2 Research recommendations

The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future.

2.1 Management of anaemia of chronic kidney disease with concurrent illness

What is the optimal management (in terms of clinical and cost effectiveness) of anaemia of chronic kidney disease (CKD) in patients who are receiving erythropoietic stimulating agents (ESAs) and have a significant concurrent acute infectious illness?

Why this is important

Chronic kidney disease is a risk factor for mortality in patients who develop acute illness. Acute illness in CKD patients is associated with development, or worsening, of anaemia.

The anaemia of end‑stage renal disease is managed primarily with ESAs and intravenous iron. When CKD patients develop acute illness, their anaemia becomes difficult to control. Acute inflammatory response usually renders patients hyporesponsive to treatments for anaemia. In addition, intravenous iron might promote bacterial infection. Many patients may end up having a blood transfusion – in part because of the lack of established guidelines on managing anaemia in CKD patients with acute illness. Little is known about the relative safety of transfusion compared with parenteral iron therapy, with or without ESA therapy.

There is a need for long‑term observational studies, as well as prospective randomised controlled trials to compare the effectiveness and safety of treating anaemia in acutely ill CKD patients with parenteral iron, erythropoiesis stimulating agents, blood transfusion or a combination of the 3 different therapies. A large epidemiological or cohort study is needed with a control group (for example, patients admitted to hospital as an emergency with an acute illness, but without anaemia). The study should be adequately powered to detect factors predictive of important end points such as patient survival, deterioration of renal function, the need to initiate renal replacement therapy and prolonged hospital stay.

2.2 Treatment of ESA resistance

In people with chronic ESA‑resistant anaemia of CKD, what is the clinical and cost effectiveness of treating with high‑dose ESA compared with blood transfusion?

Why this is important

People with ESA hyporesponsiveness show evidence of increased morbidity and mortality compared with those who respond well to ESA therapy. Poor response to ESA therapy during the haemodialysis treatment period is thought to be associated with worse post‑transplant long‑term outcomes, including increased all‑cause death and higher risk of graft failure. Little is known about the potential risks of maintaining people with CKD on high doses of ESA therapy while they are waiting for a kidney transplant. It is unclear whether high‑dose ESA should be continued in people with ESA resistance in an attempt to limit the number of blood transfusions, or whether people should stop ESA treatment and be treated with transfusions alone. The adverse effects differ between the strategies and are likely to have implications for cost and quality of life.

Further research is needed to understand the clinical and cost‑effectiveness of these 2 strategies. Long‑term prospective observational or matched case‑controlled studies are needed to assess the relative safety of large‑dose ESA versus no ESA, with or without blood transfusions, on long‑term patient and graft survival.

2.3 Treatment of ESA resistance in haemodialysis patients

What is the most effective type of intervention to treat haemodialysis patients with ESA‑resistant anaemia?

Why this is important

Around 5% to 10% of patients with end‑stage renal disease show resistance to ESAs. ESA hyporesponsiveness in chronic haemodialysis patients may be associated with increased morbidity and mortality. In addition, pre‑transplantation ESA hyporesponsiveness is thought to be associated with increased kidney allograft failure and patient mortality. Studies have shown that immunosuppressants, antioxidants, anti‑cytokine therapies and high‑flux membranes vary in how much they improve responsiveness to ESA therapy, but all the studies used a small sample size. There is inadequate evidence identified from available literature to inform recommending any intervention to improve ESA responsiveness.

Adequately powered randomised controlled trials are needed to establish the safety and efficacy of interventions to improve responsiveness to ESA therapy.

2.4 Iron therapies for conservative care of anaemia of CKD

What is the clinical and cost effectiveness of different iron therapies for people with anaemia of CKD opting for conservative care (defined in relation to haemodialysis)?

Why this is important

Conservative care for end‑stage renal disease aims to provide control of symptoms, with an emphasis on maintaining the person's quality of life. Anaemia management is a key element of conservative care. People opting for conservative care may prefer to receive treatment closer to home rather than in hospital, even if the treatments available in hospital are more effective. It is important to take into account quality of life and patient choice, as well as medical risks and benefits, when deciding on an anaemia treatment plan. Further research is needed into the clinical and cost‑effectiveness of different iron therapies for people opting for conservative care.

2.5 Target haemoglobin levels in conservative management of anaemia of CKD

In people with anaemia of CKD opting for conservative management, what is the clinical and cost effectiveness of treating to differing target haemoglobin (Hb) levels?

Why this is important

Most studies of ESA therapy involved people who differ considerably from those opting for conservative management. Trial evidence relates to people who tend to be younger, with fewer comorbidities. There are many people, mainly older people in their later seventies and eighties, who opt for conservative management of CKD instead of haemodialysis. They often have several comorbidities. They will usually be treated with an ESA in accordance with guidelines for anaemia management in CKD, with the standard target Hb range, although there is little information on the best target Hb level for this relatively older, less active group of people. A 'usual' target Hb level might reduce their anaemia symptoms. However, a lower target level might have no adverse impact on their health‑related quality of life, while reducing the need for healthcare interventions that impair quality of life. A 'lower than usual' or 'permissive' target Hb level might reduce the need for intravenous iron, ESA and hospital or clinic appointments. A trial is needed to compare a 'usual' target Hb level with a 'permissive' target Hb level.

  • National Institute for Health and Care Excellence (NICE)