End-stage renal disease in diabetes patients is known to be the leading cause of increased risk for premature mortality [27]. Only having clear and reliable biomarkers for early diabetic kidney damage detection will lead to early interventions [26]. In the present study, we assessed the value of serum cystatin C as a biomarker for diabetic nephropathy in children and young adults with T1D diagnosis.
The main finding of our study was that using cystatin C helped to find those young T1D patients who may be suffering from early kidney damage, as one third of the whole cohort was classified with worse eGFR level when using cystatin C vs. creatinine. As demonstrated in Tsai et al. study with adult population using eGFR based on cystatin C helped to reclassify kidney function from preserved to reduced, especially in patients with diabetes [29], this means cystatin C could be used as earlier predictor of kidney damage compared to creatinine. There are few studies of prognostic value of serum cystatin C in children with diabetes, yet, most studies evaluated cystatin C in children with acute kidney injury. The 2017 meta-analysis of Nakhjavan-Shahraki et al. showed that serum cystatin C is potentially a more sensitive marker of acute kidney damage in children compared to serum creatinine [11].
Consistent with the Third National Health and Nutrition Examination Survey (NHANES III), our study showed that the levels of serum cystatin C were higher in children compared to adults [30] and were significantly higher in males compared to females in all age groups [31, 32]. On the other hand, Norlund et al. did not find any differences of cystatin C levels between genders [33]. These discrepancies might be explained by different age distribution of the studied cohorts: the median of age of our diabetic cohort was 16.2 years, while Norlund et al. included healthy adult patients above the age of 20 years.
A negative correlation between serum cystatin C and HbA1c was found in our investigation which is in agreement with the SEARCH for Diabetes in Youth Study and the results from Maahs et al. study [13, 32], however, the importance of these findings in clinical practice remains unclear. Furthermore, our study showed a linear negative correlation between cystatin C and HDL cholesterol. A low HDL level is used as one of the criteria for clinical diagnosis of metabolic syndrome [34]. The cross-sectional study with 925 dyslipidemic patients showed progressive increase in cystatin C, with the increasing number of metabolic syndrome components [35]. Patients with higher level of cystatin C have been shown to be at a twofold increased risk of cardiovascular events even after adjusting for a large variety of potential confounders [36]. The recent meta-analysis of over 22 000 participants from 14 studies showed, that higher cystatin C levels were strongly and independently associated with specific endpoints like stroke, myocardial infarction and heart failure [37].
One of the limitations of our study is that we did not measure GFR as it is considered to be the best assay of kidney function [38]. However, it would be clinically and ethically difficult to perform, especially in children, as it requires intravenous injection of the filtration marker. Therefore, most of the contemporary studies use estimated GFR levels for evaluation of kidney function either in children or in adults [38].
The other challenge that our study has faced was the lack of pediatric normative values for serum cystatin C. However, this is a worldwide issue, even for the most frequently used biomarkers, as neutrophil gelatinase-associated lipocalin, kidney injury molecule-I, and serum cystatin C, there are insufficient reference values in pediatric population [28].