The use of erythropoietin-stimulating agents for patients with chronic kidney disease has been the subject of considerable controversy over the last few years. This controversy was underscored by the recent U.S. Food and Drug Administration  “black box warning” for administering ESAs and the policy changes enacted by the Centers for Medicare & Medicaid Services limiting the indications for ESA use. The net result of these policy changes has been a dramatic decline in ESA utilization and hemoglobin levels in CKD patients. The driving force for these policy changes has been the growing concerns for the safety and efficacy of ESAs to treat anemia in CKD patients and the limited data indicating clear benefits of therapy, other than transfusion avoidance.

What has been the impact on patients of the reduced ESA utilization and Hb levels?

There is no good evidence to support a worsened morbidity or mortality with reductions in ESA utilization. (Conversely, prior studies have never clearly shown improved outcomes with increases in ESA use and Hb levels). Some studies have suggested that there has been a recent increase in transfusions in CKD patients (with a potential for limiting acceptable transplant donors), but the data supporting this are somewhat debatable.

But what about the impact on the patient perceptions of their health-related quality of life (HRQOL)? Many senior nephrologists recall that before ESAs were available,  patients routinely complained about loss of energy, fatigue, limited exercise tolerance, and restrictions on performance of the normal activities of  daily living. And, they recall the dramatic improvements in these symptoms that occurred after ESA therapy became part of the routine care for CKD patients. Of particular note in this regard have been the patient testimonials at the FDA and CMS hearings on ESA therapy with reports of dramatic amelioration of symptoms of fatigue and improvements in activity levels.

Studies examining the impact of anemia on HRQOL have been challenging to interpret. Early studies suggested an improvement in a variety of domains, but these studies were generally neither randomized nor blinded. More recent studies are complicated by the heterogeneity of patients enrolled, the use of a variety of diverse HRQOL instruments, and by the use of different target, achieved, and baseline Hb levels.

For example, in these studies, the targeted Hb level was often different than the achieved Hb level. More importantly, the baseline and achieved Hb levels were different in the various studies. This is particularly noteworthy because recent studies have suggested that the most dramatic improvements in HRQOL measures occur when baseline Hb levels are below 10 g/dl and that increments in HRQOL measures diminish or become negligible when baseline Hb levels are above 10 g/dl and are increased by one or two g/dl. 1-3  

 How should the clinician interpret this information and how should the observations be incorporated into medical practice? This was debated by the group brought together to develop the KDIGO anemia guidelines for the International Society of Nephrology. These guidelines emphasize the importance of the individualization of anemia therapy, taking into account potential risks of therapy and the possible amelioration of symptoms attributable to or associated with anemia. And, of particular importance, the guidelines note (in an ungraded guideline) that some patients may have improvements in HRQOL symptoms at higher Hb levels ("Individualization of therapy will be necessary as some patients may have improvements in quality of life at Hb concentration above 11.5 g/dl (115 g/l) and will be prepared to accept the risks.") 4 The point to emphasize here is not that the guidelines are recommending that Hb levels be targeted above 11.5 in a routine treatment algorithm, but that the clinician must carefully assess the symptoms of the patient and adjust the use of ESA therapy based on the individual response to the treatment. The potential risks of therapy need to be carefully explained.    

What are the symptoms most often attributable to anemia? Four recent reviews suggest that the major impact of anemia on HRQOL measures involves the effect on the patients' perception of fatigue, energy, and physical functioning. 1-3,5 Thus, routinely assessing these domains in CKD patients with anemia is critically important, particularly as ESA dosing and Hb levels decline. This can be done by incorporating questions about these domains into routine office visits or by using one of several patient-reported outcome measures and including them as part of routine patient care. Instruments that can be used include the  physical functioning and energy/vitality domains of the  SF-36 health survey (Medical Outcomes Trust, Boston, Mass.), one of the several fatigue questionnaires described on the PROMIS website, the FACT-Fatigue questionnaire,  or other questionnaires. 6,7

 But might anemia impact on other domains that are important for an individual patient? The answer is surely yes. This is illustrated in the following case.

JB was referred for management of his CKD. He is an 84 year old retired history professor, still actively involved in writing academic articles. Recently, he reports that he has had difficulty finishing his academic work — he attributes this to difficulty concentrating and focusing on his work. His physical activity is very limited and has been for several years because of coronary artery disease and reduced cardiac function. JB has an eGFR of 22, which has been slowly declining. After appropriate evaluation, the etiology of his CKD has been attributed to ischemic renal disease. His hemoglobin level has also been gradually decreasing and on referral was 10.0 g/dl. A standard anemia evaluation was performed and the anemia was attributed to his CKD; no other cause was noted. The use of ESAs was discussed with JB and his spouse. The potential risks were noted and the potential impact on his HRQOL discussed. Because of the importance attributed by both the patient and his spouse to his major complaint of difficulty concentrating on his academic work, ESA therapy was initiated; no other clear therapeutic options were available. Hb levels gradually increased to 12.0 gm/dl. JB reported a striking improvement in his concentrating ability and his academic productivity markedly increased. On careful questioning, there was no change in JB's physical functioning with the ESA therapy.

Was JB's symptomatic improvement related to ESA therapy and the increase in his Hb level? It is hard to be sure, but no other changes were made in his treatment regimen. Since the potential benefits of ESA therapy were discussed with the patient and his spouse, could his improvement represent a placebo effect? Yes — but the symptomatic benefit and improvement in his quality of life were dramatic and must be emphasized.

Conclusions

The case illustrates the importance of paying attention to how patients feel and carefully listening to them to better understand what domains are important for them to maximize their quality of  life. I think it is our responsibility as health care providers to work with each patient to improve his or her quality of life––but to do so we must engage them in a process of shared decision making. 8 We need to listen carefully to each patient and try to grasp his or her perception of their quality of life. We need to offer them the therapeutic options that are available, explaining the potential advantages of treatment as well as the risks and benefits of the therapy. We need to engage in shared decision making with the patient and his or her family, recognizing that the ultimate decision rests with the patient. 8 It is our job as health care providers to make available to the patient and his or her family objective information from which they can make an informed decision; it is not our job to make decisions for the patient.      

References

1. Johanssen KL, Finkelstein FO, Revicki DA, Evans C, Wan S, Gitlin M, Agodoa IL Systematic review of the impact of erythropoiesis-stimulating agents on fatigue in dialysis patients. Nephrol Dial Transplant. 2012,  27:2418-25

2. Gandra SR, Finkelstein FO,  Bennett AV, Lewis EF, Brazg T, Martin ML. Impact of erythropoiesis stimulating agents on energy and physical function in non-dialysis chronic kidney disease patients with anemia: a systematic review. Amer J. Kidney Dis, 55:519-34, 2010

3. Johansen KL. Finkelstein FO, Revicki DA, Gitlin M, Evans C, Mayne TJ. A systematic review and meta analysis of exercise tolerance and physical functioning in patients on dialysis treated with erythropoiesis stimulating agents. Am J Kidney Dis, 55:535-548, 2010

4. . www.theisn.org 

5. Leaf DE, Goldfarb DS. Interpretation and review of health-related quality of life data in CKD patients receiving treatment for anemia. Kidney Int 75: 15–24, 2009

6. www.nihpromis.org

7. Yellen SB, Cella DF, Webster K, Blendowski C, Kaplan E. Measuring fatigue and other anemia-related symptoms with the Functional Assessment of Cancer Therapy (FACT) measurement systemJ Pain Symptom Manage. 1997 Feb;13(2):63-74

8. Lee EO, Ezekiel EJ. Shared decision making to improve care and reduce costs. New Eng J Med 368:1, 2013