Francesco Locatelli

Almost all of the papers dealing with chronic kidney disease (CKD) invariably start underlining that morbidity and mortality rate of this patient population is unacceptably high. Conversely, very few papers have considered quality of life and none selected quality of life as the primary end point. This reflects a clear bias for doctors and investigators, possibly because the treatment of CKD, especially in stage 5 on dialysis or with transplantation, is life-saving. Thus, the efforts of nephrologists were and are still concentrated in reducing the mortality and the morbidity of patients, without carefully considering quality of life. This attitude has been amplified by the influence of evidence-based medicine and regulatory authorities: the only end points that really matter are the hard-ones. Surrogate end points, especially when they are not easily quantifiable, are considered often insufficient to prove the efficacy of a given treatment. This process has markedly improved the scientific quality of clinical trials. However, we are reaching the paradox that no clinical trial is capable of proving efficacy on hard end points. Recently, almost all large, well-designed clinical trials testing a variety of treatments have given negative results. This has led physicians back to the importance of individualizing the cure of the single patient according to his characteristics and it is revaluating a comprehensive view of the possible associated benefits of a given treatment.

Introduction: Erythropoiesis-stimulating agents (ESAs) have been the main therapy for anemia in CKD patients since the late eighties. Since then, treatment indications have progressively changed, together with a progressive increase in therapeutic targets, in terms of hemoglobin levels. Areas covered: This paper discusses possible concerns about ESA use and increased cardiovascular risk (in particular stroke), hypertension, cancer progression and the development of pure red cell aplasia. A literature search was done on PubMed to obtain studies about the adverse effects of ESA in the CKD population. Expert opinion: The publication of the TREAT study has largely contributed to the concerns about ESA use, indicating that complete anemia correction may not be safe in the CKD population. This may be particularly true in high-risk patients, especially if hyporesponsive to ESA treatment. However, there is a gray area of no evidence either way for intermediate levels (11.5 – 13 g/dl), in comparison with higher or lower levels. New recommendations about ESA use in the CKD population by the Food and Drug Administration seem to move toward treatment individualization.

The European Renal Best Practice (ERBP), which are issued by ERA–EDTA, are suggestions for clinical practice in areas in which evidence is lacking or weak, together with position statements on recently published randomized controlled trials, or on existing guidelines and recommendations. In 2009, the Anaemia Working Group of ERBP published its first position statement about the haemoglobin target to aim for with erythropoietin-stimulating agents (ESA) and on issues that were not covered by K-DOQI in 2006–07. This second position paper of the group follows the publication of the Trial to Reduce Cardiovascular Events with Aranesp^® Therapy (TREAT) Study. This multi-centre, placebo-controlled trial compared cardiovascular and renal outcomes in 4038 patients with type 2 diabetes, chronic kidney disease not on dialysis, and anaemia who were randomized to complete anaemia correction (haemoglobin target of 13 g/dL using darbepoetin alfa) or placebo (with a haemoglobin rescue value of 9 g/dL). Following the findings of the TREAT study, the Anaemia Working Group of ERBP maintains its view that ‘Hb values of 11–12 g/dL should be generally sought in the CKD population without intentionally exceeding 13 g/dL’ and that the doses of ESA therapy to achieve the target haemoglobin should also be considered. More caution is suggested when treating anaemia with ESA therapy in patients with type 2 diabetes not undergoing dialysis (and probably in diabetics at all CKD stages). In those with ischaemic heart disease or with a previous history of stroke, possible benefits should be weighed up against an increased risk of stroke recurrence, when deciding which Hb level to aim for. These recommendations are not intended to represent a new guideline as they are not the result of a systematic review of the evidence.

Although the prognosis of patients who have diabetes and are receiving renal replacement therapy has greatly improved, survival and medical rehabilitation rates continue to be significantly worse than those of nondiabetic patients, mainly because of pre‐existing severely compromised cardiovascular conditions. In this scenario, the nephrology community had to do its best in order to offer the best treatment options to these patients using a multifaceted approach. The most common RRT modality in patients with diabetes is still hemodialysis, but it gives rise to a number of clinical problems, in particular difficulties in the management of the vascular access and high frequency of intradialytic hypotension. Recent data suggest that efficient high‐flux treatments have the potential of improving morbidity and mortality of diabetics with ESRD. Sodium profiling during the dialysis session may be also of importance in reducing intradialytic hypotension and helping in achieving the prescribed body weight. Patients who have diabetes and are on peritoneal dialysis have to face a progressive increase in peritoneal permeability, loss of ultrafiltration, and peritoneal fibrosis, all phenomena being accelerated in patients with diabetes and ultimately leading to an increased technique failure. However, the two dialytic modalities are comparable in terms of outcomes in the short term.

The clinical benefits of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARB) are well established in chronic kidney disease (CKD) patients with diabetic and non-diabetic nephropathies. But despite appearance, the magnitude of this effect has been questioned particularly in mild, proteinuric nephropathies. Given that the single agents can achieve only partial and not durable suppression of the renin-angiotensin system (RAS), it has been hypothesized that dual blockage with ACE inhibitors and ARBs would be most beneficial in the management of progressive CKD than either agent alone. Available evidence indicates significant anti-proteinuric effect, but long-term data in CKD patients are lacking. Recently, the findings of the ONTARGET trial even questioned the safety of this therapeutic approach. Given that preventing cardiovascular complications is extremely important in CKD and RAS inhibition may be useful in this setting, benefits of RAS blockade must be weighed against its possible adverse effects particularly in elderly patients.

Over the last few years, much has been done to develop guidelines on the basis of the strongest possible evidence because this allows an accurate description of the quality and/or degree of uncertainty of the recommendations and provides physicians with a valuable tool for judicious decisions. However, creating and updating evidence-based guidelines is extremely costly, and so the nephrological community has been trying to build up a single set of international guidelines under the aegis of Kidney Disease Improving Global Outcomes (KDIGO) [ 1 ]. As part of this unifying effort, the working group responsible for the 2006 update of the National Kidney Foundation–Kidney Disease Outcome Quality Initiative (NKF-KDOQI) guidelines on anaemia management in patients with chronic kidney disease (CKD) [ 2 ], and the 2007 update on haemoglobin (Hb) targets [ 3 ], included members from Europe, Middle East, Mexico and Canada. However, this international effort may not be correctly perceived by European nephrologists, who sometimes feel that differences in practice patterns make it difficult to apply guidelines developed outside Europe; on the other hand, the latest update of the European Best Practice Guidelines (EBPG) [ 4 ] may appear outdated in some respects.