Unique hemoglobin A1c level distribution and its relationship with mortality in diabetic hemodialysis patients
Authors: Junichi Hoshino, Maria Larkina, Angelo Karaboyas, Brian A. Bieber, Yoshifumi Ubara, Kenmei Takaichi, Tadao Akizawa, Takashi Akiba, Shunichi Fukuhara, Ronald L. Pisoni, Akira Saito, Bruce M. Robinson
Journal: Kidney International (2017)

Diabetic hemodialysis patients with hemoglobin A1c (HbA1c) levels below 6.5% and over 8.0% face a higher mortality risk. To determine the optimal glycemic control in Japanese patients, we examined the association between HbA1c and mortality in 2,300 Japanese diabetic patients on maintenance hemodialysis with HbA1c levels determined at enrollment in the Japanese Dialysis Outcomes and Practice Patterns Study (JDOPPS) phases 2-5, using Cox regression analysis with adjustment for baseline age, sex, dialysis vintage, 12 general comorbidities, hemoglobin, albumin and creatinine levels, and insulin use; stratification by JDOPPS phase; and facility clustering taken into account. Overall, 54% of patients had HbA1c levels under 6.0, including 14% with HbA1c levels under 5.0. Insulin or oral diabetes medications were used less frequently in patients with higher HbA1c levels. The dependence of mortality on HbA1c level was U shaped. When the group with the lowest mortality (HbA1c 6.0-7.0) was used as a reference, the hazard ratios for HbA1c categories under 5.0, 5.0-6.0, 7.0 to under 8.0, and 8.0 and greater were, respectively, 1.56 (95% confidence interval, 1.05-2.33), 1.26 (0.92-1.71), 1.23 (0.79-1.89), and 2.10 (1.32-3.33) in the adjusted model. The HbA1c level was not associated with self-reported hypoglycemic episodes in JDOPPS phase 5. The HbA1c levels in diabetic hemodialysis patients differ considerably between Japan and those reported from Western countries. Thus, our findings highlight the importance of domestic guidelines for glycemic control by race and country. Diabetic hemodialysis patients with hemoglobin A1c (HbA1c) levels below 6.5% and over 8.0% face a higher mortality risk. To determine the optimal glycemic control in Japanese patients, we examined the association between HbA1c and mortality in 2,300 Japanese diabetic patients on maintenance hemodialysis with HbA1c levels determined at enrollment in the Japanese Dialysis Outcomes and Practice Patterns Study (JDOPPS) phases 2-5, using Cox regression analysis with adjustment for baseline age, sex, dialysis vintage, 12 general comorbidities, hemoglobin, albumin and creatinine levels, and insulin use; stratification by JDOPPS phase; and facility clustering taken into account. Overall, 54% of patients had HbA1c levels under 6.0, including 14% with HbA1c levels under 5.0. Insulin or oral diabetes medications were used less frequently in patients with higher HbA1c levels. The dependence of mortality on HbA1c level was U shaped. When the group with the lowest mortality (HbA1c 6.0-7.0) was used as a reference, the hazard ratios for HbA1c categories under 5.0, 5.0-6.0, 7.0 to under 8.0, and 8.0 and greater were, respectively, 1.56 (95% confidence interval, 1.05-2.33), 1.26 (0.92-1.71), 1.23 (0.79-1.89), and 2.10 (1.32-3.33) in the adjusted model. The HbA1c level was not associated with self-reported hypoglycemic episodes in JDOPPS phase 5. The HbA1c levels in diabetic hemodialysis patients differ considerably between Japan and those reported from Western countries. Thus, our findings highlight the importance of domestic guidelines for glycemic control by race and country. Hemoglobin A1c (HbA1c) is the most commonly used measure for monitoring glycemic control in diabetic patients. The 2012 Kidney Disease Outcomes Quality Initiative (KDOQI) Clinical Practice Guidelines highlight the complexities of deciding the most appropriate target range for glycemic control in diabetic dialysis patients, indicating that HbA1c levels of ∼7.9% were associated with greater survival in some observational studies, with higher risks of death observed for HbA1c levels <6.5% and >8.0%.1KDOQI Clinical Practice Guideline for Diabetes and CKD: 2012 update.Am J Kidney Dis. 2012; 60: 850-886Abstract Full Text Full Text PDF PubMed Scopus (951) Google Scholar Other glycemic measures, such as levels of fructosamine and glycated albumin, have been proposed as alternatives for assessing glycemic control in these patients. However, evidence that these indicators better predict outcomes of glycemic control and its relationship with subsequent morbidity or mortality in diabetic dialysis patients compared with HbA1c is still insufficient.2Mehrotra R. Kalantar-Zadeh K. Adler S. Assessment of glycemic control in dialysis patients with diabetes: glycosylated hemoglobin or glycated albumin?.Clin J Am Soc Nephrol. 2011; 6: 1520-1522Crossref PubMed Scopus (39) Google Scholar Countries display large differences in hemodialysis (HD) patient characteristics and related practices, including patient case mix, methods and quality of dialysis therapy, dietary habits, exercise levels, and medication prescriptions.3Ethier J. Mendelssohn D.C. Elder S.J. et al.Vascular access use and outcomes: an international perspective from the Dialysis Outcomes and Practice Patterns Study.Nephrol Dial Transplant. 2008; 23: 3219-3226Crossref PubMed Scopus (443) Google Scholar, 4Saran R. Bragg-Gresham J.L. Levin N.W. et al.Longer treatment time and slower ultrafiltration in hemodialysis: associations with reduced mortality in the DOPPS.Kidney Int. 2006; 69: 1222-1228Abstract Full Text Full Text PDF PubMed Scopus (434) Google Scholar, 5Saran R. Bragg-Gresham J.L. Rayner H.C. et al.Nonadherence in hemodialysis: associations with mortality, hospitalization, and practice patterns in the DOPPS.Kidney Int. 2003; 64: 254-262Abstract Full Text Full Text PDF PubMed Scopus (370) Google Scholar, 6Robinson B.M. Zhang J. Morgenstern H. et al.Worldwide, mortality risk is high soon after initiation of hemodialysis.Kidney Int. 2014; 85: 158-165Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar, 7Robinson B.M. Port F.K. International hemodialysis patient outcomes comparisons revisited: the role of practice patterns and other factors.Clin J Am Soc Nephrol. 2009; 4: S12-S17Crossref PubMed Scopus (36) Google Scholar For example, the target endotoxin level in ultrapure dialysate and measured C-reactive protein levels are lower in Japan than those in Europe,4Saran R. Bragg-Gresham J.L. Levin N.W. et al.Longer treatment time and slower ultrafiltration in hemodialysis: associations with reduced mortality in the DOPPS.Kidney Int. 2006; 69: 1222-1228Abstract Full Text Full Text PDF PubMed Scopus (434) Google Scholar, 8Schiffl H. High-flux dialyzers, backfiltration, and dialysis fluid quality.Semin Dial. 2011; 24: 1-4Crossref PubMed Scopus (37) Google Scholar, 9Nakai S. Hanafusa N. Masakane I. et al.An overview of regular dialysis treatment in Japan (as of 31 December 2012).Ther Apher Dial. 2014; 18: 535-602Crossref PubMed Scopus (108) Google Scholar and large differences exist in the dietary habits and nutritional measures of HD patients in Japan compared with those in the United States and Europe. Furthermore, a recent study demonstrated substantial differences by race in insulin resistance.10Kodama K. Tojjar D. Yamada S. et al.Ethnic differences in the relationship between insulin sensitivity and insulin response: a systematic review and meta-analysis.Diabetes Care. 2013; 36: 1789-1796Crossref PubMed Scopus (378) Google Scholar Therefore, the above differences among countries and by race may affect the association of HbA1c levels with outcomes in the HD patient population. There is a clear need to determine adequate HbA1c levels according to race and country. This is especially important for diabetic HD patients in Asia, where use of renal replacement therapy in this patient population is expected to rise sharply in the next decade.11Liyanage T. Ninomiya T. Jha V. et al.Worldwide access to treatment for end-stage kidney disease: a systematic review.Lancet. 2015; 385: 1975-1982Abstract Full Text Full Text PDF PubMed Scopus (1118) Google Scholar Here, we investigated the relationship of HbA1c level with mortality in a large cohort of diabetic Japanese HD patients using data from the Japanese Dialysis Outcomes and Practice Patterns Study (JDOPPS) of 2002 to 2015.12Pisoni R.L. Gillespie B.W. Dickinson D.M. et al.The Dialysis Outcomes and Practice Patterns Study (DOPPS): design, data elements, and methodology.Am J Kidney Dis. 2004; 44: 7-15Abstract Full Text Full Text PDF PubMed Scopus (253) Google Scholar During the first 4 months of JDOPPS phase 5, among diabetic patients in the study sample, 6%, 7%, 9%, and 67%, had HbA1c reported in 1, 2, 3, and all 4 of the 4 study months, respectively, with 10% having no reported HbA1c. The facility distribution in the frequency of measuring HbA1c for diabetic patients during the first 4 study months is shown Supplementary Figure S1 for JDOPPS phase 4 and 5 facilities. These results indicate that JDOPPS HD facilities routinely measure HbA1c in their diabetic patients (almost monthly for the majority of facilities). A substantial shift in HbA1c control was observed in diabetic Japanese HD patients from 2002 to 2004 (phase 2) to 2012 to 2015 (phase 5) (Figure 1). The percentage of diabetic HD patients with intermediate HbA1c levels (5.0 to <7.0) gradually increased from 57% in phase 2 to 75% in phase 5. Furthermore, the percentage of patients in the highest HbA1c category (≥8.0) decreased from 9% in 2002 to 2004 (phase 2) to 4% by 2012 to 2015 (phase 5). The majority of study patients (97%) had type 2 diabetes as a cause of end-stage renal disease, and 86% of study patients had a prescription for erythropoietin-stimulating agents at DOPPS study enrollment. Patient characteristics by HbA1c category for all patients in 2002 to 2015 are shown in Table 1. The group with HbA1c levels of 5.0 to <6.0 had the largest proportion of patients (40%), followed by the groups with HbA1c levels <5.0 (14%), 6.0 to <7.0 (27%), 7.0 to <8.0 (12%), and ≥8.0 (7%). Patients with lower HbA1c levels were more likely to be older and male and had lower dialysis vintage (years since dialysis initiation). In our cohort, 33% of diabetic HD patients were prescribed either oral diabetic pills or insulin, 23% of them were prescribed oral medication, and 12% were prescribed insulin (not exclusive). Patients with higher HbA1c levels were generally more likely to be prescribed a diabetes medication; the prevalence of prescription of insulin or oral medication was 18% among patients with an HbA1c level <5.0 and 41% among patients with an HbA1c level ≥8.0. Similarly, the incidence of insulin prescription was 5% and 21% in the groups with HbA1c levels <5.0 and ≥8.0, respectively. Interestingly, the prevalence of having an indicator of poor nutrition (body mass index <17.5 or serum albumin level <3.0 g/dl) showed a U-shaped relationship with HbA1c levels, with the highest prevalence of poor nutrition indicators seen at the highest and lowest HbA1c levels, whereas the lowest prevalence of poor nutrition was observed at HbA1c levels of 5.0 to <7.0.Table 1Characteristics of diabetic patients from the Japanese Dialysis Outcomes and Practice Patterns Study (JDOPPS) (2002–2015) by HbA1c categoryPatient characteristicsHbA1c category<5.05.0 to <6.06.0 to <7.07.0 to <8.0≥8.0Total sample313931617284155Demographic characteristics and laboratory parameters Male sex (%)7374686559 Age, yr65.4 (11.2)65.2 (10.7)63.7 (10.5)63.3 (10.7)60.7 (11.3) Dialysis vintage, yr3.4 (3.9)3.3 (3.9)3.6 (4.1)4.1 (4.2)3.9 (3.9) BMI, kg/m221.7 (3.6)22.0 (3.5)22.0 (3.3)22.0 (3.6)21.8 (3.6) Intradialytic weight loss, % of post-HD weight3.2 (2.1)3.5 (1.9)3.7 (2.4)4.0 (1.9)4.4 (1.7) Normalized PCR0.88 (0.21)0.91 (0.22)0.92 (0.2)0.97 (0.23)0.95 (0.21) Creatinine, mg/dl9.3 (2.7)9.3 (3.0)9.6 (2.8)9.4 (2.8)9.4 (2.8) Albumin, g/dl3.62 (0.55)3.68 (0.48)3.69 (0.45)3.71 (0.45)3.66 (0.49) CRP,aOnly facilities with at least 50% of patients with CRP were used for CRP median calculation. Values shown are median [interquartile range]. mg/l1.00 [3.35]1.00 [2.60]1.50 [3.50]1.55 [2.50]2.00 (3.70) Type 1 diabetes as cause of ESRD (%)12447Comorbidities (%) Coronary heart disease3940363948 Cancer (other than skin)1211877 Other cardiovascular diseases3331262928 Cerebrovascular disease1918151614 Congestive heart failure2828283237 Gastrointestinal bleeding76535 Hypertension8684838483 Lung disease34343 Neurologic disease129888 Psychiatric disorders65577 Peripheral vascular disease2024262930 Recurrent cellulitis, gangrene5791010Patients on medication (%) Diabetes medication (insulin or oral)1832414641 Insulin510152021 Oral diabetes medicationbOral diabetes medication included the following classes of agents: α-glucosidase inhibitors, meglitinides, metformin, sulfonylurea, and thiazolidinediones.1323282922 ESA9189818588Poor nutrition markers (%) BMI <17.5 kg/m211691111 Albumin <3.0 g/dl106568 BMI <17.5 or albumin <3.01912141520Follow-up No. of death events50120603327 Death events1613101217 Follow-up time: total person-years53916871165531277 Follow-up time, yr1.90 [0.86–2.65]1.90 [0.97–2.68]1.99 [1.18–2.71]1.98 [1.17–2.71]1.90 [1.1–2.59]Values are shown as mean (SD), %, or median [interquartile range].BMI, body mass index; CRP, C-reactive protein; ESA, erythropoietin-stimulating agent; ESRD, end-stage renal disease; HbA1c, hemoglobin A1c; HD, hemodialysis; PCR, protein catabolic rate.a Only facilities with at least 50% of patients with CRP were used for CRP median calculation. Values shown are median [interquartile range].b Oral diabetes medication included the following classes of agents: α-glucosidase inhibitors, meglitinides, metformin, sulfonylurea, and thiazolidinediones. Open table in a new tab Values are shown as mean (SD), %, or median [interquartile range]. BMI, body mass index; CRP, C-reactive protein; ESA, erythropoietin-stimulating agent; ESRD, end-stage renal disease; HbA1c, hemoglobin A1c; HD, hemodialysis; PCR, protein catabolic rate. Among patients with HbA1c levels <6.0, the prevalence of prescription of oral diabetes medications increased from 18% to 23%, respectively, between phases 2 and 5. In contrast, the corresponding prevalence for insulin varied between 8% and 11%, with no clear trend detected. A clear U-shaped relationship was observed between HbA1c levels and mortality in both unadjusted and adjusted models (Figure 2). When the group with HbA1c levels of 6.0 to <7.0 was used as a reference, the hazard ratios of mortality for HbA1c categories <5.0, 5.0 to <6.0, 7.0 to <8.0, and ≥8.0 were, respectively, 1.56 (95% confidence interval [CI] 1.05–2.33), 1.26 (95% CI 0.92–1.71), 1.23 (95% CI 0.79–1.89), and 2.10 (95% CI 1.32–3.33) in the adjusted model, with the lowest mortality seen for patients with HbA1c levels of 6.0 to <7.0. The overall P value (type 3) for HbA1c as a categorical variable was 0.02 in the adjusted model and 0.01 in the unadjusted model. Similar results were observed when the HbA1c level was averaged over 8 months instead of using a single baseline value (Supplementary Figure S2). In other analyses, no association was observed between the interaction of an HbA1c level <6.0 (vs. ≥6.0) with the use of any diabetic medication (vs. no use) and mortality (P = 0.62). To check the association of the continuous HbA1c measure while capturing the proper functional form, spline regression was performed with 3 knots. The results (Supplementary Figure S3) from the spline model yielded a nadir of HbA1c 6.1%, with a pattern consistent with that seen in the main categorical HbA1c model. Additionally, we explored a model with smaller increments of HbA1c between 5.0% and 7.0% (Supplementary Figure S4), which was consistent with the main HbA1c and spline regression models in showing a lowest mortality risk between 6.0% and 6.5%. Converting HbA1c values from Japan Diabetes Society (JDS) standardized units into National Glycohemoglobin Standardization Program (NGSP) standardized units, using NGSP = (1.02*JDS) + 0.25 conversion, produced very similar results to those of the main model (Supplementary Figure S5). When patients with NGSP-equivalent HbA1c levels of 6.0 to <7.0 were used as a reference, hazard ratios of mortality for HbA1c categories <5.0, 5.0 to <6.0, 7.0 to <8.0, and ≥8.0 were, respectively, 1.75 (95% CI 1.11–2.75), 1.06 (95% CI 0.79–1.44), 1.19 (95% CI 0.83–1.70), and 1.66 (95% CI 1.11–2.49) in the adjusted model. Subgroup analysis was carried out regarding the association of HbA1c level with mortality for patients having a serum albumin concentration of <3.5 or ≥3.5 g/dl (Supplementary Figure S6). Similar to Figure 2, we observed a U-shaped relationship between HbA1c categories and mortality regardless of whether the serum albumin level was <3.5 or ≥3.5 g/dl. We found no evidence of interaction (P = 0.85), but the statistical power was limited by the sample size, particularly in the low albumin level group (27% of all HbA1c patients). Because poor nutritional status is considered as a potential confounder of the HbA1c/mortality association, in addition to body mass index and albumin, we also performed sensitivity analyses additionally adjusting the main model for normalized protein catabolic rate, which was found to have no impact on the HbA1c/mortality relationship. Although the primary analyses were adjusted for continuous hemoglobin, we carried out sensitivity analyses of HbA1c with mortality stratified by hemoglobin level (<10 g/dl vs. ≥10 g/dl). Similar to albumin results previously cited, we found no evidence of interaction (P = 0.44), but the statistical power was limited by the sample size, particularly in the low hemoglobin level group. Inclusion of erythropoietin-stimulating agent use had little effect on the HbA1c/mortality relationship. In JDOPPS phase 5 (2012–2015), 34% of the 319 patients responding to the question about blood sugar reported experiencing episodes of low blood sugar in the past month, and 11% of the 296 patients responding to the question about hypoglycemic episodes experienced a hypoglycemic episode within the previous 3 months. We did not observe an association between HbA1c categories and either outcome, although the sample size as indicated was limited. In this large cohort study, diabetic HD patients' mortality displayed a U-shaped relationship with HbA1c levels, with the lowest mortality risk seen in Japanese HD patients with HbA1c levels of 6.0 to 7.0. This result differs from those reported in previous studies from the United States and from the 12 DOPPS countries, in which the lowest mortality was found in patients with HbA1c levels of 7.0 to 8.0.13Ricks J. Molnar M.Z. Kovesdy C.P. et al.Glycemic control and cardiovascular mortality in hemodialysis patients with diabetes: a 6-year cohort study.Diabetes. 2012; 61: 708-715Crossref PubMed Scopus (138) Google Scholar, 14Ramirez S.P. McCullough K.P. Thumma J.R. et al.Hemoglobin A(1c) levels and mortality in the diabetic hemodialysis population: findings from the Dialysis Outcomes and Practice Patterns Study (DOPPS).Diabetes Care. 2012; 35: 2527-2532Crossref PubMed Scopus (79) Google Scholar We also found that >50% of Japanese diabetic HD patients had a controlled HbA1c level <6.0. Large differences were observed in the distribution of HbA1c levels among Japanese versus US diabetic HD patients. When compared with recent (2012–2015) US-DOPPS data, the percentage of diabetic HD patients with an HbA1c level ≥7.0 was ∼2.4-fold lower in Japan (15%) versus the United States (32%–38%), whereas those with HbA1c levels <6.0 was ∼1.5-fold higher in Japan (55%) versus the United States (35%–40%).15Arbor Research Collaborative for Health. DOPPS Practice Monitor. Available at: http://www.dopps.org/dpm/. Accessed: December 16, 2016.Google Scholar Furthermore, the proportion of diabetic HD patients with HbA1c levels of 5.0 to <6.0 increased continuously in Japan from 33% in JDOPPS phase 2 (2002–2004) to 46% in JDOPPS phase 5 (2012–2015). This shift in HbA1c distribution over time may be influenced by the first diabetes Japanese guidelines being published in 2002, stating the importance of strict glycemic control in patients with normal renal function.16Akanuma Y. [Practice guideline for the treatment of diabetes in Japan].J Jpn Diabet Soc. 2002; 45 ([article in Japanese]): 5-75Google Scholar, 17The Japan Diabetes Society. Evidence-based Practice Guideline for the Treatment for Diabetes in Japan 2013. Available at: http://www.jds.or.jp/modules/en/index.php?content_id=44. Accessed December 16, 2016.Google Scholar Although the guideline was not for HD patients, it may have contributed to the decrease in the percentage of diabetic HD patients with high HbA1c levels (≥7.0) from 25% in phase 2 to 15% in phase 5. Considering the fact that the mortality rate for HD patients was lowest in Japan among the many countries that have participated in DOPPS,6Robinson B.M. Zhang J. Morgenstern H. et al.Worldwide, mortality risk is high soon after initiation of hemodialysis.Kidney Int. 2014; 85: 158-165Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar it appears paradoxical and worth further investigation that the majority of Japanese diabetic patients on HD have HbA1c levels lower than the universally recommended values. One possible explanation for this paradox may be racial differences, which have not been accounted for in recommendations for HbA1c control. Although the U-shape HbA1c/mortality relationship that we observe is consistent with findings of previous studies in HD patients, the HbA1c level associated with the lowest mortality risk differs among studies in Western countries (7%–8%13Ricks J. Molnar M.Z. Kovesdy C.P. et al.Glycemic control and cardiovascular mortality in hemodialysis patients with diabetes: a 6-year cohort study.Diabetes. 2012; 61: 708-715Crossref PubMed Scopus (138) Google Scholar, 14Ramirez S.P. McCullough K.P. Thumma J.R. et al.Hemoglobin A(1c) levels and mortality in the diabetic hemodialysis population: findings from the Dialysis Outcomes and Practice Patterns Study (DOPPS).Diabetes Care. 2012; 35: 2527-2532Crossref PubMed Scopus (79) Google Scholar, 18Hill C.J. Maxwell A.P. Cardwell C.R. et al.Glycated hemoglobin and risk of death in diabetic patients treated with hemodialysis: a meta-analysis.Am J Kidney Dis. 2014; 63: 84-94Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar) and Asian countries such as Japan and China (6%–7%19Li X. Xu X. Liu J. et al.HbA1c and survival in maintenance hemodialysis patients with diabetes in Han Chinese population.Int Urol Nephrol. 2014; 46: 2207-2214Crossref PubMed Scopus (6) Google Scholar, 20Hayashino Y. Fukuhara S. Akiba T. et al.Diabetes, glycaemic control and mortality risk in patients on haemodialysis: the Japan Dialysis Outcomes and Practice Pattern Study.Diabetologia. 2007; 50: 1170-1177Crossref PubMed Scopus (54) Google Scholar). Genetic studies have shown numerous alleles associated with increased HbA1c levels, some of which are not associated with fasting glucose level or 2-hour glucose tolerance test response.21Bonnefond A. Vaxillaire M. Labrune Y. et al.Genetic variant in HK1 is associated with a proanemic state and A1C but not other glycemic control-related traits.Diabetes. 2009; 58: 2687-2697Crossref PubMed Scopus (29) Google Scholar Furthermore, compared with Caucasians, Asians reportedly have higher insulin sensitivity, with a lower insulin response resulting in less insulin secretion, whereas African Americans have opposite characteristics, with higher insulin resistance.10Kodama K. Tojjar D. Yamada S. et al.Ethnic differences in the relationship between insulin sensitivity and insulin response: a systematic review and meta-analysis.Diabetes Care. 2013; 36: 1789-1796Crossref PubMed Scopus (378) Google Scholar Therefore, it is possible that the target glycemic control level for Asian diabetic dialysis patients may be lower than that for Caucasians or African Americans. Indeed, the number of adults with diabetes has been reported to be 10.8, 102.9, and 22.4 million, respectively, in Japan, China, and the United States.22NCD Risk Factor Collaboration (NCD-RisC)Worldwide trends in diabetes since 1980: a pooled analysis of 751 population-based studies with 4.4 million participants.Lancet. 2016; 387: 1513-1530Abstract Full Text Full Text PDF PubMed Scopus (2335) Google Scholar Therefore, the prevalence of diabetes in Japan, China, and the United States is 8.51% (10.8 of 126.93 million), 7.49% (102.9 of 1374.62 million), and 6.97% (22.4 of 321.6 million), respectively, suggesting a higher prevalence of diagnosed diabetes in Japan or China than in the United States.22NCD Risk Factor Collaboration (NCD-RisC)Worldwide trends in diabetes since 1980: a pooled analysis of 751 population-based studies with 4.4 million participants.Lancet. 2016; 387: 1513-1530Abstract Full Text Full Text PDF PubMed Scopus (2335) Google Scholar Differences in HbA1c levels between Japanese and US diabetic HD patients may also reflect differences in lifestyle, dietary habits, and/or diabetes management. Based on analysis of DOPPS data in 11 countries participating in phases 2 to 5, 66% of patients were prescribed either oral diabetic pills or insulin in non-Japanese countries overall compared with 33% in Japan; in Japan, 23% of diabetic patients were prescribed oral medication and 12% prescribed insulin (not exclusive), whereas in other DOPPS countries, 18% of diabetic HD patients were prescribed an oral medication for diabetes and 53% were prescribed insulin. Moreover, the proportion of medication use for diabetic HD patients with HbA1c >7% was much lower in Japan than that in 11 other DOPPS countries (45% vs. 86%). Thus, it appears that diabetic management of HD patients in Japan is very unique; prescription of insulin is much lower in Japan than in the remaining DOPPS countries as a whole. In addition, Goodkin et al.23Goodkin D.A. Bragg-Gresham J.L. Koenig K.G. et al.Association of comorbid conditions and mortality in hemodialysis patients in Europe, Japan, and the United States: the Dialysis Outcomes and Practice Patterns Study (DOPPS).J Am Soc Nephrol. 2003; 14: 3270-3277Crossref PubMed Scopus (633) Google Scholar described a lower overall comorbidity burden for HD patients in Japan compared with the United States and Europe, although diabetes prevalence among Japanese HD patients is in the top one-third of 12 DOPPS countries in DOPPS phase 4. Consistent with Goodkin et al., we found that across 12 comorbidity classes in cross sections of DOPPS phase 2 to 5 diabetic patients, the comorbidity average (SD) burden was 2.65 (1.74) in Japan and 3.47 (2.02) in the other 11 DOPPS countries (range, 2.61 in the United Kingdom to 4.14 in Belgium), suggesting healthier case-mix characteristics in Japan. Thus, it is conceivable that differences in observed HbA1c levels among diabetic HD patients in Japan and the United States may, in part, reflect differences of lifestyle or case-mix characteristics. HbA1c differences between Japan and the United States may also reflect differences in metabolism and/or clearance of diabetic medications and those of renal gluconeogenesis. Spontaneous normalization of HbA1c levels and discontinuation of diabetic medications upon development of end-stage renal disease has been described as a "burnt out diabetes phenomenon."24Rhee C.M. Leung A.M. Kovesdy C.P. et al.Updates on the management of diabetes in dialysis patients.Semin Dial. 2014; 27: 135-145Crossref PubMed Scopus (88) Google Scholar, 25Kalantar-Zadeh K. Derose S.F. Nicholas S. et al.Burnt-out diabetes: impact of chronic kidney disease progression on the natural course of diabetes mellitus.J Renal Nutr. 2009; 19: 33-37Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar The racial difference in these factors may contribute to the higher proportion of Japanese patients with HbA1c levels <6.0%. "Reverse epidemiology" has been observed for several factors, such as body mass index and blood pressure control, in which the relationship between these factors and mortality differs substantially in HD patients compared with the general population.26Kalantar-Zadeh K. Streja E. Kovesdy C.P. et al.The obesity paradox and mortality associated with surrogates of body size and muscle mass in patients receiving hemodialysis.Mayo Clin Proc. 2010; 85: 991-1001Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar, 27Kalantar-Zadeh K. Kilpatrick R.D. McAllister C.J. et al.Reverse epidemiology of hypertension and cardiovascular death in the hemodialysis population: the 58th annual fall conference and scientific sessions.Hypertension. 2005; 45: 811-817Crossref PubMed Scopus (195) Google Scholar Another such relationship appears to be that of HbA1c level and mortality. The current and previous studies have consistently shown a U-shaped HbA1c/mortality relationship in HD patients. The reason for the increased mortality in HD patients with lower HbA1c levels remains a mystery. In this study, >50% of diabetic HD patients in Japan had an HbA1c level <6.0, displaying an overall higher mortality rate than patients with an HbA1c levels of 6% to 7%. This association between higher mortality and lower HbA1c level remained even after rigorous adjustment for demographic characteristics, numerous baseline comorbidities, and patient nutrition status. Although hypoglycemia is common in diabetic HD patients, we did not observe an association between the likelihood of patients reporting a hypoglycemic episode within the previous 3 months and baseline HbA1c level. The hazard ratio of mortality among patients with a baseline HbA1c level <6.0 (vs. ≥6.0) did not depend on whether the patients were prescribed insulin. Thus, to help understand the reasons underlying the consistent observation of higher mortality rates in diabetic HD patients with lower HbA1c levels (i.e., <6.0), an additional longitudinal study with detailed capture of intervening events and laboratory measures may be necessary. Differences in methodology between studies, including patient sample selection and data analyses, may cause additional biases