Degree Of Proteinuria Research Articles

Changes of calcium and phosphorus levels and the correlation analysis in patients with type 2 diabetes mellitus and diabetic nephropathy

Objective To analyze serum calcium and phosphorus levels and its related factors of clinical type 2 diabetes mellitus(T2DM) with overt diabetic kidney disease(T2-dDKD). Methods Ninety cases of T2DM patients according to K/DOQI Recommendations in 2007 were selected as the study subjects.Based on the patients’ 2 times mean urinary albumin/creatinine ratio(ACR), these people were divided into three groups, namely Normal albuminuria group(30 patients, ACR 300 mg/gCr). Thirty cases of healthy at the same period were selected as the Control group.Serum calcium, phosphorus, hs-CRP, IL-6, HbA1c were detected.And glomerular filtration rate(eGFR) was calculated. Results The eGFR in Normal albuminuria group was more higher than other groups(P<0.05), the eGFR of Microalbuminuria group was significantly lower than other groups(P<0.05). Subgroups of T2DM with different albuminuria presence and severity, duration was also different between the groups, the more albumin in urine, the longer its duration.The contents of HbA1c in the groups of varying degrees of albuminuria increased as urinary albumin aggravation(HbA1c was (8.87±2.44)%, (9.27±2.74)%, (11.04±2.86)% respectively, P<0.05), but there was not statistically significant between Microalbuminuria group((9.27±2.74)%) and Normal albuminuria group((8.87±2.44)%). Compared with Control group, in subgroups of T2DM, serum calcium was decreased((2.22±0.19) mmol/L, (2.16±0.14) mmol/L, (2.13±0.18) mmol/L, and the Contorl group was (2.32±0.11) mmol/L, P<0.05), and serum phosphorus((1.16±0.31) mmol/L, (1.42±0.52) mmol/L, (1.98±0.58) mmol/L, and the Control group was (1.08±0.28) mmol/L), hs-CRP((4.82±0.89) mmol/L, (8.46±2.85) mmol/L, (13.09±3.49) mmol/L, and the Control group was (2.46±0.48) mmol/L), IL-6((10.32±4.19) pg/L, (14.78±4.34) pg/L, (16.67±6.62) pg/L, and the Control group was (7.03±2.15) pg/L) were increased(P<0.05). In subgroups of T2DM, hs-CRP was significantly increased with the increase of the serum albumin((4.82±0.89) mmol/L, (8.46±2.85) mmol/L, (13.09±3.49) mmol/L, P<0.05), there were no statistical significance about blood phosphorus among Macroalbuminuria group(1.98±0.58) mmol/L), control group((1.08±0.28) mmol/L), normal albuminuria group((1.16±0.31) mmol/L) and albumin urinary group(1.42±0.52) mmol/L). Serum phosphorus in Microalbuminuria group were positively correlated with hs-CRP, IL-6, HbA1c(r=0.431, 0.384, 0.517 respectively, P<0.05). Serum phosphorus in Macroalbuminuria group were positively correlated with hs-CRP, IL-6, HbA1c(r=0.825, 0.622, 0.683 respectively, P<0.01), but negatively with eGFR(r=0.600, P<0.01). Conclusion Serum phosphorus metabolism is abnormal in patients with diabetic nephropathy, hs-CRP, IL-6, and HbA1c are the related factors influencing the progression of serum phosphorus in patients with diabetic nephropathy. Key words: Diabetic kidney disease; Calcium; Phosphorus; High sensitive C reactive protein; Interleukin 6

Decreased expression of circulating microRNA-126 in patients with type 2 diabetic nephropathy: A potential blood-based biomarker.

Circulating microRNAs (miRNAs) have been proposed as promising biomarkers for multiple diseases. miR-126 is reported to be associated with type 2 diabetes mellitus (T2D), diabetic nephropathy (DN) and end stage renal disease. The aim of this study was to investigate the expression of circulating miR-126 and to assess its potential as a blood-based biomarker for DN in T2D patients. In 52 patients with T2D without history of DN (with noromoalbuminuria), 50 patients with T2D and DN (29 with microalbuminuria and 21 with macroalbuminuria), and 50 non-diabetic healthy controls, the expression of circulating miR-126 in peripheral whole blood was evaluated by quantitative polymerase chain reaction. The expression levels of circulating miR-126 were significantly decreased in T2D patients and further decreased in DN patients compared with those in the controls. Multivariate logistic regression analysis confirmed the independent association of lower miR-126 levels with T2D [adjusted odds ratio (OR), 0.797; 95% confidence interval (CI), 0.613-0.960] and DN (adjusted OR, 0.513; 95% CI, 0.371-0.708). miR-126 levels were associated with the degree of albuminuria and showed significantly low expression in DN patients with microalbuminuria (adjusted OR, 0.781; 95% CI; 0.698-0.952) and further lower expression in DN patients with macroalbuminuria (adjusted OR, 0.433; 95% CI, 0.299-0.701), respectively compared with T2D patients with normoalbuminuria. miR-126 levels negatively correlated with albuminuria positively with glomerular filtration rate (P<0.05), and in addition, negatively correlated with fasting glucose, glycated hemoglobin, triglyceride and LDL (P<0.05). Stepwise multiple regression analysis identified albuminuria as a significant predictor of miR-126 (P<0.001). miR-126 in peripheral blood yielded area under the receiver operating characteristic curves of 0.854 (95% CI, 0.779-0.929) and 0.959 (95% CI, 0.916-1.000) in the differentiation of DN patients from T2D patients and DN patients from non-diabetic controls respectively. These data suggest that decreased expression of circulating miR-126 is associated with the development of DN in T2D patients, and may be a promising blood-based biomarker for DN risk estimation.

Idiopathic membranous nephropathy combined with IgA nephropathy––two cases report and literature review

Objectives To describe the clinical and pathological characteristics of idiopathic membranous nephropathy combined with IgA nephropathy, and guide clinical treatment. Methods Two patients were confirmed to have idiopathic membranous nephropathy combined with IgA nephropathy by clinical characteristics and renal pathology(light microscope、immunofluorescence、electron microscope). We analyzed the clinical and pathological data and reviewed literature. Results Two patients were all young male, 44 and 38 years old. Blood pressure and renal function of two patients were normal. One patient had nephritic syndrome and microscopic hematuria, the other had asymptomatic proteinuria. Two patients were excluded secondary kidney disease. The treatment of idiopathic membranous nephropathy combined with IgA nephropathy was based on degree of albuminuria, and treated with good results. Conclusions Idiopathic membranous nephropathy combined with IgA nephropathy has low incidence, and hasn't special clinical manifestation.It has the pathological characteristics of membranous nephropathy and IgA nephropathy. Clinical manifestation more like membranous nephropathy. Individualization therapy is very essential. Key words: Glomerulonephritis, Membranous; Glomerulonephritis, IGA

Role of matrix metalloproteinase-9 in chronic kidney disease: a new biomarker of resistant albuminuria

Resistant albuminuria, developed under adequate chronic blockade of the renin-angiotensin system, is a clinical problem present in a small number of patients with chronic kidney disease (CKD). The mechanism underlying this resistant albuminuria remains unknown. Matrix metalloproteinases (MMPs) are involved in the pathophysiology of cardiovascular and renal diseases. In the present study we tested the role of MMPs in resistant albuminuria. First we evaluated gelatinase MMP-2 and MMP-9 activity by zymography in the Munich Wistar Frömter (MWF) rat, a model of progressive albuminuria, and subsequently in patients with resistant albuminuria. Markers of oxidative stress were observed in the kidneys of MWF rats, together with a significant increase in pro-MMP-2 and active MMP-9 forms. These changes were normalized together with reduced albuminuria in consomic MWF-8(SHR) rats, in which chromosome 8 of MWF was replaced with the respective chromosome from spontaneously hypertensive rats. The MMP-2 and MMP-9 protein levels were similar in patients with normal and resistant albuminuria; however, high circulating levels of collagen IV, a specific biomarker of tissue collagen IV degradation, were observed in patients with resistant albuminuria. These patients showed a significant increase in gelatinase MMP-2 and MMP-9 activity, but only a significant increase in the active MMP-9 form quantified by ELISA, which correlated significantly with the degree of albuminuria. Although the expression of the tissue inhibitor of MMP-9 (TIMP)-1 was similar, a novel AlphaLISA assay demonstrated that the MMP-9-TIMP-1 interaction was reduced in patients with resistant albuminuria. It is of interest that oxidized TIMP-1 expression was higher in patients with resistant albuminuria. Therefore, increased circulating MMP-9 activity is associated with resistant albuminuria and a deleterious oxidative stress environment appears to be the underlying mechanism. These changes might contribute to the progression of CKD in these patients.

Association between albuminuria and abnormal cardiac findings in patients with type 2 diabetic nephropathy: role of urine albumin excretion

Background Diabetic patients have higher morbidity and mortality from cardiovascular diseases compared with nondiabetic patients, particularly in the case of patients with high urinary albumin excretion (UAE). The main aims of our study were to detect abnormal cardiac findings in patients with type 2 diabetic nephropathy (DN) and its relation to increased levels of UAE. Patients and methods Our descriptive cross-sectional study consisted of 105 diabetic patients with documented DN who attended the diabetic outpatient clinic of the Internal Medicine Department, Assiut University Hospital, and underwent routine investigation, glycated hemoglobin (HbA1c), 24 h UAE, and transthoracic echocardiography. Results We evaluated 105 patients with type 2 DN (56 men and 49 women) who were divided into two groups: group I included those with microalbuminuria (39%) (age: 54.3 ± 14.4 years) and group II included those with macroalbuminuria (61%) (age: 59.7 ± 7.9 years). There was a significant relationship between the degree of albuminuria and occurrence of left ventricular hypertrophy and segmental wall motion abnormality in both groups (P Conclusion Our data indicate a possible link between abnormal cardiac findings and progression of DN. We suggest that assessment of cardiac morbidity by means of echocardiography in patients with DN be mandatory for early preventive strategies.

The landscape of treatment of chronic kidney disease in hereditary ATTR amyloidosis

Hereditary transthyretin amyloidosis (ATTR) is an autosomal dominant disease, caused by mutations in the TTR gene, the most prevalent being V30M. Although each TTR variant has a different involvement, peripheral neuropathy and cardiomyopathy are predominant. Kidney deposits are well recognized since the original description of the disease as well as a renal phenotype is also likely. Kidney involvement with proteinuria and progressive renal failure is a major cause of morbidity and mortality in ATTR amyloidosis. However, kidney impairment is not as common as in AA or AL amyloidosis. Epidemiological studies from Portugal and Sweden reveal that approximately one third of the patients display varying degrees of albuminuria and renal dysfunction. Dialysis improves the prognosis and survival, but morbidity and mortality are higher than in other populations given this treatment. The low level of proteinuria or slight renal impairment does not suppose a so heavy glomerular and vascular deposition of amyloid as in ATTR, particularly in V30M mutation. Moreover, severity of renal amyloid deposition did not consistently parallel that of myelinated nerve fiber loss, with dissociation between kidney and neurological involvement. These are pitfalls that motive troublesome criteria for therapy in ATTR nephropathy. Twenty five years ago, liver transplantation (LT) was introduced as a treatment of ATTR, since this suppresses the production of circulating mutant TTR and theoretically stops the amyloid formation and disease progression, but uncertainties remain about its role on kidney deposits. Renal dysfunction pre LT and acute renal injury post LT are risk factors for chronic renal disease development after LT. The approach for stage 4 or 5 kidney disease remains the combined or sequential liver-kidney transplantation in eligible patients. However, in the majority of patients, hemodialysis is the unique option even in the presence of a well-functioning liver graft. Tafamidis, a TTR stabilizing drug, was described as having a benefit effect on albuminuria and renal function. Non-steroidal anti-inflammatory drugs showed efficacy stabilizing ATTR in early forms of amyloid neuropathy. However, studies with diflunisal noted decline in eGFR even with exclusion of patients with significant renal impairment. RNA interference (RNAi) is an endogenous cellular mechanism for controlling gene expression with application to ATTR neuropathy. The therapeutic value in kidney disease with successfully silenced intraglomerular genes in mouse models was proved, raising the possibility of a future role for renal ATTR amyloidosis. Antisense oligonucleotides are also under clinical trials; renal epithelial cells efficiently take up oligonucleotides without apparent degradation, rendering the kidney an excellent target for site-directed antisense therapy, but also a site of antisense toxicity. Other several natural products that inhibit TTR amyloid fibril formation where progressively investigated to stop neuropathy, but the specificity for renal disease was never evaluated. Until now, doubts remain about the role of new therapies in nephropathy, if there are preferential indications for a specific one and if dialysis patients should be included in a particular treatment.

Caveolae may enable albumin to enter human renal glomerular endothelial cells.

Caveolae on human renal glomerular endothelial cells (HRGECs) are increased in glomerular disease and correlate with the degree of albuminuria. To assess the mechanism by which caveolae contribute to albuminuria, we investigated whether albumin enters into HRGECs through caveolae. HRGECs were incubated with Alexa Fluor 488 labeled BSA or transferrin, followed by immunofluorescence localization with antibody to caveolin-1 (Cav-1), the main structural protein of caveolae, or clathrin, the major structural protein of clathrin coated pits, to assess whether BSA colocalized with Cav-1. HRGECs were also incubated with albumin and caveolae disrupting agents, including methyl beta cyclodextrin (MBCD) and nystatin, to determine whether disrupting caveolae interfered with albumin endocytosis into HRGECs. HRGECs were also incubated with albumin after transfection with Cav-1 small interfering RNAs (siRNAs). Labeled BSA colocalized with Cav-1, but not with clathrin. In contrast, labeled transferrin colocalized with clathrin, but not with Cav-1. Incubation of HRGECs with MBCD or nystatin, or transfection with Cav-1 siRNA, significantly reduced the intracellular amounts of albumin and Cav-1, relative to normal HRGECs, as shown by western blotting and immunofluorescence. These findings indicate that albumin enters HRGECs through the caveolae, suggesting that caveolae play an important role in the pathogenesis of albuminuria by providing a pathway through which albumin can enter glomerular endothelial cells.

Neutrophil gelatinase-associated lipocalin and Cathepsin L as early predictors of kidney dysfunction in children with type 1 diabetes.

The aim of this study was to evaluate serum levels and urinary excretion of neutrophil-gelatinase associated lipocalin (respectively sNGAL and uNGAL) and urinary excretion of Cathepsin L (uCathL) in children with type 1 diabetes mellitus (DM1) who presented normoalbuminuria and the estimated glomerular filtration rate (eGFR) above 90 mL/min/1.73 m2. The study group consisted of 63 children with a diabetes duration of 5.16 ± 3.39 years. The degree of albuminuria was based on urine albumin-to-creatinine ratio (ACR), while eGFR was based on serum cystatin C. Glomerular hyperfiltration (GH) was defined as an eGFR value above 135 mL/min/1.73 m2. Children with DM1 showed significantly higher concentrations of uNGAL, and lower sNGAL and uCathL. Significant changes of uNGAL and uCathL levels were even found in children without GH and with optimal glycaemic control (HbA1c < 7.5%). Positive correlations between uNGAL, ACR and eGFR were shown, as well as between uCathL and eGFR. Significant changes in the concentration of markers of early kidney injury: sNGAL, uNGAL, and uCathL, can occur in children with DM1 and normoalbuminuria. The changes of uNGAL and uCathL can be even found in children without GH and with optimal glycaemic control. The earliest signs of diabetic kidney dysfunction seem to result from tubular damage.

Urinary Angiotensin Converting Enzyme 2 Increases in Patients With Type 2 Diabetic Mellitus

Background/Aims: Angiotensin converting enzyme 2 (ACE2) is highly expressed in the kidney and recognized to be renoprotective by degrading Angiotensin II to Angiotensin (1-7) in diabetic nephropathy. However, little is known about the role of urinary ACE2 (UACE2) in diabetes. The present study was performed to evaluate UACE2 levels in type 2 diabetic patients with various degrees of albuminuria and its associations with metabolic parameters. The effect of RAS inhibitors on UACE2 excretion was also assessed. Methods: A total of 132 type 2 diabetic patients with different degrees of albuminuria and 34 healthy volunteers were studied. UACE2 levels and activity were measured. Results: Compared to healthy controls, UACE2 to creatinine (UACE2/Cr) levels were significantly increased in both albuminuric and non-albuminuric diabetic patients. UACE2/Cr levels were much higher in hypertensive diabetic patients compared with their normotensive counterparts and treatment with RAS inhibitors markedly attenuated the augmentation. Furthermore, UACE2/Cr was positively correlated with fasting blood glucose, hemoglobin A1C (HbA1C), triglyceride, and total cholesterol. In multiple regression analysis, UACE2/Cr was independently predicted by HbA1C and RAS inhibitors treatment. Conclusions: UACE2 increased in type 2 diabetic patients with various degrees of albuminuria and RAS inhibitors suppresses UACE2 excretion. UACE2 might potentially function as a marker for monitoring the metabolic status and therapeutic response of RAS inhibitors in diabetes.

Tumor Necrosis Factor-Alpha and 8-Hydroxy-2'-Deoxyguanosine are Associated with Elevated Urinary Angiopoietin-2 Level in Type 2 Diabetic Patients with Albuminuria

Background/Aims: We previously showed that urine and serum Angiopoietin-2 (Ang-2) levels increased significantly with the degree of albuminuria in diabetes patients, but the reasons remain unclear. Consequently we aimed to determine whether there was an association between Ang-2, inflammatory cytokines (TNF-α and IL-18) and reactive oxygen species (8-OHdG and SOD) in type 2 diabetes patients with albuminuria. Methods: This retrospective study evaluated 113 patients with type 2 diabetes and normoalbuminuria, microalbuminuria, or macroalbuminuria and 30 healthy controls. Serum and urine TNF-α, IL-18 and 8-OHdG levels were measured by ELISA. Superoxide dismutase (SOD) activity was determined by spectrophotometry. Results: Serum and urine TNF-α, IL-18 and 8-OHdG levels increased significantly with the degree of albuminuria, and were positively correlated with increased Ang-2. In contrast, SOD activity decreased with the degree of albuminuria and was negatively correlated with Ang-2. Multivariable linear regression analysis revealed that serum Ang-2 level was independently associated with serum levels of TNF-α (P<0.001), 8-OHdG (P=0.001), and IL-18 (P=0.003). Urinary Ang-2 level was independently associated with urinary TNF-α (P<0.001) and 8-OHdG (P=0.004) levels. Conclusion: TNF-α and 8-OHdG are associated with elevated urinary Angiopoietin-2 levels in type 2 diabetic patients with albuminuria.

Urinary angiopoietin-2 is associated with albuminuria in patients with type 2 diabetes mellitus.

Aims. To evaluate the levels of angiopoietin-1 (Ang-1), Ang-2, and vascular endothelial growth factor (VEGF) in serum and urine, and their association with albuminuria in patients with type 2 diabetes mellitus. Methods. In 113 type 2 diabetic patients with normoalbuminuria, microalbuminuria, and macroalbuminuria and 30 healthy controls, the levels of Ang-1, Ang-2, and VEGF in serum and urine were measured by enzyme-linked immunosorbent assay (ELISA). Results. Urinary and serum levels of Ang-2 were significantly higher in diabetic patients with normoalbuminuria than in healthy controls. Increased urinary Ang-2 level was positively associated with the degree of albuminuria. Urinary Ang-1 levels were significantly higher in normoalbuminuria patients and lower in macroalbuminuria patients than in controls. The levels of urinary VEGF increased in the albuminuria subgroup, though serum levels of Ang-1 and VEGF did not change. Urinary Ang-2 levels were correlated positively with albuminuria and negatively with glomerular filtration rate (GFR). Stepwise multiple regression analysis identified albuminuria (P < 0.001) and GFR (P = 0.001) as significant predictors of urinary Ang-2. Conclusions. Our data suggest that urinary Ang-2 is stepwise increased with renal damage in patients with type 2 diabetes mellitus and is associated with albuminuria.

Proteins from the 18 glycosyl hydrolase family are associated with kidney dysfunction in patients with diabetes type 2

Objectives: To investigate chitotriosidase (CHIT1) activity and chitinase-3-like protein 1 (YKL-40) concentration in plasma of type 2 diabetic patients and evaluate their relationship with kidney dysfunction.Materials and methods: 94 diabetic subjects and 33 controls were enrolled in the study. Plasma CHIT1 activity and YKL-40 concentration were measured along with routine laboratory parameters.Results: Levels of CHIT1 and YKL-40 in plasma of type 2 diabetic patients increased progressively with the degree of albuminuria. CHIT1 discriminated normoalbuminuric subjects from those with abnormal albuminuria better than YKL-40.Conclusions: CHIT1represent a supportive biomarker connected with development of diabetic vascular complications, especially kidney dysfunction.

Soluble urokinase plasminogen activator receptor levels are elevated and associated with complications in patients with type 1 diabetes.

Soluble urokinase plasminogen activator receptor (suPAR) is a marker of inflammation and endothelial dysfunction. We investigated the associations between suPAR and diabetes, including diabetes duration and complications, in patients with type 1 diabetes. From 2009 to 2011, 667 patients with type 1 diabetes and 51 nondiabetic control subjects were included in a cross-sectional study at Steno Diabetes Center, Gentofte, Denmark. suPAR levels were measured with an enzyme-linked immunosorbent assay. The investigated diabetic complications were cardiovascular disease (CVD: previous myocardial infarction, revascularisation, peripheral arterial disease and stroke), autonomic dysfunction (heart rate variability during deep breathing <11 beats min(-1) ), albuminuria [urinary albumin excretion rate (UAER) ≥30 mg/24 h] or a high degree of arterial stiffness (pulse wave velocity ≥10 m s(-1) ). Analyses were adjusted for gender, age, systolic blood pressure, estimated glomerular filtration rate, UAER, glycated haemoglobin (HbA1c ), total cholesterol, body mass index, C-reactive protein, antihypertensive treatment and smoking. Soluble urokinase plasminogen activator receptor levels were lower in control subjects versus all patients, in control subjects versus normoalbuminuric patients (UAER <30 mg/24 h), in normoalbuminuric patients with short (<10 years) versus long diabetes duration and were increased with degree of albuminuria (adjusted P < 0.001 for all). Furthermore, suPAR levels were higher in patients with versus without CVD (n = 144; 21.3%), autonomic dysfunction (n = 369; 59.2%), albuminuria (n = 357; 53.1%) and a high degree of arterial stiffness (n = 298; 47.2%) (adjusted P ≤ 0.024). The adjusted odds ratio (95% confidence interval) values per 1 ln unit increase in suPAR were as follows: 2.5 (1.1-5.7) for CVD: 2.7 (1.2-6.2) for autonomic dysfunction; 3.8 (1.3-10.9) for albuminuria and 2.5 (1.1-6.1) for a high degree of arterial stiffness (P ≤ 0.039). The suPAR level is higher in patients with type 1 diabetes and is associated with diabetes duration and complications independent of other risk factors. suPAR is a potential novel risk marker for the management of diabetes.

The NLRP3/ASC inflammasome promotes T-cell-dependent immune complex glomerulonephritis by canonical and noncanonical mechanisms

Interleukin (IL)-1β contributes to renal injury in immune complex glomerulonephritis. However, production of mature IL-1β depends on activation of the inflammasome that cleaves pro-IL-1β into its secretable form. A functional role of the NLRP3-containing inflammasome, which responds to various endogenous danger signals, was found in tubulointerstitial nephropathies, but its function in glomerular disease has not been established. To determine whether NLRP3 and its adapter molecule ASC contribute to glomerulonephritis, we induced T-cell-dependent autologous nephrotoxic serum nephritis in Nlrp3- and Asc-deficient mice. Renal expression of NLRP3/ASC inflammasome components and pro-IL-1β increased during nephrotoxic serum nephritis and was abundant in renal dendritic cells. This was associated with renal production of mature IL-1β, indicating inflammasome activation. Nlrp3 and Asc deficiency significantly attenuated glomerular injury, renal leukocyte infiltration, and T-cell activation. Production of mature IL-1β was abrogated in Asc-deficient mice, consistent with a loss of inflammasome-dependent IL-1β activation. Surprisingly, renal IL-1β secretion remained intact in Nlrp3-deficient mice, indicating noncanonical pro-inflammatory effects of NLRP3 in autologous nephrotoxic serum nephritis. This may include NLRP3-mediated glomerular release of pro-inflammatory high-mobility group box 1 protein as a noncanonical function of NLRP3/ASC in glomerulonephritis. Thus, therapeutic blockade of the NLRP3/ASC/IL-1β axis may be beneficial in glomerulonephritis.

The Total Urine Protein-to-Creatinine Ratio Can Predict the Presence of Microalbuminuria

BackgroundThe Kidney Disease: Improving Global Outcomes chronic kidney disease (CKD) guidelines recommend that CKD be classified based on the etiology, glomerular filtration rate (GFR) and degree of albuminuria. The present study aimed to establish a method that predicts the presence of microalbuminuria by measuring the total urine protein-to-creatinine ratio (TPCR) in patients with cardiovascular disease (CVD) risk factors.Methods and ResultsWe obtained urine samples from 1,033 patients who visited the cardiovascular clinic at St. Luke's International Hospital from February 2012 to August 2012. We measured the TPCR and the urine albumin-to-creatinine ratio (ACR) from random spot urine samples. We performed correlation, receiver operating characteristic (ROC) curve, sensitivity, and subgroup analyses. There was a strong positive correlation between the TPCR and ACR (R2 = 0.861, p<0.001). A ROC curve analysis for the TPCR revealed a sensitivity of 94.4%, a specificity of 86.1%, and an area under the curve of 0.903 for detecting microalbuminuria for a TPCR cut-off value of 84 mg/g of creatinine. The subgroup analysis indicated that the cut-off value could be used for patients with CVD risk factors.ConclusionsThese results suggest that the TPCR with an appropriate cut-off value could be used to screen for the presence of microalbuminuria in patients with CVD risk factors. This simple, inexpensive measurement has broader applications, leading to earlier intervention and public benefit.

Investigation of Urinary Angiotensinogen in Renal Transplant Recipients

BackgroundRecent studies have indicated that angiotensinogen (AGT) is also locally produced in the kidney and that urinary AGT is a marker of local renal renin-angiotensin system activation. Because urinary AGT levels are significantly higher in patients with chronic kidney disease (CKD) than in patients without CKD and correlate with urinary albumin and other levels, urinary AGT is increasingly recognized as a marker for CKD monitoring, prognosis, and treatment. In this study, we investigated urinary AGT levels in renal transplant recipients. MethodsAmong the patients who were treated as outpatients at the Department of Urology of Osaka City University Hospital from March 2012 to April 2013, 146 stable renal transplant recipients and 50 donors who gave informed consent were studied. Urinary AGT and creatinine (Cr) levels were measured. The urinary AGT-to-Cr ratio was calculated, and its correlation with clinical parameters was examined. ResultsThe urinary AGT-to-Cr ratio of the renal transplant recipients was significantly higher than that of the renal transplant donors (P = .0143). Furthermore, the urinary AGT-to-Cr ratio had a significantly positive correlation with the urinary albumin-to-Cr ratio (ACR; r = 0.39, P < .0001), while on the other hand, it had a significantly negative correlation with estimated glomerular filtration rate (eGFR; r = −0.31, P = .0002). Multiple linear regression analysis of factors associated with eGFR showed that urinary AGT was a significant and independent factor after adjusting for age, sex, and ACR. ConclusionsOur results indicated that urinary AGT levels were elevated in renal transplant recipients. In addition, urinary AGT significantly correlated with renal function and degree of albuminuria.

Effects of Melanocortin 1 Receptor Agonists in Experimental Nephropathies

Nephrotic syndrome, characterized by massive proteinuria, is caused by a large group of diseases including membranous nephropathy (MN) and focal segmental glomerulosclerosis (FSGS). Although the underlying mechanisms are beginning to unravel, therapy is unspecific and far from efficient. It has been suggested that adrenocorticotropic hormone (ACTH) has beneficial effects in patients with MN and possibly in other nephrotic diseases. We have previously reported that ACTH may act directly on podocytes through the melanocortin 1 receptor (MC1R). In the present study, we evaluate the effect of highly specific MC1R agonists in two different nephrotic disease models. Experimental MN: Passive Heymann nephritis (PHN) was induced in rats that were treated for four weeks with MS05, a selective MC1R agonist, or saline. The degree of albuminuria was significantly reduced over time and the effect was sustained one week after treatment withdrawal (p<0.05). Experimental FSGS: Based on a dose-response study, two doses of adriamycin were used for induction of nephropathy in Balb/c mice. Mice were treated with either a synthetic MC1R agonist (BMS-470539), with α-melanocyte stimulating hormone (α-MSH) or with saline. There was no beneficial effect of treatment. In summary, MC1R agonists reduce albuminuria and improve morphology in experimentally induced MN whereas they have no effect in experimental FSGS. The results illustrate the differences in these podocytopathies in terms of signaling mechanisms underlying proteinuria, and progression of disease.

Short-Term Prognosis of Living-Donor Kidney Transplantation From Hypertensive Donors With High-Normal Albuminuria

High-normal albuminuria (HNA) is an independent predictor of cardiovascular risk in the general population. Although hypertensive donor (HTD) candidates with HNA were considered acceptable donors by the Amsterdam Forum 2004, the transplant prognosis of HTDs with HNA has not been determined. Therefore, we investigated the transplant prognosis of HTDs with HNA. We retrospectively analyzed 52 adult living-donor kidney transplants performed at Kagawa University Hospital. HNA was defined as albuminuria of 15 to 30 mg/g Cr. Changes in kidney function of donors and recipients were assessed up to 2 years after transplantation. Overall, 38 donors were normotensive and 14 were hypertensive. Nine of 14 HTDs exhibited HNA before donation. More HTDs with HNA had arteriosclerotic vasculopathy or glomerulosclerosis than did normotensive donors (NTDs). Hypertension and the degree of albuminuria did not affect the donors' posttransplantation kidney function. The risk of discompensatory changes in kidney function after donation was significantly higher in HTDs with HNA than in NTDs (odds ratio, 10.5; 95% confidence interval, 1.51-72.9; P=0.02). In multivariate analysis, the coexistence of hypertension and HNA was not significantly associated with discompensatory changes after donation (adjusted odds ratio, 6.04; 95% confidence interval, 0.19-192; P=0.31). Recipients of HTDs with HNA had similar allograft survival rates but lower allograft function compared with recipients of NTDs. Although further studies are needed to confirm our results, the short-term prognosis of living-donor kidney transplantation was similar between HTDs with HNA and NTDs.

Kidney function, albuminuria and life expectancy.

BackgroundLower estimated glomerular filtration rate is associated with reduced life expectancy. Whether this association is modified by the presence or absence of albuminuria, another cardinal finding of chronic kidney disease, is unknown.ObjectiveOur objective was to estimate the life expectancy of middle-aged men and women with varying levels of eGFR and concomitant albuminuria.DesignA retrospective cohort study.SettingA large population-based cohort identified from the provincial laboratory registry in Alberta, Canada.ParticipantsAdults aged ≥30 years who had outpatient measures of serum creatinine and albuminuria between May 1, 2002 and March 31, 2008.MeasurementsPredictor: Baseline levels of kidney function identified from serum creatinine and albuminuria measurements. Outcomes: all cause mortality during the follow-up.MethodsPatients were categorized based on their estimated glomerular filtration rate (eGFR) (≥60, 45–59, 30–44, and 15–29 mL/min/1 · 73 m2) as well as albuminuria (normal, mild, and heavy) measured by albumin-to-creatinine ratio or urine dipstick. The abridged life table method was applied to calculate the life expectancies of men and women from age 40 to 80 years across combined eGFR and albuminuria categories. We also categorized participants by severity of kidney disease (low risk, moderately increased risk, high risk, and very high risk) using the combination of eGFR and albuminuria levels.ResultsAmong men aged 50 years and with eGFR ≥60 mL/min/1.73 m2, estimated life expectancy was 24.8 (95% CI: 24.6-25.0), 17.5 (95% CI: 17.1-17.9), and 13.5 (95% CI: 12.6-14.3) years for participants with normal, mild and heavy albuminuria respectively. Life expectancy for men with mild and heavy albuminuria was 7.3 (95% CI: 6.9-7.8) and 11.3 (95% CI: 10.5-12.2) years shorter than men with normal proteinuria, respectively. A reduction in life expectancy was associated with an increasing severity of kidney disease; 24.8 years for low risk (95% CI: 24.6-25.0), 19.1 years for moderately increased risk (95% CI: 18.7-19.5), 14.2 years for high risk (95% CI: 13.5-15.0), and 9.6 years for very high risk (95% CI: 8.4-10.8). Among women of similar age and kidney function, estimated life expectancy was 28.9 (95% CI: 28.7-29.1), 19.8 (95% CI: 19.2-20.3), and 14.8 (95% CI: 13.5-16.0) years for participants with normal, mild and heavy albuminuria respectively. Life expectancy for women with mild and heavy albuminuria was 9.1 (95% CI: 8.5-9.7) and 14.2 (95% CI: 12.9-15.4) years shorter than the women with normal proteinuria, respectively. For women also a graded reduction in life expectancy was observed across the increasing severity of kidney disease; 28.9 years for low risk (95% CI: 28.7-29.1), 22.5 years for moderately increased risk (95% CI: 22.0-22.9), 16.5 years for high risk (95% CI: 15.4-17.5), and 9.2 years for very high risk (95% CI: 7.8-10.7).LimitationsPossible misclassification of long-term kidney function categories cannot be eliminated. Possibility of confounding due to concomitant comorbidities cannot be ruled out.ConclusionThe presence and degree of albuminuria was associated with lower estimated life expectancy for both gender and was especially notable in those with eGFR ≥30 mL/min/1.73 m2. Life expectancy associated with a given level of eGFR differs substantially based on the presence and severity of albuminuria.Electronic supplementary materialThe online version of this article (doi:10.1186/s40697-014-0033-6) contains supplementary material, which is available to authorized users.

Decreased Activated Protein C Levels are Inversely Associated with the Urinary Albumin Excretion Rate in Patients with Type 2 Diabetes

Activated protein C (APC) plays a vital renoprotective role against diabetic nephropathy in STZ-induced diabetic mice by inhibiting endothelial cell and podocyte apoptosis. This study aimed to examine the relationship between the degree of albuminuria and APC levels in patients with type 2 diabetes. Ninety-four patients with type 2 diabetes and 38 healthy subjects were recruited into this study. The urinary albumin concentrations of urine collected over 24 hours were measured by ELISA to evaluate the mean urinary albumin excretion rate (UAER). The HbA1c levels were determined using an HPLC assay. There was no significant difference in the APC levels between diabetic patients with normoalbuminuria and controls, although APC levels were significantly lower in diabetic patients with microalbuminuria (23.06 +/- 19.82 vs. 54.58 +/- 53.63 pg/mL, p < 0.05) or macroalbuminuria (8.06 +/- 10.09 vs. 54.58 +/- 53.63 pg/mL, p < 0.05) as compared to control subjects. In addition, in comparison to diabetic patients with normoalbuminuria, APC levels were lower in diabetic patients with microalbuminuria (23.06 +/- 19.82 vs. 55.69 +/- 31.98 pg/mL, p < 0.05) and they were the lowest in diabetic patients with macroalbuminuria (8.06 +/- 10.09 vs. 55.69 +/- 31.98 pg/mL, p < 0.05). Multivariate regression and ROC analysis found that the levels of APC and HbA1c were independent risk factors for UAER levels (R2(ad) = 0.61, f = 25.69, p < 0.01) and the value of APC < or = 41.588 pg/mL indicated elevated albuminuria in patients with type 2 diabetes. Decreased APC levels in patients with type 2 diabetes may serve as a biomarker to indicate the early development of diabetic nephropathy.