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Placenta Jul 2023Preeclampsia (PE) pathogenesis is explained by the two-stage disorder theory. However, mechanisms underlying hypertension and proteinuria in PE remain unclear. The role...
INTRODUCTION
Preeclampsia (PE) pathogenesis is explained by the two-stage disorder theory. However, mechanisms underlying hypertension and proteinuria in PE remain unclear. The role of (pro)renin receptor (PRR) in PE pathology has received special attention. We examined endothelin-1 (ET-1) production via placental PRR in a PE mouse model.
METHODS
At 14.5 day-post-coitum (DPC), we performed a reduced uterine perfusion pressure (RUPP) operation, ligating the uterine arteriovenous vessels in female mice. We also infused these mice with a PRR inhibitor, decoy peptide in the handle region of prorenin (HRP) for mice (NH2-RIPLKKMPSV-COOH). At 18.5 DPC, blood, urine, and placenta were collected; fetus and placenta were weighed. We evaluated placental hypoxia using quantitative polymerase chain reaction (PCR), with hypoxia-inducible factor-1α (HIF-1α) as index. We also evaluated PRR, transforming growth factor-β1 (TGF-β1), and ET-1 expression in the placenta using quantitative PCR and western blotting. ET-1 concentration in blood plasma was assessed using enzyme-linked immunosorbent assay.
RESULTS
Blood pressure and proteinuria significantly increased, and fetal and placental weights decreased in RUPP mice. HIF-1α, PRR, TGF-β1, and ET-1 expressions considerably increased in RUPP mice placentas. ET-1 concentration in RUPP mice blood plasma was markedly increased. PRR inhibitor suppressed these changes.
DISCUSSION
In PE model mice that underwent RUPP treatment, placental hypoxia increased PRR and ET-1 expression suggesting a causative relationship between ET-1 and intracellular PRR signaling. RUPP treatment, when combined with HRP, reversed the effect of elevated ET-1 levels in the model. This study may help to elucidate the pathogenesis of PE considering PRR and ET-1.
Topics: Animals; Female; Mice; Pregnancy; Disease Models, Animal; Endothelin-1; Placenta; Pre-Eclampsia; Prorenin Receptor; Proteinuria; Transforming Growth Factor beta1
PubMed: 37167782
DOI: 10.1016/j.placenta.2023.05.002 -
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 -
BioMed Research International 2016Focal segmental glomerulosclerosis (FSGS) is a common cause of proteinuria and nephrotic syndrome leading to end stage renal disease (ESRD). There are two types of FSGS,... (Review)
Review
Focal segmental glomerulosclerosis (FSGS) is a common cause of proteinuria and nephrotic syndrome leading to end stage renal disease (ESRD). There are two types of FSGS, primary (idiopathic) and secondary forms. Secondary FSGS shows less severe clinical features compared to those of the primary one. However, secondary FSGS has an important clinical significance because a variety of renal diseases progress to ESRD thorough the form of secondary FSGS. The defining feature of FSGS is proteinuria. The key event of FSGS is podocyte injury which is caused by multiple factors. Unanswered questions about how these factors act on podocytes to cause secondary FSGS are various and ill-defined. In this review, we provide brief overview and new insights into FSGS, podocyte injury, and their potential linkage suggesting clues to answer for treatment of the disease.
Topics: Glomerulosclerosis, Focal Segmental; Humans; Kidney Failure, Chronic; Podocytes; Proteinuria
PubMed: 27088082
DOI: 10.1155/2016/1630365 -
Hematology. American Society of... Dec 2017Sickle cell disease (SCD) is an autosomal recessive disease in which homozygosity for a single point mutation in the gene encoding the β-globin chain produces... (Review)
Review
Sickle cell disease (SCD) is an autosomal recessive disease in which homozygosity for a single point mutation in the gene encoding the β-globin chain produces hemoglobin S molecules that polymerize within the erythrocyte during deoxygenation; the result is sustained hemolytic anemia and vaso-occlusive events. As patients live to adulthood, the chronic impact of sustained hemolytic anemia and episodic vaso-occlusive episodes leads to progressive end-organ complications. This scenario culminates in the development of 1 or more major cardiovascular complications of SCD for which there are no approved or consensus therapies. These complications include elevated pulmonary artery systolic pressure, pulmonary hypertension, left ventricular diastolic heart disease, dysrhythmia, sudden death, and chronic kidney disease with associated proteinuria, microalbuminuria, and hemoglobinuria. In patients with advancing age, cardiopulmonary organ dysfunction and chronic kidney injury have significant effects on morbidity and premature mortality. Over the last 15 years, a number of tests have been validated in multiple replicate cohort studies that identify patients with SCD at the highest risk of experiencing pulmonary and systemic vasculopathy and death, providing for screening strategies tied to targeted, more aggressive diagnostic and therapeutic interventions.
Topics: Anemia, Sickle Cell; Cardiovascular Diseases; Humans; Proteinuria; Renal Insufficiency, Chronic
PubMed: 29222288
DOI: 10.1182/asheducation-2017.1.423 -
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 -
The Journal of Small Animal Practice Aug 2021To describe the incidence, severity and progression of proteinuria over the first 6 months of masitinib treatment in tumour-bearing dogs without pre-existing...
OBJECTIVES
To describe the incidence, severity and progression of proteinuria over the first 6 months of masitinib treatment in tumour-bearing dogs without pre-existing proteinuria. To describe the effect of treatment on urine protein:creatinine and renal parameters in patients with pre-existing proteinuria.
MATERIALS AND METHODS
Records were reviewed from patients receiving masitinib for neoplasms between June 1, 2010, and May 5, 2019. Patients without pre-treatment and at least one urine protein:creatinine after ≥7 days treatment were excluded. Signalment, tumours and concurrent diseases, treatments, haematology, biochemistry and urinalysis results before, during and after treatment for up to 202 days were collected. Patient visits were grouped into six timepoints for analysis.
RESULTS
Twenty-eight dogs were included. Eighteen percent of dogs non-proteinuric at baseline (four of 22) developed proteinuria during treatment, all within 1 month of treatment initiation. One dog developed hypoalbuminaemia, none developed oedema or ascites, azotaemia or were euthanased/died due to proteinuria. Masitinib was immediately discontinued in both dogs in which urine protein:creatinine greater than 2.0 was detected and in both, proteinuria improved. Six dogs with pre-treatment proteinuria were treated with masitinib, significant worsening of proteinuria did not occur. Neither azotaemia nor severe hypoalbuminaemia occurred.
CLINICAL SIGNIFICANCE
Proteinuria, when it occurs, tends to develop within 1 month of masitinib commencement and may progress rapidly. Weekly proteinuria monitoring should be considered for the first month and a urine protein:creatinine greater than 0.5 should prompt reassessment within 1 week. Masitinib treatment can be considered in patients with pre-treatment proteinuria and does not inevitably cause worsening of proteinuria.
Topics: Animals; Benzamides; Creatinine; Dog Diseases; Dogs; Neoplasms; Piperidines; Proteinuria; Pyridines; Thiazoles
PubMed: 33634470
DOI: 10.1111/jsap.13305 -
Scientific Reports Mar 2022Attribute-based medicine is essential for patient-centered medicine. To date, the groups of patients with chronic kidney disease (CKD) requiring urate-lowering therapy... (Randomized Controlled Trial)
Randomized Controlled Trial
Attribute-based medicine is essential for patient-centered medicine. To date, the groups of patients with chronic kidney disease (CKD) requiring urate-lowering therapy are clinically unknown. Herein, we evaluated the efficacy of febuxostat using a cross-classification, attribute-based research approach. We performed post hoc analysis of multicenter, randomized, double-blind, placebo-controlled trial data for 395 patients with stage 3 CKD and asymptomatic hyperuricemia. Participants were divided into febuxostat or placebo groups and subcohorts stratified and cross-classified by proteinuria and serum creatinine concentrations. In patients stratified based on proteinuria, the mean eGFR slopes were significantly higher in the febuxostat group than in the placebo group (P = 0.007) in the subcohort without proteinuria. The interaction between febuxostat treatment and presence of proteinuria in terms of eGFR slope was significant (P for interaction = 0.019). When cross-classified by the presence of proteinuria and serum creatinine level, the mean eGFR slopes significantly differed between the febuxostat and placebo groups (P = 0.040) in cross-classified subcohorts without proteinuria and with serum creatinine level ≥ median, but not in the cross-classified subcohorts with proteinuria and serum creatinine level < median. Febuxostat mitigated the decline in kidney function among stage 3 CKD patients with asymptomatic hyperuricemia without proteinuria.
Topics: Creatinine; Febuxostat; Female; Gout Suppressants; Humans; Hyperuricemia; Male; Proteinuria; Renal Insufficiency, Chronic; Treatment Outcome; Uric Acid
PubMed: 35260678
DOI: 10.1038/s41598-022-07737-9 -
Pharmaceutical Biology Dec 2024Yi-Shen-Hua-Shi (YSHS) is a traditional Chinese medicine that treats chronic kidney disease (CKD). However, its efficacy in reducing proteinuria and underlying... (Randomized Controlled Trial)
Randomized Controlled Trial
CONTEXT
Yi-Shen-Hua-Shi (YSHS) is a traditional Chinese medicine that treats chronic kidney disease (CKD). However, its efficacy in reducing proteinuria and underlying mechanisms is unknown.
OBJECTIVE
This single-center randomized controlled trial explored whether YSHS could improve proteinuria and modulate the gut microbiota.
MATERIALS AND METHODS
120 CKD patients were enrolled and randomized to receive the renin-angiotensin-aldosterone system (RAAS) inhibitor plus YSHS ( = 56) or RAAS inhibitor ( = 47) alone for 4 months, and 103 patients completed the study. We collected baseline and follow-up fecal samples and clinical outcomes from participants. Total bacterial DNA was extracted, and the fecal microbiome was analyzed using bioinformatics.
RESULTS
Patients in the intervention group had a significantly higher decrease in 24-h proteinuria. After 4 months of the YSHS intervention, the relative abundance of bacteria that have beneficial effects on the body, such as , , and increased significantly, while pathogenic bacteria such as the and decreased. However, we could not find these changes in the control group. Redundancy analysis showed that the decline in 24-h proteinuria during follow-up was significantly correlated with various taxa of gut bacteria, such as and the genus in the YSHS group. KEGG analysis also showed the potential role of YSHS in regulating glycan, lipid, and vitamin metabolism.
DISCUSSION AND CONCLUSION
The YSHS granule reduced proteinuria associated with mitigating intestinal microbiota dysbiosis in CKD patients. The definite mechanisms of YSHS to improve proteinuria need to be further explored.
TRIAL REGISTRATION
ChiCTR2300076136, retrospectively registered.
Topics: Humans; Gastrointestinal Microbiome; Male; Dysbiosis; Female; Renal Insufficiency, Chronic; Proteinuria; Middle Aged; Drugs, Chinese Herbal; Feces; Aged; Adult; Medicine, Chinese Traditional
PubMed: 38720666
DOI: 10.1080/13880209.2024.2345080 -
Diabetes Research and Clinical Practice Oct 2022Proteinuria is a risk factor for cerebral infarction. It is known that proteinuria can change over time. However, published data is scarce for the association between...
BACKGROUND
Proteinuria is a risk factor for cerebral infarction. It is known that proteinuria can change over time. However, published data is scarce for the association between changes in proteinuria and the risk of cerebral infarction.
METHOD
Study participants were 276,861 Koreans who were assessed for urine dipstick proteinuria both in 2003-2004 and 2007-2008. They were categorized into four groups by changes in proteinuria over 4 years (negative: negative → negative, resolved: proteinuria ≥ 1+ → negative, incident: negative → proteinuria ≥ 1+, persistent: proteinuria ≥ 1+ → proteinuria ≥ 1 + ). We used multivariate adjusted Cox-proportional hazard model in calculating the adjusted hazard ratios (HR) and 95% confidence interval (CI) for cerebral infarction until 2013 according to changes in proteinuria.
RESULT
Adjusted HR and 95% CI for cerebral infarction significantly increased in order of persistent, incident, and resolved proteinuria, compared with negative proteinuria (negative: reference, resolved: 1.166 [1.009-1.347], incident: 1.345 [1.188-1.522], and persistent: 1.443 [1.089-1.912]). In gender subgroup analysis, men showed the more clear association between changes in proteinuria and the risk of cerebral infarction (negative: reference, resolved: 1.284 [1.057-1.560], incident: 1.351 [1.149-1.589], and persistent: 1.428 [1.014-2.012]).
CONCLUSION
All types of proteinuria changes were associated with the increased risk of cerebral infarction, even in participants with once manifested but vanishing proteinuria.
Topics: Male; Humans; Proteinuria; Risk Factors; Proportional Hazards Models; Cerebral Infarction; Republic of Korea
PubMed: 36122864
DOI: 10.1016/j.diabres.2022.110090 -
American Journal of Nephrology 2022We examined the association of proteinuria with the risk for heart failure (HF) and other cardiovascular disease (CVD) events in patients with prior history of breast,...
INTRODUCTION
We examined the association of proteinuria with the risk for heart failure (HF) and other cardiovascular disease (CVD) events in patients with prior history of breast, colorectal, or stomach cancer using a nationwide population-based database.
METHODS
We conducted this retrospective observation study using the JMDC Claims Database and analyzed 55,191 patients with prior history of breast, colorectal, or stomach cancer. The median age was 54 (48-60) years, and 20,665 participants (37.4%) were men. Using urine dipstick data at baseline, 3,945 and 1,521 participants were categorized as having trace and positive proteinuria, respectively. Using Cox proportional hazards models, we examined the relationship of proteinuria with the incidence of HF and other CVD events.
RESULTS
Over a mean follow-up of 2.8 ± 2.2 years, 1,597 HF, 124 myocardial infarction, 1,342 angina pectoris, 719 stroke, and 361 atrial fibrillation events were recorded. Kaplan-Meier curves showed that the cumulative incidence for HF increased with proteinuria category (log-rank p < 0.001). After multivariable adjustment, hazard ratios of trace and positive proteinuria for HF were 1.24 (95% CI, 1.04-1.47) and 1.62 (95% CI, 1.30-2.02), respectively. The presence of proteinuria was also associated with a higher risk for angina pectoris and atrial fibrillation.
DISCUSSION
Proteinuria was associated with a greater risk of developing HF and other CVD events in patients with prior history of cancer. The optimal management strategy for patients with proteinuria and cancer needs to be established for the prevention of HF in cancer patients.
Topics: Male; Humans; Middle Aged; Female; Atrial Fibrillation; Retrospective Studies; Stomach Neoplasms; Heart Failure; Angina Pectoris; Proteinuria; Colorectal Neoplasms; Risk Factors
PubMed: 36543162
DOI: 10.1159/000527703