Therapeutic targets for the anemia of predialysis chronic kidney disease: a meta-analysis of randomized, controlled trials
==========================================================================================================================

* Hongyong Liu
* Yuqiu Ye
* Yanbing Chen
* Yunqiang Zhang
* Shaomin Li
* Wentao Hu
* Rongqian Yang
* Zhesi Zhang
* Hongquan Peng
* Linsheng Lv
* Xun Liu

## Abstract

Anemia is one of the major complications in predialysis patients with chronic kidney disease (CKD). A clearer cognition of the prognostic impact of hemoglobin (Hb) or hematocrit (Hct) target on the outcomes of predialysis patients with CKD is significant. This article aims to establish the suitable hemoglobin target to provide clinical guidance. MEDLINE, EmBase, the Cochrane Library and other databases were searched with both MeSH terms and keywords to gather researches that assessed all-cause mortality, stroke, treatment of renal replacement, and transfusion. The meta-analysis was accomplished via Revman 5.3 version. Totally, 13 eligible studies involving 7606 patients were included. There was a significantly lower risk of transfusion (risk ratio (RR) 0.59, 95% CI 0.52 to 0.67; p<0.00001) in the higher hemoglobin group than in the lower one. However, no significant difference was found in all-cause mortality (RR 1.10, 95% CI 0.98 to 1.23; p=0.11), stroke (RR 1.32, 95% CI 0.82 to 2.10; p=0.25) and treatment of renal replacement including hemodialysis, peritoneal dialysis and renal transplant (RR 1.08, 95% CI 0.95 to 1.22; p= 0.23) between the higher hemoglobin group and the lower one. The results favor the higher hemoglobin target. To target the higher hemoglobin when treating predialysis patients with CKD may decrease the risk of transfusion without increasing the risk of death, stoke, and treatment of renal replacement.

*   anemia
*   prognosis
*   kidney diseases

### Significance of this study

#### What is already known about this subject?

*   To our best knowledge, anemia aggravates exercise tolerance, cognitive competence, and reduces the quality of life both in predialysis and dialysis patients.

*   Kidney Disease Improving Global Outcomes Guidelines have been developed for the hemoglobin targets, but there remains considerable controversy regarding the appropriate Hb or Hct levels as shown by the wide variation that still exists in anemia management practices between and within countries.

*   Interventional evidence has been pointing in a different direction. A meta-analysis found that predialysis and dialysis patients treated with erythropoiesis-stimulating agents targeting the higher hemoglobin do not lower mortality and may increase cardiovascular risk.

#### What are the new findings?

*   There was a significantly lower risk of transfusion in the higher hemoglobin group than in the lower one.

*   No significant difference was found in all-cause mortality, stroke, and treatment of renal replacement including hemodialysis, peritoneal dialysis and renal transplant between the higher hemoglobin group and the lower one. The results favor the higher hemoglobin target.

*   Due to lack of relative articles of studying higher Hb (such as >150 g/L), we cannot summarize and give the answer of upper limit of Hb concentration.

#### How might these results change the focus of research or clinical practice?

*   Overall, our studies favor the higher hemoglobin target in predialysis patients.

## Introduction

Chronic kidney disease (CKD) is a global public health problem, because of its high prevalence, heavy economic burden, and poor prognosis.1 2 Patients with CKD easily suffered from anemia due to endogenous erythropoietin deficiency, shortened red blood cell (RBC) survival, and uremic inhibitors.3 Recombinant human erythropoietin and the analogues are widely used to treat anemia. To our best knowledge, anemia aggravates exercise tolerance, cognitive competence, and reduces quality of life both in predialysis and dialysis patients.4–6 Anemia also can exert adverse influence on cardiovascular system such as left ventricular hypertrophy or dilation, arrhythmia, and myocardial ischemia.7 8 Reversing anemia may reduce the risk. However, it is reported that adverse effects of the higher hemoglobin level include the development of systemic hypertension, site access thrombosis in dialysis patients with arteriovenous shunts, and increased risk of cardiovascular events.9 Interventional evidence has been pointing in a different direction. A meta-analysis10 found that predialysis and dialysis patients treated with erythropoiesis-stimulating agents (ESAs) targeting the higher hemoglobin do not lower mortality and may increase cardiovascular risk.

Kidney Disease Improving Global Outcomes (KDIGO) Guidelines have been developed for the hemoglobin targets, but there remains considerable controversy regarding the appropriate Hb or Hct levels as shown by the wide variation that still exists in anemia management practices between and within countries. The aim of this systematic review is to summarize the benefits and harms of lower versus higher hemoglobin in the treatment of the anemia of only predialysis CKD using existing randomized controlled trial data.

## Materials and methods

### Data sources and literature searches

We conducted a systematic review and meta-analysis according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines (see supplementary file S1 Appendix 1).11 We electronically searched MEDLINE literature to collect all relevant literature using the search terms or synonyms *‘Chronic kidney disease’, ‘CKD’, hemoglobin, Hb, Hematocrit, Hct, ‘erythropoiesis stimulating agent, recombinant human erythropoietin, rhuEPO, darbepoetin, erythropoietin,’* from inception to December 25, 2017. Randomized controlled clinical trials were also searched via EMBASE (1974 to December 2017), the Cochrane Controlled Clinical Trials Register Database (through December 2017), the Cochrane Renal Group Specialized Register of Randomized Controlled Trials (through December 2017) and the ClinicalTrials.gov website.

### Supplementary file 1

[[jim-2018-000915supp001.docx]](pending:yes) 

We also searched (manually) the abstracts of conference proceedings of the American Society of Nephrology from 1998 to 2017. However, we did not have access to RCTs that were not reported. Our searches have no restriction on language. Finally, we found 786 studies for the analysis. After screening, 13 studies12–24 were included in the analysis (figure 1).

![Figure 1](/https://d3hme472k3gd2d.cloudfront.net/content/jim/early/2019/02/27/jim-2018-000915/F1.medium.gif)

[Figure 1](/content/early/2019/02/27/jim-2018-000915/F1)

Figure 1 
Flow diagram of studies considered for inclusion.

### Study selection

All RCTs that studied predialysis CKD adults (age >18 years) and compared higher Hb target to lower ones were included. We excluded the studies as follows: duplicate publication; personal perspective, academic conferences, reviews, and meta-analysis articles; animal and cell experiment; literature that studies dialysis patients; population age<18 years; sample size <50. Titles and abstracts were reviewed and evaluated by two reviewers independently, as well as the full-text articles.

### Data extraction and quality assessment

Data were independently extracted by two authors (Yuqiu Ye and Shaomin Li). Search strategies of all databases could be found in online supplementary file 2. The following data were extracted: country of origin; year of publication; sample size; mean age; percentage of men; mean or median follow-up time; prevalence of diabetes; prevalence of hypertension; different Hb (or Hct) targets; number of endpoints outcomes.

### Supplementary file 2

[[jim-2018-000915supp002.doc]](pending:yes) 

We also extracted trial characteristics, trial intervention. Regularly, several items such as independent randomization center, random allocation, blindness, adequate allocation concealment, intention-to-treat for RCTs were recorded. The quality of trials was assessed by Review Manager 5.3 (Oxford, UK) according to the Cochrane Handbook for Systematic Reviews of Interventions. Discrepancies concerning extraction and/or assessment of the quality of data were addressed by the third person if necessary.

### Synthesis and analysis of data

The software Review Manager 5.3 was used to implement meta-analysis. Risk ratios (RRs) were used to pool results for dichotomous outcomes (eg, all-cause mortality). We use a fixed-effects (used if I2<25%) and a random-effects model (used if I2>50%) to analyze data. 95% CIs were provided for all pooled estimates. Heterogeneity was assessed using the Cochrane Q test. I2 index (which describes the percentage of total variation across studies due to true heterogeneity rather than chance) and p values were also used. Publication bias was assessed using Funnel plots.

We performed the sensitivity analysis by removing the low-quality trials. We treated the trials with more than two ‘high risk’ according to Review Manager 5.3 as low-quality trials.

## Results

### Selection and characteristics of studies

Detailed characteristics and a summary of all studies are displayed in Table 1. Multiple publications were excluded from studies. Unique results were extracted and studies (as well as abstracts) containing unique results were also displayed. The average age of each group ranged from 56.5 to 68 years. The sample size of the studies varied from 83 to 4038. Duration of follow-up was from 9 months to 48 months.

View this table:
[Table 1](/content/early/2019/02/27/jim-2018-000915/T1)

Table 1 
Main characteristics of 27 studies selected for a meta-analysis

### Effects of higher or lower hemoglobin on all-cause mortality

In an analysis of 10 studies with 7270 participants reporting on all-cause mortality, no significant difference was found in all-cause mortality in the fixed effects model (RR 1.10, 95% CI 0.98 to 1.23; p=0.11) (figure 2).

![Figure 2](/https://d3hme472k3gd2d.cloudfront.net/content/jim/early/2019/02/27/jim-2018-000915/F2.medium.gif)

[Figure 2](/content/early/2019/02/27/jim-2018-000915/F2)

Figure 2 
Metagraph of all-cause mortality.

### Effects of higher or lower hemoglobin on stroke

Five studies with 6319 participants reported on stroke. No significant difference was found in stroke in the random effects model with heterogeneity between studies (RR 1.32, 95% CI 0.82 to 2.10; p=0.25) (figure 3).

![Figure 3](/https://d3hme472k3gd2d.cloudfront.net/content/jim/early/2019/02/27/jim-2018-000915/F3.medium.gif)

[Figure 3](/content/early/2019/02/27/jim-2018-000915/F3)

Figure 3 
Metagraph of stroke.

### Effects of higher or lower hemoglobin on treatment of renal replacement

In an analysis of 12 studies with 7523 participants reporting on treatment of renal replacement including hemodialysis, peritoneal dialysis, or renal transplant, no significant difference was found in any treatment of renal replacement in the fixed effects model (RR 1.08, 95% CI 0.95 to 1.22; p=0.23) (figure 4).

![Figure 4](/https://d3hme472k3gd2d.cloudfront.net/content/jim/early/2019/02/27/jim-2018-000915/F4.medium.gif)

[Figure 4](/content/early/2019/02/27/jim-2018-000915/F4)

Figure 4 
Metagraph of treatment of renal replacement.

### Effects of higher or lower hemoglobin targets on transfusion

Three studies with 4194 participants reported on transfusion. A significant decrease in the risk of transfusion was found in the higher Hb target group by 41% in the fixed effects model without heterogeneity between studies (RR 0.59, 95% CI 0.52 to 0.67; p<0.00001) (figure 5).

![Figure 5](/https://d3hme472k3gd2d.cloudfront.net/content/jim/early/2019/02/27/jim-2018-000915/F5.medium.gif)

[Figure 5](/content/early/2019/02/27/jim-2018-000915/F5)

Figure 5 
Metagraph of transfusion.

### Sensitivity analysis and publication bias

Pfeffer *et al* (2009)22provided well-designed RCTs that have the biggest sample size and may impact on clinical outcome mainly, such as transfusion and stroke.

Figure 6 shows a funnel plot of the studies. All studies lie inside the 95% CIs, with an even distribution around the vertical, indicating no obvious publication bias.

![Figure 6](/https://d3hme472k3gd2d.cloudfront.net/content/jim/early/2019/02/27/jim-2018-000915/F6.medium.gif)

[Figure 6](/content/early/2019/02/27/jim-2018-000915/F6)

Figure 6 
The funnel plot of this study.

## Discussion

This meta-analysis evaluated current evidence from RCTs comparing different hemoglobin targets in predialysis patients. The result suggested that compared with lower hemoglobin, higher hemoglobin target significantly reduced the risk of transfusion. Meanwhile, no significant difference in all-cause mortality, stroke, and any treatment of renal replacement was observed between two groups.

The impact of maintaining different hemoglobin targets on survival of predialysis patients was investigated previously in observational studies and RCTs, showing inconsistent results. The former suggested that higher hematocrits (33%–36%) reduced risk for death by 7%.25 However, recent meta-analyses of only RCTs with samples varying from 464 to 7902 participants indicated no reduction of all-cause mortality and even higher risk of death in patients with CKD with higher Hb target than those with lower ones.10 26 27 The articles that studied renal replacement therapy patients such as hemodialysis, peritoneal dialysis, and kidney transplant were not involved in the analysis of results. In light of the deficit in the ability of observational studies to discover causality between intervention and clinical outcome, the present evidence seemed to suggest no favorable association between higher hemoglobin and survival advantage in CKD populations.

Importantly, no significant difference was found in stroke between two groups, not in line with a recent meta-analysis investigating different dose of erythropoiesis-stimulating agents in patients with CKD.10 It is reported that the higher hemoglobin was associated with increased risk of stroke. The underlying mechanism might partly be the facilitation of spontaneous platelet aggregation by EPO used to treat anemia and its interaction with blood coagulation factors, both leading to tendency of thrombosis.28 29 According to our result, the higher hemoglobin target did not put patients with CKD at increased risk of stroke. However, trial reports did not specify whether stroke events were fatal or not.

Benefit of the higher hemoglobin target was the reduction of transfusion rate. The discretionary and abused use of blood products may have negative consequences including immune disorders, pulmonary complications, increased the chance of infection, longer intensive care unit stay, RBC alloimmunization, and increased overall mortality.30–33 In addition to the health risks associated with transfusions, blood products are an increasingly hospitalization expense. It is reported that medical institutions in the USA pay approximately US$225 per unit of RBCs, let alone but the triple cost of the administrative and labor costs associated with receipt, storage, transportation, and transfusion of the blood products.34 As such, reducing the unnecessary use of blood products has the potential to control hospital costs associated with blood products and reduce transfusion-related morbidities. But we failed to conduct the risk benefit analysis or cost of ESA use. In detail, we cannot assess number needed to treat, differing risk populations, or whether trials of short duration in healthier patients can really assess the thrombotic or stroke risk of ESAs.

The effect of the hemoglobin target on renal function still remains uncertain. No protection effect of the higher hemoglobin target on outcome of renal replacement therapy was found in the current study or in a previous meta-analysis.10 Although Strippoli *et al* reported a lower end-point serum creatine clearance in the lower hemoglobin group, the risk of end-stage renal disease did not decrease accordingly.26 

The KDIGO guideline suggested HB≤11.5 g/L for patients with CKD according to the upper HB boundary of the lower Hb level group in major ESA RCTs, and uncertainty still existed on the effect of Hb concentration between 11.5 and 13.0 g/L.35 In addition, emphasis was put on individual treatment balancing the pros and cons of ESA therapy and blood transfusion.35 In the current study, the Hb concentrations in two groups were approximately 120–140 g/L and 90–110 g/L. On the basis of current clinical data, a higher hemoglobin target was recommended for patients with CKD. Importantly, in cases that tended to develop anemia-related symptom such as fatigue and decreased physical function, and those required higher hemoglobin target to avoid episode of cardiovascular disease like heart failure, coronary artery disease, maintaining a higher Hb concentration might be beneficial. As we know, the standards for blood transfusions vary from patient to country. In the USA, most institutions do not transfuse for hemoglobin’s 8 or higher in the absence of symptomatology. In China, patients with absence of symptomatology, generally Hb less than 7 g/L, may be considered blood transfusions. If this practice is in place elsewhere, it may make the finding of fewer transfusions in the higher target range more of an artifact of regulation rather than a biological phenomenon.

In this meta-analysis, there were several limitations that must be taken into consideration. First, we cannot specify the proper hemoglobin or hematocrit level in predialysis patients. In detail, over all studies, the lower Hb boundary of the high Hb group overlapped the upper boundary of the low Hb group when compared among studies. In at least three studies, the upper and lower limits come very close such as Pfeffer (2009),22 Rossert (2007), Villar (2011),12 and Cianciaruso (2008).17 But the level of the Hb or Hct interval can also be distinguished. We reanalyzed the data excluding above studies, but the results for all-cause mortality, stroke, transfusion, and renal replacement therapy were unchanged (see online supplementary files S3-S6). Several studies included concentration on the clinical outcome of different Hct levels and cannot explain the corresponding Hb levels. The missing element is the dose of ESA used in some studies. Second, for the characteristics of studies, such as the sample, the follow-up periods are hugely different, which might increase heterogeneity and bias the results. Third, unpublished reports could not be identified, which might have biased our results. Finally, due to lack of relative articles of studying higher Hb (such as>150 g/L), we cannot summarize and give the answer of upper limit of Hb concentration.

## Conclusion

In this meta-analysis pooling, available RCTs suggested that targeting the higher hemoglobin target when treating predialysis patients decreases risk of transfusion and had no significant effect on increased risk of death, risk of stroke, and any treatment of renal replacement. Overall, our studies favor the higher hemoglobin target in predialysis patients.

### Supplementary file 3

[[jim-2018-000915supp003.jpg]](pending:yes) 

### Supplementary file 4

[[jim-2018-000915supp004.jpg]](pending:yes) 

### Supplementary file 5

[[jim-2018-000915supp005.jpg]](pending:yes) 

### Supplementary file 6

[[jim-2018-000915supp006.jpg]](pending:yes) 

## Footnotes

*   HL, YY and YC contributed equally.

*   Contributors Conceived and designed the experiments: XL, HL, YY. Performed the experiments: YZ, SL, HP. Analyzed the data: WH, RY, YC. Contributed reagents/materials/analysis tools: ZZ, LL, YC. Wrote the paper: YY, SL, XL.

*   Funding This study was supported by the National Natural Science Foundation of China (Grant No. 81873631, Grant No.81370866), the Third Affiliated Hospital of Sun Yat-Sen University, Clinical Research Program (Grant No.YHJH201806).

*   Competing interests None declared.

*   Provenance and peer review Not commissioned; externally peer reviewed.

*   Correction notice This article has been corrected since it was published Online First. The affiliations for Rongqian Yang, Zhesi Zhang, Hongquan Peng and Yanbing Chen have been corrected.

*   Patient consent for publication Not required.

## References

1.   Zhang Q-L , Rothenbacher D . Prevalence of chronic kidney disease in population-based studies: Systematic review. BMC Public Health 2008;8:117.[doi:10.1186/1471-2458-8-117](http://dx.doi.org/10.1186/1471-2458-8-117) 
    
    

2.   Zhang L , Wang F , Wang L , et al . Prevalence of chronic kidney disease in China: a cross-sectional survey. Lancet 2012;379:815–22.[doi:10.1016/S0140-6736(12)60033-6](http://dx.doi.org/10.1016/S0140-6736(12)60033-6) 
    
    [CrossRef](/lookup/external-ref?access_num=10.1016/S0140-6736(12)60033-6&link_type=DOI) 
    
    [PubMed](/lookup/external-ref?access_num=22386035&link_type=MED&atom=%2Fjim%2Fearly%2F2019%2F02%2F27%2Fjim-2018-000915.atom) 
    
    [Web of Science](/lookup/external-ref?access_num=000300983400031&link_type=ISI) 

3.   McGonigle RJS , Wallin JD , Shadduck RK , et al . Erythropoietin deficiency and inhibition of erythropoiesis in renal insufficiency. Kidney Int 1984;25:437–44.[doi:10.1038/ki.1984.36](http://dx.doi.org/10.1038/ki.1984.36) 
    
    [CrossRef](/lookup/external-ref?access_num=10.1038/ki.1984.36&link_type=DOI) 
    
    [PubMed](/lookup/external-ref?access_num=6727139&link_type=MED&atom=%2Fjim%2Fearly%2F2019%2F02%2F27%2Fjim-2018-000915.atom) 
    
    [Web of Science](/lookup/external-ref?access_num=A1984SL15300013&link_type=ISI) 

4.   Kovesdy CP , Trivedi BK , Kalantar-Zadeh K , et al . Association of anemia with outcomes in men with moderate and severe chronic kidney disease. Kidney Int 2006;69:560–4.[doi:10.1038/sj.ki.5000105](http://dx.doi.org/10.1038/sj.ki.5000105) 
    
    [CrossRef](/lookup/external-ref?access_num=10.1038/sj.ki.5000105&link_type=DOI) 
    
    [PubMed](/lookup/external-ref?access_num=16395253&link_type=MED&atom=%2Fjim%2Fearly%2F2019%2F02%2F27%2Fjim-2018-000915.atom) 
    
    [Web of Science](/lookup/external-ref?access_num=000234989800023&link_type=ISI) 

5.   McClellan WM , Jurkovitz C , Abramson J . The epidemiology and control of anaemia among pre-ESRD patients with chronic kidney disease. Eur J Clin Invest 2005;35:58–65.[doi:10.1111/j.1365-2362.2005.01532.x](http://dx.doi.org/10.1111/j.1365-2362.2005.01532.x) 
    
    [CrossRef](/lookup/external-ref?access_num=10.1111/j.1365-2362.2005.01532.x&link_type=DOI) 
    
    [PubMed](/lookup/external-ref?access_num=16281960&link_type=MED&atom=%2Fjim%2Fearly%2F2019%2F02%2F27%2Fjim-2018-000915.atom) 

6.   Singh AK . What is causing the mortality in treating the anemia of chronic kidney disease: erythropoietin dose or hemoglobin level? Curr Opin Nephrol Hypertens 2010;19:420–4.[doi:10.1097/MNH.0b013e32833cf1d6](http://dx.doi.org/10.1097/MNH.0b013e32833cf1d6) 
    
    [CrossRef](/lookup/external-ref?access_num=10.1097/MNH.0b013e32833cf1d6&link_type=DOI) 
    
    [PubMed](/lookup/external-ref?access_num=20689425&link_type=MED&atom=%2Fjim%2Fearly%2F2019%2F02%2F27%2Fjim-2018-000915.atom) 
    
    [Web of Science](/lookup/external-ref?access_num=000281091300002&link_type=ISI) 

7.   Hirakata H , Tsubakihara Y , Gejyo F , et al . Maintaining high hemoglobin levels improved the left ventricular mass index and quality of life scores in pre-dialysis Japanese chronic kidney disease patients. Clin Exp Nephrol 2010;14:28–35.[doi:10.1007/s10157-009-0212-4](http://dx.doi.org/10.1007/s10157-009-0212-4) 
    
    [CrossRef](/lookup/external-ref?access_num=10.1007/s10157-009-0212-4&link_type=DOI) 
    
    [PubMed](/lookup/external-ref?access_num=19763743&link_type=MED&atom=%2Fjim%2Fearly%2F2019%2F02%2F27%2Fjim-2018-000915.atom) 

8.   Sikole A , Polenakovic M , Spirovska V , et al . analysis of heart morphology and function following erythropoietin treatment of anemic dialysis patients. Artif Organs 1993;17:977–84.[doi:10.1111/j.1525-1594.1993.tb03179.x](http://dx.doi.org/10.1111/j.1525-1594.1993.tb03179.x) 
    
    [PubMed](/lookup/external-ref?access_num=8110072&link_type=MED&atom=%2Fjim%2Fearly%2F2019%2F02%2F27%2Fjim-2018-000915.atom) 
    
    [Web of Science](/lookup/external-ref?access_num=A1993MN55100003&link_type=ISI) 

9.   Strippoli GFM , Navaneethan SD , Craig JC , et al . Haemoglobin and haematocrit targets for the anaemia of chronic kidney disease. Cochrane Database Syst Rev 2006;2.[doi:10.1002/14651858.CD003967.pub2](http://dx.doi.org/10.1002/14651858.CD003967.pub2) 
    
    

10.  Vinhas J , Barreto C , Assunção J , et al . Treatment of anaemia with erythropoiesis-stimulating agents in patients with chronic kidney disease does not lower mortality and may increase cardiovascular risk: a meta-analysis. Nephron Clin Pract 2012;121:c95–101.[doi:10.1159/000345158](http://dx.doi.org/10.1159/000345158) 
    
    [CrossRef](/lookup/external-ref?access_num=10.1159/000345158&link_type=DOI) 
    
    [PubMed](/lookup/external-ref?access_num=23182871&link_type=MED&atom=%2Fjim%2Fearly%2F2019%2F02%2F27%2Fjim-2018-000915.atom) 

11.  Liberati A , Altman DG , Tetzlaff J , et al . The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol 2009;62:e1–34.[doi:10.1016/j.jclinepi.2009.06.006](http://dx.doi.org/10.1016/j.jclinepi.2009.06.006) 
    
    [CrossRef](/lookup/external-ref?access_num=10.1016/j.jclinepi.2009.06.006&link_type=DOI) 
    
    [PubMed](/lookup/external-ref?access_num=19631507&link_type=MED&atom=%2Fjim%2Fearly%2F2019%2F02%2F27%2Fjim-2018-000915.atom) 

12.  Villar E , Lièvre M , Kessler M , et al . Anemia normalization in patients with type 2 diabetes and chronic kidney disease: results of the NEPHRODIAB2 randomized trial. J Diabetes Complications 2011;25:237–43.[doi:10.1016/j.jdiacomp.2011.03.003](http://dx.doi.org/10.1016/j.jdiacomp.2011.03.003) 
    
    [PubMed](/lookup/external-ref?access_num=21601481&link_type=MED&atom=%2Fjim%2Fearly%2F2019%2F02%2F27%2Fjim-2018-000915.atom) 

13.  Gouva C , Nikolopoulos P , Ioannidis JP , et al . Treating anemia early in renal failure patients slows the decline of renal function: a randomized controlled trial. Kidney Int 2004;66:753–60.[doi:10.1111/j.1523-1755.2004.00797.x](http://dx.doi.org/10.1111/j.1523-1755.2004.00797.x) 
    
    [CrossRef](/lookup/external-ref?access_num=10.1111/j.1523-1755.2004.00797.x&link_type=DOI) 
    
    [PubMed](/lookup/external-ref?access_num=15253730&link_type=MED&atom=%2Fjim%2Fearly%2F2019%2F02%2F27%2Fjim-2018-000915.atom) 
    
    [Web of Science](/lookup/external-ref?access_num=000222578400039&link_type=ISI) 

14.  Ritz E , Laville M , Bilous RW , et al . Target level for hemoglobin correction in patients with diabetes and CKD: primary results of the Anemia Correction in Diabetes (ACORD) Study. Am J Kidney Dis 2007;49:194–207.[doi:10.1053/j.ajkd.2006.11.032](http://dx.doi.org/10.1053/j.ajkd.2006.11.032) 
    
    [CrossRef](/lookup/external-ref?access_num=10.1053/j.ajkd.2006.11.032&link_type=DOI) 
    
    [PubMed](/lookup/external-ref?access_num=17261422&link_type=MED&atom=%2Fjim%2Fearly%2F2019%2F02%2F27%2Fjim-2018-000915.atom) 
    
    [Web of Science](/lookup/external-ref?access_num=000248567500005&link_type=ISI) 

15.  Tsubakihara Y , Gejyo F , Nishi S , et al . High target hemoglobin with erythropoiesis-stimulating agents has advantages in the renal function of non-dialysis chronic kidney disease patients. Ther Apher Dial 2012;16:529–40.[doi:10.1111/j.1744-9987.2012.01082.x](http://dx.doi.org/10.1111/j.1744-9987.2012.01082.x) 
    
    [CrossRef](/lookup/external-ref?access_num=10.1111/j.1744-9987.2012.01082.x&link_type=DOI) 
    
    [PubMed](/lookup/external-ref?access_num=23190512&link_type=MED&atom=%2Fjim%2Fearly%2F2019%2F02%2F27%2Fjim-2018-000915.atom) 

16.  Kuriyama S , Tomonari H , Yoshida H , et al . Reversal of anemia by erythropoietin therapy retards the progression of chronic renal failure, especially in nondiabetic patients. Nephron 1997;77:176–85.[doi:10.1159/000190270](http://dx.doi.org/10.1159/000190270) 
    
    [CrossRef](/lookup/external-ref?access_num=10.1159/000190270&link_type=DOI) 
    
    [PubMed](/lookup/external-ref?access_num=9346384&link_type=MED&atom=%2Fjim%2Fearly%2F2019%2F02%2F27%2Fjim-2018-000915.atom) 
    
    [Web of Science](/lookup/external-ref?access_num=A1997XZ67900007&link_type=ISI) 

17.  Cianciaruso B , Ravani P , Barrett BJ , et al . Italian randomized trial of hemoglobin maintenance to prevent or delay left ventricular hypertrophy in chronic kidney disease. J Nephrol 2008;21:861–70.
    
    [PubMed](/lookup/external-ref?access_num=19034870&link_type=MED&atom=%2Fjim%2Fearly%2F2019%2F02%2F27%2Fjim-2018-000915.atom) 
    
    [Web of Science](/lookup/external-ref?access_num=000269099600008&link_type=ISI) 

18.  Revicki DA , Brown RE , Feeny DH , et al . Health-related quality of life associated with recombinant human erythropoietin therapy for predialysis chronic renal disease patients. Am J Kidney Dis 1995;25:548–54.[doi:10.1016/0272-6386(95)90122-1](http://dx.doi.org/10.1016/0272-6386(95)90122-1) 
    
    [CrossRef](/lookup/external-ref?access_num=10.1016/0272-6386(95)90122-1&link_type=DOI) 
    
    [PubMed](/lookup/external-ref?access_num=7702049&link_type=MED&atom=%2Fjim%2Fearly%2F2019%2F02%2F27%2Fjim-2018-000915.atom) 
    
    [Web of Science](/lookup/external-ref?access_num=A1995QQ63600004&link_type=ISI) 

19.  Drüeke TB , Locatelli F , Clyne N , et al . Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med 2006;355:2071–84.[doi:10.1056/NEJMoa062276](http://dx.doi.org/10.1056/NEJMoa062276) 
    
    [CrossRef](/lookup/external-ref?access_num=10.1056/NEJMoa062276&link_type=DOI) 
    
    [PubMed](/lookup/external-ref?access_num=17108342&link_type=MED&atom=%2Fjim%2Fearly%2F2019%2F02%2F27%2Fjim-2018-000915.atom) 
    
    [Web of Science](/lookup/external-ref?access_num=000241997300004&link_type=ISI) 

20.  Singh AK , Szczech L , Tang KL , et al . Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med 2006;355:2085–98.[doi:10.1056/NEJMoa065485](http://dx.doi.org/10.1056/NEJMoa065485) 
    
    [CrossRef](/lookup/external-ref?access_num=10.1056/NEJMoa065485&link_type=DOI) 
    
    [PubMed](/lookup/external-ref?access_num=17108343&link_type=MED&atom=%2Fjim%2Fearly%2F2019%2F02%2F27%2Fjim-2018-000915.atom) 
    
    [Web of Science](/lookup/external-ref?access_num=000241997300005&link_type=ISI) 

21.  Levin A , Djurdjev O , Thompson C , et al . Canadian randomized trial of hemoglobin maintenance to prevent or delay left ventricular mass growth in patients with CKD. Am J Kidney Dis 2005;46:799–811.[doi:10.1053/j.ajkd.2005.08.007](http://dx.doi.org/10.1053/j.ajkd.2005.08.007) 
    
    [CrossRef](/lookup/external-ref?access_num=10.1053/j.ajkd.2005.08.007&link_type=DOI) 
    
    [PubMed](/lookup/external-ref?access_num=16253719&link_type=MED&atom=%2Fjim%2Fearly%2F2019%2F02%2F27%2Fjim-2018-000915.atom) 
    
    [Web of Science](/lookup/external-ref?access_num=000233933400002&link_type=ISI) 

22.  Pfeffer MA , Burdmann EA , Chen CY , et al . A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med 2009;361:2019–32.[doi:10.1056/NEJMoa0907845](http://dx.doi.org/10.1056/NEJMoa0907845) 
    
    [CrossRef](/lookup/external-ref?access_num=10.1056/NEJMoa0907845&link_type=DOI) 
    
    [PubMed](/lookup/external-ref?access_num=19880844&link_type=MED&atom=%2Fjim%2Fearly%2F2019%2F02%2F27%2Fjim-2018-000915.atom) 
    
    [Web of Science](/lookup/external-ref?access_num=000271898600007&link_type=ISI) 

23.  Rossert J , Levin A , Roger SD , et al . Effect of early correction of anemia on the progression of CKD. Am J Kidney Dis 2006;47:738–50.[doi:10.1053/j.ajkd.2006.02.170](http://dx.doi.org/10.1053/j.ajkd.2006.02.170) 
    
    [CrossRef](/lookup/external-ref?access_num=10.1053/j.ajkd.2006.02.170&link_type=DOI) 
    
    [PubMed](/lookup/external-ref?access_num=16632012&link_type=MED&atom=%2Fjim%2Fearly%2F2019%2F02%2F27%2Fjim-2018-000915.atom) 
    
    [Web of Science](/lookup/external-ref?access_num=000237627500003&link_type=ISI) 

24.  Roth D , Smith RD , Schulman G , et al . Effects of recombinant human erythropoietin on renal function in chronic renal failure predialysis patients. American Journal of Kidney Diseases 1994;24:777–84.[doi:10.1016/S0272-6386(12)80671-8](http://dx.doi.org/10.1016/S0272-6386(12)80671-8) 
    
    [PubMed](/lookup/external-ref?access_num=7977319&link_type=MED&atom=%2Fjim%2Fearly%2F2019%2F02%2F27%2Fjim-2018-000915.atom) 
    
    [Web of Science](/lookup/external-ref?access_num=A1994PR32900005&link_type=ISI) 

25.  Collins AJ , Ma JZ , Xia A , et al . Trends in anemia treatment with erythropoietin usage and patient outcomes. American Journal of Kidney Diseases 1998;32:S133–41.[doi:10.1016/S0272-6386(98)70176-3](http://dx.doi.org/10.1016/S0272-6386(98)70176-3) 
    
    [CrossRef](/lookup/external-ref?access_num=10.1016/S0272-6386(98)70176-3&link_type=DOI) 
    
    [PubMed](/lookup/external-ref?access_num=9892380&link_type=MED&atom=%2Fjim%2Fearly%2F2019%2F02%2F27%2Fjim-2018-000915.atom) 

26.  Strippoli GF , Navaneethan SD , Craig JC . Haemoglobin and haematocrit targets for the anaemia of chronic kidney disease. Cochrane Database Syst Rev 2006:CD003967.[doi:10.1002/14651858.CD003967.pub2](http://dx.doi.org/10.1002/14651858.CD003967.pub2) 
    
    

27.  Strippoli GF , Craig JC , Manno C , et al . Hemoglobin targets for the anemia of chronic kidney disease: a meta-analysis of randomized, controlled trials. J Am Soc Nephrol 2004;15:3154–65.[doi:10.1097/01.ASN.0000145436.09176.A7](http://dx.doi.org/10.1097/01.ASN.0000145436.09176.A7) 
    
    [Abstract/FREE Full Text](/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6ODoiam5lcGhyb2wiO3M6NToicmVzaWQiO3M6MTA6IjE1LzEyLzMxNTQiO3M6NDoiYXRvbSI7czo0MjoiL2ppbS9lYXJseS8yMDE5LzAyLzI3L2ppbS0yMDE4LTAwMDkxNS5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30=) 

28.  Taylor JE , Belch JJ , McLaren M , et al . Effect of erythropoietin therapy and withdrawal on blood coagulation and fibrinolysis in hemodialysis patients. Kidney Int 1993;44:182–90.[doi:10.1038/ki.1993.229](http://dx.doi.org/10.1038/ki.1993.229) 
    
    [PubMed](/lookup/external-ref?access_num=8355460&link_type=MED&atom=%2Fjim%2Fearly%2F2019%2F02%2F27%2Fjim-2018-000915.atom) 
    
    [Web of Science](/lookup/external-ref?access_num=A1993LG81600025&link_type=ISI) 

29.  Taylor JE , Henderson IS , Stewart WK , et al . Erythropoietin and spontaneous platelet aggregation in haemodialysis patients. Lancet 1991;338:1361–2.[doi:10.1016/0140-6736(91)92239-X](http://dx.doi.org/10.1016/0140-6736(91)92239-X) 
    
    [CrossRef](/lookup/external-ref?access_num=10.1016/0140-6736(91)92239-X&link_type=DOI) 
    
    [PubMed](/lookup/external-ref?access_num=1682739&link_type=MED&atom=%2Fjim%2Fearly%2F2019%2F02%2F27%2Fjim-2018-000915.atom) 
    
    [Web of Science](/lookup/external-ref?access_num=A1991GR77300006&link_type=ISI) 

30.  Plumb JO , Grocott MP . Liberal or restrictive transfusion after cardiac surgery. N Engl J Med 2015;373:192–3.[doi:10.1056/NEJMc1505810](http://dx.doi.org/10.1056/NEJMc1505810) 
    
    

31.  Reeves BC , Murphy GJ . Increased mortality, morbidity, and cost associated with red blood cell transfusion after cardiac surgery. Curr Opin Cardiol 2008;23:607–12.[doi:10.1097/HCO.0b013e328310fc95](http://dx.doi.org/10.1097/HCO.0b013e328310fc95) 
    
    [CrossRef](/lookup/external-ref?access_num=10.1097/HCO.0b013e328310fc95&link_type=DOI) 
    
    [PubMed](/lookup/external-ref?access_num=18830077&link_type=MED&atom=%2Fjim%2Fearly%2F2019%2F02%2F27%2Fjim-2018-000915.atom) 
    
    [Web of Science](/lookup/external-ref?access_num=000260405800013&link_type=ISI) 

32.  Shaw RE , Johnson CK , Ferrari G , et al . Blood transfusion in cardiac surgery does increase the risk of 5-year mortality: results from a contemporary series of 1714 propensity-matched patients. Transfusion 2014;54:1106–13.[doi:10.1111/trf.12364](http://dx.doi.org/10.1111/trf.12364) 
    
    

33.  Paone G , Likosky DS , Brewer R , et al . Transfusion of 1 and 2 units of red blood cells is associated with increased morbidity and mortality. Ann Thorac Surg 2014;97:87–94.[doi:10.1016/j.athoracsur.2013.07.020](http://dx.doi.org/10.1016/j.athoracsur.2013.07.020) 
    
    [CrossRef](/lookup/external-ref?access_num=10.1016/j.athoracsur.2013.07.020&link_type=DOI) 
    
    [PubMed](/lookup/external-ref?access_num=24094521&link_type=MED&atom=%2Fjim%2Fearly%2F2019%2F02%2F27%2Fjim-2018-000915.atom) 
    
    [Web of Science](/lookup/external-ref?access_num=000329155900023&link_type=ISI) 

34.  Shander A , Hofmann A , Ozawa S , et al . Activity-based costs of blood transfusions in surgical patients at four hospitals. Transfusion 2010;50:753–65.[doi:10.1111/j.1537-2995.2009.02518.x](http://dx.doi.org/10.1111/j.1537-2995.2009.02518.x) 
    
    [CrossRef](/lookup/external-ref?access_num=10.1111/j.1537-2995.2009.02518.x&link_type=DOI) 

35. Group KDIGOKCW. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Supp 2013;3:1–150.