Increase In Protein Excretion Research Articles

Features of the development of experimental nephropathy in rats during the use of doxorubicin

BACKGROUND. One of the most frequently reproduced models of NS is doxorubicin (adriamycin) nephropathy in rats. However, the mechanisms of its development remain insufficiently studied, and it is not entirely clear to which form of NS the nephrotoxicity induced by doxorubicin should be attributed.THE AIM. Reproduction of doxorubicin nephropathy in rats in an attempt to morphologically identify the resulting pathology and determine the role of free radical oxidation (FRO) in the development of this model of nephrotoxicity.MATERIALS AND METHODS. Nephropathy was reproduced by a single intravenous administration of doxorubicin to male Wistar rats. In the urine, the content of creatinine, daily proteinuria, and albumin release were determined. Histological examination of the kidneys was performed using a Libra 120 electron microscope (Carl Zeiss, Germany). The total prooxidant activity, total antioxidant activity, the concentration of thiobarbiturate-reactive products, and the activity of antioxidant enzymes were assessed in the blood and kidney.RESULTS. Against the background of a gradual decrease in the glomerular filtration rate, a significant consistent increase in protein excretion was recorded, largely due to an increase in albumin excretion. Electron microscopic examination revealed a decrease in the number of small (foot) processes of podocytes, their fusion, sclerotic lesions of the elements of the capillary glomerulus, thinning of the GBM, sclerosis of the interstitium. There was a sharp activation of blood OPA and an increase in the content of TBRP. At the same time, such fast-responding antioxidant enzymes as CAT and SOD were activated. The blood TAA decreased in parallel with the decrease in GPO activity.CONCLUSION. Intravenous administration of doxorubicin to rats induced the development of toxic kidney damage with signs of NS. A characteristic indicator was the development of PU against the background of a decrease in GFR from day 5 and increased many times by the end of the observation period. The greatest contribution to the development of PU was made by an in-crease in albumin excretion. Morphological examination of the kidneys using electron microscopy made it possible to conclude with a high degree of probability that the developed pathology and FSGS are similar. At the same time, FRO activation was recorded, which was expressed in a sig-nificant pro-oxidant effect and a significant decrease in the antioxidant activity of the blood.

Late first trimester circulating microparticle proteins predict the risk of preeclampsia

We hypothesize that first trimester circulating micro particle (CMP) proteins will define preeclampsia risk while identifying clusters of disease subtypes among cases. We performed a nested case–control analysis among women with and without preeclampsia. Cases diagnosed < 34 weeks’ gestation were matched to controls. Plasma CMPs were isolated via size exclusion chromatography and analyzed using global proteome profiling based on HRAM mass spectrometry. Logistic models then determined feature selection with best performing models determined by cross-validation. K-means clustering examined cases for phenotypic subtypes and biological pathway enrichment was examined. Our results indicated that the proteins distinguishing cases from controls were enriched in biological pathways involved in blood coagulation, hemostasis and tissue repair. A panel consisting of C1RL, GP1BA, VTNC, and ZA2G demonstrated the best distinguishing performance (AUC of 0.79). Among the cases of preeclampsia, two phenotypic sub clusters distinguished cases; one enriched for platelet degranulation and blood coagulation pathways and the other for complement and immune response-associated pathways (corrected p < 0.001). Significantly, the second of the two clusters demonstrated lower gestational age at delivery (p = 0.049), increased protein excretion (p = 0.01), more extreme laboratory derangement (p < 0.0001) and marginally increased diastolic pressure (p = 0.09). We conclude that CMP-associated proteins at 12 weeks’ gestation predict the overall risk of developing early preeclampsia and indicate distinct subtypes of pathophysiology and clinical morbidity.

Development of Maternal Syndrome in the Dahl Salt‐Sensitive Rats Is Dependent on T Cells

Preeclampsia (PE) is characterized by hypertension and proteinuria (maternal syndrome) during pregnancy. We previously demonstrated that Dahl SS rats fed low salt develop maternal syndrome relative to virgin controls. Since T cells are important to amplify salt‐sensitive hypertension, we tested the hypothesis that T cells mediate the development of maternal syndrome in the Dahl SS. We tested this hypothesis in two ways: 1) by utilizing Dahl SS rats lacking T cells, SSCD247−/− rats, to investigate their pregnancy phenotype and 2) by reconstituting T cells into SSCD247−/− rats via adoptive transfer of splenocytes from Dahl SS donors. Eight week old SSCD247−/− rats were implanted with radio‐telemeters for continuous measurement of mean arterial pressure (MAP) and allowed to recover for a week. In addition to measurement of MAP, overnight urine samples were collected for proteinuria analysis before mating and throughout pregnancy. SSCD247−/− rats were mated with same age and strain males and virgin controls were run in parallel. In contrast to pregnant SS which demonstrate elevated blood pressure and proteinuria in pregnancy, the increase in protein excretion in late pregnancy relative to baseline (52.2±8 vs 23.4±3.6 mg/day, p&lt;0.05, n=10/group) in mated SSCD247−/− rats is significantly less than in the pregnant SS. Moreover, the increased protein excretion is accompanied with a significant decrease in MAP at gestational day 20 from (117±2mmHg) compared to the virgin SSCD247−/− at gestational day 20 (132±4mmHg, p&lt;0.0001). The blunted proteinuria and decreased MAP in the SSCD247−/− compared to the SS suggests that T cells mediate the maternal syndrome in the SS. To further interrogate the role of T cells in the pathogenesis of maternal syndrome, we reconstituted T cells in SSCD247−/− rats via adoptive transfer of splenocytes (~10 million) from SS rats by intraperitoneally injection at postnatal day 5 before the thymus was fully formed. The recipients designated for the mated group were mated at 8 weeks of age with SSCD247−/− rats. Animals underwent the same protocol as previously mentioned. At baseline, there was no significant difference in protein excretion between recipient virgin and mated groups (44.1±7.5 vs. 27.0±5.6 mg/day, p&gt;0.05) or MAP (122±5 vs. 121±4 mmHg, p&gt;0.05, n=5/group). The mated recipients develop a pregnancy‐specific increase in protein excretion throughout pregnancy that is absent in the virgin controls (100.9±8 vs. 53.3±6 mg/day, p&lt;0.01). Despite the proteinuria, not all mated SSCD247−/− receiving the splenocyte transfer developed increased MAP; however, there was a significant increase in infiltrating leukocytes into the kidneys with ~7% of CD3+ T cells, which were primarily CD4+ T cells (~70%). Interestingly, a direct comparison of the mated recipients compared to the mated SSCD247−/− rats reveals that introducing T cells into the SSCD247−/− rat is sufficient to induce a maternal syndrome‐like level of proteinuria, highlighting the importance of T cells as a mechanism of maternal syndrome.Support or Funding InformationSupported by HL116264, 18POST33990140 and 15SFRN2391002

Effect of Fructose Overconsumption since Early Age on Renal Function and Sympathetic Nerve Activity

Increased consumption of ready‐to‐eat foods and beverages that contain high fructose content may contribute to the onset of cardiovascular and renal diseases. Moreover, fructose overload in diet since prenatal period may increase the risk of the offspring to diseases later in life. Thus, the objective of this study was to evaluate the effects of increased consumption of fructose since prenatal period until adulthood on: blood pressure, renal function and renal sympathetic nerve activity of the offspring at adulthood.MethodsFemales Wistar rats were randomly assigned to groups: Control (C) and Fructose (F). The C group received food and drinking water ad libitum, and F group received food and D‐fructose solution (20%) for drinking ad libitum. In F, the offer of D‐fructose solution begun 1 week before mating and continued during pregnancy and lactation. After birth, the progeny was limited to 8 offspring and designated as Control Offspring (CO) and Fructose Offspring (FO). At 21st day of life, male offspring were placed in collective cages and received the same treatment of the dams. The experiments were performed at 4 months old rats. Direct measurement of systolic arterial blood pressure and mean arterial blood pressure (SAP and MAP), and the registration of the renal sympathetic nerve activity (RSNA) were performed in 6 animals of each group (CO and FO). The renal function parameters were evaluated in other 6 rats of each group. Renal parameters evaluated: glomerular filtration rate (GFR ‐ inulin clearance), renal plasma flow (RPF ‐ PAH clearance), protein excretion (EProt), urine osmolarity (Uosm), urinary excretion/24 h (V), sodium (ENa+) and potassium (EK+) excretion. The study was approved by the Ethical Research Committee of the Universidade Federal de São Paulo (protocol: 2757270117).ResultsCompared with CO group, FO presented higher values of SAP (FO: 165 ± 5 vs CO: 141 ± 6 mmHg) and MAP (FO: 130 ± 5; CO: 110 ± 4 mmHg). FO had decreased GFR (FO: 5.1 ± 0.7; CO: 8.4 ± 0.5 ml/min/kg), Uosm (FO: 305 ± 60; CO: 1522 ± 81 mosm/l) and potassium excretion (FO: 182 ± 18; CO: 302 ± 28 mM/24 h). The urine excretion and protein excretion were increased in FO compared with CO group (V: FO: 52 ± 1; CO: 14 ± 0.7 ml/24 h; EProt: FO: 10.3 ± 1; CO: 6.4 ± 1 mg/24 h). There were no significant differences between the groups regarding the baseline RSNA (FO: 59 ± 4; CO: 71 ± 14 spikes/s), RPF (FO: 15.0 ± 2; CO: 16.2 ± 1 ml/min/kg) and sodium excretion (FO: 91.2 ± 15; CO: 85.7 ± 15 mM/24 h). Values are presented as mean ± sem, p ≤ 0.05.ConclusionsOur data show that increased consumption of fructose since early age leads to increase in blood pressure and alterations in renal function in the offspring (reduced: GFR, urine osmolarity and potassium excretion; and increased protein excretion).Support or Funding InformationCAPESThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

MEXIDOL EFFECT ON THE MORPHOFUNCTIONAL STATE OF KIDNEYS DURING PROGRESSION OF FIRST FEVER STAGE

Structural-functional state of kidneys under conditions of aseptic fever development, induced by pyrogenal (25 mg/kg) injection, was studied in the experiment on 36 white non-linear male rats weighting 0.16-0.2 kg, maintained on hypo-sodium diet. The identified changes included reduction of glomerular filtration rate and proximal sodium reabsorption, increase of protein excretion, vacuolar epithelial dystrophy of the proximal tubules, and focal character of changes in protein properties with the shift of colouring to red colour during the first fever stage. Determined modifications reflect the intensification of the compensatory reactions, directed on the providing of body temperature rise during the first fever stage through increasing of heat production and limitation of heat loss. A significant protective effect of mexidol on the structural-functional state of kidneys during the progression of first fever stage is demonstrated.

Drinking water salinity and kidney health in southwest coastal Bangladesh: baseline findings of a community-based stepped-wedge randomised trial

BackgroundDrinking water salinity has contributed to scarcity of potable water in southwest coastal Bangladesh. Drinking saline water has been associated with high blood pressure among communities in southwest coastal Bangladesh, but the effect of water salinity on kidney health is unknown. We aimed to understand the association between drinking water salinity and urinary protein excretion from the baseline findings of a community-based stepped-wedge randomised trial. MethodsWe collected 24-h urine from 1185 participants from 532 households and 16 communities in three districts (Khulna, Satkhira, and Bagerhat) of southwest coastal Bangladesh between Nov 17, and Dec 21, 2016, and measured urinary sodium and total protein. We measured electrical conductivity in sampled households' stored drinking water. We estimated water chloride concentration by using a published conversion factor and then estimated daily sodium intake by drinking water assuming sodium ions will be coupled with chloride in water. Among normotensive participants who reported exclusively drinking household stored water, and did not report kidney or heart diseases or diabetes, we determined the effects of daily sodium intake by water and urinary sodium on total protein using hierarchical models accounting for household and community level clustering, and adjusted for age, sex and, weight. FindingsMean urinary sodium was 164 mmoL/24 h and total protein was 402 mg/24 h. Mean sodium intake through drinking water was 17 mmoL per day. For each 1000 μS/cm higher in drinking water electrical conductivity, there was a 8·2 mmoL/24 h (95% CI 5·3–11·1) higher excretion of 24-h urinary sodium. For each 10 mmoL increase in estimated daily sodium intake through drinking water, there was a 15·9 mg/24 h (95% CI 0·3–31·6) increase in total protein. We estimated a 62·9 mg/24 h (95% CI 29·7–96·1) increase in total protein for each 100 mmoL/24 h increase urinary sodium. We identified 37% participants that had mild proteinuria (total protein: 300–500 mg/24 h) and 20% had moderate or substantial proteinuria (total protein: >500 mg/24 h). InterpretationDrinking water sodium and urinary sodium were associated with increased protein excretion—a powerful marker for progressive kidney disease—in southwest coastal Bangladesh. Interventions aimed at lowering drinking water salinity could provide benefit to kidney health. FundingWellcome Trust, UK.

Urine Protein SDS-PAGE Reveals Different Profiles in Iraqi Children with Kala-azar

Urine proteomics have been an area of interest and recently in Kala-azar as an alternative sample type for serum or plasma. Because of simplicity, noninvasiveness of collection and simpler matrix. Many studies had detected an increased protein excretion in the urine of patients with active Kala-azar due to renal involvement particularly by an immunological related mechanism(s). This study have demonstrated the presence of three different protein profiles in Iraqi children (Patients: including 60 children aged 4-60 months) with defined Kala-azar using the conventional SDS-PAGE on urine samples. Urine protein profile in Kala-azar patients revealed three groups of banding patterns: group-1(33.4)% of the patients show the pattern of 5 bands with a MW. Ranged (512.861-158.489), groups-2, 3 were (55, 11.6) % of the patients showing 2 banding proteins with a MW. ranged (512.861-199.526) , (199.526-181.97) respectively. These findings may be correlated with other epidemiological studies that revealed the presence of different clinical presentations like fever, spleenomegally, hepatomegally, thrombocytopaenia, and different response to leishmania therapy. Furthermore, the presence of different protein patterns may also be related to the chronicity of infection and the degree of renal involvement. The presence of a similar protein band between group-1 and 2 may be of diagnostic purpose and further studies on expanded number of patients are required to identify that kind of protein or other urine protein profiles. &#x0D; Key words: Protein band, protein pattern, sodium dodecyl sulphate-poly acrylamide gel electrophoresis (SDS-PAGE), urine proteome, visceral leishmaniasis.

20 Defective placental bed vascular remodeling precedes manifestations of superimposed preeclampsia in stroke-prone spontaneously hypertensive rats

Introduction Pregnant women suffering from chronic hypertension are at increased risk of developing superimposed preeclampsia (SPE), often associated with poor fetal and maternal outcomes. Most animal models available to date reproduce ‘de novo' PE-like features through different experimental approaches, but the development of a SPE syndrome in pregnant animals with pre-existing arterial hypertension has been greatly overlooked in basic research pertaining hypertensive pregnancies. Objectives To characterize timed pregnancies in the Stroke Prone Spontaneously Hypertensive Rat (SHRSP) strain, a well-known model for essential hypertension, focusing on the development of clinical, fetal and placental manifestations of SPE. Methods SHRSP and Wistar Kyoto (WKY) females (10–12weeks old, N =5animals/day analyzed) were mated to congenic males and checked daily for vaginal plugs, denoted as gestation day (GD) 1. Blood pressure (BP) was determined by the tail-cuff method pre-mating and on the morning of GD1, 7, 9, 13, 17 and 19. On the selected dates, females were housed in metabolic cages for collection of 24h urine samples. Following collection of blood samples, animals were euthanized and implantation sites isolated for morphological analyzes. Fetal and placental weights were recorded on GD 18 and GD20. Results Compared to WKY, the SHRSP exhibited a significant elevation of baseline hypertension towards the last third of pregnancy (i.e, from GD13 to GD20) together with increased protein excretion, considered diagnostic hallmarks for SPE. Renal compromise was also evident as a progressive decrease of urinary output and histopathological changes in the glomerular and tubulointerstitial compartments of SHRSP kidneys. The SHRSP offspring were growth restricted and morphometrical analyzes showed underlying abnormal placentation, including signs of placental insufficiency such as decreased fetal to placental weight ratio and hypertrophy of the labyrinth layer linked to defective vascularization. Notably, our analysis also showed that the onset of the maternal syndrome was preceded by incomplete remodeling of the placental bed spiral arteries, which showed luminal narrowing and decreased densities of perivascular uterine NK cells at GD14 followed by defective infiltration of endovascular trophoblasts at GD18. Conclusion Our data confirms the characterization of pregnant SHRSP as a model reproducing clinical diagnostic traits and the underlying placental pathology observed in preeclampsia superimposed on chronic hypertension. This novel model provides an attractive system for interventional studies and dissection of the multifactorial origins of hypertensive disorders of pregnancy.

Association between urine protein/creatinine ratio and cognitive dysfunction in Lewy body disorders

BackgroundImpaired renal function and proteinuria have been associated with cognitive impairment and dementia. Chronic kidney disease is considered to be an independent risk factor for Lewy body spectrum disorders (LBD). However, few studies have mentioned an association between proteinuria and cognition in LBD. We investigated the relationship between proteinuria and cognitive dysfunction in patients with Parkinson's disease (PD) and dementia with Lewy bodies (DLB). MethodsAmong 186 patients with LBD, 53 had PD-normal cognition (PD-NC), 76 had PD-mild cognitive impairment (PD-MCI), 43 had PD-dementia (PDD) and 14 had DLB. The urine protein/creatinine ratio was calculated using the spot urine test and brain magnetic resonance scans was obtained in all patients. ResultsThe urine protein/creatinine ratio was significantly higher in patients with PDD and DLB than in those with PD-MCI, PD-NC patients and healthy controls, and was correlated with white matter hyperintensities on magnetic resonance imaging. All abnormal neuropsychological test results were associated with increased urine protein/creatinine ratio. After controlling for age, education, symptom duration, diabetes mellitus, hypertension, and parkinsonian motor severity, the urine protein/creatinine ratio was significantly associated with decreased cognition. ConclusionThe urine protein/creatinine ratio was associated with cognitive status in LBD. These finding suggests that increased protein excretion is associated with cognitive dysfunction in patients with LBD.

A cross-sectional study of renal donors

BACKGROUND: Living kidney donors donate half of their nephrons there are endowed with. The loss of one of their kidneys leads to hyperfiltration and compensatory changes in the remnant kidney. The degree of hyperfiltration, increase in protein excretion, increase in blood pressure, Hb status and development of metabolic complication is of interest. SUBJECTS AND METHODS: Thirty kidney donors were evaluated with BP recording, urinalysis, renal fuction tests, kidney size and glycemic status. Their eGFR was calculated by CG formula, aMDRD and CKD EPI creatinine equations. The GFR was measured by 99mTc-DTPA .All observations were compared with pre-donation data. The earliest period of evaluation was done 4 months post-donation and the latest patient was evaluated 13 years post donation. The median period of evaluation was 29 months. RESULTS: GFR measured by 99mTc-DTPA of the remnant kidney in all the donors was well within the normal range. And the degree of compensatory increase was more for younger donors. Peri-opertive complications occurred in 16.5%. Impaired fasting glucose was seen in 5 (16.5%), of which 4 of them were obese. Hypertension was seen in 6%. Though there increase in spot PCR post-donation, it was well within normal limits. eGFR calculated by CG formula, aMDRD and CKD EPI creatinine equations did not correlate with the GFR measured by 99mTc-DTPA, both pre and post donation. There was significant compensatory increase in kidney size. CONCLUSIONS: Renal compensation, in size and function leads to increase in GFR to normal levels. Impaired fasting glucose seen in 16.5% of our donors raises concern and stresses the need for stringent post-operative donor follow-up.

Catheter-based induction of renal ischemia/reperfusion in swine: description of an experimental model.

Several techniques to induce renal ischemia have been proposed: clamp, PVA particles, and catheter‐balloon. We report the development of a controlled, single‐insult model of unilateral renal ischemia/reperfusion (I/R) without contralateral nephrectomy, using a suitable model, the pig. This is a balloon‐catheter‐based model using a percutaneous, interventional radiology procedure. One angioplasty balloon‐catheter was placed into the right renal artery and inflated for 120 min and reperfusion over 24 h. Serial serums were sampled from the inferior vena cava and urine was directly sampled from the bladder throughout the experiment, and both kidneys were excised after 24 h of reperfusion. Analyses of renal structure and function were performed by hematoxylin–eosin/periodic Acid‐Schiff, serum creatinine (SCr), blood urea nitrogen (BUN), fractional excretion of ions, and glucose, SDS‐PAGE analysis of urinary proteins, and serum neutrophil gelatinase‐associated lipocalin (NGAL). Total nitrated protein was quantified to characterize oxidative stress. Acute tubular necrosis (ATN) was identified in every animal, but only two animals showed levels of SCr above 150% of baseline values. As expected, I/R increased SCr and BUN. Fractional sodium, potassium, chloride, and bicarbonate excretion were modulated during ischemia. Serum‐nitrated proteins and NGAL had two profiles: decreased with ischemia and increased after reperfusion. This decline was associated with increased protein excretion during ischemia and early reperfusion. Altogether, these data show that the renal I/R model can be performed by percutaneous approach in the swine model. This is a suitable translational model to study new early renal ischemic biomarkers and pathophysiological mechanisms in renal ischemia.

Plasmapheresis combined with rituximab for refractory idiopathic membranous nephropathy

Idiopathic membranous nephropathy (IMN) is known to be one of the most common causes of nephrotic syndrome in adults [1]. Severe therapy-refractory IMN is a life-threatening disease and demands new treatment options. We report the first successful treatment for severe therapy-refractory INM with a combination of plasmapheresis and rituximab. A 34-year-old male Caucasian was admitted to the hospital with newly developed peripheral edema. Kidney function was normal, whereas proteinuria exceeded 6.2 g protein/g creatinine (normal value: \0.15 g protein/g creatinine) and the serum albumin level was decreased (2.6 g/ dl, normal value: 3.5–5.4 g/dl). Kidney biopsy showed typical membranous glomerulopathy with subepithelial immunoglobulin-containing deposits along the glomerular basement membrane. The causes of secondary membranous nephropathy (MN) such as hepatitis, HIV, autoimmune disease and cancer were excluded. A high titer of anti-phospholipase A2 receptor antibody was detected in serum (1:640) by indirect immunofluorescence. Initially, the patient was treated with an angiotensinconverting enzyme (ACE) inhibitor, an angiotensin II receptor blocker (ARB), an anticoagulant and prednisolone (60 mg/day, progressively tapered to 5 mg/day). Six months later, his condition deteriorated. Serum creatinine level increased to 1.5 mg/dl (135 lmol/l) while serum albumin declined to 1.5 g/dl (15 g/l). The patient was still heavily proteinuric (4.6 g protein/g creatinine). The treatment was then complemented by cyclosporine (CsA) and switched later to tacrolimus (Tac) due to side effects. However, his condition further deteriorated rapidly with increased protein excretion (8.8 g protein/g creatinine). He gained 20 kg in 3 weeks and showed increased peripheral edema and dyspnea. We decided to perform a combined treatment with plasmapheresis (d1-3, d5, d7) followed by two infusions of rituximab (d8 ? d28). Each plasmapheresis was performed over 2–3 h, using 5,000 ml of fresh frozen plasma (FFP), approximately 1.2 times the circulating plasma volume, as a replacement fluid. Subsequently, the patient received intravenous infusions of rituximab (375 mg/m, d8 ? d28). Complete remission of nephrotic syndrome was achieved 8 weeks later. The concentration of anti-PLA2R antibodies in the serum was continuously reduced during the treatment and eventually disappeared during remission (Fig. 1). Protein excretion was below 0.3 g/day in eight consecutive visits under ACE inhibitor/ARB treatment. Despite numerous studies, the optimal treatment for IMN remains disputable. Remuzzi et al. [2] reported the therapeutic benefit of rituximab in high-risk patients with IMN. However, remission was achieved in a relatively long time frame, between 3.2 and 12.0 months. As our patient was non-responsive to conservative treatment and immunosuppression including steroids, CsA and Tac, his condition was too critical to allow time for exclusive rituximab treatment to take effect. Therefore, the patient received plasmapheresis treatments in order to rapidly eliminate all possible antibodies and immune M. Wen C. Kuchle O. Sarkar L. Renders U. Heemann C. Schmaderer (&) Department of Nephrology, Klinikum rechts der Isar, Technische Universitat Munchen, Ismaninger Strase 22, 81675 Munich, Germany e-mail: christoph.schmaderer@lrz.tu-muenchen.de

Clinical Implications

HomeHypertensionVol. 62, No. 5Clinical Implications Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBClinical Implications Originally published1 Nov 2013https://doi.org/10.1161/01.hyp.0000436210.57019.2eHypertension. 2013;62:809HT/PET-MPs (Gestational Hypertension and Preeclampsia/Toxemia-Microparticles) Affect Trophoblast and Endothelial Function (page 893)Hypertensive disorders of pregnancy are common vascular pathologies having severe implications for maternal and fetal health. Unraveling the complex pathogenesis of gestational vascular complications is crucial for their prevention and improved management.Previously, microvesicles (MVs) were shown to affect coagulation and inflammation in pregnancy. Our study demonstrates that MVs obtained from women with gestational hypertension and preeclampsia present higher levels of antiangiogenic proteins and proinflammatory cytokines. The present study shows that in contrast to MVs of healthy pregnant women, gestational vascular complication MVs do not induce early stage trophoblast migration (Figure S5), inhibit endothelial tube formation, and cause massive apoptosis in term trophoblasts. This indicates the involvement of MVs in placental development at early gestational ages and in placental health at late stages of pregnancy.Recent studies suggested that LMWH (low molecular weight heparin) could improve the outcome of women with gestational vascular complications. The mechanisms through which LMWH exert its effect are multifaceted, involving maternal and placental anticoagulation, as well as anti-inflammatory and complement pathway activity. The findings of the current study highlight that MVs are a new critical player participating in physiological mechanisms of placental development and in the pathology of hypertensive disease in pregnancy. Furthermore, these data could foster our understanding of LMWH effects in this challenging clinical setting.Download figureDownload PowerPointAmyloid-β Peptides (page 966)Alzheimer disease (AD) is the most common form of dementia with 27 million known cases worldwide. Its incidence is rapidly increasing, and there are no effective treatments. The cause is essentially unknown. Initially, defective cholinergic signaling was implicated. Subsequently, the role of amyloid deposits and the amyloid precursor protein was added to the picture. Amyloid-β (Aβ) is a peptide of 36 to 43 amino acids that is processed from amyloid precursor protein. A specific isoform of apolipoprotein, APOE4, is a major genetic risk factor for AD. Apolipoproteins enhance the breakdown of Aβ, but APOE4 is not very effective, leading to an excess amyloid buildup in the brain. Tau proteins stabilize microtubules. They are abundant in neurons of the central nervous system. Hyperphosphorylated tau pairs with other threads of tau eventually forming neurofibrillary tangles inside nerve cell bodies. Viruses, prions, oxidative stress, biometal biology, and numerous other factors are also implicated in AD including small-vessel vascular disease. Could AD be in part a vascular disorder? Indeed, amyloid can cause abnormal vascular reactivity. We found that Aβ induced vasoconstriction of coronary arteries in Langendorff-perfused rat hearts. Aβ bound to the α1 adrenoreceptor, thereby inducing a signal-transduction cascade with cytosolic calcium and extracellular-related kinase phosphorylation in vascular smooth muscle cells. Thus, Aβ itself could be a vascular signaling molecule. Aβ induced vasoconstriction, decreased coronary blood flow, and exhibited α1 adrenoreceptor–mediated signaling. Nonetheless, an in vivo model is necessary to pursue translation of our findings. The implications from our work are that successful therapies directed at AD will probably contain a component addressing the participation of blood vessels. The α1 adrenoreceptor has appeal as a target because the compounds are clinically in use. Furthermore, our notion could be investigated epidemiologically.Download figureDownload PowerPointHypoxia and Development of Nephropathy (page 914)It is well established that kidney hypoxia is present in diseases closely associated with development of nephropathy, such as diabetes mellitus and hypertension. The hypothesis that chronic kidney hypoxia results in the development of nephropathy was originally proposed in 1998 and has since gained increasing support. However, the specific contribution of kidney hypoxia for the development of nephropathy is difficult to determine because of the presence of confounding factors, such as hyperglycemia, hypertension, and oxidative stress. To identify the specific role of kidney hypoxia, Friederich-Persson et al treated normoglycemic control rats with dinitrophenol, a mitochondrial uncoupler, which increases the mitochondrial oxygen consumption. Consequently, treatment with dinitrophenol increased total kidney oxygen consumption and resulted in kidney hypoxia. Interestingly, this resulted in nephropathy evidenced as increased protein excretion and tubulointerstitial damage. Importantly, there was no hyperglycemia, hypertension, or increased oxidative stress levels after dinitrophenol treatment. Thus, the main conclusion was that kidney tissue hypoxia is an independent pathway for the development of nephropathy. Being able to detect and target early alterations in intrarenal oxygen metabolism may be important for patients at risk of developing nephropathy. As such, interventions to prevent excessive kidney oxygen consumption or to restore kidney tissue oxygen availability may prove beneficial in preventing nephropathy in patients.Download figureDownload PowerPoint Previous Back to top Next FiguresReferencesRelatedDetails November 2013Vol 62, Issue 5 Advertisement Article InformationMetrics © 2013 American Heart Association, Inc.https://doi.org/10.1161/01.hyp.0000436210.57019.2e Originally publishedNovember 1, 2013 PDF download Advertisement

Reduced uterine perfusion pressure model is not successful to mimic severe preeclampsia

The aim of the study was to investigate maternal (hemoglobin, hematocrit, and biochemical parameters of blood and urine) and fetal parameters (number and weight of alive fetus) of preeclampsia in a rat model. Placental oxidative stress markers (protein carbonyl, malondialdehyde) and placental antioxidant values (CuZn-superoxide dismutase, glutathione peroxidase) were also measured. Preeclampsia was induced experimentally in timed-pregnant Sprague–Dawley rats by using the reduced uterine perfusion pressure (RUPP) model. Placental oxidative stress that plays a key role in the pathophysiology of placenta-related disorders, most notably preeclampsia (PE) and intrauterine growth restriction (IUGR) were demonstrated by using RUPP model. On day 14 of gestation, silver clips were placed around the aorta below the renal arteries and on the left and right uterine arcade at the ovarian artery. In the RUPP model animals (n = 15), when compared with the normotensive controls (n = 15), arterial pressure on day 19 of gestation was significantly higher in the RUPP rats (151.7 ± 17.6 mmHg) than normal pregnant rats (113.9 ± 11.4 mmHg). The RUPP rats showed a significant increase in protein excretion when compared with the normal pregnant rats (0.3 ± 0.04 vs 0.47 ± 0.07 g/dL) (p < 0.05). Associated with the hypertension in RUPP rats, placental levels of malondialdehyde (2.4 ± 0.2 vs. 1.6 ± 0.2 umol/gm tissue) and protein carbonyl (1.4 ± 0.3 vs. 0.9 ± 0.3 nmol/mg protein) were increased, while superoxid dismutase (0.03 vs 0.42 U/mg protein) and glutathione peroxidase (1.04 ± 0.31 vs 0.76 ± 0.22 U/g protein) were decreased. Pup number (6.6 ± 3.1 vs. 9.93 ± 2.0) and litter weight (17.4 ± 7.7 vs. 22.9 ± 6.7 g) were lower in the preeclamptic group. None of the complete blood counts and biochemical values other than sodium and chlorine were significantly different in preeclamptic group. Our findings suggest that the RUPP model cannot mimic severe preeclampsia; however, further studies using different settings may be helpful to obtain a preeclampsia model that is capable of succesfully producing severe preeclampsia findings.

World Kidney Day 2011: Protect Your Kidneys, Save Your Heart

March 10, 2011 will mark the celebration of the 6th World Kidney Day (WKD), an annual event jointly sponsored by the International Society of Nephrology and the International Federation of Kidney Foundations. Since its inception in 2006, WKD has grown dramatically to become the most widely celebrated event associated with kidney disease in the world and the most successful effort to raise awareness among both the general public and government health officials about the dangers of kidney disease, especially chronic kidney disease (CKD). In 2011, WKD will call attention to the large, and often unappreciated, role played by kidney dysfunction in increasing premature cardiovascular disease, the most common cause of morbidity and mortality worldwide [1]. Can a focus on early detection and prevention of kidney disease really improve long term cardiovascular health? In this editorial, we hope to convey the message that increased attention to the kidneys can indeed improve long-term health outcomes by reducing both kidney and cardiovascular disease and should therefore be a central component of any global health strategy intended to reduce the enormous and growing burden of chronic non-comunicable diseases (NCDs).

Giuseppe Remuzzi—a pioneer in nephrology

Giuseppe Remuzzi—a pioneer in nephrology

Posttransplant HLA Alloreactivity in Stable Kidney Transplant Recipients—Incidences and Impact on Long-Term Allograft Outcomes

Humoral alloreactivity is well established to predict adverse allograft outcomes. However, in some recipients, alloantibodies may also occur in the absence of graft dysfunction. We evaluated if and how often complement- and noncomplement-fixing alloantibodies are detectable in stable recipients and whether, in this context, they affect long-term outcomes. Sera obtained from 164 kidney transplant recipients at 2, 6 and 12 months were evaluated by FlowPRA screening and single-antigen testing for detection of IgG- or C4d-fixing HLA panel reactivity and donor-specific antibodies (DSA). Applying stringent criteria, we selected 34 patients with an uneventful 1-year course (no graft dysfunction or rejection) and excellent graft function at 12 months [estimated glomerular filtration rate (eGFR) >or=60 mL/min and proteinuria <or=0.5 g/24 h]. Nine (27%) and 5 (15%) of these recipients tested positive by [IgG] and [C4d]FlowPRA screening, respectively. In five cases, DSA were identified. Frequencies of positive test results and DSA binding intensities were not significantly lower than those documented for patients who did not fulfill the above criteria. In recipients with an excellent 1-year course, FlowPRA reactivity was not associated with lower eGFR or increased protein excretion during 68-month median follow-up. Our results suggest cautious interpretation of antibody monitoring in patients with normal-functioning grafts.

Excretion of Proteins by Rat Kidney during Various Types of Diuresis

Experiments on healthy rats showed that increased diuresis induced by administration of water, polyethylene glycol 400, furosemide, or 1-desamino-arginine-vasotocin is associated with increased protein excretion by the kidneys. The results can be explained by enhanced filtration of plasma proteins in glomeruli during polyuria of various geneses.

Renal medullary NADPH oxidase activity in DOCA‐salt hypertensive rats

Both endothelin-1 (ET-1) and oxidative stress are elevated in experimental forms of hypertension. We hypothesized that DOCA salt hypertension increases ET-1 which stimulates NADPH oxidase in the kidney. Four groups of rats were studied for a period of 3 weeks; placebo, DOCA (200 mg; subcutaneous), DOCA + the ETA receptor antagonist, ABT-627 (10–30 mg/kg/day), and DOCA + the nonspecific vasodilator, hydralazine (HYD) (10–15 mg/kg/day). ABT and HYD treated rats had lower mean arterial pressures (149 ± 12 and 139 ± 15 mmHg, respectively) than DOCA (174 ± 12 mmHg, p<0.05) as measured by telemetry. Protein excretion was increased in DOCA rats (103 ± 16 mg/day) and ABT (104 ± 41 mg/day) compared to placebo (22 ± 6 mg/day, p<0.05) and HYD (37 ± 13 mg/day, p<0.05). There was no difference in NADPH oxidase activity, determined by lucigenin chemiluminescence, in the renal cortex between placebo and DOCA groups. Renal inner medullary NADPH oxidase activity was increased in DOCA, ABT, and HYD compared to placebo (17.3 ± 1.3, 17.0 ± 1.1, 16.2 ± 0.2, 9.8 ± 1.7 cpm/μg, respectively, p<0.05). These data indicate that increased inner medullary NADPH oxidase activity and increased protein excretion in DOCA is independent of ET-1. Funded by HL60653, HL64776 and AHA0340113N.

Glomerular Filtration Rate and Albumin Excretion After Maximal Exercise in Aging Sedentary and Active Men

From 30 years onwards there is a linear reduction of renal function of about 0.41% per year. Aging induces progressive impairment of glomeruli leading to an increase in protein excretion. The purpose of the present study was to investigate the effect of maximal exercise on glomerular filtration rate (GFR) and albumin excretion in an aging population. This is a cross-sectional study from 213 healthy men, sedentary or endurance-trained, aged 20-30 and 50-80 years submitted to maximal exercise on a cycle ergometer. Blood and urine samples were obtained at rest and after the strenuous exercise. We evaluated the GFR by measuring creatinine clearance and the urine albumin excretion rate. After exercise, the older adults had a lesser reduction in GFR (mean 12%) than the young participants (mean 28%). As compared to those at rest, the increase of postexercise albumin excretion rates was lower in older participants (mean 7-fold) versus the young population (mean 20-fold). It appears that the exercise impact on some renal functions is related to the absolute load imposed on the individuals (r2 = 0.693). As far as GFR and urine albumin excretion are concerned, regular endurance training does not induce any signs of potential incipient nephropathy in a healthy aging population.