5 Discussion
In this study we evaluated the relations between different indices of glucose metabolism and the development of CKD in a large population of middle-aged Chinese individuals from the REACTION study. The results showed that 3 indices of glucose metabolism, 2h OGTT, HbA1c, and HOMA-IR were significantly associated the development of CKD, independent of potential confounding risk factors. Of the 3 indices, HOMA-IR exhibited the best predictive ability. To the best of our knowledge, this is the first and largest population-based cohort study to examine the best index of glucose metabolism for predicting the development of CKD. Because the only effective treatment for ESRD is transplantation, controlling risk factors for the development of CKD, and screening methods to determine persons at greater risk of developing CKD are important for decreasing the number of patients develop ESRD. The findings of the present study may assist in identifying persons who are at risk of developing CKD and who may benefit from early interventions.
CKD is becoming a global health problem, and global deaths from kidney disease have risen by 83% since 199021. Glucose metabolism has been shown to be an important factor in the development of CKD12,22,23. Our finding that an elevated 2h OGTT and an elevated HbA1c level are independent risk factors for development of CKD is consistent with that of prior studies23,24. Gabir et al. 24 studies 5023 Pima Indian adults, and with a follow-up period of 10 years showed that a 2h OGTT can predict the development of CKD. Markus et al.23 studies 7728 subjects with a median follow-up of 8.7 years; 871 (11.3%) developed CKD and HbA1c was an independent predictors for the development of CKD.
However, there have been conflicting reports of the association of CKD development and glucose metabolism. In a study in Germany, Schottker et al. 25 followed 3,538 participants during for 8 years and found that pre-diabetes might not contribute to the development of CKD, and that preventive efforts such as regular exercise might reduce the risk of developing CKD26. An animal study using rats showed that physical training increased insulin sensitivity by enhancing muscle glucose uptake and glucose utilization via glycolysis 27. A study of hemodialysis patients showed that moderate physical training, using of plasma insulin level for patients reduces by the 40%28. In addition, some cross-sectional studies showed that neither glucose tolerance nor insulin secretion were associated with CKD. Hanssen et al.29 studies 1796 persons with normal glucose metabolism, 478 with pre-diabetes, and 669 with type 2 DM, and reported no association of CKD with 2h OGTT or HbA1c. However, the follow-up was relatively short, and the results can be interpreted as short or intermediate follow-up periods might not capture the associations of 2h OGTT or HbA1c with CKD. It is possible that there might be geographic or race variability with respect to the association of 2h OGTT and HbA1c and the development of CKD, as study has shown that both are predictors of insulin resistance, which is strongly associated with the development of CKD30. Clinical significance of each indicator is expected to be studied in the future and further explored with long-term and multi-stage longitudinal measures to better define the relationship.
The results of this study showed that HOMA-IR was the strongest predictor of the development of CKD in middle-aged and elderly Chinese. The HOMA-IR reflects a pathological state in which target tissues fail to respond normally to the biological effects of insulin, and is generally considered as an important influential factor for development of CKD. A study using NHANES data showed that individuals with the highest insulin levels had a 2.65 times greater risk for the development of CKD (95% CI: 1.25-5.62)31. Ma et al.32 studied 3,237 middle-aged and elderly Chinese persons with a 3-year follow-up and showed that an elevated HOMA-IR was associated with accelerated progression of CKD. Huh et al.33 studied 6,065 Korean persons without CKD at baseline, and over a follow-up period of 10 years showed that insulin resistance was independent risk factor for development of CKD. However, a prospective study of 73 non-diabetic subjects with CKD showed that of incident CKD in Korean population. However, a prospective study of 73 non-diabetic subjects with CKD showed that HOMA-IR was not significantly different in patients with or without renal endpoints 34. And the findings of the study might not extend to our study since it was conducted from one region of Turkey with small sample (n=73).
There are some theories as to why insulin resistance increases the risk of developing CKD. First, normally, insulin binds to the insulin receptor can activate insulin receptor substrate-1 (IRS-1), which can phosphorylated phosphatidylinositol 3-kinase (PI3-K). Under insulin resistance conditions, Impaired PI3-K lead to reductions in bioavailable nitric oxide (NO) directly resulting in the development of endothelial dysfunction and CKD 35. Secondly, insulin resistance promotes CKD at the molecular level by inflammation through endoplasmic reticulum (ER) stress, and is involved in the pathophysiology of chronic kidney injury with tubulointerstitial damage 36. Moreover, insulin resistance can increase the levels of inflammatory, cytokines, which can lead to basement membrane thickening, glomerular mesangial expansion, and the loss of slit pore diaphragm integrity, ultimately leading to glomerulosclerosis and tubule-interstitial injury37. Thirdly, insulin resistance may cause overproduction of LDL-C and contribute to hypertriglyceridemia, which can result in renal disease38. Triglyceride-rich apolipoprotein B-containing lipoproteins promote the progression of renal insufficiency 39. Lastly, insulin resistance promotes CKD by worsening renal hemodynamics through mechanisms such as activation of the sympathetic nervous system, sodium retention, decreased Na+, K+-ATPase activity, and increased GFR40,41.
The causes of insulin resistance are complex and multifactorial, and involve genetic factors such as post-receptor signaling defects, an unhealthy lifestyle that includes a lack of physical activity and poor diet which can lead to obesity, obesity, medications, aging, metabolic acidosis, oxidative stress, inflammation, vitamin D deficiency, uremic toxicity, and anemia, as shown by previous human and animal studies. Other co-morbid conditions that are strongly associated with insulin resistance are hypertension, diabetes, and hyperlipidemia.
Several limitations of in this study need to be addressed. First, by including only middle-aged and elderly Chinese subjects, the results might not apply to different races or a population of younger individuals. Secondly, our study population was predominantly female; this was partially because we invited person ≥40 years old to participate and females are predominant in this age range in China. Third, as with any observational study all confounding factors that may contribute to the development of CKD may not have been included in the models. Fourth, the ”gold-standard” for documenting insulin resistance is the euglycemic clamp test. However, the euglycemia clamp test is time-consuming and requires trained personal so it is rarely used in large epidemiological studies. HOMA-IR is a common method used to assess insulin resistance in large epidemiological studies, and it is relatively well-correlated with the euglycemia clamp technique (r=0.88)42. Fifth, we defined the CKD based on the first measurements of eGFR and UACR; however, the gold standard is two measurement results. This approach may have reduced the accuracy of our results; however, the results of 1 measurement correlate well with those of 2 measurements and use of 1 measurement is common in large epidemiology studies43. Finally, the follow-up rate in this study of 71% was relatively low; however, large epidemiological investigations rarely studies can achieve follow-up rate of ≥85%44,45. It is worth noting that the follow-up rate of another REACTION study with a defined 3-year follow-up in Shandong Province, China, from 2012 to 2015 was 77.8%, which was similar to that of our study32.