Published online Nov 15, 2019. doi: 10.4239/wjd.v10.i11.517
Peer-review started: August 26, 2019
First decision: September 21, 2019
Revised: October 6, 2019
Accepted: October 18, 2019
Article in press: October 18, 2019
Published online: November 15, 2019
A number of researches show the heterogeneity of the natural course of chronic kidney disease (CKD) in patients with diabetes. Moreover, it has been shown that natural course of diabetic kidney disease is being transformed with increasing prevalence of declined renal function not accompanied by elevation of albuminuria. The trend is more evident in patients with type 2 diabetes (T2D). Currently, little is known about the mechanisms that determine the development of the albuminuric or nonalbuminuric phenotype of CKD. It was suggested that an increase in albuminuria may be a consequence of podocytopathy, while a decrease in renal function is associated with the involvement of tubulointerstitium.
The main topic of this study is in-depth clinical characteristics and identification of the risk factors and biomarkers of albuminuric and non-albuminuric CKD phenotypes in patients with T2D. The results may provide further progress in understanding of individual differences in the natural course of diabetic kidney disease and generation differentiated approaches to prevention and treatment of this complication.
The study aimed to identify the risk factors and urinary biomarkers of albuminuric and non-albuminuric CKD in patients with long-term T2D. Wherein, we tested the hypothesis that albuminuric and non-albuminuric CKD phenotypes correspond to different pathways of diabetic kidney disease progression.
Three hundred and sixty patients with T2D duration of at least 10 years from the date of diagnosis were included in this observational cross-sectional study. The associations of a panel of demographic and clinical characteristics, complications, comorbidities, and metabolic parameters with albuminuric and non-albuminuric CKD were analyzed. The urinary excretion of nephrin and podocin, two podocyte-specific markers, and WAP-four-disulfide core domain protein 2 (WFDC-2), a marker of tubulointerstitial fibrosis, was determined by ELISA in defined CKD phenotypes.
In this study we identified the risk factors of three CKD phenotypes in T2D patients. According to our data, non-albuminuric CKD is associated with age ≥ 65 years, female sex, diabetes duration ≥ 15 years, and the use of diuretics. Male sex, smoking, waist-to-hip ratio > 1.0 and HbA1c > 8.0% are risk factors for elevated albuminuria not accompanied by a decrease in estimated glomerular filtration rate (eGFR). Duration of diabetes ≥ 15 years and the use of calcium channel blockers seem to be risk factors for albuminuria with decreased eGFR. We also found some differences in predictors of decreased eGFR and increased albuminuria. In multivariate logistic regression analysis, age, HbA1c, female sex and diuretics were significant predictors for reduced eGFR, while waist-to-hip ratio, HbA1c and male sex were associated with elevated urinary albumin-to-creatinine ratio (UACR). In accordance with the tested hypothesis, we found the differences in urinary biomarkers of podocyte and tubulointerstitium involvement in patients with different CKD phenotypes. Excretion of nephrin and podocin was increased in patients with albuminuria, regardless of decline in renal function, correlating positively with UACR. At the same time, in women, WFDC-2 excretion was increased in those with reduced renal function, correlating negatively with eGFR.
To our knowledge, this is the first study addressing the diversity in clinical characteristics and urinary biomarkers in T2D subjects with different CKD phenotypes. The results of this study provide new data on the risk factors and mechanisms of different variants of CKD in patients with long-term T2D. Firstly, by matching a panel of clinical and laboratory parameters of T2D patients who had an increase in albuminuria, a decrease in eGFR, or both deviations, with parameters in T2D patients with normoalbuminuria and preserved renal function, we showed the differences in profiles of the risk factors for CKD phenotypes. According to our data, non-albuminuric CKD phenotype is associated with age, female sex, diabetes duration, and the use of diuretics, whereas male sex, smoking, abdominal obesity and poor glycemic control are risk factors for elevated albuminuria. Secondly, we demonstrated some features in the urinary excretion of biomarkers, reflecting the podocyte and interstitial involvement, in patients with different CKD phenotypes. A significantly more demonstrative increase in the excretion of nephrin and podocin in patients with elevated UACR compared to those without could suggests that albuminuric CKD is associated with more severe podocyte involvement. The increase in urinary excretion of WFDC-2 in women with T2D and decreased eGFR apparently indicates more advanced tubulointerstitial fibrosis. The data provide further evidence that albuminuric and non-albuminuric CKD phenotypes correspond to different pathways of diabetic kidney disease progression. The diversity in the profiles of risk factors should be taken into account by clinicians in the management of diabetes.
Since our study has a cross-sectional design, it does not prove causality. Accordingly, significance of some identified risk factors needs further confirmation. In particular, the role of abdominal obesity, insulin resistance, diuretics and calcium channel blockers needs to be verified in prospective studies. The assessment of the predictive value of the studied biomarkers in albuminuric and non-albuminuric CKD phenotypes is a challenge for future research. The studies of the renoprotective potential of antihyperglycemic, antihypertensive and other therapeutic agents in different CKD phenotypes are urgently needed.