Part1:Associations Of Serum Insulin-Like Growth Factor 1 With New Cardiovascular Events And Subsequent Death in Hemodialysis Patients: The DREAM Cohort
Mar 03, 2022
Contact: emily.li@wecistanche.com
Rino Nakaya1,Tetsuo Shoji2.3, Yuki Nagata2.3. Shinya Nakatani1,Katsuhito Mori4. Tomoaki Morioka1. Yoshihiro TSsujimoto° and Masanori Emoto1,3.4
'Department of Metabolism,Endocrinology and Molecular Medicine,Osaka City University Graduate School of Medicine,Osaka, Japan
'Department of Vascular Medicine,Osaka City University Graduate School of Medicine,Osaka,Japan
3Vascular Science Center for Translational Research, Osaka City University Graduate School of Medicine, Osaka, Japan 4Department of Nephrology, Osaka City University Graduate School of Medicine, Osaka, Japan 5Division of Internal Medicine,Aijinkai Healthcare Corporation Inoue Hospital, Suita,Japan.
Aim: Patients with chronic kidney disease (CKD) have elevated risk of death from cardiovascular disease(CVD). A low serum insulin-like growth factor 1(IGF-1)level is known to predict a higher risk for all-cause mortality in incident dialysis patients, although it is unknown whether IGF-1 predicts cardiovascular outcomes.
Methods: This was a prospective cohort study of maintenance hemodialysis patients followed up for 5 years. Serum IGF-1 levels were measured at baseline, and patients were divided into IGF-1 tertiles. The key outcomes were all-cause mortality, a composite of new CVD,and death after new CVD events.Additional outcomes were hospitalization for infection and subsequent death. Association was analyzed using Cox proportional hazards models.
Results: In the 516 patients that were analyzed, we identified 106 all-cause deaths, 190 new CVD events, and 61 subsequent deaths.In addition, there were 169 hospitalizations for infection and 47 subsequent deaths. The risk of all-cause death was the highest in the lowest IGF-1 tertile, and this association remained significant in multivariable-adjusted models. Regarding CVD outcomes, IGF-1 was not associated with new CVD events but significantly associated with subsequent death in adjusted models. Similarly, IGF-1 was not an independent predictor of hospitalization for infection, but it predicted subsequent death.
Conclusions: A low IGF-1 level was not a significant predictor of new CVD events but an independent predictor of subsequent death in hemodialysis patients. Since similar associations with infection outcomes were observed, IGF-1 may be a biomarker of fragility or frailty in this population.
Keywords: Chronic kidney disease, Insulin-like growth factor 1, Dialysis, Cardiovascular disease, Frailty
Introduction
The risk of cardiovascular death is 10-30 times higher in patients with kidney failure undergoing hemodialysis as compared with the general population1. Hemodialysis patients have a higher risk not only for the incidence of cardiovascular disease
(CVD)but also for death after CVD events2. These two factors synergistically increase the risk of cardiovascular death).
The elevated risk of CVD death in patients with chronic kidney disease(CKD), including those on hemodialysis, has been explained by the traditional and nontraditional risk factors4). Obesity is one of the major cardiovascular risk factors in the general population. However, low body mass is the established predictor of death in patients with kidney failure5)Low body mass in dialysis patients is not necessarily explained by decreased nutritional intake, and there is complex pathophysiology termed protein-energy wasting (PEW)by which patients lose body protein and fat5. In addition to decreased intake, inflammation, and oxidative stress, some metabolic and endocrinologic abnormalities could contribute to PEW in patients with kidney failure by increasing catabolism and/or decreasing anabolism. Such metabolic and endocrinologic abnormalities, which are associated with mortality risk, include insulin resistance, high blood glucose levels due to insulin resistance8, low testosterone levels", low adrenal androgen dehydroepiandrosterone sulfate levels10, low free triiodothyronine levels1), and low insulin-like growth factor 1(IGF-1)levels12). Thus, these factors may be the nontraditional risk factors in this population.
Growth hormone (GH) is secreted from the anterior lobe of the pituitary and acts in the liver to produce IGF-1.IGF-1 is bound to its specific binding proteins3in the circulation, having a relatively stable serum level without apparent circadian rhythm unlike GH14). Although the action of IGF-1 on glucose uptake is less than 10% of that of insulin, IGF-1 is more potent on cell differentiation and proliferation than insulin, contributing to the growth and maintenance of the musculoskeletal system15. A low IGF-1 level is associated with low handgrip strength and low physical performance in elderly people16. In acromegaly with elevated GH and IGF-1 levels, hypertension, diabetes, and dyslipidemia are common7, and CVD is the main cause of death in this patient group18. Thus, the excess of GH and/or IGF-1 appears to increase CVD risk. Conversely, a lower IGF-1 level was also reported to be associated with acute coronary syndrome in the general population 19).
Regarding IGF-1 in patients with kidney failure, a low IGF-1 level was reported to predict all-cause mortality among patients starting treatment with hemodialysis or peritoneal dialysis2and patients on incident hemodialysis20). A low IGF-1 level was associated with low handgrip strength in hemodialysis patients21). So far, however, no study has examined whether IGF-1 predicts the risk of the occurrence of new CVD events or the risk of death after CVD events in patients with kidney failure. Although the risks for these two CVD outcomes are elevated in patients with kidney failure, information on the predictors of the latter outcome is quite limited.
Identifying the factors associated with post-event mortality risk would enhance our understanding of the mechanism for the extremely high mortality rate in this population.
Aim
This study was started to examine the associations between serum IGF-1 concentration and the two CVD outcomes in a cohort of hemodialysis patients.
Methods
Study Design
This is a single-center prospective cohort study of patients on maintenance hemodialysis. In this analysis, the key exposure was IGF-1 serum levels. The key outcomes were all-cause mortality, new CVD events,and death after new CVD events. In additional analyses, we examined the associations of serum IGF-1 with hospitalization for infection and death after hospitalization for infection.
Study Participants
The participants of this analysis were prevalent hemodialysis patients with serum IGF-1 measurement at baseline who were selected from the 518 total participants of the DREAM cohort, which was followed up from the end of 2004 to the end of 2009. The DREAM cohort study was conducted in accordance with the Declaration of Helsinki and the Ethical Guidelines for Clinical Studies by the Ministry of Health,Labor and Welfare of Japan (the original 2003version, which was modified in 2004 and 2006). The protocol was approved by the ethics committee of Inoue Hospital (approval no. 121). All participants gave written informed consent prior to enrollment. The DREAM cohort study was registered in the University hospital Medical Information Network Clinical Trial Registry (UMIN-CTR; ID, UMIN000006168).
Serum IGF-1 Assay
Blood was taken from blood access before the start of dialysis at the beginning of the week, and serum was separated and kept frozen at -80℃.IGF-1 was measured later using fresh frozen samples with an immunoradiometric assay at Special Reference Laboratory(Tokyo,Japan). The intra- and inter-assay coefficients of variation were <2.4% and <2.6%, respectively.
Outcomes
The preplanned key outcomes of this study were all-cause mortality, new CVD events, and death after CVD events. In this cohort, CVD events were defined as a composite of ischemic heart disease, stroke, peripheral arterial disease (PAD), congestive heart failure (CHF), valvular disease, and sudden death during the observation period. Death after a CVD event was defined as all-cause death after the new CVD event. The detailed definitions of CVD events were previously described10) and available in Supplemental Table 1.
To interpret the results regarding the two CVD outcomes, we performed additional analyses of the associations of IGF-1 with infection outcomes. As additional outcomes, we identified hospitalization for infection and subsequent death. We defined hospitalization for infection as hospitalization for which the main reason was infectious disease observed during the study period. Death after infection was defined as all-cause death after the hospitalization for infection.
We also recorded, if any, transition from hemodialysis to peritoneal dialysis or kidney transplantation and transfer to other institutions during the 5-year observation period.
Other Variables
We collected data on major demographic factors (age, sex, diabetic kidney disease or not, duration of hemodialysis treatment, and prior CVD), traditional risk factors (current smoking,hypertension, and dyslipidemia), nontraditional risk factors related to PEW and inflammation (body mass index [BMI], serum albumin, and C-reactive protein [CRP), mineral bone disorder (MBD) of CKD(serum calcium,phosphate, intact parathyroid hormone [PTH], and use of vitamin D receptor activator [VDRA), and renal anemia (hematocrit, dose of erythropoiesis-stimulating agent [ESA], and use of intravenous iron). These data were obtained from medical records. Free T4 and thyroid-stimulating hormone (TSH) were also measured because hypothyroidism is known to lower serum IGF-1 levels22.
Hypertension was defined as 140/90 mmHg or higher and/or antihypertensive medication use23). Dyslipidemia was defined as non-high-density lipoprotein cholesterol (Non-HDL-C)≥ 150 mg/dL and/or high-density lipoprotein cholesterol (HDL-C)≤ 40 mg/dL and/or statin use. These lipid levels were derived from the target levels for patients with CKD recommended by the clinical practice guideline of the Japanese Society of Atherosclerosis2.Hypothyroidism
was defined by 1) being treated with levothyroxine replacement (treated hypothyroidism) or 2)low free T4(<0.8 ng/dL)with high TSH(>4.0 IU/L)25.No patients had central hypothyroidism (low free T4 with low TSH). Statistical Methods
The patients of this analysis were divided into IGF-1 tertiles, and the baseline characteristics were compared across IGF-1 tertiles. Categorical variables were summarized as numbers (percentages) and compared using x2 test. Continuous variables were summarized as medians (interquartile ranges) and compared using the Kruskal-Wallis test. Factors associated with IGF-1 were evaluated using multivariable-adjusted linear regression analysis in which serum IGF-1 level was logarithmically transformed to fit the model.
We first examined the unadjusted association of IGF-1 tertile with all-cause mortality using the Kaplan-Meier analysis with log-rank test. Then, the association was evaluated using multivariable-adjusted Cox proportional hazards models. First,the hazard ratio was calculated using an unadjusted Cox model (model 1). Then, adjustment was done for the major demographic factors (model 2).In addition to the major demographic factors, further adjustment was done for the traditional risk factors(model 3), the variables related to PEW and inflammation (model 4), the parameters of CKD-MBD(model5), those related with renal anemia (model 6), or the presence of hypothyroidism (model 7).
To explore the association between IGF-1 and cause-specific death, all-cause mortality was divided into cardiovascular death, non-cardiovascular death, and death from unknown cause depending on the record of the direct causes of death. Non-cardiovascular causes were further divided into infection and other than infection. Because of the small numbers of these divided outcomes, IGF-1 was handled as a continuous variable, the hazard ratio was expressed per 1-SD higher IGF-1,and adjustment was done only for age and sex.
The association between IGF-1 and new CVD events was analyzed similarly to the analysis of all-cause mortality using the same statistical models for adjustment.
The association between IGF-1 and death after a new CVD event was analyzed using the Kaplan-Meier method and a multivariate-adjusted Cox proportional hazards model. For this purpose, time from the first new CVD event to all-cause death was analyzed in patients who had new CVD events. Because of the limited number of deaths after CVD events, IGF-1 was handled as a continuous variable, hazard ratio was expressed per 1-SD higher IGF-1,and adjustment was done for the five major demographic factors.
As an additional analysis, we also investigated the associations of IGF-1 with hospitalization for infection and death after infection. Multivariable-adjusted Cox analysis was conducted using the same approach as described for the analysis of death after a new CVD event.
A two-sided P value < 0.05 was considered statistically significant. All these analyses were performed using JMP version 14.2(SAS Institute Japan Ltd. Tokyo, Japan).
Results
Study Participants
The patients for this analysis were selected from 518 total participants of the DREAM cohort. Because two participants were excluded because of missing data of IGF-1, the remaining 516 patients were analyzed(Fig.1). Table 1 presents patient characteristics at baseline according to IGF-1 tertile. The patients with lower IGF-1 levels had higher age, lower BMI, lower albumin,lower phosphate levels, and higher prevalence of hypothyroidism, whereas there was no significant difference in CRP among the IGF-1 tertiles. Multivariable-adjusted linear regression analysis revealed that age, sex, the duration of dialysis, BMI, serum albumin, and the presence of hypothyroidism were independently associated with serum IGF-1 level (Supplemental Table 2).
IGF-1 and All-Cause Mortality
During the 5-year observation period, 106 (21%)participants died. Based on the direct cause of death, 38 patients died from cardiovascular causes(sudden death, N=14; heart failure,N=13; stroke,N=5;ischemic heart disease, N=3; arrhythmia, N=2; and ischemic colitis, N=1)and 48 patients died from non-cardiovascular causes(infection, N=24; malignancy, N=8; respiratory failure, N=3; hepatic cirrhosis,N=2; uremia,N=2; and others,N=9), whereas the direct cause of death was unknown for 20 patients. The Kaplan-Meier analysis showed that the risk of all-cause mortality was different among the IGF-1 tertiles(Fig.2A). The association between IGF-1 and all-cause mortality was further analyzed using Cox proportional hazards models(Table 2). IGF-1 was found to be associated with all-cause mortality in various models adjusted for the major demographic factors and the factors related with PEW and inflammation, parameters of CKD-MBD, variables of renal anemia, or presence of hypothyroidism. Also, adjustment for the traditional risk factors (model 3) gave a marginally significant result.
IGF-1 and Cause-Specific Death
The Kaplan-Meier curves were significantly different by tertile of IGF-1 regarding cardiovascular and non-cardiovascular death, but not for death from unknown cause(Fig.2B). The inverse associations of IGF-1 and cardiovascular and non-cardiovascular death remained significant in Cox models, in which IGF-1 was entered as a continuous variable and adjusted for age and sex. When non-cardiovascular causes were further divided into infection and other than infection, these outcomes were inversely associated with IGF-1(Supplemental Table 3).
IGF-1 and CVD Outcomes
New CVD events were recorded in 190 patients (37%). The Kaplan-Meier analysis showed that IGF-1 tertile was significantly associated with new CVD events (Fig.3A).However, this association was no longer significant when analyzed using Cox models adjusted for the major demographic factors(Table 3).
Of the 190 patients who experienced new CVD events, 61 patients died after such event. Based on the direct cause of death,38 patients died from cardiovascular causes (sudden death, N=14; heart failure, N=13; stroke, N=5; ischemic heart disease, N=3;arrhythmia, N=2; and ischemic colitis, N=1)and 14 patients died from non-cardiovascular causes (infection, N=9; respiratory failure,N=2; and others, N=3), whereas the direct cause was unknown for the remaining 9 patients. The Kaplan-Meier analysis showed that a lower IGF-1 level was significantly associated with a higher risk of death after new CVD event(Fig.4A). This association remained significant when analyzed using a Cox model adjusted for the possible confounders(Table 4).
IGF-1 and Infection Outcomes
We identified 169 patients (33%)who experienced hospitalization for infection. The Kaplan-Meier analysis showed that IGF-1 tertile was significantly associated with hospitalization for infection (Fig.3B). However, this association was no longer significant when analyzed using Cox models adjusted for the major demographic factors(Table3).
Of the 169 patients with hospitalization for infection, 47 patients died after infection. Based on the direct cause of death, 13 patients died from cardiovascular causes (sudden death, N=5; heart failure, N=5; ischemic heart disease, N=2; and stroke, N=1) and 29 patients died from noncardiovascular causes(infection, N=22; uremia, N=2; and others, N=5), whereas the direct cause was unknown for the remaining 5 patients. The Kaplan-Meier analysis showed that a lower IGF-1 level was significantly associated with a higher risk of death after infection(Fig.4B). This association remained significant when analyzed using a Cox model adjusted for the possible confounders(Table ④).
