Anemia Management and Outcomes in Kidney Transplant Recipients

Posttransplantation anemia (PTA) is an oft-neglected aspect of posttransplantation care that is associated with adverse outcomes for the kidney allograft and the recipient. The prevalence of anemia in kidney transplant recipients (KTRs) is very high, ranging from 25% to 40% depending on the definitions used, parameters measured, and average time since transplantation across study populations (13). The American Society of Transplantation (AST) and the World Health Organization have defined anemia as hemoglobin <13 g/dL in men or <12 g/dL in women. On the basis of these definitions, at the time of kidney transplantation, the majority of patients have anemia due to chronic kidney disease (CKD)–related erythropoietin (EPO) deficiency and resistance and also iron deficiency.

The customary treatment targets for the correction of anemia in CKD patients also do not aspire to normalize hemoglobin concentrations. After successful kidney transplantation, endogenous production of EPO may increase, and resistance to EPO may decline with improvement in the uremic milieu, leading to resolution of anemia 3 to 6 months after transplantation. However, the majority of KTRs have allograft function that corresponds to CKD stages 3 through 5, and they have persistent anemia for as long as 6 to 12 months after transplantation (late PTA).

Consequences of PTA

Cardiovascular disease remains the leading cause of death among KTRs (4), and some studies have purported a relation between PTA and cardiovascular death (5). A relationship between PTA and mortality has been described in some studies (6, 7), whereas others have found no such association (8). Molnar et al. (7) followed up 938 KTRs for 4 years and showed that all-cause mortality was 69% (95% confidence interval: 12% to 156%) higher in patients with anemia (per AST definition) at baseline. Conversely, a prospective study of 438 KTRs followed up for >7 years reported that a hemoglobin concentration <10 g/dL was not associated with increased mortality or graft loss (9). However, an association of PTA with increased risk of graft failure has been shown quite consistently (68). The adverse effects of anemia on quality of life are well known, and findings have been replicated in patients with PTA (10).

Causes of PTA

Besides the risk factors for anemia shared with CKD patients who have not undergone transplantation, PTA has a unique set of additional causes. Although every effort should be made to determine the precise cause of a patient’s PTA, it usually is a multifactorial process. Transplant function is the most important correlate of anemia, and anemia worsens as graft function declines (3, 11). Transplant recipients who experience rejection episodes or have more than one transplant have a higher incidence of anemia (12). In the immediate posttransplantation period, surgical blood loss and induction immunosuppression contribute to anemia, and delayed graft function can amplify the problem.

Late PTA can be due to several causes (Figure 1). Anti- metabolites (azathioprine and mycophenolic mofetil) and mTOR inhibitors (sirolimus and everolimus) can cause anemia by bone marrow suppression, and anemia is more severe when these two drug classes are combined. Interestingly, anemia of mTOR inhibitors presents with microcytosis. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, which are used in the treatment of posttransplantation erythrocytosis, also lead to PTA. Calcineurin inhibitors (tacrolimus and cyclosporine) can cause thrombotic microangiopathy. Donor-derived antibodies against recipients’ red blood cells can cause immune-mediated hemolysis (passenger lymphocyte syndrome), which is a rare cause of PTA.

/kidneynews/11_5/9/graphic/9f1.jpg

Management and hemoglobin targets

When we consider the adverse associations of anemia with quality of life, graft survival, and possibly mortality, it would stand to reason that correction of anemia and normalization of hemoglobin could potentially mitigate these consequences. Intuitively, the initial step in management would be to identify any reversible causes, including iron deficiency, and treat them appropriately. However, some of the potentially causative factors of PTA are difficult to avoid, including the medications used for immunosuppression and infection prophylaxis. One target amenable to therapeutic intervention is absolute or relative deficiency of endogenous erythropoietin, which can partly be treated by the administration of erythropoiesis stimulating agents (ESAs). Recent studies in animal models have shown that ESAs may prevent allograft nephropathy by mechanisms other than anemia correction, including preservation of intragraft expression of angiogenic factors, upregulation of antiapoptotic factors, and immunomodulating effects (1315).

Owing to a lack of randomized controlled trials of the effects of anemia correction in KTRs, the transplantation community has been relying mostly on data from patients with CKD and anemia. The enthusiasm about the use of ESA for anemia correction was curbed by findings from the Normal Hematocrit Study in patients receiving dialysis and the CHOIR, CREATE, and TREAT studies in non–dialysis-dependent CKD (1619). These trials showed either no benefit or even cardiovascular harm with the use of ESAs to achieve higher hemoglobin concentrations. Consequently, the current guidelines for the management of PTA recommend following the targets suggested for anemia in CKD patients without a transplant while acknowledging the dearth of data in KTRs (20, 21).

An observational study by Heinze et al. (22) retrospectively analyzed 1794 transplant recipients in the Austrian Dialysis and Transplant Registry and showed an increase in mortality if hemoglobin was corrected to more than 12.5 g/dL by the use of ESAs, thus reinforcing the trial data in CKD patients. Interestingly, patients with higher hemoglobin levels without the use of EPO had better survival rates in this study. However, this paradigm was challenged by two recent prospective studies showing a benefit of ESA use in KTRs. Choukroun et al. (23), in a randomized controlled trial, showed that targeting a hemoglobin level of 13.0 to 15.0 g/dL by using epoietin-β led to improved graft survival and quality of life without increasing the risk of adverse cardiovascular events.

In a recent randomized controlled trial from Japan, a hemoglobin target of 12.5 to 13.5 g/dL (with use of ESA) was associated with a reduction of decline in kidney function over a follow-up time of >3 years in the chronic phase of allograft nephropathy, without any serious adverse events (24). Of note, the target hemoglobin in the high-hemoglobin group was achieved after 18 months in this 3-year study. These studies are compared in Table 1. The contradictory results among various studies of ESAs in CKD and KTRs can theoretically be explained by the differences in baseline cardiovascular risk status, the doses of ESAs used, and the rate of correction of anemia, along with the immunologic and nonimmunologic mechanisms of anemia in KTRs that are different from those in patients with CKD without KTR.

/kidneynews/11_5/9/graphic/9t1.png
 

In summary, the burden of PTA in KTR remains high and causes significant morbidity and mortality in these patients. Any PTA should be proactively addressed as part of holistic management of KTRs. Identifying a specific cause remains vital so that any reversible factors can be eliminated. The target hemoglobin and use of ESAs remain controversial, but recent evidence challenges the paradigm of extrapolating the evidence in CKD patients to KTRs and suggests that trying to normalize hemoglobin by using ESAs may be beneficial by appropriate patient selection and by decelerating the rate of correction of anemia. Newly introduced therapeutic agents targeting hypoxia-inducible factor pathways have the potential for a positive impact but also for undesired off-target effects. Therefore, it is mandatory that these new agents be specifically and thoroughly studied in KTRs.

May 2019 (Vol. 11, Number 5)

References

1. Choukroun G, et al. Incidence and management of anemia in renal transplantation: an observational-French study. Nephrol Ther 2008; 4:575–583.

2. Molnar MZ, et al. Prevalence and management of anaemia in renal transplant recipients: data from ten European centres. Nephron Clin Pract 2011; 117:c127–c134.

3. Vanrenterghem Y, et al. Prevalence and management of anemia in renal transplant recipients: a European survey. Am J Transplant 2003; 3:835–845.

4. Awan AA, et al. Trends in the causes of death among kidney transplant recipients in the United States (1996–2014). Am J Nephrol 2018; 48:472–481.

5. Imoagene-Oyedeji AE, et al. Posttransplantation anemia at 12 months in kidney recipients treated with mycophenolate mofetil: risk factors and implications for mortality. J Am Soc Nephrol 2006; 17:3240–3247.

6. Kamar N, Rostaing L. Negative impact of one-year anemia on long-term patient and graft survival in kidney transplant patients receiving calcineurin inhibitors and mycophenolate mofetil. Transplantation 2008; 85:1120–1124.

7. Molnar MZ, et al. Anemia is associated with mortality in kidney-transplanted patients: a prospective cohort study. Am J Transplant 2007; 7:818–824.

8. Winkelmayer WC, et al. A prospective study of anaemia and long-term outcomes in kidney transplant recipients. Nephrol Dial Transplant 2006; 21:3559–3566.

9. Winkelmayer WC, et al. Percentage of hypochromic red blood cells is an independent risk factor for mortality in kidney transplant recipients. Am J Transplant 2004; 4:2075–2081.

10. Kawada N, et al. Negative effects of anemia on quality of life and its improvement by complete correction of anemia by administration of recombinant human erythropoietin in posttransplant patients. Clin Exp Nephrol 2009; 13:355–360.

11. Mix TC, et al. Anemia: a continuing problem following kidney transplantation. Am J Transplant 2003; 3:1426–1433.

12. Kamar N, et al. Impact of post-transplant anemia on patient and graft survival rates after kidney transplantation: a meta-analysis. Clin Transplant 2012; 26:461–469.

13. Cassis P, et al. Erythropoietin, but not the correction of anemia alone, protects from chronic kidney allograft injury. Kidney Int 2012; 81:903–918.

14. Diskin CJ, et al. Beyond anemia: the clinical impact of the physiologic effects of erythropoietin. Semin Dial 2008; 21:447–454.

15. Purroy C, et al. Erythropoietin receptor-mediated molecular crosstalk promotes T cell immunoregulation and transplant survival. J Am Soc Nephrol 2017; 28:2377–2392.

16. Drueke TB, et al. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med 2006; 355:2071–2084.

17. Singh AK, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med 2006; 355:2085–2098.

18. Pfeffer MA, et al. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med 2009; 361:2019–2032.

19. Besarab A, et al. The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med 1998; 339:584–590.

20. KDOQI, National Kidney Foundation. IV. Clinical practice recommendations for anemia in chronic kidney disease in transplant recipients. Am J Kidney Dis 2006; 47:S109–S116.

21. Kasiske BL, et al. KDIGO clinical practice guideline for the care of kidney transplant recipients: a summary. Kidney Int 2010; 77:299–311.

22. Heinze G, et al. Mortality in renal transplant recipients given erythropoietins to increase haemoglobin concentration: cohort study. BMJ 2009; 339:b4018.

23. Choukroun G, et al. Correction of postkidney transplant anemia reduces progression of allograft nephropathy. J Am Soc Nephrol 2012; 23:360–368.

24. Tsujita M, et al. The effect of maintaining high hemoglobin levels on long-term kidney function in kidney transplant recipients: a randomized controlled trial [published online ahead of print Dec 17, 2017]. Nephrol Dial Transplant doi: 10.1093/ndt/gfy365.