Cras Academy

Non-dialysis CKD anaemia: what matters to patients?

admin — Wed, 13 Jul 2011 11:41:55 +0000

Re-evaluating anaemia management in non-dialysis CKD. June 2011

The problem

Anaemia in non-dialysis chronic kidney disease (ND-CKD) is associated with increased rates of mortality and cardiovascular events, and with faster progression to end-stage renal disease (Thorpe et al, 2009). Anaemia management using erythropoiesis stimulating agents (ESAs) in patients with end-stage renal disease is recognised as beneficial (Parfrey, 2010, 2011; Johansen et al, 2010). However, there is little evidence that treating anaemia with ESAs can translate into improved outcomes in ND-CKD patients with anaemia, and aggressive targeting of higher haemoglobin (Hb) levels with ESAs may put patients at increased risk of stroke or cancer (Parfrey, 2011, Locatelli et al, 2010; Singh, 2010).
What does this mean for the future of anaemia management in ND-CKD? What are the key factors in deciding how to manage anaemia in these patients?

Managing symptoms, not markers?

Fatigue is a common symptom of anaemia in ND-CKD patients (Shlipak et al, 2011). It is also observed in patients with iron deficiency, a frequent cause of anaemia, and contributes to reduced physical performance (Haas and Brownlie, 2001). Thus, anaemia is associated with impaired health-related quality of life (QoL) in ND-CKD (Figure), which worsens as kidney function declines (Farag et al, 2011; Shlipak et al, 2011).

Fatigue is a cardinal symptom of chronic heart failure (CHF) (Hass and Brownlie, 2001), and CHF is also associated with impaired QoL (Juenger et al, 2002). A recent study by Shlipak et al (2011) revealed that many CKD patients without a formal CHF diagnosis recorded themselves as having symptoms of advanced heart failure (dyspnoea, fatigue and oedema) (Shlipak et al, 2011).

CHF is a common comorbidity of CKD, and together with anaemia forms the Cardio-Renal Anaemia Syndrome (CRAS) (Kazory and Ross, 2009; Silverberg, 2009). Given the role of fatigue in the contributory conditions of CRAS, should physicians consider reducing fatigue and improving QoL as valid short-term outcomes of anaemia management, in addition to improving long-term outcomes in end-stage renal disease (Johansen et al, 2010; Parfrey, 2010)?

If you want to know more about fatigue and QoL in CKD and its comorbidities, we invite you to visit www.cras-academy.com. Here you can find more about the issues raised in this newsletter, through video presentations by leading experts, downloadable slide kits and other materials. New items are added regularly, so don’t forget to check for updates.

Figure. Anaemia in ND-CKD is associated with reduced QoL measured using the Kansas City Cardiomyopathy Questionnaire (KCCQ) (Shlipak et al, 2011)

Optimising anaemia management in ND-CKD: the role of intravenous iron

Clinical guidelines and best practice position statements call for use of iron and ESAs to optimally manage anaemia in ND-CKD (Locatelli et al, 2010; NICE, 2011; KDOQI, 2003). The results of a meta-analysis (Rosen-Zvi et al, 2008) and recent clinical trial evidence (Qunibi et al, 2011) strongly indicate that intravaneous (i.v.) iron is more effective than oral iron in ND-CKD patients with anaemia. What do recent studies tell us about the benefits of i.v. iron beyond raising Hb levels?

The FAIR-HF (Ferric carboxymaltose Assessment in patients with IRon deficiency and chronic Heart Failure) is a phase III, randomised, double-blind, placebo-controlled study of 459 CHF patients with iron deficiency with or without anaemia (Anker et al, 2009).

Among the randomised patients, 42.3% (194/459) had impaired renal function (eGFR <60 mL/min/1.73 m2), i.e. were cardio-renal- or CRAS-type patients. A post-hoc analysis of these patients showed that treatment with i.v. ferric carboxymaltose (FCM) gave significant improvements (P<0.05 vs placebo) in (Ponikowski et al, 2010):

self-reported patient global assessment and NYHA class (the primary endpoints in the original analysis)
QoL, assessed using the generic EQ-5D tool and the specific Kansas City Cardiomyopathy Questionnaire (KCCQ)
physical performance, measured using the 6-minute walk test distance.

The benefits of FCM were seen after just 4 weeks of treatment, and a more detailed analysis revealed that QoL improvements due to i.v. FCM were most noticeable in (Comin Colet et al, 2010):

mobility, self-care and pain/discomfort EQ-5D domains
KCCQ summary scores as well as symptom, physical limitation and QoL sub-scores (Table).

In the whole FAIR-HF trial population, i.v. FCM also demonstrated a good level of safety and tolerability compared with placebo (Anker et al, 2009).

Additional studies are required to investigate the potential benefits and optimal usage of i.v. iron in patients with CRAS-like disease, such as FIND-CKD (Ferric Carboxymaltose Assessment in Subjects With Iron Deficiency Anaemia and Non-dialysis-dependent CKD, ClinicalTrials.gov identifier: NCT00994318 ) in ND-CKD patients. Two recently announced studies in CHF patients, CONFIRM-HF (ferric CarboxymaltOse evaluatioN on perFormance in patients with IRon deficiency in coMbination with chronic Heart Failure; EudraCT number: 2011-001695-19) (Ponkowski et al, 2011) and EFFECT-HF (EFfect of Ferric carboxymaltose on Exercise Capacity in paTients with iron deficiency and chronic Heart Failure; EudraCT number: 2011-000603-40) have been designed to confirm and further evaluate the effects of i.v. FCM on physical performance and exercise capacity.

Table. Effects of ferric carboxymaltose on CHF-specific HRQoL at week 24 as measured using the KCCQ summary scores and individual domains, showing no effect of baseline eGFR on treatment effect.

Anker et al. N Engl J Med. 2009;361:2436-48.
Comin Colet et al, 2010. Poster Sa528 at ERA-EDTA, Munich, Germany
Farag et al. Clin Nephrol. 2011;75:524-33.
Gandra et al. Am J Kidney Dis 2010;55:519-534.
Haas and Brownlie. J Nutr. 2001;131(2S-2):676S-688S.
Johansen et al. Am J Kidney Dis 2010;55:535-548
Juenger et al. Heart 2002 March; 87(3): 235–241.
Kazory and Ross. J Am Coll Cardiol 2009;53:639-47
KDOQI. Am J Kidney Dis 2006;47:S1-S146
Locatelli et al. Nephrol Dial Transplant 2010;25: 2846–2850
NICE (CG114) 2011
Parfrey. Am J Kidney Dis 2010;55:423-425
Parfrey. Curr Opin Nephrol Hypertens 2011;20:177–181.
Ponikowski et al, 2010. Poster Sa 684 at ERA-EDTA, Munich, Germany
Ponikowski et al, 2011. Poster at HFA, Gothenburg, Sweden
Qunibi et al. Nephrol Dial Transplant 2011;26:1599-607
Rosen-Zvi et al. Am J Kidney Dis 2008;52:897-906
Silverberg et al. Acta Haematol 2009;122:109–119
Singh. Curr Diab Rep. 2010;10:291-6.
Shlipak et al. J Cardiac Fail 2011;17:17-23
Thorp et al. Nephrology 2009;14:240–246
Van Veldhuisen et al, 2011. Poster at HFA, Gothenburg, Sweden

Good or bad news for anaemia management in CRAS patients?

admin — Tue, 21 Jun 2011 09:32:14 +0000

Erythropoiesis stimulating agents (ESAs) appear to have a better safety profile in patients with heart failure compared with patients with renal disease. What does this mean for anaemia management in patients with CRAS? This is one of the issues raised by the authors of a new review paper in Nature Reviews Cardiology. Professor Van Veldhuisen and colleagues also consider the impact of anaemia management on symptoms, functional capacity and quality of life in heart failure, as well as looking at the potential physiological explanations for the different efficacy and safety profiles of ESAs in heart failure and in kidney disease. Iron deficiency is common in CHF, and has both haematopoietic and non- haematopoietic effects that lead to reduced physical performance, impaired quality of life and ultimately to increased mortality. In this context, the authors reflect on the implications of recent trials showing the benefits of intravenous iron therapy in patients with heart failure. PubMed abstract here

Serum iron markers are inadequate for guiding iron repletion in chronic kidney disease

admin — Wed, 11 May 2011 09:55:49 +0000

P Ferrari, H Kulkarni, S Dheda

Clin J Am Soc Nephrol 2010

This US based study examined the relationship between parenteral iron therapy, conventional serum iron markers and liver iron concentration (LIC) using magnetic resonance R2 relaxometry in 25 ID predialysis CKD patients before, and 2 and 12 weeks after single high-dose i.v. iron and in 15 chronic haemodialysis (HD) patients with elevated serum ferritin (>500 μg/L).

The results suggest that in haemodialysis patients transferrin saturation and ferritin are poor indicators of body iron load.

Click here to go to the Clinical Journal of the American Society of Nephrology website.

Chronic Kidney Disease−Associated Anemia: New Remedies

admin — Wed, 11 May 2011 09:55:22 +0000

L Del Vecchio, A Cavalli, B Tucci et al.

Curr Opin Invest Drugs 2010;11:1030–1038

The first ESA became available some 20 years ago, but since then there has been much research into developing new agents improving on the characteristics of this naturally occurring molecule. This review discusses new therapeutic options for the treatment of CKD-associated anaemia, including ESAs and IV iron molecules. The review also provides some interesting insight into approaches such as gene therapy, in particular inhibition of transcription factors, that still remain a way from applicable in clinical practice but have been resurrected more recently.

Click here to go to the journal website Curr Opinion Invest Drugs

Proteinuria Induced by Parenteral Iron in Chronic Kidney Disease–A Comparative Randomized Controlled Trial

admin — Wed, 11 May 2011 09:54:39 +0000

R Agarwal, DJ Leehey, SM Olsen et al.

Clin J Am Soc Nephrol 2010

In this study patients with iron deficiency anaemia and CKD were stratified by ACEI/ARB use and randomized to IV iron sucrose or ferric gluconate for 5 weeks (33 patients and 29 patients, respectively). Urine protein/urine creatinine ratio was measured before each dose and frequently thereafter for 3 hours. Neither preparation of IV iron increased the predose level of proteinuria, but the proteinuric response to IV iron was dependent on the type of iron and ACEI/ARB use. Without ACEIs/ARBs, ferric gluconate tended to cause less proteinuria with repeated iron administration; iron sucrose did not mitigate or aggravate proteinuria. However, in contrast to ferric gluconate, which produced only mild transient proteinuria in patients receiving ACEIs/ARBs, iron sucrose produced a consistent and persistent proteinuric response that was on average 78% greater than that reported with ferric gluconate. The data from this study suggest that suggest that nephrotoxicity of iron may depend on type of IV iron and on ACEI/ARB use.

Click here to go to the PubMed abstract Agarwal et al., 2010

Extraordinary Popular Delusions and the Madness of Crowds: Puncturing the Epoetin Bubble–Lessons for the Future

admin — Wed, 11 May 2011 09:53:44 +0000

D Goldsmith

Nephrol Dial Transplant 2010

This article by Goldsmith reviews the dilemmas that physicians face in using ESAs in CKD, he suggests key clinical and biological research priorities, and concurs with other leading authors in this area that a more patient-focused, individualized approach to anaemia management should be adopted.

Click here to go to the Journal home page

The Cardiorenal Anaemia Syndrome in Systolic Heart Failure: Prevalence, Clinical Correlates, and Long-Term Survival

admin — Wed, 11 May 2011 09:53:10 +0000

D Scrutinio, A Passantino, D Santoro

Eur J Heart Fail 2010

In this study the authors assessed the prevalence and clinical correlates of CRAS in systolic heart failure and the relationship between renal dysfunction and anaemia on hard clinical outcomes. In the 951 patients with CHF and systolic dysfunction assessed the prevalence of CRAS was 21.1%. Age, body mass index, diabetes, ischaemic aetiology, LVEF and treatment with renin-angiotensin system inhibitors were independently related to CRAS. During a median follow-up of 3.7 years, the primary outcome of all-cause mortality or urgent heart transplantation occurred in 404 patients (42.5%). Importantly, compared with patients with preserved renal function and normal Hb levels, those with CRAS had a significantly increased risk for the primary outcome – in fact 3-year urgent heart transplantation-free survival was 86% in patients with preserved renal function and normal Hb compared with only 47% in those with CRAS. Among patients with renal dysfunction, the adjusted HR for the primary outcome increased by 17% for each 1 g/dL decrease below a Hb value of 13.0 g/dL.

The authors conclude that despite a relatively low prevalence, CRAS contributes to considerable mortality due to CHF.

Click here to go to the European Journal of Heart Failure

Anaemia in heart failure: a prospective evaluation of clinical outcome in a community population

admin — Wed, 11 May 2011 09:52:35 +0000

T Stewart, J Freeman, J Stewart

Heart Lung Circ 2010

In the Australian study 959 patients hospitalized with HF were prospectively examined for a number of parameters; 38% (n=369) had anaemia (Hb <12.0 g/dL), which was normochromic normocytic in 87.8%. Of those who had haematinic studies, 15.5% had a confirmed haematinic deficiency. Although, anaemic patients were of similar age to non-anaemic patients, they were more likely to have elevated creatinine (48% versus 29%), hyponatraemia (20% versus 15%) and LVEF >40% (49% versus 39%) and were less likely to receive ACE inhibitors (72% versus 78%). At 12 months the anaemic patients had higher HF readmission rates (22.4% versus 15.7%), more multiple non-HF readmissions (12.4% versus 6.3%, p=0.001) and a higher mortality rate (16.4% versus 10.5%). This study is a simple examination of community patients, but one that demonstrates that anaemia is common (38%) in community patients hospitalized with HF, and is associated with increased risk of cardiac complications including HF and non-HF readmissions, and increased mortality. A haematinic deficiency was identified in 15.5% of patients. Anaemia is a common, multifactorial, but potentially treatable cause of adverse outcome in HF.

Click here to go to Heart Lung Circulation

The role of erythropoiesis stimulating agents and intravenous (IV) iron in the cardio renal anemia syndrome

admin — Wed, 11 May 2011 09:51:45 +0000

DS Silverberg

Heart Fail Rev 2010

In this article Donald Silverberg, the originator of the concept of CRAS, reviews the use of ESAs and i.v. iron in CRAS. He concludes that adequately powered long-term placebo-controlled studies of ESA and IV iron in CHF are still needed and are currently being carried out.

Click here to go to Heart Failure Reviews

Ferric Carboxymaltose in Patients with Heart Failure and Iron Deficiency

admin — Wed, 11 May 2011 09:50:56 +0000

S Anker, C Colet, G Filippatos et al.

N Engl J Med 2009;361:2436–2448

“Iron deficiency may impair aerobic performance. This study aimed to determine whether treatment with IV iron (FCM) would improve symptoms in patients who had HF, reduced LVEF, and ID, either with or without anemia. METHODS: We enrolled 459 patients with CHF of NYHA functional class II or III, a LVEF of 40% or less (for patients with NYHA class II) or 45% or less (for NYHA class III), iron deficiency (ferritin level <100 microg per liter or between 100 and 299 microg per liter, if the transferrin saturation was <20%), and a Hb level of 95 to 135 g per liter. Patients were randomly assigned, in a 2:1 ratio, to receive 200 mg of IV (FCM) or saline (placebo). The primary end points were the self-reported Patient Global Assessment and NYHA functional class, both at Week 24. Secondary end points included the distance walked in 6 minutes and the health-related QoL. RESULTS: Among the patients receiving FCM, 50% reported being much or moderately improved, as compared with 28% of patients receiving placebo, according to the Patient Global Assessment (odds ratio for improvement, 2.51; 95% CI, 1.75 to 3.61). Among the patients assigned to FCM, 47% had an NYHA functional class I or II at week 24, as compared with 30% of patients assigned to placebo (odds ratio for improvement by one class, 2.40; 95% CI, 1.55 to 3.71). Results were similar in patients with anemia and those without anemia. Significant improvements were seen with in the distance on the 6-minute walk test and QoL assessments. The rates of death, adverse events, and serious adverse events were similar in the two study groups. CONCLUSIONS: Treatment with IV FCM in patients with CHF and ID, with or without anemia, improves symptoms, functional capacity, and QoL; the side-effect profile is acceptable. (ClinicalTrials.gov number, NCT00520780). Copyright 2009 Massachusetts Medical Society”

Recent developments in the management of CHF in patients with an impaired LVEF have changed the natural history of this clinical syndrome and improved patients’ outcomes. However, the normal daily activities of many patients with HF remain restricted; they report symptoms of fatigue and dyspnea that adversely affect their QoL, leading to high morbidity. Therapeutic options to improve functional capacity in patients with HF are limited, and novel therapies are needed.

Numerous mechanisms unrelated to hemodynamic dysfunction may underlie impaired exercise tolerance in patients with CHF. Among them, inadequate oxygen supply and impaired oxygen use by skeletal muscle during exercise contribute to poor clinical status. In addition, anemia may aggravate symptoms in patients with HF. Targeting these abnormalities may confer functional benefits to such patients.