|Year : 2019 | Volume
| Issue : 3 | Page : 160-163
Postrenal transplant anemia and pure red cell aplasia
Praveen Kumar Etta
Department of Nephrology and Renal Transplantation, Virinchi Hospitals, Hyderabad, Telangana, India
|Date of Submission||29-Jun-2019|
|Date of Decision||03-Sep-2019|
|Date of Acceptance||03-Sep-2019|
|Date of Web Publication||17-Sep-2019|
Dr. Praveen Kumar Etta
Department of Nephrology and Renal Transplantation, Virinchi Hospitals, Hyderabad, Telangana
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Etta PK. Postrenal transplant anemia and pure red cell aplasia. Indian J Transplant 2019;13:160-3
Posttransplant anemia (PTA) in renal transplant (RT) recipients is the most common blood disorder that contributes to significant morbidity and occasional mortality. In this commentary, we briefly reviewed various causes of PTA and pure red cell aplasia (PRCA), with a special emphasis on erythropoiesis-stimulating agent (ESA)-induced PRCA (ESA-PRCA).
| Epidemiology|| |
Both the World Health Organization and the American Society of Transplantation define anemia as hemoglobin (Hb) <13 g/dl for men and <12 g/dl for women. PRCA is characterized by severe anemia due to bone marrow (BM) failure, described in detail below. The prevalent rates of PTA vary depending upon the definitions used, time since RT, infections, immunosuppressives, and other drugs exposure. While PTA is almost universal within the 1st month of RT, prevalence falls to 30%–40% at the end of 1 year. PTA typically improves within 2–4 months after RT with endogenous erythropoietin (EPO) production from the allograft and recovery from the uremic milieu. Early PTA occurring within first 6 months after RT is usually due to iron deficiency. Late PTA (after 6 months) is usually due to graft dysfunction, drugs, and infections. A recent study of 336 RT recipients (RTRs) analyzed various factors associated with PTA in the 1st year after RT and has found prevalence of 32.7% (moderate–severe anemia of 15.2%) at 12 months; lower kidney function, female gender, transferrin saturation (TSAT) below 10%, and proteinuria were associated with moderate–severe anemia. A recent retrospective cohort study of 266 RTRs noted the prevalence of PTA at 6 months (early PTA) as 51.3% and at 2 years (late PTA) as 36.6%. The most recent, larger study of 1139 RTRs showed 36.2% prevalence of PTA.
| Etiopathogenesis|| |
The pathogenesis of PTA among RTRs is complex and usually multifactorial, including iron and EPO deficiency, graft dysfunction, immunosuppressives, and other medications and an inflammatory state causing EPO resistance. The common causes of PTA are listed in [Table 1].
| Drugs|| |
In general, every drug used after RT except steroids can cause PTA. Although calcineurin inhibitors do not cause BM suppression usually, they can cause thrombotic microangiopathy (TMA). Although very rare, tacrolimus-induced PRCA has been reported. Both the antimetabolites such as azathioprine and mycophenolate mofetil (MMF) antimetabolites can cause BM suppression. Mammalian (mechanistic) target of rapamycin inhibitors (mTORi) can induce BM suppression; less frequently, they can also cause TMA. PTA from mTORi is characterized by microcytosis possibly due to decreased proliferation of erythroid precursors or interference in iron homeostasis. The effect of mTORi on erythropoiesis may be more severe than that observed with MMF. In one study, the prevalence of PTA at 1-year posttransplant was significantly higher with sirolimus than MMF (57 vs. 31%). The combination of sirolimus and MMF may be associated with a much more increased risk of PTA. The lymphocyte-depleting agents, antithymocyte globulin (ATG) and muromonab-CD3 (OKT3), can induce BM suppression. Antimicrobial agents including ganciclovir, valganciclovir, dapsone, and trimethoprim-sulfamethoxazole (TMP-SMX) can also cause BM suppression. In glucose 6-phosphate dehydrogenase deficiency, dapsone and TMP-SMX may provoke hemolytic anemia. There are reports of hemolysis induced by ATG and high-dose intravenous immunoglobulin (IVIG, 2 g/kg). The use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers is also associated with anemia in a dose-dependent fashion and they are useful to treat posttransplant erythrocytosis.
| Infections and Systemic Inflammation|| |
Viruses including parvovirus B19 (PVB19), hepatitis B and C, herpes viruses, cytomegalovirus, Epstein–Barr virus, human immunodeficiency virus, and rarely, BK virus can cause BM suppression. Other indolent infections including bacterial, fungal, viral, tuberculosis, and parasitic causes can lead to anemia of chronic disease secondary to impaired erythropoiesis. PVB19 binds to the blood group P antigen receptor and causes apoptosis of erythrocyte progenitors; the presence of giant proerythroblasts with glassy intranuclear viral inclusions (lantern cells) in the BM is characteristic. Very rarely, it can induce pancytopenia and TMA. Reduction of immunosuppression and IVIG therapy are useful in PVB19 and other infections. Systemic inflammation and infections possibly cause derangements in iron utilization, functional iron deficiency state, and EPO resistance. Interleukin-6 is a major regulator of hepcidin production. Hepcidin levels have been found to be elevated in many RTRs, especially in patients with graft dysfunction leading to poor iron absorption and mobilization for erythropoiesis. The combination of high ferritin and low TSAT usually indicates anemia of chronic disease.
| Passenger Lymphocyte Syndrome|| |
Passenger lymphocyte syndrome (PLS) is a very rare cause of acute-onset hemolytic anemia that usually occurs following solid organ and/or BM transplantation from a donor with O blood group into a recipient with A or B blood group or from an Rh-negative donor into an Rh-positive recipient. Most cases of PLS are due to ABO or Rh mismatch, but antibodies (Abs) against Kidd and Lewis blood group systems have also been reported to cause PLS. Donor B lymphocytes and plasma cells produce Abs against recipient red blood cells (RBCs), leading to hemolysis. This is usually observed within the first few weeks posttransplant. It is usually self-limiting as ABO Abs clear out within a maximum span of 3 months. The diagnosis is made by the direct Coombs test and identifying Abs in serum. The risk and degree of hemolysis is lowest in RT followed by liver and highest in heart-lung transplants. Corticosteroids are often used for treatment. Severe cases may require treatment with plasma exchange (PLEX), IVIG, or rituximab.
| Other Causes|| |
Allograft rejection also correlates with anemia; possible mechanisms include suboptimal graft function with EPO deficiency, more intensified immunosuppression, systemic inflammation, and EPO resistance. Posttransplantation lymphoproliferative disorder (PTLD) may induce immune hemolytic anemia, in addition to BM infiltration.
| Management|| |
RTRs whose Hb levels fail to normalize by 3 months or develop new-onset anemia after improvement in Hb level should undergo a diagnostic evaluation and management, as PTA requiring transfusions is a risk factor for immunological sensitization, which may affect future re-transplantation. Serum ferritin and TSAT are poor markers of iron deficiency in RTRs. Elevated serum ferritin levels may relate to systemic inflammation and functional iron deficiency. The results are conflicting with regard to the prognosis of RTRs with PTA, which may be a marker or risk factor for cardiovascular disease (CVD) and chronic allograft nephropathy. Although most RTRs can be classified as having chronic kidney disease (CKD) by the Kidney Disease: Improving Global Outcomes (KDIGO) definition, it is unclear whether findings in CKD population should be extrapolated to RTRs who may have different mechanisms causing anemia and EPO resistance. Although there is no clear consensus, PTA may be associated with adverse CVD, increased mortality, and graft loss. In a prospective cohort study of 938 RTRs, PTA was associated with an increased risk of mortality and allograft failure. Another prospective study analyzed 825 RTRs over more than 8 years found no relationship of anemia to mortality in multivariate analyses. The Assessment of Lescol in Renal Transplantation study of 2102 RTRs found that PTA was a predictor of graft loss but not cardiovascular events and all-cause mortality. Two recent studies concluded that PTA was significantly associated with mortality, graft dysfunction, and failure.,
In cases of anemia persisting or occurring >3 months posttransplant, ESA may be initiated in patients with renal dysfunction after correcting nutritional deficiencies. ESA use possibly associated with increased risk of recurrent cancer along with hypertension, thrombotic events, and stroke. The risks from ESA therapy are higher in those with CVD, prior thrombotic events, stroke, or cancer. Caution is exerted for oral iron which may bind with immunosuppressant medications, such as MMF. The optimum target Hb level for transplant recipients with stable graft function is not known. Observational studies in RTRs have suggested that mortality may be increased with Hb levels >12.5 g/dL., The correction of anemia and progression of renal insufficiency in transplant patients study, an open-label study, involving 125 RTRs with an estimated glomerular filtration rate <50 mL/min/1.73 m2 randomized patients to receive ESA with a target of 13–15 g/dL (complete correction group) or 10.5–11.5 g/dL (partial correction group). Compared with the partial correction group, the complete correction group had a reduced progression of allograft nephropathy, lower rate of end-stage renal disease, and higher death-censored graft survival. In contrast, majority trials in CKD patients have shown no benefit with higher Hb targets. Correction of Hb and Outcomes in Renal Insufficiency and Trial to Reduce Cardiovascular Events with Aranesp Therapy trials found an increased risk of CVD and no delay in progressive renal failure by targeting normalization of Hb with ESA therapy., The Cardiovascular Reduction Early Anemia Treatment Epoetin beta trial found that randomization to a higher Hb target significantly increased the likelihood of initiating chronic dialysis.
| Acquired Pure Red Cell Aplasia|| |
Acquired PRCA is a rare condition characterized by severe anemia, low reticulocyte count, and virtual absence of erythroid precursors (<5%) in the BM, with all other cell lines remaining unaffected. The common causes of acquired PRCA are listed in [Table 2]; most of them are relevant to transplant setting. Among the identified causes, PRCA is most commonly caused by PVB19 infection among RTRs; other associations identified are thymoma, myelodysplastic syndromes, lymphoma (including PTLD), leukemia, systemic autoimmune disorders, and drugs.
| Erythropoiesis-Stimulating Agent-Induced Pure Red Cell Aplasia|| |
ESA-PRCA results from the induction of neutralizing Abs directed against the EPO (anti-EPO Abs). It was first reported in 1998. Although cases have now been described with all recombinant EPO (rEPO) formulations, the great majority of cases in early 2000s occurred in patients with CKD who received subcutaneous epoetin alfa (Eprex), after a change in the formulation in which human serum albumin was eliminated and replaced by polysorbate-80, and with use of prefilled syringes with uncoated rubber stoppers. The recently published international prospective registry, prospective immunogenicity surveillance registry, demonstrated that PRCA is rare with currently available ESAs.
Anti-EPO Abs cross-react not only with the endogenous EPO but also with all rEPO molecules including darbepoetin alfa (DA) and block the interaction between EPO and its receptor. PRCA generally does not occur, unless the patient has been on EPO for at least 8 weeks, and typically occurs after 6–18 months of exposure. The 2012 KDIGO guidelines suggest to investigate for ESA-PRCA when a patient receiving ESA therapy for more than 8 weeks develops the following three criteria: decline in Hb level of >0.5–1 g/dL/week or transfusion requirement of at least one to two units/week, normal platelet and white blood cell count, and absolute reticulocyte count of <10,000/μL.
Depending on glycosylation and sialic acid content, several forms of rEPO products are available. DA is the second-generation ESA with two extra carbohydrate chains and eight extra sialic acid residues as compared with epoetin alfa; these modifications may make this molecule more resistant to Ab development. Hence, PRCA due to DA is extremely rare and never reported in RTRs. In a case published in this issue, the authors have found ESA-PRCA after treatment with DA in an RTR and anti-EPO was positive by enzyme-linked immunosorbent assay (ELISA).
Although identification of anti-EPO Abs is essential to the diagnosis of ESA-PRCA, not all patients with anti-EPO Abs develop PRCA. Several assays are available to detect anti-EPO Abs. For detection of anti-EPO Abs, first, some form of screening assay, then confirmatory assay, and finally, a bioassay to assess for neutralizing characteristics are used. ELISA is more widely available; it has lower sensitivity and specificity and permits high throughput. It is rapid, relatively easy to use, and relatively inexpensive; thus, it is often used as screening assay for Ab detection. Both false-positive and false-negative results can occur. Radioimmunoprecipitation (RIP) assay appears to be the most accurate test for detecting anti-EPO Abs. However, it is not standardized, may not detect low-affinity Abs, requires radiolabeled antigen, and is time consuming and difficult to automate. Surface plasmon resonance (Biacore) analysis enables the detection of rapidly dissociating, low-affinity Abs that are not detected by ELISA and RIP assays; however, it requires expensive, dedicated equipment. Bioassays are functional assays, help in assessing the neutralizing capability of the anti-EPO Abs, in which patient serum or immunoglobulin inhibits RBC precursor growth in BM or cell line cultures.
In addition to discontinuing all forms of rEPO including DA, immunosuppressive therapy is required to eradicate Abs. Corticosteroids, cyclophosphamide, and cyclosporine have been tried; refractory cases may need therapy with IVIG, PLEX, and rituximab. In the case published in this issue, the patient was treated with increased doses of corticosteroids and IVIG with complete recovery. Rechallenge with EPO is considered in special circumstances if anti-EPO Ab levels are very low, administering EPO intravenously, and closely monitoring the absolute reticulocyte count, anti-EPO Ab levels, and systemic reactions. KDIGO recommends treatment with peginesatide in patients with ESA-PRCA. Peginesatide is a synthetic, peptide-based pegylated ESA that acts by stimulating the EPO receptor, but it had been withdrawn later from the market due to unexplained serious adverse drug reactions.
| Conclusions|| |
In conclusion, PTA is highly prevalent and has multifactorial etiology including graft dysfunction, iron and EPO deficiency, EPO resistance, infections, immunosuppressive, and other drugs. Accurate diagnosis and identification of underlying causes are crucial for its management. PRCA is most commonly caused by viral infections among RTRs, and ESA-PRCA can result due to immunological reaction against ESA.
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[Table 1], [Table 2]