Stages Of Nephropathy Research Articles

Metformin attenuates renal tubulointerstitial fibrosis via upgrading autophagy in the early stage of diabetic nephropathy

This study aimed at comparing the effects of metformin on tubulointerstitial fibrosis (TIF) in different stages of diabetic nephropathy (DN) in vivo and evaluating the mechanism in high glucose (HG)-treated renal tubular epithelial cells (RTECs) in vitro. Sprague–Dawley (SD) rats were used to establish a model of DN, and the changes of biochemical indicators and body weight were measured. The degree of renal fibrosis was quantified using histological analysis, immunohistochemistry, and immunoblot. The underlying relationship between autophagy and DN, and the cellular regulatory mechanism of metformin on epithelial-to-mesenchymal transition (EMT) were investigated. Metformin markedly improved renal function and histological restoration of renal tissues, especially in the early stages of DN, with a significant increase in autophagy and a decrease in the expression of fibrotic biomarkers (fibronectin and collagen I) in renal tissue. Under hyperglycemic conditions, renal tubular epithelial cells inactivated p-AMPK and activated partial EMT. Metformin-induced AMPK significantly ameliorated renal autophagic function, inhibited the partial EMT of RTECs, and attenuated TIF, all of which effectively prevented or delayed the onset of DN. This evidence provides theoretical and experimental basis for the following research on the potential clinical application of metformin in the treatment of diabetic TIF.

The impact of central obesity on the risk of hospitalization or death due to heart failure in type 1 diabetes: a 16-year cohort study

BackgroundObesity and type 2 diabetes are well-known risk factors for heart failure (HF). Although obesity has increased in type 1 diabetes, studies regarding HF in this population are scarce. Therefore, we investigated the impact of body fat distribution on the risk of HF hospitalization or death in adults with type 1 diabetes at different stages of diabetic nephropathy (DN).MethodsFrom 5401 adults with type 1 diabetes in the Finnish Diabetic Nephropathy Study, 4668 were included in this analysis. The outcome was HF hospitalization or death identified from the Finnish Care Register for Health Care or the Causes of Death Register until the end of 2017. DN was based on urinary albumin excretion rate. A body mass index (BMI) ≥ 30 kg/m2 defined general obesity, whilst WHtR ≥ 0.5 central obesity. Multivariable Cox regression was used to explore the associations between central obesity, general obesity and the outcome. Then, subgroup analyses were performed by DN stages. Z statistic was used for ranking the association.ResultsDuring a median follow-up of 16.4 (IQR 12.4–18.5) years, 323 incident cases occurred. From 308 hospitalizations due to HF, 35 resulted in death. Further 15 deaths occurred without previous hospitalization. The WHtR showed a stronger association with the outcome [HR 1.51, 95% CI (1.26–1.81), z = 4.40] than BMI [HR 1.05, 95% CI (1.01–1.08), z = 2.71]. HbA1c [HR 1.35, 95% CI (1.24–1.46), z = 7.19] was the most relevant modifiable risk factor for the outcome whereas WHtR was the third. Individuals with microalbuminuria but no central obesity had a similar risk of the outcome as those with normoalbuminuria. General obesity was associated with the outcome only at the macroalbuminuria stage.ConclusionsCentral obesity associates with an increased risk of heart failure hospitalization or death in adults with type 1 diabetes, and WHtR may be a clinically useful screening tool.

Correlation between serum ferritin and proteinuria as marker of diabetic nephropathy stage in type 2 diabetic patients

Background: Increased iron reserves in the body have been linked to the development of type 2 diabetes, as well as diabetic nephropathy, retinopathy and vascular dysfunction. Serum ferritin has been related to the occurrence of CKD. Aim of study: Aiming to look into the link between serum ferritin and proteinuria as a diabetic nephropathy marker in type 2 diabetic patients. subjects and methods: It involved 50 individuals of the same age and gender who were split into two groups: 25 type 2 diabetic patients with proteinuria and 25 apparently healthy volunteers (hospital personnel) with no history of diabetes who served as the control group. The Enzyme-linked immunosorbent assay (ELIZA) kit for quantitative detection of human serum ferritin was used to estimate serum ferritin. Results: In the current study, serum ferritin levels in diabetics with proteinuria showed a high significant rise when compared to the control group. (p < 0.001). The comparative present study, the mean ± SD of diabetic patients with nephropathy, serum ferritin was 513.91±260.06 than that of control 133.42±186.66. The current study found a high significant positive relationship between ferritin and 24h protein in diabetic patients with nephropathy(r=0.512, p=0.009), show no significant positive association in control group (r=0.02, p=0.94). Conclusion: serum ferritin can be considered as an independent predicting marker of diabetic nephropathy as well as an excellent diagnostic marker for patients with clinical diabetic nephropathy.

Role of Klotho in Hyperglycemia: Its Levels and Effects on Fibroblast Growth Factor Receptors, Glycolysis, and Glomerular Filtration.

Hyperglycemic conditions (HG), at early stages of diabetic nephropathy (DN), cause a decrease in podocyte numbers and an aberration of their function as key cells for glomerular plasma filtration. Klotho protein was shown to overcome some negative effects of hyperglycemia. Klotho is also a coreceptor for fibroblast growth factor receptors (FGFRs), the signaling of which, together with a proper rate of glycolysis in podocytes, is needed for a proper function of the glomerular filtration barrier. Therefore, we measured levels of Klotho in renal tissue, serum, and urine shortly after DN induction. We investigated whether it influences levels of FGFRs, rates of glycolysis in podocytes, and albumin permeability. During hyperglycemia, the level of membrane-bound Klotho in renal tissue decreased, with an increase in the shedding of soluble Klotho, its higher presence in serum, and lower urinary excretion. The addition of Klotho increased FGFR levels, especially FGFR1/FGFR2, after their HG-induced decrease. Klotho also increased levels of glycolytic parameters of podocytes, and decreased podocytic and glomerular albumin permeability in HG. Thus, we found that the decrease in the urinary excretion of Klotho might be an early biomarker of DN and that Klotho administration may have several beneficial effects on renal function in DN.

Динаміка метаболічних параметрів та вмісту VEGF в сироватці крові хворих на діабетичну хворобу нирок під впливом комплексної нефропротекторної терапії

The goal of many studies around the world is to find preventive agents that may slow the progression of diabetic nephropathy in patients with type 2 diabetes mellitus at different stages of the disease, accordingly to preventing the progression of chronic kidney disease. The purpose of the work was to study the effect of complex nephroprotective therapy with the use of an inhibitor of the sodium glucose co-transporter 2 and spathogenetic therapy on metabolic parameters and the level of vasculoendothelial growth factor in blood serum of diabetic nephropathy patients at different stages of the disease. Materials and methods. 78 patients with type 2 diabetes mellitus were examined. Depending on the presence of albuminuria and glomerular filtration rate level, patients with diabetes mellitus were divided into the following groups: group I – patients with type 2 diabetes mellitus with normal glomerular filtration rate and albuminuria (n=62), group II – patients with type 2 diabetes mellitus with decreased glomerular filtration rate and albuminuria (n=16). The concentration of the vasculoendothelial growth factor was determined by enzyme-linked immunosorbent assay before and after 12 months of pathogenetic therapy. The glomerular filtration rate was calculated using the CKD EPI formula (KDIGO 2012). Patients of the first cohort received basic therapy, which included: blockers of the renin-angiotensin-aldosterone system, a coenzyme A reductase inhibitor and metformin, patients of the second cohort additionally received a sodium glucose co-transporter 2 inhibitor. Results and discussion. A decrease in vasculoendothelial growth factor levels in blood serum was found in all groups of examined patients, both under the influence of standard nephroprotective therapy, and with the use of complex treatment with an additional prescription of the sodium glucose co-transporter 2 inhibitor dapagliflozin. The highest level of response to treatment was observed in the group with the early stages of nephropathy. The therapy led to a significant improvement in the lipid spectrum of blood serum (increase of high-density lipoprotein cholesterol, decrease of total cholesterol, triglycerides and low-density lipoproteins) in all study groups. Conclusion. A decrease in serum vasculoendothelial growth factor levels against the background of an improvement in the basic clinical and laboratory parameters indicates not only an improvement kidneys function, but also a decrease in cardiovascular risk in this category of patients. The results of investigation indicate the feasibility of practical use of study vasculoendothelial growth factor serum level of diabetic nephropathy patients as an early diagnostic marker of cardiac disorders, prognosis assessment and improvement of the cardionephroprotective strategy

CYSTATIN C AS A MARKER OF KIDNEY FUNCTION IN PATIENTS WITH DIABETES MELLITUS AND PURINE METABOLISM DISORDERS

Chronic kidney disease is a pressing issue for healthcare systems over the world; its prevalence has reached 13% in Western countries. In recent years, cystatin C has been proposed as a more reliable endogenous marker of renal function, especially for the diagnosis of initial changes in glomerular filtration rate. The aim of this study is to analyze the signs of chronic kidney disease in patients with type 2 diabetes mellitus depending on the level of uricemia by using cystatin C in real clinical practice. The study included 127 patients with type 2 diabetes mellitus (mean age = 60.0 years [52.0; 66.0]; sex ratio: 55 men/ 72 women) who received oral hypoglycemic therapy. All subjects, depending on the stage of diabetic nephropathy were divided into groups: group 1 (n=80) included patients with asymptomatic diabetic nephropathy (normoalbuminuria below 30 mg/day)); group 2 (n=22) involved patients with microalbuminuria (30-300 mg/day); group 3 (n=17) included patients with proteinuria; group 4 (n=8) comprised patients with chronic renal failure. Glomerular filtration rate was calculated according to the formulas of Chronic Kidney Disease Epidemiology Collaboration taking into account the concentration of cystatin C (Chronic Kidney Disease Epidemiology Collaboration cys), by Cockcroft-Gault and Modification of Diet in Renal Disease Study using a calculator of the National Institute of Diabetes and Digestive and Kidney Diseases. In patients with type 2 diabetes mellitus, the development of chronic kidney disease is also predetermined by the following comorbid conditions as hypertension, chronic pyelonephritis, hyperuricemia, and asymptomatic urolithiasis, along with diabetic nephropathy. Glomerular filtration rate values in patients with type 2 diabetes mellitus assessed by Chronic Kidney Disease Epidemiology Collaboration cys are more reliable than those assessed by using the formulas of Cockcroft-Gault and Modification of Diet in Renal Disease Study, especially at the limit level of glomerular filtration rate ˂60 ml/min/1.73m2. In patients with type 2 diabetes mellitus, the level of circulating cystatin C is associated with body mass index, waist circumference, blood uric acid concentration and albuminuria levels. The blood concentration of cystatin C in the patients with type 2 diabetes mellitus is determined by the blood concentration of creatine and uric acid.

The expression of POMC and AgRP in brain and kidney tissues at different stages of diabetic nephropathy rats

Abstract Objective To explore the changes of proopiomelanocortin (POMC) and Agouti-Related Peptide (AgRP) expression in brain and kidney tissues under insulin intervention at different stages of diabetic nephropathy (DN) rats. Methods The male Sprague-Dawley (SD) rats of DN were treated with high-fat diet for 8 weeks and induced by intraperitoneally injection of streptozotocin (30 mg/kg) for one time. Then DN rats were also injected insulin subcutaneously at 2–5 U/(kg·24 h) from initiation of the streptozotocin. Kidney tissue, blood sample, and 24 h-urine were collected to detect the ratio of kidney/body weight, blood glucose and 24-h urinary albumin excretion rate at different stages (4, 8, 12, and 16 weeks). Immunohistochemistry assay was used to measure the expression of POMC and AgRP at different stages of DN rats. Results The DN rats were established successfully. With the progression of DN, blood glucose, 24-h urinary albumin excretion rate and kidney body weight ratio increased significantly, while decreased when insulin was injected. Immunohistochemistry showed that the expression levels of POMC were decreased gradually in brain and kidney tissues. Conversely, the expression of AgRP in kidney was highest at week 8 and then decreased gradually. The effect of insulin on normalizing POMC and AgRP expression in brain and renal tissues was also observed in DKD rats. Conclusion With the progression of DN, the expression of POMC and AgRP in kidney tissues was observed at different stages of disease, and their expressions were significantly normalized by insulin. The mechanism of in situ expression of POMC and AGRP in kidney to the progression of DN needs further investigations.

MO649DIAGNOSTIC TESTS OF NOVEL URINARY BIOMARKERS TO IDENTIFY EARLY STAGES OF NEPHROPATHY IN NON HYPERTENSIVE TYPE 2 DIABETIC MELLITUS

Abstract Background and Aims Activation of RAS and tubulointerstitial damage might be seen in pre-albuminuria stage of diabetic nephropathy. Here, diagnostic tests of urinary Angiotensinogen, Cystatin C, Neutrophil gelatinase associated lipocalin and IL 18 have been studied in pre-microalbuminuria diabetic patients. Method Total 952 Diabetic screened for Nephropathy (e-GFR ≥120&amp;ACR≥30), among them 120 cases were followed up for one year. At one year they were classified in to Hyperfiltration43, Normoalbuminuria29 and Microalbuminuria48 groups. Another 63 Diabetes without nephropathy were included as controls. Hypertension, on ACEI/ARB, e-GFR&amp;lt;60ml/min/1.73m2 and all Macroalbuminuria conditions were excluded. All were subjected to urine protein, ACR, HbA1c,e-GFR, along with urinary bio markers(IL-18, Cystatin-C, NGAL and Angiotensinogen). Comparative analysis of all groups, Diagnostic tests, correlation and logistic regression were analysed. Results Urinary IL18/Cr, Cystatin /Cr. and Angiotensiogen /Cr. levels were higher in groups of hyper filtration (13.47, 12.11 &amp; 8.43mg/g), Normoalbuminuria (9.24,11.74&amp;9.15mg/g) and microalbuminuria(11.59,14.48&amp;10.24mg/g) than controls(7.38,8.39&amp;1.26mg/g) but not NGAL/Cr. in all groups. High levels were significant in all except Cystatin/Cr. &amp; IL18/Cr. in normoalbuminuria group. The AUC, sensitivity and specificity of Angiotensinogen (0.9, 90% and 80%) ACR (0.69, 40% and 100%) and e-GFR (0.6,37 and 100%)respectively. AUC of other biomarkers viz, IL 18/cr. Cystatin/Cr and NGAL/Cr. were 0.65, 0.64 and 0.51 respectively. Angiotensinogen/Cr and IL18/Cr showed correlation with log albuminuria r-0.3 p 0.00 and r-0.28 p 0.00 respectively; NGAL with log e-GFR (r-0.28 p0.00).Multivariate logistic analysis showed Odds of contracting nephropathy is 7.5 times having higher values of Log Angio/Cr. Conclusion Urinary Angiotensinogen has higher diagnostic value than ACR and e-GFR followed by IL 18 and Cystatin to diagnose DN at the pre-albuminuric stages but not urinary NGAL.

Factors Influencing Renal Parenchymal Stiffiness in Patients with Diabetic Nephropathy.

ObjectiveGlomerulosclerosis and tubulointerstitial fibrosis are associated with lower renal parenchymal resilience. The purpose of this study is to determine the factors influencing renal resilience in patients with diabetic nephropathy (DN).MethodsWe recruited 56 healthy volunteers and 187 patients with DN. All the participants were evaluated using shear-wave elastography (SWE), and the size of their kidneys and Young’s modulus values for the parenchyma were recorded. A total of 187 patients with DN are allocated to three groups according to their urinary albumin-to-creatinine ratio: normoalbuminuric (<30 mg/g creatinine), microalbuminuric (30–300 mg/g), and macroalbuminuric (≥300 mg/g) groups. Renal resilience is compared between the stages of diabetic nephropathy and the healthy control group, and the factors affecting the stiffiness of the renal parenchyma in DN are analyzed.ResultsThe renal parenchyma is harder in participants with DN than in healthy participants (P < 0.001), and the stiffiness increases with the progression of the disease (P < 0.001). Multivariate logistic regression analysis shows that disease stage (β = 0.789, P < 0.001), duration of diabetes (β = 0.028, P < 0.001), and serum creatinine (SCr) concentration (β = 0.001, p < 0.001) influence the stiffiness of the renal parenchyma.ConclusionWe show that SWE can be used to measure changes in the stiffiness of the renal parenchyma in patients with DN. Furthermore, Young’s modulus of the renal parenchyma is related to the duration of diabetes, urinary albumin excretion, and SCr concentration. Thus, SWE can be used to objectively and non-invasively stage DN.

Quantitative Analyses of Foot Processes, Mitochondria, and Basement Membranes by Structured Illumination

IntroductionFoot process effacement and mitochondrial fission associate with kidney disease pathogenesis. Electron microscopy is the gold-standard method for their visualization, but the observable area of electron microscopy is smaller than light microscopy. It is important to develop alternative ways to quantitatively evaluate these microstructural changes because the lesion site of renal diseases can be focal.MethodsWe analyzed elastica-Masson trichrome (EMT) and periodic acid-Schiff (PAS) stained kidney sections using structured illumination microscopy (SIM).ResultsEMT staining revealed three-dimensional (3D) structures of foot process, whereas ponceau xylidine acid fuchsin azophloxine solution induced fluorescence. Conversion of foot process images into their constituent frequencies by Fourier transform showed that the concentric square of (1/4)2-(1/16)2 in the power spectra (PS) included information for normal periodic structures of foot processes. Foot process integrity, assessed by PS, negatively correlated with proteinuria. EMT-stained sections revealed fragmented mitochondria in mice with mitochondrial injuries and patients with tubulointerstitial nephritis; Fourier transform quantified associated mitochondrial injury. Quantified mitochondrial damage in patients with immunoglobulin A (IgA) nephropathy predicted a decline in estimated glomerular filtration rate (eGFR) after kidney biopsy but did not correlate with eGFR at biopsy. PAS-stained sections, excited by a 640 nm laser, combined with the coefficient of variation values, quantified subtle changes in the basement membranes of patients with membranous nephropathy stage I.ConclusionsKidney microstructures are quantified from sections prepared in clinical practice using SIM.

Diagnostic efficacy of serum and urinary netrin-1 in the early detection of diabetic nephropathy

This study aimed to assess the diagnostic value of serum and urinary netrin-1 in patients with type 2 diabetes mellitus (T2DM) at different stages of diabetic nephropathy (DN) and to...

POS-143 SYPHILIS INDUCED MEMBRANOUS NEPHROPATHY. A CASE REPORT

The rate of reported cases of syphilis is rising. More than 85% of primary and secondary syphilis occurs in men. This is attributed to increased cases of men who have sex with men. It accounts for more than 50% of all cases of primary and secondary syphilis. Renal manifestations of syphilis may present with variable degrees of proteinuria, acute nephritis with hypertension (HTN) or acute kidney injury (AKI). Pathologically, membranous or endocapillary GN may be seen. We present a case of secondary syphilis in a young man with severe nephrotic syndrome, AKI and HTN A 28 years old male patient presents to the ER with severe facial edema for 2 days and skin rash for one week. He presents mouth and genital ulcers one month ago. He has no urinary symptoms, headache, fever or arthralgia. He had multiple unprotected sexual relations with the same sex for few months. His past and family history is irrelevant, and he doesn’t take any medication. Physical examination reveals generalized edema, maculopapular rash all over the body and increased blood pressure. Chest, heart, abdominal and neurological examination in normal. nPCR testing of CSF is negative. Lab work shows severe nephrotic syndrome with 24 h proteinuria of 32.89 g and serum Albumin of 9 g/L. Urine sediment reveals hyaline, granular, waxy casts and microscopic hematuria. Serum creatinine is increased with very low natriuresis denoting prerenal factor due to severe hypovolemia secondary to nephrotic syndrome. Liver enzymes are elevated. Blood picture is normal. Immunological profile including ANCA, Anti GBM, ANA, Anti ds DNA, ENA screen, RF, C3, C4, PPE is normal. VRDL and Syphilis RPR returns positive. Serology of other sexually transmitted and infectious diseases as HIV, HBV, HCV, CMV, Toxoplasma, gonorrhea, chlamydia is negative. Renal biopsy makes the diagnosis of Membranous Nephropathy (MN) stage 1. The absence of PLA2R antibodies and IgG4 with the predominance of IgG3 favors secondary form of MN. The patient received Benzathine penicillin, Albumin/Furosemide, anti-hypertensive treatment and thromboprophylaxis. Prognosis is excellent with dramatic response to penicillin, disappearance of proteinuria and normalization of renal function and liver enzymes after 4 weeks. The presence of nephrotic syndrome with maculopapular rash occurring in a male patient with history of unprotected sexual relations with the same sex may be related to renal complication of syphilis. The most common pathology is MN. Treatment of the cause is associated with complete cure and excellent prognosis.

Glomerular filtration rate decline in T2DM following diagnosis. The Verona newly diagnosed diabetes study-12

AimsNephropathy is a complication of type 2 diabetes, with increased albuminuria and reduced glomerular filtration rate (GFR) as biomarkers. Rates of progression to end-stage-renal disease are variable among patients. In this study we have examined the GFR decline in newly diagnosed T2DM. MethodsA cohort of 410 patients with newly diagnosed T2DM and with at least four serum creatinine during the follow-up period were recruited. A linear model was used to calculate the decline in eGFR. A multivariable logistic model was used to identify independent predictors of rapid eGFR decline. ResultsAverage follow-up was 12.4 years. The eGFR change was −0.80 ± 2.23 ml/min/1.73 m2 per year. Patients were arbitrarily stratified into rapid decliners (≤-3.0 ml/min/1.73 m2 per year), moderate decliners (-2.9/-1 ml/min/1.73 m2 per year) and slow/no decliners (>-1.0 ml/min/1.73 m2 per year). Subjects in the 3 categories were 11.4%, 27.3%, and 61.3%, respectively. Albuminuria was the stronger predictor of rapid eGFR decline. ConclusionsA rapid decline in eGFR occurs in approximately 1 out of 10 newly diagnosed subjects. This rapid decline can be predicted by widely accessible clinical features, such as albuminuria. Identification of rapid decliners may help to reduce progression toward advanced stages of nephropathy.

Antiinflammatory Actions of Klotho: Implications for Therapy of Diabetic Nephropathy.

Klotho was initially introduced as an antiaging molecule. Klotho deficiency significantly reduces lifespan, and its overexpression extends it and protects against various pathological phenotypes, especially renal disease. It was shown to regulate phosphate and calcium metabolism, protect against oxidative stress, downregulate apoptosis, and have antiinflammatory and antifibrotic properties. The course of diabetes mellitus and diabetic nephropathy resembles premature cellular senescence and causes the activation of various proinflammatory and profibrotic processes. Klotho was shown to exert many beneficial effects in these disorders. The expression of Klotho protein is downregulated in early stages of inflammation and diabetic nephropathy by proinflammatory factors. Therefore, its therapeutic effects are diminished in this disorder. Significantly lower urine levels of Klotho may serve as an early biomarker of renal involvement in diabetes mellitus. Recombinant Klotho administration and Klotho overexpression may have immunotherapeutic potential for the treatment of both diabetes and diabetic nephropathy. Therefore, the current manuscript aims to characterize immunopathologies occurring in diabetes and diabetic nephropathy, and tries to match them with antiinflammatory actions of Klotho. It also gives reasons for Klotho to be used in diagnostics and immunotherapy of these disorders.

Kidney stones and moderate proteinuria as the rare manifestations of Gitelman syndrome

BackgroundGitelman syndrome (GS) is an autosomal recessive inherited salt-losing tubulopathy (SLT). Here, we describe, for the first time, a case of GS without Gitelman-like features and with concomitant kidney stones, cysts and diabetic nephropathy (DN).Case presentationWe described a male patient had a 19-year history of recurrent fatigue. From childhood, he had polydipsia and polyuria, paroxysmal tetany and palpitation. Serum biochemistry revealed chronic hypokalemia, metabolic alkalosis, normomagnesemia, mildly elevated Cr. Concomitant 24 h urine collection showed inappropriate renal potassium wasting, borderline hypercalciuria, moderate proteinuria consisting of major glomerular. Ultrasound of urinary tract showed bilateral and multiple kidney stones and cysts. Whole exome sequencing (WES) identified compound heterozygous mutations of SLC12A3. The unusual association of SLTs and glomerular proteinuria prompted us to perform a renal biopsy. Renal pathology showed renal involvement consistent with GS and early stage of diabetic nephropathy (DN). After treatment with KCl, magnesium oxide, perindopril and acarbose, the patient had been cured. The fatigue didn’t relapse.ConclusionGS had high variability of phenotype, GS may have no Gitelman-like features, kidney stones are not the exclusion criteria of GS. Renal biopsy should be warranted for GS patients with moderate to massive glomerular proteinuria.

Arteriolar hyalinosis is related to rapid GFR decline and long-standing GFR changes observed on renal biopsies in normo-microalbuminuric type 2 diabetic patients

Whether or not renal structural changes, especially arteriolar hyalinosis, are related to the rate of renal functional decline and increase in urinary albumin excretion (UAE) at the early stage of diabetic nephropathy in patients with type 2 diabetes is still unknown. Our previous study determined that arteriolar hyalinosis is an independent risk factor for low GFR. We sought to determine whether arteriolar hyalinosis is also a risk factor for rapidly progressive decline in GFR. We evaluated 22 type 2 diabetic patients with normo- or microalbuminuria who took part in the previous study, to clarify which renal histological factors were associated with changes in UAE and the glomerular filtration rate (GFR) during 11.0 ± 3.0 years of follow-up. Light and electron microscopy-based morphometric analyses were performed to quantitatively evaluate the glomerular and interstitial structural changes. In all 22 patients, the GFR was significantly decreased from baseline to follow-up, while the UAE did not change markedly between the 2 periods. After 11 ± 3 years of follow-up, the GFR was significantly lower in the rapid decliner group (annual rate of GFR decline ≥3.0%) than in the non-rapid decliner group (p = 0.017). The index of arteriolar hyalinosis (IAH) at baseline in the rapid decliners was significantly larger than in the non-rapid decliners (p = 0.015). The IAH showed a significant negative correlation with the GFR at follow-up (r = 0.50, p = 0.018) and the annual rate in the GFR decline (r = 0.47, p = 0.027) and significant positive correlations with UAE at follow-up (r = 0.46, p = 0.034) and the annual rate in the UAE increase (r = 0.57, p = 0.005). The GFR at follow-up in patients with IAH ≥2.0 was significantly decreased from baseline (p = 0.042) and significantly lower than that of the patients with IAH <2.0 (p = 0.026), which did not decrease significantly from baseline. The frequency of rapid decliners was larger in the IAH ≥2.0 than in the IAH <2.0 patients (p = 0.037). Aggravated arteriolar hyalinosis was a risk factor for a rapid GFR decline. This finding might reflect initial changes in early diabetic nephropathy.

Correlation between Serum Bone Turnover Markers and Estimated Glomerular Filtration Rate in Chinese Patients with Diabetes.

Objective Diabetes is a growing global public health concern with many significant disease complications. Multiple studies show that bone turnover markers (BTMs) are decreased in diabetes patients, indicating impaired bone metabolism in diabetes patients. A recent study also showed that in diabetes patients, BTMs are correlated with urine albumin to creatinine ratio, an indicator of nephropathy. However, whether BTMs are correlated with estimated glomerular filtration rate (eGFR) in diabetes remains unknown. This retrospective study accessed correlations between serum BTMs and eGFR in Chinese patients with diabetes and compare levels of BTMs and eGFR between diabetic patients and healthy individuals. Methods This study analyzed data from 221 diabetic patients (include type1 and type 2 diabetes) and 155 healthy individuals. Serum BTM levels and eGFR were compared between diabetic patients and healthy individuals. Pearson correlation analysis was used to assess correlations between BTMs and eGFR. Multiple logistic regression analysis adjusted for gender and age was performed to measure odd ratio (OR) and 95% confidence interval (95% CI) of BTMs on diabetes. Results Patients with diabetes had significant lower 25-hydroxyvitamin D (25(OH)D) levels (15.07 ± 6.20 ng/mL) than healthy group (17.89 ± 6.41 ng/mL) (P < 0.05). For patients with diabetes, eGFR was negatively correlated with osteocalcin (OC) (r = −0.434, P < 0.05), procollagen type 1 intact N-terminal propeptide (P1NP) (r = −0.350, P < 0.05), and β-carboxy-terminal cross-linking telopeptide of type I collagen (β-CTX) (r = −0.179, P < 0.05) levels. For healthy people, eGFR was negatively correlated with 25(OH)D (r = −0.290, P < 0.05) levels. Multiple logistic regression analysis adjusted for age and gender (mean age of diabetes was 64.9 years and the percentage of female was 66.9%, mean age of healthy people was 48.4 years and the percentage of female was 37.4%) showed that 25(OH)D (OR = 0.909, 95%CI = 0.862 − 0.959, P < 0.05) was protective factors for diabetes. Conclusions In the stage of diabetic nephropathy, bone turnover may accelerate. It is important to detect BTMs in the stage of diabetic nephropathy.

Hyperglycemic levels in early stage of diabetic nephropathy affect differentially renal expression of claudins-2 and -5 by oxidative stress

AimsThis study attempts to elicit whether the level of hyperglycemia in an early stage of diabetic nephropathy changes the renal expression of claudins-2 and -5 and to determine the involvement of glucose-induced oxidative stress. Main methodsStreptozotocin-induced type-1 and type-2 diabetic (DM1, DM2)-rat models were used. At 14-week old, the rats were placed in metabolic cages to evaluate proteinuria, creatinine clearance, and electrolyte excretion. Proximal tubules and glomeruli were isolated and analyzed by Western blot and immunofluorescence. Renal oxidative stress and metalloproteinase activities were evaluated. Key findingsWe found that claudin-5 expression in glomeruli and claudin-2 expression in proximal tubules were significantly reduced in DM1 versus DM2 model, paralleling with higher proteinuria and loss of sodium and potassium reabsorption, increased malondialdehyde levels, but lower antioxidant capacity in both models. Enzymatic activity of MMP-2 and-9 was increased in both diabetic groups versus control being higher in DM1 than DM2, suggesting higher claudin's degradation. SignificanceThe level of hyperglycemia determines the time-dependent progression to diabetic nephropathy; hyperglycemia-induced oxidative stress parallels an increase in metalloproteinases (MMPs) activities consequently affecting the integrity of claudin-2 and -5 in glomerulus and proximal tubule. Our results suggest that chronic high-glycemia levels in early stages of diabetic nephropathy decrease expression of claudins-2 and -5, increase oxidative stress, and induce MMP-activity faster than chronic middle-glycemia levels.

Clinical, Laboratory, Instrumental, Anamnestic Characteristics in Children With Type I Diabetes Mellitus and Early Stage of Diabetic Nephropathy.

Type 1 diabetes (T1D) is mainly a disease of children and young adults. Diabetic nephropathy (DN) is a common finding in diabetic patients. Microalbuminuria is the earliest clinical evidence of DN. Aim of the study was analysis of clinical, laboratory, instrumental, anamnestic examinations data in pediatric patients with T1D and early stage of DN in order to evaluate possible factors associated with early stage of DN and predictors of DN development and progression. A survey of 105 children (62 males, 43 females) with T1D and DN aged 5 to 17 years in Endocrinology unit on Clinical Pediatric Hospital №6 (Kyiv, Ukraine) done. Following clinical and biochemical characteristics found associated with an early DN: inflammatory phenotype (increased ESR, decreased albumin/globulin ratio), functional cardiovascular disorders (increased systolic blood pressure, “minor” ECG changes), signs of secondary metabolic disorders (high HbA1c, increased serum cholesterol level, increase ALAT and ASAT levels). Kidney function impairment at early stage of DN shows: higher MAU grade, GFR decline, rise in serum creatinine level as compared to T1D group. Presence of concomitant kidney and endocrine disease; positive family history found in a bigger number of patients with DN. DKA episodes number found as a factor associated with higher levels of MAU in children with DN. Patients who had microalbuminuria and more than 5 episodes of DKA/year (poorly controlled T1D) have higher progression rate to macroalbuminuria as compared to those who have less than 5 episodes of DKA/year after a 6-year follow-up study.

Does N-Carboxymethyl Lysine Serve as a Prognostic Biomarker of Diabetic Nephropathy?

Introduction: The occurrence and progression of diabetic nephropathy to end stage disease mandates an early detection of kidney damage. Glycation and oxidation injury form an essential element in the evolution of diabetic complications both microvascular and macrovascular. Aim: To study the trends in the N-Carboxymethyl lysine levels in various stages of diabetic nephropathy and assess its efficacy as a prognostic marker for diabetic nephropathy. Materials and Methods: The study included 125 Type 2 diabetic individuals- 45 patients with normoalbuminuria, 40 patients having microalbuminuria and 40 with macroalbuminuria {based on the Albumin-Creatinine Ratio (ACR)}. Forty five non-diabetic healthy individuals were included as a control group. Serum N-carboxymethyl lysine quantification was done for all the study participants and compared and correlated with other parameters across various groups. Results: The fasting and postprandial sugar, glycosylated haemoglobin, triglycerides, duration of diabetes, systolic and diastolic blood pressure, Body Mass Index (BMI), all were strong risk factors for Diabetic Kidney Disease (DKD) progression which significantly correlated positively with microalbumin and urine ACR (uACR) and negatively with Glomerular Filtration Rate (GFR). The serum N-carboxymethyl lysine was observed to be significantly increased as the ACR increased and in comparison to the controls, respectively (p-value &lt;0.001). The GFR showed significant negative correlation with levels of serum N-carboxymethyl lysine whereas positively correlated with fasting and postprandial sugar, glycosylated haemoglobin, triglyceride levels, duration of diabetes, systolic and diastolic blood pressure, BMI, microalbumin and uACR. Conclusion: N-carboxymethyl lysine in serum can serve as an early marker for diabetic nephropathy and its progression and severity.