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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 -
Journal of Cardiology Nov 2021
Topics: Atrial Fibrillation; Creatinine; Humans; Proteinuria
PubMed: 34332838
DOI: 10.1016/j.jjcc.2021.07.003 -
MMW Fortschritte Der Medizin Jun 2022
Review
Topics: Hematuria; Humans; Kidney Diseases; Proteinuria; Urinalysis
PubMed: 35731406
DOI: 10.1007/s15006-022-1166-7 -
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 -
Current Opinion in Nephrology and... May 2023The use of corticosteroids to treat IgA nephropathy (IgAN) has been limited by many controversies related to uncertain benefit and safety concerns. Recent trials have... (Review)
Review
PURPOSE OF REVIEW
The use of corticosteroids to treat IgA nephropathy (IgAN) has been limited by many controversies related to uncertain benefit and safety concerns. Recent trials have tried to address these limitations.
RECENT FINDINGS
After being paused because of an excess of adverse events in the full-dose steroid arm, the TESTING trial compared a reduced dose of methylprednisolone to placebo in patients with IgAN after optimization of supportive therapy. Steroid treatment was associated with a significant reduction in the risk of a 40% decline in estimated glomerular filtration rate (eGFR), kidney failure and kidney death as well as a sustained decrease in proteinuria compared with placebo. Serious adverse events were more frequent with the full dose regimen but less common in the reduced dose regimen. A phase III trial evaluating a new formulation of targeted-release budesonide showed a significant reduction in short-term proteinuria and has resulted in accelerated FDA approval for use in the United States. In a subgroup analysis of DAPA-CKD trial, sodium-glucose transport protein 2 inhibitors reduced the risk of kidney function decline in patients who have completed or are not eligible for immunosuppression.
SUMMARY
Both reduced-dose corticosteroids and targeted-release budesonide are new therapeutic options that can be used in patients with high-risk disease. More novel-targeted therapies with a better safety profile are currently under investigations.
Topics: Humans; Glomerulonephritis, IGA; Immunosuppressive Agents; Adrenal Cortex Hormones; Budesonide; Steroids; Glomerular Filtration Rate; Proteinuria
PubMed: 36866805
DOI: 10.1097/MNH.0000000000000881 -
Pediatric Transplantation Feb 2018Proteinuria has been shown to be an important and potentially treatable risk factor for graft loss. The aim of this study was to evaluate prevalence, etiology, and...
Proteinuria has been shown to be an important and potentially treatable risk factor for graft loss. The aim of this study was to evaluate prevalence, etiology, and outcome of proteinuria during the follow-up of children with renal transplantation. We retrospectively reviewed the files of renal transplanted children between 2006 and 2016 in our center. All patients were interpreted with respect to the demographic data and clinical and laboratory features including information about proteinuria. Chi-square test and Mann-Whitney U test were used for analysis. Fifty-two children were eligible for the study. Proteinuria was observed in 34 (65%) and nephrotic range proteinuria was detected in 5 (9.6%) patients. Etiology of proteinuria could be identified in 21 patients. Acute rejection and uncontrolled hypertension were the most frequent causes of proteinuria. Proteinuria had resolved during the follow-up in 59% of the patients. We found that children with and without proteinuria had similar glomerular filtration rate at the end of 50 months of follow-up period. Proteinuria seems to be a common complication in renal transplant recipients. Graft functions can be preserved by immediate evaluation of increasing proteinuria, and by fixing treatable causes rapidly and efficiently during the follow-up in majority of the patients.
Topics: Adolescent; Child; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Hypertension; Kidney Transplantation; Male; Outcome Assessment, Health Care; Postoperative Complications; Prevalence; Proteinuria; Retrospective Studies; Risk Factors
PubMed: 28994226
DOI: 10.1111/petr.13068 -
Journal of the American Society of... Aug 2020
Topics: Albumins; Albuminuria; Creatinine; Humans; Proteinuria
PubMed: 32737208
DOI: 10.1681/ASN.2020050707 -
Cell Reports Apr 2023Recent epigenome-wide studies suggest an association between blood DNA methylation and kidney function. However, the pathological importance remains unclear. Here, we...
Recent epigenome-wide studies suggest an association between blood DNA methylation and kidney function. However, the pathological importance remains unclear. Here, we show that the homing endonuclease I-PpoI-induced DNA double-strand breaks in kidney glomerular podocytes cause proteinuria, glomerulosclerosis, and tubulointerstitial fibrosis with DNA methylation changes in blood cells as well as in podocytes. Single-cell RNA-sequencing analysis reveals an increase in cytotoxic CD8 T cells with the activating/costimulatory receptor NKG2D in the kidneys, which exhibit a memory precursor effector cell phenotype, and the CD44 memory CD8 T cells are also increased in the peripheral circulation. NKG2D blockade attenuates the renal phenotype caused by podocyte DNA damage. Blood methylome shows increased DNA methylation in binding sites for STAT1, a transcription factor contributing to CD8 T cell homeostasis. Collectively, podocyte DNA damage alters the blood methylome, leading to changes in CD8 T cells, which contribute to sustained renal injury in chronic kidney disease.
Topics: Humans; Podocytes; DNA Methylation; CD8-Positive T-Lymphocytes; NK Cell Lectin-Like Receptor Subfamily K; Kidney; Proteinuria; Renal Insufficiency, Chronic; DNA Damage; DNA
PubMed: 36989112
DOI: 10.1016/j.celrep.2023.112302 -
Pediatric Nephrology (Berlin, Germany) May 2017Proteinuria in children with chronic kidney disease (CKD) is common and its etiology differs from that in adults. How proteinuria influences the rate of progression of... (Review)
Review
Proteinuria in children with chronic kidney disease (CKD) is common and its etiology differs from that in adults. How proteinuria influences the rate of progression of CKD has been analyzed in multiple retrospective clinical studies and more recently in a few prospective ones. In this review I summarize the results, strengths and weaknesses of each of these studies. The findings of several retrospective studies in children with CKD have confirmed what we have learned from adult studies on the association between proteinuria and worsening kidney function. Larger prospective clinical studies have examined the effects of proteinuria on the rate of decline of kidney function and the risk of end-stage kidney disease. They have also considered children with glomerular and, more importantly, the more common, congenital causes of CKD. Current studies have important strengths but also a few weaknesses that limit the validity of the conclusions which can be drawn. There is still a need for large clinical trials that focus primarily on studying the influence of proteinuria on kidney function and on finding remedies that delay progression.
Topics: Child; Clinical Trials as Topic; Disease Progression; Humans; Proteinuria; Renal Insufficiency, Chronic; Renin-Angiotensin System
PubMed: 27350622
DOI: 10.1007/s00467-016-3448-8 -
Clinical Journal of the American... Jun 2023Eculizumab is a monoclonal antibody for the treatment of atypical hemolytic uremic syndrome (aHUS). Kidney damage, a common condition in patients with aHUS, may result...
BACKGROUND
Eculizumab is a monoclonal antibody for the treatment of atypical hemolytic uremic syndrome (aHUS). Kidney damage, a common condition in patients with aHUS, may result in proteinuria. Because proteinuria may affect the pharmacokinetics of therapeutic proteins such as eculizumab, the aim of our study was to investigate the effect of proteinuria on eculizumab pharmacokinetics.
METHODS
This study was an ancillary study of a previously performed pharmacokinetic-pharmacodynamic study of eculizumab in aHUS. Proteinuria, measured as urinary protein-creatinine ratios (UPCR), was investigated as covariate for eculizumab clearance. Thereafter, we evaluated the effect of proteinuria on the exposure to eculizumab in a simulation study for the initial phase and for a 2-weekly and 3-weekly interval in the maintenance phase.
RESULTS
The addition of UPCR as a linear covariate on clearance to our base model resulted in a statistically improved fit ( P < 0.001) and reduction of unexplained variability in clearance. From our data, we predicted that in the initial phase, 16% of the adult patients with severe proteinuria (UPCR >3.1 g/g) will have inadequate complement inhibition (classical pathway activity >10%) on day 7 of treatment, compared with 3% of the adult patients without proteinuria. None of the pediatric patients will have inadequate complement inhibition at day 7 of treatment. For the 2- and 3-weekly dosing intervals, we predicted that, respectively, 18% and 49% of the adult patients and, respectively, 19% and 57% of the pediatric patients with persistent severe proteinuria will have inadequate complement inhibition, compared with, respectively, 2% and 13% of the adult patients and, respectively, 4% and 22% of the pediatric patients without proteinuria.
CONCLUSIONS
Severe proteinuria is associated with a higher risk of underexposure to eculizumab.
CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER
CUREiHUS, Dutch Trial Register, NTR5988/NL5833.
Topics: Adult; Humans; Child; Atypical Hemolytic Uremic Syndrome; Antibodies, Monoclonal, Humanized; Kidney Function Tests; Proteinuria
PubMed: 36913245
DOI: 10.2215/CJN.0000000000000145