Guideline 6.1 Peri-Transplant Anaemia & Guideline 6.2 Blood Transfusion

Guideline 6.1 – Peri-Transplant Anaemia:

We suggest that anaemia management should be optimal pre-transplant in all people with CKD on the transplant wait-list, to minimise the risk of a post-transplant transfusion. (2B)

Guideline 6.1.1

We suggest for people with CKD undergoing kidney transplantation, that recombinant EPO maybe continued, after a shared decision of the risks and benefits with the patient, until endogenous EPO production is sufficient to maintain Hb concentrations. For HIF-PHI therapy we make no recommendation until further data is available. (2C)

Guideline 6.2 – Blood Transfusion:

We suggest for stable non-bleeding individuals who clinically require a red cell transfusion, using single unit transfusion, where possible. (2B)

Rationale

Anaemia post-transplant is extremely common; the aetiology of which is multi-factorial and influenced by the timing post-transplant (Table 1) (1-3).

Apart from the usual causes of anaemia due to CKD, kidney transplant recipients have various unique factors predisposing to anaemia.

Factors causing post-transplant anaemia (PTA):

1. GFR: anaemia in people with a kidney transplant reflects the degree of GFR similar to other people with CKD (3).
2. Immunosuppressive medications: Mycophenolate and azathioprine are myelosuppressive agents. Calcineurin inhibitors may cause anaemia by microangiopathic haemolysis (4-8). OKT3 may also cause haemolytic uraemic syndrome (HUS) (9-10). Tacrolimus has also been associated with anaemia (11-13). It may interfere with post erythropoietin receptor binding intracellular signalling and may occasionally cause HUS (13-14).
3. Angiotensin converting enzyme (ACE) inhibitor and angiotensin receptor blocker (ARB) use: ACE inhibition has been linked with anaemia (3, 15). Its pathogenesis is multifactorial and may include inhibition of endogenous EPO production, production of an erythropoiesis-inhibiting protein (16) and inhibition of angiotensin II mediated stimulation of erythrocyte precursors (17).
4. Antibiotic use: various common antibiotics may cause anaemia including trimethoprim-sulfamethoxazole.
5. Infections: viral infections such as cytomegalovirus and parvovirus B19 and antiviral agents such as ganciclovir may cause anaemia in people with a kidney transplant (18-19).
6. Malignancy: malignancies including post-transplant lymphoproliferative disorder may result in anaemia.
7. Haemolytic anaemia: haemolytic anaemia may result from HUS or minor blood group incompatibility in people with a kidney transplant (20-22).
8. Rejection episodes: Acute rejection may cause reduced endogenous EPO production (23). Severe vascular rejection may cause microangiopathy.
9. Chronic inflammation: Failing kidney transplant causes a chronic inflammatory state resulting in EPO hypo-responsiveness.

Early post-transplant anaemia (PTA) can be seen in the first 6 months following transplantation due to iron deficiency and the slow production of EPO from the new transplant graft (24).

The prevalence of red cell transfusions early post-transplant is high, averaging 40% in reported series (25). Risk factors for peri-transplant transfusion include female gender, non-white ethnicity, time on dialysis pre-transplant and receiving a deceased donor transplant. The requirement of a peri-transplant transfusion has been shown to be associated with poor allograft outcomes, through mechanisms which are yet to be elucidated (25). Patient blood management, that is optimal management of anaemia and preserving a patient’s own blood, are therefore important in the early post-transplant period (26-28). Optimal anaemia management of the person with CKD prior to transplantation, as has been set out in this guideline, is important to minimise complications of anaemia.

Although blood loss occurring via the transplant surgery itself will contribute to early post-transplant anaemia, transfusion usually occurs in the first two weeks post-transplant (25). Endogenous EPO is sustained from 28 days post-transplant in the setting of primary graft function (29). Studies have shown that in the early post-transplant period ESA (erythropoiesis stimulating agent) is safe and effective, although the dose required may be higher than in the pre-transplant period (30, 31). Given the increasing use of marginal donor kidneys, associated with delayed graft function and suboptimal function, there may be a longer requirement for EPO.

When a red cell transfusion is required clinically post-transplant in the stable patient, single unit transfusions should be utilised where possible (3). Although red cell transfusions are recognised to be associated with HLA sensitisation in the pre-transplant setting, less data are available on the risk of de novo alloimmune responses post-transplant whilst receiving immunosuppression (25, 32). There are data that the development of de novo transfusion specific antibodies post-transplant can occur post-transplant; plus, additional evidence of a potential link between the receipt of a red cell transfusion and de novo donor specific antibodies (32). Limiting exposure to multiple red cell donors is therefore advisable, if possible.

Late transplant anaemia occurs more than 6 months after transplantation and can be seen in up to 36% of patients (33). This is influenced by the function of the transplant graft, but also a combination of the factors listed above as well as iron deficiency.

After the early post-transplant period, the frequency of transfusions is markedly reduced. Anaemia management is more in line with that of CKD, however, there remain specific risk factors for anaemia which will be present and need consideration in terms of reversibility and management.

The JACK-II study looked at the association between PTA and graft function in 1307 kidney transplant recipients. This study found that 46.3% of the cohort had PTA at 7 years post transplantation, with low Hb levels associated to an increase in transplant graft failure (hazard ratio = 1.83, 95% CI: 1.66– 2.02, P < 0.001) (34).

This association was previously reported in the TransQol-HU Study, looking at a cohort of 938 kidney transplant recipients with a 4-year follow-up period. This study showed that mortality and graft failure were significantly higher in people who were anaemic vs those who were not anaemic. Mortality rates were reported at 18% vs 10% (p<0.001) and graft failure rates were 17% vs 6% (p<0.001) (35).

Gafter-Gvili et al. assessed 266 people and found that 51.3% experienced early PTA and 36.6% experiences late PTA. The study found that there was higher mortality after 4 years in those who experienced early PTA, which processed to late PTA vs those who did not have anaemia and lower Hb was associated with increased mortality (hazard ratio [HR] 0.716, 95% confidence intervals [CI] 0.541-0.948, for every increment of 1 g/dL) and increase graft failure (HR 0.775, 95% CI: 0.619-0.969, for every increment of 1 g/dL) (36).

Scechter et al. (33) also found similar results in their cohort of 1139 kidney transplant recipients. 36.2% of the cohort had PTA and 11.7% had severe anaemia (Hb <11g/dL). Early PTA was associated with graft loss or mortality (hazard ratio (HR) 3.64, 95% CI: 2.34–5.66, p < 0.001) but a weaker association as seen with late PTA (HR 1.44, 95% CI: 0.97–2.13, 0.07). Severe anaemia was associated with an increase in all-cause mortality. It was also found that PTA secondary to AKI, acute rejection, infection is associated with a higher risk of death or graft loss (HR 9.32, 95% CI: 5.3–26.41, p < 0.001 and HR 3.99, 95% CI: 2.01–7.95, p < 0.001, respectively) (33).

Safety of ESA in transplant patients

A few early retrospective studies suggested increased incidence of delayed graft function in people on ESA prior to transplantation (37, 38). However, Registry data has since shown reduced incidence of delayed graft function despite increasing use of ESA. It has also been shown that ESA use prior to kidney transplantation does not reduce production of or response to endogenous EPO (39, 40). Studies in the early post-transplant period did not show significant adverse events including delayed graft function or hypertension (41, 42). Studies in the late transplant period have shown increased incidence of hypertension (43, 44). ESAs, most probably, do not accelerate rate of graft function decline and one study suggested that correction of anaemia slowed the decline in allograft function (45).

In another prospective study that assessed the effect of correction of anaemia on progression of kidney Insufficiency in people with a kidney transplant; 128 people from 17 centres in France treated with ESA were randomised to full correction of anaemia (haemoglobin values130–150 g/l, n=63) versus partial correction of anaemia (Hb value 105–115 g/l, n=62).This study found that in the group of patients with a haemoglobin level close to normal (~130 g/L), the rate of decline of kidney function was lower compared with the group of control participants, and the number of people reaching end-stage kidney disease and the number of graft failures was lower in this treatment group compared with the control group, suggesting that correcting anaemia in people with a kidney transplant reduces the rate of decrease of kidney function and reduces the number of grafts lost (46).

A similar study from Japan compared the effect of maintaining higher Hb levels (125-135 g/L, n=64) using ESAs with maintaining Hb at 105-115 g/L (n=63). This study found that those people in the lower Hb target group (mean levels 115 ± 12 g/L) had significantly higher rate of eGFR decline at 12, 18, 24 and 36 (p=0.02) months, compared to those in the higher Hb target group. Similar levels of adverse events were seen in both groups (47).

A further single centre study showed no change in the rate of decline in allograft function over 2 years with epoetin beta therapy (target Hb 115-135 g/L). However, the study did show significant increase in the vitality and mental health domains of the medical outcomes short form health survey (48).

Efficacy of ESA in people with a kidney transplant

Studies in the early post-transplant period have shown that ESA is effective in these people, although the dose required may be higher than in pre-transplant period (41, 42). Similarly, studies in late post-transplant period have shown efficacy of ESA in these people (43, 44, 49, 50).

In the Neo-PDGF study, high dose epoetin beta (30,000 IU) was administered during the first 2 weeks around kidney transplantation. Doses were given just before surgery, 12-24 h after transplantation, at 7 days and at 14 days post transplantation. When compared to the group not receiving any ESA, there was found to be significantly increased haemoglobin levels at 1 month after transplantation (mean Hb 111 g/L vs 105 g/L p=0.038. However, there was no significant difference in the incidence of delayed graft function (32% vs 38.5%), the incidence of slow graft function (26 vs 25%) or eGFR (42,7 vs 44.3 ml/min/1.73m2) of epoetin beta versus control (51).

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