stakeholder comments on draft scope - with developer's

Anaemia management in chronic kidney disease guideline – stakeholder comments received on draft scope, with developer’s responses7 June – 5 July 2004

National Institute for Clinical Excellence of 63


Organisation Section Comments Response

Addenbrooke's NHS Trust

Section 4.1

The Scope indicates that ‘The guideline will offer best practice advice on the care of people who have a clinical diagnosis of anaemia associated with chronic kidney disease’, and specifies which groups will and will not be covered. In several of the groups that the Scope does not intend to cover there will be patients where chronic kidney disease may be a contributory factor, but not the sole factor in causing anaemia. Examples would be patients with myeloma (haematological disease) or vascultiis (inflammatory disease), where there may be impaired renal function as a consequence of the primary disease. It would be helpful to clarify whether such patients would be included in the Scope.

We are not seeking to cover the management of complicating factors in any detail. The primary focus of the remit and Scope is on anaemia management in CKD.


Section 4.2

It would be helpful to make this more explicit, so that guidelines are prepared for the specific role of primary, secondary and tertiary care.

Thank you. The remit we have been given is to develop a single guideline and not individual sector delivery.


Section 4.3.c

The provision of guidelines on the management of nutritional status, dialysis adequacy and hyperparathyroidism is to be welcomed, but these are major tasks, each of which could warrant a NICE guideline in its own right.

These issues will be covered but only as they relate to anaemia management in CKD.

Aintree Hospitals NHS Trust

This organisation was approached but did not respond.

Aksys Healthcare Ltd 4.3 Clinical Management

We consider the following two factors as important additions that must be included in this technology assessment. Whilst neither of the two factors serve as first line approaches in anaemia management, they have important influences on its management and clinical outcomes:

Thank you but this is a guideline and not a technology assessment.

Aksys Healthcare Ltd 4.3.c DIALYSIS FREQUENCYEvidence will be submitted showing that more frequent dialysis leads to better removal of uraemic toxins, higher haematocrit and haemoglobin levels and a lowered need for Erythropoeitin Stimulating Agents (ESA).

Thank you, noted.

Aksys Healthcare Ltd 4.3.c ULTRAPURE DIALYSATEEvidence will be submitted showing that ultrapure dialysate leads to reduced endotoxin levels that are associated with the inflammatory response and ESA resistance.

Thank you, noted.

Amgen UK Ltd Amgen considers the draft Scope to be well considered, and wishes to make no comment.

Thank you.




Anaemia Nurse Specialist Association (ANSA)

4.1.1 Population: There should be links with the Diabetes NSF with regard to the problem with Diabetes & anaemia. It would be appropriate to develop guidelines that could overlap with these two disease areas. A clear definition is needed for CKD related to level of kidney function.

We will use the stages 1–5 in the guideline (but not in the scope) as a more accurate method of defining CKD.


4.1.1 Transplantation should not be restricted to directly following surgery. It should include all patients who have a transplant as they can become anaemic and require treatment, which is essential to prevent any cardiovascular complications. Clear parameters regarding transplantation need to be agreed.

Thank you. When the transplant is failing this is encompassed under the category of pre dialysis.We confirm that the Scope includes failing transplant.Those who have well functioning transplants may not have anaemia; hence we would not need to expand to encompass the whole of the transplant period.


4.1.2 Groups’ not covered- haematological disease, Myeloma and CKD are closely linked. Whilst the primary cause of anaemia is myeloma, there are patients with ESRD & myeloma who are on dialysis. It is possible to carry out erythropoietin predication tests for patients who have haematological disorders to see if they would respond to treatment and to check erythropoietin levels. Perhaps it would be appropriate to have a more in depth screening process for this type of patient.

The Scope of the guideline pertains to anaemia caused by CKD. Hence we are only seeking to exclude the treatment of malignancy where it is the primary cause of anaemia. The guideline will only deal with the treatment of renal contribution to anaemia in myeloma.


4.1.2 Anaemia caused by acute/chronic inflammatory states requires clarification. It needs to be disease specific as many Vasculitis patients have renal disease.

Re infections/chronic inflammation – we agree that dialysis patients are subject to infection. However, it is anaemia that is the focus of the guideline and hence it is the impact of infection on anaemia. This will be included in the Scope when considering management of, and factors, which have an impact on anaemia in renal disease under section 4.3c.


4.1.2 Children should be included, as they will become the adults with renal failure. There is a great deal of evidence to prove the benefits of treating anaemia early and preventing cardiovascular complications. Children should not be denied access to treatment, which may happen if they are not included in the guidelines.

We accept that this is a valid point and hence the Scope and guideline will include children.


4.2 Healthcare setting is unclear as to how, where and by whom the care will given. In the UK the majority of renal units use the expertise of nurses to run their anaemia management programmes. This proves to be efficient and cost effective and beneficial to the patient. This role has been promoted nationally and internationally by the Anaemia Nurse Specialist Association

Thank -you. We need a firm evidence-base for healthcare setting issues. Published evidence that these factors are important can then be considered. It would be extremely helpful if you could please submit any references directly pertaining to this that you would wish the developers to consider during the stakeholder evidence submission stage.




and has resulted in nurses in Europe adopting a similar role.Prior to such posts anaemia management was fragmented and uncontrolled. To manage anaemia across primary, secondary & tertiary care will require close monitoring, but it must be clear who will be responsible and accountable for the patient’s treatment.Renal Nurses play a key role in the management of anaemia in patients with CKD and EKD and this should not be overlooked when deciding where and who should manage these patients across health care settings.





4.3 Diagnostic evaluation differs depending on which criteria are used, often dependent on the tests that the pathology labs are capable of carrying out. A decision needs to be made as to which tests are most relevant, evidence based and available.

Thank you. We agree.


4.3 Target levels – should not say target levels but criteria for point of referral, A target is an aim not a starting point.

Thank you, we will delete ‘target’ and insert ‘threshold’.


4.3 Management factors – should they be the same for CKD and EKD.

Thank you, yes, they will be the same whether EKD means early or established KD by you in this context.


Nutritional status – an agreed marker is needed here such as albumin when considering haematinics.

We are referring to the use of conventional haematinics here (for example ferritin and B12). The context of ‘haematinics’ as a term only is made reference to in Scope.


4.3 Dialysis adequacy should have recommendations regarding water quality, dialysers, vascular access, time and frequency of treatment.

Thank you but this is not a guideline about dialysis. It is anaemia that is the focus of the guideline and hence it is the impact of these on the anaemia. This will be included in the Scope when considering management of, and factors, which have an impact on anaemia in renal disease under section 4.3c.


4.3 Transplantation should be included here as some of the immuno suppressant therapy can cause anaemia due to the effect of the bone marrow.

Thank you but this is not a guideline on transplantation.


4.3 Assessment & Optimisation of Hb etc. should make recommendations for targets and upper/lower parameters of Hb , iron status, Should discuss type of drug therapy recommended.There are current issues with use of iron dextran and is use has been questioned by the new European Best Practice Guidelines for anaemia management.

Thank you, the evidence-base will be considered here.


4.3 Monitoring treatment should include management of non-response to treatment. Also should address who manages this group of patients, how often and where.



4.3 Funding has not been included but it is an area of concern as postcode prescribing does exist especially for patients not receiving dialysis and inequity of funding results in poor service provision and is detrimental to the patient. Patients who are denied treatment are compromised and should not be put at risk due to lack of resources and funding.

Funding generally lies outside of the remit. We need a firm evidence-base for healthcare setting issues.. Published evidence that these factors are important can then be considered. It would be extremely helpful if you could please submit any references directly pertaining to this that you would wish the developers to consider during the stakeholder evidence submission stage.




If there is indeed a published evidence-base relevant to these factors we will be able to consider this.





General Overall the document is very positive and addresses the key issues. Concerns regarding evidence are such that several of the studies being carried out in patients with CKD and anaemia will not have been completed when these guidelines are being devised. Evidence from these studies could well have an influence on future practice.

We will strive to include the evidence base as far as we can but there has to be an agreed date cut off point. The published guideline will be reviewed at a 2-year period in order to decide whether an update of the evidence is required.


General The renal registry may not be a true picture of anaemia management across the country as many units are not able to submit data due to software incompatibility. Most units undertake regional audits and it may be pertinent to collect data from units which cannot submit to the registry by other means.

Thank you.

Anglesey Local Health Board


Association of Renal Industries

4.1.1 a)& title

The population should include patients with stages 1-V CKD as defined in the KDOQI guidelines and adopted by the UK renal community. This a more accurate method of defining CKD.

Thank you we agree and will use the stages 1–5 in the guideline (but not in the Scope).


4.1.1b Transplant patients should be considered CKD patients and staged and managed appropriately not just directly after transplant surgery.

Thank you we agree and will use the stages 1–5 in the guideline (but not in the Scope).When the transplant is failing this is encompassed under the category of pre dialysis. We confirm that the Scope includes failing transplant.Those who have well functioning transplants may not have anaemia; hence we would not need to expand to encompass the whole of the transplant period.


4.1.2 Chronic inflammatory disease could be caused by non biocompatible dialysis solutions and membranes or the materials in which they are packed, catheters and infection. Water quality and protein-energy malnutrition can also be contributing factors inflammation.It may not be appropriate to exclude all patients with haematological disease or malignancy if their primary cause of anaemia is renal failure.

Re infections/chronic inflammation – we agree that dialysis patients are subject to infection. However, it is anaemia that is the focus of the guideline and hence it is the impact of infection on anaemia. This will be included in the Scope when considering management of, and factors, which have an impact on anaemia in renal disease under section 4.3c.The Scope of the guideline pertains to anaemia caused by CKD. Hence we are only seeking to exclude the treatment of malignancy where it is the primary cause of anaemia.


4.1.2b Is the exclusion of children appropriate as this is a small but important treatment group who would benefit from good anaemia management.



4.3 a In vitro diagnostics should include test which monitor nutritional status prealbumin, Vit B12, and folate. Markers of infection and inflammation, CRP, cytokines such as TNFα, interleukin-6.

Thank you for your suggestion. We will consider the evidence base.




Differential tests diagnosis of anaemia, ESR, & fibrinogen. Iron status, total iron binding capacity (TIBC) transferring and ferritin.





4.3 b Account should be taken of normal ranges for different patient groups, male/female, young/old. A “one size fits all may not be appropriate. It may be more relevant to have targets which state that Hb levels should not fall below a certain level for a patient group which should help to minimise the consequences of chronic anaemia such as LVH etc. Preventing chronic anaemia in the CKD population is probably more effective than trying to build patients back up to a certain HB level.

Thank you.


4.3 c Nutritional status should take account of both protein/energy malnutrition and the use of phosphate binders. The type of binder needs to be considered and the affect each has on the patient. Particular note of the use of aluminium based binders and the potential effect on bone marrow and the development of microcytic anaemia needs to be taken and its use limited to the absolute minimum and carefully monitored.

Thank you. This is not specific to anaemia management. This is considered to be part of the general management of CKD not anaemia.


4.3 c hPTH the importance of the early intervention of dietary management and the use of phosphate binders, vitamin D analogues and other interventions as they become available, to reduce the risk of parathyroid hyperplasia at an early stage.

Thank you. This is not specific to anaemia management. This is considered to be part of the general management of CKD not anaemia.


4.3 c As well as dialysis adequacy the quality of dialysis should be considered, biocompatible membranes and solutions, strategies for minimising infection from access sites and water quality.

It is anaemia that is the focus of the guideline and hence it is the impact of infection on anaemia. This will be included in the Scope when considering management of, and factors, which have an impact on anaemia in renal disease under section 4.3c.


3b RRT patient numbers. Need to use data from the 2003 registry data giving figures for 2002. Estimate for England and Wales 32,500 patients with 46% transplanted patients.

When the Scope was written, recently published update figures were not available. 2003 figures will have now been used to update the Scope.


3d Update information from the 2003 renal registry document.Effective use of IV iron and EPO should be considered in stages 1-1V.

Thank you – noted.


Overall comment

The Scope is quite wide ranging and does go beyond the narrow remit of EPO therapy which is to be commended. However note does need to be taken of the confounding factors which may work against efficient and effective anaemia management.

Thank you.

Association of the British Pharmaceuticals Industry,(ABPI)


Barking, Havering & This organisation was approached but did not respond.




Redbridge NHS TrustBarts and The London NHS Trust

This is a very important topic in renal medicine. Proper management of anaemia and the introduction of erythropoeisis stimulating agents (ESA) and intravenous iron therapy has revolutionised the quality of life of these patients.

However, I am interested as the why this topic has been commissioned as there are already several generally accepted detailed guidelines published on this subject. For the NICE guidelines to be helpful the Scope needs to be reviewed. It needs to consider the practicalities of administration and funding of such programs. The European and K/DOQI guidelines are clear in the targets that we should be aiming for, how best we achieve them, but do not look at the UK specific issues of delivery. For the perspective of a renal physician, the biggest issue is the funding and prescribing of ESA. Many units are faced with extremely complicated arrangements in order to ensure that patients are receiving the appropriate products at the right doses in a timely fashion. This is because we are having to negotiate with primary care continuously. This leads to both clinical and staff inefficiencies. The end result is patients suffering. This Scope should therefore also examine the most efficient way to run and fund a anaemia program.

The question about the selection of the topic lies outside the consultation on the development of the Scope. NICE are referred topics from the Department of Health via a topic selection process. Details of the process can be found at http://www.dh.gov.uk/Consultations/ClosedConsultations/ClosedConsultationsArticle/fs/en?CONTENT_ID=4016963&chk=7lPThG

Service delivery models and funding are generally outside the Scope of a NICE clinical guideline.

Bedfordshire & Hertfordshire NHS Strategic Health Authority


Birmingham Heartlands & Solihull NHS Trust

General The term established renal failure (used interchangably with end stage renal failure) is confusing. The term established renal failure doesn't define the degree of renal failure and there is considerable potential for readers to confuse this with the term chronic kidney disease (CKD). End stage renal failure does define the degree of renal failure clearly and should be the preferred term.

Thank you. This will be reflected within the staging terms that we will use.

We will use the stages 1–5 in the guideline (but not in the Scope).


4.1.1 Patients with a failing renal transplant are a particular sub group of CKD (pre-dialysis) who may have significant anaemia. For completeness it would be helpful in the Scope to acknowledge this sub group which represents an overlap between CKD, pre-

We confirm that we include patients with poorly functioning transplants within 4.1.1. of the Scope and that they will be included in the guideline.




dialysis and renal replacement therapy (transplant).





4.3 c) The guideline should include recommendations about the type of vascular access to be used in haemodialysis patients. This should be a native AV fistula whenever possible. Temporary vascular access use (i.e. catheters) is associated with a lower haemoglobin concentration, probably due to the fact that dialysis adequacy is worse and infection rates, and hence erythropoetin resistance, are greater with catheters. [References: Patient characteristics associated with hemoglobin concentrations: the DOPPS. Pisoni RL, Prutz KG, Canaud B et al. J Am Soc Nephrol 2003; 14: 265A. Erythropoietin therapy and associated haemodialysis patient characteristics: DOPPS results. Pisoni RL, Young EW Gillespe BW et al. J Am Soc Nephrol 2003; 14: 267A.]

Thank you.


4.3 c) The optimal management of anaemia in CKD should minimise the use of blood transfusion. The importance of this cannot be over emphasised given the restricted supply of blood products, their expense and the amount of blood products administered in renal units. It would be helpful to include in the Scope - guidelines on best practice in relation to blood transfusion in this patient group.

Thank you. This is already covered by the Scope.

British Association for Paediatric NephrologyAnd Royal College of Paediatrics & Child Health

4.1.2 b Following on from the Stakeholder meeting held on Monday 28th

June, we wish to reiterate our view that under 16 year olds should be included within the Scope of this guideline.

1. The remit from the Department of Health was to “develop a guideline ………… for ………. people with poor renal function.” It is therefore discriminatory against children to exclude them simply on account of their age.

2. The underlying causes and the underlying principles for the treatment of renal anaemia in children are essentially the same as they are in adults. It is therefore logical to include children within the remit of the guidelines.

3. We understand that there is a concern that there would be inadequate resources to cope with the additional work required to include children within the guidelines. In comparison to the adult literature on erythropoietin there is only a very small body of evidence specifically relating to children. It is therefore unlikely that this will





make a material difference to the amount of evidence that needs reviewing. There would however be a need for considering the children separately because of the differences in target haemoglobin levels and drug dosing.

4. There are in the United Kingdom some 800 children with end stage renal failure and a considerably greater number of children with chronic renal failure (pre-dialysis). These guidelines will therefore potentially benefit a large number of children and young people.

We are concerned for the plight of children with chronic, uncommon diseases. These children tend to be excluded from chronic disease initiatives (e.g. National Service Frameworks, Clinical Guidelines) but also excluded from Paediatric initiatives because they are a small group of children in comparison to those with common childhood disorders. The anaemia guidelines are a great opportunity to ensure that children and young people receive the same high quality management as their adult counterparts.




British Association for Paediatric Nephrology

4.1.2 b) The BAPN wishes the guideline to include children & young people under 16 yrs. Reasons for inclusion:1. Under 16’s with CKD fulfil the inclusion criteria in section

4.1.12. The anaemia in under 16s due to CKD has essentially the

same causation and impact as in adults3. Under 16s are included in the renal NSF.4. Under 16s with CKD will be disadvantaged in comparison to

adults if not included.5. Whilst the evidence base for management is not as well

documented for children, this is in itself a strong reason for developing a guideline.


British Dietetic Association

General When does a patient become predialysis. As there is a shift of emphasis from hospital Nephrology (in centre) to community / primary care Nephrology (out of centre) what about the many patients that are classed as General Nephrology being managed in the primary care that are anaemic and may benefit from therapy.



People directly after transplant – suggest this may need to be expanded to encompass the whole of the transplant period particularly failing transplant.

Thank you. When the transplant is failing this is encompassed under the category of pre dialysis. We confirm that the Scope includes failing transplant. Those who have well functioning transplants may not have anaemia; hence we would not need to expand to encompass the whole of the transplant period.


More consideration needed about whether to include paediatrics or not. As far as I am aware paediatrics tend to remain in paediatrics up until 18yrs or full time secondary education.

We accept that this is a valid point and hence the Scope and guideline will include children. This has been changed in the Scope.


Address the aspect of patient education. It won’t matter what gold standard of therapy you come up with if patients are not educated appropriately then the effectiveness of the treatment is lost.

Patient education is a generic issue across all guidelines. We will look specifically for literature pertaining to anaemia in CKD for example self-management / management plans.


? Address compliance issues. This is a generic issue across all guidelines. It has been recognised that this needs to be addressed in a separate guideline dedicated to concordance issues.


? Look at measurements of improved therapy on QOL issues for patients.

QoL outcome measures will be addressed in the evidence base.


Comments on Nutrition

Whole heartedly agree that nutritional status of an individual will have an impact on anaemia but evidence will be limited.

Thank you.





Nutritional status affects anaemia but this is also true if reversed i.e. anaemia will affect nutritional status.

Thank you, noted.


Limited evidence about the micronutrient nutritional status of our patients most evidence concentrates on macro nutrients – protein / calorie.

Thank you. There is limited evidence on micronutrient nutritional status (e.g. carnatine). We will be led by the evidence base.


Limited evidence generally. Thank you.


Not sure whether by increasing the iron, B12 and folate content of the diet will improve serum levels and ultimately anaemia management.

Thank you, noted.


Also not sure whether by improving general nutritional status this will impact on anaemia management, similarly whether improving anaemia management results in an improvement in anaemia.

Thank you, noted.

British Geriatrics Society

4.1 Population

4.11 Groups that will be covered

Whilst there has been no specific exclusion of older people with chronic kidney disease (CKD) it should be noted and possibly mentioned in the Scope that older people should be included. CKD is a disease of older people increasing from 1,900 people per million age 50-59 years to 17,000 people per million age 70-79 years. Most of these older patients are at stages 3 and 4 CKD and are not on dialysis.

Thank you. We are not excluding the elderly.


4.2 Healthcare setting

It is worth noting that many patients with CKD are under the care of secondary care physicians who are not renal physicians. The care of patients with anaemia caused by CKD under other hospital teams should not be included.

Thank you. This is already covered by the Scope in section 4.2.


4.3 Clinical management

4.3a Detection and diagnosis of anaemia in CKD- CKD in older people has been missed on many occasions due to the use of serum creatinine as a marker of glomerular filtration rate (GFR). This will be improved with the use of calculated clearances such as the MDRD and the Cockcroft and Gault equation. The Scope should take this into account.

We agree.

British National Formulary (BNF)


British Psychological Society, The


British Renal Association, The


British Renal Society General Excellent document : focussed , deliverable, clear and hopefully will complement Renal NSF.

Thank you.




British Renal Society Section 3 d

There is clear agreement by clinicians on “optimal management renal anaemia. The variations in different regions is rather due to differences in funding and commissioning arrangements.

Thank you.

British Renal Society We welcome an evidence based guideline, however we hope that UK experience will be looked at even if the publications of single centres are not from large RCTs provided such experience is multidisciplinary. We hope to supply a list of some of the abstracts on anaemia management presented in the past at our symposia.

Thank you.

British Renal Society Section 4.1.1

Predialysis CKD hopefully does not only refer to advanced CKD (GFR <20), one particular group of patients of concern are diabetics who may develop anaemia requiring treatment at earlier stages of CKD.

We will use the stages 1–5 in the guideline (but not in the Scope).

British Renal Society Section 4.1.2

I would concur with the exclusion criteria .The evidence for most of the conditions excluded is patchy , otherwise the guideline will be full of Class C evidence, however we would hope that at the time of guideline review in the future consideration would be given to these groups depending on evidence available.

Thank you.

British Renal Society Section 4.3 c

The guideline should include when treatment will be withdrawn in refractory/resistant anaemia when there is lack of response to erythropoiesis stimulating agents.

Thank you the evidence base will be considered

CHI This organisation was approached but did not respond.Cochrane Renal Group, NHMRC Centre for Clinical Research Excellence, University of Sydney, Australia and Dept of Emergency & Organ Transplantation, University of Bari, Italy


Conwy and Denbighshire NHS Trust


Countess of Chester Hospital NHS Foundation Trust


Department of Health The Department of Health has no comments on the draft Scope Thank you.




of the anaemia management in chronic kidney disease appraisal.




Department of Health - Publication of the National Service Framework for Renal Services, Part One: Dialysis and Transplantation (Gateway reference 1611)


Diabetes UK General and4.1.1

Diabetes is the most common cause of kidney failure in the westernised world affecting as many as 40% of patients on dialysis. In the UK this figure is estimated at 15% of dialysis patients also having diabetes. However, it is also accepted that the prevalence of diabetes is notably undiagnosed in patients with kidney failure.Because of this, we strongly feel that people with diabetes should be considered as a separate subgroup within this guidance.

People with diabetes are included within the evidence base (and hence this is not excluded when searching the literature). However, people with diabetes will not be considered as a separate subgroup as this is outside of the Scope.

Diabetes UK 4.3.c Erythropoietin deficiency is probably more common in patients with diabetes, although the precise reason for this is unclear. This again raises the need for a separate subgroup within this guidance for people with diabetes.

People with diabetes are included within the evidence base (and hence this is not excluded when searching the literature). However, people with diabetes will not be considered as a separate subgroup as this is outside of the Scope.

East Kent Hospitals NHS Trust


Genzyme Products Ltd 4.1.1 a) The population should specify that the guidelines will include patients with Chronic Kidney Failure Stages 1-5 and specific criteria for determining these stages 1-5 CKD (according to UK practice guidelines, European Best Practice Guidelines, and Kidney Disease Outcomes Quality Initiative/KDOQI).


Genzyme Products Ltd 4.3. a) The Scope recommends that anaemia due to haematological malignancy, acute and chronic inflammatory disorders and HIV should not be covered. The problem is that the cause of anaemia in ESRD due to these conditions will be difficult to distinguish from anaemia due to the anaemia caused by these conditions themselves. The clinical question raised is the process of distinguishing between the causes of anaemia in ESRD – how will the guideline propose to diagnose causes of anaemia in ESRD?

Thank you. Regarding the last sentence – this will be covered in guideline but it is premature to include detail here.




Genzyme Products Ltd 4.3. General

A separate section on factors related to resistance to anaemia therapy should be added as this can be quite complex.

Thank you, this is addressed in maintaining threshold levels under section 4.3.b of the Scope.

Genzyme Products Ltd 4.3. General

Clarification on measuring certain outcomes in anaemia, i.e., evidence on mortality, morbidity and quality of life (also likely included).

The evidence base will be considered.

Genzyme Products Ltd 4.3. c) The guideline should address the clinical question raised regarding management of factors which have an impact on anaemia in renal disease as relates to bone and mineral metabolism. These include treatment of factors such as hyperparathyroidism and hyperphosphatemia in which the choice of treatment can impact the severity of anaemia and the resistance or success of anaemia treatment such as erythropoietin and Vitamin D efficacy. Phosphate binders such as aluminium-based binders and related toxicity have been shown to have an impact on bone marrow health, erythropoietin efficacy, and progression of anaemia. Control of hyperparathyroidism with different binders is likely to have different impacts on anaemia levels.

Thank you, noted.

Genzyme Products Ltd 4.3. c) The terminology on ‘optimization of hemoglobin’ and ‘targets’ should be clarified as a more accurate description would be ‘improvement and maintenance of haemoglobin within a defined range’.

Thank you. Please see Scope for amended text 4.3.c. The word ‘target’ will be deleted and amended to ‘threshold’.

Genzyme Products Ltd 4.3. c) Inflammation as a factor related to the management of anaemia should be addressed, as relates to levels of C-reactive protein (CRP), a marker of inflammation. The presence of inflammation has been associated with increased resistance to erythropoietin treatment; therefore reducing the levels of inflammation would be favourable for the management of anaemia. Management of hyperohosphatemia with different binders is likely to have different impacts on inflammation and anaemia.

Thank you, noted.

Gloucestershire Hospitals NHS Trust


Guys & St Thomas NHS Trust

4.1.1 The use of the term pre-dialysis CKD should not restrict the guideline to those patients known to renal services and being considered/prepared for dialysis. The guideline should cover all patients with CKD irrespective of the stage of CKD, and whether or not they are under renal or other services (diabetic clinic, primary care).

Yes, we agree with your comment. We will consider them if the anaemia is due to CKD.

Guys & St Thomas 4.1.1 Patients soon after transplant and those with longer standing Thank you. When the transplant is failing this is




NHS Trust patients with impaired graft function and anaemia should be considered separately.

encompassed under the category of pre dialysis. We confirm that the Scope includes failing transplant. Those who have well functioning transplants may not have anaemia; hence we would not need to expand to encompass the whole of the transplant period.


4.1.2 a) This should be worded as to avoid interpretation that pts with CKD causing anaemia who have one of these co-morbid states should be treated in a different fashion.Patients with co-morbid conditions contributing to both anaemia and renal failure should not be covered by these exclusions.

Thank you, noted.The guideline specifically deals with anaemia caused by chronic kidney disease. Patients with these co-morbidies have other causes of anaemia and are therefore being excluded.


4.3 b) This might be more accurately an Hb range in which treatment for anaemia should be commenced, and a level below which Hb should not be allowed to fall. Careful consideration needs to be given as to whether minimal acceptable levels or desirable targets are stated, and whether these targets apply to individual patients or to cohorts.



4.3 b) It should be considered whether an overall target range for Hb level should be given, or whether different target ranges are desirable in different conditions (heart disease, diabetes, young patients).

Thank you.


4.3.c) Recommendations on iron use should include recommendations that the best measures of iron stores and iron availability be readily available.

Thank you – we will consider the evidence base.


4.3 c) An indication as to the use of blood transfusions should be considered, as there is likely to be greater restrictions on blood stocks in the next few years and tighter controls on blood transfusions generally. It should be made clear that blood transfusions are not to be used to maintain Hb in target range.

Thank you. This is already covered by the Scope.


4.3 c) It may be desirable to give guidance on those patients who exhibit resistance to treatment, in terms of their identification, investigation and management.

Thank you – the evidence base will be considered.

Hammersmith Hospitals NHS Trust

4.3 The guideline should be as explicit as possible about the actions that needs to be undertaken to optimise anaemia, prior to instituting EPO therapy. (Not just Ix required).

Yes, we agree and acknowledge this.


4.3 What maintenance targets of Hb should be aimed at and how specific co-morbidities may influence that target.



4.3 Defining which conditions/patients should be excluded from requirement to reach anaemia targets (ie those in whom this would result in significant iron overload).






4.3 Comments on type and route of therapy. Thank you – noted.


4.3 Guidelines on the assessment of complications of EPO therapy – recommendations for BP monitoring.



4.3 Management of poor responders. Thank you – the evidence base will be considered.


4.3 Actions to be taken if Hb overshoots desired target range Hb. Thank you. This will be considered.

International Myeloma Foundation (UK)


Kidney Alliance, The This organisation was approached but did not respond.King's College Hospital NHS Trust


Long Term Medical Conditions Alliance


Media Innovations Limited

General comments:

1. Existing Guidelines for Renal Anaemia: National and international guidelines (Renal Association, European Renal Association, Dialysis Outcomes Quality Initiative (DOQI), and other national bodies) are available for the management of renal anaemia covering much of the population suggested in the NICE scoping document. 1.1 These have typically been through several versions already. 1.2 They concentrate in particular on the ‘targets’ for haemoglobin (and iron) to be achieved in individual patients. 1.3 They have reviewed the extensive literature on the use of Epoetins and Iron therapy, as well as contingent clinical factors as outlined in the NICE scoping document. 1.4 They too attempt to provide ‘recommendations for good practice that are based on the best available evidence of clinical (but not cost) effectiveness’ [2a].1.5 Despite these efforts, clinical studies (ESAM, DOPPS) and Registry data show systematic underachievement in managed renal anaemia in Europe and there is ‘wide variation in practice’.



2. Aspirations for Guidelines: Whether or not there is ‘lack of agreement on the optimal management’ rather depends on the definition of ‘optimal’, but certainly processes are varied and depend on a range of principles of staffing and clinical methods [2d].2.1 Whether ‘an evidence based guideline would improve the

Thank you, noted.




standards of care across renal units’ remains to be seen, since that has not occurred necessarily as a consequence of the existing work.2.2 There has been an annual improvement in both pre-dialysis and dialysis related Haemoglobin outcomes as documented by the UK Renal Registry (UKRR) that probably represents an intuitive effect of improving clinical practice on the part of renal units generally. 2.3 Unfortunately, great and sophisticated effort, however transparent, is no guarantee that any subsequent guideline will be effective in improving clinical outcomes and costs. 2.4a By contrast, a guideline statement is likely to beneficially influence ‘appropriate commissioning of cost-effective treatments’ in this area, in part because it is apparent that lack of investment in Epoetin has occurred regionally in England, with consequences for Haemoglobin outcomes. The extent and specificity of the relation between funding and performance have not been clearly described, the UKRR finding it hard to compile Epoetin doses, in particular, from clinical databases. 2.4b It is worth emphasising that the cost-effectiveness of Epoetin is especially dependent on the pricing of the agents, with recent competition creating discounts of up to 50% in some areas. Improvements in clinical practice are unlikely to challenge that scale of cost reduction.





3. Characteristics of current guidelines: Existing guidelines are imperfect. They often incorporate an element of yardstick or clinical performance measure, without acknowledging that is the case (for example, in the past, 85% compliance with a guideline statement as a criterion of performance).3.1 Alternatively, in recent versions, they appear to abrogate the responsibility for any yardstick whatsoever. 3.2 Even more mischievously, they tend to create ‘pseudo-algorithms’ for management from the literature of clinical efficacy, typically untested in general populations for practical effect. This is demonstrably misleading in the case of European guidelines for the control of high Se Ferritin levels, for example. 3.4 Lastly, despite the fact that unit performance must be represented by summary statistics, the guideline documents rehearse individual patient management exhaustively but give little or no guidance on how to manage a patient population to achieve desirable outcomes overall.3.5 Little work has been done in this area, general distributions being simply compiled from the sum of individual clinical encounters.

Thank you, noted.


4. Necessary features of anaemia outcomes: As indicated in UKRR Reports (www.renalreg.com), the currently achievable haemoglobin and iron outcomes to give any desired unit profile can be precisely known (Rose-Day plots).4.1 The clinical technology to allow their definition on a predictable and consistent basis is not practised except in a few northern UK renal units. 4.2 The evidence that this is feasible has been ignored by recent European guideline authors. 4.3 This may have been in part because literature search techniques are incomplete for the supporting experimental papers. This is reflected in their absence in the Cochrane renal database and will be repeated unless especial care is taken in the NICE searches for supporting evidence. 4.4 There is also a strong undercurrent of cultural antipathy for the management of patient sets or groups for optimal management, rather than individuals, even though this may be




beneficial overall. Part of this in Europe and the US can be related to the financing of medical care in different Health Care Systems.





5. The necessary Guideline: The issue then resolves into the need for a guideline that does not simply repeat the aspirational ‘target’ values for individuals that are unachievable, except systematically, at unit level, but goes some way to explain how predictable, consistent and cost effective results may be brought about through appropriate clinical processes. 5.1 The ‘optimal’ clinical outcomes from any given spend on Epoetin and Iron are unlikely to be achieved from unsystematic, piecemeal clinical management. 5.2 An effective system also has clinical benefit, since any anaemic patients stand out from the adequately managed population as ‘non-responders’ and are revealed as in need of clinical attention. 5.3 In addition, the facilitation of recurrent audit of anaemia management is an important part of clinical and cost-effectiveness.

Thank you, noted.


6. The advantage of the NICE: It is easier to frame an ideal guideline than produce it, of course, but there are possibilities that have not been considered by previous authors in this area that fit well with the NICE remit. 6.1 The focus of the NICE on the clinical technologies required to manage patient sets coincides with available, mature work in renal anaemia on the benefit of managing renal unit cohorts to achieve predictable haemoglobin and iron outcomes at the individual level. 6.2 By these means a platform of unit achievement can be reliably achieved, with individual modulation if believed necessary. 6.3 Further evidence will be presented to demonstrate these assertions in the later part of this exercise by the Media Innovations Group of the University of Leeds.

Thank you, noted.

Media Innovations Limited 4.1

4.1.2

Specific Comments by section: PopulationThese categories presumably exclude Primary Red Cell Aplasia (PRCA-EPO), the consequence of developing neutralising antibodies to epoetins.Dialysis patients are subject to frequent infections and any management system will need to address/make provision for

PRCA – This will be considered when addressing EPO and route of administration.

Re infections/chronic inflammation – we agree that dialysis patients are subject to infection. However, it is anaemia that is the focus of the guideline and hence it is the impact of infection on anaemia. This will be included in the Scope when




the response to acute infection/inflammation in that setting.Haemodialysis patients, in particular, are considered by many to express a chronic inflammation as a background to their illness, modified perhaps by the conditions of dialysis, so that some inflammatory component will need to be addressed, if not Primary inflammatory diseases.

considering management of, and factors, which have an impact on anaemia in renal disease under section 4.3c.





4.2 Healthcare settingThe NHS care of chronic illness is in a state of flux and is likely to change over the next few years. It will be important to keep open the potential for commentary on management in all three settings, including by nurses and nurse practitioners/’anaemia co-ordinators’.The home delivery of epoetin by the companies or their associates and the effect on VAT charges of different prescribing mechanisms will also need to be considered.

Thank you. We need a firm evidence-base for healthcare setting issues. Published evidence that these factors are important can then be considered. It would be extremely helpful if you could please submit any references directly pertaining to this that you would wish the developers to consider during the stakeholder evidence submission stage.If there is indeed a published evidence-base relevant to these factors we will be able to consider this. Health Economic cost effective evidence will also be taken into account.


4.3 Clinical management[a] Guidance on the investigation of potential blood loss would be of interest since haemodialysis patients often show evidence of persistent minor bowel losses that can be misconstrued as requiring expensive imaging for diagnosis.

[b] The use of ‘target’ here appears to be an error, since threshold would be more apposite. There has been much confusion in clinical intervention in the terminology of aims, goals and targets that have been clarified in the field of renal anaemia, at least. This has been shown to have an important bearing on the principles of management.

[c] Mention should be made of the dialytic features that influence renal anaemia as well as dialysis adequacy, which would include water treatment, chloramines, dialysis frequency and, possibly, dialyser type.

The meaning of the ‘optimisation of haemoglobin (and iron stores)’ will need to be considered precisely; for individuals or unit cohorts, over time, variability etc.? What exactly would be ‘optimised’?

The opportunity costs of clinical time and effort should also be considered since this is demonstrable, sometimes expressed in the employment of a separate nurse/pharmacist co-ordinator. This has also been prompted by the need to undertake administrative functions in order to run the epoetin contract or undertake the multiple liaisons required to make ‘shared care’ effective in a locality.

Thank youa. This is outside of the remit and Scope.

b. Yes we agree, this has been amended.

c. It is anaemia that is the focus of the guideline and hence it is the impact of these on the anaemia. This will be included in the Scope when considering management of, and factors, which have an impact on anaemia in renal disease under section 4.3c.

d. Opportunity costs – we need a firm evidence-base for this to be considered. Published evidence that these factors are important can then be considered. It would be extremely helpful if you could please submit any references directly pertaining to this that you would wish the developers to consider during the stakeholder evidence submission stage. A health economist will guide us.




Medicines and Healthcare Products Regulatory Agency (MHRA)


Mid Essex Hospitals NHS Trust

4.1.2a Clarification is required on anaemia as a result of chronic/acute inflammatory disease states – we presume pts on RRT who have episodes of sepsis will be covered from their diagnosis of CKD and not excluded because of their inflammatory state. In addition, if a CKD who doesn’t have anaemia per se but suffers it as a result of sepsis – will they be covered?


Mid Essex Hospitals NHS Trust

4.1.2b We believe that children should be included in the Scope as they are treated with the same drugs in the same way and progress on to adults with CKD. The long-term effects of anaemia are well documented and guidelines are needed to treat the children effectively in order that they don’t become adults with CKD with significant LVH which could have been prevented by effective, consistent treatment guidelines.


National Kidney Federation (NFK)

Section 2b You use the phrase – “ Where a Framework has been published”. The Renal NSF has only been part published – part two is still awaited. It is essential that guidelines encompass the advice expected in Part two of the NSF. Part two will deal with early detection and prevention of renal disease and that means that the vast majority of patients will be contained in the part two area. If part two of the NSF is not published in time for the guidelines then it is vital that the guidelines cover potential renal patients not yet receiving renal replacement therapy, either pre dialysis or earlier. The advancement of renal disease is now classified in groups from one to five. The guidelines must cover all five categories whether they are in the care of GP’s or renal units.

Thank you – we will use the stages 1–5 in the guideline (but not in the Scope).


Section 3b Please check again the figure 45,000 as the national Kidney Federation is expecting the current ( 2004 ) numbers of ESRF patients (37,500) to rise to between 60,000 and75,000 in ten years time.

The figures quoted were obtained from the NSF. This is part of the background of the Scope and not part of the evidence base for the guideline. The latest published evidence has been used in the guideline.


Section 3d An evidence based guideline will only improve standards of care across renal units if the guidelines can be “enforced” at commissioning level. The numbers of renal patients are deemed so low, as to be ignored by commissioners unless there is to be an element of compulsion.

NICE guidelines are not compulsory. However, once the development and validation phases of the guideline is complete the work will be available on our website, and proactively disseminated within the NHS.





Section 4.1

Population – see my first comment. Thank you.


Section 4.3b

Haemoglobin target levels. If, for example, it is desired to achieve a certain standard i.e, 11g/dl then to result in an average of 11g/dl the target must of mathematical necessity be pitched higher than the average required. In other words the target must be 12 or 13 g/dl to allow the average of 11g/dl to be achieved. An average is exactly that – a middle position. It would be no good setting a target of 11g/dl if you wanted to achieve an average standard across patients of 11g/dl.

Thank you.


General Renal patients require relief from Anaemia and it does not matter to them whether this relief is achieved by the Use of Iron supplement or Erythropoietin or a combination of both. Patients would support a cost effective solution that enabled more patients to obtain relief from anaemia, however they would not support a reduction in the amount of Erythropoitin prescribed purely for cost cutting reasons – the control of Anaemia is an important quality of life issue to all renal patients.

Thank you

National Kidney Research Fund, The

general The view of The National Kidney Research Fund is that it is well put together, and complete, and all the stated objectives are sensible. We do not have any specific criticisms.

Benchmarks are the more recent guidelines and recommendations for the target haemoglobin level for successful treatment, derived from European Best Practice, and from K-DOQI. When new Renal Association guidelines emerge these will need to be taken into account as well.

Thank you.

National Public Health Service - Wales

General Content with Scope. Thank you.

Nebo a/s COMMENT ONE, Part 4.1.1. b

Relevance of dividing the patient groups in regard to the level of kidney function:

The guidelines issue the following groups: Pre-dialysis CKD also known as pre renal replacement

therapy and pre end stage renal disease People with established renal failure receiving renal

replacement therapy

Thank you, we agree and will use the stages 1–5 in the guideline (this was not felt to be necessary in the Scope).

With regard to GFR as a tool we agree that this would be a useful development. However it is currently beyond the remit and Scope.




People with established renal failure receiving conservative management

People directly after transplant surgery

We agree on the relevance of differentiating between different patient groups in regard to the level of kidney function, since both the prognosis and in many cases the treatment will vary depending on the type of patient. We although recommend that each group is made more specific by using for example the DOQI criteria for degree of renal function.

We agree with the overall term pre-dialysis as this would aid in the early identification, diagnosis and subsequent management of patients.The terminology is very important in the context of increasing the focus on early detection and intervention thereby delaying the need for renal replacement therapy.

We consider it important to use haemoglobin in combination with GFR as a tool to identify pre-dialysis patients in general practice as early as possible. Earlier diagnosis and treatment improve prognosis and patients’ choice regarding renal replacement therapy.




Nebo a/s COMMENT TWO, Part 4.1.1. b

Relevance of dividing the patient groups in regard to the type of renal replacement therapy:

The terminology “renal replacement therapy”, should be made more explicit to define the two options of renal replacement therapy i.e. CAPD and haemodialysis (as the treatment strategies in these two groups often will vary).

We confirm that the wording ‘renal replacement therapy’ will include both peritoneal dialysis and haemodialysis.

Nebo a/s COMMENT THREE, 4.3 b)

This statement is not very clear in regard to the use of the wording “target”, we recommend a statement such as; “A threshold for the haemoglobin concentration below which treatment of anaemia should be initiated.”

The word ‘target’ will be deleted and amended with ‘threshold’.

Nebo a/s COMMENT FOUR, 4.3 c)

Erythropoiesis should replace haemoglobin so that the phrase will be; “Assessment and optimization of erythropoiesis, including iron supplements (iron stores) and erythropoiesis stimulating agents.”

See amended wording in the Scope.

Nebo a/s COMMENT FIVE, 4.3 c)

Always should replace normal in the following sentence;“Note that guidelines recommendations will always fall within licensed indication in UK; exceptionally and only where clearly supported by evidence and where no license alternative is available use outside license indication may be recommended.”

Thank you for your comment. This phrase is part of our standard wording for scopes. There are occasions where evidence has supported the recommendations outside of the license. Exceptionally, and when this occurs it would be made explicit within the guideline so that practitioners are aware of it. .

Nebo a/s GENERAL Having attended the stakeholder meeting June 28, we were somewhat concerned that the discussion in relation to patient representation focused on the participation of two haemodialysis patients. We consider it more appropriate that patients reflect the different management stages/options, especially predialysis, as this group of patients that has the greatest Scope to influence their choice and clinical/economical outcome.

Thank you. The patient representation will be appropriate for the guideline. We take note of your helpful comments.

NHS Modernisation Agency, The


NHS Quality Improvement Scotland


North Sheffield PCT 4.3 The guideline should be explicit as to what the expected benefits of anaemia treatment (for each of the four groups of patients) would be. In particular, is it expected to be on improvement in quality of life alone, or is it also expected to lead to a reduction in mortality.

Explicit outcomes will be considered from the evidence base.

Ortho Biotech 4.1.2 There may be difficulties entirely excluding anaemia associated with haematological disease from the guideline. For instance,

Thank you. We look forward to what the HTA says.




the technology appraisal on erythropoietins for chemotherapy related anaemia will report by the end of 2005 – the renal guideline will need to consider the recommendation in this guidance to ensure equity of funding and access to EPO for renal and haematology patient groups.




Ortho Biotech 4.3.c It would be useful for the guideline to consider making recommendations concerning route of administration for erythropoiesis stimulating agents (intravenous and subcutaneous).

Thank you, the evidence base will be considered.

Ortho Biotech 4.4 Although stated by NICE to be outside its remit (stakeholder meeting on June 28th), this particular guideline would benefit from considering recommendations concerning the most appropriate mechanism for commissioning recommended interventions for anaemia management in patients with CKD. Otherwise, there is a real danger of non-uniform implementation of the guidance, leading to postcode prescribing of agents such as erythopoiesis stimulating agents.

Thank you for your comment. It is outside the scope of this guideline to prescribe commissioning mechanisms to the NHS.

Plymouth Hospitals NHS Trust


Princess Alexandra Hospital NHS Trust


Qualipharm (UK) Ltd General/Title

As discussed at the meeting classifying CKD in stages I – V as per KDOQI encouraging assessment of renal function by GFR /CCr estimation.

Thank you – we agree and will use the stages 1–5 in the guideline (but not in the Scope).

Qualipharm (UK) Ltd 2 b) final sentence

Important fact is that only module I & II (Part 1) of renal NSF is available. The vital aspect of ‘Pre Dialysis’ treatment and module 3 may not be published until 2005 or even 2006.

Thank you. We will endeavour to work closely with the NSF team.

Qualipharm (UK) Ltd 3 b) The number of patients is likely to rise rapidly and these are the tip of the iceberg. Early diagnosis and treatment may have significant benefits on population health and in the long term reduce burden on NHS.


Qualipharm (UK) Ltd 3 d) Renal Registry Report for 2003 looking at 2002 data is now available. This demonstrates very clearly where units are performing well. It could also prove useful looking at Hbs before dialysis and relationship with mortality.

Thank you – the Scope will be updated.

Qualipharm (UK) Ltd 4.1.1 b) final sentence

‘directly after transplant’ is too narrow. I agree with X who mentioned that other patients with some degree of renal impairment would re-enter as Stage I – V CKD as confirmed by GFR evaluation.

Thank you – we agree.

Qualipharm (UK) Ltd 4.1.2 a) Exclusion of certain patients must be more clearly defined. Many patients may have a complex anaemia whereby renal failure is a major contributory factor. This may exclude such patients as Myeloma’s from treatment which could improve QOL significantly and future renal function being restored.

The Scope of the guideline pertains to anaemia caused by CKD. Hence we are only seeking to exclude the treatment of malignancy where it is the primary cause of anaemia. The guideline will only deal with the treatment of renal contribution to anaemia in myeloma.




Qualipharm (UK) Ltd 4.3 b) ‘Targets for Haemoglobin’. I agree with comments at the meeting that this area needs careful consideration. If target means patients should have a Hb > 11g/dl appropriate treatment should be initiated once their Hb is below this figure. Also if all patients are to have Hbs above 11g/dl recommended, then consideration should be paid to population dynamics and statistics in order to fully achieve this. It can be done cost effectively too.It was revealing to find out at the meeting that the initial Remit which quoted a Hb of > 11g/dl , an internationally accepted standard, is not fixed. This has important implications;Does this mean that stakeholder contributions will have to provide supportive evidence to demonstrate that keeping Hbs > 11g/dl is worthwhile as well as providing clinical publications which outline the interventions and their cost effectiveness in order to achieve this level.

We will consider the evidence base for the correct Hb target level.

Qualipharm (UK) Ltd Appendix Hopefully full consideration and appropriate comment will be given to any future innovative product developments and/or the availability of ‘bio-similar’ products. Virtually all current evidence and guidelines have assessed the use of oral iron salts which have been proven to be of limited use for patients already on ESAs. Their traditional side effects also contribute to poor compliance and uraemic patients do not benefit much either. An effective oral iron formulation which can overcome the current limitations of oral iron salts could have a major impact on the ability to treat more patients earlier. This would allow more patients to benefit from earlier effective treatment in the primary care environment. This approach will reduce the need for IV Iron therapy and the associated costs of travel to hospital, medical staff time etc. Falling Hbs have been shown to contribute to the progression of the renal disease.The license patent protection for Epoetins is running out soon, which could allow for the introduction of bio-similar products. This could impact on the cost of treating individual patients and provide an opportunity to treat more patients earlier in the course of their disease for the same cost.

Thank you – the guideline can only consider products with a current evidence base.

Renal Association This organisation was approached but did not respond.Renal Nutrition Group, British Dietetic





AssociationRichmond & Twickenham PCT


Roche Products Limited General,including guidance title

Roche welcomes the fact that the original remit and consequent Scope covers the broad management of anaemia in chronic kidney disease (CKD) and not just anaemia in renal failure.

Guidance on the management of anaemia in renal failure only would have been less useful because the inclusion of early CKD addresses an area in which there is a greater unmet clinical need and also greater variation in clinical practice. This approach is also supported by the fact that the forthcoming NSF for CKD will complement the current NSF for renal failure. Roche recommends that both areas will be given equal attention in the guideline. It may also be useful to investigate during the development of the guideline the impact of other co-morbidities such as cardiac risk on CKD patients.

Thank you.

Roche Products Limited General Roche suggests that the terminology for classifying different renal health states be reviewed.

This is because the current descriptions may be inappropriate; CKD (‘irreversible and progressive’), established renal failure / end stage renal failure (‘progressed to RRT’, ‘irreversible, long-term’), and pre-dialysis CKD are all mentioned, but only effectively delineate two groups. Roche recommends that GFR-based staging definitions should be used in addition or instead, as this would allow a more accurate classification of early CKD severity.The most widely used system is the K-DOQI scale.


Roche Products Limited General Roche would like to seek further guidance regarding the economic evaluation of therapies within NICE clinical guidelines.This includes an identification of the requirements for cost effectiveness analysis of treatments (e.g. which costs, outcomes, time horizons, etc., should be included) for economic submissions within clinical guidelines, and are there any other differences compared to technology assessments that need to be considered?

All evidence should be submitted in the normal way. Please see attached link to Guidelines process manual on the NICE website – http://www.nice.org.uk/page.aspx?o=114268 .

Roche Products Limited 4.1.1a4.3a

Roche would like to seek clarity on the population groups that will be covered.

The guideline addresses people with anaemia secondary to CKD and therefore cannot include people until they have


http://www.nice.org.uk/page.aspx?o=114268



4.1.1a presently identifies people ‘who have a clinical diagnosis’ of anaemia, but does not include people with undiagnosed anaemia in CKD. However, 4.3a includes ‘Detection and diagnosis’ of anaemia.

The definitions need to be made more explicit regarding undiagnosed groups within the guideline.

been identified.

The Scope does not include screening populations.




Roche Products Limited 4.3a Roche recommends that the guideline also covers the detection and diagnosis of CKD itself (independent / prior to detection and diagnosis of related anaemia).

This is because early CKD (e.g. at stages 3 / 4) is presently underdiagnosed which will result in a consequent underdiagnosis of related anaemia. Further related issues, such as which healthcare professionals (e.g. GPs/ diabetologists, rather than nephrologists?) could identify such patients and how GFR (rather than creatinine testing?) should be incorporated.

The Scope does not include screening populations.

The Scope pertains to anaemia in CKD not CKD as the primary disease.

Roche Products Limited 4.24.3c

Roche welcomes the fact that the Healthcare Setting section covers the full range of healthcare professionals who may be involved in this disease area.

Roche hopes that this approach will also be applied to section 4.3c, and in particular, the use of r-HuEPOs for haemoglobin management (such as epoetin-beta (NeoRecormon). We suggest that this section should provide guidance on which groups of healthcare staff might best deliver these therapies. This is because the current paradigm largely limits prescribing of r-HuEPOs to nephrology specialists (due to a historical emphasis on treatment of renal failure). However, it is anticipated that earlier treatment of CKD will increasingly involve other healthcare staff (such as GPs and diabetologists).

In addition, ‘delivery’ may involve both initiation and maintenance of therapy – guidance on who should best manage each phase would be useful.

Thank you. We need a firm evidence-base for healthcare setting issues. Published evidence that these factors are important can then be considered. It would be extremely helpful if you could please submit any references directly pertaining to this that you would wish the developers to consider during the stakeholder evidence submission stage.


Roche Products Limited 4.3 c As discussed at the Stakeholders Meeting on 28.6.04, Roche would also like to reiterate that the available r-HuEPO products differ significantly (e.g.; in optimal route of administration and dosing requirements) and this should be evaluated during the development of the clinical guideline

We would also therefore suggest that provision be made to allow assessment of these products separately (as well as from

Thank you.

Consideration of separate products will only be made if there is a strong evidence base for doing so.

Only licensed products will be considered.




a ‘class’ perspective) within any clinical and cost effectiveness analysis.

Roche would also like to point out that clinical development is presently underway of a new treatment agent CERA which is expected to be launched in 2007. It may be possible to include some data relating to CERA during the development of the clinical guideline and we would like to discuss this further with the guideline developers.




Roche Products Limited 4.3 c Roche would like to clarify what is meant by ‘optimisation’, in relation to haemoglobin.

This term was used helpfully in the remit, and appeared to refer to optimal haemoglobin from a clinical effectiveness perspective (e.g. European and K-DOQI standards), towards which an assessment of cost effective interventions would be geared. This perspective is less clear in the Scope for the guideline.

Will haemoglobin treatment targets be defined a priori, or will this treatment outcome standard be part of what the guideline decides based on economic assessments?

The evidence base will be considered.

Royal College of Anaesthetists

General Very little of this Scope relates directly to anaesthesia and critical care but there are important points to make from this perspective.A recent review was published on-line by The Critical Care Forum on 14 June at http://ccforum.com/supplements/8/S2.

Thank you.


3d Most patients with CRF have adapted physiologically to their anaemia and, as long as circulating blood volume is maintained, will cope reasonably well with anaesthesia and surgery.In patients who are anaemic and unable or unwilling to receive blood before or during surgery, rEPO can usefully raise the haemoglobin level.Milligan LJ. Anaesthesia and critical care of Jehovah's Witnesses. Continuing Education in Anaesthesia Critical Care and Pain 2004; 4:35-39.

Thank you for the references.


4.1.2 Although the Scope does not cover anaemia caused by acute inflammatory disease I think it is worth mentioning the unique circumstances of the anaemia seen in critically ill patients.

The remit and Scope do not include the critically ill. Multiple organ failure is not related to the remit of CKD.


4.3a Some of the anaemia seen in ICUs could be ameliorated by careful attention to blood sampling practices.Napolitano LM. Scope of the problem: epidemiology of anemia and use of blood transfusions in critical care. Critical Care 2004; 8(Suppl 2):S1-S8.

Thank you – the guideline relates specifically to anaemia in CKD and not to other causes.


4.3b In general, critically ill patients do not gain a survival advantage from a transfusion trigger above 70 g/L haemoglobin.Hebert PC. A multi-center, randomized, controlled clinical trial of transfusion requirements in critical care. NEJM 1999; 340:409-17.

Thank you.


http://ccforum.com/supplements/8/S2




4.3b There is some debate as to whether patients with active cardiac disease benefit from a higher transfusion trigger.Freudenberger RS. Is there an optimal haemoglobin level in the cardiac intensive care unit? Curr Opin Crit Care 2003; 9:356-6.

Thank you.


4.3b It is unlikely that a fixed transfusion trigger will apply to patients with active cardiac disease.Fakhry SM. How low is too low? Cardiac risks with anemia.Critical Care 2004; 8(Suppl 2):S11-S14.

Thank you.


4.3c In critically ill patients with elevated cytokines EPO levels may be high initially and fall later. The anaemia seen in the critically ill does not seem to be predominantly due to abnormally low levels of EPO but rather to a failure of its effect. Pharmacological doses of rEPO may be necessary to stimulate erythropoesis.Elliot JM. Erythropoietin mimics the acute phase response in critical illness Critical Care 2003, 7:R35-R40.

Thank you.


Thank you for the evidence submission.

Royal College of General Practitioners


Royal College of Nursing (RCN)

General This is a straightforward document and is clearly primarily about the investigation and non-transfusion management of patients with chronic renal disease.

Thank you.


General It is surprising there is no mention of blood transfusion as an option for the management of anaemia even if it is then excluded from the Scope of this exercise.

Thank you. This is not excluded.


General Primary health care management of Anaemia is a major challenge and the NICE guidelines must reflect the existing evidence as outlined within the recently published NSF Renal Service (2004).

Thank you.


4.1.2. [b] Concerns that children have been excluded from these draft guidelines. Whilst children represent a relatively small population in comparison to the adult population it is essential that their needs are not excluded from this important guideline.



General The specific needs of the older patient with renal failure needs to be much more explicit in the guidelines as these patients with renal anaemia may not be managed by a Nephrologist.

Thank-you. Older patients are included. Care will be addressed but not who will provide such care.





General What about funding of anaemia management drug therapies? How will the guidelines reflect this? This is particularly important when the treatment between primary and secondary care is taken into consideration, which could lead to local inequalities in terms of clinical management & services provided.

The guideline developers are not asked to consider funding but rather the cost effectiveness of treatment options.


What about patients who are not being referred to a Nephrologist? Is the term predialysis too broad? And therefore it might be best if this is considered as Chronic Kidney Disease stages 1 – 5. The staging of treatment for renal anaemia maybe an issue the guidelines need to reflect.

Thank you – we agree and will use the stages 1–5 in the Guideline (but not in the Scope).


4.1.2 What about dialysis sepsis induced dialysis anaemia? This needs further clarification as the draft guidelines indicates that anaemia caused by acute and chronic inflammatory disease states is to be excluded.



Clinical management 4.3

What about the actual ergonomics of clinical management & delivery? Questions such as by who and how; this will highlight important manpower issues which could impact upon the successful implementation of the guidelines. Whilst there will be issues related to local delivery this needs to be considered more in the development of these guidelines.

Thank you. This is outside of the remit and Scope of the guideline.


4.3 a Detection of Chronic Kidney Disease: consideration should be given to other markers identified, as Creatinine Clearance is not a particularly good marker. What about consideration of GFR reporting system. I understand in France the GFR is also reported at the same time as the Creatinine Clearance

We agree that this would be a useful development. However it is currently beyond the remit and Scope.


What about the administration of products in primary care i.e. Iron particularly this will be an issue for patients who do not wish to travel long distance to hospital when it could be administered in the primary care setting?

Thank you. We have noted this and accept that this is a good point for the future. Administration of products and sector will be considered in relation to the evidence base.


What about the development of a diagnostic pathway between primary and secondary care. Could this be considered within the draft guidelines?

Thank you.We have noted this point, however it is outside the current remit of AMCKD guideline.The diagnosis and management of anaemia in CKD including referral where appropriate will be considered.


What about routes and timing of administration? Will guidelines reflect patient preferences?

Yes this will be addressed.

Royal College of Consideration needs to be made regarding service Thank you. This is outside of the remit of the guideline as it




Nursing (RCN) configurations and the development of these guidelines needs to be balanced against agreed priorities.

pertains to commissioning.

Royal College of Paediatrics and Child Health

4.1.2b The Royal College of Paediatrics and Child Health would wish to see the Guideline extended to include children under 16 years of age. Whilst the number of studies performed in this field involving paediatric patients is smaller that the number involving adults, particularly with reference to high quality RCTs, a number of studies do exist and it would be appropriate for these to be used in preparation of the Guideline.


Royal College of Paediatrics and Child Health (2)

4.1.2.b 100 new cases of end stage renal disease occur in UK children annually. Why not include children in the guideline? On what grounds are children to be excluded?


Royal College of Pathologists

General The Scope should include consideration of the most effective way of prescribing erythropoietin (Epo) - GP v. hospital and the allocation of resources to prescribers.

Thank you. This is outside of our current remit and Scope.

Royal College of Pathologists

Section 4. Population

The Scope should make specific comment about anaemia in patients with haematological disease AND chronic kidney disease, where patients may still benefit from the use of Epo. A special case is myeloma, where renal impairment and anaemia at presentation are common. The UK myeloma guidelines recommend the use of Epo in anaemic myeloma patients.

The Scope of the guideline pertains to anaemia caused by CKD. Hence we are only seeking to exclude the treatment of malignancy where it is the primary cause of anaemia.

The guideline will only deal with the treatment of renal contribution to anaemia in myeloma.

Royal College of Physicians of London

General comments:

National and international guidelines are already available for the management of renal anaemia. However despite extensive literature review on most of the topics outlined in the scoping document they focus on desired outcomes and not the means by which to achieve these desired outcomes, nor are they focused on cost effectiveness. The DOPPS and ESAM studies demonstrate geographical differences in outcome and the UK Renal Registry additionally demonstrates consistent differences in performance between units across time (in the era of de-anonymised data). As part of the audit loop and in addition to the benchmarking the Registry provides, exploration of differences in funding and / or practice (the means by which they achieve these outcomes) between units across the UK could provide a way to improve outcomes generally.



Changes that could be made at a political level following recommendations from NICE, to create a level playing field in funding for EPT across the NHS might provide the opportunity for the greatest improvement in outcome for patients.

Service delivery models and funding is generally outside the Scope of a NICE clinical guideline.




Differences in EPT funding generate different difficulties in the management of this patient population. EPT may be funded, partially funded, not funded, funded via hospital based health care providers or via general practice (whilst treatment is managed almost uniformly by the hospital based nephrologist / anaemia co-ordinator).





Recent developments relating to Primary Red Cell Aplasia appears to have created a more competitive market and lower costs. The upcoming end of the licence for erythropoietin requires guidance on the use of generic products particularly in the light of the development of PRCA relating to subcutaneous administration of erythropoietin-alpha, but also on the potential for large potential cost savings in using generic EPT.

PRCA is an important issue that will be dealt with under the effectiveness of EPOs.


The guidelines must add value over and above the national and international guidelines that already exist. The areas that appear to have been overlooked in these previous documents are cost effectiveness and the guidance on how to produce a predictable, sustainable and prescribed outcome for renal anaemia across renal units.

Thank you.

Royal College of Physicians of London 4.1

4.1.1

Specific Comments by section:Population The immediate post transplant period is often associated with anaemia and requirements for post-operative blood transfusion, and it has been observed that the greater the degree of anaemia preoperatively, the greater the risk of requiring transfusion. However, the guideline should include all patients with a renal transplant (not necessarily just ‘directly after transplant surgery’). Chronic failure of renal transplants also produces the anaemia of erythropoietin deficiency as for native chronic renal insufficiency. Thus transplant patients with adequately functioning grafts can develop anaemia secondary to erythropoeitin deficiency, functional iron deficiency, chronic inflammation (i.e. rejection), infection or other causes as for pre-dialysis / dialysis patients. In addition transplant patients are on immunosuppressive agents that can suppress marrow function (i.e. azathioprine).There is no current consensus as to when it is appropriate to discontinue erythropoietic therapies, but it is most usual to discontinue therapy at the time of transplantation. Some transplants have delayed graft function but erythropoietic therapy is still discontinued.

Thank you.When the transplant is failing this is encompassed under the category of pre dialysis.We confirm that the Scope includes failing transplant.Those who have well functioning transplants may not have anaemia; hence we would not need to expand to encompass the whole of the transplant period.Regarding transplant patients with adequately functioning grafts and anaemia, we note your points and these will be addressed.We are also mindful of considering the treatment of anaemia caused by kidney disease and not that necessarily caused by the treatment.Your last point is noted, thank you.


Diagnosis and recommended management of Erythropoietin Associated Primary Red Cell Aplasia should be discussed.

We agree this is an important issue, which will be dealt with under the effectiveness of EPOs.

Royal College of Physicians of London 4.1.2

These categories presumably exclude Primary Red Cell Aplasia (PRCA-EPO), the consequence of developing

We agree this is an important issue, which will be dealt with under the effectiveness of EPOs.




neutralising antibodies to epoetins.





Dialysis patients are frequently subject to chronic inflammation and / or acute infections and exclusion of these patients from the guidelines will reduce the value of the subsequent advice to the clinical nephrologist.



Patients with renal failure and a malignancy should not necessarily be excluded from management of renal anaemia.



4.2 Healthcare settingThe current legal loophole of VAT reimbursement on home administered erythropoietic therapy (EPT) needs analysis as any cost benefit in VAT rebait may be lost in reduced compliance in selfadministered compared to hospital based patients (nurse administered).

Thank you, noted.


4.3 Clinical management[a] Intravenous iron:Does intravenous iron have a place in the treatment of renal anaemia prior to commencement of EPT in CKD. Is there any benefit (improvement in Hb or reduction in EPT dose) gained in administering intravenous iron to haemodialysis patients with a ferritin greater than 500ng/mlWhat is the most cost effective range for ferritin in haemodialysis patients on EPT?What is the most cost effective range for ferritin in peritoneal dialysis patients?What is the most cost effective range for ferritin in pre-dialysis patients?

Thank you for suggesting these questions.


The Revised European Best Practice Guideline minimum standard for Hb is that all patients have a Hb > 11g/dl? Is this European standard compatible with avoiding Hb values > 14g/dl as recommended in the same new European guidelines? The DOQI guideline of 11-12g/dl (even with use a 3 month averaged mean) is not a achievable outcome in a dialysis patient population so is not necessarily a more useful (or realistic) benchmark than the UK minimum standard.

Thank you, we will look at the evidence-base for target Hb as part of Scope.


[b] On what evidence of improved cost effectiveness should NICE move to a recommendation other than that of the previous Renal Association and Royal College of Physicians

Thank you. This is dependent upon the current evidence-base. We will also be taking health economic advice on this.




(UK minimum standards document) of 85% > 10g/dl? This prior recommendation also provides a practical benchmark against which unit performance can be measured.





The use of a threshold or trigger Hb value that should initiate work-up and then initiation of EPT would be useful than a ‘target’. Intervention values for Hb requiring subsequent changes in EPT dose necessary to achieve the desired outcome distribution for the treated population would be of more practical value than a target.

Thank you.


[c] Guidance on the cost benefit to choice of dialyser membrane, route of EPT administration, use of ultrapure water (for haemodialysis) or any given type of peritoneal dialysis fluid (biocompatibilty), achievement of higher dialysis dose and provision of prompt and definitive vascular access should be given.

Thank you. These will be looked at in so far as they impact on anaemia management only.


The ‘optimisation of haemoglobin (and iron stores)’ needs detailed clarification for each patient population (pre-, haemo, or peritoneal-dialysis) in terms of cost benefit as explored above in 4.3[a].

Thank you. We will be led by the evidence-base and health economic input.


Would uniform central (hospital) funding for all EPT improve the Hb outcome for patients and remove the problem of post-code differences in outcome for this expensive therapy(see general comments).

We agree with this statement and consider it a valid point, however the guideline cannot consider commissioning issues, as it is not within the remit of Scope. This is a service delivery issue, which we are not allowed to address under the current commission.

Royal College of Physicians/British Geriatrics Society

4.1 Population

4.11 Groups that will be covered

Whilst there has been no specific exclusion of older people with chronic kidney disease (CKD) it should be noted and possibly mentioned in the Scope that older people should be included. CKD is a disease of older people increasing from 1,900 people per million age 50-59 years to 17,000 people per million age 70-79 years. Most of these older patients are at stages 3 and 4 CKD and are not on dialysis.

Thank you. We are not excluding the elderly.

Royal College of Physicians/British Geriatrics Society

4.3 Clinical management

4.3a Detection and diagnosis of anaemia in CKD- CKD in older people has been missed on many occasions due to the use of serum creatinine as a marker of glomerular filtration rate (GFR). This will be improved with the use of calculated clearances such as the MDRD and the Cockcroft and Gault equation. The Scope should take this into account.

We agree.

Royal Pharmaceutical Society of Great Britain This is to advise that the Royal Pharmaceutical Society of Great

Britain will not be submitting comments on the above consultation.

Thank you.

Scottish Intercollegiate This organisation was approached but did not respond.




Guidelines Network (SIGN)Sheffield Teaching Hospitals NHS Trust

4.1 The focus should be on the Hb which requires treatment and not be determined by a particular population such as dialysis status.There is, of course, a problem with identification of people with chronic kidney disease (CKD) within the population - and thus those who would benefit from this form of anaemia management. Currently many such patients do not get referred, or are referred late.There is some ambiguity of groups which will be covered - thus in 4.1.2 many renal patients have haematological problems (eg myeloma) or malignancy or chronic inflammation (eg rheumatoid arthritis).Since numbers of children who are affected are small they do not need to be the subject of this guideline - which is about delivering optimal anaemia management to a large population of patients cost effectively. Children can be dealt with on an individual basis - costs are not so important because of the smaller numbers.

We agree the aim is to correct anaemia associated with CKD.


Children – we accept that this is a valid point and hence the Scope and guideline will include children.

Sheffield Teaching Hospitals NHS Trust

4.1 Part 'a' is sufficient, but part 'b', whilst attempting to clarify, actually confuses matters. An example of this is the statement "people directly after transplant surgery". How long after surgery is "directly" and why not anybody who has a transplant and has anaemia. Some transplants function for years at a level which equates with moderate renal failure, but not severe enough to warrant RRT. At what point does a failing transplant warrant intervention for anaemia? Finally, whilst it may appear pedantic, does the SCOPE document mean renal transplant or any transplant?

Thank you. We agree with your point but it is difficult to define. Potentially this is until, or if, stable transplant function is achieved.As the Scope and guideline pertains to anaemia management in CKD we are referring to renal transplant. We have amended the wording accordingly.


4.2 The guidelines should not miss the opportunity of delivering renal care in the primary care setting - eg GP based intravenous iron clinics.

Thank you. The guideline pertains primarily to anaemia management in CKD (not the delivery of renal care in the primary care setting).

We need a firm evidence-base for healthcare setting issues. Published evidence that these factors are important can then be considered. It would be extremely helpful if you could please submit any references directly pertaining to this that you would wish the developers to consider during the stakeholder evidence submission stage.





4.2 It states that people who have haematological or malignant disease will not be covered as CKD is not the principal cause of anaemia. Patients such as those with myeloma can go on to require renal replacement therapy. Anaemia in this cohort is usually quite severe and as a result would suggest that they will become a disadvantaged group as their main source of care moves from the haemotologists to the nephrologists, as each will claim the other should be providing the anaemia therapy.

A proportion of those with CKD may require little or no intervention for their anaemia, however from time to time they may have inflammatory episodes which will impact on their anaemia. The Scope document at present excludes this group. Finally, being pedantic again, it has been suggested in many texts that CKD itself is an inflammatory condition, thus precluding anyone with CKD from the remit of the SCOPE document.

The Scope of the guideline pertains to anaemia caused by CKD. Hence we are only seeking to exclude the treatment of malignancy where it is the primary cause of anaemia. The guideline will only deal with the treatment of renal contribution to anaemia in myeloma.The publication of this guideline should not disadvantage patients who require clinical care from both the haematologist and nephrologist. Local arrangements should be in place to address these issues.Re infections/chronic inflammation – we agree that dialysis patients are subject to infection. However, it is anaemia that is the focus of the guideline and hence it is the impact of infection on anaemia. This will be included in the Scope when considering management of, and factors, which have an impact on anaemia in renal disease under section 4.3c.We note your final sentence and thank you for making us aware of this.


4.3 The ergonomics of anemia management are very important and should be considered for review. It is of paramount important to ensure cost-effective use of expensive products, avoidance of waste, optimization of compliance, and to build in quality assurance and audit to support this. For example if Hb is permitted to over-shoot the target range, or if drug doses are missed, this results in un-necessary expense.

We agree. Health Economic advice will be taken and we will be guided by the evidence-base.


General I feel the SCOPE should not only look at what are the best interventions, but also the most effective means of delivering those interventions. Huge sums of money are wasted each year due to compliance issues and ineffective monitoring of the treatment given. I suggest that what may appear on paper to be most efficacious, in actual practice is compromised due to limitations of having real people involved in the implementation. Therefore the intervention most easily implemented and adhered to may actually be superior to that which initially appears most cost effective.

Thank you. Commissioning questions regarding the allocation of resources are currently outside of the Scope.

Shire Pharmaceuticals Limited

General We strongly support this Scope. Thank you.

Shire Pharmaceuticals Limited

4.3 c) A specific item could usefully be added to the 4th stab point: ‘..including agents which promote erythrocyte stability.’

We are not sure of your meaning here. Please provide us with further information.

Society of District This organisation was approached but did not respond.




General Hospital NephrologistsSouth Manchester University Hospital NHS Trust

General I just have a few general comments on the subject above:- As you are aware we are obliged to implement the Department of Health Better Blood Transfusion 2 which is aimed at encouraging alternatives to allogeneic blood transfusion. Being a Haematologist and a member of the Hospital Transfusion Team I have this urge to see that the NICE Guidance gives more support for the use of Erythropoietin in both Renal and other anaemias where the product might be of value.- I did not get it clearly why children under 16 years are not included (may be they have another group dealing with them)? Otherwise this is this group you would want to restrict use of blood. -Another reason why I am in favour of giving Erythropoietin to patients with non-renal diseases with severe anaemia is in one case whwn there might be overlap with kidney disease and because of the fact that in some case when you have achieved a reasonable level of Haemoglobin when a patient is not symptomatic (eg: 100g/l) the patient could be observed off therapy. Furthermore, there is improvement in the performance status/quality of life when people are on erythropoietin even earlier before there has been a significant rise in haemoglobin level. -Very soon the cost of blood will exceed the cost of using alternatives to blood transfusion when you put together the cost of blood collection and processing, patient time and hospital costs. Of course, in most cases patients who require blood transfusion would need a minimum of 2 units of blood at a given time and we have cases where patients come in weekly or worse still twice weekly for blood transfusion. -The Pharmaceutical Companies are keen to offer help with regard to patient monitoring such as assy of erythropoetin and offering the agent free for a limited trial period which I think should be encouraged since in that way more needy patients would be offered treatment. As more usage of erythropoietin goes up the cost of patient care in these categories will fall, I should think so.

We have been specifically asked to consider only anaemia in CKD and anything else is outside of the Scope. We confirm that children are included and that blood transfusion is included. The evidence base will be considered.

Syner-Med (PP) Ltd “general” / Title

Suggestion to amend to include “Anaemia management in people with chronic kidney disease (CKD) as per K DOQI staging I to IV and transplants”. REASON – KDOQI staging :





(1) provides precise definition of the degree of renal failure being referred to, and reduces ambiguity (2) follows most up to date convention (3) Estimates of CCr/GFR are more reliable measures of renal function and moves away from less reliable measures such as serum Creatinine which is commonly used outside Nephrology.




Syner-Med (PP) Ltd 2 b) last sentence

Specify for the purpose of clarity “part one of the NSF including module 1 (renal replacement therapy) and module 2 (Transplantation) was published in January 2004. Part 3 covering Module 3 (predialysis) and module 4 (conservative management / alternative strategies) will probably not be published until 2005.”

Thank you. We will be working closely with the NSF team.

Syner-Med (PP) Ltd 3 b) Point of factThe number of patients with CKD is set to grow quite dramatically in the next 10 years and the number of predialysis patients will be greater than the figure stated. See NHANES data for the USA. The data given re. England only included patients on dialysis and post Tx. Many more patients will be anaemic with CKD stages I-V and not be on dialysis or have had a Tx. The numbers quoted here fail to address the vast number of patients with all stages of CKD who may never be referred to a Nephrologist but may be anaemic and should be treated.


Syner-Med (PP) Ltd 3 d) The UK Renal Registry document referred to is for 2002. The 2004 document is now available and comments may need updating in light of more up to date information. The graph used by X in his presentation on Monday is especially worthy of note. This showed clearly that although Hb outcomes have improved the Hb in incident patients lags far behind prevalent patients. It is during the CKD stages I-IV that much of the damage due to anaemia takes place, damage that cannot be reversed by treated on dialysis.

Thank you – the Scope will be updated.

Syner-Med (PP) Ltd 3 d) second sentence

Whilst not questioning the restriction on the availability of ESA’s 30-50% of CKD patients stages I-IV have been shown to respond to Intra Venous Iron supplementation alone. There are other therapeutic options which are more cost effective and should be considered for inclusion prior to ESA therapy. References: Jenkins K, poster Brit Renal Soc, May 2004. Silverberg DS Kidney Int. Vol 55 Suppl 69, S79-S85.


Syner-Med (PP) Ltd 4.1.1 b) last sentence

“….people directly after transplant surgery”Suggest deleting the word “directly” because transplant patients need their anaemia managing throughout their life. They need their anaemia managing post operatively, but as their transplant eventually fails they need more intensive management once again. Its important not to imply that anaemia management has been completed after the post operative phase.

Thank you, yes we agree, we have deleted the word ‘directly’. When the transplant is failing this is encompassed under the category of pre dialysis. We confirm that the Scope includes failing transplant. Those who have well functioning transplants may not have anaemia; hence we would not need to expand to encompass the whole of the transplant period.




Syner-Med (PP) Ltd 4.1.2 a) Whilst fully accepting the need to exclude non-renal anaemia if is important to consider the that, due in part to the age of CKD patients it is likely they will suffer from a number of co-morbid conditions. In the light of this it is important not to exclude patients where more than CKD alone is contributing to the anaemia. An example could be a patient with Myeloma who may well be anaemic and CKD is the major contributor to the anaemia. By excluding haematological malignancy one would exclude a large proportion of myeloma patients who are usually managed by haematologists and are often not referred to Nephrology departments until end stage (i.e CKD stage V).


The guideline will only deal with the treatment of renal contribution to anaemia in myeloma.

Syner-Med (PP) Ltd 4.3 b) “Criteria for the target levels of haemoglobin concentration for initiating the treatment of anaemia” It is unclear what this means precisely. If the target is 11g/dl, then surely anyone below this value goes onto treatment. If it is being suggested that there is a value below which the haemoglobin level has to fall before treatment can be initiated e.g. 10g/dl this is not optimum treatment. It can be argued that any one with a falling haemoglobin level should go onto therapy as this is sub optimal for this individual. However, using 11g/dl as a threshold is not unreasonable as this is also the target end point. Allowing the haemoglobin level to fall further than necessary will result in further disease progression and should not be recommended.

The word ‘target’ will be deleted and amended to ‘threshold’.

Syner-Med (PP) Ltd Appendix The example give of achieving the accepted international standards (K-DOQI and EBPG II) of 11g/dl is still a level of Hb well below the normal. Hb varies between individuals and this should be taken into account. A male with an Hb of 17g/dl when healthy would feel the consequences of a fall to 14g/dl. The whole issue of what outcome is desired is one that will need careful examination. Part of the problem in renal patients is that the Hb is allowed to fall, often to levels well below 10g/dl (see European Survey of Anaemia Management). Having fallen to such low level the body adapts. If the Hb has been at a low level for a long period pushing the Hb too high may have a negative effect. The ideal could be not to allow the patients Hb to fall in the first place. The question may be rather than asking what Hb level to move a patient to, ask the question of what is the minimum level of Hb

Thank you.




that should be tolerated. Recent work in patients with CHF has shown that anaemia is associated with significantly worse outcomes. Most CHF patients have a degree of CKD and many have anaemia. Likewise many CKD patients will have either LVH or overt CHD in part associated with their anaemia. The view in cardiology is that a level Hb of <13g/dl is associated with poorer outcomes in CHF. Some would find it strange that a CKD sharing many of the same problems is often treated to achieve a lower Hb.




Syner-Med (PP) Ltd Overall Comment

The Scope covers many of the issues but it may benefit form being more specific in what is to be included. Examples would include, water quality, dialyser membrane compatibility, etc. At the stakeholder meeting comments were made re. the exclusion of children which will be a concern of anyone involved in paediatrics. Not all the treatments used in children are licensed for use and it may be difficult to offer guidelines on the use of unlicensed treatments.

Thank you. These will be looked at in so far as they impact on anaemia management only.

In relation to children we note your helpful comments. Children will now be included due to the weight of stakeholder comments. We will be mindful of the unlicensed treatments.

The Royal Society of Medicine


UK Anaemia Title 1. Does the title imply that patients in KDOQI stages I-V who develop anaemia will all be treated if anaemia develops regardless of stage?

2. Will all treatments of anaemia be included eg iron deficiency, and will the recognition and treatment of iron deficiency be recommended prior to the initiation of ESA therapy especially as there may be a huge cost saving.

1. Yes it does as long as CKD.

2. Yes.

UK Anaemia 2 a)

2 b)

1. Will this guideline supersede any part of the renal NSF in any way

1. How will NICE support the NSF if the NICE guideline recommendation is different. Could the NICE guideline effectively delay diagnosis and treatment.

2. There is a significant time delay before Module 3 & 4 are in the public arena, how will the NICE guideline affect pre-dialysis and palliative care patients.

We will be working closely with the NSF team so that the clinical guideline and the NSF are complementary.

As both NSF and guidelines are in development at the moment we are unable to be more specific at this stage.

UK Anaemia 3 a) 1. ESR or CKD etc may not always end with the patient receiving dialysis, a) the patient may die from other co-morbid disease b) the patient may choose palliative care, c) with proactive care the progression of CKD may be so far delayed that dialysis will never become a reality. d) should anaemia be treatment when it is first evident patients may not compound CKD with heart failure. 70% of ALL patient commencing dialysis have significant left ventricular hypertrophy.

Does this imply that these patients with be omitted from the

Points a to d will be included under conservative management in the Scope.

3b (1) – This is background information – thank you for these statements.

3c - When the Scope was written, recently published update figures were not available. 2003 figures have now been used to update the Scope.




3 b)

3 c)

3 d)

guidelines.

1. If you concentrate on people with CKD as their primary diagnosis then the estimation may be correct, however with the growing incidence of diseases such as diabetes and heart disease and their impact on renal function the estimate is grossly inaccurate.

2. There is no estimate of the % of patients with such diseases who are not diagnosed. It is pertinent to consider the USA experience and NHANES.

1. PLEASE NOTE THAT YOU REFER TO THE RENAL REGISTRY 2002 NOT 2004.

2. There is failure to treat patients approaching dialysis early and commence dialysis before the patient becomes symptomatic.

3. Patients commencing HD lose residual renal function at a faster rate than patients on PD.

4. The renal registry does not provide critical information on patients commencing HD with a functioning fistula versus those with a temporary or permanent neck line against their actual haemoglobin at commencement and over the following 3 months.

5. The UK (bar USA) has one of the highest rates of patients commencing HD with a neck line.

1. There is wide variation in the treatment of anaemia because there is gross disparity in funding such treatment nationally.

2. Proactive units recognise and treat iron deficiency early thus improving and maintaining haemoglobin and delaying the need for ESA therapy thus affording a huge financial saving whilst initiating appropriate therapy early.




UK Anaemia 4.1.1 b) 1. Will you define pre-dialysis as approaching dialysis or according to KDOQI stages (preferably stage III-IV). The definition “approaching dialysis” is too late “the damage is already done” Using KDOQI staging and defining the criteria for “diabetic and non-diabetic” patients will optimise the patients chances of receiving treatment at the appropriate time.

2. Some patient post renal transplant may continue to have sub-optimal renal function and will continue to require anaemia management.

1. Thank you – we agree and will use the stages 1–5 in the guideline (but not in the Scope).

2. Thank you – noted.

UK Anaemia 4.1.2 a) 1. Many renal patients have co-morbid disease. 25% of patients diagnosed with Multiple Myloma will have significant renal impairment. Myloma will be the primary diagnosis and CRD secondary these patients will be managed by a haematologist.


UK Anaemia 4.2 1. It should be emphasised that anaemia management with nephrological support may be effectively managed in primary care and may be more cost effective and patient friendly.

Thank you. We need a firm evidence-base for healthcare setting issues. Published evidence that these factors are important can then be considered. It would be extremely helpful if you could please submit any references directly pertaining to this that you would wish the developers to consider during the stakeholder evidence submission stage.


UK Anaemia 4.3 b) 1. WHO definition of anaemia:women <12g/dlmen <13g/dl

It is imperative that the Hb should only be allowed to FALL to a target of 11g/dl implying that therapy should be commenced before this occurs. To aim for a blanket level of ALL patients achieving a Hb of 11g/dl the target needs to be at least 2g higher.

Thank you.

UK Anaemia Appendix 1. WHO definition of anaemia:women <12g/dlmen <13g/dl

2. Hb should be individualised.

3. Diabetic patients should be treated at a higher GFR. Low Hb

Thank you.




and swings in the level of Hb will have a detrimental effect on blood glucose monitoring.

4. Anaemia should be corrected early to prevent left ventricular hypertrophy.

5. Anaemia has been shown to contribute directly to early death in patients with CRF – DOPPS Study.

6. Patients with cardiac disease compound their disease with low Hb. Hb <13g/dl associated with poorer outcome.

7. Quality of life should be a measurement of an appropriate Hb level.




UK Renal Pharmacy Group

4.1.1. Whole-heartedly agree with the groups to be covered. Do we need to include people with failing transplants?

Yes, we are including people with failing transplants.


4.1.1. Where the guidance says it will include people directly after transplant surgery, how long are they proposing to follow-up the patients post-transplant?

Thank you.

We agree with your point but it is difficult to define. Potentially this is until, or if, stable transplant function is achieved.


4.3 (c) Management of, and factors which have an impact on anaemia in renal disease – is there a place here to add concomitant medication? Certain drugs, or combinations of drugs are well-known to cause anaemia, so need to be considered.

Concomitant medication will be considered amongst the evidence base outcomes where relevant.


4.3 Clinical management – should a section be included here on what to do with non-responders, what further tests should be carried out, and how should they now be managed?

Thank you – the evidence base will be considered.

University Hospital Birmingham NHS Trust


Vitaline Pharmaceuticals UK Ltd

4.1.1.a CKD should be classified into the 5 stages of CKD as defined by the K.DOQI guidelines.



4.1.1.b We agree with the overall term of ‘pre-dialysis’ as including the patients as described in stages 1-4 K-DOQI.’Pre Dialysis’ is commonly described by patients and clinicians especially in primary care. This term aids identification, diagnosis and communication of the guideline and the subsequent management of the patients.



4.1.1.b People directly after transplant surgery, this statement needs to refer to the continuation of anaemia monitoring of these patients, not just directly following transplant.

We agree with your point but it is difficult to define. Potentially this is until, or if, stable transplant function is achieved.

When the transplant is failing this is encompassed under the category of pre dialysis.

We confirm that the Scope includes failing transplant.

Those who have well functioning transplants may not have anaemia; hence we would not need to expand to encompass the whole of the transplant period.

Vitaline Pharmaceuticals UK

4.3.a The detection and diagnosis of anaemia in CKD should encompass clear in vitro diagnostic tests and should include

In relation to GFR – we agree that this would be a useful development. However it is currently beyond the remit and




Ltd GFR as this is not a standard primary care test at present. Differential tests for anaemia to include FBC, Hb, TIBC ,Ferritin and hypochromic red blood cells. Markers for inflammation and infection should also be included.

Scope.

In relation to differential test for anaemia – thank you for your suggestion. We will consider the evidence base.


4.3.b This statement is not clear and we recommend a ‘threshold of 11g/dl below which patients should have their anaemia managed accordingly as treatment is not initiated at a target level.

The word target will be deleted and amended to threshold.


4.3.c iPTH levels should be measured in accordance to K DOQI staging and phosphate binders initiated as appropriate for an elevated PTH or phosphate level to reduce the risk of hyperparathyroidism.

Thank you – we will consider the evidence base.


4.3.c Vitamin supplementation should be considered as appropriate. Thank you.


4.3.c Anaemia management with regard to dialysis types needs to be clearly defined between the different types of RRT as there are varying impacts on their lifestyle and number of hospital visits as well as adequacy.

Thank you we will consider the evidence base.


4.3.c Should read ‘assessment and optimisation of Erythropoiesis’, to include iron stores, Iron supplements and epo when stores are adequate.

Thank you. The wording has been amended – please see amended text in the Scope.


4.3 Note: We recommend this statement is changed to read – The guideline recommendations will ALWAYS fall within the UK license indications, exceptionally and only where clearly supported by evidence and where no licensed alternative is available.

It would be helpful to know why you recommend this change. NICE have recommended indications outside of the licence, exceptionally and where supported by the evidence.


General Following on from the Stake Holders meeting on 28.6.04 we have concerns re; the Patient representation focused on having 2 haemodialysis patients as being representative of the renal community. We consider it more appropriate that the patients represent the various stages and RRT options especially the pre dialysis, as these patients have the greatest opportunity to influence their choice and clinical and economical outcome long term.

Thank you. The patient representation will be appropriate for the guideline. We take note of your helpful comments.

Welsh Assembly Government (formerly National Assembly for Wales)

Thank you for inviting comments from the Welsh Assembly Government about the draft Scope for the above guideline. We have no comment to make at this time.

Thank you.


stakeholder comments on draft scope - with developer's

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