Diabetes mellitus (DM) has grown up to be an important issue of global public health because of its high incidence rate. Diabetic kidney disease (DKD) is the main cause of end-stage kidney disease (ESKD). Therefore, early diagnosis and timely prevention and treatment of DKD are essential for the progress of DM. The clinical diagnosis and staging of DKD are mostly based on the urinary albumin excretion rate (UAER) and estimated glomerular filtration rate (eGFR). However, clinically, DKD patients show normoalbuminuric diabetic kidney disease (NADKD) instead of clinical proteinuria. The old NADKD concept is no longer suitable and should be updated accordingly with the redefinition of normal proteinuria by NKF/FDA (National Kidney Foundation/Food and Drug Administration). Based on the relevant guidelines of DM and chronic kidney disease (CKD) and combined with the current situation of clinical research, the review described NADKD from the aspects of epidemiology, pathological mechanism, disease diagnosis, clinical characteristics and biomarkers, to arouse the new understanding of NADKD in the medical profession and pay attention to it.
Humans ; Diabetic Nephropathies/etiology* ; Diabetes Mellitus, Type 2/complications* ; Albuminuria ; Kidney ; Proteinuria/complications*

Diabetes mellitus (DM) has grown up to be an important issue of global public health because of its high incidence rate. Diabetic kidney disease (DKD) is the main cause of end-stage kidney disease (ESKD). Therefore, early diagnosis and timely prevention and treatment of DKD are essential for the progress of DM. The clinical diagnosis and staging of DKD are mostly based on the urinary albumin excretion rate (UAER) and estimated glomerular filtration rate (eGFR). However, clinically, DKD patients show normoalbuminuric diabetic kidney disease (NADKD) instead of clinical proteinuria. The old NADKD concept is no longer suitable and should be updated accordingly with the redefinition of normal proteinuria by NKF/FDA (National Kidney Foundation/Food and Drug Administration). Based on the relevant guidelines of DM and chronic kidney disease (CKD) and combined with the current situation of clinical research, the review described NADKD from the aspects of epidemiology, pathological mechanism, disease diagnosis, clinical characteristics and biomarkers, to arouse the new understanding of NADKD in the medical profession and pay attention to it.
Humans ; Diabetic Nephropathies/etiology* ; Diabetes Mellitus, Type 2/complications* ; Albuminuria ; Kidney ; Proteinuria/complications*

Objective Injured tubular reabsorption is highlighted as one of the causes of increased albuminuria in the early stage of diabetic nephropathy; however, the underlying mechanism has not been fully elucidated. In this study, we aimed to explore whether reducing inflammation and remodeling the insulin signaling pathway could improve albumin uptake of renal tubules. Methods 8-week-old male db/db mice (n=8), a type 2 diabetic nephropathy model, administered with nuclear factor kappa-B (NF-κB) inhibitor parthenolide (PTN, 1 mg/kg) intraperitoneally every other day for 8 weeks, were as the treatment group. Meanwhile, the age-matched male db/m mice (n=5) and db/db mice (n=8) were treated with saline as the control group and type 2 diabetic nephropathy group. When the mice were sacrificed, blood and urine were collected to examine homeostasis model assessment of insulin resistance (HOMA-IR) and urine albumin creatinine ratio, and kidney samples were used to analyze histopathologic changes with periodic acid-Schiff (PAS) staining, NF-κB p65, phosphorylation of AKT (p-AKT), amnionless and cubilin expressions with immunohistochemistry as well as western blot, and the albumin uptake of renal tubules by using immunofluorescence. In addition, HKC cells were divided into the insulin group treated with insulin alone, the TNF-α group treated with insulin and tumor necrosis factor (TNF-α), and the TNF-α+PTN group exposed to PTN, insulin and TNF-α. The levels of albumin uptake and expression levels of NF-κB p65, p-IRS-1/IRS-1, p-AKT/AKT, amnionless and cubilin in HKC cells were measured. Results Compared with the db/db group, the db/db+PTN group demonstrated decreased levels of HOMA-IR (36.83±14.09 vs. 31.07±28.05) and urine albumin creatinine ratio (190.3±7.3 vs. 143.0±97.6 mg/mmol); however, the differences were not statistically significant (P>0.05). Periodic acid-Schiff staining showed PTN could alleviate the glomerular hypertrophy and reduce the matrix in mesangial areas of db/db mice. The renal expression of NF-κB p65 was increased and p-AKT (s473) decreased in the db/db group compared with the db/m group (P<0.05). PTN significantly reduced the renal expression of NF-κB p65 and ameliorated the decline of p-AKT (s473) compared with the db/db group (P<0.05). Compared with the db/m group, the expression of amnionless and cubilin decreased and albumin uptake in tubules were reduced in the db/db group (P<0.05), and PTN could significantly increase the expression of cubilin (P<0.05), and improve albumin uptake in tubules. Insulin promoted albumin uptake and the expression of amnionless and cubilin in HKC cells (P<0.05). TNF-α stimulated the expression of NF-κB p65, increased p-IRS-1 (s307) and reduced p-AKT (s473) in HKC cells (P<0.05). In the TNF-α+PTN group, the expression of NF-κB p65 declined and p-IRS-1 (s307) and p-AKT (s473) were restored, compared with the TNF-α group (P<0.05). The expression of amnionless and cubilin decreased in the TNF-α group (P<0.05), and PTN could significantly increase the expression of cubilin (P<0.05). Conclusions Inflammation caused damage to insulin signaling, which reduced amnionless-cubilin expression and albumin uptake. PTN could reduce inflammation and remodel the impaired insulin signaling pathway, which promoted the expression of cubilin and albumin uptake. Our study can shed light on the role of inflammation in the reduction of albumin uptake of renal tubules in type 2 diabetic nephropathy.
Albumins/pharmacokinetics* ; Albuminuria/urine* ; Animals ; Anti-Inflammatory Agents, Non-Steroidal/pharmacology* ; Cell Line ; Creatinine/urine* ; Diabetes Mellitus, Type 2/complications* ; Diabetic Nephropathies/metabolism* ; Humans ; Insulin Resistance ; Kidney Tubules, Proximal/metabolism* ; Male ; Mice ; NF-kappa B/metabolism* ; Receptors, Cell Surface/metabolism* ; Sesquiterpenes/pharmacology*

BACKGROUND: To investigate the effects of dipeptidyl peptidase-4 (DPP-4) inhibitors on renal outcomes in patients with type 2 diabetes. METHODS: MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched to identify randomized controlled trials (RCTs) of DPP-4 inhibitors from inception to September 2017. We selected eligible RCTs comparing DPP-4 inhibitors with placebo or other antidiabetic agents and reporting at least one renal outcome. A meta-analysis was conducted to calculate standardized mean differences, weighted mean differences (WMDs), relative risks (RRs), and 95% confidence intervals (CIs) for each renal outcome. RESULTS: We included 23 RCTs with 19 publications involving 41,359 patients. Overall changes in urine albumin-to-creatinine ratio were comparable between DPP-4 inhibitors and controls (P=0.150). However, DPP-4 inhibitors were associated with significantly lower risk of incident microalbuminuria (RR, 0.89; 95% CI, 0.80 to 0.98; P=0.022) and macroalbuminuria (RR, 0.77; 95% CI, 0.61 to 0.97; P=0.027), as well as higher rates of regression of albuminuria (RR, 1.22; 95% CI, 1.10 to 1.35; P<0.001) compared with controls. Although DPP-4 inhibitors were associated with small but significantly lower estimated glomerular filtration rate (WMD, −1.11 mL/min/1.73 m2; 95% CI, −1.78 to −0.44; P=0.001), there was no difference in the risk of end-stage renal disease between two groups (RR, 0.93; 95% CI, 0.76 to 1.14; P=0.475). CONCLUSION: DPP-4 inhibitors had beneficial renal effects mainly by reducing the risk of development or progression of albuminuria compared with placebo or other antidiabetic agents.
Albuminuria ; Diabetes Complications ; Diabetes Mellitus, Type 2 ; Diabetic Nephropathies ; Dipeptidyl-Peptidase IV Inhibitors ; Glomerular Filtration Rate ; Humans ; Hypoglycemic Agents ; Kidney Failure, Chronic

OBJECTIVETo evaluate the renal protective effect of Tangshenkang Granule () in a rat model of diabetic nephropathy (DN).

METHODSForty male Sprague-Dawley rats were randomly divided into control, DN, Tangshenkang and benazepril groups. DN model was established in the rats of DN, Tangshenkang and benazepril groups. Tangshenkang Granule solution and benazepril hydrochloride solution were intragastrically administered daily to the rats in the Tangshenkang and benazepril groups for 8 weeks, respectively. Urinary albumin and creatinine were detected. The albumin/creatinine (ACR) was calculated in addition to 24 h urinary protein (24-h UPr), serum creatinine (Scr), blood urea nitrogen (BUN), total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and creatinine clearance rate (Ccr). Right kidneys were harvested for pathological observation using periodic acid-silver methenamine-Masson staining. The average glomerular diameter (DG), average glomerular (AG) and mesangial areas (AM) were measured. The thickness of glomerular basement membrane (TGBM) was detected using transmission electron microscope.

RESULTSCompared with rats in the control group, rats in the DN group showed significantly decreased body weight, increased hypertrophy index, 24-h urinary volume, 24-h UPr, ACR, Scr, BUN, Ccr, blood lipids as well as renal pathological indices including DG, AG, AM, AM/AG and TGBM (P <0.05). Compared with the DN group, the weights of rats in the Tangshenkang and benazepril groups were significantly increased, and the renal hypertrophy indices were significantly decreased (P <0.05). The 24-h urinary volumes, ACR, 24-h UPr, Scr, BUN, Ccr, LDL, DG, AG, AM and TGBM were obviously decreased (P <0.05). Compared with the benazepril group, the Tangshenkang group showed significantly decreased levels of ACR, 24-h UPr, AG and AM (P <0.05).

CONCLUSIONSTangshenkang Granule decreased the urinary protein, attenuated the high glomerular filtration rate and improved lipid metabolism in DN rats, and prevented further injury induced by diabetic nephropathy.

Albuminuria ; complications ; Animals ; Basement Membrane ; drug effects ; metabolism ; Blood Urea Nitrogen ; Body Weight ; drug effects ; Creatinine ; blood ; urine ; Diabetic Nephropathies ; blood ; drug therapy ; physiopathology ; urine ; Disease Models, Animal ; Drugs, Chinese Herbal ; pharmacology ; therapeutic use ; Hypertrophy ; Kidney Function Tests ; Kidney Glomerulus ; drug effects ; pathology ; physiopathology ; Lipid Metabolism ; drug effects ; Lipids ; blood ; Male ; Rats, Sprague-Dawley

PURPOSE: Diabetic nephropathy is a serious complication of type 2 diabetes mellitus, and delaying the development of diabetic nephropathy in patients with diabetes mellitus is very important. In this study, we investigated inflammation, oxidative stress, and lipid metabolism to assess whether curcumin ameliorates diabetic nephropathy. MATERIALS AND METHODS: Animals were divided into three groups: Long-Evans-Tokushima-Otsuka rats for normal controls, Otsuka-Long-Evans-Tokushima Fatty (OLETF) rats for the diabetic group, and curcumin-treated (100 mg/kg/day) OLETF rats. We measured body and epididymal fat weights, and examined plasma glucose, adiponectin, and lipid profiles at 45 weeks. To confirm renal damage, we measured albumin-creatinine ratio, superoxide dismutase (SOD), and malondialdehyde (MDA) in urine samples. Glomerular basement membrane thickness and slit pore density were evaluated in the renal cortex tissue of rats. Furthermore, we conducted adenosine monophosphate-activated protein kinase (AMPK) signaling and oxidative stress-related nuclear factor (erythroid-derived 2)-like 2 (Nrf2) signaling to investigate mechanisms of lipotoxicity in kidneys. RESULTS: Curcumin ameliorated albuminuria, pathophysiologic changes on the glomerulus, urinary MDA, and urinary SOD related with elevated Nrf2 signaling, as well as serum lipid-related index and ectopic lipid accumulation through activation of AMPK signaling. CONCLUSION: Collectively, these findings indicate that curcumin exerts renoprotective effects by inhibiting renal lipid accumulation and oxidative stress through AMPK and Nrf2 signaling pathway.
Albuminuria ; Animals ; Anti-Inflammatory Agents, Non-Steroidal/*therapeutic use ; Curcumin/*pharmacology ; Diabetes Mellitus, Type 2/*metabolism/urine ; Diabetic Nephropathies/complications/*drug therapy/metabolism/pathology ; Gene Expression/drug effects ; Inflammation ; Kidney/drug effects/metabolism/physiopathology ; Kidney Glomerulus/metabolism/physiopathology ; Lipid Metabolism/*drug effects ; Male ; Malondialdehyde/metabolism/urine ; Oxidative Stress/*drug effects ; Rats ; Rats, Inbred OLETF ; Rats, Long-Evans ; Superoxide Dismutase/metabolism

OBJECTIVETo investigate the effect of Xuezhikang (, XZK) on renal cell apoptosis in diabetic rats and the possible mechanism.

METHODSSixty-six rats were randomly divided into 3 groups: the normal, model and XZK groups. In each group, the rats were further randomly divided into 3-month and 6-month subgroups, respectively. Diabetes of rats was induced by a single intraperitoneal injection of 1% streptozocin at 60 mg/kg body weight. Rats in the XZK group received gastric perfusion of XZK (1200 mg/kg body weight) everyday for 3 or 6 months, while rats in the normal and model groups received equal volume of saline. Twenty-four hours' urine was collected for urinary albumin excretion (UAE) measurement. Periodic acid-Schiff (PAS) and Masson's trichrome staining were used for saccharides and collagen detection. Cell apoptosis of renal cortex was investigated by TdT-mediated dUTP nick end labeling (TUNEL) staining. Bax and Bcl-2 expressions were detected by immunohistochemistry and Western blot, respectively. Cytochrome C (Cyt C) and caspase-9 concentration were detected by Western blot.

RESULTSCompared with the model group, XZK treatment could significantly decrease the kidney hypertrophy index, 24 h UAE, renal cell apoptosis, cytoplasmic Cyt C level and active caspase-9 level, as well as suppress the increment of Bax and up-regulate the expression of Bcl-2, leading to the suppression of Bax/Bcl-2 ratio at 3 and 6 months (P<0.05 or P<0.01). Moreover, XZK treatment could alleviate the deposition of PAS-stained saccharides and Masson's trichromestained collagen to different extent.

CONCLUSIONSRenal cell apoptosis was observed in diabetic kidney, in which mitochondrial apoptotic pathway might be involved. XZK treatment could attenuate pathological changes in diabetic kidney and reduce renal cell apoptosis, probably via the suppression of Bax/Bcl-2 ratio, which lead to inhibition of Cyt C release and following caspase-9 activation.

Albuminuria ; blood ; complications ; Animals ; Apoptosis ; drug effects ; Blood Glucose ; metabolism ; Caspase 9 ; metabolism ; Cytochromes c ; metabolism ; Diabetes Mellitus, Experimental ; blood ; drug therapy ; metabolism ; pathology ; Drugs, Chinese Herbal ; pharmacology ; therapeutic use ; Hypertrophy ; In Situ Nick-End Labeling ; Kidney ; drug effects ; pathology ; Kidney Glomerulus ; pathology ; Lipids ; blood ; Male ; Mesangial Cells ; drug effects ; pathology ; Proto-Oncogene Proteins c-bcl-2 ; metabolism ; Rats, Sprague-Dawley ; Streptozocin ; bcl-2-Associated X Protein ; metabolism

Chronic kidney disease is a leading public health problem related to poor quality of life and premature death. As a resource for evidence-informed health policy-making, we evaluated the prevalence of chronic kidney disease using the data of non-institutionalized adults aged ≥ 20 years (n = 15,319) from the Korean National Health and Nutrition Examination Survey in 2011-2013. Chronic kidney disease was defined as a urine albumin-to-creatinine ratio ≥ 30 mg/g or an estimated glomerular filtration rate < 60 mL/min/1.73 m2 using the Chronic Kidney Disease-Epidemiology Collaboration equation. The total prevalence estimate of chronic kidney disease for adults aged ≥ 20 years in Korea was 8.2%. By disease stage, the prevalence of chronic kidney disease was as follows: stage 1, 3.0%; stage 2, 2.7%; stage 3a, 1.9%; stage 3b, 0.4%; and stages 4-5, 0.2%. When grouped into three risk categories according to the 2012 Kidney Disease: Improving Global Outcomes guidelines, the proportions for the moderately increased risk, high risk, and very high risk categories were 6.5%, 1.2%, and 0.5%, respectively. Factors including older age, diabetes, hypertension, cardiovascular disease, body mass indexes of ≥ 25 kg/m2 and < 18.5 kg/m2, and rural residential area were independently associated with chronic kidney disease. Based on this comprehensive analysis, evidence-based screening strategies for chronic kidney disease in the Korean population should be developed to optimize prevention and early intervention of chronic kidney disease and its associated risk factors.
Adult ; Aged ; Albuminuria/complications ; Creatine/urine ; Female ; Glomerular Filtration Rate ; Humans ; Kidney/physiology ; Male ; Middle Aged ; *Nutrition Surveys ; Prevalence ; Renal Insufficiency, Chronic/*epidemiology/pathology ; Republic of Korea/epidemiology ; Risk Factors ; Severity of Illness Index

Rheumatoid arthritis (RA) is associated with significant cardiovascular (CV) morbidity and mortality. Increased urinary albumin excretion is a marker of CV risk. There are only few data on urinary albumin excretion in RA patients. Aim of the present study was to investigate urinary albumin excretion in RA patients and analyze, whether there is an association between urinary albumin excretion and vascular function as measured by the augmentation index (AIx). In a total of 341 participants (215 with RA, 126 without RA) urinary albumin-creatinine ratio (ACR) was determined and the AIx was measured. The Kolmogorov-Smirnov-test was used to cluster patient groups whose distributions of ACR can be considered to be equal. A crude analysis showed a median ACR of 6.6 mg/g in the RA group and 5.7 mg/g in patients without RA (P > 0.05). In order to account for diabetes (DM) we formed 4 distinct patient groups. Group 1: RA-/DM- (n = 74); group 2: RA+/DM- (n = 195); group 3: RA-/DM+ (n = 52); group 4: RA+/DM+ (n = 20). Clustering of these groups revealed two distinct patient groups: those without RA and DM, and those with either RA or DM or both. The latter group showed statistically significant higher ACR (median 8.1 mg/g) as the former (median 4.5 mg/g). We found no significant correlation between AIx and ACR. Urinary albumin excretion in patients with RA or DM or both is higher than in subjects without RA and DM. This can be seen as a sign of vascular alteration and increased CV risk in these patients.
Aged ; Albumins/analysis ; Albuminuria/*complications ; Arthritis, Rheumatoid/complications/*diagnosis ; Cardiovascular Diseases/etiology ; Cluster Analysis ; Creatinine/urine ; Diabetes Mellitus, Type 2/complications ; Female ; Humans ; Male ; Middle Aged ; Pulse Wave Analysis ; Risk Factors ; Vascular Stiffness/*physiology

BACKGROUND/AIMS: Advanced age is a known risk factor of poor outcomes for colitis, including Clostridium difficile infection (CDI). The present study compares the clinical outcomes of young and old patients hospitalized for CDI. METHODS: The clinical records of patients admitted from January 2007 to December 2013 with a diagnosis of CDI were analyzed. Patient baseline characteristics, clinical courses, and outcomes were compared with respect to age using a cut-off 65 years. RESULTS: Of the 241,391 inpatients registered during the study period, 225 (0.1%) with a diagnosis of CDI were included in the study. The mean patient age was 67.7 years. Seventy-two patients (32.0%) were younger than 65 years and 153 patients (68.0%) were 65 years old or more. The male to female ratio in the younger group was 0.8, and 0.58 in the older group. All 225 study subjects had watery diarrhea; six patients (8.3%) complained of bloody diarrhea in the young group and 21 patients (13.7%) in the old group (p=0.246). Right colon involvement was more common in the old group (23.5% vs. 42.7%, p=0.033). Furthermore, leukocytosis (41.7% vs. 67.3%, p=0.000), a CDI score of > or =3 points (77.8% vs. 89.5%, p=0.018), and hypoalbuminemia (58.3% vs. 76.5%, p=0.005) were more common in the old group. Failure to first line treatment was more common in the old group (17 [23.6%] vs. 58 [37.9%], p=0.034). CONCLUSIONS: Severe colitis and failure to first line treatment were significantly more common in patients age 65 years or more. More aggressive initial treatment should be considered for older CDI patients.
Adult ; Age Factors ; Aged ; Aged, 80 and over ; Albuminuria/etiology ; Anti-Bacterial Agents/therapeutic use ; Clostridium Infections/complications/*diagnosis/drug therapy ; Diarrhea/complications ; Female ; Hospitalization ; Humans ; Leukocytosis/etiology ; Male ; Middle Aged ; Retrospective Studies ; Risk Factors ; Severity of Illness Index