There remains concern in the nephrology community that results of the hemoglobin A1c (HbA1c) assay for assessing glycemic control in diabetic patients with end-stage kidney disease (ESKD) differ from those in patients without kidney disease. This apprehension stems from the markedly shorter red blood cell (RBC) life span in patients on dialysis and from the fact that hemoglobin, critical to formation of HbA1c, resides in RBCs and requires sufficient time to interact with glucose to form HbA1c. Excessive production of immature RBCs from erythropoietin-stimulating agents further affects interactions between glucose and hemoglobin. There is potential harm when using HbA1c in patients on dialysis. The risk of hypoglycemia requiring hospitalization was 2-fold higher in patients with estimated glomerular filtration rate (eGFR) <15 mL/min/1.73 m2 or on dialysis compared with those having an eGFR 30–45 mL/min/1.73 m2 . Inaba et al. first documented differential relationships between serum glucose concentration and HbA1c in a cohort of Japanese patients with diabetes on hemodialysis (HD), relative to without nephropathy . They further demonstrated that the glycated albumin (GA) assay provided a truer picture of recent glycemic control in patients on HD. Replication of the superiority of GA versus HbA1c rapidly followed in European Americans and African Americans with diabetes on HD . Ten years have elapsed since the nephrology community became aware of the suboptimal clinical performance of the HbA1c assay in ESKD. This Editorial reviews the current status of assessing glycemic control in patients with diabetes and advanced chronic kidney disease (CKD). It includes the utility of other tests of glycemic control in this population, including fructosamine and GA as presented in this issue of Nephrology Dialysis Transplantation . The HbA1c assay is considered the standard for assessment of blood sugar control in patients with diabetes and ESKD . It is the most widely used assay of its type in dialysis patients from the USA. For any given level of glycemic control, HbA1c values are markedly lower in patients on HD compared with those with normal kidney function. The magnitudes of differences are striking and may give dialysis patients and their physicians a false sense of security that blood sugars are lower than they actually are. This concern underlies the search for alternative assays, as reported by Hoshino et al.  and others. Seminal studies including up to 54 757 prevalent patients on HD from large dialysis organizations assessed association between HbA1c concentrations and survival [6–8]. Ricks et al. reported that the adjusted all-cause hazard ratio (HR) for death based on increments in baseline HbA1c of 8.0–8.9%, 9.0–9.9% and ≥ 10% (compared with reference 7.0–7.9%) were 1.06 [95% confidence interval (CI) 1.01–1.12], 1.05 (0.99–1.12) and 1.19 (1.12–1.28), respectively . Using time-averaged HbA1c, HRs were 1.11 (1.05–1.16), 1.36 (1.27–1.45) and 1.59 (1.46–1.72), respectively. Fully adjusted models also showed symmetric increases in mortality with lower time-averaged HbA1c levels compared with reference values [6.0–6.9%, HR 1.05 (95% CI 1.01–1.08); 5.0–5.9%, 1.08 (1.04–1.11) and ≤5%, 1.35 (1.29–1.42)]. In contrast, Williams et al. did not observe these associations between baseline HbA1c and survival in 24 875 prevalent patients with diabetes on HD . Only extremes of high and low HbA1c values were associated with shortened survival on dialysis. These extreme values captured just 14% of patients and there was poor discriminatory ability for outcomes based on HbA1c in the remaining 86%. A subsequent report in this sample reached similar conclusions using time-averaged HbA1c and longer follow-up . These authors caution against extrapolating HbA1c results in populations without CKD to those in dialysis units. Thus, the two largest studies yielded conflicting findings. When a test is ordered in a patient on dialysis, results are expected to have clinical utility and assist in management. For HbA1c, values reflect the percentage of total hemoglobin that is glycosylated. However, the relationships between ambient blood glucose control and HbA1c differ markedly between populations with ESKD and those without nephropathy [2, 3]. The conclusions Kalantar-Zadeh et al.  and Ricks et al.  reached differ when considering associations between HbA1c and survival in unadjusted and adjusted statistical models. In unadjusted models, higher HbA1c associated with ‘longer’ survival; this paradoxical result might be mediated by improved nutritional status. In contrast, case-mix adjusted and case-mix plus malnutrition-inflammation complex syndrome (MICS)-adjusted HbA1c models reached different conclusions. In fully adjusted models, U-shaped relationships were observed between HbA1c and survival; HbA1c ≥8% was associated with ‘shorter’ survival. It is important to understand how to apply the required statistical adjustments to assess HbA1c results, because treating physicians are typically unable to consider their effects. Their case-mix model adjusted for nine covariates: age, sex, race, ethnicity, dialysis vintage, primary insurance, marital status, single pool Kt/V (dialysis dose) and residual renal function. To these nine covariates, their case-mix plus MICS-adjusted model further included body mass index, normalized protein catabolic rate, serum albumin, total iron-binding capacity, ferritin, creatinine, phosphorus, calcium, bicarbonate, white blood cell count, lymphocyte percentage and hemoglobin for a total of 21 adjustments. It is not feasible to rapidly perform these complex adjustments in the clinical setting. HbA1c was also evaluated in prevalent patients with diabetes on peritoneal dialysis (PD). Duong et al.  evaluated 2798 PD patients and observed that only time-averaged HbA1c values ≥8% (but not baseline HbA1c) were positively associated with all-cause mortality; association was strongest in patients with higher hemoglobin concentrations (≥11 g/dL). Their analyses included extensive adjustment for covariates when considering associations with HbA1c, just as in prior reports in HD [6, 8]. Finally, a meta-analysis in 83 684 diabetic HD patients revealed that higher mortality was seen with HbA1c values >8.5%; this analysis adjusted only for age, sex, type of diabetes, dialysis vintage and hemoglobin concentration . All of the aforementioned analyses are elegant and their results are important. However, conclusions are difficult to use in the clinic. Many patients and physicians falsely assume that the HbA1c values from the lab reflect published associations with mortality based on extensive covariate adjustment [6, 8, 10]. A series of studies assessed associations between the fructosamine and GA assays with death and hospitalizations in patients with ESKD; these reports yielded more consistent results than HbA1c. Table 1 displays results of all studies with at least 75 patients identified by PubMed search of ‘glycated albumin and dialysis’. Although GA and fructosamine reflect shorter windows of glycemic control (∼17 days) than the HbA1c (∼90 days), both have proven useful in patients on dialysis. This is in spite of theoretical limitations of GA resulting from loss of albumin in urine and peritoneal dialysate. Inaba et al. , Peacock et al.  and Freedman et al.  reported that the HbA1c significantly underestimated glycemic control in patients with ESKD on HD and PD, whereas GA more accurately reflected recent glycemic control. Cross-sectional analyses in the Atherosclerosis Risk In Communities population-based study confirmed that fructosamine and GA were as or more strongly associated with microvascular complications as HbA1c . Beyond this, longitudinal analyses from our group reported that GA was more strongly associated with mortality and hospitalizations than HbA1c [14, 15]. A significant association between GA and death was observed in 444 prevalent dialysis patients with diabetes followed for a mean of 2.33 years [14, 15]. In patients on dialysis, serial GA and plasma glucose concentrations were associated with cardiovascular disease (CVD)-related hospitalizations and GA associated with length of stay for CVD hospitalizations, whereas HbA1c did not . In spite of this evidence, fructosamine and GA have not been widely embraced by clinicians who care for patients with diabetes on dialysis [5, 21]. Table 1 Outcomes in patients with ESKD based on newer glycemic control assays Author Patients (n) and dialysis modality/follow-up (mos) Assay Endpoints Outcomes Okada et al.  78 HD/36 GA, HbA1c Death, CVD No GA or HbA1c association with death, GA association with CVD Fukuoka et al.  98 HD/47 GA, HbA1c Death, CVD death GA association with death and CVD death Freedman et al.  444 HD+PD/28 GA, HbA1c Death, hosp GA association with death and hosp Murea et al.  444 HD+PD/28 GA, HbA1c CVD hosp, LOS GA association with CVD hosp and LOS Shafi et al.  503 HD/42 GA, fructosamine Death, CVD death, hosp Fructosamine and GA association with death and CVD death Lu et al.  176 HD/51 GA Death GA association with death Chen et al.  1255 HD/48 GA, HbA1c Death GA association with death Hoshino et al.  22 441 HD/12 GA, HbA1c Death GA stronger association with death than HbA1c Author Patients (n) and dialysis modality/follow-up (mos) Assay Endpoints Outcomes Okada et al.  78 HD/36 GA, HbA1c Death, CVD No GA or HbA1c association with death, GA association with CVD Fukuoka et al.  98 HD/47 GA, HbA1c Death, CVD death GA association with death and CVD death Freedman et al.  444 HD+PD/28 GA, HbA1c Death, hosp GA association with death and hosp Murea et al.  444 HD+PD/28 GA, HbA1c CVD hosp, LOS GA association with CVD hosp and LOS Shafi et al.  503 HD/42 GA, fructosamine Death, CVD death, hosp Fructosamine and GA association with death and CVD death Lu et al.  176 HD/51 GA Death GA association with death Chen et al.  1255 HD/48 GA, HbA1c Death GA association with death Hoshino et al.  22 441 HD/12 GA, HbA1c Death GA stronger association with death than HbA1c mos, months; hosp, hospitalizations; LOS, length of hospital stay. Table 1 Outcomes in patients with ESKD based on newer glycemic control assays Author Patients (n) and dialysis modality/follow-up (mos) Assay Endpoints Outcomes Okada et al.  78 HD/36 GA, HbA1c Death, CVD No GA or HbA1c association with death, GA association with CVD Fukuoka et al.  98 HD/47 GA, HbA1c Death, CVD death GA association with death and CVD death Freedman et al.  444 HD+PD/28 GA, HbA1c Death, hosp GA association with death and hosp Murea et al.  444 HD+PD/28 GA, HbA1c CVD hosp, LOS GA association with CVD hosp and LOS Shafi et al.  503 HD/42 GA, fructosamine Death, CVD death, hosp Fructosamine and GA association with death and CVD death Lu et al.  176 HD/51 GA Death GA association with death Chen et al.  1255 HD/48 GA, HbA1c Death GA association with death Hoshino et al.  22 441 HD/12 GA, HbA1c Death GA stronger association with death than HbA1c Author Patients (n) and dialysis modality/follow-up (mos) Assay Endpoints Outcomes Okada et al.  78 HD/36 GA, HbA1c Death, CVD No GA or HbA1c association with death, GA association with CVD Fukuoka et al.  98 HD/47 GA, HbA1c Death, CVD death GA association with death and CVD death Freedman et al.  444 HD+PD/28 GA, HbA1c Death, hosp GA association with death and hosp Murea et al.  444 HD+PD/28 GA, HbA1c CVD hosp, LOS GA association with CVD hosp and LOS Shafi et al.  503 HD/42 GA, fructosamine Death, CVD death, hosp Fructosamine and GA association with death and CVD death Lu et al.  176 HD/51 GA Death GA association with death Chen et al.  1255 HD/48 GA, HbA1c Death GA association with death Hoshino et al.  22 441 HD/12 GA, HbA1c Death GA stronger association with death than HbA1c mos, months; hosp, hospitalizations; LOS, length of hospital stay. With this background, Hoshino et al. reported associations between a single GA or HbA1c value with subsequent 1-year mortality in a cohort of prevalent Japanese HD patients with diabetes . They reviewed retrospective annual questionnaires in the Japanese Society for Dialysis Therapy database. More than 22 000 prevalent patients had data on GA and HbA1c and were included in the main analysis encompassing ∼21 000 person years of follow-up and capturing 1886 deaths. Demographic information, clinical data, type of diabetes mellitus (Type 1 or Type 2) and history of macrovascular complications (prior myocardial infarction, stroke or peripheral arterial disease) were included. Medications for diabetes were included in the data set and the survey responses were complemented by ‘single-point in time’ clinical characteristics including serum albumin, hemoglobin and dialysis adequacy (Kt/V). GA testing employed the Lucica GA-L kit (Asahi-Kasei Pharma Corp., Tokyo, Japan), a precise enzymatic method performed in analogous fashion across all dialysis units. Their primary analysis evaluated the relationship between enrollment (not initiation of HD) GA and 1-year mortality in patients who had enrollment GA and HbA1c values. Participant categorizations were based on deciles of glycemic control using the enrollment GA. Those in the final analysis were on average, older, more often male and received maintenance HD for ∼5.5 years. Nearly 40% had a prior history of myocardial infarction, cardiac ischemia, stroke or peripheral arterial disease such as amputation. Individuals in the 15.6–18.2% GA decile experienced the lowest adjusted 1-year mortality. Adjustments were made for demographic and clinical variables as well as adequacy of dialysis. The resultant mortality curve was J shaped. In the cohort on HD, GA values >22.9% and <12.5% were associated with significantly higher risk of mortality. As noted by the authors, this was a higher ‘optimal’ GA range relative to patients with diabetes who were not on dialysis. The lowest mortality rate in individuals with diabetes lacking nephropathy was with GA values in the 11.9–15.8% range . Analyses of enrollment HbA1c included parallel adjustments for the same covariables as GA. Enrollment HbA1c values in the 5.8–6.3% range were associated with the lowest mortality and values <5.3% or >7.6% had the highest mortality. This was similar to previous studies that demonstrated comparable U-shaped mortality curves in patients with diabetes and ESKD. Statistical investigations comparing whether GA or HbA1c were superior in prediction of 1-year mortality indicated that the C-statistic improved from 0.7634 to 0.7793 (95% CI 0.7647–0.7912; P = 0.08) in the GA model. In contrast, there was a smaller improvement to 0.7701 in the HbA1c model (95% CI 0.7586–0.7816; P = 0.88). In other words, GA was slightly more strongly associated with 1-year mortality in their population than HbA1c. The authors urged caution in patients on dialysis with very high and very low GA levels due to their association with higher mortality. This observation is in-line with previous reports. This study had limitations. The authors concede that the observational and associative nature of their results limits their ability to inform outcomes and they could not test for association with macrovascular complications of diabetes. The GA measurement recorded in the survey reflected a single point in time in these prevalent patients on HD and the authors could not capture the predictive value of multiple, longitudinal GA measurements or perform time-averaged analyses. In addition, the enrollment GA was simply an observed result not targeting any particular goal level of blood sugar control. Other factors can impact GA, such as nutritional status and inflammation. Selection bias could have prevented the capture of all relevant data in the full study population. More than 32 000 patients were excluded from analyses due to absence of both an enrollment GA and HbA1c value. Finally, data on use of erythropoietin stimulating agents was lacking. Nonetheless, the analyses by Hoshino et al. have value. Results in their large sample add to the growing body of evidence that assessing recent glycemic control with HbA1c in patients with diabetes and ESKD does not accurately associate with outcomes unless extensive adjustment for covariates is included. Once more clinically useful glycemic control assays are identified for use in ESKD, the HbA1c assay should no longer be used. The current manuscript builds on the physiologic foundations in other observational investigations that advocate for use of GA to measure glycemic control in patients with ESKD. The Lucica GA-L assay kit used by Hoshino et al.  and us [14, 15] was recently approved for use in the USA by the Food and Drug Administration. In the past, this assay was unavailable in the USA. Hoshino et al.  are continuing to lay the groundwork for establishment of clinically useful ranges of GA values in the population with ESKD, particularly those on HD. Longer term follow-up of this cohort will likely provide additional information, particularly if longitudinal measures of GA and HbA1c can be incorporated. HbA1c performed poorly in the current investigation of patients with ESKD. Many reports suggest that the GA and fructosamine assays outperform HbA1c in patients with ESKD. It is time for a well-powered prospective study to test associations between longitudinal assessments of glycemic control such as fasting plasma glucose, HbA1c, fructosamine and GA with hard outcomes, death and adjudicated CVD events, in incident patients with ESKD performing HD and PD. All of these assays are currently available in Asia, Europe and the USA and a prospective study of this type is required to end the debate. Follow-up studies can then determine the optimal range of glycemic control to target with treatment using the top performing assay. These steps will be required to improve clinical outcomes. FUNDING B.I.F. previously received research support from Asahi Kasei Pharma Corporation (Tokyo, Japan) for investigator-initiated research. CONFLICT OF INTEREST STATEMENT None declared. The results presented in this article have not been published previously in whole or part. (See related article by Hoshino et al. 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Nephrology Dialysis Transplantation – Oxford University Press
Published: Mar 21, 2018
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