Cystatin C and Its Role in Patients with Type 1 and Type 2 Diabetes Mellitus
Diabetes mellitus is the commonest cause of CKD. It is the leading cause of new patients requiring renal replacement therapy, accounting for 40%, 34%, and 30% of cases in United States, Germany, and Australia, respectively. Recent studies have shown that a low-molecular weight protein, cystatin C, freely filtered by the kidneys is a novel biomarker that may be used for detection of early renal dysfunction in patients with type 1 or type 2 diabetes. Cystatin C has also been shown to detect cardiovascular disease in patients with diabetes and it may also be linked with incident type 2 diabetes in obese patients. We aim to review current evidence based literature on use of cystatin C for early detection of diabetic nephropathy due to type 1 and type 2 diabetes in comparison to conventional methods and explore its association with other comorbidities.
Diabetic nephropathy is classically defined by the presence of proteinuria, in the absence of other renal disease. It is a common problem that is most likely to occur in patients who have poor glycemic control, hypertension, glomerular hyperfiltration, or a genetic predisposition. The lifetime risk of nephropathy is estimated to be equivalent in type 1 and type 2 diabetes . It is more prevalent among African Americans, Asians, and Native Americans than Caucasians [2, 3].
Microalbuminuria precedes the development of macroalbuminuria and is predictive of future nephropathy. The onset of macroalbuminuria in the absence of effective therapy is followed by a slowly progressive decline in glomerular filtration rate (GFR) .
Current KDIGO guideline is the first to incorporate cystatin C based formulas in addition to creatinine and GFR estimating formulae when the latter are less accurate as in severe muscle wasting when tubular secretion of creatinine is affected by drugs. Moreover these can be used in special circumstances when knowledge of the exact GFR is important as in adjusting dosage of toxic drugs that are excreted by the kidneys or determining eligibility for kidney donation .
Screening for Microalbuminuria. In patients with type 2 diabetes screening for diabetic nephropathy must be initiated at the time of diagnosis, since >7% of them already have microalbuminuria at initial presentation [6, 7]. For patients with type 1 diabetes, the first screening has been recommended at 5 years after diagnosis . However, in EURODIAB IDDM complication study group it is demonstrated that in type 1 diabetes the prevalence of microalbuminuria can reach 18% before 5 years, especially in patients with poor glycemic and lipid control and normal to high blood pressure levels . Therefore, in type 1 diabetes, screening for microalbuminuria may be performed 1 year after diagnosis, especially in patients with poor metabolic control. If microalbuminuria is absent, the screening must be repeated annually for both type 1 and 2 diabetic patients .
Monitoring of Renal Function. Although the measurement of UAE (urinary albumin excretion) is the cornerstone for the diagnosis of diabetic nephropathy, there are some patients with either type 1 or type 2 diabetes who have decreased glomerular filtration rate (GFR) in the presence of normal UAE [9, 10]. In patients with type 1 diabetes, this phenomenon is more common among females with longstanding diabetes, hypertension, and/or retinopathy . For patients with type 2 diabetes in NHANES III (Third National Health and Nutrition Examination Survey), low GFR (<60 mL/min) was present in 30% of patients in the absence of micro- or macroalbuminuria and retinopathy . Although renal biopsy was not performed, this observation was probably related to renal parenchymal disease rather than classical diabetic glomerulosclerosis. These studies indicate that normoalbuminuria does not predict decline in GFR in type 1 and type 2 diabetic patients.
GFR is the best parameter of overall kidney function  and should be measured or estimated in all diabetic patients for timely intervention in this population since large, prospective, randomized studies (UKPDS, STENO 2, and ADVANCE) have shown that early therapeutic intervention in diabetic patients can delay onset and progression of complications.
2. Methods of Estimating (GFR)
2.1. Clearance Methods
Measurements of GFR are traditionally based on the renal clearance of a marker in plasma, expressed as the volume of plasma completely cleared of the marker per unit time. The ideal marker should be endogenous, freely filtered by glomerulus, neither reabsorbed nor secreted by the renal tubule, and eliminated only by the kidney. Various markers used to measure GFR include exogenous (inulin and iothalamate) or endogenous (urea and creatinine) substances  (Table 1).
2.2. Prediction of GFR from Plasma Creatinine
In 1976, Cockcroft and Gault published an equation to predict creatinine clearance based on age, weight, height, and plasma creatinine, together with correction factors . Although helpful, it has many inherent limitations.
Among adults, the MDRD study equation provides a clinically useful estimate of GFR (up to approximately 90 mL/min/1.73 m2) (S). The MDRD study equation has the advantages of having been based on(i)GFR measured directly by urinary clearance of 125-Iothalamate;(ii)a large sample of >500 individuals with a wide range of kidney diseases;(iii)inclusion of both European-American and African-American participants;(iv)validation in a large () separate group of individuals as part of its development .In May 2009, Levey et al. reported that the CKD-EPI creatinine equation was somewhat more precise than the MDRD study equation, especially at higher GFRs. Using the new equation could decrease false-positive results .
3. Cystatin C as a Method of Estimating GFR
Cystatin C is considered a good marker of kidney function as it is filtered solely by the glomerulus, is not handled by the renal tubules, and is generated at a constant rate by all cells in the body.
Two meta-analyses have concluded that serum cystatin C is superior to serum creatinine as a marker of kidney function [17, 18]. One of them evaluated Twenty-nine studies (21 in adults) reported before 2009 which, compared serum creatinine with cystatin C in CKD patients. Of those, 17 showed that cystatin C was a better predictor of GFR, while 12 showed no difference in the prediction of GFR . When compared to MDRD formula, the cystatin C formula is more likely to be predicted if GFR is below or above 60 mL/min/1.73 m2 () . The addition of age, sex, and race to cystatin C helps make it more accurate, but combining these factors with serum creatinine may provide the best estimation of GFR. In a recent study by Levey et al., an equation that used both serum creatinine and cystatin C with age, sex, and race was better than equations that use only one of these markers . Other authors suggested that an equation that uses both serum creatinine and cystatin C with age, sex, and race would be better than equations that use only one of these serum markers [20, 21].
3.1. Clinical Considerations with Varying Degrees of Kidney Function
3.1.1. Early Kidney Disease
Cystatin C may detect mild-to-moderate decreases in GFR that are not evident with serum creatinine-based measurements. Some studies suggest that CysC-GFR was better than creatinine-based estimates of GFR at GFR levels >60 mL/min/1.73 m2 (CKD stages 1 and 2) .
In addition, Cys-GFR appeared to be better correlated with microalbuminuria, while MDRD and CG creatinine estimates of GFR tend to reflect only proteinuria . Using CysC-GFR, over one-third of type 1 diabetes patients with microalbuminuria at the time of enrollment already had evidence of mild (CysC-GFR < 90) or moderate (CysC-GFR < 60 mL/min/1.73 m2) CKD .
3.1.2. Kidney Transplantation
CysC-GFR after transplant has been used to detect allograft dysfunction and monitor drug nephrotoxicity, with reported diagnostic value . In kidney transplant patients, cystatin C was reported to be more sensitive than serum creatinine for detecting decreases in GFR and delayed graft function, offering an opportunity for timely intervention .
Follow-up studies have found that GFR was overestimated by 30% when derived from plasma creatinine levels . On the other hand cystatin C underestimated GFR by 14%, and it was still more sensitive in detecting kidney damage, with no false-negative results .
3.1.3. Acute Kidney Injury (AKI)
Serum cystatin C has been reported to outperform conventional biomarkers in the prediction of AKI and to have prognostic value of the need for kidney transplant and in-hospital mortality . Cystatin C has been reported to increase about one to two days earlier than serum creatinine in patients developing AKI. AKI is not rare in hospitalized patients, with a mortality rate estimated to be between 30% and 90% .
4. Cystatin C in Type 1 Diabetes
In the early 1980s, three landmark studies of patients with type 1 diabetes identified “microalbuminuria” as the first detectable functional abnormality [31–33]; however, estimation of GFR remains critical to assessment of renal function.
Tan et al. carried out the first published study, which simultaneously examined the relative precision and correlation of plasma cystatin C with routine clinical measures and a reference method (GFR-IO). This study included 40 volunteers with normal plasma creatinine levels. Twenty-nine subjects were type 1 diabetic patients with varying degrees of albuminuria. The authors demonstrated that cystatin C proved to be more reliable than 24-hour creatinine clearance and was superior to plasma creatinine as well as the Cockcroft-Gault estimation. Amongst a subgroup of 8 diabetic patients (with GFR-IO less than the minimum value in nondiabetic subject), only 2 were identified with subnormal GFR using plasma creatinine whereas all 8 subjects were shown to have elevated serum cystatin C concentrations. Additionally, 14 diabetic subjects were noted to have increased serum cystatin C concentrations compared to only 1 patient with elevated plasma creatinine levels when analyzed against the gold standard reference measures . Observations from this study led to the conclusion that, in patients with type 1 diabetes, cystatin C is a promising new marker of early renal dysfunction as it is more accurate than current measures for GFR estimation.
Subsequently, Buysschaert et al. assessed the performance of cystatin C in 46 patients with type 1 diabetes spanning a wide range of renal functions in comparison to serum creatinine. This study also concluded that serum cystatin C is a better determinant of estimated GFR when compared to the conventional serum creatinine measurement . Both these studies demonstrated that serum cystatin C performed better than serum creatinine in the evaluation of renal dysfunction in patients with type 1 diabetes.
Christensson et al. investigated the accuracy of serum cystatin C versus serum creatinine for the early detection diabetic nephropathy in addition to the effect of age on these two GFR markers. This study included a large cohort of type 1 () and type 2 () diabetic patients. Serum cystatin C was shown to have no major advantage versus age-adjusted serum creatinine in the evaluation of GFR < 60 mL/min. However, it is important to note that serum cystatin C was more effective in the diagnosis of mild diabetic nephropathy (as defined by GFR < 80 mL/min) than serum creatinine suggesting that serum cystatin C is useful for the identification of early diabetic nephropathy .
In a more recent study, Pucci et al. compared the accuracy of cystatin C with creatinine and the Cockcroft-Gault formula and MDRD study equation for the assessment of early decline in renal function in diabetic patients with renal impairment. It included the largest cohort of type 1 diabetic patients () and demonstrated that cystatin C better correlated with GFR than creatinine-based formulae. This study also proved that cystatin C is more sensitive for detecting early renal function impairment than creatinine and creatinine-based formulae. The mean cystatin C concentrations showed statistically significant stepwise increase as GFR declined allowing very early detection of reduction in renal function. Interestingly, at GFR cut-points of 90 mL/min and 75 mL/min, the diagnostic efficiency of cystatin C was better .
Furthermore, over a median 23 years of follow-up, cross-sectional and longitudinal analyses of 1441 participants in the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study with type 1 diabetes revealed that mean rate of change in eGFR was similar when estimates were calculated using creatinine, cystatin C, or both markers. The association of BP and HbA1c with change in eGFR was strongest for estimates calculated using cystatin C and, a combination of creatinine and cystatin C. This study demonstrated that use of cystatin C in addition to creatinine might not be of significance in clinical practice; however, it has the potential to further unravel the pathophysiological changes leading to loss of GFR in type 1 diabetes .
5. Cystatin C in Type 2 Diabetes Mellitus
Screening for diabetic nephropathy is recommended as early intervention delays the progression of kidney disease . So far annual screening for microalbuminuria is the modality used for detecting diabetic nephropathy . Recently, interest has grown in the use of another surrogate marker, cystatin C, in detection of renal disease in type 2 diabetes mellitus. It has been noted that patients with type 2 diabetes and microangiopathy have statistically significant higher levels of cystatin C than healthy individuals . In 52 Caucasian patients with type 2 diabetes, cystatin C was found to be a better marker of kidney disease measured by serum creatinine or Cockcroft and Gault GFR estimation. The study clearly demonstrated that serum concentration progressively increased as glomerular filtration rate decreased .
Similarly, Mojiminiyi et al. conducted studies in Kuwait to evaluate the role of cystatin C in patients with type 2 diabetes mellitus. In one study, they evaluated the use of cystatin C as a marker of nephropathy in 77 patients with type 2 diabetes who were normoalbuminuric, microalbuminuria, and macroalbuminuric. In this study with microalbuminuria being the “gold standard,” the sensitivity of cystatin C was 40% and the specificity was 100% for the detection of nephropathy. Cystatin C identified 40% of the patients with diabetic nephropathy as compared to serum creatinine, which only identified 12% . In another study, cystatin C, beta-2 microglobulin, and serum creatinine were measured in 105 patients with type 2 diabetes mellitus and compared to the measured creatinine clearance and the estimated creatinine clearance using the Cockroft and Gault formula. Cystatin C was found to have the highest sensitivity for detection of estimated creatinine clearance of less than 60 mL/min/1.73 m2 at routine cut-off values. Additionally, cystatin C was best for discriminating between microalbuminuria and normoalbuminuria in those with type 2 diabetes resulting in the conclusion that cystatin C might be a more useful marker than creatinine for detection of early diabetic nephropathy in type 2 patients with diabetes .
In Egypt, El-Shafey et al. have demonstrated the usefulness of cystatin C in a small study that included 40 patients with type 2 diabetes mellitus. Cystatin C showed significant correlation with serum creatinine, creatinine clearance, and 24-hour urinary albumin . Another small study demonstrated the superiority of cystatin C in detecting early disease in type 2 diabetes patients as compared to routine tests. Cystatin C detected renal abnormality in 19% of patients not diagnosed by routine tests. Hence, the authors recommended incorporating cystatin C when testing for renal function . Similar results have also been reported by other study groups who propose the use of cystatin C based formulae as it has been shown to be comparable  or superior  to creatinine-based estimations of GFR in patients with type 2 diabetes.
In a recent study, Jeon et al. examined the relationship between cystatin C and albumin to creatinine ratio (ACR). Increase in levels of serum cystatin C was noted with progression of CKD from stages I to III. Also, rise in serum cystatin paralleled progression from normoalbuminuria to microalbuminuria, thereby revealing a positive correlation between serum cystatin C and ACR. The investigators concluded that serum cystatin C is a useful in early detection of diabetic nephropathy as it reflects reduction in GFR as well as rise in ACR . The role of serum and urinary cystatin C in impaired renal function in addition to the optimum cut-off point at which impaired renal function may be detected has been evaluated in 742 patients with type 2 diabetes. Therefore, the investigators concluded that urinary cystatin C and duration of diabetes could be used as indicators of early renal damage .
6. Cystatin C as a Predictor of CV Disease in Diabetes Mellitus
Like microalbumin, cystatin C is linked to cardiovascular disease. It was shown that cystatin C level, independent of renal function, was associated with insulin resistance and inflammation. This may explain the association between cystatin C and cardiovascular disease in type 2 diabetes .
Furthermore, there is mounting evidence that cystatin C may be a predictor of adverse outcomes independent of renal function. Higher levels of cystatin C have been associated with a twofold increased risk of cardiovascular events even after adjusting for well-known risk factors  in addition to higher mortality in patients with acute coronary syndromes . In unadjusted models, higher concentrations have been associated with the degree of endotheliosis in conditions believed to be attributable to endothelial damage .
In a recent trial Panaich et al. have tried to explore the link between cystatin C and anthropometric measures and its influence on cardiovascular mortality, and they found that cystatin C corelated better with measures of visceral adiposity that included waist circumference and waist to hip ratio compared to BMI. It appeared to predict cardiovascular outcomes better in those with measures that do not suggest obesity than those who have abnormal anthropometric measures .
Maahs et al. examined the hypothesis that, in patients with Type 1 diabetes, cystatin C could predict progression of subclinical coronary atherosclerosis (SCA). Additionally they postulated that this biomarker would be a stronger predictor of SCA compared to serum creatinine and commonly used creatinine-based formulae. This is the first study to compare cystatin C to other measures of renal function as a predictor of SCA in this particular subpopulation. The investigators concluded that increasing serum cystatin C was a better predictor of SCA progression than serum creatinine and serum creatinine derived estimates of GFR . This observation is consistent with findings from previous studies in other populations; however, more evidence is required to validate these findings and provide insight into the association between cystatin C and coronary artery disease.
Trying to explore the link between cystatin C and increased cardiovascular risk, Lee et al. studied 478 patients with type 2 diabetes mellitus. They measured the degree of insulin resistance by using the homeostasis model assessment (HOMA-IR) and indicators of metabolic syndrome. Estimated glomerular filtration rate (eGFR) was derived from the MDRD equation. After adjusting for age, sex, body mass index, and eGFR, the cystatin C level increased significantly in proportion to the number of metabolic syndrome components present. The authors concluded that cystatin C is significantly associated with insulin resistance and biomarkers reflecting inflammation independent of renal function. These components may have a role in addition to that of eGFR in explaining the link between cystatin C and CVD in type 2 diabetes mellitus patients .
7. Cystatin C as a Predictor of Diabetes Mellitus
There is growing interest in the association of cystatin C and the development of type 2 diabetes mellitus. A cohort of 3472 nondiabetic individuals was followed up for 15 years where the incidence of diabetes was found to be 9.6% (diabetes defined as treatment with insulin, oral hypoglycemic agents, and/or diet or high levels of HbA1c). The incidence was highest in those with higher cystatin C levels at baseline independent of confounding risk factors. Future research should be directed to evaluate the possible role of cystatin C in the pathogenesis of type 2 diabetes . Reutens et al., in their study to evaluate the association between cystatin C and incident diabetes mellitus, included 2849 patients without overt nephropathy and found that cystatin C levels at baseline, after adjustment for age and gender, were significantly associated with incident diabetes on univariate analysis (). This association was independent of baseline kidney function, fasting blood glucose, and HbA1c levels. When BMI, waist circumference, and baseline insulin resistance were used as covariates they showed an interaction with cystatin C levels. They concluded that cystatin C was associated with incident diabetes but only in those with central adiposity or insulin resistance .
8. Contraindications to Use of Cystatin C
Cystatin C levels change with alterations in thyroid function and should not be considered for evaluation of GFR without assessing thyroid function tests . They are also liable to change in patients with CKD receiving glucocorticoids .
Cystatin C is an important marker in detecting early kidney dysfunction in both type 1 and type 2 diabetes compared to creatinine based formulae. It is also an important predictor of cardiovascular disease in patients with diabetes. Recent studies have stated the association between cystatin C and incident type 2 diabetes, especially in obese patients.
Cystatin C has a potential to be used in in early detection of diabetic nephropathy, even before development of microalbuminuria, which will allow for timely intervention and management of diabetic nephropathy. However, it is currently not widely available and not all assays have been universally calibrated. Both these factors limit its use in clinical practice at present.
We suggest that future studies utilize cystatin C to study the changes occurring in diabetic nephropathy due to glomerular damage and tubular damage in addition to further assessing its relationship with decline in renal function due to type 1 and type 2 diabetes.
|CKD:||Chronic kidney disease|
|GFR:||Glomerular filtration rate|
|UAE:||Urinary albumin excretion|
|NHANES:||Third National Health and Nutrition Examination Survey|
|UKPDS:||United Kingdom prospective diabetes study|
|AKI:||Acute kidney injury|
|HOMA-IR:||Homeostasis model assessment of insulin resistance.|
Conflict of Interests
The authors declare that there is no conflict of interests regarding the publication of this paper.
Alaaeldin M. Bashier wrote (cystatin C and incident diabetes, cystatin C and CVD, abstract, and conclusion), reviewed, and edited the paper. Ayman Aly Seddik Fadlallah wrote (Methods of GFR detection), edited, and reviewed the paper. Nada Alhashemi wrote the paper (cystatin C in type 2 diabetes). Puja Murli Thadani wrote the paper (cystatin C in Type 1 Diabetes). Elamin Abdelgadir reviewed the paper and edited it. Fauzia Rashid wrote the paper (Introduction).
E. Ritz and S. R. Orth, “Nephropathy in patients with type 2 diabetes mellitus,” The New England Journal of Medicine, vol. 341, no. 15, pp. 1127–1133, 1999.View at: Publisher Site | Google Scholar
US Renal Data System, USRDS 2003 Annual Data Report: Atlas of End-Stage Renal Disease in the United States, National Institute of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Md, USA, 2003.
B. A. Young, C. Maynard, and E. J. Boyko, “Racial differences in diabetic nephropathy, cardiovascular disease, and mortality in a national population of veterans,” Diabetes Care, vol. 26, no. 8, pp. 2392–2399, 2003.View at: Publisher Site | Google Scholar
I. H. de Boer, T. C. Rue, P. A. Cleary et al., “Long-term renal outcomes of patients with type 1 diabetes mellitus and microalbuminuria: an analysis of the diabetes control and complications trial/epidemiology of diabetes interventions and complications cohort,” Archives of Internal Medicine, vol. 171, no. 5, pp. 412–420, 2011.View at: Publisher Site | Google Scholar
“KDIGO 2012 clinical practice guideline for evaluation and management of chronic kidney disease,” Kidney International Supplements, vol. 3, no. 1, pp. 1–150, 2013.View at: Google Scholar
A. I. Adler, R. J. Stevens, S. E. Manley, R. W. Bilous, C. A. Cull, and R. R. Holman, “Development and progression of nephropathy in type 2 diabetes: the United Kingdom Prospective Diabetes Study (UKPDS 64),” Kidney International, vol. 63, no. 1, pp. 225–232, 2003.View at: Publisher Site | Google Scholar
“American Diabetes Association: nephropathy in diabetes (Position Statement),” Diabetes Care, vol. 27, supplement 1, pp. S79–S83, 2004.View at: Google Scholar
J. M. Stephenson and J. H. Fuller, “Microalbuminuria is not rare before 5 years of IDDM: EURODIAB IDDM Complications Study Group and the WHO Multinational Study of Vascular Disease in Diabetes Study Group,” Journal of Diabetes and Its Complications, vol. 8, no. 3, pp. 166–173, 1994.View at: Google Scholar
M. L. Caramori, P. Fioretto, and M. Mauer, “Low glomerular filtration rate in normoalbuminuric type 1 diabetic patients: an indicator of more advanced glomerular lesions,” Diabetes, vol. 52, no. 4, pp. 1036–1040, 2003.View at: Publisher Site | Google Scholar
R. J. MacIsaac, C. Tsalamandris, S. Panagiotopoulos, T. J. Smith, K. J. McNeil, and G. Jerums, “Non-albuminuric renal insufficiency in type 2 diabetes,” Diabetes Care, vol. 27, no. 1, pp. 195–200, 2004.View at: Publisher Site | Google Scholar
H. J. Kramer, Q. D. Nguyen, G. Curhan, and C.-Y. Hsu, “Renal insufficiency in the absence of albuminuria and retinopathy among adults with type 2 diabetes mellitus,” The Journal of the American Medical Association, vol. 289, no. 24, pp. 3273–3277, 2003.View at: Publisher Site | Google Scholar
A. S. Levey, J. Coresh, E. Balk et al., “National Kidney Foundation practice guidelines for chronic kidney disease: evaluation, classification, and stratification,” Annals of Internal Medicine, vol. 139, no. 2, pp. 137–I47, 2003.View at: Publisher Site | Google Scholar
H. W. Smith, “The reliability of inulin as a measure of glomerular filtration,” in The Kidney: Structure and Function in Health and Disease, H. W. Smith, Ed., pp. 231–238, Oxford University Press, New York, NY, USA, 1951.View at: Google Scholar
D. W. Cockcroft and M. H. Gault, “Prediction of creatinine clearance from serum creatinine,” Nephron, vol. 16, no. 1, pp. 31–41, 1976.View at: Publisher Site | Google Scholar
L. A. Stevens, J. Coresh, T. Greene, and A. S. Levey, “Assessing kidney function—measured and estimated glomerular filtration rate,” The New England Journal of Medicine, vol. 354, no. 23, pp. 2473–2483, 2006.View at: Publisher Site | Google Scholar
A. S. Levey, L. A. Stevens, C. H. Schmid et al., “A new equation to estimate glomerular filtration rate,” Annals of Internal Medicine, vol. 150, no. 9, pp. 604–612, 2009.View at: Publisher Site | Google Scholar
V. R. Dharnidharka, C. Kwon, and G. Stevens, “Serum cystatin C is superior to serum creatinine as a marker of kidney function: a meta-analysis,” American Journal of Kidney Diseases, vol. 40, no. 2, pp. 221–226, 2002.View at: Publisher Site | Google Scholar
J. F. Roos, J. Doust, S. E. Tett, and C. M. J. Kirkpatrick, “Diagnostic accuracy of cystatin C compared to serum creatinine for the estimation of renal dysfunction in adults and children—a meta-analysis,” Clinical Biochemistry, vol. 40, no. 5-6, pp. 383–391, 2007.View at: Publisher Site | Google Scholar
R. Hojs, S. Bevc, R. Ekart, M. Gorenjak, and L. Puklavec, “Serum crystatin C-based equation compared to serum creatinine-based equations for estimation of glomerular filtration rate in patient with chronic kidney disease,” Clinical Nephrology, vol. 70, no. 1, pp. 10–17, 2008.View at: Publisher Site | Google Scholar
L. A. Stevens, J. Coresh, C. H. Schmid et al., “Estimating GFR using serum cystatin C alone and in combination with serum creatinine: a pooled analysis of 3,418 individuals with CKD,” American Journal of Kidney Diseases, vol. 51, no. 3, pp. 395–406, 2008.View at: Publisher Site | Google Scholar
G. J. Chwartz, A. Munoz, and M. F. Schneide, “New equations to estimate GFR in children with CKD,” Journal of the American Society of Nephrology, vol. 20, no. 3, pp. 629–637, 2009.View at: Publisher Site | Google Scholar
G. Jerums, E. Premaratne, S. Panagiotopoulos, S. Clarke, D. A. Power, and R. J. MacIsaac, “New and old markers of progression of diabetic nephropathy,” Diabetes Research and Clinical Practice, vol. 82, no. 1, pp. S30–S37, 2008.View at: Publisher Site | Google Scholar
E. T. Rosolowsky, M. A. Niewczas, L. H. Ficociello, B. A. Perkins, J. H. Warram, and A. S. Krolewski, “Between hyperfiltration and impairment: demystifying early renal functional changes in diabetic nephropathy,” Diabetes Research and Clinical Practice, vol. 82, no. 1, pp. S46–S53, 2008.View at: Publisher Site | Google Scholar
U. Pöge, T. Gerhardt, B. Stoffel-Wagner et al., “Cystatin C-based calculation of glomerular filtration rate in kidney transplant recipients,” Kidney International, vol. 70, no. 1, pp. 204–210, 2006.View at: Publisher Site | Google Scholar
T. Le Bricon, E. Thervet, M. Benlakehal, B. Bousquet, C. Legendre, and D. Erlich, “Changes in plasma cystatin C after renal transplantation and acute rejection in adults,” Clinical Chemistry, vol. 45, no. 12, pp. 2243–2249, 1999.View at: Google Scholar
T. Le Bricon, E. Thervet, M. Froissart et al., “Plasma cystatin C is superior to 24-h creatinine clearance and plasma creatinine for estimation of glomerular filtration rate 3 months after kidney transplantation,” Clinical Chemistry, vol. 46, no. 8, pp. 1206–1207, 2000.View at: Google Scholar
H. Popper and H. Mandel, “Filtrations and reabsorption sleistung in der nievenpathologic,” Ergebnisse der inneren Medizin und Kinderheilkunde, vol. 53, p. 685, 1937.View at: Google Scholar
U. Pöge, T. Gerhardt, A. Bökenkamp et al., “Time course of low molecular weight proteins in the early kidney transplantation period—influence of corticosteroids,” Nephrology Dialysis Transplantation, vol. 19, no. 11, pp. 2858–2863, 2004.View at: Publisher Site | Google Scholar
A. Haase-Fielitz, R. Bellomo, P. Devarajan et al., “Novel and conventional serum biomarkers predicting acute kidney injury in adult cardiac surgery—a prospective cohort study,” Critical Care Medicine, vol. 37, no. 2, pp. 553–560, 2009.View at: Publisher Site | Google Scholar
S. Herget-Rosenthal, G. Marggraf, J. Hüsing et al., “Early detection of acute renal failure by serum cystatin C,” Kidney International, vol. 66, no. 3, pp. 1115–1122, 2004.View at: Publisher Site | Google Scholar
C. E. Mogensen and C. K. Christensen, “Predicting diabetic nephropathy in insulin-dependent patients,” The New England Journal of Medicine, vol. 311, no. 2, pp. 89–93, 1984.View at: Publisher Site | Google Scholar
H. H. Parving, B. Oxenbøll, P. A. Svendsen, J. S. Christiansen, and A. R. Andersen, “Early detection of patients at risk of developing diabetic nephropathy. A longitudinal study of urinary albumin excretion,” Acta Endocrinologica, vol. 100, no. 4, pp. 550–555, 1982.View at: Google Scholar
G. C. Viberti, R. J. Jarrett, and H. Keen, “Microalbuminuria as predictor of nephropathy in diabetics,” The Lancet, vol. 2, no. 8298, p. 611, 1982.View at: Publisher Site | Google Scholar
G. D. Tan, A. V. Lewis, T. J. James, P. Altmann, R. P. Taylor, and J. C. Levy, “Clinical usefulness of cystatin C for the estimation of glomerular filtration rate in type 1 diabetes: reproducibility and accuracy compared with standard measures and iohexol clearance,” Diabetes Care, vol. 25, no. 11, pp. 2004–2009, 2002.View at: Publisher Site | Google Scholar
M. Buysschaert, I. Joudi, P. Wallemacq, and M. P. Hermans, “Performance of serum cystatin-C versus serum creatinine in subjects with type 1 diabetes,” Diabetes Care, vol. 26, no. 4, article 1320, 2003.View at: Publisher Site | Google Scholar
A. G. Christensson, A. O. Grubb, J.-Å. Nilsson, K. Norrgren, G. Sterner, and G. Sundkvist, “Serum cystatin C advantageous compared with serum creatinine in the detection of mild but not severe diabetic nephropathy,” Journal of Internal Medicine, vol. 256, no. 6, pp. 510–518, 2004.View at: Publisher Site | Google Scholar
L. Pucci, S. Triscornia, D. Lucchesi et al., “Cystatin C and estimates of renal function: searching for a better measure of kidney function in diabetic patients,” Clinical Chemistry, vol. 53, no. 3, pp. 480–488, 2007.View at: Publisher Site | Google Scholar
I. H. de Boer, W. Sun, P. A. Cleary et al., “Longitudinal changes in estimated and measured GFR in type 1 diabetes,” Journal of the American Society of Nephrology, vol. 25, no. 4, pp. 810–818, 2014.View at: Publisher Site | Google Scholar
R. G. Nelson, D. J. Pettitt, M. J. Carraher, H. R. Baird, and W. C. Knowler, “Effect of proteinuria on mortality in NIDDM,” Diabetes, vol. 37, no. 11, pp. 1499–1504, 1988.View at: Publisher Site | Google Scholar
National Kidney Foundation, “KDOQI clinical practice guidelines and clinical practice recommendations for diabetes and chronic kidney disease,” American Journal of Kidney Diseases, vol. 49, no. 2, supplement 2, pp. S12–S179, 2007.View at: Publisher Site | Google Scholar
M. Knapik-Kordecka, A. Piwowar, and M. Warwas, “Levels of cystatin C, activity of antipapain and antitrypsin in plasma of patients with diabetes mellitus type 2,” Wiadomości Lekarskie, vol. 53, no. 11-12, pp. 617–622, 2000.View at: Google Scholar
M. Mussap, M. D. Vestra, P. Fioretto et al., “Cystatin C is a more sensitive marker than creatinine for the estimation of GFR in type 2 diabetic patients,” Kidney International, vol. 61, no. 4, pp. 1453–1461, 2002.View at: Publisher Site | Google Scholar
O. A. Mojiminiyi, N. Abdella, and S. George, “Evaluation of serum cystatin C and chromogranin A as markers of nephropathy in patients with Type 2 diabetes mellitus,” Scandinavian Journal of Clinical and Laboratory Investigation, vol. 60, no. 6, pp. 483–489, 2000.View at: Publisher Site | Google Scholar
O. A. Mojiminiyi and N. Abdella, “Evaluation of cystatin C and β-2 microglobulin as markers of renal function in patients with type 2 diabetes mellitus,” Journal of Diabetes and its Complications, vol. 17, no. 3, pp. 160–168, 2003.View at: Publisher Site | Google Scholar
E. M. El-Shafey, G. F. El-Nagar, M. F. Selim, H. A. El-Sorogy, and A. A. Sabry, “Is serum cystatin C an accurate endogenous marker of glomerular filteration rate for detection of early renal impairment in patients with type 2 diabetes mellitus?” Renal Failure, vol. 31, no. 5, pp. 355–359, 2009.View at: Publisher Site | Google Scholar
N. V. McNamara, R. Chen, M. R. Janu, P. Bwititi, G. Car, and M. Seibel, “Early renal failure detection by cystatin C in Type 2 diabetes mellitus: varying patterns of renal analyte expression,” Pathology, vol. 41, no. 3, pp. 269–275, 2009.View at: Publisher Site | Google Scholar
S. Bevc, R. Hojs, R. Ekart, M. Završnik, M. Gorenjak, and L. Puklavec, “Simple cystatin C formula for estimation of glomerular filtration rate in overweight patients with diabetes mellitus type 2 and chronic kidney disease,” Experimental Diabetes Research, vol. 2012, Article ID 179849, 8 pages, 2012.View at: Publisher Site | Google Scholar
S. J. Oh, J. I. Lee, W. C. Ha et al., “Comparison of cystatin C- and creatinine-based estimation of glomerular filtration rate according to glycaemic status in Type 2 diabetes,” Diabetic Medicine, vol. 29, no. 7, pp. e121–e125, 2012.View at: Publisher Site | Google Scholar
Y. L. Jeon, M. H. Kim, W.-I. Lee, and S. Y. Kang, “Cystatin C as an early marker of diabetic nephropathy in patients with type 2 diabetes,” Clinical Laboratory, vol. 59, no. 11-12, pp. 1221–1229, 2013.View at: Publisher Site | Google Scholar
X. Rao, M. Wan, C. Qiu, and C. Jiang, “Role of cystatin C in renal damage and the optimum cut-off point of renal damage among patients with type 2 diabetes mellitus,” Experimental and Therapeutic Medicine, vol. 8, no. 3, pp. 887–892, 2014.View at: Google Scholar
S.-H. Lee, S.-A. Park, S.-H. Ko et al., “Insulin resistance and inflammation may have an additional role in the link between cystatin C and cardiovascular disease in type 2 diabetes mellitus patients,” Metabolism: Clinical and Experimental, vol. 59, no. 2, pp. 241–246, 2010.View at: Publisher Site | Google Scholar
W. Koenig, D. Twardella, H. Brenner, and D. Rothenbacher, “Plasma concentrations of cystatin C in patients with coronary heart disease and risk for secondary cardiovascular events: more than simply a marker of glomerular filtration rate,” Clinical Chemistry, vol. 51, no. 2, pp. 321–327, 2005.View at: Publisher Site | Google Scholar
T. Jernberg, B. Lindahl, S. James, A. Larsson, L.-O. Hansson, and L. Wallentin, “Cystatin C: a novel predictor of outcome in suspected or confirmed non-ST-elevation acute coronary syndrome,” Circulation, vol. 110, no. 16, pp. 2342–2348, 2004.View at: Publisher Site | Google Scholar
H. Strevens, D. Wide-Swensson, A. Grubb et al., “Serum cystatin C reflects glomerular endotheliosis in normal, hypertensive and pre-eclamptic pregnancies,” BJOG, vol. 110, no. 9, pp. 825–830, 2003.View at: Publisher Site | Google Scholar
S. S. Panaich, V. Veeranna, C. Bavishi, S. K. Zalawadiya, A. Kottam, and L. Afonso, “Association of cystatin C with measures of obesity and its impact on cardiovascular events among healthy U. S. adults,” Metabolic Syndrome and Related Disorders, vol. 12, pp. 472–476, 2014.View at: Publisher Site | Google Scholar
D. M. Maahs, L. G. Ogden, A. Kretowski et al., “Serum cystatin C predicts progression of subclinical coronary atherosclerosis in individuals with type 1 diabetes,” Diabetes Care, vol. 56, pp. 2774–2779, 2007.View at: Google Scholar
K. Sahakyan, K. E. Lee, A. Shankar, and R. Klein, “Serum cystatin C and the incidence of type 2 diabetes mellitus,” Diabetologia, vol. 54, no. 6, pp. 1335–1340, 2011.View at: Publisher Site | Google Scholar
A. T. Reutens, F. Bonnet, O. Lantieri, R. Roussel, and B. Balkau, “The association between cystatin C and incident type 2 diabetes in relation to central adiposity,” Nephrology Dialysis Transplantation, vol. 28, no. 7, pp. 1820–1829, 2013, http://www.ncbi.nlm.nih.gov/pubmed/23291367.View at: Publisher Site | Google Scholar
P. Wiesli, B. Schwegler, G. A. Spinas, and C. Schmid, “Serum cystatin C is sensitive to small changes in thyroid function,” Clinica Chimica Acta, vol. 338, no. 1-2, pp. 87–90, 2003.View at: Publisher Site | Google Scholar
A. Bökenkamp, J. A. E. Van Wijk, M. J. Lentze, and B. Stoffel-Wagner, “Effect of corticosteroid therapy on serum cystatin C and β2-microglobulin concentrations,” Clinical Chemistry, vol. 48, no. 7, pp. 1123–1126, 2002.View at: Google Scholar