A1C and Survival in Upkeep Hemodialysis Sufferers

A1C and Survival in Maintenance Hemodialysis Patients
June 6, 2021 0 Comments

Summary

OBJECTIVE—The optimum goal for glycemic management has not been established in diabetic dialysis sufferers.

RESEARCH DESIGN AND METHODS—To handle this query, the nationwide database of a giant dialysis group (DaVita) was analyzed by way of time-dependent survival fashions with repeated measures.

RESULTS—Of 82,933 sufferers present process upkeep hemodialysis (MHD) in DaVita outpatient clinics over 3 years (July 2001 by means of June 2004), 23,618 diabetic MHD sufferers had A1C measurements at the least as soon as. Unadjusted survival analyses indicated paradoxically decrease loss of life hazard ratios (HRs) with larger A1C values. Nevertheless, after adjusting for potential confounders (demographics, dialysis classic, dose, comorbidity, anemia, and surrogates of malnutrition and irritation), larger A1C values have been incrementally related to larger loss of life dangers. In contrast with A1C within the 5–6% vary, the adjusted all-cause and cardiovascular loss of life HRs for A1C ≥10% have been 1.41 (95% CI 1.25–1.60) and 1.73 (1.44–2.08), respectively (P < 0.001). The incremental increase in death risk for rising A1C values was monotonic and robust in nonanemic patients (hemoglobin >11.0 g/dl). In subgroup analyses, the affiliation between A1C >6% and elevated loss of life threat was extra distinguished amongst youthful sufferers, those that had undergone dialysis for >2 years, and people with larger protein consumption (>1 g · kg−1 · day−1), blood hemoglobin (>11 g/dl), or serum ferritin values (>500 ng/ml).

CONCLUSIONS—In diabetic MHD sufferers, the apparently counterintuitive affiliation between poor glycemic management and better survival is defined by such confounders as malnutrition and anemia. All issues equal, larger A1C is related to elevated loss of life threat. Decrease A1C ranges not associated to malnutrition or anemia seem like related to improved survival in MHD sufferers.

Sufferers with continual kidney illness (CKD) stage 5 present process upkeep dialysis remedy have a excessive mortality, presently over 20% per yr within the U.S. and primarily attributed to heart problems (1). Nevertheless, in observational research of dialysis populations, most conventional cardiovascular threat components, together with metabolic syndrome elements akin to hyperlipidemia and weight problems, don’t exhibit standard affiliation with mortality (2). Certainly, weight problems and hyperlipidemia seem like paradoxically related to higher survival (3–5). The sturdy affiliation between indicators of excellent diet and improved survival is regarded as an essential etiology for the counterintuitive cardiovascular constellations noticed within the CKD inhabitants (2,6).

Diabetes is a consequence of the metabolic syndrome and a powerful cardiovascular threat issue (7). Regardless that the annual incidence of diabetes firstly of dialysis has proven much less progress in recent times (8), diabetes contains virtually one-half of all causes of end-stage CKD within the U.S. dialysis inhabitants (1,9). A number of research point out larger comorbidity and poorer end result in diabetic dialysis sufferers in contrast with nondiabetic topics (1,10–12). Tight glycemic management as measured by A1C ranges (e.g., <6 or 7%) decreases the danger of creating retinopathy, nephropathy, and neuropathy within the basic inhabitants (13,14). A1C is a strong predictor of cardiovascular problems, together with myocardial infarctions and hospitalizations for coronary artery illness (7,15). Regardless of the foregoing supportive information, there have been only a few research to look at the affiliation between A1C and medical end result within the dialysis inhabitants (16–20). All of those research however one (20) had small pattern sizes (≤150 topics). Three of those research (16,17,19) have been carried out completely in Asian dialysis populations. In a current examine by Williams et al. (20) in 24,875 U.S. diabetic dialysis sufferers, no correlation between A1C and survival at 12 months was discovered. This discovering has led to confusion and critical questions concerning the function of glycemic management and utility of A1C in diabetic dialysis sufferers, who comprise virtually one-half of all dialysis sufferers within the U.S. (21). It was prompt that the rules of glycemic management for people with out superior CKD might not apply to the dialysis inhabitants (20,21).

Given the recognized associations between glycemic management and survival within the non-CKD diabetic inhabitants and the confounding function of diet and anemia in dialysis survival, we hypothesized that the underlying affiliation between A1C and survival in dialysis sufferers is much like that of the overall inhabitants if appropriately managed for confounders. We sought to discover the underlying nature of those associations in a big and modern nationwide database of dialysis sufferers utilizing time-dependent repeated-measures fashions.

RESEARCH DESIGN AND METHODS

We extracted, refined, and examined information from all people with CKD stage 5 who underwent upkeep hemodialysis (MHD) remedy from July 2001 by means of June 2004 in 1 of the 580 outpatient dialysis services of DaVita, a big dialysis group within the U.S. The examine was authorised by related institutional assessment committees; due to the big pattern dimension, the anonymity of the sufferers studied, and the nonintrusive nature of the analysis, the requirement for a written consent kind was exempted.

Scientific and demographic measures

The creation of the cohort has been described beforehand (5,22). To reduce measurement variability, all repeated measures for every affected person throughout any given calendar quarter, i.e., over a 13-week interval, have been averaged and the abstract estimates utilized in all fashions. Averaged values have been obtained for as much as 12 calendar quarters (q1 by means of q12) for every laboratory and medical measure for every affected person over the 3-year cohort interval. Dialysis classic was outlined because the period of time between the first day of dialysis remedy and the first day the affected person entered the cohort. The primary (baseline) studied quarter for every affected person was the calendar quarter through which affected person’s classic was >90 days throughout at the least half of the time of that given quarter.

13-week averaged postdialysis weight and baseline peak have been used to calculate BMI (weight in kilograms divided by the sq. of peak in meters). The dose of administered recombinant human erythropoietin (rHuEPO, EPOGEN; Amgen, Thousand Oaks, CA) was additionally calculated for every calendar quarter (23). The computerized causes of loss of life have been obtained, and cardiovascular loss of life was outlined as loss of life because of myocardial infarction, cardiac arrest, coronary heart failure, cerebrovascular accident, and different cardiac causes.

Along with the presence or absence of diabetes, histories of tobacco smoking and preexisting comorbid situations have been obtained by linking the DaVita database to the Medical Proof Type 2728 of the U.S. Renal Information System (USRDS) (24) and categorized into 10 comorbid situations: ischemic coronary heart illness, congestive coronary heart failure, standing submit−cardiac arrest, standing submit–myocardial infarction, pericarditis, cardiac dysrhythmia, cerebrovascular occasions, peripheral vascular illness, continual obstructive pulmonary illness, and most cancers.

Blood samples have been drawn utilizing uniform methods in all dialysis clinics and have been transported to the DaVita Laboratory in Deland, Florida, inside 24 h. All laboratory values, together with A1C, have been measured by automated and standardized strategies. Most laboratory values have been measured month-to-month. Hemoglobin was measured at the least month-to-month in all sufferers and weekly to biweekly in most sufferers. A1C was often measured semiannually or quarterly. Kt/V was used to estimate dialysis dose, and normalized protein equal of complete nitrogen look, also referred to as normalized protein catabolic price, was measured month-to-month as a measure of day by day protein consumption. Most blood samples have been collected predialysis aside from the postdialysis serum urea nitrogen to calculate urea kinetics.

Epidemiologic and statistical strategies

Survival analyses together with Kaplan-Meier, log-rank exams, and time-dependent Cox proportional hazard regressions with repeated quarterly measures examined whether or not the 3-year survival charges have been related to A1C. For every evaluation, three fashions have been examined based mostly on the extent of multivariate adjustment, as follows: 1) unadjusted mannequin that included mortality information, A1C classes, and entry calendar quarter (q1 by means of q12); 2) case-mix adjusted fashions that included all the above plus age, intercourse, race and ethnicity (African People and different self-categorized blacks, non-Hispanic Caucasians, Asians, Hispanics, and others), diabetes, 10 preexisting comorbid states, historical past of tobacco smoking, classes of dialysis classic (<6 months, 6 months to 2 years, 2–5 years, and ≥5 years), main insurance coverage (Medicare, Medicaid, personal, and different), marital standing (married, single, divorced, widowed, and different or unknown), standardized mortality ratio of the dialysis clinic throughout entry quarter, dialysis dose as indicated by Kt/V (single pool), presence or absence of a dialysis catheter, and residual renal perform through the entry quarter, i.e., urinary urea clearance; and 3) malnutrition-inflammation complicated syndrome (MICS)-adjusted fashions that included all the covariates within the case-mix mannequin in addition to 13 surrogates of dietary standing and irritation, together with BMI, rHuEPO dose, and 11 laboratory surrogates of MICS with recognized affiliation with medical outcomes in MHD sufferers (5) together with complete nitrogen look, serum ranges of albumin, complete iron-binding capability, ferritin, creatinine, phosphorus, calcium, and bicarbonate and blood white blood cell depend, lymphocyte proportion, and hemoglobin.

Lacking covariate information (beneath 2% for many laboratory and demographic variables and beneath 18% for any of the ten comorbid situations) have been imputed by the imply or median of the prevailing values, whichever was most applicable. All descriptive and multivariate statistics have been carried out with SAS model 9.1 (SAS Institute, Cary, NC) and Stata model 9.0 (Stata, Faculty Station, TX).

RESULTS—

The unique 3-year (July 2001 by means of June 2004) nationwide database of all DaVita MHD sufferers included 102,255 cumulative topics. After deleting these sufferers who didn’t preserve past 45 days of hemodialysis remedy, 82,933 MHD sufferers remained for analyses, of whom 37,049 sufferers (45%) originated from the primary calendar quarter dataset (q1) and the remaining from the following calendar quarters (q2 by means of q12).

Desk 1 reveals baseline demographic, medical, and laboratory traits of the studied MHD sufferers through the baseline calendar quarter; 23,618 sufferers had diabetes and at the least one A1C measurement. Of the 56,771 sufferers who didn’t have any A1C testing, 24% additionally carried an unique analysis of diabetes. The BMI was larger and serum albumin and creatinine ranges have been decrease in these whose A1C was measured, indicating that diabetic MHD sufferers tended to be extra overweight however with worse dietary standing. Amongst bivariate associations examined, A1C had destructive correlations with age (r = −0.25), serum creatinine (r = −0.10), and prescribed rHuEPO dose (r = −0.10), suggesting that youthful sufferers and people with lowered muscle mass tended to have larger A1C values.

We divided A1C values into seven a priori chosen classes, i.e., <5%, ≥10%, and 1% increments in between. Figure 1 shows 3-year death hazard ratios (HRs) according to the A1C values at three multivariate adjustment levels. Case-mix adjustment led to a striking alteration in the direction of the associations, in that a significant upward trend in death risk was observed for A1C values >6% (P for pattern <0.001). Absolutely adjusted all-cause loss of life HRs (95% CIs) for A1C increments of seven–7.9, 8–8.9, 9–9.9, and ≥10%, in contrast with 5.0–5.9%, have been 1.08 (1.01–1.15), 1.13 (1.04–1.24), 1.18 (1.05–1.33), and 1.41 (1.25–1.60), respectively. The adjusted cardiovascular loss of life HR (95% CI) for A1C ≥10% was 1.73 (1.44–2.08).

We additionally carried out subgroup analyses to look at the existence of interplay between anemia and A1C. In 19,306 or 82% of diabetic MHD sufferers, blood hemoglobin was >11.0 g/dl, per the goal anemia remedy (25). Determine 2 reveals the identical analyses as in Fig. 1 for nonanemic (A) and anemic (B) MHD sufferers. Amongst nonanemic sufferers, A1C >6% was incrementally and monotonically related to elevated loss of life threat, whereas in anemic sufferers the affiliation didn’t present mentioned sample.

After dichotomizing A1C values at 6% threshold stage within the unadjusted mannequin, the 3-year loss of life HR (95% CI) for all-cause mortality for having an A1C >6% in all MHD sufferers was 0.87 (0.82–0.89, P < 0.001). Nevertheless, after multivariate adjustment, the loss of life HR was 1.05 (1.01–1.10, P = 0.04), exhibiting that the counterintuitive affiliation between larger values of A1C and elevated loss of life threat in unadjusted fashions was as a result of confounding impact of demographic and medical components. Subsequent subgroup analyses have been carried out to look at the statistical interplay by estimating the 3-year HRs of loss of life for A1C ≥6% amongst related demographic, medical, and laboratory classes of MHD sufferers (Fig. 3). The same reversal of the path of the associations was noticed in most classes. The affiliation between excessive A1C and elevated cardiovascular loss of life threat was extra distinguished amongst MHD sufferers who have been youthful than 65 years, who had undergone dialysis for >2 years, and who had larger protein intakes (>1 g · kg−1 · day−1), larger hemoglobin ranges (>11 g/dl), or larger serum ferritin values (>500 ng/ml).

CONCLUSIONS—

We discovered that in 23,618 MHD sufferers from a big nationwide dialysis group, decrease A1C values appeared related to larger mortality charges. Nevertheless, after adjusting for potential confounders, larger A1C values have been incrementally related to elevated loss of life dangers. The affiliation between larger A1C values and mortality was extra distinguished and monotonous amongst youthful sufferers, those that had undergone dialysis longer, and people with larger protein consumption, blood hemoglobin, or serum ferritin ranges. Therefore, in diabetic MHD sufferers, the apparently counterintuitive affiliation or lack of any apparent affiliation between the poor glycemic management and better survival seems to be largely because of confounding by demographics, anemia, and dietary components. These findings might have essential medical implications, particularly since they suggest that glycemic management is useful for this inhabitants so long as a decreased A1C just isn’t a results of malnutrition, anemia, or different confounders.

Diabetes constitutes a significant well being downside amongst CKD sufferers and is presently the main reason behind end-stage (stage 5) CKD (1). Within the non-CKD inhabitants, glycemic management is prime to the administration of diabetes and its problems and requires serial monitoring of blood glucose or A1C. Improved glycemic management has been reported to sluggish the development of nephropathy (14,26). Diabetes can be a longtime threat issue for heart problems, which is the primary reason behind loss of life in CKD sufferers (7). Crude mortality of upkeep dialysis sufferers is presently 21–23% per yr within the U.S., a mortality price that’s worse than most cancers on the daybreak of the twenty first century (27).

In accordance with our present examine, the diploma of glycemic management seems related to mortality in a direct, incremental vogue. The adjusted associations between larger A1C and elevated loss of life threat (Fig. 1) point out a dose-response phenomenon, particularly after adjustment for demographics and markers of diet and irritation. Of main medical curiosity is the interplay between anemia and mortality predictability of A1C (Fig. 2).

Glycosylated hemoglobin, also referred to as A1C, is an Amadori-modified protein or a kind of superior glycation finish product (AGE), a measure of continual hyperglycemia, and a delicate and dependable marker of impaired glucose metabolism (26,28,29). Some research have proven A1C to be a predictor of future CVD occasions within the basic inhabitants (7,30), whereas others have discovered no such affiliation. (31). Different potential measures of long-term glycemic management akin to fructosamine rely on regular serum albumin ranges, that are ceaselessly irregular in dialysis sufferers (32).

The literature in regards to the relation between glycemic management and survival within the CKD inhabitants is considerably restricted. In a cohort of 840 nondiabetic sufferers with reasonable CKD, who participated within the Modification of Weight loss plan in Renal Illness trial, A1C was a predictor of all-cause mortality (33). Wu et al. (16) studied 137 MHD sufferers with sort 2 diabetes and reported that cumulative survival charges have been decrease within the poor glycemic management group than within the good glycemic management group (16). In one other observational examine in 114 diabetic MHD sufferers in Japan, the 7.5-year loss of life threat of sufferers with A1C ≥8% was larger than in these with A1C <6.5% (19). Nevertheless, a current examine utilizing a big nationwide database didn't point out any affiliation between A1C and 1-year survival in 24,875 MHD sufferers from Fresenius dialysis clinics within the U.S. (20). Regardless that the dearth of a survival affiliation or pattern within the foregoing examine could possibly be as a result of short-term follow-up and different methodological variations together with use of conventional and non–time-dependent survival fashions and lack of stratified analyses to detect interactions, this examine has led to some confusion amongst each physicians and sufferers concerning the function of glycemic management in dialysis sufferers (21).

It is very important notice that in a current observational examine, larger AGE ranges in 312 MHD sufferers have been discovered to be paradoxically related to higher survival over 32 months of follow-up (34). One other cohort examine discovered a paradoxically inverse affiliation between A1C and survival in continual coronary heart failure sufferers (35). The authors defined their counterintuitive discovering as one more manifestation of “reverse epidemiology,” through which the dominating function of malnutrition and cachexia in resulting in short-term mortality might overwhelm the influence of standard threat components (36). Whether or not the advantage of excessive serum AGEs in these kind of observational research is an epiphenomenon or displays a greater dietary help wants additional examine. On this regard, an attention-grabbing discovering in our analyses was the stronger affiliation between excessive A1C and elevated all-cause and cardiovascular loss of life threat amongst youthful sufferers, those that had undergone dialysis for >2 years, and people with larger protein consumption (>1 g · kg−1 · day−1), larger hemoglobin (>11 g/dl), or larger serum ferritin values (>500 ng/ml). These findings might point out the potential interplay of things associated to diet, irritation, and anemia with indexes of glycemic management. Therefore, an unusually low A1C <5% in dialysis sufferers might herald the existence of different threat components akin to malnutrition with related elevated loss of life threat (Figs. 1 and a couple of).

Our examine was restricted to comorbidity information from the dialysis initiation kind (kind 2728), through which comorbid situations are considerably underreported (24). Furthermore, we didn’t have the info on insulin or oral hypoglycemic brokers and their doses, and we didn’t examine affected person compliance with diabetes remedy. Nevertheless, the required dose of those drugs could be confounded by the residual renal perform and its deterioration over time (18). One other potential limitation is lack of specific laboratory markers of irritation akin to C-reactive protein. Nevertheless, we used information on serum albumin, ferritin, complete iron-binding capability, white blood cells, lymphocyte proportion, hemoglobin, and administered rHuEPO dose, which have important associations with irritation in MHD sufferers (5). Our examine is predicated on a 3-year interval of the cohort, fairly than a longitudinal follow-up of a few years, and can’t be generalized to peritoneal dialysis sufferers. Nonetheless, over half of dialysis sufferers are useless inside 3 years. Therefore, any perception into the short-term survival of dialysis sufferers is of main medical relevance. Further exams of glycemic monitoring akin to serial blood glucose ranges weren’t examined in our examine. In dialysis sufferers, predialysis remedy blood glucose might not optimally signify the typical stage of serum glucose, whereas A1C is a greater instrument to that finish. The strengths of our examine embrace modern nature, uniform laboratory measurements from one single laboratory, giant pattern dimension, 3-month averaged laboratory information, and use of time-dependent survival fashions.

In conclusion, we confirmed that tight glycemic management in CKD sufferers who endure MHD could also be related to higher survival, particularly amongst sure subgroups of those sufferers. Our outcomes might have implications not just for the administration of diabetic MHD sufferers but in addition for the nondiabetic affected person on dialysis. Since insulin resistance is widespread within the CKD inhabitants, there could also be an impact of glycemic management on survival on this inhabitants as nicely. Diligent glycemic management could also be an efficient measure to enhance survival in CKD. Extra potential, managed research are wanted to confirm the true relationships between totally different strategies of diabetes administration and end result in MHD sufferers.

HRs of all-cause (A) and cardiovascular (B) mortality for the complete vary of A1C in 23,618 diabetic MHD sufferers over 3 years (July 2001 by means of June 2004). Case-mix mannequin is adjusted for age, intercourse, race/ethnicity, preexisting comorbid states, tobacco smoking, dialysis classic, main insurance coverage, marital standing, standardized mortality ratio, dialysis dose, dialysis catheter, and residual renal perform. MICS-adjusted mannequin contains all the case-mix covariates in addition to BMI, common dose of rHuEPO, and 11 laboratory variables of diet and irritation.

” data-icon-position=”” data-hide-link-title=”0″>Figure 1—

Determine 1—

HRs of all-cause (A) and cardiovascular (B) mortality for the complete vary of A1C in 23,618 diabetic MHD sufferers over 3 years (July 2001 by means of June 2004). Case-mix mannequin is adjusted for age, intercourse, race/ethnicity, preexisting comorbid states, tobacco smoking, dialysis classic, main insurance coverage, marital standing, standardized mortality ratio, dialysis dose, dialysis catheter, and residual renal perform. MICS-adjusted mannequin contains all the case-mix covariates in addition to BMI, common dose of rHuEPO, and 11 laboratory variables of diet and irritation.

HRs of all-cause mortality for the complete vary of A1C in 19,306 diabetic MHD sufferers with blood hemoglobin ≥11.0 g/dl (A) and 4,312 diabetic MHD sufferers with hemoglobin <11 g/dl (B) over 3 years (July 2001 by means of June 2004). Case-mix mannequin is adjusted for age, intercourse, race/ethnicity, preexisting comorbid states, tobacco smoking, dialysis classic, main insurance coverage, marital standing, standardized mortality ratio, dialysis dose, dialysis catheter, and residual renal perform. MICS-adjusted mannequin contains all the case-mix covariates in addition to BMI, common dose of rHuEPO, and 11 laboratory variables of diet and irritation.

” data-icon-position=”” data-hide-link-title=”0″>Figure 2—

Determine 2—

HRs of all-cause mortality for the complete vary of A1C in 19,306 diabetic MHD sufferers with blood hemoglobin ≥11.0 g/dl (A) and 4,312 diabetic MHD sufferers with hemoglobin <11 g/dl (B) over 3 years (July 2001 by means of June 2004). Case-mix mannequin is adjusted for age, intercourse, race/ethnicity, preexisting comorbid states, tobacco smoking, dialysis classic, main insurance coverage, marital standing, standardized mortality ratio, dialysis dose, dialysis catheter, and residual renal perform. MICS-adjusted mannequin contains all the case-mix covariates in addition to BMI, common dose of rHuEPO, and 11 laboratory variables of diet and irritation.

HRs of all-cause (A) and cardiovascular (B) mortality for the dichotomized A1C ≥6% in numerous subgroups of 23,618 MHD sufferers over 3 years. Adjusted mannequin is managed for age, intercourse, race/ethnicity, preexisting comorbid states, tobacco smoking, dialysis classic, main insurance coverage, marital standing, standardized mortality ratio, dialysis dose, dialysis catheter, residual renal perform, BMI, common dose of rHuEPO, and 11 laboratory variables of diet and irritation.

” data-icon-position=”” data-hide-link-title=”0″>Figure 3—

Determine 3—

HRs of all-cause (A) and cardiovascular (B) mortality for the dichotomized A1C ≥6% in numerous subgroups of 23,618 MHD sufferers over 3 years. Adjusted mannequin is managed for age, intercourse, race/ethnicity, preexisting comorbid states, tobacco smoking, dialysis classic, main insurance coverage, marital standing, standardized mortality ratio, dialysis dose, dialysis catheter, residual renal perform, BMI, common dose of rHuEPO, and 11 laboratory variables of diet and irritation.

Desk 1—

Demographic, medical, and laboratory traits in 82,958 MHD sufferers through the 3-year cohort (July 2001 to June 2004, i.e., 12 calendar quarters) together with 23,618 diabetic MHD sufferers who underwent A1C measurement

Acknowledgments

This examine was supported by American Coronary heart Affiliation Grant #0655776Y, Philanthropist Mr. Harold Simmons (to Okay.Okay.-Z.), and medical analysis grants from DaVita (to Okay.Okay.-Z. and Okay.S.)

Elements of this examine have been introduced in summary kind through the American Society of Nephrology annual convention, 12–16 November 2006, San Diego, CA. Elements of those information have been provided by the USRDS, and the findings don’t signify the opinion of the U.S. authorities or the USRDS.

Coauthors’ contributions: Okay.Okay.-Z. contributed to the design and funding of the examine, collation and evaluation of information, and writing of the manuscript and its revisions. C.S.S., D.L.R., and R.D.Okay. contributed to the evaluation of the info and reviewed and authorised the ultimate manuscript. C.J.M. contributed to the design of the examine, provision of information, and last assessment and approval of the manuscript. J.D.Okay., S.G., D.W., and Okay.S. contributed to the examine design and manuscript preparation.

Footnotes

  • Printed forward of print at http://care.diabetesjournals.org on 2 March 2007. DOI: 10.2337/dc06-2127.

    A desk elsewhere on this difficulty reveals standard and Système Worldwide (SI) models and conversion components for a lot of substances.

    The prices of publication of this text have been defrayed partly by the cost of web page expenses. This text should due to this fact be hereby marked “commercial” in accordance with 18 U.S.C Part 1734 solely to point this truth.

    • Accepted February 13, 2007.
    • Obtained October 16, 2006.

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