Renal Filtration Research Articles

Dynamic Contrast Enhanced (DCE) MRI-Derived Renal Perfusion and Filtration: Experimental Protocol.

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can provide a noninvasive way for assessing renal functional information following the administration of a small molecular weight gadolinium-based contrast agent. This method may be useful for investigating renal perfusion and glomerular filtration rates of rodents in vivo under various experimental (patho)physiological conditions. Here we describe a step-by-step protocol for DCE-MRI studies in small animals providing practical notes on acquisition parameters, sequences, T1 mapping approaches and procedures.This chapters is based upon work from the COST Action PARENCHIMA, a community-driven network funded by the European Cooperation in Science and Technology (COST) program of the European Union, which aims to improve the reproducibility and standardization of renal MRI biomarkers. This experimental protocol chapter is complemented by two separate chapters describing the basic concept and data analysis.

Analysis Protocol for Dynamic Contrast Enhanced (DCE) MRI of Renal Perfusion and Filtration.

Here we present an analysis protocol for dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) data of the kidneys. It covers comprehensive steps to facilitate signal to contrast agent concentration mapping via T1 mapping and the calculation of renal perfusion and filtration parametric maps using model-free approaches, model free analysis using deconvolution, the Toft's model and a Bayesian approach.This chapter is based upon work from the COST Action PARENCHIMA, a community-driven network funded by the European Cooperation in Science and Technology (COST) program of the European Union, which aims to improve the reproducibility and standardization of renal MRI biomarkers. This analysis protocol chapter is complemented by two separate chapters describing the basic concept and experimental procedure.

Which Better Determines the Renal Function and Glomerular Filtration Rate: Renal Parenchymal Thickness or Renal Resistive Index?

Resistive index (RI) could provide more useful diagnostic and prognostic information for kidney disease than parenchymal thickness (PT) only. The aims of this study were to find the association between PT, glomerular filtration rate (GFR), and RI and their determination of renal function. B-mode and Doppler ultrasonography and standard biochemical laboratory testing (urea and creatinine) were performed among 75 participants (57.1 ± 10.6 years). We measured PT and RI and calculated GFR. The mean and standard deviation were 0.671 ± 0.041, 12.24 ± 1.98 mm, and 86.38 ± 15.96 mL/min/1.73 m2 for RI, PT, and GFR, respectively. The mean RI in two subgroups with PT smaller or greater than 12.5 mm was RI1 = 0.692 ± 0.038 or RI2 = 0.648 ± 0.03 (P <0.0001). Strong inverse correlation between RI (y) and PT (x) presented by the linear regression equation: y = 0.744 + (-0.005932 x). By multiple regression, we show GFR and PT as predictors for increasing of RI (R2 = 0.2063, βst = -0.0009176, P = 0.0012 and βst = -0.006003, P = 0.0078), respectively. Renal RI inversely strongly correlates with the PT and GFR. Renal PT and GFR are independent predictors for increasing of RI in general population.

Оценка уровня кальциемии у пациентов с сахарным диабетом по данным обследования в мобильном медицинском центре (Диамодуль)

Background. Diabetes mellitus (DM) is characterized by multiple risk factors for the combined development of disorders of phosphorus-calcium metabolism, due to more frequent overweight, decreased renal filtration function and vitamin D deficiency in this category of patients. Aim. To assess the level of calcium in blood serum and its correlations with parameters of carbohydrate metabolism, body mass index (BMI) and renal function in patients with type 1 and type 2 diabetes. Materials and methods. The object of the study: adult patients with type 1 diabetes (T1DM) and type 2 diabetes (T2DM) ≥18 years old who underwent examination in Diamodule (n=294) in 2019 in the Voronezh region, who were additionally tested for serum calcium. The examination at the mobile medical center includes: assessment of anthropometric data (height, weight, BMI), biochemical data of blood lipids and creatinine levels with calculation of glomerular filtration rate (GFR-EPI), albuminuria and the albumin/creatinine in a single portion of urine, measurement of glycated hemoglobin (HbA1c), blood pressure, electrocardiogram, consultation with a cardiologist, ophthalmologist, specialist of the Diabetic Foot office, diabetologist. All biochemical parameters was carried out using commercial kits on a biochemical express analyzer Spotchem EZ ArkraySP-4430. Determination of HbA1c, albuminuria, albumin/creatinine was performed by immunochemical method on a DCA Vantage analyzer. Data analysis was carried out using the Statistica v.13.3 software package (TIBCO Software Inc., USA). The results are presented as medians and quartiles [25; 75], the level of reliability is taken as p&lt;0.05. Results. Hypocalcemia (serum calcium level less 2.15 mmol/L) was detected in 88.3% of patients with T1DM and 73.6% of patients with T2DM. The level of serum calcium in T1DM was 1.96 [1.83; 2.07], in T2DM – 2.04 [1.97; 2.16] (p&lt;0.001) with significant differences in GFR: in T1DM 69.6 [57.8; 82.5], with T2DM 50.5 [44.1; 59.9] (p&lt;0.001). We observed correlation between GFR and calcium level r=-0.3 (p&lt;0.05,). GFR&lt;60 ml/min/1.73 m² was observed in 30.5% of T1DM patients, in 75.0% of T2DM. The HbA1c in T1DM was 8.7% [7.7; 9.8], in T2DM – 8.3% [6.8; 9.4] (p=0.01). Obesity was revealed in T1DM in 12.3%, in T2DM in 71.4%; the median BMI in T1DM was 25.5 kg/m2 [21.9; 28.4], in T2DM – 33.2 kg/m2 [29.7; 37.9]. There was correlation between BMI and calcium level r=0.26 (p&lt;0.05). Conclusion. The results of the study revealed a high prevalence of hypocalcemia among patients with diabetes, the most pronounced in type 1 diabetes. In the presence of a correlation between calcium and GFR, there was a high incidence of hypocalcemia in patients with T1DM, even in the absence of a significant decrease in GFR, which may indicate to additional risk factors. Since the assessment of the level of calcium is not included in the list of standard clinical examination, it is recommended to include this parameter and conduct regular screening in risk groups, which include patients with diabetes. More extensive research is needed to analyze the factors.

THE EFFECT OF SMOKING ON NUTRITIONAL STATUS, SEVERITY OF THE DISEASE AND THE DEVELOPMENT OF SYSTEMIC EFFECTS IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE

The aim: To determine the effect of smoking on indicators of nutritional status in patients with chronic obstructive pulmonary disease (COPD). Materials and methods: A study included 91 patients with COPD. Patients were divided into two groups depending on the status of smoking: smokers and non-smokers. Everyone underwent an assessment of the severity of COPD, a study of nutritional status, a laboratory study of kidney function and blood lipid profile. Results: It was found that in smokers with COPD, the disease proceeds with more pronounced shortness of breath. There is also a development of sarcopenic obesity in those patients who smoke. In turn, it was found that bronchial obstruction increases with a decrease in muscle tissue content. Renal filtration function is reduced in smokers and non-smokers. Conclusions: 1. Patients suffering from COPD have a violation of nutritional status. Smoking patients develop sarcopenic obesity, which progresses with an increase in the degree of nicotine addiction, correlates with the "pack / year" index and is a predictor of increased mortality in this category of patients. 2. Increased bronchial obstruction in smokers with COPD is observed with an increase in smoking history, the number of cigarettes smoked and with a decrease in body weight. 3. Reducing the pool of muscle tissue can be considered as an early predictor of more frequent exacerbations in smoking patients with COPD. 4. The systemic effects of COPD include impaired renal function, more pronounced in smokers with COPD.

ENDOGENOUS INTOXICATION SYNDROME ACTIVITY IN BILIARY AUTONOMIC VISCERO-VISCERAL CARDIONEUROPATHY

Toxic excess of biologically active substances named middle molecules (MM), which include byproducts of normal and altered metabolism, products of inflammation and oxidation, bacterial remnants, antibodies and immunoactive substances, plays an important role in pathogenesis of gallbladder diseases and biliary autonomous viscero-visceral cardioneuropathy (BAVVCNP). In order to assess activity of the endogenous intoxication syndrome secondary to BAVVCNP, we examined 20 patients with coronary heart disease to determine the levels of MM in the blood (total and at 238, 254, 266, and 280 nm waves); the levels of MM in urine (at 238, 254, 266, 282, 288, and 310 nm waves) with calculation of aromaticity index (MM 238/280), peptide-nucleotide index (MM 238/266), distribution index (MM 280/254), and L-arginine, and nitrites of the urine. The results were statistically processed. It was revealed that in case of BAVVCNP the severity of the endogenous intoxication syndrome was higher for all specific parameters of endotoxicosis, and especially for the total level of MM in blood (0.77 ± 0.13 units vs. 0.46 ± 0.13 units, p = 0.08), the MM level at 238 nm wave (1.53 ± 0.55 vs. 0.49 ± 0.06, p = 0.08) and hydrophilic MM level in the urine at 288 nm long waves (0.72 ± 0.12 vs. 0.40 ± 0.11, p = 0.05) and 310 nm (0.27 ± 0.08 vs. 0.10 ± 0.03, p &lt;0.05). According to the literature, this may indicate an increase in levels of cholecystokinin, leptin, endothelin, proinflammatory interleukins and tumor necrosis factor α. According to the correlation analysis, activation of endogenous intoxication syndrome was associated with lipid distress syndrome, increased leptin content and accelerated renal filtration.

The Renal Extracellular Matrix as a Supportive Scaffold for Kidney Tissue Engineering: Progress and Future Considerations.

During the past decades, diverse methods have been used toward renal tissue engineering in order to replace renal function. The goals of all these techniques included the recapitulation of renal filtration, re-absorptive, and secretary functions, and replacement of endocrine/metabolic activities. It is also imperative to develop a reliable, up scalable, and timely manufacturing process. Decellularization of the kidney with intact ECM is crucial for in-vivo compatibility and targeted clinical application. Contemporarily there is an increasing interest and research in the field of regenerative medicine including stem cell therapy and tissue bioengineering in search for new and reproducible sources of kidneys. In this chapter, we sought to determine the most effective method of renal decellularization and recellularization with emphasis on biologic composition and support of stem cell growth. Current barriers and limitations of bioengineered strategies will be also discussed, and strategies to overcome these are suggested.

Endothelial KCa 1.1 and KCa 3.1 channels mediate rat intrarenal artery endothelium-derived hyperpolarization response.

Endothelium-derived hyperpolarization (EDH)-mediated response plays an essential role in the control of kidney preglomerular circulation, but the identity of the K+ channels involved in this response is still controversial. We hypothesized that large- (KCa 1.1), intermediate- (KCa 3.1) and small (KCa 2.3) -conductance Ca2+ -activated K+ (KCa ) channels are expressed in the endothelium of the preglomerular circulation and participate in the EDH-mediated response. We study the functional expression of different K+ channels in non-cultured, freshly isolated native endothelial cells (ECs) of rat intrarenal arteries using immunofluorescence and the patch-clamp technique. We correlate this with vasorelaxant responses ex vivo using wire myography. Immunofluorescence revealed the expression of KCa 1.1, KCa 3.1 and KCa 2.3 channels in ECs. Under voltage-clamp conditions, acetylcholine induced a marked increase in the outward currents in these cells, sensitive to the blockade of KCa 1.1, KCa 3.1 and KCa 2.3 channels respectively. Isometric myography experiments, under conditions of endothelial nitric oxide synthase and cyclooxygenase inhibition, showed that blockade either of KCa 1.1 or KCa 3.1 channels was able to reduce the endothelium-derived vasorelaxation of isolated interlobar arteries, while their combined blockade completely abolished it. In contrast, blockade of KCa 2.3 channels did not reduce this vasorelaxant response, despite being functionally expressed in the endothelial cells. This study shows that KCa 1.1 and KCa 3.1 channels are functionally expressed at the renal vascular endothelium and play a central role in the EDH-mediated relaxation of kidney preglomerular arteries, which is important in the control of renal blood flow and glomerular filtration rate.

Clinical-instrumental correlations of local elastic properties of the thoracic aorta in patients with coronary atherosclerosis

Introduction . This is part of research with aim of increasing the effectiveness of echocardiography in patients with coronary atherosclerosis by assessing local elastic properties of the thoracic aorta using modern ultrasound technologies. Aim . To analyze correlations between deterioration of local elastic properties of the thoracic aorta, impairment of renal filtration function, severity of left ventricular hypertrophy and ischemic heart disease (IHD) risk factors in patients with coronary atherosclerosis. Materials and methods . From 2016 to 2019, 109 patients aged 39 to 82 years, who were divided into 2 groups according to the results of invasive coronarography, were examined: 64 patients with coronary atherosclerosis and 45 patients without coronary atherosclerosis. Using transthoracic echocardiography, the following were obtained: coefficient of distensibility, compliance coefficient, Peterson’s elasticity modulus, stiffness index of the ascending thoracic aorta. Analysis of correlations between these indices, indicators of IHD risk factors, left ventricular mass index (LVMI), glomerular filtration rate (GFR) was done. Results . Group without coronary atherosclerosis showed negative correlations of compliance coefficient with LVMI (r=–0.421), positive correlations of Peterson’s elasticity modulus and stiffness index with LVMI (r=0.304, r=0.397). Group with coronary atherosclerosis showed negative correlations of the coefficient of distensibility with LVMI (r=–0.331), Peterson’s elasticity modulus and stiffness index with GFR (r=–0.473, r=–0.469). Positive correlations were found between coefficients of compliance and distensibility with GFR (r=0.418, r=0.473), Peterson’s elasticity modulus and the stiffness index with LVMI (r=0.33, r=0.304). Conclusion . Research reveals relationship between the local elastic properties of the thoracic aorta, GFR and severity of LV hypertrophy in patients with coronary atherosclerosis and the effectiveness of echocardiographic technologies in their assessment.

Hyperaldosteronemia as a risk factor of renal dysfunction in patients with heart failure with preserved ejection fraction

Objective: To assess the relationship between plasma aldosterone levels and renal function in patients with heart failure with preserved ejection fraction (HFpEF).Materials and methods: A cross-sectional study included 158 patients with confirmed HFpEF. Patients with primary hyperaldosteronism, edema syndrome, end stage renal disease and taking mineralocorticoid receptor antagonists were excluded. Renal function was assessed by determining daily urinary albumin excretion (UAE) and calculating the glomerular filtration rate (GFR). Plasma aldosterone was measured by enzyme immunoassay.Results: The patients were divided into two groups: 99 patients had normal (40-160 pg/ml) aldosterone plasma level (nAld) and 59 patients had high (&gt; 160 pg/ml) aldosterone level (hAld). hAld patients had significantly higher UAE (median 342 mg/day [interquartile value 253; 453] versus 116 mg/day [32; 255], p &lt; 0.001), and lower GFR (52 ml/min/1.73 m2 [46; 67.5] versus 66 ml/min/1.73 m2 [53; 79]) compared to nAld. The prevalence of impaired renal filtration function and severe albuminuria was higher in hAld group then in nAld (p &lt; 0.001). In binomial logistic regression models adjusted for age, severity of HFpEF and comorbidities high aldosterone plasma level were independent risk factors of significant (&lt; 60 ml/min/1.73 m2) decrease in GFR (odds ratio 4.25, 95% confidence interval 2.01-16.6) and very high (&gt; 300 mg/day) albuminuria (odds ratio 2.23, 95% confidence interval 1.24-9.63).Conclusion: In HFpEF plasma aldosterone levels are closely related to renal function. Secondary hyperaldosteronism is associated with an increased risk of impaired renal filtration and severe albuminuria.

Forecast and clinical-diagnostic significance of increased expression of beta-2microglobulin in the urine in the process of nephropathy formation in essential hypertension

Introduction. At present, it is obvious that the prognosis for the life of patients with essential hypertension, according to the cardiovascular continuum, is clearly determined primarily by the involvement in the pathological process of target organs and the severity of their structural and functional changes.The aim of the study is to identify the clinical-diagnostic and prognostic value of B2-MGU as a marker of kidney damage in essential hypertension.Materials and methods. To achieve this goal, 46 patients with essential hypertension (45.65% women and 54.35% men) aged from 28 to 71 years (mean age was 51.88 ± 2.17 years), I-II stage of the disease with level of hypertension I-III degree, varying degrees of risk, who did not receive systematic adequate antihypertensive therapy and in which as a result of comprehensive clinical, laboratory and instrumental studies there were no evidence of clinically significant chronic kidney disease. The control group consisted of 17 healthy individuals.Results. In patients with essential hypertension is forming hypertensive nephropathy, which is characterized by statistically significant excessive excretion of beta-2-microglobulin in the urine compared with almost healthy individuals. In patients with increased excretion of beta-2-microglobulin violations of intrarenal hemodynamics were registered significantly more often, violations of functional renal reserve, violations of vascular resistance of renal vessels, in a significantly higher percentage there were pathological changes in circadian rhythm of blood pressure and renal filtration function, the prevalence of concentric and eccentric hypertrophy, proteinuria, which indicates an important clinical, diagnostic and prognostic value of hyper-beta-2-microglobulinuria.Conclusions. The indicator beta-2-microglobulinuria can be used as an adequate marker of hypertensive nephropathy, as having high sensitivity, specificity, positive and negative prognosis.

Fragmented QRS as a predictor of subclinical cardiovascular disease in patients with chronic kidney disease.

Fragmented QRS (fQRS) on surface electrocardiogram is correlated with increased cardiovascular risk and mortality in normal population. To investigate the presence of fQRS and its association with subclinical atherosclerosis and vascular calcification in chronic kidney disease (CKD) patients without cardiovascular disease. A total of 129 CKD (63 males and 66 females) patients was enrolled for the study. Carotid intima-media thickness (CIMT) measurement and coronary artery calcification score (CACS) were performed by the same radiologist. A 12-lead electrocardiogram recording was used to detect fQRS. The mean age was 55.1 ± 15.1 years. fQRS was detected in 45% of patients. There was not any significant difference between patients with or without fQRS in terms of demographic parameters and comorbid diseases except for diabetes and hyperlipidaemia. The mean CIMT of CKD patients was 0.66 ± 0.18 mm and it was significantly higher in fQRS(+) group compared to the fQRS(-) group. Similarly CACS values were higher in fQRS(+) group. In the logistic regression analysis, fQRS remained significantly associated with CIMT (β = 0.220, t = 2.567, P = 0.011) (independent variables: CIMT, CACS, sodium and glomerular filtration rate (modification of diet in renal disease-glomerular filtration rate)). This is the first study in the literature showing the relation of fQRS with CIMT and CACS in patients with CKD without known cardiovascular disease.

Kardiologiczne, niekardiologiczne powikłania i czynniki predykcyjne przedłużonej hospitalizacji u pacjentów bez cukrzycy z zawałem serca leczonych pierwotną przezskórną angioplastyką wieńcową

Introduction. Prolonged patient stay after acute myocardial infarction (MI) results in higher costs. This study evaluated factors prolonging hospitalization after admission due to MI. Complications which also influence on longer hospital stay: both cardiac (CC) and non-cardiac (NCC), were analysed. Material and methods. The authors included prospectively 131 patients with MI undergoing primary percutaneous intervention. Following factors were collected: demographic and anthropomorphic data, types of infarction, 12-lead electrocardiography (ECG), echocardiography, standard blood tests including admission blood glucose level, fasting glycaemia, oral glucose tolerance test (OGTT) at discharge as well as renal filtration and lipid parameters. Length of hospital stay of Results. The mean age of patients was 62 ± 10.9 years, 71.8% were male. Factors which correlated significantly with longer hospitalisation were: older age (R = 0.47, p = 0.001), higher fasting glycaemia (R = 0.25, p = 0.027), reduced left ventricular ejection fraction (LVEF) (R = –0.36, p = 0.04), occurrence of ST-elevation MI (p = 0.0166), presence of CC (p = 0.0007) and NCC (p = 0.0001). Age, high blood glucose in OGTT and LVEF remained significant in a multivariate model predicting the duration of stay (R2 = 0.32). Factors predicting hospital stay ≥ 6 days in the multivariate model were: older age (p = 0.000), hip circumference (p = 0.014), anterior wall MI (p = 0.026) and usage of glycoprotein IIb/IIIa inhibitors (p = 0.022) with and area under the receiver operating characteristic curve (ROC): 0.792 [95% confidence interval (CI) 0.71–0.87] with specificity 71% and sensitivity 79%. Factors influencing CC occurrence in the multivariate model were: estimated glomerular filtration rate (p = 0.009), LVEF (p = 0.003) with ROC 0.735 (95% CI 0.65–0.82) with specificity 76% and sensitivity 60%. Factors influencing the occurrence of NCC were hyperlipidaemia (p = 0.021), and LVEF (p = 0.004) with an ROC: 0.792 (95% CI 0.71–0.87) with specificity 55% and sensitivity 90%. Conclusions. LVEF, age and blood glucose levels significantly prolonged hospital stay. The major factor associated with an increased risk of both CCs and NCCs was LVEF.

Features of the course of nephropathies in combination with CAKUT-syndrome in young children

Background . Children with CAKUT-syndrome (congenital malformations of the urinary tract) quickly develop an inflammatory process, which, in combination with dysplasia and/or urodynamic disorders, creates a high risk of developing early chronic renal failure. Purpose of the study : to identify the main factors of the formation, features of the clinical course of nephropathies, morphometric parameters and features of the organ blood flow of the kidneys in young children against the background of CAKUT syndrome. Methods . Study design: It carried out a cohort prospective study. The main group included 26 children with pyelonephritis against the background of CAKUT syndrome at the age from zero to 36 months of life, the comparison group consisted of 29 children with non-obstructive pyelonephritis of the same age. It carried out a comparative analysis of antenatal and postnatal anamnesis, clinical, laboratory and instrumental data in the considered groups of children with nephro-urological pathology. Additionally, it researches the morphometric parameters of the kidneys and the Doppler indices of the renal vessels. The research conducted during 2016–2018. Results . In children with a chronic course of nephropathy in combination with CAKUT-syndrome, possible predictors of an early onset of the disease are: anemia, damage to the urinary tract with pathological urinary syndrome during pregnancy and a combination with defects of this system in the woman herself, and the development of placental insufficiency. In the group with CAKUT syndrome, a decrease in renal filtration function (in 88.5% of children) and persistent trace proteinuria (in 65.4% of children) are recorded by the end of the first year of life. According to ultrasound, in addition to signs of obstructive nephropathy, it recorded decreases in the thickness of the parenchyma and a violation of organ hemodynamics with an increase in the resistance index. In the observed group of children, CAKUT syndrome combined in 100% of cases with connective tissue dysplasia syndrome also. Conclusion . Thus, CAKUT syndrome leads to early realization of nephropathies in children with a rapid decline in renal function.

Abstract 16998: Gender and Age Specific Baseline Predictors of MACE in PEACE Trial Identified by Machine Learning

Introduction: The NHLBI supported Prevention of Events with Angiotensin-Converting Enzyme (ACE) Therapy trial (PEACE) (NCT00000558) found that the addition of ACE inhibitor trandolapril to conventional therapy in 8290 patients with stable coronary artery disease and preserved ejection fraction provided no benefit against MACE (cardiovascular death, nonfatal myocardial infarction, or the need for coronary revascularization), the composite primary endpoint. We reused publicly available individual patient-level PEACE data from NHLBI Data Repository (BioLINCC) to perform hypothesis-generating secondary analyses by machine learning (ML) using random survival forest (RSF) to identify gender and age group specific predictors for MACE. Methods: RSF was performed on 50 baseline variables for the MACE outcome in male and female and in age group (&lt;60, 60-69, &gt;69) cohorts. The top ten predictors identified in each cohort were included in a multivariate analysis using a Cox proportional hazards model with a multiple regression approach. Results: The top 10 predictors for the MACE selected by RSF are shown in Figure 1. Expected cardiovascular (CV) risk predictors like blood pressure, Canadian CV Society angina classification (CCS), age, and a history of various CV procedures consistently emerge amongst the top ten predictors of the primary MACE outcome across all gender and age specific subgroups. Interestingly, RSF also identified renal function biomarkers like serum potassium and glomerular filtration rate as common top ten predictors. Conclusion: Using ML, we uncovered in an unbiased fashion, gender and age groups specific unanticipated top predictors for MACE in PEACE trial. This underscores the value of gender and age specific predictors to examine the efficacy and outcomes of therapeutic interventions in advancing precision and personalized medicine.

Percutaneous transluminal renal angioplasty attenuates poststenotic kidney mitochondrial damage in pigs with renal artery stenosis and metabolic syndrome.

Percutaneous transluminal renal angioplasty (PTRA) has been used to treat renovascular disease (RVD), a chronic condition characterized by renal ischemia and metabolic abnormalities. Mitochondrial injury has been implicated as a central pathogenic mechanism in RVD, but whether it can be reversed by PTRA remains uncertain. We hypothesized that PTRA attenuates mitochondrial damage, renal injury, and dysfunction in pigs with coexisting renal artery stenosis (RAS) and metabolic syndrome (MetS). Four groups of pigs (n = 6 each) were studied after 16 weeks of diet-induced MetS and RAS (MetS + RAS), MetS + RAS treated 4 weeks earlier with PTRA, and Lean and MetS Sham controls. Single-kidney renal blood flow (RBF) and glomerular filtration rate (GFR) were assessed in vivo with multidetector computed tomography, and renal tubular mitochondrial structure and function and renal injury ex vivo. PTRA successfully restored renal artery patency, but mean arterial pressure remained unchanged. Stenotic kidney RBF and GFR, which fell in MetS + RAS compared to MetS, rose after PTRA. PTRA attenuated MetS + RAS-induced mitochondrial structural abnormalities in tubular cells and peritubular capillary endothelial cells, decreased mitochondrial H2 02 production, and increased renal cytochrome-c oxidase-IV activity and ATP production. PTRA also improved cortical microvascular and peritubular capillary density and ameliorated tubular injury and tubulointerstitial fibrosis in the poststenotic kidney. Importantly, renal mitochondrial damage correlated with poststenotic injury and dysfunction. Renal revascularization attenuated mitochondrial injury and improved renal hemodynamics and function in swine poststenotic kidneys. This study suggests a novel mechanism by which PTRA might be relatively effective in ameliorating mitochondrial damage and improving renal function in coexisting MetS and RAS.

Kaempferol attenuates streptozotocin-induced diabetic nephropathy by downregulating TRAF6 expression: The role of TRAF6 in diabetic nephropathy

Ethnopharmacological relevanceKaempferia rhizome is a famous traditional herbal medical in tropical and subtropical areas. Kaempferol (KPF) is one of the main bioactive compounds in Kaempferia rhizome, with anti-oxidant/anti-inflammatory effects demonstrated in various disease models, including cancers, obesity and diabetes. Aim of the studyInflammation plays an important role in the pathogenesis of diabetic nephropathy (DN). TRAF6 functions as a signal transducer in toll-like receptor 4 and NF-κB pro-inflammatory signaling pathway. We aimed at investigate whether KPF is able to mitigate inflammatory responses by regulating TRAF6 in DN. Material and methodsC57BL/6 mice were injected with streptozotocin to induce type 1 DN. NRK-52E, a tubular epithelial cell line, was used for in vitro analysis. TRAF6 was knockdown using siRNA in vitro and AAV2/2-shRNA in vivo. The anti-DN and inflammatory effects of KPF or knockdown of TRAF6 were evaluated by investigating renal filtration index, pathological changes of kidney tissue. Proinflammatory cytokine levels were detected using ELISA. NF-κB pathway and protein levels of related pathways were detected through Western blot. ResultsKPF significantly reduced renal inflammation, fibrosis, and kidney dysfunction in diabetic mice. These effects were associated with a downregulation of TRAF6 in diabetic mouse kidneys, indicating the potential role of TRAF6. Knockdown of TRAF6 in mice through AAV2-shTRAF6 confirmed the importance of TRAF6 in DN. In vitro, treatment of KPF in NRK-52E cells attenuated high glucose (HG)-induced inflammatory and fibrogenic responses, associated with downregulated TRAF6 expression. The conclusion was further confirmed in NRK-52E cells by knocking down the expression and by overexpression of TRAF6. ConclusionOur findings provide direct evidence that TRAF6 mediates diabetes-induced inflammation leading to renal dysfunction. We also show that KPF is a potential therapeutic agent to reduce inflammatory responses in DN. Also, TRAF6 may represent an interesting target to combat DN.

Positron Emission Tomography-Magnetic Resonance Imaging Pharmacokinetics, In Vivo Biodistribution, and Whole-Body Elimination of Mn-PyC3A.

Mn-PyC3A is an experimental manganese (Mn)-based extracellular fluid magnetic resonance imaging (MRI) contrast agent that is being evaluated as a direct replacement for clinical gadolinium (Gd)-based contrast agents. The goals of this study were to use simultaneous positron emission tomography (PET)-MRI to (1) compare the whole-body pharmacokinetics, biodistribution, and elimination of Mn-PyC3A with the liver-specific contrast agent mangafodipir (Mn-DPDP), (2) determine the pharmacokinetics and fractional excretion of Mn-PyC3A in a rat model of renal impairment, and (3) compare whole-body elimination of Mn-PyC3A to gadoterate (Gd-DOTA) in a rat model of renal impairment. Mn-PyC3A and Mn-DPDP were radiolabeled with the positron emitting isotope Mn-52 via Mn2+ exchange with 52MnCl2. Dynamic simultaneous PET-MRI was used to measure whole-body pharmacokinetics and biodistribution of Mn-52 immediately and out to 7 days after an intravenous 0.2 mmol/kg dose of [52Mn]Mn-PyC3A to normal or to 5/6 nephrectomy rats or a 0.01 mmol/kg dose of [52Mn]Mn-DPDP to normal rats. The fractional excretion and 1- and 7-day biodistribution in rats after the injection of 2.0 mmol/kg [52Mn]Mn-PyC3A (n = 11 per time point) or 2.0 mmol/kg Gd-DOTA (n = 8 per time point) were quantified by gamma counting or Gd elemental analysis, respectively. Comparisons of Mn-PyC3A pharmacokinetics and in vivo biodistribution in normal and 5/6 nephrectomy rats and comparisons of ex vivo Mn versus Gd biodistribution data in 5/6 nephrectomy were made with an unpaired t test. Dynamic PET-MRI data demonstrate that both [52Mn]Mn-PyC3A and [52Mn]Mn-DPDP were eliminated by mixed renal and hepatobiliary elimination but that a greater fraction of [52Mn]Mn-PyC3A was eliminated by renal filtration. Whole-body PET images show that Mn-52 from [52Mn]Mn-PyC3A was efficiently eliminated from the body, whereas Mn-52 from [52Mn]Mn-DPDP was retained throughout the body. The blood elimination half-life of [52Mn]Mn-PyC3A in normal and 5/6 nephrectomy rats was 13 ± 3.5 minutes and 23 ± 12 minutes, respectively (P = 0.083). Area under the curve between 0 and 60 minutes postinjection (AUC0-60) in the bladder of normal and 5/6 nephrectomy rats was 2600 ± 1700 %ID/cc*min and 750 ± 180 %ID/cc*min, respectively (P = 0.024), whereas AUC0-60 in the liver of normal and 5/6 nephrectomy rats was 33 ± 13 %ID/cc*min and 71 ± 16 %ID/cc*min, respectively (P = 0.011), indicating increased hepatobiliary elimination in 5/6 nephrectomy rats. The %IDs of Mn from [52Mn]Mn-PyC3A and Gd from Gd-DOTA recovered from 5/6 nephrectomy rats 1 day after injection were 2.0 ± 1.1 and 1.3 ± 0.34, respectively (P = 0.10) and 7 days after injection were 0.14 ± 0.11 and 0.41 ± 0.24, respectively (P = 0.0041). Mn-PyC3A has different pharmacokinetics and is more efficiently eliminated than Mn-DPDP in normal rats. Mn-PyC3A is efficiently eliminated from both normal and 5/6 nephrectomy rats, with increased fractional hepatobiliary excretion from 5/6 nephrectomy rats. Mn-PyC3A is more completely eliminated than Gd-DOTA from 5/6 nephrectomy rats after 7 days.

Kidney Physiology in Pregnancy.

A woman's body undergoes a myriad of changes throughout the course of a normal gestation. The kidneys play a central role in driving adjustments that guarantee maternal and fetal well-being, including a dramatic increase in glomerular filtration rate, alterations in tubular function, and changes in electrolyte and acid/base handling. Early in gestation, systemic vasodilation, driven by both a change in quantity of and response to various hormones, leads to increased renal blood flow and glomerular filtration rate. Vasodilation also results in activation of the renin-angiotensin-aldosterone axis, which combined with changing tubular handling causes alterations in total body stores of electrolytes and total body water, resulting in a lower serum sodium concentration. In addition, mild proteinuria, glucosuria, and a decrease in serum calcium and magnesium are common. The primary acid/base change seen in pregnancy is a mild respiratory alkalosis due to progesterone effects. This article provides an overview of the current understanding of the healthy response of the kidneys to pregnancy, an understanding of which is key to caring for the pregnant patient, and early identification of alterations that may indicate underlying kidney pathology in pregnancy.

Mortality risk assessment in type 2 cardiorenal syndrome: comparative study

Abstract Background Type 2 cardiorenal syndrome is a serious, life threatening clinical condition, associated with adverse clinical outcomes. Although several prognostic biomarkers have been reported, early and accurate prognosis still remains a challenge. Aims This study was aimed to identify the best prognostic renal markers, to develop and validate an individualized predictive formula for the mortality risk in type 2 cardiorenal patients. Methods A total of 170 hospitalized patients (between 2014 and 2018) were included in this study. Renal function and glomerular filtration rate (GFR) was assessed using the most popular formulas for GFR estimation: the Cockcroft-Gault (CG), the four-variable Simplified Modification of Diet in Renal Disease (sMDRD), CKD-Epidemiology Collaboration (CKD-EPI) based on serum cystatin-C, creatinine and their combination, and the simple cystatin-C formula. All data were used to screen the predictors via univariate and multivariate analyses. A model was developed based on these predictors and validated by internal validation. The model validation comprised discriminative ability determined by the area under the curve (AUC) of receiver operating characteristic (ROC) curve and the predictive accuracy by calibration plots. Results During a mean follow-up of 6 months, 29 (16.2%) deaths were recorded. In an adjusted model, renal biomarkers and estimated glomerular filtration rate showed different prognostic value according to the area under the curve. Area under the ROC curve was 0.58 (95% CI:0.47–0.69, P=0.05) for serum creatinine, 0.67 (95% CI: 0.56–0.79, P&amp;lt;0.05) for serum cystatin-C; 0.76±0.05 (95% CI: 0.67–0.82, P&amp;lt;0.01) for CKD-EPI formula based on serum cystatin-C; 0.73±0.06 (95% CI: 0.65–0.79, P&amp;lt;0.01) for simple formula based on serum cystatin-C; 0.72±0.05 (95% CI: 0.64–0.79, P&amp;lt;0.01) for CKD-EPI formula based on serum cystatin-C and serum creatinine; 0.617±0.06 (95% CI: 0.53–0.69, P&amp;lt;0.01) for CKD-EPI formula based on serum creatinine; 0.615±0.06 (95% CI: 0.53–0.69, P&amp;lt;0.01) for sMDRD formula and 0.58±0.07 (95% CI: 0.53–0.69, P&amp;lt;0.01) for CG formula. Multivariate logistic regression revealed that cardiovascular disease length, psycho-emotional stress, NYHA class, hemoglobin, serum cystatin-C and GFR using the simple cystatin-C formula were independently associated with mortality in type 2 cardorenal syndrome. A model developed based on the seven variables had a specificity of 79.31%, and sensitivity 78.72% (P&amp;lt;0.01), while AUC was 0.792 (P&amp;lt;0.01), in internal validation. Conclusion GFR is an independent predictor for short term mortality of type 2 cardiorenal syndrome. Cystatin-C based formulas seems to offer improved prognostication in this population, while CG formula and serum creatinine fail to predict short term mortality The proposed model could predict the individualized mortality risk with good accuracy, high discrimination, and potential clinical applicability in cardiorenal patients. Funding Acknowledgement Type of funding source: None