Study of Anemia After Late Introduction of Everolimus in the Immunosuppressive Treatment of Renal Transplant Patients

doi:10.1016/j.transproceed.2007.06.032

Transplantation Proceedings

Volume 39, Issue 7, September 2007, Pages 2242-2244

https://doi.org/10.1016/j.transproceed.2007.06.032 Get rights and content

Abstract

Introduction

mTOR inhibitors (imTOR) are immunosuppressive drugs that have a concentration-related effects on hematopoiesis, potentially resulting in anemia. The reason is uncertain, but a pathogenic link between sirolimus-induced anemia and the appearance of an inflammatory state was recently suggested. Because inflammation-related anemia is characterized by a functional iron deficiency, we studied whether everolimus influenced iron homeostasis.

Methods

We studied iron homeostasis in 43 patients after late introduction of everolimus into the immunosuppressive treatment. Thirty-seven patients (86%) were receiving mycophenolate. Hemoglobin concentration, red blood cell count, mean corpuscular volume, serum iron, ferritin, C-reactive protein levels, and transferrin saturation were evaluated 3 months before and 1, 3, and 6 months after the switch.

Results

The percentage of anemic patients preconversion was 18.6% and it was 34.9% at 3 months and 18.6% at 6 months. We did not observe a significant reduction in hemoglobin, but there was increased red blood cell count after everolimus introduction, with a significant reduction in mean corpuscular volume. Serum iron and transferrin saturation levels were also markedly reduced after the switch, while ferritin serum concentrations remained stable. An improvement in renal function was observed.

Conclusions

The anemia caused by everolimus—microcytosis, low serum iron, despite high ferritinemia, and elevated C-reactive protein levels—was consistent with the anemia of a chronic inflammatory state. This alteration occurred within the first months postconversion and disappeared at 6 months. The combination of mycophenolate and everolimus seemed to be useful without significant secondary effects.

Section snippets

Materials and Methods

We studied iron homeostasis in 43 patients after late introduction of everolimus in the immunosuppressive treatment. Hemoglobin concentration, red blood cell count, mean corpuscular volume, serum iron, and ferritin levels as well as transferrin saturation were evaluated 3 months before as well as 1, 3, and 6 months after the switch. Anemia was defined as an hemoglobin level < 12 g/dL in men and <11.5 g/dL in women.

The changes in variables with time (pre- and posttreatment) were estimated by

Results

The causes for everolimus switching were cardiovascular disease (n = 16), tumors (n = 11), chronic allograft nephropathy (n = 8), calcineurin inhibitor toxicity (n = 4), and others (n = 4). The median time from transplant was 82 months (range 6 to 160). Forty patients (93%) were previously treated with calcineurin inhibitors (50% cyclosporine and 50% tacrolimus). These drugs were discontinued in all patients after the introduction everolimus [median time for the calcineurin inhibitor

Discussion

With regard to immunosuppression and its potential role in posttransplant anemia, the use of mycophenolate mofetil (MMF), sirolimus, or a combination of MMF and calcineurin inhibitor therapy seemed to be associated with a relatively high prevalence of anemia with a significant difference in hemoglobin values between patients being treated with these agents and those not on treatment. The TRESAM survey² showed that therapy with MMF or azathioprine was associated with a greater likelihood of

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Cited by (26)

Anemia and Immunosuppressive Regimen in Renal Transplanted Patients: Single-Center Retrospective Study
2016, Transplantation Proceedings
Citation Excerpt :
Other data arise from smaller studies whose aim was to evaluate PTA. The rate of PTA was similar in liver transplanted patients treated with Rad or Cya [12], whereas in a late conversion study [13], the switch from Cya to Rad caused an increase in the percentage of patients affected by PTA from 18% to 34% that returned to 18% 6 months after the conversion. Our study has several limitations, being a retrospective, observational, small monocentric study.
We compared retrospectively the level of hemoglobin and the percentage of patients with anemia among 59 kidney transplant recipients receiving everolimus, cyclosporine, and corticosteroids and 128 treated with cyclosporine, mycophenolic acid, and corticosteroids. We also compared age at the time of transplantation, sex and ferritine, serum creatinine, creatinine clearance, folic acid, cyanocobalamine levels, use od recombinant erythropoietin, mean corpuscolar volume at the last ambulatory control. Statistical analysis included Student t test, χ² test, and logistic regression. The analysis was performed using SPSS software. We observed no difference in terms of hemoglobin levels in patients treated with everolimus (12.9 ± 1.6 vs 12.7 ± 1.5 g/dL). Anemia (defined as hemoglobin <13 g/dL in men and <12 g/dL in women, or need to use erythropoietin) was found in 49% and 45% of patients in the 2 groups respectively (P = .6). The other parameters evaluated were similar except for the mean corpuscular volume, which was significantly lower in the everolimus group. In the multivariate analysis only serum creatinine and estimated glomerular filtration rate influenced the level of hemoglobin. We observed no differences in terms of development of anemia in renal transplanted patients treated with everolimus-based regimen.
Everolimus-induced hematologic changes in patients with metastatic breast cancer
2015, Clinical Breast Cancer
Everolimus, which inhibits the mammalian target of rapamycin (mTOR), is increasingly used in breast cancer and familiarity with its full range of toxicity is critical for practicing oncologists.
We studied hematologic changes in 31 patients with metastatic breast cancer treated in a phase II clinical trial using everolimus. Complete blood counts were collected at baseline, 2 weeks, 4 weeks, every 4 weeks during treatment, and 1 month after discontinuation. Adverse events were defined using Common Toxicity Criteria version 3. Linear mixed models with fixed effects of time and random intercepts and slopes were used to study trends and comparisons were conducted using paired t tests.
Anemia was reported in 22 patients (71%), thrombocytopenia in 17 (55%), and leukopenia in 14 (45%). These were predominantly grade 1 or 2 and did not require dose modification. Red blood cell mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) both decreased significantly over time (P < .0001) starting at 2 weeks with no significant change in mean corpuscular hemoglobin concentration (MCHC) (P = .104). Both MCV and MCH increased 1 month after treatment discontinuation (P values < .0001 and .0003, respectively) indicating reversibility of this effect. Although total leukocyte counts remained largely stable, lymphocyte percentage progressively decreased over time with a trend for increased neutrophils.
In addition to anemia, leukopenia, and thrombocytopenia, everolimus consistently induces red cell microcytosis and reduced hemoglobin content. Lymphopenia may contribute to immune suppression and increased risk of infection. Familiarity with these hematologic changes is prudent as more patients are treated with this class of drugs.
Strategies for the management of adverse events associated with mTOR inhibitors
2014, Transplantation Reviews
Citation Excerpt :
Immunosuppression with mTOR inhibitors can promote anemia and delay improvement in hemoglobin levels after surgery [94]. Anemia associated with mTOR inhibitors is characterized by microcytosis (ie, marked decline in mean corpuscular volume of red blood cells [RBCs]) and low serum iron levels [10,95,96]. It is generally mild, dose-dependent, and reversible upon discontinuation of treatment [10].
Mammalian target of rapamycin (mTOR) inhibitors are used as potent immunosuppressive agents in solid-organ transplant recipients (everolimus and sirolimus) and as antineoplastic therapies for various cancers (eg, advanced renal cell carcinoma; everolimus, temsirolimus, ridaforolimus). Relevant literature, obtained from specific PubMed searches, was reviewed to evaluate the incidence and mechanistic features of specific adverse events (AEs) associated with mTOR inhibitor treatment, and to present strategies to effectively manage these events. The AEs examined in this review include stomatitis and other cutaneous AEs, wound-healing complications (eg, lymphocele, incisional hernia), diabetes/hyperglycemia, dyslipidemia, proteinuria, nephrotoxicity, delayed graft function, pneumonitis, anemia, hypertension, gonadal dysfunction, and ovarian toxicity. Strategies for selecting appropriate patients for mTOR inhibitor therapy and minimizing the risks of AEs are discussed, along with best practices for identifying and managing side effects. mTOR inhibitors are promising therapeutic options in immunosuppression and oncology; most AEs can be effectively detected and managed or reversed with careful monitoring and appropriate interventions.
Blood disorders after kidney transplantation
2014, Transplantation Reviews
Post transplant anemia (PTA) is a common issue in kidney transplant recipients. Most importantly it is associated with an impaired allograft function. Other important factors associated with PTA are immunosuppressive drugs (MPA, AZA and SRL), iron deficiency, infections (Parvo B19), older donor age, rejection episodes, an increased inflammatory state, and erythropoietin hyporesponsiveness. As there are no adequately powered RCTs in the kidney transplant population on anemia treatment with ESA, we have to rely on what we know from the large RCTs in the CKD population. The recently published KDIGO guidelines do not recommend treatment with ESA if Hb is > 10 g/dl. Repletion of iron stores is emphasized. Post transplant leukopenia (PTL) and thrombocytopenia (PTT) are frequent complications especially in the first six months after kidney transplantation. Myelosuppression caused by immunosuppressive agents (MPA, AZA, SRL, rATG), antimicrobial drugs (VGCV), and CMV infection is the predominant cause. There are no widely accepted guidelines on treatment strategies, but most often dose reduction or discontinuation of causative medication is done. Most clinicians tend to decrease MPA dose, but this is eventually associated with an increase in acute rejection episodes. VGCV dose reduction (preemptive treatment instead of CMV prophylaxis) may be a successful strategy. In severe cases G-CSF treatment is an important management option and seems to be safe.
Anemia in kidney transplants without erythropoietic agents: Levels of erythropoietin and iron parameters
2012, Transplantation Proceedings
To study the association between hemoglobin, endogenous erythropoietin (EPO) levels and ferric parameters in kidney recipients not treated with EPO-stimulating agents.
Transverse study of 219 kidney transplant outpatients. The median time after transplantation was 54 months (P_25–75, 23–107). We assessed blood counts, ferric parameters, EPO levels, renal function (MDRD-4), and adjuvant treatment. We performed a linear regression analysis to predict hemoglobin.
Median EPO values were 14.05 mUI/mL (P_25–75 = 10.2–19.7). Applying the formulas described by Beguin, kidney transplant recipients showed a low observed/expected ratio of erythropoietin and of transferrin. Considering anemia to be an hemoglobin of < 12 g/dL in women and < 13 g/dL in men, 24.2% of subjects were anemic (n = 53), including 2.3% with hemoglobin < 11 g/dL. Anemic patients displayed worse renal function (49.2 ± 18.5 versus 55.46 ± 16.58 mL/min/1.73 m² in nonanemic; P = .021). There were no differences in C-reactive protein. The patients receiving a combination of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB) showed the highest prevalence of anemia compared with other groups (42.9%, P = .027). EPO levels were significantly lower among patients treated with these drugs (P = .041), without differences in transferrin and ferritin. The percentage of anemic patients treated with mammalian target of rapamycin inhibitors (mTORi) was 31% versus 22.2% among those not receiving these immunosuppressants (P = .23). Although there were no differences in hemoglobin levels, patients treated with mTORi, showed higher EPO levels (P = .005) and lower mean corpuscular volume (P < .001). Regarding the etiology of chronic kidney disease, less frequently anemic patients were those with polycystic kidney disease (8.6% versus 26.7% in the rest, P = .021). The formula obtained by multiple linear regression to calculate hemoglobin was: hemoglobin = 11829–0909 * log (EPG level) − 0455 (if female) + 0.010 * 0.013 * transferrin + 0.013 * creatinine clearance (r = .424, P < .001).
Treatment with ACEI and/or ARBs seemed to produce a defect in the synthesis of EPO, while those treated with mTORi, a hyporesponsive state.
Everolimus and enteric-coated mycophenolate sodium Ab initio after liver transplantation: Midterm results
2012, Transplantation Proceedings
Citation Excerpt :
These results suggested that EVR and EC-MPS ab initio may be used to prevent renal dysfunction especially among patients who showed renal impairment before surgery. As reported by Masetti23 and Sanchez Fructuoso,24 hematologic side effects of the antimetabolite in association of PSI were rare. In our cohort only one patient who developed leukopenia after 9 months completely recovered after EC-MPS withdrawal, suggesting the hematotoxicity was rare and easily managed.
Everolimus (EVR) use in liver transplantation (OLT) has been prescribed with calcineurin inhibitors (CNIs), steroids, and monoclonal antibodies. The aim of our study was to evaluate the safety, feasibility, and impact on renal function of EVR ab initio, in combination with enteric-coated mycophenolate sodium (EC-MPS) without the use of induction treatment, steroids, or CNIs.
We retrospective analyzed nine consecutive patients who underwent OLT at our institution. The initial dose of EVR (1.5 mg/d) was adjusted to achieve trough levels of 8 to 12 ng/mL. EC-MPS introduced at 1080 mg/d was maintained at the same dose over time.
At a mean follow-up of 21.48 (standard deviation [SD] 1.4) months from OLT, 7/9 recipients were alive with stable graft function. The 2-year patient and graft survivals were 77%. One recipient died due to cerebral hemorrhage and one, lung failure. No clinical evidence of an acute rejection episode was observed. Mean estimated glomerular filtration rate value, according to the Modification of Diet in Renal Disease formula increased from 59.5 (SD 9.89) mL/min/1.73 m² at OLT to 100.2 (SD 47.5) mL/min/1.73 m² (P = .03) after 12 months and 98.71 (SD 33.74) mL/min/1.73 m² (P = .03) after 24 months' follow-up.
A double immunosuppression therapy with EVR and EC-MPS ab initio seemed to be efficacions and safe, representing a valid alternative to CNIs to prevent renal failure after OLT.

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ImmunosuppressionComplication: Metabolic disorderStudy of Anemia After Late Introduction of Everolimus in the Immunosuppressive Treatment of Renal Transplant Patients

Abstract

Introduction

Methods

Results

Conclusions

Section snippets

Materials and Methods

Results

Discussion

Am J Transplant

Blood

J Heart Lung Transplant

Pharmacoepidemiology of anemia in kidney transplant recipients

J Am Soc Nephrol

Sirolimus in association with mycophenolate mofetil induction for the prevention of acute graft rejection in renal allograft recipients

Transplantation

Immunosuppression
Complication: Metabolic disorder
Study of Anemia After Late Introduction of Everolimus in the Immunosuppressive Treatment of Renal Transplant Patients