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Annual Review of Physiology Feb 2017Cells lining the proximal tubule (PT) of the kidney are highly specialized for apical endocytosis of filtered proteins and small bioactive molecules from the glomerular... (Review)
Review
Cells lining the proximal tubule (PT) of the kidney are highly specialized for apical endocytosis of filtered proteins and small bioactive molecules from the glomerular ultrafiltrate to maintain essentially protein-free urine. Compromise of this pathway results in low molecular weight (LMW) proteinuria that can progress to end-stage kidney disease. This review describes our current understanding of the endocytic pathway and the multiligand receptors that mediate LMW protein uptake in PT cells, how these are regulated in response to physiologic cues, and the molecular basis of inherited diseases characterized by LMW proteinuria.
Topics: Animals; Endocytosis; Humans; Kidney Glomerulus; Kidney Tubules, Proximal; Proteinuria; Receptors, Cell Surface
PubMed: 27813828
DOI: 10.1146/annurev-physiol-022516-034234 -
Biomedicine & Pharmacotherapy =... Jan 2019Preeclampsia (PE) is a unique pathophysiologic situation that physiologic interests of mother, fetus, and placenta diverge. PE is related to the increased circulating... (Review)
Review
Preeclampsia (PE) is a unique pathophysiologic situation that physiologic interests of mother, fetus, and placenta diverge. PE is related to the increased circulating antiangiogenic factors originated from hypoxic placenta. It is simply defined by the new onset of hypertension (≥140/90 mmHg) and proteinuria (≥0.3 g/day) after 20 weeks of gestation. PE is associated with kidney dysfunction due to deficiency in podocyte specific vascular endothelial growth factor (VEGF). Hypoxic placenta in PE patients produces increased levels of fms-like tyrosine kinase 1(sFlt-1), a soluble receptor of VEGF. sFlt-1 abrogates binding of VEGF to its receptor on endothelial cells and podocytes, and ultimately damages the filtration barrier. Glomerular endotheliosis and thrombotic microangiopathy (TMA) are the main features of kidney involvement in PE and can induce clotting and vessel occlusion. This complex pathophysiology is ameliorated after delivery; however, permanent kidney damages may remain and is intensified thereafter. This review aims to highlight the biochemical, genetic, and immunological-involved factors in the initiation of PE and explores the relationship between the kidney and PE. This work mainly discusses the pathologic mechanisms of kidney involvement in PE through the lens of the imbalanced VEGF-VEGF receptor signaling pathway.
Topics: Animals; Biomarkers; Female; Humans; Kidney; Kidney Diseases; Podocytes; Pre-Eclampsia; Pregnancy; Proteinuria
PubMed: 30399576
DOI: 10.1016/j.biopha.2018.10.082 -
Free Radical Biology & Medicine Nov 2023Podocyte injury is a hallmark of glomerular disease and one of the leading causes of chronic kidney disease (CKD). Peroxisome proliferator-activated receptor α (PPARα)...
Podocyte injury is a hallmark of glomerular disease and one of the leading causes of chronic kidney disease (CKD). Peroxisome proliferator-activated receptor α (PPARα) plays a key role in podocyte fatty acid oxidation (FAO). However, the underlying regulatory mechanisms remain unresolved. Trim63 is an E3 ubiquitin ligase that has been shown to inhibit PPARα activity; however, its role in fatty acid metabolism in the kidney has not been elucidated to date. In this study, we investigated the effects of overexpression and knockdown of Trim63 in Adriamycin (ADR)-induced nephropathy and diabetic nephropathy models and a podocyte cell line. In both rodents and human patients with proteinuric CKD, Trim63 was upregulated, particularly in the podocytes of injured glomeruli. In the ADR-induced nephropathy model, ectopic Trim63 application aggravated FAO deficiency and mitochondrial dysfunction and triggered intense lipid deposition, podocyte injury, and proteinuria. Notably, Trim63 inhibition alleviated FAO deficiency and mitochondrial dysfunction, and markedly restored podocyte injury and renal fibrosis in ADR-induced and diabetic nephropathy (DN) models. Additionally, Trim63 was observed to mediate PPARα ubiquitination and degradation, leading to podocyte injury. We demonstrate the pathological role of Trim63, which was previously unrecognized in kidney tissue, in FAO deficiency and podocyte injury. Targeting Trim63 may represent a viable therapeutic strategy for podocyte injury and proteinuria.
Topics: Humans; Podocytes; PPAR alpha; Diabetic Nephropathies; Ubiquitin-Protein Ligases; Proteinuria; Doxorubicin; Renal Insufficiency, Chronic; Fatty Acids
PubMed: 37793501
DOI: 10.1016/j.freeradbiomed.2023.09.039 -
PloS One 2014Aflibercept is a human recombinant fusion protein with antiangiogenic effects that functions as a decoy receptor to bind vascular endothelial growth factor A.... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Aflibercept is a human recombinant fusion protein with antiangiogenic effects that functions as a decoy receptor to bind vascular endothelial growth factor A. Proteinuria is one of its major adverse effects with a substantial variation in the incidence rate, and the overall risk of proteinuria has not been systematically studied. We performed a meta-analysis of published clinical trials to quantify the incidence and relative risk of proteinuria in cancer patients treated with aflibercept.
METHODS
The electronic databases were searched, including PubMed, Embase, Cochrane databases, and ASCO (American Society of Clinical Oncology) abstracts. Eligible studies were phase II and III prospective clinical trials of cancer patients treated with aflibercept with toxicity data on proteinuria. Overall incidence rates, relative risk (RR), and 95% confidence intervals (CI) were calculated using fixed or random effects models depending on the heterogeneity of the included studies.
RESULTS
A total of 4,596 patients with a variety of solid tumors from 16 prospective clinical trials were included for the meta-analysis. The overall incidences of all-grade and high-grade proteinuria in cancer patients were 33.9% (95% CI: 27.3-42.1%) and 7.9% (95% CI: 6.1-10.2%). The relative risks of proteinuria of aflibercept compared to control were increased for all-grade (RR = 1.41, 95% CI: 1.13-1.77) and high-grade (RR = 6.18, 95% CI: 3.78-10.12) proteinuria. The risk of developing all-grade and high-grade proteinuria with aflibercept was substantially higher than that of bevacizumab (all-grade: RR 1.85, 95% CI: 1.63-2.11; high-grade: RR 2.37, 95% CI: 1.84-3.05).
CONCLUSIONS
Aflibercept is associated with an increased risk of developing proteinuria. Appropriate monitoring and treatment is strongly recommended to prevent potential renal damage. Future studies are still needed to investigate the risk reduction and possible use of aflibercept in cancer patients.
Topics: Clinical Trials as Topic; Female; Humans; Incidence; Male; Neoplasms; Proteinuria; Receptors, Vascular Endothelial Growth Factor; Recombinant Fusion Proteins
PubMed: 25365378
DOI: 10.1371/journal.pone.0111839 -
Lancet (London, England) May 2019Previous prospective cohort studies have shown that angiogenic factors have a high diagnostic accuracy in women with suspected pre-eclampsia, but we remain uncertain of... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Previous prospective cohort studies have shown that angiogenic factors have a high diagnostic accuracy in women with suspected pre-eclampsia, but we remain uncertain of the effectiveness of these tests in a real-world setting. We therefore aimed to determine whether knowledge of the circulating concentration of placental growth factor (PlGF), an angiogenic factor, integrated with a clinical management algorithm, decreased the time for clinicians to make a diagnosis in women with suspected pre-eclampsia, and whether this approach reduced subsequent maternal or perinatal adverse outcomes.
METHODS
We did a multicentre, pragmatic, stepped-wedge cluster-randomised controlled trial in 11 maternity units in the UK, which were each responsible for 3000-9000 deliveries per year. Women aged 18 years and older who presented with suspected pre-eclampsia between 20 weeks and 0 days of gestation and 36 weeks and 6 days of gestation, with a live, singleton fetus were invited to participate by the clinical research team. Suspected pre-eclampsia was defined as new-onset or worsening of existing hypertension, dipstick proteinuria, epigastric or right upper-quadrant pain, headache with visual disturbances, fetal growth restriction, or abnormal maternal blood tests that were suggestive of disease (such as thrombocytopenia or hepatic or renal dysfunction). Women were approached individually, they consented for study inclusion, and they were asked to give blood samples. We randomly allocated the maternity units, representing the clusters, to blocks. Blocks represented an intervention initiation time, which occurred at equally spaced 6-week intervals throughout the trial. At the start of the trial, all units had usual care (in which PlGF measurements were also taken but were concealed from clinicians and women). At the initiation time of each successive block, a site began to use the intervention (in which the circulating PlGF measurement was revealed and a clinical management algorithm was used). Enrolment of women continued for the duration of the blocks either to concealed PlGF testing, or after implementation, to revealed PlGF testing. The primary outcome was the time from presentation with suspected pre-eclampsia to documented pre-eclampsia in women enrolled in the trial who received a diagnosis of pre-eclampsia by their treating clinicians. This trial is registered with ISRCTN, number 16842031.
FINDINGS
Between June 13, 2016, and Oct 27, 2017, we enrolled and assessed 1035 women with suspected pre-eclampsia. 12 (1%) women were found to be ineligible. Of the 1023 eligible women, 576 (56%) women were assigned to the intervention (revealed testing) group, and 447 (44%) women were assigned to receive usual care with additional concealed testing (concealed testing group). Three (1%) women in the revealed testing group were lost to follow-up, so 573 (99%) women in this group were included in the analyses. One (<1%) woman in the concealed testing group withdrew consent to follow-up data collection, so 446 (>99%) women in this group were included in the analyses. The median time to pre-eclampsia diagnosis was 4·1 days with concealed testing versus 1·9 days with revealed testing (time ratio 0·36, 95% CI 0·15-0·87; p=0·027). Maternal severe adverse outcomes were reported in 24 (5%) of 447 women in the concealed testing group versus 22 (4%) of 573 women in the revealed testing group (adjusted odds ratio 0·32, 95% CI 0·11-0·96; p=0·043), but there was no evidence of a difference in perinatal adverse outcomes (15% vs 14%, 1·45, 0·73-2·90) or gestation at delivery (36·6 weeks vs 36·8 weeks; mean difference -0·52, 95% CI -0·63 to 0·73).
INTERPRETATION
We found that the availability of PlGF test results substantially reduced the time to clinical confirmation of pre-eclampsia. Where PlGF was implemented, we found a lower incidence of maternal adverse outcomes, consistent with adoption of targeted, enhanced surveillance, as recommended in the clinical management algorithm for clinicians. Adoption of PlGF testing in women with suspected pre-eclampsia is supported by the results of this study.
FUNDING
National Institute for Health Research.
Topics: Adult; Algorithms; Female; Fetal Growth Retardation; Gestational Age; Humans; Hypertension; Infant, Newborn; Outcome Assessment, Health Care; Perinatal Death; Placenta Growth Factor; Pre-Eclampsia; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Proteinuria
PubMed: 30948284
DOI: 10.1016/S0140-6736(18)33212-4 -
Journal of Cardiology Nov 2021
Topics: Atrial Fibrillation; Creatinine; Humans; Proteinuria
PubMed: 34332838
DOI: 10.1016/j.jjcc.2021.07.003 -
Biochimica Et Biophysica Acta.... Jun 2023Podocytes have been indicated to be a critical factor for the development of diabetic kidney disease. Podocyte loss leads to irreversible glomerular injury and...
OBJECTIVE
Podocytes have been indicated to be a critical factor for the development of diabetic kidney disease. Podocyte loss leads to irreversible glomerular injury and proteinuria in animal models. As terminal differentiated cells, autophagy is crucial for maintaining podocyte homeostasis. Previous studies have shown that Uncoupling proteins 2 (UCP2) regulate fatty acid metabolism, mitochondrial calcium uptake and reactive oxygen species (ROS) production. This study aimed to investigate whether UCP2 promote autophagy in podocyte and further explore the regulation mechanism of UCP2.
METHODS
For podocyte-specific UCP2-KO mice, we cross bred UCP2f mouse strain with the podocin-Cre mice. Diabetic mice were obtained by daily intraperitoneally injections of 40 mg/kg streptozotocin for 3 days. After 6 weeks, mice were scarified, and kidney tissues were analyzed by histological stain, Western blot, Immunofluorescence, and immunohistochemistry. Also, urine samples were collected for protein quantification. For in vitro study, podocytes were primary cultured from UCP2f mouse or transfected with adeno-associated virus (AAV)-UCP2.
RESULTS
Diabetic kidney showed elevated expression of UCP2 and specific ablation of UCP2 in podocyte aggravates diabetes-induced albuminuria and glomerulopathy. UCP2 protects hyperglycemia-induced podocyte injury by promoting autophagy in vivo and in vitro. Rapamycin treatment significantly ameliorates streptozotocin (STZ)-induced podocyte injury in UCP2 mice.
CONCLUSION
UCP2 expression in podocyte increased under diabetic condition and appeared to be an initial compensatory response. UCP2 deficiency in podocyte impaired autophagy and exacerbates podocyte injury and proteinuria in diabetic nephropathy.
Topics: Mice; Animals; Diabetic Nephropathies; Podocytes; Diabetes Mellitus, Experimental; Streptozocin; Uncoupling Protein 2; Proteinuria; Autophagy
PubMed: 37023910
DOI: 10.1016/j.bbadis.2023.166705 -
Saudi Journal of Kidney Diseases and... Aug 2022Acute and chronic kidney diseases are common and are associated with the risk of kidney failure. Early detection of these disorders prevents their progression to kidney...
Acute and chronic kidney diseases are common and are associated with the risk of kidney failure. Early detection of these disorders prevents their progression to kidney damage in later stages. The aim of this study was to investigate the prevalence of proteinuria and hematuria in a rural population in Yasuj, Iran. In this cross-sectional study, 676 people (350 females and 326 males) participated. People with positive dipstick test results entered the second screening and the urinary protein-to-creatinine ratio (UPCR) was measured. People with UPCR ≥150 mg/g were evaluated for demographic and biochemical indicators. In the initial screening, 72 subjects (10.6%) tested positive by the dipstick test with trace proteinuria or higher. The UPCR results showed that this ratio was above 150 mg/g in 42 patients (6.2%), which was approximately equivalent to more than 150 mg of protein excreted per day. There was no significant relationship between the prevalence of proteinuria and the demographic and biochemical markers. Briefly, it seems that the prevalence of proteinuria found by the dipstick test was similar to that in other parts of the world. However, according to the UPCR index, the percentage of proteinuria was significantly higher than in other studies. Because of the unknown mechanism of proteinuria, more studies based on genetic tests and kidney biopsies are needed to determine the causes of proteinuria.
Topics: Female; Male; Humans; Hematuria; Iran; Prevalence; Rural Population; Cross-Sectional Studies; Proteinuria
PubMed: 37675751
DOI: 10.4103/1319-2442.384193 -
Journal of Nephrology Apr 2021Proteinuria has been commonly reported in patients with COVID-19. However, only dipstick tests have been frequently used thus far. Here, the quantification and... (Observational Study)
Observational Study
BACKGROUND
Proteinuria has been commonly reported in patients with COVID-19. However, only dipstick tests have been frequently used thus far. Here, the quantification and characterization of proteinuria were investigated and their association with mortality was assessed.
METHODS
This retrospective, observational, single center study included 153 patients, hospitalized with COVID-19 between March 28th and April 30th, 2020, in whom total proteinuria and urinary α-microglobulin (a marker of tubular injury) were measured. Association with mortality was evaluated, with a follow-up until May 7th, 2020.
RESULTS
According to the Kidney Disease Improving Global Outcomes staging, 14% (n = 21) of the patients had category 1 proteinuria (< 150 mg/g of urine creatinine), 42% (n = 64) had category 2 (between 150 and 500 mg/g) and 44% (n = 68) had category 3 proteinuria (over 500 mg/g). Urine α-microglobulin concentration was higher than 15 mg/g in 89% of patients. After a median follow-up of 27 [14;30] days, the mortality rate reached 18%. Total proteinuria and urinary α-microglobulin were associated with mortality in unadjusted and adjusted models. This association was stronger in subgroups of patients with normal renal function and without a urinary catheter.
CONCLUSIONS
Proteinuria is frequent in patients with COVID-19. Its characterization suggests a tubular origin, with increased urinary α-microglobulin. Tubular proteinuria was associated with mortality in COVID-19 in our restropective, observational study.
Topics: Aged; Aged, 80 and over; Belgium; Biomarkers; COVID-19; Female; Humans; Male; Middle Aged; Prevalence; Prognosis; Proteinuria; Retrospective Studies; Survival Rate
PubMed: 33484426
DOI: 10.1007/s40620-020-00931-w -
Journal of the American Society of... Aug 2020
Topics: Albumins; Albuminuria; Creatinine; Humans; Proteinuria
PubMed: 32737208
DOI: 10.1681/ASN.2020050707