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Medecine Sciences : M/S 2019The renal filtration is ensured by the kidney glomeruli selective for filtering the blood. The main actor of the glomerular filter is the podocyte whose interlaced... (Review)
Review
The renal filtration is ensured by the kidney glomeruli selective for filtering the blood. The main actor of the glomerular filter is the podocyte whose interlaced pedicels bear protein complexes (nephrin, podocin, etc.) creating a molecular sieve (slit diaphragm) to achieve the filtration. Alterations of these podocytes lead to massive proteinuria, which characterizes the nephrotic syndrome. The idiopathic form is one of the most malignant and essentially comprises two entities: minimal change disease and focal segmental glomerulosclerosis. Many observations indicated that (1) immune cells are involved and that (2) there are several permeability factors in the blood that affect the morphology and function of podocytes (slit diaphragm with fractional foot processes fusion/effacement). Evidence for a permeability factor was chiefly derived from remission of proteinuria observed after implantation of a kidney with FSGS in healthy recipients or with other kidney diseases. Today, we are moving towards a multifactorial conception of the nephrotic syndrome where all these barely known factors could be associated according to a sequential kinetic mechanism that needs to be determined.
Topics: Blood Cells; Blood Proteins; Glomerulosclerosis, Focal Segmental; Humans; Kidney; Kidney Glomerulus; Nephrotic Syndrome; Podocytes; Proteinuria; Risk Factors
PubMed: 31532378
DOI: 10.1051/medsci/2019128 -
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 -
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 -
Kidney International Sep 2022Primary Coenzyme Q10 (CoQ) deficiency is an ultra-rare disorder caused by defects in genes involved in CoQ biosynthesis leading to multidrug-resistant nephrotic syndrome...
Primary Coenzyme Q10 (CoQ) deficiency is an ultra-rare disorder caused by defects in genes involved in CoQ biosynthesis leading to multidrug-resistant nephrotic syndrome as the hallmark kidney manifestation. Promising early results have been reported anecdotally with oral CoQ supplementation. However, the long-term efficacy and optimal prescription remain to be established. In a global effort, we collected and analyzed information from 116 patients who received CoQ supplements for primary CoQ deficiency due to biallelic pathogenic variants in either the COQ2, COQ6 or COQ8B genes. Median duration of follow up on treatment was two years. The effect of treatment on proteinuria was assessed, and kidney survival was analyzed in 41 patients younger than 18 years with chronic kidney disease stage 1-4 at the start of treatment compared with that of an untreated cohort matched by genotype, age, kidney function, and proteinuria. CoQ supplementation was associated with a substantial and significant sustained reduction of proteinuria by 88% at 12 months. Complete remission of proteinuria was more frequently observed in COQ6 disease. CoQ supplementation led to significantly better preservation of kidney function (5-year kidney failure-free survival 62% vs. 19%) with an improvement in general condition and neurological manifestations. Side effects of treatment were uncommon and mild. Thus, our findings indicate that all patients diagnosed with primary CoQ deficiency should receive early and life-long CoQ supplementation to decelerate the progression of kidney disease and prevent further damage to other organs.
Topics: Ataxia; Dietary Supplements; Humans; Kidney; Mitochondrial Diseases; Muscle Weakness; Mutation; Nephrotic Syndrome; Proteinuria; Steroids; Ubiquinone
PubMed: 35643375
DOI: 10.1016/j.kint.2022.04.029 -
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 -
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 -
Trials Mar 2024Proteinuria is a modifiable risk factor for chronic kidney disease (CKD) progression in children. Finerenone, a selective, non-steroidal, mineralocorticoid receptor... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
Proteinuria is a modifiable risk factor for chronic kidney disease (CKD) progression in children. Finerenone, a selective, non-steroidal, mineralocorticoid receptor antagonist (MRA) has been approved to treat adults with CKD associated with type 2 diabetes mellitus (T2DM) following results from the phase III clinical trials FIDELIO-DKD (NCT02540993) and FIGARO-DKD (NCT02545049). In a pre-specified pooled analysis of both studies (N = 13,026), finerenone was shown to have an acceptable safety profile and was efficacious in decreasing the risk of adverse kidney and cardiovascular outcomes and of proteinuria.
OBJECTIVE
FIONA and the associated open-label extension (OLE) study aim to demonstrate that combining finerenone with an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) is safe, well-tolerated, and effective in sustainably reducing urinary protein excretion in children with CKD and proteinuria.
DESIGN
FIONA (NCT05196035; Eudra-CT: 2021-002071-19) is a randomized (2:1), double-blind, placebo-controlled, multicenter, phase III study of 6 months' duration in approximately 219 pediatric patients. Patients must have a clinical diagnosis of CKD (an eGFR ≥ 30 mL/min/1.73 m if ≥ 1 to < 18 years or a serum creatinine level ≤ 0.40 mg/dL for infants 6 months to < 1 year) with significant proteinuria despite ACEi or ARB usage. The primary objective is to demonstrate that finerenone, added to an ACEi or ARB, is superior to placebo in reducing urinary protein excretion. FIONA OLE (NCT05457283; Eudra-CT: 2021-002905-89) is a single-arm, open-label study, enrolling participants who have completed FIONA. The primary objective of FIONA OLE is to provide long-term safety data. FIONA has two primary endpoints: urinary protein-to-creatinine ratio (UPCR) reduction of ≥ 30% from baseline to day 180 and percent change in UPCR from baseline to day 180. A sample size of 198 participants (aged 2 to < 18 years) in FIONA will provide at least 80% power to reject the null hypothesis of either of the two primary endpoints.
CONCLUSION
FIONA is evaluating the use of finerenone in children with CKD and proteinuria. Should safety, tolerability, and efficacy be demonstrated, finerenone could become a useful additional therapeutic agent in managing proteinuria and improving kidney outcomes in children with CKD.
TRIAL REGISTRATION
ClinicalTrials.gov NCT05196035. Registered on 19 January 2022.
Topics: Adult; Humans; Child; Diabetes Mellitus, Type 2; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Renal Insufficiency, Chronic; Proteinuria; Mineralocorticoid Receptor Antagonists; Diabetic Nephropathies; Naphthyridines
PubMed: 38509517
DOI: 10.1186/s13063-024-08021-z -
European Journal of Medical Research Aug 2022This study aimed to analyze the distribution of IgG subclass in diabetic nephropathy (DN) and its association with clinicopathological features.
PURPOSE
This study aimed to analyze the distribution of IgG subclass in diabetic nephropathy (DN) and its association with clinicopathological features.
METHODS
This is a single-center retrospective study enrolling 108 patients with biopsy-proven DN. Immunofluorescence and immunohistochemistry staining were applied, and clinicopathological features and renal outcomes were compared between patients with different patterns or categories of IgG subclass deposition.
RESULTS
Both IgG and its subclasses colocalized with collagen IV α5 on glomerular basement membrane (GBM) and some of tubular basement membrane (TBM). IgG1 and the Mixed type were two predominant types of deposition, no matter on GBM or TBM, and IgG1 showed a much higher deposition rate on GBM than that on TBM (P = 0.004). IgG subclass deposit on multi-location was more associated with a shorter duration of nephropathy and severer tubular interstitial injury (P < 0.05). The mixed type of IgG subclass deposit on GBM was merely associated with higher levels of proteinuria, whereas the deposition on TBM was more associated with higher levels of proteinuria, lower levels of albumin, more KIM-1 positive area, and thicker TBM (P < 0.05). Survival analysis revealed that none of the pattern or the category of IgG subclass deposit was a risk factor or a renal outcome indicator.
CONCLUSIONS
IgG subclass was selectively deposited along GBM and/or TBM in DN, and the mixed type of IgG subclass deposition on TBM had more clinical significance than the isotype and that on GBM. IgG subclass deposition is merely a manifestation or a consequence rather than a cause in DN.
Topics: Diabetes Mellitus; Diabetic Nephropathies; Humans; Immunoglobulin G; Kidney; Proteinuria; Retrospective Studies
PubMed: 35953864
DOI: 10.1186/s40001-022-00779-9 -
Seminars in Nephrology Sep 2021Serum creatinine and level of proteinuria, as biomarkers of chronic kidney disease (CKD) progression, inadequately explain the variability of glomerular filtration rate... (Review)
Review
Serum creatinine and level of proteinuria, as biomarkers of chronic kidney disease (CKD) progression, inadequately explain the variability of glomerular filtration rate decline, and are late markers of glomerular filtration rate decline. Recent studies have identified plasma and urine biomarkers at higher levels in children with CKD and also associate independently with CKD progression, even after adjustment for serum creatinine and proteinuria. These novel biomarkers represent diverse biologic pathways of tubular injury, tubular dysfunction, inflammation, and tubular health, and can be used as a liquid biopsy to better characterize CKD in children. In this review, we highlight the biomarker findings from the Chronic Kidney Disease in Children cohort, a large longitudinal study of children with CKD, and compare results with those from other pediatric CKD cohorts. The biomarkers in focus in this review include plasma kidney injury molecule-1, monocyte chemoattractant protein-1, fibroblast growth factor-23, tumor necrosis factor receptor-1, tumor necrosis factor receptor-2, soluble urokinase plasminogen activator receptor, and chitinase-3-like protein 1, as well as urine epidermal growth factor, α-1 microglobulin, kidney injury molecule-1, monocyte chemoattractant protein-1, and chitinase-3-like protein 1. Blood and urine biomarkers improve our ability to prognosticate CKD progression and may improve our understanding of CKD pathophysiology. Further research is required to establish how these biomarkers can be used in the clinical setting to improve the clinical management of CKD.
Topics: Biomarkers; Chemokine CCL2; Child; Chitinase-3-Like Protein 1; Creatinine; Disease Progression; Female; Glomerular Filtration Rate; Humans; Longitudinal Studies; Male; Proteinuria; Renal Insufficiency, Chronic
PubMed: 34916002
DOI: 10.1016/j.semnephrol.2021.09.003