Blood disorders after kidney transplantation.

Transplantation Reviews xxx (2013) xxx–xxx

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Transplantation Reviews journal homepage: www.elsevier.com/locate/trre

Blood disorders after kidney transplantation Roman Reindl-Schwaighofer a, Rainer Oberbauer a, b,⁎ a b

Department of Nephrology, KH Elisabethinen, Linz, Austria Department of Nephrology, Medical University of Vienna, Vienna, Austria

a b s t r a c t 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 N 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. © 2013 Elsevier Inc. All rights reserved.

1. Introduction Kidney transplantation is by far the best treatment option for patients with end stage renal disease. It enhances quality of life as well as survival, but restoration of normal GFR can usually not be accomplished and adverse effects of the indispensable immunosuppressive regimen such as bone marrow and blood disorders have to be addressed. Peripheral blood cytopenias either in isolation (anemia, leukopenia and thrombocytopenia) or involving all three cell lines (pancytopenia) are common findings, but less frequently more specific hematological disorders including the passenger lymphocyte syndrome (PLS), post transplant erythrocytosis (PTE), thrombotic microangiopathy (TMA), post transplant lymphoproliferative disorder (PTLD), and the hemophagocytic syndrome (HPS) have been described. Recently published reviews focused on post transplant anemia (PTA) prevalent in the kidney transplant population [1–3]. Hematologists naturally have emphasized the interference with the hematopoietic system including more specific hematological disorders [4,5]. In this review we will focus on the challenges in

⁎ Corresponding author. Department of Internal Medicine 3, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria. Tel.: +43 1 40400 4390; fax: +43 1 40400 4392. E-mail address: [email protected] (R. Oberbauer).

daily clinical routine and summarize current knowledge on treatment strategies. 2. Post transplant anemia (PTA) In addition to the factors associated with anemia in native chronic kidney disease (CKD) such as iron and nutrient deficiency, recurrent infections, chronic inflammation, and certain medications including angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB), anemia in renal allograft recipients is driven by additional factors. Specifically the mandatory immunosuppressive medication, antimicrobial drugs, recurring episodes of acute or chronic rejections, and an altered inflammatory state caused by the presence of alloantigen account for the observed high prevalence of PTA. Especially in the light of safety concerns associated with boostering hemoglobin values above 12.5 g/dl by the use of erythropoietin stimulating agents (ESA), treatment strategies in PTA have to be discussed (Fig. 1) [6]. 2.1. Epidemiology Anemia is an important issue after kidney transplantation and more focus has been put on this prevalent condition in recent years. The stated prevalence estimates may vary considerably between various reports depending on the laboratory parameters included (hematocrit vs. hemoglobin levels) and the definition of anemia itself.

0955-470X/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.trre.2013.10.001

Please cite this article as: Reindl-Schwaighofer R, Oberbauer R, Blood disorders after kidney transplantation, Transplant Rev (2013), http:// dx.doi.org/10.1016/j.trre.2013.10.001

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R. Reindl-Schwaighofer, R. Oberbauer / Transplantation Reviews xxx (2013) xxx–xxx

Fig. 1. Survival analysis of transplant recipients who did and did not use ESA: adjusted mortality hazard ratio for hemoglobin level (reference level 12.5 g/dl). Reprint from Heinze et al., BMJ 2009 [6].

The two largest cohort analysis (cross-sectional) on the prevalence of PTA in European kidney transplant recipients by Vanrenterghem et al. in 2003 and Molnar et al. in 2011 showed a prevalence of PTA of 39% and 42%, respectively [7,8]. Severe anemia (defined as Hb b 11 g/dl in men and b10 g/dl in women) was reported in 9% and 14% of patients, respectively. The latter identifies patients that ought to be treated according to current guidelines. Reported prevalence rates of recent studies on PTA are summarized in Table 1. Anemia after kidney transplantation shows a biphasic pattern with an initially high incidence of anemia early after transplantation. With improving renal function and consecutive reduction of immunosuppression the hemoglobin levels normally rise steadily within the first months and can achieve normal-range values within the first year. Consecutively, with progressive allograft dysfunction over time, anemia becomes again more prevalent. In a recently published study by Jones et al. prevalence of anemia decreased within the first year after transplantation from 89% at one month to 49% after the first year and remained stable with 44% after the second year [9]. Mix et al. reported a subsequent increase of prevalence from 21% at one year to 36% at 4 years [10]. 2.2. Risk factors associated with PTA At the time of transplantation virtually all patients are anemic secondary to reduced endogenous erythropoietin synthesis and iron deficiency in patients with advanced kidney disease. Furthermore recent guidelines recommend an even more restrictive use of erythropoietin stimulating agents (ESA) in patients on maintenance hemodialysis and suggest that ESA therapy should be used to avoid having the Hb concentration fall below 9 g/dl by starting ESA therapy at Hb values between 9 and 10 g/dl [11]. In the early postoperative period anemia is further aggravated by surgical blood losses, frequent blood sampling and a delayed graft function with initially deferred restoration of endogenous erythropoietin levels, and a high erythro-

poietin resistance caused by the persisting uremic state [12,13]. Blood losses by frequent blood draws may cumulate to approximately 500 ml in a three months period [14,15]. Iron stores may be rapidly depleted following initial enhanced erythropoiesis with rising erythropoietin levels. Additionally ESA and iron supplementation are often discontinued at the time of transplantation [15]. Aggressive hydration in the early post operative period causing anemia by dilution, side effects of the immunosuppressive drugs, and concurrent infections further cause a reduction of Hb-values. Poesen et al. showed, that in the early post operative period almost 30% of patients had an Hb b 8 g/dl or required transfusion [14]. In patients with a well functioning allograft, anemia usually resolves within the first few months after transplantation with normalization of erythropoietin levels [10,16]. Anemia late after transplantation is predominantly caused by a decline in renal allograft function [17]. Among patients with serum creatinine levels above 2 mg/dl anemia was reported in up to 60% [18]. Chadban et al. compared the prevalence of anemia in kidney transplant recipients to the prevalence of anemia in a cohort of GFR matched Australian adults [19]. Transplant status had the strongest association with anemia and the observed incidence of anemia in transplant patients was almost 10-fold higher than in the GFRmatched general population. Several trials reported an association of donor age above 60 years with PTA (Table 2). This is normally attributed to the decreased rate of erythropoietin production in older organs [7,20,21]. Interestingly, the type of donor (living versus deceased) seems to have no effect on hemoglobin levels after transplantation [10,22]. Other factors that remained independently associated with anemia in multivariate analysis in observational studies include acute rejection episodes, recent infections, hypoalbuminemia, CRP elevation, metabolic acidosis, and African American race [7,23]. Iron deficiency is a common finding in transplant recipients and iron status may sometimes not be appropriately evaluated even in cases of severe anemia (only 36% of patients with Hct b30% in a study by Mix et al.) [8,10,24]. Lorenz et al. reported a prevalence of iron deficiency of 20% at a mean time of five years after transplantation (defined as a percentage of hypochromic red blood cells ≥ 2.5%) [25]. Evaluation of transferrin saturation and ferritin were poor markers to detect iron deficiency as ferritin levels may be elevated independently of iron stores in an inflammatory state or in case of iron overload, whereas the proportion of hypochromic red blood cells (≥2.5%) proved a statistically significant correlation with the risk for anemia. Others reported similar and even higher rates of iron deficiency (up to 44% in the early post operative period) using ferritin and transferrin saturation as biomarkers [15,17]. Even in the long term follow up of kidney transplant recipients with normal Hb levels iron deficiency has been reported in up to 62% of patients [26]. 2.3. Infections associated with PTA All kinds of infections may cause or aggravate anemia in the post transplant setting (anemia of chronic disease) including tuberculosis and other bacterial infections in the immunocompromised host. Especially viral infections that may directly interfere with myelopoiesis play an important role including cytomegalovirus (CMV), Epstein-Barr virus (EBV), varicella zoster virus (VZV), human herpes virus-6 (HHV-6), human herpes virus-8 (HHV-8), and BK virus. Parvovirus B19 (PV B19) directly interferes with erythropoiesis. Infection is associated with the clinical picture of anemia with reticulocytopenia and erythroid maturation arrest at pro-normoblast stage in immunocompromised patients. Diagnosis is based on ELISA for anti-PV B-19 specific antibodies or a PCR assay for PV-B19 DNA, but immunocompromised hosts may not be able to mount a sufficient antibody response [27]. In a bone marrow aspirate pathognomonic findings of viral infection such as giant pro-erythroblasts with



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Table 1 Prevalence of PTA and associated risk factors. Author et al. year

Number of patients

Time of Hb assessment after Tx

Prevalence of anemia

Anemia definition

Patient characteristics associated with anemia (in multivariate analysis)

Therapy

Additional information

WHO severe Hb b11 g/dl

percentage of hypochromic red blood cells (HRBC) ≥2.5%, AZA, older age; female sex eGFR, lower serum CO2 (metabolic acidosis)

ESA in 7%, Iron in 6% of all patients

iron deficiency in 20.1% (defined as HRBC ≥2.5%)

Severe anemia

Lorenz 2002 [25]

438

4.9a (95% CI 4.5–5.2)

40%

Yorgin 2002 [167]

128

@ 1a:

12%

Vanrenterghem 2003 [7]

4,263

@ 5a: 6 mo to 5a

26% 39%

9%

WHO severe b11 g/dl in males, b10 g/dl in female

Mix 2003 [10]

240

@ TX:

76%

48%

Hct b36%

21% 36% 41%

7% 20% 6%

Severe Hct b30%

192

@ 1a: @ 4a: @ 6 mo:

@ 1a:

45%

5% 7%

b11 g/dl in female Severe b10 g/dl WHO severe b11 g/dl in males, b10 g/dl in female b12 g/dl in male

Shibagaki 2004 [24]

Molnar 2005 [168]

959

60 mo ± 46 mo

34%

Fernandez Fresnedo 2005 [169]

397

@1 mo

48%

Shah 2006 [37]

1,511

@ 6 mo: @ 1a: 8.5a ± 7a

30% 16% 46%

Imoagene-Oyedeji 2006 [20]

6

@ 1 mo

16%

Hct b33%

b12 g/dl in males

ESA 7% of anemic patients, iron in 58% of anemic patients

Donor age N60, acute rejection episodes, other than first transplant, ACEi/ARB, MPA; AZA, recent infection; Female gender

ESA in 18% of severely anemic patients

ESA in 25% and iron in 36% of patients with Hct b33%

Hct b33%: only 26% had iron studies

eGFR, female gender, African American race

ESA in 3% of all patients, oral iron supplementation in 8% of all patients

Iron status only assessed in 43% of anemic patients

eGFR, serum albumin, CRP

ESA in 30% of severely anemic patients

Iron deficiency in 11%, only 4% received iron substitution

eGFR, MPA,

b11 g/dl in female 3%

72%

WHO severe b10 g/dl b12 g/dl

Age, female gender, eGFR, serum ferritin, ACEi Anemia @ 3 mo, donor age and creatinine @ 3 mo were predictive for anemia @ 12 mo

@ 3 mo @ 12 mo 7.6a (0.25a–33a)

40% 20% 31%

b12.5 g/dl in male

eGFR, transplant status

Comparing transplant recipients to GFR matched general population

eGFR, low serum albumin, higher CRP

Anemia was associated with mortality; HR: 1.69 (95% CI: 1.12–2.56)

Chadban 2007 [19]

851

Molnar 2007 [23]

938

55 mo

33%

b12 g/dl in female WHO

Kamar 2008 [21]

339

1a

32%

WHO

Chhabra 2008 [66]

1,023

After 3 mo

13%

b11 g/dl

Molnar 2011 [8]

5,834

b6 mo–N5a

42%

Jones 2012 [9]

530

@ 1 mo:

89

@ 1a: @ 2a:

50 44

14%

PTA @12 mo is associated with increased risk for death

Donor's age, serum creatinine

WHO severe b11 g/dl in males, b10 g/dl in female

eGFR, serum ferritin, female gender

WHO

eGFR; gender, serum bicarbonate, ACEi, African American race

prominent intranuclear inclusions and cytoplasmic vacuolations and the absence of intermediate and late-stage normoblasts may be detected [28,29]. Respiratory transmission is the most common way of infection in the community and primary infection mostly occurs during childhood. More than 70 percent of adults have measurable B19-specific IgG antibodies [30]. Kidney transplant recipients may further acquire symptomatic PV B-19 infection through the transplanted graft, or by reactivation of an endogenous latent or persistent infection following immunosuppression [31]. PV-B19 DNA is frequently found in the tissues of healthy individuals with circulating

ESA treatment in 10% of all patients

ESA used in 28% of severely anemic patients; ESA use increased with CKD stage ESA in 31%–51% of patients with severe anemia; iron in 10% of patients in the early postoperative period

PTA was associated with graft and patient survival Iron status was available for 57% of patients: 47% showed ferritin levels b100 ng/ml Anemia was significantly associated with death

anti-B19 antibodies suggesting an incomplete viral eradication following primary infection. A recently published restrospective study on the prevalence of PV-B19 infection in anemic transplant recipients was able to show a statistically significant correlation between active PV-B19 infection and anemia [32]. Transplant recipients and other immunocompromised hosts may not be able to mount a neutralizing antibody response to clear viremia and persistent viral infection may result in the chronic suppression of erythropoiesis with the development of chronic anemia. The median time to onset of anemia after transplantation is seven weeks [27]. As


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Table 2 Association of PTA with outcome (graft and patient survival). Author et al. year

Number of patients

Follow up (average)

Association with outcome in multivariate analysis patient survival

Graft survival

Winkelmayer 2006 [22]

825

8a

No association of anemia with decreased patient survival

Anemia vs normal HR 1.327 95% CI 1.02–1.59

Imoagene-Oyedeji 2006 [20]

626

5a

Molnar 2007 [23]

938

4a

Chhabra 2008 [66]

1,023

4a

Moore 2008 [70]

3,859

4a

Hb b versus N 12 g/dl HR: 3.0 95% CI: 1.3–6.7 Anemia vs normal HR: 1.69; 95% CI: 1.115–2.560 Hb b11 vs 11 g/dl HR 3.18; 95% CI 1.74–5.82 No association of anemia with decreased patient survival

Vanreterghen 2008 [68]

1,160

8a

Heinze 2009 [6]

1,794

6a

Kolonko 2009 [65]

385

5a

Jones 2012 [9]

530

3a

there is no specific antiviral drug available, treatment strategies include a reduction of immunosuppression, infusion of intravenous immunoglobulins (IVIG) and erythropoietin substitution. No RCTs exist on the efficacy of IVIG for the treatment of chronic PV B-19 infection, but case reports and small case series showed that treatment with IVIG may significantly reduce viral load in immunocompromised hosts including patients with HIV and hematological disorders, or patients following solid organ transplantation [33]. IVIG contain high titers of neutralizing anti-parvovirus IgG [34]. There is no consensus on the dose of IVIG administration, but 0.4-0.5 g/kg for 5 (to 10) consecutive days resulting in a cumulative dose of about 2-4 g/ kg seems to be a reasonable dose [27,33,35,36]. Although clinical improvement with reticulocytosis, increased hemoglobin levels, and a decline in serum viral DNA is observed in most cases, complete eradication of viremia may not occur. Thus relapses are frequently observed and reported in up to 28% of transplant patients [27], but may be successfully treated with another course if IVIG. 2.4. Drugs associated with PTA Drugs interfering with myeloproliferation are an important cause of PTA in the late post transplant period. Antiproliferative agents such as azathioprine (AZA) and mycophenolic acid (MPA) have a direct antiproliferative effect on bone marrow and are a common cause of PTA [7,20,37,38]. Both, MPA and AZA, interfere with nucleic acid synthesis in hematopoietic cells inducing pancytopenia [39]. MPA inhibits the enzyme inosine monophosphate dehydrogenase, the rate-limiting enzyme for the de novo purine synthesis during

Hct 50% vs. 38% HR 1.75 95% CI 1.03–2.46 Hb 11 vs. 12.5 g/dl ESA treated HR 4.7 95% CI 2.1–10.5 Not ESA treated HR 2.5 95% CI 1.5–4.0 Hb 14 vs. 12.5 g/dl ESA treated HR 2.8 95% CI 1.0–7.9 Not ESA treated HR 0.7 95% CI 0.4–1.5 No association of anemia with decreased patient survival Hb b9 g/dl vs normal HR 3.8 95% CI 1.5–15.4

Anemia vs normal HR: 2.46 95% CI: 1.485–4.090 Hb b11 vs 11 g/dl HR 2.67; 95% CI 1.85–3.85 1 g/dl rise in Hb lowers risk for graft loss HR: 0.91 95% CI: 0.89–0,93

Anemia versus normal HR: 4.11 95% CI 2.02–8.37 Hb b9 g/dl vs normal HR 5.25 95% CI 1.7–16.7

lymphocyte proliferation and the pharmacologic effect is relatively selective to proliferating lymphocytes, but still, cytopenia is a frequently observed complication. AZA is associated with macrocytic anemia and can cause megaloblastic changes in the bone marrow [40]. Measurements of MPA exposure (through levels, area under the curve) showed conflicting data and did not result in an improvement of treatment strategies so far [41]. It has been suggested that genetic polymorphisms play a role in MPA-related hematologic toxicity [42]. Patients on sirolimus (SRL)-based immunosuppressive regimens show even higher prevalence rates of anemia (up to 57% in one study) [43–45]. A meta-analysis of mTOR inhibitors (mTORi) showed a dose dependent increase in the risk for anemia when compared to immunosuppressive regimens based on calcineurin inhibitors (CNI) [46]. Additionally SRL is associated with microcytosis even in cases without anemia [47]. Besides an antiproliferative effect other possible pathophysiological mechanisms of SRL-induced anemia and microcytosis have been suggested. These include an increase in erythropoietin resistance, a chronic inflammatory state caused by Il-10 dependent inflammatory autoregulation, and a functional iron deficiency or iron absorption defect that is mediated by an interference of SRL with hepcidin [48–50]. Microcytosis correlates with SRL levels and shows a complete reversibility after SRL discontinuation. Similar effects with late introduction of everolimus have also been reported in a small study suggesting a class effect of mTORi [51]. Calcineurin inhibitors (CNI) do not directly cause anemia, although one study suggests an association with the use of tacrolimus [38]. In



addition CNI are associated with thrombotic microangiopathy in the post transplant period [52]. Mono- or polyclonal antibodies such as OKT3 and rabbit anti thymocyte globulin (rATG) can have toxic effects on the bone marrow and decrease Hb concentration [38]. Treatment with alemtuzumab based maintenance therapy was associated with a high incidence of severe acquired red cell aplasia and autoimmune hemolytic anemia [53]. Non-depleting introduction therapy (e.g. basiliximab) led to a lower incidence of anemia compared to rATG induction [54]. Belatacept has so far not been associated with an increased rate of anemia [55]. Other substances that are associated with anemia after kidney transplantation include ACEis and ARBs, as well as antibacterial drugs such as dapsone and trimethoprim that interfere with glucose-6phosphate dehydrogenase and folic acid homeostasis [56,57]. 2.5. PTA and outcome The leading cause of death in the kidney transplant population is cardiovascular disease. Anemia is an independent predictor of left ventricular hypertrophy and congestive heart failure in transplant patients and both end points are independent risk factors for cardiovascular mortality [58–61]. Furthermore, early PTA is associated with post-transplant cardiovascular risk in diabetic patients [62]. An association of lower hemoglobin levels and mortality has been reported in patients with chronic kidney disease and in patients on dialysis, but in the context of PTA conflicting results have been published [63,64]. An increase in overall mortality and graft loss has been described in some studies, but PTA had no effect on graft loss and patient survival in others [6,9,20–23,65–71]. A recent meta-analysis by Kamar et al. showed that the association between PTA and death of a patient with a functioning graft varies with PTA definition and adjustment for confounding factors, but in all sub-meta-analyses PTA was significantly associated with death-censored graft loss [72]. In a recent study in 530 renal transplant patients Jones et al. examined the impact of anemia as a time varying variable on graft survival as well as patient survival. Severe anemia (defined as an Hb in men b9 g/dl and an Hb in women b8 g/dl) was independently associated with graft failure (HR: 5.3,95% CI 1.7–16.7) and the grade of anemia remained a significant predictor for death (increasing from moderate to severe anemia, HR of 2.2 to 4.8, respectively) and remained statistically significant after multivariate analysis [9]. Besides the association with cardiovascular disease, anemia may also contribute to a more rapid decline in allograft function. Initial studies in patients with native CKD suggested that treatment of anemia may be associated with a slower decline of renal function, but this has not been confirmed in recent large randomized trials [73–75]. As an underlying pathophysiological mechanism the so called cardiorenal anemia syndrome has been proposed linking anemia with heart failure and chronic kidney disease [76]. The three conditions are thought to form a vicious circle in which each condition may cause or be caused by another. Anemia can worsen congestive heart failure (CHF) and may reduce GFR, whereas CHF causes a decline in renal function (reduced renal perfusion or increased renal venous pressure) and promote anemia. An impaired renal function finally results in anemia (renal anemia) and can further worsen CHF (e.g. by volume overload). It remains a matter of dispute whether anemia is a risk factor itself (and therefore a treatment target to improve outcome) or merely reflects a comorbid and complex condition resulting in adverse outcomes. 2.6. Treatment of PTA Treatment of PTA is quite variable across different centers as there are no widely accepted guidelines for the treatment of PTA [8]. In the

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TRESAM study only 18% of patients with severe anemia were treated with ESA [7]. More recently, Molnar et al. showed equally low rates of ESA treatment [8]. The reason for this observation is not completely understood. Conflicting data on association of PTA with patient and graft outcome may have influenced more restrictive treatment strategies. More recently a low rate of ESA treatment may be due to emerging safety concerns regarding the use of ESA. Iron: Evaluation of iron status and repletion of iron stores are a cornerstone of anemia treatment in CKD and have to be emphasized in PTA as well [11]. A recent trial found no difference in the effect of oral and intravenous iron substitution with regard to restoration of hemoglobin levels [77]. As stated before, in the context of SRL-induced PTA, intravenous iron may prove more efficient. ESA: In the last few years large randomized controlled trials in the setting of advanced chronic kidney disease have been published (TREAT, CHOIR, CREATE) and an increase in mortality and cardiovascular as well as cerebrovascular events in patients with higher hemoglobin target levels has been observed [73–75]. In patients on dialysis a similar association with an increase in adverse outcomes has already been described in the late 1980s in the “normal hematocrit study” [78]. The pathophysiological mechanisms that account for this increase in cardiovascular events are not fully understood. A plausible explanation is the depletion of iron stores with stimulated erythropoiesis that consecutively leads to a relative thrombocytosis, which predisposes patients to thromboembolic events [79]. Besides, targeting Hb levels of N13 g/dl in the CKD population did not show to slow the decline of GFR. These results led to the adaption of current treatment guidelines on anemia. According to the most recent KDIGO guidelines published in 2012 the initiation of ESA in CKD patients is now not recommended if Hb is N 10 g/dl. The ERBP (European Renal Best Practice) position endorsed by the ERA-EDTA (European Renal Association – European Dialysis and Transplant Association) however represents a more liberal approach suggesting that the Hb should not fall below 10 g/dl [11,80]. ESA treatment may be started at a higher threshold in patients with symptomatic ischemic heart disease or young patients with a low risk profile to improve quality of life. A large cohort analysis by Regidor et al. in dialysis patients treated with ESA showed that Hb levels between 12 and 13 g/dl were associated with the lowest mortality [81]. In kidney transplant recipients receiving ESA a similar U-shaped association between anemia and outcome has been reported in a cohort study based on data recorded in the Austrian Dialysis and Transplant Registry (OEDTR) [6]. A secondary analysis of the TREAT study [75] showed that a poor initial response to ESA increased the risk for cardiovascular and allcause mortality in CKD patients [82] and resulted in higher doses of ESA needed to achieve treatment targets. In a post hoc analysis of the CHOIR trial a dose dependent increase in the risk for adverse outcomes was observed [83]. High levels of endogenous erythropoietin and the need for high doses of ESA are indicative of erythropoietin hyporesponsiveness, which itself is associated with adverse outcomes in both, CKD and transplant patients [84–86]. Besides infections and uremic state with failing graft function, an additional reason for ESA hyporesponsiveness in the transplant patients may be an increased inflammatory state in the presence of alloantigen [87]. In a meta-analysis of RCTs on anemia treatment in CKD Koulouridis et al. analyzed the association of ESA dose and cardiovascular events and all cause mortality, but could not prove statistically significant association in all models [88]. The need for greater ESA doses may simply reflect sicker patients generating confounding (indication bias) in statistical analysis [89]. Further trials that examine the effect of ESA dose rather than target hemoglobin levels on outcome and include adjustment for cardiovascular risk factors and inflammation are needed. The CAPRIT study (a multicenter randomized controlled trial) recently investigated the effect of partial (10.5 g/dl) vs. complete (13–


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15 g/dl) correction of Hb in 128 kidney transplant recipients [90]. The complete correction group showed a slower decline in GFR (2.4 ± 1.1 ml/min vs. 5.9 ± 1.1 ml/min), and improved Quality of Life. In terms of safety there was no increase in the risk for cardiovascular events. The study population showed an overall low cardiovascular risk profile and thus only a very small number of cardiovascular events were documented. Therefore the study is not adequately powered to draw definite conclusions on patient outcome associated with the use of ESA. ESA treatment in the early post operative period: In animal models of ischemia-reperfusion injury erythropoietin showed a nephroprotective effect, but so far the experimental findings could not be translated into clinical outcome and treatment strategies. Martinez et al. evaluated the effect of high epoetin-beta doses early after transplantation but failed to find a benefit [91]. Some important questions remain unanswered: There are conflicting data on outcome associated with post transplant anemia, but most studies showed that hemoglobin levels inversely correlate with graft and patient survival. We do not know whether anemia is a treatment target to improve outcomes or rather a marker of underlying problems. With increasing concerns towards an uncritical use of ESA, blood transfusions have already become more frequent in dialysis patients, but a restrictive approach has to be recommended in the transplant population, because of the adverse effects associated with transfusion [92]. Summarizing what we know: As there are no large randomized controlled trials in kidney transplant patients adequately powered to evaluate the effects of ESA treatment on outcome, and one large cohort analysis shows an increase in mortality associated with ESA treatment, we have to extrapolate what we know from CKD patients to the transplant population: According to the KDIGO guidelines on anemia in CKD published in 2012 and the ERBP position paper commenting these guidelines, the threshold to start ESA treatment should be somewhere around 10 g/dl and repletion of iron stores has to be endorsed even in patients with apparently adequate iron stores, so assessment of iron status plays an important role in the routine follow up of transplant patients [11,80]. 3. Post transplanterythrocytosis (PTE) PTE is usually defined as an Hb value N17 g/dl (or hematocrit N 51%) after kidney transplantation. It usually is observed among patients with excellent allograft function [65]. Kiberd et al. reported falling incidence rates of PTE from 19% in those transplanted between 1993 and 1996 compared to 8% in those transplanted between 1997 and 2005 [93]. This decline was attributed to a greater use of ACEis/ ARBs and antiproliferative immunosuppression. It usually occurs in patients that are still harboring their native kidneys and in those who showed preserved erythropoiesis prior to transplantation (e.g. Autosomal dominant polycystic kidney disease). Further risk factors that are associated with PTE include male gender, no history of acute rejection, renal artery stenosis and smoking [94–96]. The exact pathophysiological mechanisms are not completely understood, but an excess erythropoietin production by the remaining native kidney, that is not affected by negative feedback mechanisms is thought to play an important role [96]. However, plasma erythropoietin levels were not elevated or even were appropriately suppressed in some patients with PTE suggesting additional pathophysiological mechanisms [97]. Factors that may enhance the sensitivity to erythropoietin or directly promote erythropoiesis include an increased expression of insulin-like growth factor-1 (IGF-1), IGF-1 binding proteins, or the serum-soluble stem cell factor (sSCF). Mutations in the genes encoding for the hypoxia inducible factors (HIF) are also associated with erythrocytosis [98]. Additionally, activation of the Angiotensin-II-receptor enhances

erythropoietin production in the allograft and increases sensitivity of red cell precursors to erythropoietin [94,96]. Erythrocytosis can increase plasma viscosity and may cause thromboembolic events. An increase in thromboembolic events (18.9% vs. 0%) was observed in one study comparing PTE and nonPTE patients [99]. Other studies did not find an association between PTE and increased risk for thromboembolisms [59]. Hemoglobin levels below 17.5 mg/dl should be targeted in normotensive patients and an ACEi or ARB is the preferred initial treatment in patients with an Hb below 18.5 mg/dl [100,101]. Inhibition of the renin angiotensin aldosterone system (RAAS) may result in a decrease in erythropoietin production, but the exact pathophysiological mechanisms are not fully understood [96]. Phlebotomy is used in patients who do not respond to treatment with ACEi and ARB and in those who present with an initial Hb greater than 18.5 mg/dl [102]. Alternatively treatment with theophylline may reduce hemoglobin levels by as much as 10–15 percent but shows a narrow therapeutic window and is associated with side effects such as headache, nervousness, and insomnia [103]. 4. Post transplant leukopenia (PTL) and pancytopenia Both, leukopenia and pancytopenia are frequently observed in kidney transplant recipients, but published data are relatively scarce regarding incidence, significance, and management strategies. The most important factors associated with myelosuppression in the post transplant period are side effects of medications (MPA, VGCV) and opportunistic infections (CMV). Most episodes occur within the first few months after transplantation while patients eventually receive induction therapy and higher doses of conventional immunosuppressive drugs to prevent acute rejection. In patients with a reduced total white blood cell count (WBC) it is important to differentiate between lymphopenia and neutropenia. Lymphopenia is most likely due to an induction therapy with a lymphocyte depleting agent (rATG, alemtuzumab) and post transplant neutropenia (PTN) is associated with an increased risk for severe infections in the transplant population [104]. Next to cardiovascular disease, infection is the second most common cause of death in kidney transplant patients [105]. 4.1. Drug induced leukopenia and pancytopenia Many of the drugs used in the pharmacological management of transplant recipients including immunosuppressive and antimicrobial agents have the potential to cause leukopenia and thrombocytopenia through a variety of pathophysiological mechanisms [106]. Some of these drugs even show synergistic toxicity when used together. Leukopenia is recognized as a frequent side effect of treatment with MPA, but anemia is even more common when given in combination with ganciclovir (GCV) or valganciclovir (VGCV), SRL, or lymphocyte depleting agents [107–110]. In a small case series reported by Rerolle et al., an unexpected high incidence of agranulocytosis (37.5%) in patients treated with VGCV and MPA was observed. Tacrolimus may further increase the bioavailability of MPA [111]. MPA-induced leukopenia is dose dependent, but reduction of MPA is associated with an increase in acute rejection episodes [112,113]. Azathioprine is a purine analogue, which can cause bone marrow suppression and induce cytopenia. Allopurinol can interfere with azathioprine metabolism causing severe myelosuppression. VGCV and GCV are also frequently administered in the post transplant period, either as treatment for CMV disease or as prophylaxis. Leukopenia has been reported in 10–13% of patients receiving VGCV with 5% of these cases being severe [114]. In a Cochrane review mTORi were associated with a greater risk of leukopenia when compared to CNI [46].



Other medications associated with leukopenia and pancytopenia include the mono- and polyclonal antibodies rabbit antithymocyte globulin (rATG) [115], alemtuzumab [110], and rituximab, and the antimicrobial agents co-trimoxazole (trimethoprim and sulfamethoxazole) and atovaquone that both show similar incidence rates of leukopenia when used as pneumocystis prophylaxis [116]. Leukopenia has also been described with ACEis, clopidogrel and omeprazole [117]. CNI are not generally associated with leukopenia. 4.2. Opportunistic infections causing pancytopenia Besides common infections and sepsis, immunosuppressed patients are prone to opportunistic infections, which may directly cause bone marrow toxicity. Most importantly, CMV infection is associated with myelosuppression in the immunocompromised host, typically occurring within the first six months following transplantation. Characteristics of CMV infection or reactivation include fever, leukopenia, and thrombocytopenia with or without specific organ involvement (pneumonitis, enteritis, hepatitis, retinitis). Rising creatinine levels due to decreased allograft function may be another leading symptom of CMV infection in the kidney transplant recipient [118]. A direct inhibition of hematopoiesis has been described [119]. Typical laboratory findings include anemia (64%), thrombocytopenia (47%), leukopenia (21%), and atypical lymphocytes on peripheral blood examination [120]. The diagnosis is based on the detection of pp65 antigen or viral DNA by PCR in the serum. Treatment regimes include intravenous administration of GCV or VGCV. Intravenous immunoglobulins may be an option in more severe cases. Foscarnet can be used as rescue therapy, but is nephrotoxic [119,120]. There are two main strategies to prevent CMV disease in patients at risk: prophylaxis and preemptive therapy. Two recently published Cochrane reviews concluded that both, prophylaxis and preemptive treatment, significantly reduced CMV disease and CMV-associated mortality in solid organ transplant recipients when compared to placebo or standard care [121]. These benefits occur in both CMV positive transplant recipients and CMV negative transplant recipients of CMV positive donor organs. No statistically significant differences in the occurrence of CMV disease or overall mortality between the two strategies were found, but further studies are needed [122]. Prophylaxis was associated with a decreased white blood cell count and leukopenia was more common with extended duration prophylaxis but severe treatment associated adverse effects did not differ between extended and three month durations of treatment. The optimal duration of antiviral prophylaxis remains undefined. Extended prophylaxis may improve clinical outcomes in the highest-risk patient populations especially in CMV negative recipients of CMV positive organs [123]. In a recent study treatment with mTORi was associated with a statistically significant reduction of CMV disease after solid organ transplantation, but further studies to validate these findings are needed [124]. Other viral infections including Human herpes virus-6 (HHV-6) and Human herpes virus-8 (HHV-8) are less common, but cases with leukopenia and pancytopenia have been described [125,126]. 4.3. Clinical implications and treatment strategies Comparing results from various studies is difficult, as there is no universal definition of leukopenia, but usually a total white blood cell count (WBC) b 3000–4000 cells/mm3 is considered to be the cut off value. Neutropenia is more clearly defined as an absolute neutrophil count (ANC) b 500/mm 3 [127]. The reported incidence rates of leukopenia and neutropenia vary considerably and are dependent on the medication used in the post transplant period. So far, there are no widely accepted treatment guidelines and only little data from retrospective studies to guide treatment. Hartmann et al. reported a

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combined incidence of either leukopenia or neutropenia of 58% in a retrospective analysis of 102 kidney and pancreas TX recipients [128]. The majority of patients in the study received rATG as induction therapy and few were treated with alemtuzumab. Maintenance immunosuppression was based on tacrolimus and MPA. All subjects received a prophylactic dose of trimethoprim/ sulfamethoxazole or dapsone and VGCV. All of these drugs are associated with leukopenia and pancytopenia. Rapid steroid withdrawal and induction therapy with alemtuzumab were independently associated with an increase in leukopenia. In this study no difference in the rates of infection or acute rejection in patients with and without leukopenia was observed. Initial intervention in most patients was a reduction of the MPA dose (66% of cases), besides reduction in VGCV dose (17% of cases) or reduction in MPA and VGCV dose (12% of cases). Additionally 49% of patients requiring a medication intervention also received a granulocyte stimulating factor (G-CSF). Reduction of VGCV, either alone or in combination with MMF, proved to be the most effective measure in reducing the need for additional intervention. In a small case series reported by Rerolle et al. the initial reduction of valganciclovir dose proofed a successful treatment strategy in most cases even without a reduction in MPA dose [108]. In another retrospective analysis of kidney transplant patients Zafrani et al. reported that 28% of patients experienced an episode of neutropenia within the first year after transplantation [104]. Outcome (graft failure, acute rejection episode and renal function at 1 year) was similar in neutropenic and non-neutropenic patients, but there were significantly more bacterial infections (urinary tract) and CMV disease in the patients with neutropenia. In this study mortality was not increased in neutropenic patients. The most frequent therapeutic modification was again a reduction in MPA dose. For every day MPA was stopped the risk for acute rejection increased (OR 1.11, 95% CI 1.02–1.22). VGCV was only discontinued in 20% of cases. The largest analysis so far was done in a retrospective cohort of 41,704 prevalent kidney transplant recipients in the US [129]. In 15% of patients neutropenia was reported. Neutropenia was associated with an increased risk for allograft loss (HR 1.59; 95% CI 1.43–1.76) and death (HR 1.74; 95% CI 1.59–1.90). G-CSF was used in 12% of cases and did not increase the risk of allograft loss. The cause of leukopenia is not always easily attributable as many factors come into play in immunosuppressed patients. Early discontinuation of MPA may be an important strategy as a close relation between duration of neutropenia and time from onset of neutropenia to MPA dose adjustment has been observed [104]. Switching from MPA to AZA may be a strategy in severe agranulocytosis to prevent rejection episodes [130]. The degree of MPA dose reduction and the threshold to start treatment with G-CSF have not been defined. Most data so far showed that the use of G-CSF is safe and did not increase the risk for allograft loss, but there are some concerns that GCSF may precipitate acute rejection [129,131]. As we do not have longterm data on the safety of G-CSF in transplant patients, caution is warranted, but G-CSF for a short period seems to be safe and may be an important strategy in severe neutropenia. As discontinuation of VGCV was a successful strategy in recent studies, changing from CMV prophylaxis to a preemptive treatment strategy is another possible intervention. Dose adjustment of VGCV based on renal function and low dose prophylaxis (450 mg/day) are strategies to minimize drug exposure. As CMV disease itself may be the cause of leukopenia or may exacerbate after discontinuation of prophylaxis, a thorough surveillance for early CMV disease or reactivation is important. When pancytopenia is attributed to rATG treatment, a dose adjustment is recommended. Dose should be halved if the platelet count falls below 50 000–75 000/mm 3 and discontinued below b 50 000/mm 3 [132].


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5. Post transplant thrombocytopenia (PTT) Isolated PTT is less common than PTA and PTL, but thrombocytopenia is frequently associated with pancytopenia. Only little data on prevalence and clinical outcome are available. In one retrospective analysis in 274 Chinese living donor recipients a prevalence rate of 33.9% within the first year after transplantation was observed (defined as a platelet count b100/mm 3). Patients with low platelet count are at increased risk of bleeding, but so far there are no data on clinical relevance of PTT following kidney transplantation. Many of the risk factors, drugs and infections that are associated with the development PTA and PTL can also induce thrombocytopenia. Drugs that are specifically associated with thrombocytopenia include SRL, MPA, AZA, rATG, OKT3 and VGCV [117]. SRL shows higher rates of thrombocytopenia when compared to (RR 7.0, 95% CI 3.0– 16.4) or AZA and MPA (RR 1.95, 95% CI 1.29–2.97) [46,133]. Interestingly a comparison of basiliximab versus rATG induction therapy showed no statistically significant difference in the rate of thrombocytopenia (defined as a platelet count below 80.000/mm 3) [134]. Drug induced thrombocytopenia associated with SRL is considered benign, as thrombocytes normally do not fall below 100.000/mm 3 [135]. Treatment is based on the discontinuation of the offending drug. Other causes of thrombocytopenia include severe sepsis, viral infection such as CMV or PV-B19 and thrombotic microangiopathy. In severe cases transfusion should be based on the available guidelines on platelet transfusion in hematological patients [136]. 6. Thrombotic microangiopathy (TMA) TMA defines a histopathological lesion that is characterized by intravascular platelet aggregation leading to thrombosis in the microcirculation, thrombocytopenia, and hemolysis in kidney, brain, and other organs. Two distinct clinical entities have been described depending on whether cerebral lesions or kidney injury cause the predominant clinical symptoms: thrombotic thrombocytopenic purpura (TTP) and the hemolytic uremic syndrome (HUS). Several pathophysiological mechanisms have been described. TTP is typically associated with severe ADAMTS 13 deficiency and patients present with neurological abnormalities. Typical HUS is caused by Shiga toxin producing Escherichia coli and patients present with acute renal failure. Atypical HUS is a heterogeneous disease that summarizes patients without history of diarrhea or Shiga toxin producing E. coli and normal ADAMTS 13 activity. More recently several mutations in genes encoding for regular proteins of the alternative complement pathway have been identified. The common clinical and laboratory features include anemia, thrombocytopenia, reticulocytosis, rising LDH levels, and fragmentocytes in the peripheral blood smear. Following kidney transplantation TMA may occur de novo, triggered by immunosuppressive drugs such as CNI and SRL or by acute antibody mediated rejection, or recur in patients with a previous history of TTP/HUS [137]. Some patients may present with disease limited to the allograft while others have additional systemic manifestations. Diagnosis should be based on renal biopsy in all cases of TMA after renal transplantation. Recurrence: The reported recurrence rates of atypical hemolytic uremic syndrome (aHUS) range from 50% to 100% depending on the individual mutation in the genes encoding for regulator proteins of the alternative complement pathway. The highest rates are seen in patients with compound mutations in the genes encoding for complement factor H (CFH) and complement factor I (CFI). Conversely, a mutation in the membrane cofactor protein (MCP) is associated with a much lower rate of recurrence (20%), as MCP is highly expressed in the kidney and potentially restored after transplantation of a new allograft. Recurrence of disease usually is seen early after transplantation (often within in days to weeks) and ultimately leads

to graft loss in more than 90% of cases. In patients with ESRD caused by typical HUS following infection with a Shiga toxin producing E. coli strain recurrence is very rare [138–140]. The transplantation of living related donor kidneys is not recommended in patients with aHUS, because an underlying genetic susceptibility cannot be completely ruled out by genetic testing and nephrectomy may trigger disease. Nephrectomy of native kidneys prior to transplantation reduced the rate of recurrence in one study but has not been repeated in other studies [141]. Preventive treatment with eculizumab successfully prevents recurrence in patients with CFH and CFI mutations and should be used in all transplant recipients with a history of aHUS [142,143]. Eculizumab is a humanized monoclonal antibody for the terminal complement factor C5 and has been approved for the treatment of aHUS by the FDA in 2011 and offers new perspectives in the treatment and prevention of aHUS after kidney transplantation. The previously stated high recurrence rates were obtained from data collected prior to the availability of eculizumab. TMA is also associated with the antiphospholipid syndrome (APS) and patients may show recurrence after transplantation. APS nephropathy is thought to be associated with complement activation. Treatment with eculizumab successfully improved graft function und resolved TMA lesions in a small case series of patients with recurrent disease that was resistant to initial plasmapheresis, but did not prevent the development of chronic vascular changes in the allograft [144]. De novo TMA has been associated with various drugs that are routinely used in kidney transplant recipients including CNI, mTORi, the monoclonal antibody muromonab-CD3 (OKT3), valaciclovir and clopidogrel [145–148]. Antibody mediated rejection (AMR), viral infections (including HIV, PV-B19, or CMV), or antiphospholipid antibodies may also trigger de novo disease in kidney transplant recipients [137,149]. Calcineurin inhibitor associated TMA (CNI-TMA) is a well recognized cause of de novo TMA in kidney transplant recipients. Various studies reported incidence rates of CNI-TMA in patients treated with cyclosporine ranging from 3% to 14%. A much lower incidence rate of only 1% has been associated with the use of tacrolimus [137,150]. Higher rates of drug associated TMA were found when CNI were administered in combination with SRL [151]. The onset of de novo TMA is usually within the first few weeks after transplantation. The pathogenesis is incompletely understood, but CNI may cause direct endothelial injury. Antibody mediated rejection (AMR) also activates the classical complement pathway and can be accompanied by the clinical and histological findings of TMA [152]. CNI and SRL should be stopped in all patients with de novo TMA and disease activity may resolve upon discontinuation of CNI [153]. In patients with progressive disease plasma exchange should be performed. Recent evidence showed that transplant recipients who develop de novo TMA may have underlying mutations in genes that are normally associated with aHUS such as CFH or CFI. A study in 24 transplant recipients that developed apparently de novo disease showed that patients had mutations in CFI and CFH in 29% of cases [138]. Consequently complement inhibition may be a promising strategy in de novo TMA and eculizumab should be administered as rescue therapy in patients that are refractory to plasma exchange [152]. So far TMA has not been associated with MPA and prednisone and a conversion to a CNI free maintenance therapy based on belatacept in patients with CNI associated TMA has to be considered [154]. 7. Post-transplant lymphoproliferative disorder (PTLD) EBV associated PTLD is a serious and potentially fatal complication in solid organ transplant recipients and may initially present as



hypoproliferative anemia or pancytopenia. Four types of PTLD have been described in transplant recipients: 1) Early lesions, a polyclonal and benign lymphoproliferation that usually presents as infectious mononucleosis-type illness and shows no evidence of malignant transformation, 2) Polymorphic PTLD, a polyclonal or monoclonal B cell proliferation that shows evidence of malignant transformation but does not meet the criteria for lymphoma, 3) Monomorphic PTLD, a monoclonal lymphoid proliferation that meets the criteria for B or Tcell lymphoma, and 4) classic Hodgkin lymphoma-type PTLD. Initial treatment is based on the reduction of immunosuppression to the minimal level that will prevent rejection of the allograft. Additional therapies include immunotherapy with the CD20 monoclonal antibody rituximab or chemotherapy regimens used in lymphoma therapy such as CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone). An immunosuppressive regimen based on belatacept is contraindicated in EBV seronegative patients because an increase in the incidence of PTLD (9-fold higher) has been observed [155]. A thorough discussion of PTLD would be beyond the scope of this review. For detailed information, the reader is referred to the comprehensive literature available on this subject including reviews of PTLD biology and evidence based treatment strategies [156–161]

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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 N10 g/dl. Assessment of iron status is important in post transplant (long term) follow up and repletion of iron stores has to be 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 and discontinuation of causative medication are done. Most clinicians tend to decrease MPA dose, but this is eventually associated with an increase in acute rejection episodes. VGCV dose reduction (e.g. 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. This study was supported by grants from the Austrian Science Fund (FWF P-21436) to R.O. There is no conflict of interest.

8. Specific hematological disorders References 8.1. Passenger lymphocyte syndrome (PLS) Early hemolysis following transplantation may be due to the passenger lymphocyte syndrome caused by minor AB0 incompatibility, especially in the case of blood group 0 donors and blood group A, B or AB recipients. The pathophysiological mechanisms of this Graft versus Host disease (GVHD) are the transfusion of lymphocytes that are capable of producing antibodies against recipient cell surface antigens including AB0 antigens but also incompatibility in the Rhesus system has been recognized [162,163]. Immunoglobulin G (IgG) antibodies directed against the recipients red blood cells (anti-A and anti-B isohemagglutinins) normally appear seven to ten days after transplantation. In patients after liver transplantation antibodies against the AB0 antigens were found in up to 37% and hemolysis occurred in 59% of patients with antibodies [164]. In kidney transplant recipients fewer lymphocytes are transfused and subsequently a lower incidence rate of antibody formation has been reported (16%) and only few patients with alloreactive antibodies show clinical signs of hemolysis (14%) [165]. Hemolysis normally resolves within a short period of time. 8.2. Hemophagocytic syndrome (HPS) HPS is a rare, but then life threatening hematological disorder. An incidence rate of 0.4% following kidney transplantation has been reported [166]. The clinical presentation includes fever, hepatosplenomegaly, pancytopenia, lymphadenopathy, skin rash, jaundice, and neurological symptoms. It is associated with PTLD and infections (cases with CMV, EBV, HHV6, HHV8, hepatitis C virus, Mycobacterium tuberculosis, Pneumocystis carinii, Bartonella henselae, and Histoplasma capsulatum have been reported). 9. Summary Blood disorders after kidney transplantation are frequently observed. Most importantly post transplant anemia (PTA) is a common issue in kidney transplant recipients. Important factors associated with PTA are a reduced allograft function, side effects of immunosuppressive drugs (MPA, AZA and SRL), iron deficiency, infections (Parvo B19), older donor age, rejection episodes, and an increased inflammatory state. As there are no adequately powered

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Blood cell disorders after liver transplantation.

Blood transfusions and kidney transplantation.

Sirolimus after kidney transplantation.

Endocrine and metabolic disorders following kidney transplantation.

Transplantation: early hospital readmissions after kidney transplantation.

Cochlear implantation after kidney transplantation.

Renovascular hypertension after kidney transplantation.

Gross hematuria after kidney transplantation.

Blood disorders typically associated with renal transplantation.

Blood transfusion effects in kidney transplantation.

Post-transplantation Malignancy After Kidney Transplantation in Turkey.

Chronic kidney disease after liver transplantation.

Risk of major hemorrhage after kidney transplantation.

Long-term allograft survival after kidney transplantation.

Endometrial carcinoma and amyloidosis after kidney transplantation.

pancreas transplantation.

Cell therapy for immunosuppression after kidney transplantation.

Development of RhD antibodies after kidney transplantation.

Development of RhD antibodies after kidney transplantation.

Mineral and bone disorder after kidney transplantation.

Changes in Frailty After Kidney Transplantation.

Huge abdominal cyst occurred after kidney transplantation.

High tacrolimus blood concentrations early after lung transplantation and the risk of kidney injury.

Kinetics of peripheral blood lymphocyte subpopulations predicts the occurrence of opportunistic infection after kidney transplantation.