrs), and median follow-up 76 (range 0-193) months. The disease severity grades were non-severe AA 38%, severe AA 38%, and very severe AA 24%, with no age-related differences. The primary treatment was IST (63%), alloHCT (10%), or palliation (27%). Distribution of initial treatment in different age groups are given in Table 1.Five-year survival of AA patients was 61%, and median survival 150 months. The 5-year survival, irrespective of treatment modality, varied in different age groups and was significantly lower in pts aged 40-59 and >60 yrs compared to young pts (p<0.05 and p<0.001, respectively); 91% in pts aged 0-18, 91% 19-39, 71% 40-59 and 38% > 60 yrs. The age-related survival difference was visible early after diagnosis: pts >60 yrs had a 3-month survival of 84% compared to 98% for pts 0-18, 98% 19-39 and 93% for 40-59 yrs (p=0.021, 0.023 and 0.151, respectively). For all pts, type of primary treatment was significantly associated with survival; alloHCT pts had a 5-year survival rate of 96%, the IST group 69%, and palliative pts 30% (p=0.009 and p<0.0001). For patients 0-39 yrs, there was no statistical difference in survival comparing primary treatment modalities (IST or alloHCT); 0-18 yrs 86% vs 100% (p=0.158), and 19-39 yrs 90% vs 100% (p=0.395); also when grouping these pts together (88 % vs 100 %, p=0.103).In patients treated with primary IST (n=161) there was no difference in 5-year survival between the age groups 0-18, 19-39 and 40-59 yrs, whereas patients above 60 yrs did significantly worse than all other age groups; 86%, 90%, 70% and 52%, respectively (p<0.005). Forty-three (27%) pts in the entire IST group were allografted after not responding to/relapsing after 1 or 2 cycles of IST, where only 2 pts (3%) >60 yrs underwent HCT compared to 14 pts (48%), 17 pts (57%) and 10 pts (30%) in the other age groups.The relative 5-year survival (i.e. the excess mortality) for all patients was 66% (95% CI 59-72). When dividing patients by the median age at diagnosis, relative 5-year survival was 85% (CI 77-90) in patients <60 yrs, while pts >60 did significantly worse, 47.0% (CI 37-57). When splitting pts into two time-periods (2000-2005 or 2006-2011), we found no difference in 5-year survival, neither for all patients nor for the different age groups.Conclusions: Younger AA patients, regardless of initial therapy, experience a very good long-term survival. Also middle-aged patients do reasonably well but for patients above the median age at diagnosis (>60 yrs), the excess mortality is still substantial. Apparently, the challenge today is how to improve the management of elderly AA patients and prospective studies to address this medical need are warranted. [Display omitted] DisclosuresBrune:Meda Pharma: Consultancy.

The occurrence of antibodies against Legionella pneumophila in patients with autoimmune rheumatic diseases.

Patients with autoimmune rheumatic diseases are more susceptible to infection, owing to the underlying disease itself or to its treatment. Most commonly, infections affect the respiratory and urinary tracts. One of the etiological factors of infections in these patients is the bacteria of the genus Legionella. The aim of the study was to assess the prevalence of anti-Legionella pneumophila (L. pneumophila) antibodies in patients with autoimmune rheumatic diseases and to analyze individual and environmental risk factors for the development of Legionella infection in patients with positive antibody results. The study group consisted of 165 patients with autoimmune rheumatic diseases and 100 healthy subjects. Serum samples were tested for the presence of specific antibodies in the immunoglobulin (Ig) M and IgG classes against L. pneumophila serogroups 1 to 7 (SG 1-7) and the IgG class for serogroup 1 (SG 1). Antibodies against L. pneumophila were found in 7 patients (4%): 5 cases with antibody positivity only in the IgG class and 2 cases with antibody positivity in both classes. In patients with positive IgG antibodies for SG 1-7, specific antibodies for L. pneumophila SG 1 were not detected. In the control group, positive results were obtained in 9 cases (9%): IgM positivity in 6 (6%) and IgG positivity in 3 (3%). The frequency of antibodies to L. pneumophila in our patients is comparable to that in healthy individuals. L. pneumophila should be recognized as a potential pathogen in patients with autoimmune rheumatic diseases. Primary disease condition, immunosuppressive therapy, and other risk factors should not be ignored in these patients.

Superior rejection profile during the first 24 months after heart transplantation under tacrolimus as baseline immunosuppressive regimen.

BackgroundThe use of tacrolimus (TAC) in patients after heart transplantation (HTX) has increased over the last few years.AimIn this retrospective study, we evaluated the effects of a TAC (conventional and extended-release TAC)-based immunosuppressive therapy regarding rejection profile in comparison to a cyclosporine A (CSA)-based regimen in patients after HTX.MethodsThe data of 233 patients who underwent HTX at the Heidelberg Heart Transplantation Center from May 1998 until November 2010 were retrospectively analyzed. Primary immunosuppressive therapy was changed from a CSA (n=114) to a TAC (n=119)-based regimen in February 2006 according to center routine. Follow-up period was 2 years post-HTX. Primary endpoint was time to first biopsy-proven rejection requiring therapy. In all patients, routine follow-up at the Heidelberg Heart Transplantation Center was mandatory.ResultsMultivariate risk factor analysis regarding time to first rejection episode showed no statistically significant differences regarding recipient age, donor age, recipient sex, donor sex, sex mismatch, ischemic time, and diagnosis leading to HTX between the two groups (all P= not statistically significant). Time to first biopsy-proven rejection was significantly longer in the TAC group (intention-to-treat analysis, n=233, log-rank test P<0.0001; per-protocol analysis, n=150, log-rank test P=0.0003). In patients who underwent a change of primary immunosuppression (n=49), a significantly longer time to first biopsy-proven rejection was also found in the primary TAC subgroup (log-rank test P=0.0297). Further subgroup analysis in the TAC subgroups showed no statistically significant differences in time to biopsy-proven rejection under extended-release TAC compared to conventional TAC (intention-to-treat analysis, log-rank test P=0.1736).ConclusionOur study demonstrated that a TAC-based primary immunosuppressive therapy is superior to a CSA-based immunosuppressive regimen in patients after HTX regarding time to first biopsy-proven rejection.

Clinical study of application of sirolimus with dose-reduced or discontinued cyclosporine A for prevention of acute rejection after kidney transplantation

To study the clinical efficacy, safety and feasibility of sirolimus (SRL) for preventing acute rejection of kidney transplantation. Thirty patients with end-stage kidney dysfunction received kidney transplants from June 2004 to December 2004. There were 21 male and 9 female aged from 22 to 67 years old, with a mean of (46.3 +/- 10.0) years old. SRL was used in primary immunosuppression therapy to prevent acute rejection after surgery, and all of them were treated in combination with dose-reduced cyclosporine A (CsA) and steroid. CsA reduction began 3 months after the surgery, the weekly dose of CsA about 10 to 25 percent reduction until completely discontinued. During a 4-year follow-up period, the adverse events, acute rejection and infection were observed and recorded in detail. The graft function and other laboratory indicators were checked and analyzed. Of the 30 patients, 4 recipients died, patients survival rate was 86.7%. In other 26 cases, 25 recipients had good graft function, the average blood creatinine was (103.8 +/- 4.6) micromol/L at the end of 4(th) year and the incidence of acute rejection was 6.7% (2/30). The side effects included hyperlipidemia, proteinuria, delayed healing incision, lactate dehydrogenase increased and joint pain. The combination of sirolimus with dose-reduced CsA till completely discontinued and steroid to prevent acute rejection of kidney transplantation is safe and efficient.

Isolated sphenoid mucormycosis presenting as visual impairment: changing trends?

Mucormycosis of the paranasal sinuses represents an important cause of morbidity and mortality in patients whose host defenses have been altered by primary disease or immunosuppressive therapy. The pattern of involvement by this fungus is changing with reports of mucormycosis occurring also in immunocompetent host. The involvement of isolated sphenoid sinus is rare. In the present case, the only presenting symptom was visual impairment. These changing trends in presentation, the extent, and the area of involvement are challenging for the otorhinolaryngologist, ophthalmologist, and neurosurgeon. High index of suspicion, prompt intervention, and aggressive therapy are required to reduce the morbidity and mortality associated with this disease.

Switch of immunosuppression from cyclosporine A to everolimus: impact on pulse wave velocity in stable de-novo renal allograft recipients

Cardiovascular mortality is extraordinarily high in renal allograft recipients and accounts for almost half of all allograft losses. Whereas the immunosuppression with calcineurin inhibitors is associated with an increased cardiovascular risk, beneficial effects of mammalian target of rapamycin inhibitors on the vascular system are suspected. In a randomized clinical trial, we evaluated the impact on pulse wave velocity (PWV) of a switch from cyclosporine A (CsA) to everolimus (EVR), 6 months after transplantation, in 27 stable de-novo renal allograft recipients. PWV was assessed before and after randomization to the different immunosuppressive protocols at 6 and 15 months post-transplantation, respectively. Seventeen out of 27 patients included in the analysis were switched to EVR; 10 out of 27 were kept on CsA. The switch of immunosuppressive therapy from CsA to EVR resulted in stable PWV (9.50+/-1.92 vs. 9.13+/-1.62 m/s, DeltaPWV= -0.37+/-1.14 m/s, P=0.16), whereas a significant increase of PWV (9.93+/-1.94 vs. 10.8+/-2.24 m/s, DeltaPWV=0.89+/-1.47 m/s, P=0.03) was observed in patients on continued CsA therapy. In renal allograft recipients, the prolonged treatment with CsA was associated with a significant increase of PWV whereas no further deterioration of large vessel compliance was observed in patients that were switched to EVR 6 months post transplantation. The cardiovascular risk profile in stable de-novo renal allograft recipients might therefore be positively impacted by an early switch of the primary immunosuppressive therapy from CsA to EVR.

Sirolimus-Based Immunosuppressive Therapy in Liver Transplant Recipient With Tacrolimus-Related Chronic Renal Insufficiency

Background While providing potent immunosuppression for liver transplant recipients, calcineurin inhibitors (CNI) exhibit nephrotoxicity as a major side effect. The purpose of this study was to evaluate the safety and efficacy of conversion from CNI to sirolimus (SRL) among liver transplant recipients with CNI-induced chronic nephrotoxicity. Methods Between January 2004 and June 2005, we performed conversion in 16 recipients after a median period of 8.5 months after liver transplantation. The indication for conversion was CNI-related nephrotoxicity with a serum creatinine (sCr) value >132.6 umol/L. Renal function was measured before and after conversion to SRL. Clinical and laboratory data related to the clinical course of the patients were recorded to investigate the safety and efficacy of conversion. Results Sixteen patients were converted to SRL after developing nephrotoxicity. Their renal function improved gradually after conversion. The levels of sCr decreased significantly within the first 30 days (164.1 ± 12.48 μmol/L to 130.1 ± 5.573 μmol/L), and over the next 60 days after conversion (97.86 ± 11.69 μmol/L to 90.7 ± 8.95 μmol/L) ( P < .01). Similarly, the mean glomerular filtration rate (GFR) increased significantly during the same period. Four recipients experienced hypercholesterolemia, 1 with ankle edema, and 1 with acute rejection. The median follow-up was 2.4 years. No patient discontinued SRL due to side effects. No patient needed dialysis or kidney transplantation during the study period. Conclusions SRL is a safe, effective replacement agent as primary immunosuppressive therapy following withdrawal of CNIs in liver transplant recipients with CNI-induced chronic nephrotoxicity.

Sirolimus en trasplante de órgano sólido pediátrico: Experiencia en 5 casos

Sirolimus (SRL) is an immunosuppressive drug increasingly used in children undergoing solid organ transplantation. SRL does not cause glucose intolerance, hypertension, nephrotoxicity or neurotoxicity offering significant potential advantages over calceneurin inhibitors (CM).To report five children treated with SRL.A retrospective review of four children undergoing orthotopic liver transplantation (OLT) and one undergoing renal transplantation with recurrent acute rejection (RAR), chronic rejection (CR) or toxicity due to CM, treated with SRL between June 2001 and November 2006.As primary immunosuppressive therapy, all patients received 3 drugs: CM (Tacrolimus (FK) or Cyclosporine), mycophenolate mofetil and steroids. Mean age at treatment with SRL was 98 months. Children undergoing OLT had a late introduction of SRL (mean time after OLT: 37 months), and mean follow-up was 24 months. In this group rescue indications of SRL were RAR in one, CR in one, thrombotic thrombocytopenic purpura (TTP) in one, food allergy in one and other CM toxicity in three. Only one did not experience adverse events due to SRL, but no one required discontinuation of SRL. There were remissions of RAR, CR, TTP and food allergy. The patient with RT was switched from FK to SRL at day 18th after RT, but he had severe neutropenia that led to discontinuation of SRL.SRL may be useful in pediatric solid organ transplant recipients suffering from RAR, CR, TTP, food allergy and CM toxicity. Careful attention should be directed to detect side effects and avoid severe complications.

Recurrence of Nephrotic Proteinuria in Children With Focal Segmental Glomerulosclerosis After Renal Transplantation Treated With Plasmapheresis and Immunoadsorption: Case Reports

Idiopathic focal segmental glomerulosclerosis (FSGS) is believed to be caused by a circulating permeability factor. FSGS recurrence is common after transplantation. The treatment is still a matter of debate; plasmapheresis (PE) and immunoadsorption (IA) are often used. We report on PE and IA in the treatment of two children with recurrent nephrotic proteinuria. Patient 1 was a 16-year-old girl who had recurrence of nephrotic proteinuria on the first day after transplantation (proteinuria-19 g/d). Primary immunosuppressive therapy was changed to high-dose cyclosporine and cyclophosphamide; plasmapheresis was started on day 4. Altogether we performed 53 PE and 38 IA procedures. During the first month, PE procedures were performed with no more than a 2-day interval between sessions, and the girl achieved partial remission (proteinuria 3 g/d). PE was then stopped. After 2 months, a relapse of heavy proteinuria occurred. This relapse was successfully treated again with intensified PE treatment. After achieving remission, a chronic PE regimen was started (PE once a week), similar to the previous series. The child remained in partial remission. Seven months after renal transplantation, she was switched from PE to IA, because of severe hypoproteinemia. Graft biopsy performed at 4 months showed effacement of the foot processes. At the present time she has a good graft function and 3 g/d proteinuria. Patient 2 was a 13-year-old girl with FSGS since 9 years. On the second day after renal transplantation she developed nephrotic proteinuria (proteinuria-14 g/d), which was treated with 39 PE and 16 IA treatments. She went into complete remission on the intensified PE regimen, had one relapse, and was switched to chronic IA. Graft biopsy performed at 2 weeks after transplantation showed effacement of the foot processes. At the present time she has good graft function and low proteinuria (0.3 g/d). In conclusion, intensified PE or IA treatments induced remission of recurrent nephrotic range proteinuria. Chronic PE or IA can maintain patients with frequent relapses in long-term remission.

Long-Term Relapse-Free Survival and Overall Survival of Patients with Acquired Primary Idiopathic Pure Red Cell Aplasia Receiving Cyclosporine: A Nationwide Cohort Study in Japan for the PRCA Collaborative Study Group.

Background: The efficacy of corticosteroids (CS), cyclophosphamide (CY) and cyclosporine (CsA) for the patients with primary or secondary pure red cell aplasia (PRCA) is between 30–56%, 7–20% and 75–87%, respectively. Although it is evident that the efficacy of CsA is the highest amongst these three drugs, CsA has remained second to third-line therapy largely because the long-term relapse-free survival (RFS) and overall survival (OS) after CsA therapy are unknown.Objectives: We conducted a nationwide survey of immunosuppressive therapy for PRCA in Japan to elucidate the long-term RFS and OS of CsA therapy for acquired primary idiopathic (API-) PRCA.Methods: Questionnaires were sent to 109 medical centers. From 1990 through 2006, we identified 174 adult patients with acquired PRCA. The underlying diseases could affect RFS and OS of immunosuppressive therapy. We, therefore, selected 64 patients (38%, median age, 56 years; range, 18 to 89 years) with API-PRCA according to the classification proposed by Dessypris and Lipton. Complete remission (CR), partial remission (PR) and no response (NR) was defined as the achievement of normal hemoglobin levels, the presence of anemia but with transfusion independence, and the continued presence of transfusion dependence, respectively. RFS was estimated as transfusion free survival without the dose escalation more than 50% of maintenance-dose. Survival was estimated by the Kaplan-Meier method and statistical difference was calculated by the generalized Wilcoxon test and qui square test.Results: The efficacy (CR+PR) of primary treatment was seen in 24 of 32 patients treated with CsA (75%), 16 of 26 patients with PSL (62%), 0 of 3 patients with CY (0%), 0 of 1 patient with anabolic steroid and was undetermined in 2 patients because of short observation periods (<1 week). Overall, 60 of 64 API-PRCA patients (94%) responded to primary or subsequent immunosuppressive therapy, and 41 and 15 patients were maintained CsA±CS (CsA-responders) or CS alone (CS-responders), respectively. The median RFS in CsA-responders was 52 months and longer than that seen in CS-responders (16 months) (p<0.01), in the median follow-up period of 36 and 8 months, respectively. In CsA-responders, three patients died due to renal failure, liver failure associated with hepatitis C infection and infection after transformation to aplastic anemia. However, overall survival was not significantly different between the two groups (p=0.104). In CsA-responders, the cease of maintenance therapy was strongly correlated with relapse (p<0.001). Eleven of 14 patients relapsed with a median interval of 10 months after discontinuing CsA (range 1.5 to 40 months), whereas only 4 of 27 patients relapsed during maintenance therapy.Conclusions: We, for the first time, demonstrated that CsA ensures prolonged PFS than CS in API-PRCA. However, most patients are still receiving CsA for maintenance therapy. Therefore, other therapeutic modalities may be required to cure API-PRCA.

A comparative randomised study of valacyclovir vs. oral ganciclovir for cytomegalovirus prophylaxis in renal transplant recipients

An open, prospective, randomised study was conducted to compare the safety and efficacy of valacyclovir vs. oral ganciclovir for cytomegalovirus (CMV) prophylaxis in renal transplant recipients. Eighty-three renal transplant recipients were assigned randomly to receive valacyclovir (n=43) or oral ganciclovir (n=40) for the first 3 months after transplantation. Both groups were similar in terms of demographics, primary renal disease, graft source, HLA matching, immunosuppressive therapy and donor-recipient CMV antibody status. CMV infection was diagnosed by detection of virus DNA in plasma with the Amplicor CMV Test. CMV disease was observed in only one patient belonging to the ganciclovir group, who developed enterocolitis 6 months post-transplantation. No difference was observed between the two treatment groups with respect to detection of CMV DNA, virus infections other than CMV, acute rejection episodes, and serum creatinine levels at 3 and 6 months following transplantation. An increased number of bacterial infections was noted in the ganciclovir group (p 0.003). No adverse reactions with either treatment were reported. The estimated cost of valacyclovir treatment was 20% higher than that of ganciclovir treatment. Overall, both valacyclovir and oral ganciclovir were found to be effective and safe for CMV prophylaxis in renal transplant recipients. Decisions regarding prophylactic regimens should include additional criteria, such as cost or possible development of resistance.

Use of Mycophenolate Mofetil in Liver Transplantation: A Literature Review

Mycophenolate mofetil (MMF) is an immunosuppressive drug, exhibiting its effect through inhibition of proliferation of T and B lymphocytes. Standard primary immunosuppressive therapy after orthotopic liver transplantation (OLT) is based on a calcineurin-inhibitor (CNI): cyclosporine or tacrolimus. Renal failure with arterial hypertension, due to CNI side-effects, is a major cause of morbidity and mortality after OLT. Several studies have shown the efficacy of MMF to improve CNI-induced nephrotoxicity, blood pressure, and uric acid concentration in liver transplant patients with concomitant reduction or withdrawal of CNI. Predose plasma mycophenolic acid concentrations (MPA) are related to adverse events, drug dose, and clinical status. Blood level values outside the suggested MPA therapeutic range are associated with acute rejection episodes and side effects, which have been described in about half of the patients treated with MMF. Most authors have described gastrointestinal and hematological side-effects, whereas these appear usually dose related, responding quickly to reduction. MMF is potent and safe immunosuppressive agent, and replacement of CNI by MMF in liver transplant patients with renal dysfunction may improve not only kidney function but also other CNI-associated side-effects, such as hypertension and hyperuricemia, with a low risk of rejection.

Hypercholesterolemia is common after pediatric heart transplantation: initial experience with pravastatin

Background Coronary allograft vasculopathy (CAV) is a progressive complication after cardiac transplantation and limits survival. Hyperlipidemia is a known risk factor for CAV, and pravastatin is effective in decreasing cholesterol levels in adults after transplantation. However, few data exist regarding lipid profiles and statin use after pediatric heart transplantation. We evaluated the prevalence of hyperlipidemia in pediatric heart transplant recipients and assessed the efficacy and safety of pravastatin therapy. Methods We performed a retrospective chart review of lipid profiles ≥1 year after surgery in 50 pediatric cardiac transplant recipients to assess the incidence of hyperlipidemia. Twenty of these patients received pravastatin for hypercholesterolemia. Their primary immunosuppression therapy was cyclosporine/prednisone plus either azathioprine or mycophenolate mofetil. We reviewed serial lipid profiles, creatinine phosphokinase, and liver enzymes. Results Overall, 36% of the patients ( n = 50) had total cholesterol (TC) concentrations > 200 mg/dl and 52% had low-density lipoprotein (LDL) >110 mg/dL beyond 1 year after transplantation. Of the 20 treated with pravastatin, TC (236 ± 51 vs 174 ± 33 mg/dl) and LDL levels (151 ± 32 vs 99 ± 21 mg/dl) decreased significantly with therapy (p < .0001). We found no symptoms; however, 1 patient had increased creatinine phosphokinase. Liver enzyme concentrations remained normal in all. Conclusions Hypercholesterolemia is prevalent in pediatric cardiac transplant recipients. Pravastatin therapy is effective in decreasing TC and LDL levels, seems to be safe, and is tolerated well. Further studies are necessary to determine whether pravastatin treatment is beneficial in decreasing CAV.

The value of tuberculin skin testing in haemodialysis patients.

Chronic haemodialysis patients are at increased risk for developing tuberculosis (TB). Appropriate screening methods to detect latent Mycobacterium tuberculosis infection are required. The aim of this prospective multi-centre study was to evaluate the tuberculin skin test (TST) as a screening method for detection of M.tuberculosis infection in haemodialysis patients. A total of 224 patients in two haemodialysis centres were prospectively tested, using 2 units of tuberculin PPD RT23. Up to three booster injections were given with a 7 day interval to patients not responding to the previous test. The results were compared with clinical and radiological data. The cumulative prevalence of a positive TST was 14.7% for the first test, 27.8% for the second test and 32.6% for the fourth test. There was no influence of age, gender, haemodialysis centre, dialysis efficiency, nutritional state, levels of zinc, vitamin D therapy, primary renal disease, (previous or active) immunosuppressive therapy or response to hepatitis B vaccination. There was a significant, but weak, correlation between TST positivity and a history of positive TST or TB. Chest radiography and positive TST were not correlated, yet a positive chest X-ray increased the detection of patients with latent M.tuberculosis infection up to 47.8%. In haemodialysis patients, a positive response of >30% to repeated TST was obtained. Two consecutive TSTs were sufficient to recruit most of the booster reactions. Since only a weak correlation was found with anamnestic data, regular TST evaluation in combination with a chest X-ray, is a useful tool to detect infection with M.tuberculosis in haemodialysis patients.