Urinary Cyclophilin A and serum Cystatin C as biomarkers for diabetic nephropathy in children with type 1 diabetes.

BACKGROUND: Currently, microalbuminuria is the gold standard for detection and prediction of diabetic nephropathy (DN). However, microalbuminuria appears once significant kidney damage has actually occurred. OBJECTIVES: We investigated the diagnostic role of urinary Cyclophilin-A (uCypA), uCypA/creatinine ratio (uCypA/Cr) and serum Cystatin-C (sCysC) as biomarkers for early detection of DN in children with type 1 diabetes mellitus (T1DM) of short duration (2-5 years) before microalbuminuria emerges. METHODS: uCypA, uCypA/Cr, and sCysC levels were assessed in three age- and sex-matched groups; microalbuminuric diabetic group (n = 31), normoalbuminuric diabetic group (n = 29), and control group (n = 30). Glomerular filtration rate was estimated (eGFR) based on both serum creatinine (eGFR-Cr) and sCysC (eGFR-CysC). RESULTS: Significantly higher sCysC and lower eGFR-CysC were detected in both diabetic groups compared to controls and in microalbuminuric compared to normoalbuminuric group. No detected significant difference in eGFR-Cr values across the studied groups. Both uCypA and uCypA/Cr were significantly elevated in microalbuminuric compared to both normoalbuminuric and control groups with no difference between normoalbuminuric and control groups. Prediction of microalbuminuria was conducted using sCysC with area under curve up to 0.980. Combined use of sCysC and uCypA had better diagnostic value than uCypA alone. CONCLUSION: sCysC is a promising early biomarker for DN in childhood T1DM before albuminuria detection. eGFR-CysC is superior to eGFR-Cr in evaluating renal status in childhood T1DM. uCypA and uCypA/Cr were useful tools in predicting microalbuminuria, although not regarded as diagnostic biomarkers for early-stage DN in T1DM children by the current study.

Assessment of two novel renal tubular proteins in type 2 diabetic patients with nephropathy.

Nephropathy is a common health issue associated with type 2 diabetes mellitus (T2DM). Treatment of diabetic nephropathy (DN) in an early stage can effectively inhibit its progression. Albuminuria is the currently accepted marker for detection of DN.This study aims to evaluate the urinary level of two novel renal tubular proteins (cyclophilin A and periostin) in patients with T2DM and among different nephropathy stages and also to validate the diagnostic accuracy of both cyclophilin A and periostin as potential markers for early prediction of DN relative to albuminuria.This cross-sectional study recruited 137 patients with T2DM, and they were divided based on their urinary albumin:creatinine ratio into T2DM with normoalbuminuria (group II), incipient T2DN with microalbuminuria (group III) and overt T2DN with macroalbuminuria (groupIV) beside 41 healthy subjects as group I Cyclophilin A and periostin were measured in the urine using ELISA. Diagnostic accuracy of both markers was determined for prediction of DN via receiver operating characteristic curve analyses.Urinary cyclophilin A and periostin levels were significantly higher in DN groups when compared with T2DM with normoalbuminuria group. For prediction of incipient and overt DN, areas under the curve (AUCs) of periostin were 0.954, 0.997 and cyclophilin A were 0.914, 0.937, respectively. AUCs of periostin were higher than that for cyclophilin A with a significant AUC difference (p=0.022) in overt DN stage.Periostin and cyclophilin A could be regarded as a potential urinary biomarker for early prediction of DN. Periostin exhibits a higher diagnostic accuracy than urinary cyclophilin A specifically in overt DN stage.

Novel findings of secreted cyclophilin A in diabetic nephropathy and its association with renal protection of dipeptidyl peptidase 4 inhibitor.

BACKGROUND: Our previous clinical indicated that urinary cyclophilin A was a good marker for diabetic nephropathy. METHODS: We used animal and cell models of diabetic nephropathy to examine the role of cyclophilin A in disease progression. RESULTS: Significantly increased urinary cyclophilin A could be detected in db/db at the 8th week. Linagliptin (3mg/kg/day and 15mg/kg/day) could suppress urinary 8-hydroxy-2'-deoxyguanosine at the 8th and 16th week but only the high dose Linagliption could suppress cyclophilin A at the 8th week. Compared to 8-hydroxy-2'-deoxyguanosine, cyclophilin A was a stronger, earlier, and more sensitive marker. Immunohistochemical staining for cyclophilin A was also positive for db/db. In cell studies, oxidative stress and hyperglycemia could stimulate MES-13 and HK-2 cells to secrete cyclophilin A. Hyperglycemia stimulated HK-2 cells to secrete TGFß1, which caused secretion of cyclophilin A. The secreted cyclophilin A further stimulated CD 147 to move outward from cytosol onto cell membrane in confocal microscopy, which was associated with the p38 MAPK pathway in the downstream. CONCLUSIONS: Secreted cyclophilin A may play an important role in diabetic nephropathy in the mouse model and is associated with TGFß1, CD 147, and the p38 MAPK pathway.

Urinary Cyclophilin A as a New Marker for Diabetic Nephropathy: A Cross-Sectional Analysis of Diabetes Mellitus.

Type 2 diabetes mellitus (DM) is the most common single cause of end-stage renal disease. Albuminuria is the most commonly used marker to predict onset of diabetic nephropathy (DN) without enough sensitivity and specificity to detect early DN. This is the first study to identify urinary cyclophilin A (CypA) as a new biomarker for early DN.We recruited DM outpatients and healthy control subjects from January 2014 to December 2014. In this cross-sectional study, patients' urine samples were collected to determine the expression of urinary CypA. We also treated mesangial (MES-13) and tubular (HK-2) cells with glucose or free radicals to observe the expression of secreted CypA in Western blot analysis.A total of 100 DN patients and 20 healthy control subjects were enrolled. All variables were matched. In univariate analysis, the concentration of urinary CypA correlated well with the progression of renal function. A significant increase in urinary CypA was noted in stage 2 DN and persisted in later stages. We could diagnose stage 2 DN using urinary CypA with a sensitivity of 90.0% and specificity of 72.7%. The area under curve was up to 0.85, indicating a good discriminatory power. In cellular models, MES-13 and HK-2 cells can both release CypA.Urinary CypA is a good biomarker for early DN detection in humans and it can be released from either mesangial or tubular cells. The underlying molecular mechanisms still need further clarification in cellular and animal studies.