Clinical Proteinuria Research Articles

Hypoxic treatment of human dual placental perfusion induces a preeclampsia-like inflammatory response

Preeclampsia is a human pregnancy-specific disorder characterized by a placental pro-inflammatory response in combination with an imbalance of angiogenic factors and clinical symptoms, including hypertension and proteinuria. Insufficient uteroplacental oxygenation in preeclampsia due to impaired trophoblast invasion during placentation is believed to be responsible for many of the molecular events leading to the clinical manifestations of this disease. We investigated the use of hypoxic treatment of the dual placental perfusion system as a model for preeclampsia. A modified perfusion technique allowed us to achieve a mean soluble oxygen tension within the intervillous space (IVS) of 5–7% for normoxia and <3% for hypoxia (as a model for preeclampsia). We assayed for the levels of different inflammatory cytokines, oxidative stress markers, as well as other factors, such as endothelin (ET)-1 that are known to be implicated as part of the inflammatory response in preeclampsia. Our results show a significant increase under hypoxia in the levels of different inflammatory cytokines, including IL-6 (P=0.002), IL-8 (P<0.0001), TNF-α (P=0.032) and IFN-γ (P=0.009) at 360 min in maternal venous samples (n=6). There was also a significant increase in ET-1 levels under hypoxia both on the maternal side at 30 min (P=0.003) and fetal side at 360 min (P=0.036) (n=6). Other markers of oxidative stress, including malondialdehyde and 8-iso-protaglandin F2α (P=0.009) also show increased levels. Overall, these findings indicate that exposure of ex vivo dually perfused placental tissue to hypoxia provides a useful model for mimicking the inflammatory response characteristic of preeclampsia. This would therefore provide a powerful tool for studying and further delineating the molecular mechanisms involved in the underlying pathophysiology of preeclampsia.

Podocyte pathology and nephropathy - sphingolipids in glomerular diseases.

Sphingolipids are components of the lipid rafts in plasma membranes, which are important for proper function of podocytes, a key element of the glomerular filtration barrier. Research revealed an essential role of sphingolipids and sphingolipid metabolites in glomerular disorders of genetic and non-genetic origin. The discovery that glucocerebrosides accumulate in Gaucher disease in glomerular cells and are associated with clinical proteinuria initiated intensive research into the function of other sphingolipids in glomerular disorders. The accumulation of sphingolipids in other genetic diseases including Tay–Sachs, Sandhoff, Fabry, hereditary inclusion body myopathy 2, Niemann–Pick, and nephrotic syndrome of the Finnish type and its implications with respect to glomerular pathology will be discussed. Similarly, sphingolipid accumulation occurs in glomerular diseases of non-genetic origin including diabetic kidney disease (DKD), HIV-associated nephropathy, focal segmental glomerulosclerosis (FSGS), and lupus nephritis. Sphingomyelin metabolites, such as ceramide, sphingosine, and sphingosine-1-phosphate have also gained tremendous interest. We recently described that sphingomyelin phosphodiesterase acid-like 3b (SMPDL3b) is expressed in podocytes where it modulates acid sphingomyelinase activity and acts as a master modulator of danger signaling. Decreased SMPDL3b expression in post-reperfusion kidney biopsies from transplant recipients with idiopathic FSGS correlates with the recurrence of proteinuria in patients and in experimental models of xenotransplantation. Increased SMPDL3b expression is associated with DKD. The consequences of differential SMPDL3b expression in podocytes in these diseases with respect to their pathogenesis will be discussed. Finally, the role of sphingolipids in the formation of lipid rafts in podocytes and their contribution to the maintenance of a functional slit diaphragm in the glomerulus will be discussed.

Effects of glucose and blood pressure control on diabetic kidney disease in old patients with type 2 diabetes.

AimsWe determined the influence of age on the effects of glucose and blood pressure control on diabetic kidney disease in patients with type 2 diabetes.MethodsA total of 721 patients with type 2 diabetes, aged 41–85 years and with an estimated glomerular filtration rate (eGFR) ≥30 mL/ [min · 1.73 m2], were enrolled in this study between August 2001 and December 2002. All participants were followed up at our clinics until December 31, 2010. Primary outcomes were the development of end-stage renal disease (ESRD) and all-cause mortality. Secondary outcomes were the development of clinical albuminuria and a severe decline in eGFR.ResultsDuring the follow-up period (median: 8.3 years), 27 (3.7%) patients developed ESRD, 130 (18.0%) patients died without developing ESRD, and 16 (2.2%) patients died after developing ESRD. Mortality rate increased with age, but the incidence rate of ESRD did not. Poor glucose and blood pressure control was associated with the development of clinical albuminuria and with a severe decline in eGFR in younger patients with diabetes, but not in older patients. The development of severe decline in eGFR and ESRD was significantly lower in the middle tertile of blood pressure (i.e., SBP of 128–141 mm Hg) in older patients.ConclusionsAdequate glucose and blood pressure control did not reduce the risk of ESRD; however, it may have delayed the onset of clinical albuminuria as well as eGFR decline in younger patients with type 2 diabetes.Electronic supplementary materialThe online version of this article (doi:10.1186/1758-5996-6-81) contains supplementary material, which is available to authorized users.

FRI0423 Miscarriage Risk Score in Mothers with Autoimmune Diseases

BackgroundAutoimmune diseases are related with poorer obstetric results than general population, specially in mothers with antiphospholipid antibodies.ObjectivesTo evaluate factors involved in the increased risk of miscarriages or pregnancy losses in...

Risk factors for predicting venous thromboembolism in patients with nephrotic syndrome: focus on haemostasis-related parameters

The venous thromboembolic events (VTE) incidence is high in nephrotic syndrome (NS). We aimed to assess prospectively the risk of VTE in a large cohort of NS patients and to identify predictive factors for VTE, especially haemostasis-related parameters. This is the prospective, observational study conducted in 256 adults with idiopathic NS. VTE were the study outcome. Clinical data, proteinuria, albuminuria, haemostasis and fibrinolysis parameters, and D-dimers were evaluated every 6 months. Median follow-up time was 24 [IQR 12–72] months. VTE cumulative and rate incidence were 11 % and 4.4 per 100 patient-years. Baseline higher proteinuria,lower serum albumin, low antithrombin III activity, and,surprisingly, high ionized calcium were VTE independent predictors. Proteinuria and serum albumin cut-offs, and positive and negative predictive values (PPV and NPV) for VTE were 9.0 g/24 h (30 % PPV and 90 % NPV) and 1.5 g/dL (69 % PPV and 93 % NPV). The rate of VTE incidence of 4.4 per 100 patient-years found in this prospective study confirms the idiopathic nephrotic syndrome as a thromboembolism-generating condition. Severe and unremitting proteinuria and hypoalbuminemia,low antithrombin III activity, and, surprisingly, high ionized calcium are independent VTE predictors.

Estimated Albumin Excretion Rate Versus Urine Albumin-Creatinine Ratio for the Estimation of Measured Albumin Excretion Rate: Derivation and Validation of an Estimated Albumin Excretion Rate Equation

Glomerular filtration rate estimation equations use demographic variables to account for predicted differences in creatinine generation rate. In contrast, assessment of albuminuria from urine albumin-creatinine ratio (ACR) does not account for these demographic variables, potentially distorting albuminuria prevalence estimates and clinical decision making. Polynomial regression was used to derive an age-, sex-, and race-based equation for estimation of urine creatinine excretion rate, suitable for use in automated estimated albumin excretion rate (eAER) reporting. The MDRD (Modification of Diet in Renal Disease) Study cohort (N=1,693) was used for equation derivation. Validation populations were the CRIC (Chronic Renal Insufficiency Cohort; N=3,645) and the DCCT (Diabetes Control and Complications Trial; N=1,179). eAER, calculated by multiplying ACR by estimated creatinine excretion rate, and ACR. Measured albumin excretion rate (mAER) from timed 24-hour urine collection. eAER estimated mAER more accurately than ACR; the percentages of CRIC participants with eAER within 15% and 30% of mAER were 33% and 60%, respectively, versus 24% and 39% for ACR. Equivalent proportions in DCCT were 52% and 86% versus 15% and 38%. The median bias of ACR was -20.1% and -37.5% in CRIC and DCCT, respectively, whereas that of eAER was +3.8% and -9.7%. Performance of eAER also was more consistent across age and sex categories than ACR. Single timed urine specimens used for mAER, ACR, and eAER. Automated eAER reporting potentially is a useful approach to improve the accuracy and consistency of clinical albuminuria assessment.

Susceptibility gene search for nephropathy and related traits in Mexican–Americans

The rising global epidemic of diabetic nephropathy (DN) will likely lead to increase in the prevalence of cardiovascular morbidity and mortality posing a serious burden for public health care. Despite greater understanding of the etiology of diabetes and the development of novel treatment strategies to control blood glucose levels, the prevalence and incidence rate of DN is increasing especially in minority populations including Mexican-Americans. Mexican-Americans with type 2 diabetes (T2DM) are three times more likely to develop microalbuminuria, and four times more likely to develop clinical proteinuria compared to non-Hispanic whites. Furthermore, Mexican-Americans have a sixfold increased risk of developing renal failure secondary to T2DM compared to Caucasians. Prevention and better treatment of DN should be a high priority for both health-care organizations and society at large. Pathogenesis of DN is multi-factorial. Familial clustering of DN-related traits in MAs show that DN and related traits are heritable and that genes play a susceptibility role. While, there has been some progress in identifying genes which when mutated influence an individual's risk, major gene(s) responsible for DN are yet to be identified. Knowledge of the genetic causes of DN is essential for elucidation of its mechanisms, and for adequate classification, prognosis, and treatment. Self-identification and collaboration among researchers with suitable genomic and clinical data for meta-analyses in Mexican-Americans is critical for progress in replicating/identifying DN risk genes in this population. This paper reviews the approaches and recent efforts made to identify genetic variants contributing to risk for DN and related phenotypes in the Mexican-American population.

Successful treatment of a mycophenolate mofetil-refractory proliferative lupus nephritis with Belimumab in a 19-year-old woman

We report the case of a 19-year-old woman with progressive proliferative lupus nephritis (LN) class III after induction and maintenance therapy with mycophenolate mofetil (MMF). Despite a satisfying clinical improvement proteinuria progressed under this medication. We treated the patient with additional belimumab after discussing other options. Following treatment with belimumab, proteinuria rapidly improved to almost normal levels and clinical remission lasted. Belimumab might hold promise for this indication.

GW24-e0452 BMI, PTH, and ambulatory SBP are related to LVH in CKD Patients

ObjectivesTo explore the incidence and affecting factors of LVH in CKD3-5 patients.Methods270 CKD3-5 patients were enrolled from Departmnt of nephrology, 3rd hospital of Sun yat-sen University in this study from...

Renal interstitial permeability changes induced by microbubble-enhanced diagnostic ultrasound

Ultrasound-targeted microbubble (MB) destruction (UTMD) has been shown to increase the glomerular permeability, providing a potential novel therapeutic approach in targeted drug release for kidney diseases. Therefore, we investigated the impact of UTMD on renal interstitial permeability using MB-mediated diagnostic ultrasound (DUS). The left kidney of Sprague–Dawley (SD) rat was insonated by UTMD with either continuous or intermittent mode for 5 min. Evans blue (EB) revealed that both modes induced renal vascular permeability increase after DUS but recovered after 24 h. Intermittent insonation caused more severe injury than continuous mode. Red blood cells leaked out of the capillaries into interstitium without glomerular capillary hemorrhage (GCH) by hematoxylin and eosin (HE) staining. Electronic microscopy revealed the disruption of focal capillary wall in interstitial tissues. Morphological results confirmed capillary wall recovered in 24 h post-treatment. Results from fluorescence-labeled MBs showed that MBs were mainly localized in the interstitial portion of the tubular region and retained at 24 h. Intriguingly, urinalysis showed no clinical proteinuria after treatment. Our results indicated that MB plus DUS specifically and reversibly enhanced the interstitial permeability without affecting glomerulus, which may be developed into a therapeutic approach for targeting drug release to individual renal compartments.

PP036. The intrarenal renin–angiotensin system and pregnancy outcome

The intrarenal renin angiotensin system (iRAS) may be activated in normal pregnancy. Failure of activation may predispose to preeclampsia. Urinary angiotensinogen/creatinine (uAGT/creat), albumin and protein/creat were measured in 10 non-pregnant and 17 pregnant non-Indigenous women and 61 Indigenous pregnant women (in whom other components of iRAS were also measured). uAGT/creat was higher in pregnancy (18.2±3.2μg/mmol, n=9 vs. 1.1±0.3μg/mmol, P=0.001, n=10). Women with clinical proteinuria and/or preeclampsia had low uAGT/creat (n=3). Hypertensive women had normal high uAGT/creat (n=4). Indigenous pregnant women had higher protein/creat (P=0.01) and lower uAGT/creat (2.9±1.0μg/mmol, P=0.010, n=51) than non-Indigenous pregnant women. Indigenous women were classified based on a uAGT/creat of <2μg/mmol (n=37) or >2.0μg/mmol (n=12). Only low uAGT/creat Indigenous pregnant women had correlations between uAGT/creat and albumin/creat (r=0.367, P=0.027), renin/creat and albumin or protein/creat (r=0.493, P=0.002, r=0.603, P<0.001). uAGT/creat levels fell with gestation (r=-0.329, P=0.047) while Cystatin C increased (r=0.592, P=0.000). The iRAS is activated in normal pregnancy. This is not the case in women with proteinuria/preeclampsia or in many Indigenous women who have higher urinary protein/creat. Therefore a low uAGT/creat in pregnancy may indicate impaired renal function and be associated with an increased risk of preeclampsia.

Changes of serum transforming growth factor beta-1 and renal arterial resistive index in hypertensive patients with microalbuminuria

Objective To investigate the changes of serum transforming growth factor hera-1 (TGF-β 1) and renal arterial resistive index (RRI) in patients with hypertension complicated by microalbuminuria.The correlation between TGF-β 1 and RRI was analyzed.Methods 92 patients with primary hypertension were assigned to normal albuminuria group (UACR ＜ 30 mg/g),microalbuminuria group (300mg/g＞UACR ≥ 30 mg/g),and clinical proteinuria group (UACR ≥ 300 mg/g) according to the level of UACR.The conrtrol group with health subjects was established.Serum TGF-β 1 levels,RRI,and related clinical indicators were measured.Results Serum TGF-β 1 levels and RRI were significantly higher in both microalbuminuria group and clinical proteinuria group than in normal albuminuria group (P ＜ 0.01).Serum TGF-β 1level was positively correlated with RRI level; levels of microalbuminuria,TGF-β 1 and RRI were all negatively correlated with estimated glomerular filtration rate (eGFR).Conclusions Levels of serum transforming growth factor beta-1 and renal arterial resistive index are higher in patients with hypertension and microalbuminuria.Both TGF-β 1 and RRI have a negative correlation with estimated glomerular fiiltration rate. Key words: Primary hypertension; Microalbuminuria; Transforming growth factor beta-1 ; Renal arterial resistive index

Probucol Suppresses Initiation of Chronic Hemodialysis Therapy and Renal Dysfunction-Related Death in Diabetic Nephropathy Patients: Sakura Study

Probucol has antioxidant as well as cholesterol-lowering effects. We examined the effect of probucol on the progression of diabetic nephropathy. We named this study 'Sakura Study' after our hospital and city. We performed a randomized, open trial on 162 type 2 diabetic patients with clinical albuminuria (urinary albumin excretion >300 mg/g creatinine). Eighty patients were assigned to probucol treatment (500 mg/day) and 82 patients to no probucol treatment. All patients were followed for five years. The primary outcome was the time to renal dysfunction events, defined as the initiation of chronic hemodialysis therapy and renal dysfunction-related death. Probucol decreased total cholesterol, HDL-cholesterol, and LDL-cholesterol compared to the control group. The serum creatinine increase rate was significantly lower (p= 0.015) in the probucol group (0.066 mg/dL/month) than in the non-probucol group (0.116 mg/dL/month). Renal dysfunction events occurred in 72 patients during this study. The 69 patients who were initiated on chronic hemodialysis comprised 42 in the non-probucol group and 27 in the probucol group. Three patients in the non-probucol group, but no patients in the probucol group died of renal dysfunction. The renal dysfunction event-free survival rate was significantly higher (log-rank: p= 0.02) in the probucol group than in the non-probucol group. Probucol suppressed the progression of diabetic nephropathy and renal dysfunction events.

Association between Salt Intake and Albuminuria in Normotensive and Hypertensive Individuals

Background. There is a little published data regarding the association between salt intake and albuminuria as an important alarm for progression of cardiovascular and renal dysfunction. We aimed to assess this relationship to emphasize the major role of restricting salt intake to minimize albuminuria and prevent these life-threatening events. Methods. The study population comprised 820 individuals. Participants were assigned to groups as follows: normal albuminuria, slight albuminuria, and clinical albuminuria. Daily salt intake was assessed on the basis of 24-hour urinary sodium excretion, since urinary sodium excretion largely equals sodium intake. Results. In normotensive participants, the mean level of urine albumin was higher in those who had higher amounts of salt intake with a significantly upward trend (the mean urinary albumin level in low-salt-diet group, in medium-salt-intake group, and in high-salt-intake group was 42.70 ± 36.42, 46.89 ± 38.91, and 53.38 ± 48.23, resp., (P = 0.017)). There was a significant positive correlation between 24-hour urinary sodium secretion and the level of urine albumin (beta = 0.130, P < 0.001). The amount of salt intake was significantly associated with urine albumin concentration (beta = 3.969, SE = 1.671, P = 0.018). Conclusion. High salt intake was shown to be associated with higher level of microalbuminuria even adjusted for potential underlying risk factors.

Proteinuria in canine patients with lymphoma

To determine if proteinuria is more common in dogs with lymphoma when compared with healthy dogs and to assess the severity and frequency of proteinuria in dogs with lymphoma. Determination of urine protein:creatinine ratio in 32 dogs with lymphoma compared with 30 healthy dogs. Canine patients with lymphoma are more likely to be proteinuric compared with healthy dogs. Proteinuria is common in dogs with lymphoma, although in most cases it is not severe. The presence of proteinuria is not linked with the stage or substage of lymphoma. Mild proteinuria is a common finding in dogs with lymphoma. The clinical impact of the proteinuria is probably low.

The relationship between insulin resistance and osteoporosis in elderly male type 2 diabetes mellitus and diabetic nephropathy

ObjectiveDiabetes is often associated with complications and comorbidities. Diabetic osteoporosis (OP) is increasingly recognized as a significant comorbidity of type 2 diabetes mellitus (T2-DM). In this study, we intended to determine whether type 2 diabetes was associated with a higher bone mineral density (BMD) in older males, and investigate the related risk factors of diabetes mellitus accompanied with OP. Materials and methodsTo assess the effects of diabetes and its complications on the risk of bone fractures, the daily glycemia, insulin and HbAlc of T2-DM patients were detected. At the same time, Dual Energy X-ray Absorptiometry (DEXA) was used to measure the BMD of whole body, lumbar spine and proximal femoral at 2-year intervals. ResultsThe BMD in elderly male patients suffered from T2-DM was associated with kidney function. The decrease of BMD in elderly male patients with T2-DM was related to HbA1c and body mass index (BMI). The BMD in group of renal function insufficiency or clinical albuminuria which are closely related with insulin insufficiency were much lower than that in the group of normal control. Additionally, a significantly lower (P<0.05) T-score was found in patients with nephropathy as compared with those without the complications. ConclusionThe elderly patients with type 2 diabetes mellitus are prone to develop OP. The insufficiency of insulin, the decreased insulin sensitivity and diabetic nephropathy are important causes for OP in the patients with type 2 diabetes.

Mean Platelet Volume and Related Factors in Patients at Different Stages of Diabetic Nephropathy

Mean platelet volume (MPV) is an independent cardiovascular disease predictor, and characteristics of MPV in patients with diabetic nephropathy (DN) are not well known. To determine the MPV levels in patients at different stages of DN. The MPV levels were investigated in healthy participants (group 1, n = 157), patients with type 2 diabetes mellitus without complication (group 2, n = 160), diabetic patients with clinical proteinuria (group 3, n = 144), and in patients with chronic kidney disease due to DN (group 4, n = 160). The MPV level was higher in all diabetic patients than that in normal participants (P < .05). The MPV values had a positive correlation with the serum creatinine and proteinuria, and a negative correlation with the glomerular filtration rate ([GFR] P < .001 for all, r values; .72, and .82, and -.92, respectively). The MPV values were higher in diabetic groups than that in normal participants. Both GFR and proteinuria were the most powerful determinants of MPV.

Serum 1,5‐anhydroglucitol is associated with diabetic retinopathy in Type 2 diabetes

To determine whether there is a relationship between 1,5-anhydroglucitol (1,5-AG), a marker of postprandial hyperglycaemia and glycaemic variability, and the presence of diabetic retinopathy and albuminuria in patients with Type 2 diabetes. Five hundred and sixty-seven patients with Type 2 diabetes (serum creatinine < 133 μmol/l), who were enrolled in the Seoul Metro-City Diabetes Prevention Program (SMC-DPP), were cross-sectionally assessed by multivariate logistic regression analysis. After controlling for age, sex, binary HbA(1c) levels, duration of diabetes, triglyceride, systolic blood pressure, smoking status, history of hypertension and dyslipidaemia, and the use of angiotensin-converting enzyme inhibitor/angiotensin receptor blocker medication, the odds ratios (95% CI) of diabetic retinopathy were 2.86 (1.12-7.25) for the first (lowest) quartile of 1,5-anhydroglucitol, 2.87 (1.25-6.61) for the second quartile and 0.88 (0.35-2.22) for the third quartile compared with the fourth quartile (P for trend = 0.010). Conversely, the associations between 1,5-anhydroglucitol and clinical albuminuria were non-significant after adjustment. Subjects with low 1,5-anhydroglucitol (< 10.0 μg/ml) were more likely to experience diabetic retinopathy than those with high 1,5-anhydroglucitol (≥ 10.0 μg/ml) under moderate glucose control (HbA(1c) < 8%, 64 mmol/mol) and there were no significant differences in the prevalence of diabetic retinopathy between the subgroup with HbA(1c) < 8% (64 mmol/mol) and low 1,5-anhydroglucitol and the subgroup with HbA(1c) ≥ 8% (64 mmol/mol). 1,5-Anhydroglucitol levels show close associations with diabetic retinopathy, especially among patients under moderate glucose control, but not with albuminuria. These results suggest that 1,5-anhydroglucitol might be a complementary marker for targeting higher risk group.

Mechanisms and effects of Abelmoschus manihot preparations in treating chronic kidney disease

Abelmoschus manihot (AM) is a medicinal plant rich in twenty kinds of separated active bio-components including flavones, polysaccharides, trannic acid, and long chain hydrocarbons. Among these, total flavones of A. manihot (TFA) are the major active component. In this review, the mechanisms of Huangkui capsule will be discussed as a preparation of AM to treat chronic kidney disease (CKD) by improving immunological reaction, inflammation, renal fibrosis, and renal tubular epithelial injury. Additionally, it has been reported that Huangkui capsule can ameliorate some clinical symptoms, proteinuria, hematuria, and renal function in patients with common CKD, such as nephrotic syndrome, diabetic nephropathy, Henoch-Schönlein purpura nephritis, IgA nephropathy, and membranous nephropathy.

Discordant phenotype in monozygotic twins with renal coloboma syndrome and a PAX2 mutation

Renal coloboma syndrome (RCS) is a highly variable syndrome characterized by renal and ocular abnormalities. It is associated in about 50 % of cases with mutations of PAX2, a gene encoding a transcription factor required during development. The case study involves two monozygotic twin sisters with RCS showing highly discordant phenotypes. Twin 1 was antenatally diagnosed with multiple cysts in the right kidney. She had complicated vacuum-assisted delivery with acute renal failure. She developed proteinuria at age 4 years, followed by a progressive rise in serum creatinine requiring renal replacement therapy at age 22. No ocular abnormalities have been detected. Twin 2 experienced rapidly reversible acute renal failure without renal morphological abnormalities at birth. At age 2 years, complete visual acuity loss of the left eye secondary to an optic disc coloboma was diagnosed. No significant events occurred until the age of 20, when clinical proteinuria was detected. Proteinuria remission was obtained by multidrug treatment. In both patients, a novel de novo mutation of PAX2 was detected, which leads to the substitution of a highly conserved cysteine (p.C52Y). The patients described provide an extreme example of clinical variability in RCS. The role of environmental, genetic, and epigenetic factors is discussed.