Glycated albumin: a tool at clinicians’ hand in managing diabetic nephropathy – Organised by WERFEN AND ASAHI-KASEI PHARMA

Symposium Summary

Written by Jasna Trbojevic-Stankovic
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Welcome & Introduction

Loreto Gesualdo, Italy

As Barry I. Freedman pointed out, assessing glycaemic control in patients with advanced CKD/ESRD is complex due to changes in glucose homeostasis, potential effects of kidney disease on glycemia assays, and altered pharmacokinetics of diabetic medications. But assuming that glycaemic control is important for outcomes of the patients, we believe the ideal assay should predict risk for cardiovascular events, survival and hospitalization. Although HbA1c has been the gold standard in patients with normal kidney function, it has been greatly questioned in patients with advanced nephropathy, particularly end-stage kidney disease (ESKD) patients on dialysis and those with a eGFR below 30 ml/min/1.73 m2. The reason is that HbA1c is determined by an interaction between haemoglobin in red cells and glucose, but in ESKD there is severely shortened red blood cell survival, ESKD patients suffer from erythropoietin, blood loss due to the dialysis, sometimes they even require blood transfusions. All this has an impact and can lower the HbA1c.

Current clinical practice in the management of Diabetic Kidney Disease

Barry I. Freedman, United States of America

Like HbA1c, glycated albumin (GA) is a glycated protein that reflects the status of blood glucose control more rapidly than HbA1c. It was therefore suggested, in a 2007 paper by Inaba et al., that GA is a far better indicator than HbA1c in haemodialysis patients with diabetes. It was shown that, in patients with no kidney disease, HbA1c was above 8%, and above 6% in dialysis patients, even though both groups had the same blood sugar levels. GA, on the other hand, was similar in both groups and obviously not impacted by kidney disease. The study group also analysed the percentage of haemodialysis patients with very good and with poor glycaemic control.

When analysis was based on HbA1c, 57.1% of the patients seemed to have excellent blood sugar control, whereas it was only 28.3% when GA was used. The difference was even more striking in those with poor glycaemic control. According to HbA1c levels, only 7.1% had poor control, whereas the figure was 36.4% when GA levels were analysed. “Nephrologists are given a false sense of security when they use HbA1c only, due to its false reduction in ESKD patients”, warned Barry I. Freedman.

Nor does higher HbA1c appear to have any reliable prognostic value in this patient group. In one study, higher unadjusted HbA1c was associated with improved survival in ESKD, due to better nutrition, but when adjusted for 20 additional co-variants, higher HbA1c was associated with poorer survival in ESKD. GA, on the other hand, was an accurate predictor of patient survival and rates of hospitalization in ESKD, with minimal or no adjustment. In one published metanalysis, it appears that HbA1c > 8.5% in ESKD patients is associated with a high risk of mortality, but it has to be kept in mind that HbA1c would probably be about 10.5% in diabetes patients without kidney disease and the same blood glucose levels. “We therefore believe that GA is a much more accurate measure of glycaemic control in patients with severe nephropathy”, Freedman concluded.

Importance of Best Practice Guidelines for Dialysis therapy as a tool for improving care of Diabetic Nephropathy patients

Masanori Abe, Japan

Masanori Abe emphasized again the importance of reliable glycaemic control in patients with diabetes and pointed out that HbA1c underestimates glycaemic status in patients on dialysis, whereas GA allows a more reliable assessment.

In an observational cohort of 178 haemodialysis patients with diabetes, the relationship between GA and all-cause mortality in patients with (n = 70) and without (n = 108) cardiovascular disease (CVD) were analysed. The subjects were divided into three categories based on the GA value at the start of the study. During the four-year follow-up, 24 of 108 (23.3%) patients without CVD and 30 of 70 (42.8%) patients with CVD died. GA, in addition to logCRP and age, was independently associated with mortality in all patients. Kaplan-Meier analysis showed lower GA levels less than 20% to be a significant predictor of lower mortality in the group without cardiovascular disease, but not in the CVD group.

In the Japanese Best Practice Guidelines, GA is therefore recommended as an index of glycaemic control in patients on haemodialysis. The target level is <20%, but in patients with CVD or those who have a tendency towards hypoglycaemia, <24% is recommended as a tentative target level. At the beginning of the haemodialysis session, postprandial plasma glucose should also be measured, the target level stated in the guidelines being <180-200 mg/dl.

Masanori Abe spoke about the phenomenon of burnout diabetes, which describes the fact that some patients have lower HbA1c levels (<6%) and glucose levels after having to start dialysis treatment. According to data from the U.S., the incidence of burnout diabetes was about 40% in a cohort of 56,000 patients, and Japanese data showed a similar incidence. To study this phenomenon, Masanori Abe and colleagues conducted a study with patients with diabetes on HD whose HbA1c levels were measured and whose antidiabetic therapy was recorded. In the HbA1cone cohort, HbA1c levels were measured, whereas HbA1c and GA levels were measured in the GA cohort. The incidence of burnout diabetes (defined as HbA1c <6% or HbA1c <6% and GA <16%) was significantly different in both groups: 18.7% in the HbA1c group, but only 5.4% in the group in which GA was also considered. “The rate is extremely low”, many patients with diabetes might not experience burn-out diabetes even when they have progressed to ESKD and required dialysis Masanori Abe concluded.

Personalized Medicine approaches in Diabetic Kidney Disease

Paola Pontrelli, Italy

Paola Prontrelli emphasized the importance of precision medicine, which is also being applied increasingly in the field of nephrology. Its goals are (1) to define specific molecular mechanisms driving the patient’s disease, (2) to characterize and identify those patients who are at high risk and (3) to identify patients who respond (or do not respond) to a specific treatment.

In the context of diabetes, precision medicine represents both an opportunity and a challenge. Diabetes exemplifies the problem of imprecise phenotype – the illness can affect the function of different organs, such as pancreas, liver, muscles, brain, and the kidneys. In 2020, the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) launched the “Precision Medicine in Diabetes” initiative, with the aim of developing precision diagnosis tools and precision therapeutics. Various consortia and projects play an important role within this initiative, among them the “BEAt DKD” project which wants to pave the way for precision medicine in the field of diabetic nephropathy. The biggest challenge is the fact that DKD is a clinical diagnosis with rather imprecise diagnostic criteria so far, the main markers being GFR and albuminuria.

However, these markers do not indicate the specific defect which causes the impairment of kidney function in the patient and, consequently, which is the best treatment for that patient. It is important, rather, to know more about the underlying histopathological characteristics of the damage, which have been divided into three different classes characterized by: the presence of diabetic glomerulosclerosis (class 1), prevailing vascular (arteriosclerotic) and ischemic glomerular changes (class 2), other glomerulonephritides superimposed on diabetic glomerulosclerosis (class 3a), or glomerulonephritides without the presence of diabetic glomerulosclerosis (class 3b). More than 45% of the patients are affected by class 3 – which means they are affected by glomerular disease, not by diabetic glomerulosclerosis.

As Paola Prontrelli pointed out, it is therefore essential to develop novel and more specific clinical and molecular markers in diabetes patients, specifically calibrated for histopathology, in order to better sub-classify the patients and estimate prognosis and treatment. As she explained, GA is an important tool that meets these requirements. It is not only more precise in monitoring glucose control, but can also identify real diabetic nephropathy and has predictive value, in that it reflects renal tubulopathy in subjects with T2DM with normo-albuminuria and normal eGFR and can therefore predict kidney tissue damage in diabetic patients.

Further reading

Inaba M, Okuno S, Kumeda Y et al. Glycated albumin is a better glycemic indicator than glycated hemoglobin values in hemodialysis patients with diabetes: effect of anemia and erythropoietin injection. J Am Soc Nephrol 2007; 18 (3): 896-903

Kalantar-Zadeh K, Kopple JD, Regidor DL et al. A1C and survival in maintenance hemodialysis patients. Diabetes Care 2007; 30 (5): 1049-55

Freedman BI, Andries L, Shihabi ZK et al. Glycated albumin and risk of death and hospitalizations in diabetic dialysis patients. Clin J Am Soc Nephrol 2011; 6 (7): 1635-43

Hill CJ, Maxwell AP, Cardwell CR, et al. Glycated hemoglobin and risk of death in diabetic patients treated with hemodialysis: a meta-analysis. Am J Kidney Dis. 2014; 63(1): 84-94.

Inaba M, Maekawa K, Okuno S et al. Impact of atherosclerosis on the relationship of glycemic control and mortality in diabetic patients on hemodialysis. Clin Nephrol 2012; 78 (4): 273-80.

Nakao T, Inaba M, Abe M et al. Best practice for diabetic patients on hemodialysis 2012. Ther Apher Dial 2015; 19 Suppl 1: 40-6

Ricks J, Molnar MZ, Kovesdy CP et al. Glycemic control and cardiovascular mortality in hemodialysis patients with diabetes: a 6-year cohort study. Diabetes. 2012; 61 (3): 708-15

Abe M, Hamanoac T, Hoshino J et al. Is there a “burnt-out diabetes” phenomenon in patients on hemodialysis? Diabetes Research and Clinical Practice 2017; 130: 211-220

Chung WK, Erion K, Florez JC et al. Precision Medicine in Diabetes: A Consensus Report From the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2020 Jul;43(7):1617-1635

Mazzucco G, Bertani T, Fortunato M et al. Different patterns of renal damage in type 2 diabetes mellitus: a multicentric study on 393 biopsies. Am J Kidney Dis 2002; 39 (4): 713-20

Huh JH, Lee M, Park SY et al. Glycated Albumin Is a More Useful Glycation Index than HbA1c for Reflecting Renal Tubulopathy in Subjects with Early Diabetic Kidney Disease. Diabetes Metab J 2018; 42(3): 215–223