Development Of Proteinuria In Patients Research Articles

Evaluation of plasma vitamin E and development of proteinuria in hypertensive patients.

The prospective relationship between plasma vitamin E levels and proteinuria remains uncertain. We aimed to evaluate the association between baseline plasma vitamin E levels and the development of proteinuria and examine any possible effect modifiers in patients with hypertension. This was a post hoc analysis of the renal sub-study of the China Stroke Primary Prevention Trial (CSPPT). In total, 780 participants with vitamin E measurements and without proteinuria at baseline were included in the current study. The study outcome was the development of proteinuria, defined as a urine dipstick reading of a trace or ≥ 1+ at the exit visit. During a median follow-up duration of 4.4 years, the development of proteinuria occurred in 93 (11.9%) participants. Overall, there was an inverse relationship between plasma vitamin E and the development of proteinuria (per standard deviation [SD] increment; odds ratio [OR]: 0.73, 95% confidence interval [CI]: 0.55-0.96). Consistently, when plasma vitamin E was assessed as quartiles, lower risk of proteinuria development was found in participants in quartiles 2-4 (≥ 7.3 μg/mL; OR: 0.57, 95% CI: 0.34-0.96) compared to those in quartile 1. None of the variables, including sex, age, and body mass index, significantly modified the association between vitamin E and proteinuria development. There was a significant inverse association between plasma vitamin E levels and the development of proteinuria in patients with hypertension. The results were consistent among participants with different baseline characteristics.

Uremic Metabolites Are Associated with Albuminuria and Estimated Glomerular Filtration Rate (eGFR) in Sickle Cell Disease

Introduction: Chronic kidney disease (CKD) is common in patients with sickle cell disease (SCD) and is associated with increased morbidity and mortality. As albuminuria and changes in estimated glomerular filtration rate (eGFR) occur well after substantial functional and structural damage have occurred, identification of novel biomarkers which could predict the development of CKD is necessary. Previous studies have shown an increase in the level of the uremic metabolite indoxyl-sulfate (IS) in urine in patients with SCD. IS and other uremic metabolites are cleared by active secretion in kidney tubule cells and their accumulation in these cells leads to increased oxidative stress, and apoptotic and necrotic cell death. In this single center, cross-sectional study, we investigated the associations between both urinary levels of uremic toxins and biomarkers of kidney tubular injury with persistent albuminuria and eGFR in patients with SCD. Methods: The participants represent a subset of patients with HbSS or HbSβ0 thalassemia enrolled in a prospective cohort study to assess the natural history of kidney disease in SCD. We excluded patients with diabetic nephropathy, cancer, connective tissue disease, other glomerular diseases, known infection with hepatitis (B or C) or HIV, end-stage kidney disease on dialysis and who had undergone bone marrow transplantation. Participants were enrolled during routine clinic visits. Urine levels of uremic toxins, indoxyl sulfate (IS) and trimethylamine-n-oxide (TMAO), and tubular injury biomarkers, monocyte chemoattractant protein-1 (MCP-1; also called CC-chemokine ligand 2 [CCL2]) and neutrophil gelatinase-associated lipocalin (NGAL) were measured using quantitative ELISA assay. All values obtained for urine biomarkers were normalized to urine creatinine. Persistent albuminuria was defined based on at least 2 of 3 spot urine albumin/creatinine ratio (ACR) values ≥30 mg/g of creatinine or a single value ≥100 mg/g. Glomerular filtration rate was estimated using the 2009 creatinine-based Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula. As the distribution of the biomarkers were skewed, the data were log-transformed. Associations between both ACR and eGFR with each of the urine biomarkers were assessed using linear regression. Results: One hundred and sixteen subjects, 26 (22.4%; ACR - median 276.5 mg/g [IQR: 156, 802]) with persistent albuminuria (PA), and 90 (77.6%; ACR - median 13 mg/g [IQR: 6.5, 25.5]) without persistent albuminuria (non-PA) were evaluated. Subjects with PA appeared to be older and had lower hemoglobin and fetal hemoglobin levels, but higher reticulocyte counts, lactate dehydrogenase levels and systolic and diastolic blood pressures than subjects with non-PA (Table 1). Log-transformed urine levels of IS (β=0.52, 95% confidence interval [CI]: 0.08, 0.96, p=0.02), MCP-1 (β=0.65, 95% CI: 0.29, 1.01, p=0.0006) and NGAL (β=0.25, 95% CI: 0.02, 0.49, p=0.03) were positively associated with log-transformed ACR (Table 2). Log-transformed urine levels of IS (β=-8.0, 95% CI: -14.7, -1.3, p=0.02), MCP-1 (β=-11.6, 95% CI: -16.9, -6.3, p<0.0001) and NGAL (β=-6.0, 95% CI: -9.4, -2.6, p=0.0008) were inversely associated with eGFR. Log-transformed urine level of TMAO was not associated with either ACR or eGFR. Conclusion: This study demonstrates a novel association of IS with albuminuria and eGFR in patients with SCD. In addition, we confirm the association of biomarkers of tubular injury, MCP-1 and NGAL, with persistent albuminuria and eGFR in SCD. Future studies will determine whether uremic metabolites may predict the development of albuminuria in patients with SCD. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Short- and long-term treatment with angiotensin-converting enzyme inhibitors or calcium channel blockers for the prevention of diabetic nephropathy progression: A meta-analysis.

Treatments with angiotensin-converting enzyme (ACE) inhibitors or calcium channel blockers (CCBs) may delay the development of albuminuria in patients with early diabetic nephropathy. However, evidence in the literature has not been consistent. The present meta-analysis aimed to compare the short- and long-term therapeutic effects of ACE inhibitors and CCBs (when used separately) for preventing the progression of nephropathy in patients with diabetes mellitus. A comprehensive search of various databases was performed from inception until March 2015 for studies in the Chinese and English languages. Randomized controlled trials (RCTs) comparing the efficacy of ACE inhibitors with that of CCBs in patients with early diabetic nephropathy were considered. A total of 12 RCTs were included with a total of 947 patients. ACE inhibitors were indicated to be more effective in reducing the albumin excretion rate than CCBs after short-term treatments (<6 months) [mean difference (MD), 32.35; 95% confidence interval (CI), 31.62-33.07; P<0.00001]. There was no difference in serum creatinine values after treatment with either drug (MD, 8.7; 95% CI, -21.5-38.91; P=0.57). Data from six studies were used to compare long-term treatment effects (≥1 year). In terms of progression to normoalbuminuria, a marginal difference was obtained between the two drugs with better outcomes with ACE inhibitors [odds ratio (OR), 0.70; 95% CI, 0.49-1.00; P=0.05]. There was no statistically significant difference between ACE inhibitors and CCBs regarding the progression from microalbuminuria to macroalbuminuria (OR, 1.78; 95% CI, 0.82-3.87; P=0.15). In conclusion, the present study indicated that the antiproteinuric efficacy of CCBs may be less than that of ACE inhibitors after short-term treatment in patients with DN. However, both types of drugs are equally effective in reducing the progression of microalbuminuria to macroalbuminuria in the long term.

Higher Serum Asprosin Level is Associated with Urinary Albumin Excretion and Renal Function in Type 2 Diabetes.

AimWe detected whether serum asprosin levels play a role in the occurrence and development of albuminuria in patients with type 2 diabetes mellitus (T2DM), which has not been previously discussed.MethodsBased on urinary albumin/creatinine ratio (UACR), 207 T2DM patients were divided into T2DM patients with normoalbuminuria (UACR<30 mg/g), microalbuminuria (30≤UACR<300 mg/g), and macroalbuminuria (UACR≥300 mg/g). Serum asprosin levels were determined by enzyme-linked immunosorbent assay.ResultsComparatively, the serum asprosin levels in T2DM patient groups with macroalbuminuria [2.37 (1.63–3.57)] and microalbuminuria [2.10 (1.60–2.90)] were significantly increased than the normoalbuminuria group [1.59 (1.18–2.09)] (P<0.001). Importantly, the serum level of asprosin was positively correlated with UACR (r=0.304, P<0.001), creatinine (r=0.157, P=0.024), blood urea nitrogen (BUN) (r=0.244, P<0.001), and negatively with glomerular filtration rate (eGFR) (r=−0.159, P=0.022). Furthermore, multiple stepwise regression analyses showed that asprosin was significantly and independently related to UACR, BUN, DBP, and LDL-C (P<0.05). Besides, after adjustment for the confounders, the serum asprosin level was constantly and independently associated with the development of albuminuria in T2DM patients [OR (95% CI): 2.003 (1.37~2.928), P <0.001].ConclusionObviously, the serum asprosin level was independently correlated with UACR in T2DM patients, which implies circulating asprosin may play an essential role in the pathogenesis of diabetic nephropathy.

The Association of Matrix Metalloproteinases with Chronic Kidney Disease and Peripheral Vascular Disease: A Light at the End of the Tunnel?

Chronic Kidney Disease (CKD) represents a risk factor for fatal and nonfatal cardiovascular (CV) events, including peripheral vascular disease (PVD). This occurs because CKD encompasses several factors that lead to poor prognoses, mainly due to a reduction of the estimated glomerular filtration rate (eGFR), the presence of proteinuria, and the uremic inflammatory milieu. The matrix metalloproteinases (MMPs) are a group of zinc-containing endopeptidases implicated in extracellular matrix (ECM) remodeling, a systemic process in tissue homeostasis. MMPs play an important role in cell differentiation, angiogenesis, inflammation, and vascular damage. Our aim was to review the published evidence regarding the association between MMPs, PVD, and CKD to find possible common pathophysiological mechanisms. MMPs favor ECM deposition through the glomeruli, and start the shedding of cellular junctions and epithelial-mesenchymal transition in the renal tubules. MMP-2 and -9 have also been associated with the presence of systemic vascular damage, since they exert a pro-inflammatory and proatherosclerotic actions. An imbalance of MMPs was found in the context of PVD, where MMPs are predictors of poor prognoses in patients who underwent lower extremity revascularization. MMP circulating levels are increased in both conditions, i.e., that of CKD and PVD. A possible pathogenic link between these conditions is represented by the enhanced production of transforming growth factor-β that worsens vascular calcifications and atherosclerosis and the development of proteinuria in patients with increased levels of MMPs. Proteinuria has been recognized as a marker of systemic vascular damage, and this may explain in part the increase in CV risk that is manifest in patients with CKD and PVD. In conclusion, MMPs can be considered a useful tool by which to stratify CV risk in patients with CKD and PVD. Further studies are needed to investigate the causal-relationships between MMPs, CKD, and PVD, and to optimize their prognostic and predictive (in response to treatments) roles.

Contraception and CKD.

In general, nephrologists give little thought to contraception, leaving this task to other practitioners, but the significant risks associated with drugs routinely prescribed to treat kidney disease; the potential for pregnancy-associated adverse outcomes in women with CKD; and the effect that

Impact of Hyperfiltration during Early Childhood on the Natural History of Albuminuria in Pediatric Sickle Cell Anemia

Introduction: Pediatric patients with Sickle Cell Anemia (SCA) are at risk for developing albuminuria. Hyperfiltration precedes the development of albuminuria in patients with diabetes but the natural history of hyperfiltration on the progression to albuminuria has not been studied in children with SCA.Methods: We have enrolled 185 participants with HbSS or SB0 thalassemia in a prospective pediatric cohort study evaluating progression to chronic kidney disease; the mean current age of participants in this cohort is 14 years. We have abstracted 817 urine microalbumin creatinine measurements and 891 estimations of GFR (eGFR) by Cystatin C. Abnormal urine albumin/creatinine is defined as >30mg/g. We defined persistent albuminuria as two abnormal spot urine microalbumin/creatinine measurements over three consecutive measurements and intermittent albuminuria as one abnormal urine measurement with two consecutive repeat measurement as normal. We performed descriptive and univariate statistics to characterize the natural history of the development of albuminuria. Next, as standard of care definitions of hyperfiltration (>140 ml/min/1.87) are not appropriate in SCA during early childhood (4-10 years of age), we a priori defined hyperfiltration as an eGFR ≥180 ml/min/1.87. We categorized patients with hyperfiltration during early childhood if the mean eGFR was >180 ml/min/1.87. We abstracted the mean white blood cell count (WBC), hemoglobin (Hb), and SCA therapy during early childhood and performed estimates of the odds ratio and used chi-squared test to compare the proportion of those who progressed to persistent albuminuria. Finally, we performed time to event analysis to obtain the estimated Kaplan-Meier curves for participants with and without hyperfiltration and used logrank test to compare their survival distributions.Results: Among the 185 participants, 55 participants (30%) were identified with at least one episode of albuminuria and 130 patients (70%) have not yet developed an episode of albuminuria. Among the 55 participants identified with an albuminuria event, 36 participants (66%) are categorized as having persistent albuminuria while 19 patients (34%) demonstrated intermittent or only one episode of albuminuria. The mean age at the identification of a first albuminuria event was 11.0 years (range 2-18 years). Comparing patients that progressed to persistent vs intermittent albuminuria, we identified no significant differences for age at first episode of albuminuria (13.2 vs 11.9 years, p=0.3) or type of SCA modifying therapy at first episode of albuminuria (p=0.4).We identified 90 participants with eGFR obtained between 4-10 years; 39 (43%) participants were categorized with hyperfiltration and 51 participants had a mean eGFR < 180 ml/min/1.87. Nine of the 39 (23%) participants categorized with hyperfiltration have progressed to develop persistent albuminuria as compared to 3 (6%) of the 51 without hyperfiltration progressed to persistent albuminuria; hyperfiltration was associated with a 4.8 higher odds of developing persistent proteinuria. (p=0.02). The mean eGFR during early childhood was also significantly higher among participants that progressed to albuminuria (186 vs 169 ml/min/1.87, p=0.04). We identified no significant impact of mean WBC (p=0.13), mean hemoglobin (p=0.07), or SCA therapy (p=0.22) in this subset of patients on progression to persistent albuminuria. As the current age of participants impacts identifying albuminuria outcomes, we performed a time to event analysis; participants identified with hyperfiltration during early childhood develop persistent albuminuria at an earlier age than participants without persistent albuminuria (logrank p=0.004). Finally, while persistent albuminuria was significantly associated with hyperfiltration during early childhood, we did not identify a difference in eGFR between patients with and without albuminuria during adolescence (Figure 1).Conclusion: Although 30% of patients with SCA will develop an episode of albuminuria during childhood, only 19% of cohort participants developed persistent albuminuria. Early hyperfiltration is predictive for developing albuminuria and therapies should target reducing hyperfiltration in the first decade of life. DisclosuresNo relevant conflicts of interest to declare.

Overexpression of acetyl CoA carboxylase β exacerbates podocyte injury in the kidney of streptozotocin-induced diabetic mice

A single nucleotide polymorphism (SNP) within the acetyl CoA carboxylase (ACC) β gene (ACACB), rs2268388, has been shown to be associated with susceptibility to development of proteinuria in patients with type 2 diabetes. To investigate the biological roles of ACCβ in the pathogenesis of diabetic nephropathy, we examined the effects of overexpression of ACACB using podocyte-specific ACACB-transgenic mice or ACACB-overexpressing murine podocytes. Podocyte-specific ACACB-transgenic mice or littermate mice were treated with streptozotocin (STZ) to induce diabetes, and 12 weeks after induction of diabetes, we examined the expression of podocyte markers to evaluate the degree of podocyte injury in these mice. We also examined the effects of ACCβ on podocyte injury in ACACB- or LacZ-overexpressing murine podocytes. Podocyte-specific ACACB overexpression did not cause visible podocyte injury in non-diabetic mice. In STZ-induced diabetic mice, ACACB-transgenic mice showed a significant increase in urinary albumin excretion, accompanied by decreased synaptopodin expression and podocin mislocalization in podocytes, compared with wild-type mice. In cultured murine podocytes, overexpression of ACACB significantly decreased synaptopodin expression and reorganized stress fibers under high glucose conditions, but not in normal glucose conditions. The decrease of synaptopodin expression and reorganized stress fibers observed in ACACB overexpressing cells cultured under high glucose conditions was reversed by a treatment of 5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside (AICAR), activator of AMP-activated protein kinase (AMPK). The excess of ACCβ might contribute to exacerbation of podocyte injury in the kidney of an animal model for diabetes mellitus, and the AMPK/ACCβ pathway may be a novel therapeutic target for the prevention of diabetes-related podocyte injury.

Obesity-related glomerulopathy: Mechanisms of development, clinical course

Obesity and overweight are recognized as epidemics of non-communicable diseases in the 21st century. The kidneys are a target organ for obesity, damage to which is considered to be an independent risk factor for the development of renal failure. Obesity-related glomerulopathy (OGP) is one of the types of renal injury in obesity, which is characterized by the development of proteinuria in patients with a body mass index (BMI) of >30 kg/m2 in the absence of other causes of kidney damage. The pathogenesis of OGP is multifactorial. It is associated with intrarenal hemodynamic disorders - the development of renal hyperfiltration, the damaging action of adipose tissue hormones (hyperleptinemia, activation of the renin-angiotensin-aldosterone system, decreased production of adiponectin); with ectopic lipid accumulation in the kidney. The morphological pattern of OGP is characterized by a low glomerular density (oligonephronia) that leads to glomerular and tubular hypertrophy; by the development of perihilar focal segmental glomerulosclerosis (FSGS), obvious podocyte damages, and the development of a fatty kidney. The clinical picture of OGP is characterized by the slow and gradual development of albuminuria, not exceeding Stage A3 (300-1999 mg/day). Approximately one-third of patients develop partial nephrotic syndrome with massive proteinuria, but without edema and hypoproteinemia. Complete nephrotic syndrome is observed in not more than 6% of patients with OGP. In the course of the disease, 50% of patients develop hypertension and more than 80% do dyslipidemia. Stages IV-V chronic kidney disease may develop 20-30 years after the disease occurs.

Plasma Soluble Urokinase Receptor Level Is Correlated with Podocytes Damage in Patients with IgA Nephropathy.

BackgroundFocal segmental glomerulosclerosis (FSGS) lesions are similar in characteristics to S lesions of the Oxford classification of IgA nephropathy (IgAN) and may predict poor prognosis. In the present study, we aimed to explore the association between plasma soluble urokinase receptor (suPAR) levels and S lesions and podocytes damage in IgAN patients.MethodsWe enrolled 569 IgAN patients with follow-up data and detected plasma suPAR levels at renal biopsy by enzyme-linked immunosorbent assay.ResultsPlasma suPAR levels in IgAN patients with or without S lesions did not differ significantly (P = 0.411). However, suPAR levels were positively correlated with proteinuria (r = 0.202, P < 0.001), and negatively correlated with estimated glomerular filtration rate (eGFR, r = –0.236, P < 0.001). In the partial correlation to adjust for eGFR, plasma suPAR levels remained positively correlated with proteinuria (r = 0.112, P = 0.023). In a Cox proportional hazards model, higher levels of plasma suPAR were not associated with poor renal outcome. Plasma suPAR levels of IgAN and primary FSGS patients with nephrotic syndrome were not significantly different (P = 0.306). Plasma suPAR levels in patients with extensive effacement of the epithelial cell foot processes of glomerular podocytes were significantly higher than those with segmental effacement on the basis of comparable eGFR (P = 0.036).ConclusionsIn IgAN patients, plasma suPAR levels were not associated with S lesions. However, they were positively associated with proteinuria and negatively associated with eGFR. In addition, plasma suPAR levels were positively associated with the effacement degree of the foot processes, which might partially contribute to the development of proteinuria in patients with IgAN.

Prevalence and associated risk factors for the development of albuminuria in patients with type 2 diabetes at NCDEG Jordan

Prevalence and associated risk factors for the development of albuminuria in patients with type 2 diabetes at NCDEG Jordan

Low serum bilirubin concentration is a novel risk factor for the development of albuminuria in patients with type 2 diabetes

ObjectiveBilirubin has been recognized as an important endogeneous antioxidant. Previous studies reported that bilirubin could prevent atherosclerosis. The aim of this study was to investigate if serum bilirubin concentration could be a predictor for the development of albuminuria in patients with type 2 diabetes. Materials and MethodsWe measured serum bilirubin in 320 consecutive patients with normoalbuminuria. We performed follow-up study to assess the development of albuminuria, mean interval of which was 3.2±0.9years. Cox proportional hazards regression was used to examine the relationship between serum bilirubin concentration and the development of albuminuria. ResultsDuring follow-up duration, 43 patients have developed albuminuria. In multivariate analysis, after adjusting for comprehensive risk factors, the risk of developing albuminuria was higher in the lowest quartile of serum bilirubin concentrations than that in the highest quartile of serum bilirubin concentrations (Hazard ratio, 5.76; 95% CI, 1.65 to 24.93). ConclusionsLow serum bilirubin concentration could be a novel risk factor for the development of albuminuria in patients with type 2 diabetes.

A difference in systolic blood pressure between arms is a novel predictor of the development and progression of diabetic nephropathy in patients with type 2 diabetes

ObjectiveRecent studies have suggested that a difference in systolic blood pressure (SBP) between arms is associated with both vascular disease and mortality. The aim of this study was to investigate the relationship between a difference in SBP between arms and change in urinary albumin excretion or development of albuminuria in patients with type 2 diabetes. MethodsWe measured SBP in 408 consecutive patients with type 2 diabetes, and calculated a difference in SBP between arms. We performed follow-up study to assess change in urinary albumin excretion or development of albuminuria, mean interval of which was 4.6 ± 1.7 years. We then evaluated the relationship of a difference in SBP between arms to diabetic nephropathy using multiple regression analysis and multiple Cox regression model. ResultsMultiple regression analyses demonstrated that a difference in SBP between arms was independently associated with change in urinary albumin excretion (β = 0.1869, P = 0.0010). Adjusted Cox regression analyses demonstrated that a difference in SBP between arms was associated with an increased hazard of development of albuminuria; hazard ratio was 1.215 (95% confidence interval 1.077–1.376). Moreover, the risk of development of albuminuria was increased in patients with a difference in SBP of equal to or more than 10 mmHg between arms; hazard ratio was 4.168 (95% confidence interval 1.478–11.70). ConclusionA difference in SBP between arms could be a novel predictor of the development and progression of diabetic nephropathy in patients with type 2 diabetes.

Visit-to-Visit Blood Pressure Variability Is a Novel Risk Factor for the Development and Progression of Diabetic Nephropathy in Patients With Type 2 Diabetes

OBJECTIVERecent study has suggested that not only the presence of hypertension but also the variability in systolic blood pressure (SBP) are risk factors for vascular disease and organ damage. The aim of this study was to investigate the relationship between visit-to-visit variability in SBP and change in urinary albumin excretion (UAE) or development of albuminuria in patients with type 2 diabetes.RESEARCH DESIGN AND METHODSWe measured SBP in 354 consecutive patients at every visit during 1 year and calculated the coefficient of variation (CV) of SBP. We performed a follow-up study to assess change in UAE or development of albuminuria, the mean interval of which was 3.76 ± 0.71 years. Then, we evaluated relationships of variability of SBP to diabetic nephropathy using multiple regression analysis and multiple Cox regression model.RESULTSMultiple regression analysis demonstrated that CV of SBP was independently associated with change in UAE (β = 0.1758; P = 0.0108). Adjusted Cox regression analyses demonstrated that CV of SBP was associated with an increased hazard of development of albuminuria; hazard ratio was 1.143 (95% CI 1.008–1.302).CONCLUSIONSVisit-to-visit variability in SBP could be a novel risk factor for the development and progression of diabetic nephropathy in patients with type 2 diabetes.

Effect of blood pressure on diabetic nephropathy

Background: Hypertension is known to be risk factor for the development of proteinuria in patients with uncontrolled diabetes mellitus type2, leads to progression of end stage renal disease Aims & Objective: To study the effect of hypertension on diabetic nephropathy in type 2 diabetic patients. Material and Methods: We investigated, progression of diabetic nephropathy by measuring arterial blood pressure , serum creatinine and glomerular filtration rate(GFR) level in 60 (35 men and 25 women) type 2 uncontrolled diabetes mellitus patients on antihypertensive treatment. Results: The survey was done for 6 months during which 30 (group 1) -uncontrolled diabetes mellitus patients with normal blood pressure were compared with 30 (group 2) -Uncontrolled diabetes mellitus patients with hypertension who had mean systolic blood pressure (SBP) was 148.86 ± 5.12 mmHg. In group 2 the mean level of serum creatinine (1.71 ± 0.46 mg/dl) was significantly higher and mean GFR (54.57 ± 35.26 ml/min) was significantly lower than group 1 (P < 0.05). Conclusion: Uncontrolled hypertension leads to progression of diabetic nephropathy with decline in GFR earlier than normotensive uncontrolled diabetic patients.

Late Conversion Is a Risk Factor for mTOR Inhibitor Induced Proteinuria

Introduction: Recently, mTOR inhibitor base regimen has emerging as a main treatment strategy to avert calcineurin inhibitor induced nephrotoxicity in solid organ transplant patients. Results from different centers have confirmed the beneficial effect of this approach in patients with initial kidney creatinine clearance greater than 40ml/min. However, proteinuria is increasingly noticed as a complication of mTOR inhibitor application. The pathological processes responsible for this adverse effect are not completely understood so far. To see if conversion timing will affect the incidence of proteinuria in these patients, we conduct the following study. Methods: Inclusion criteria: kidney transplant recipients regularly follow-up in our clinic fulfilled the following criteria were recruited into this study: 1, creatinine clearance greater than 40ml/min; 2, daily urine protein loss less than 800mg. Exclusion criteria: patients with multiple organ transplantation, pregnancy, poor compliance or allergy to mTOR inhibitor are excluded. Once included, patients were put on everolimus 1.5mg per day. The dosage of everolimus was adjusted to keep their trough serum level between 3-8ng/ml. Their calcineurin inhibitor was reduced by half initially and tapered to the minimal dose within 2-4 weeks i.e. cyclosporin 25mg/ day or tacrolimus 0.5mg/day. Mycophenolic acid dosage were cut immediately by half and tapered as necessary, while steroid dosage was kept at 5mg per day or less. Graft function, hemogram, daily urine protein and biochemistry data including fasting sugar, liver function and lipid profiles were checked regularly. Results: In total, 18 patients were recruited into this study. After follow-up for 6 months, their creatinine clearance improved from 72.4± 5.6ml/min to 85.3± 9.8ml/min. Further analysis showed that five out of seven patients with transplantation duration longer than one year had aggravated proteinuria, which is defined as increase daily urine protein loss from their baseline level for more than 500mg. In eleven patients with transplantation duration less than one year, none has aggravated proteinuria after receiving everolimus treatment. Other factors such as underlying disease, age, baseline graft function, baseline proteinuria, lipid profiles and fasting sugar were all similar in both groups. Conclusion: In this preliminary study, we found that transplantation duration longer than one year is an important risk factor for the development of proteinuria in patients receiving mTOR inhibitor treatment.

Urinary heparanase activity in patients with Type 1 and Type 2 diabetes

A reduced heparan sulphate (HS) expression in the glomerular basement membrane of patients with overt diabetic nephropathy is associated with an increased glomerular heparanase expression. We investigated the possible association of urinary heparanase activity with the development of proteinuria in patients with Type 1 diabetes (T1D), Type 2 diabetes (T2D), or membranous glomerulopathy (MGP) as non-diabetic disease controls. Heparanase activity, albumin, HS and creatinine were measured in the urine of patients with T1D (n=58) or T2D (n=31), in patients with MGP (n=52) and in healthy controls (n=10). Heparanase messenger RNA (mRNA) expression in leukocytes was determined in a subgroup of patients with T1D (n=19). Urinary heparanase activity was increased in patients with T1D and T2D, which was more prominent in patients with macroalbuminuria, whereas no activity could be detected in healthy controls. Albuminuria levels were associated with increased urinary heparanase activity in diabetic patients (r=0.20; P<0.05) but not in patients with MGP (r=0.11; P=0.43). A lower urinary heparanase activity was observed in diabetic patients treated with inhibitors of the renin-angiotensin-aldosterone system (RAAS), when compared to diabetic patients treated with other anti-hypertensives. Additionally, urinary heparanase activity was associated with age in T1D and MGP. In MGP, heparanase activity and β2-microglobulin excretion correlated. In patients with T1D, no differences in heparanase mRNA expression in leukocytes could be observed. Urinary heparanase activity is increased in diabetic patients with proteinuria. However, whether increased heparanase activity is a cause or consequence of proteinuria requires additional research.

Serum uric acid levels predict the development of albuminuria over 6 years in patients with type 1 diabetes: Findings from the Coronary Artery Calcification in Type 1 Diabetes study

Recent studies suggest that uric acid is a mediator of diabetic nephropathy. We hypothesized that elevated serum uric acid levels are a strong predictor of albuminuria in patients with type 1 diabetes. We analyzed data from the Coronary Artery Calcification in Type 1 Diabetes study, a prospective observational study. A stepwise logistic regression model was applied to predict the development of micro- or macroalbuminuria after 6 years of follow-up in 324 participants who had no evidence of micro- or macroalbuminuria at baseline. A P-value <0.1 was used as the criteria for entry into and removal from the model. The following factors were selected in the stepwise multivariate model as predictors of micro- or macroalbuminuria at the 6-year follow-up visit: baseline serum uric acid levels, HbA(1c) and pre-albuminuria. For every 1-mg/dl increase in serum uric acid levels at baseline, there was an 80% increased risk of developing micro- or macroalbuminuria at 6 years (odds ratio 1.8; 95% confidence interval 1.2, 2.8; P = 0.005). Additional covariates considered in the stepwise model were sex, age, duration of diabetes, angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker treatment, waist circumference, waist/hip ratio, body mass index, systolic and diastolic blood pressure, smoking, serum creatinine, cystatin C, high-density lipoprotein cholesterol and triglycerides. Elevated serum uric acid levels are a strong predictor of the development of albuminuria in patients with type 1 diabetes.

Drug Discovery for Overcoming Chronic Kidney Disease (CKD): Pharmacological Effects of Mineralocorticoid-Receptor Blockers

There is increasing evidence demonstrating that the renoprotective effects of mineralocorticoid receptor (MR) blockade are independent of the effects exerted by renin-angiotensin inhibitors. MR is expressed not only in tubular cells but also in other renal cells including glomerular mesangial cells, podocytes, and renal interstitial fibroblasts. Animal experiments have shown that MR blockers prevent aldosterone-induced proteinuria, glomerular injury, and tubulointerstitial fibrosis. In vitro studies have also demonstrated that MR blockers inhibit aldosterone-induced renal cell damage. Recent clinical studies have shown that treatment with MR blockers attenuates the development of proteinuria in patients with chronic kidney disease (CKD) and hypertension, independent of changes in blood pressure. In some cases, MR blockers elicit potent renoprotective effects in conditions where aldosterone levels are not elevated. These data suggest that treatment with MR blockers may possibly present an effective therapeutic strategy for patients with CKD.

Higher Levels of HDL Cholesterol Are Associated With a Decreased Likelihood of Albuminuria in Patients With Long-Standing Type 1 Diabetes

The objective of this study was to determine whether high levels of HDL cholesterol are associated with a lower prevalence of albuminuria We analyzed the lipid profiles of patients with type 1 diabetes of > or = 20 years duration in 42 patients with albuminuria (28 microalbuminuria and 14 macroalbuminuria) and 65 patients without increased albumin excretion before any interventions with either statins or ACE inhibitors. Several characteristics were similar in the two groups: sex, age, duration of diabetes, total cholesterol, LDL cholesterol, and triglycerides. By univariate analysis, significant differences (P < 0.01) were found in HDL cholesterol (albuminuria 1.42 mg/dl, no albuminuria 1.71 mg/dl, P < 0.01), HbA1c (A1C) (albuminuria 8.5%, no albuminuria 7.5%), and proportions with no, background, and proliferative retinopathy (albuminuria 2.4, 16.7, and 81%; no albuminuria 24.6, 52.3, and 23.1%, respectively). When adjusted for age and sex, a 0.26-mmol/l (10-mg/dl) increase in HDL cholesterol is associated with an odds ratio (OR) of 0.70 (95% CI 0.54-0.90) for having albuminuria. In a multivariate model that adjusted for age, sex, diabetes duration, and A1C, for every 0.54-mmol/l (21-mg/dl) increase in HDL cholesterol, patients are approximately half (OR 0.51 [95% CI 0.30-0.86]) as likely to have albuminuria, even after controlling for A1C. Higher HDL cholesterol levels may be protective against the development of albuminuria in patients with type 1 diabetes. Whether this is due to the HDL cholesterol levels or whether they serve as a marker for some other mechanism remains to be determined.