Aims/Introduction Urinary kidney injury molecule‐1 (KIM‐1) has been associated with proximal tubular damage in human and animal studies. Although it has been recognized as a biomarker of acute kidney injury and chronic kidney disease, its significance in the serum remains unclear. Therefore, we examined the relationship of serum and urinary KIM‐1 levels with renal parameters in patients with type 2 diabetes. Materials and Methods Serum and urinary KIM‐1 levels, together with urinary liver‐type fatty acid‐binding protein, were measured in 602 patients with type 2 diabetes and an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2. These were then compared with the urinary albumin‐to‐creatinine ratio and eGFR. Results The serum and urinary KIM‐1 levels were significantly different among the three (eGFR ≥60, 45–59, <45 mL/min/1.73 m2) groups. These levels were positively associated with the albumin‐to‐creatinine ratio and negatively associated with eGFR. In a multivariate logistic model, both serum and urinary KIM‐1 were associated with an increased albumin‐to‐creatinine ratio (>30 mg/g Cr), but only the serum KIM‐1 was associated with a lower eGFR (<60 mL/min/1.73 m2), after adjustment for covariates. Conclusions Renal parameters appear to be strongly associated with serum KIM‐1, and not urinary KIM‐1, in patients with type 2 diabetes and an eGFR ≥30 mL/min/1.73 m2.

Diabetic kidney disease (DKD) is among the most common and serious complications of both type 1 and type 2 diabetes. In this study, we used KK/Ta‐Ins2Akita (KK‐Akita) mice as a model of DKD and KK/Ta (KK) mice as controls to identify novel factors related to the development/progression of DKD. Capillary electrophoresis coupled with mass spectrometry analysis revealed that circulating Asp (l‐aspartic acid) levels in diabetic KK‐Akita mice tend to be lower than those in control KK mice. Therefore, we evaluated the effect of Asp supplementation to prevent the progression of DKD in KK‐Akita mice. Mice were divided into three groups: (a) untreated KK mice (Control group), (b) untreated KK‐Akita mice (DKD group), and (c) treated (double‐volume Asp diet) KK‐Akita mice (Tx group). Kidney sections were stained with fluorescein isothiocyanate‐labeled lectins, wheat germ agglutinin (WGA), and anti‐endothelial nitric oxide synthase (eNOS) antibody for evaluation of endothelial surface layer (ESL) and NO synthesis. The mesangial area and glomerular size in the DKD group were significantly larger than those in the Control group; however, there was no significant difference in those between the DKD and Tx groups. Albuminuria, the ratio of foot process effacement, and thickness of glomerular basement membrane in the Tx group were significantly lower than those in the DKD group. Furthermore, the expression levels of glomerular WGA and microvascular eNOS in the Tx group improved significantly and approached the level in the Control group. In conclusion, the improvement of albuminuria in the Tx group may be caused by the reduction of oxidative stress in the kidneys, which may lead to the subsequent improvement of glomerular ESL.

Diabetic nephropathy is one of the most frequent complications in type 1 and type 2 diabetes and the leading cause of chronic kidney disease (CKD) in patients starting renal replacement therapy in developed countries. Early detection along with multifactorial treatments, such as blood glucose control with sodium glucose cotransporter 2 inhibitors and blood pressure control with renin-angiotensin system blockers, are of particular importance to prevent disease progression and reduce mortality. In clinical settings, diabetic nephropathy is typically diagnosed by detecting microalbuminuria, the earliest indicator of this disease, in patients with diabetes for whom other causes of albuminuria are absent. However, recent renal biopsy based studies have demonstrated that albuminuria is neither a specific nor a sensitive biomarker for the development of diabetic nephropathy. The classical diabetic nephropathy is characterized by the progressive increase of albuminuria from normoalbuminuria to microalbuminuria and macroalbuminuria, declining glomerular filtration rate (GFR), and eventual end-stage renal disease. However, the clinical course of diabetic nephropathy has changed profoundly in recent years, due to the diversification of diabetes, therapeutic successes, as well as an aging population. Indeed, CKD attributable to diabetes which runs an atypical clinical course (i.e., so-called non-albuminuric renal function decline) has increased over the past decades. The paradigm shift from albuminuria-based to GFR-based kidney disease results in a new concept of diabetic kidney disease (DKD). This review article describes the concept of DKD, and differences between classical diabetic nephropathy and DKD.

Aims/Introduction Increased concentrations of serum tumor necrosis factor (TNF) receptors (TNFRs; TNFR1 and TNFR2) are positively associated with the urinary albumin‐to‐creatinine ratio (ACR), and negatively associated with the estimated glomerular filtration rate (eGFR) in patients with type 2 diabetes. However, the mechanism underlying this increase and the relationship between TNFRs in serum, and urine and kidney measures (ACR and eGFR) are unclear. Materials and Methods This was a cross‐sectional study that included 499 patients with type 2 diabetes and eGFR ≥60 mL/min/1.73 m2. The concentrations of TNFRs in serum and urine, and their respective fractional excretion, were measured. Results Serum and urinary TNFR levels were positively associated with the ACR, and negatively associated with the eGFR. The fractional excretion of TNFRs did not differ between patients with an eGFR ≥90 and those with an eGFR 60–89 mL/min/1.73 m2, and also did not correlate with eGFR. After adjustment for relevant covariates, the serum TNFRs were associated with a lower eGFR (60–89 mL/min/1.73 m2) and an increased ACR (≥30 mg/gCr), but urinary TNFRs were associated with an increased ACR (≥30 mg/gCr) alone, in the multivariate logistic model. Conclusions The pattern of fractional excretion TNFRs showed that an increase in serum TNFRs might result from their increased systemic production, including in the kidney, rather than being a simple reflection of GFR decline. Kidney measures appear to be strongly associated with serum TNFRs rather than urinary TNFRs in patients with type 2 diabetes and normal renal function.

Progranulin (PGRN), a growth factor, is abundantly expressed in a broad range of tissues and cell types with pleiotropic functions including inflammation, neurodegeneration, and facilitating lysosome acidification. PGRN binds to TNF receptors (TNFR) and inhibits downstream inflammatory signaling pathways. TNFR is a well-known predictor of glomerular filtration rate (GFR) decline in a variety of diseases. Therefore, we measured circulating PGRN in addition to TNFR using an enzyme-linked immunosorbent assay and explored whether it predicted renal prognosis in 201 Japanese patients with type 2 diabetes. During a median follow-up of 7.6 years, 21 participants reached primary renal endpoint, which involves a decline of at least 57% in eGFR from baseline, or the onset of end-stage renal disease. Univariate Cox regression analysis revealed that classical renal measures (GFR and albuminuria), two TNF-related biomarkers (PGRN and TNFR), and BMI were associated with this outcome. Multivariate analysis demonstrated that high levels of PGRN [HR 2.50 (95%CI 2.47–2.52)] or TNFR1 [HR 5.38 (95%CI 5.26–5.50)] were associated with this outcome after adjusting for relevant covariates. The high levels of PGRN as well as TNFR1 were associated with a risk of primary renal outcome in patients with type 2 diabetes after adjusting for established risk factors.