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Renal Failure 2023Diabetic kidney disease (DKD) is a primary cause of end-stage renal disease. Proteinuria is a clinical indicator of the different stages of DKD, and podocyte injury is a... (Review)
Review
Diabetic kidney disease (DKD) is a primary cause of end-stage renal disease. Proteinuria is a clinical indicator of the different stages of DKD, and podocyte injury is a major cause of proteinuria. Podocyte-specific proteins (PSPs) play important roles in the normal filtration of podocytes. Studies have shown that natural active compounds (NACs) can ameliorate proteinuria; however, the mechanism related to PSPs needs to be explored. In this study, the five stages of DKD related to proteinuria and the functions of PSPs are displayed separately. Mechanisms for ameliorating proteinuria and improving the PSPs of the 15 NACs are summarized. The and mechanistic research showed that five compounds, astragaloside IV, ligustrazine, berberine, emodin and resveratrol, exerted renal protective effects AMPK signaling, icariin and berberine TLR4 signaling, hirudin and baicalin MAPK signaling, curcumin and baicalin NF-κB signaling, and emodin protein kinase RNA-like endoplasmic reticulum kinase signaling. The 13 PSPs were divided into five categories: actin cytoskeleton, basal domain, apical domain, slit diaphragm, and others. In conclusion, anti-inflammatory effects, anti-oxidative stress, and enhanced autophagy are the main mechanisms underlying the ameliorative effects of NACs. Podocyte apoptosis is mainly related to nephrin and podocin, which are the most studied slit diaphragm PSPs.
Topics: Humans; Podocytes; Diabetic Nephropathies; Emodin; Berberine; Proteinuria; Diabetes Mellitus
PubMed: 38073545
DOI: 10.1080/0886022X.2023.2290930 -
Scientific Reports May 2024Understanding the association between dipstick-detected proteinuria and oculomotor cranial nerve palsy (CNP) could have significant implications for understanding the...
Understanding the association between dipstick-detected proteinuria and oculomotor cranial nerve palsy (CNP) could have significant implications for understanding the mechanism of CNP development and for developing preventive strategies against CNP development in patients with proteinuria. This study aimed to determine the relationship between dipstick-determined proteinuria and ocular motor CNP using National Sample Cohort (NSC) database from Korea's National Health Insurance Service (NHIS). A nationwide population-based cohort study was conducted using data from the NSC database of Korea's NHIS. These data were collected from 2009 to 2018. A one-year time lag was established to prevent a situation in which the causal link was inverted. Participants aged 20 years or more who were diagnosed with proteinuria in 2009 were included. Individuals with specific pre-existing CNP, missing data, and those who were newly diagnosed with CNP or who died within one year of being tested were excluded. The study population was classified into six groups according to the degree of proteinuria (negative, trace, or between 1 + and 4 +) based on the urine dipstick test. A Cox proportional hazard regression analysis was performed to determine the linkage between the degree of proteinuria and ocular motor CNP. A total of 5,807 (0.14% of subjects) with ocular motor CNP were assigned to the ocular motor CNP group and 4,047,205 subjects were assigned to the control group. After full adjustment of comorbidities, hazard ratios (HRs) for 1 + , 2 + , 3 + and 4 + proteinuria groups were 1.449 (95% confidence interval [CI] 1.244-1.687), 2.081 (1.707-2.538), 1.96 (1.322-2.904), and 3.011 (1.507-6.014), respectively, for developing ocular motor CNP compared to the proteinuria-negative group. In subgroup analysis, the HR of patients with proteinuria for the development of ocular motor CNP was higher in the younger age group (less than 40 years) (P = 0.0242) and the group with DM (P = 0.04). Our population-based cohort study demonstrated a significant association between proteinuria and the incidence of CNP, suggesting that urine protein level could be a new clinical marker for predicting the development of CNP.
Topics: Humans; Male; Female; Middle Aged; Proteinuria; Republic of Korea; Adult; Oculomotor Nerve Diseases; Aged; Risk Factors; Cohort Studies; Young Adult; Proportional Hazards Models
PubMed: 38797738
DOI: 10.1038/s41598-024-62576-0 -
Clinical and Experimental Nephrology Sep 2023In the primary analysis of the PREDICT trial, a higher hemoglobin target (11-13 g/dl) with darbepoetin alfa did not improve renal outcomes compared with a lower... (Randomized Controlled Trial)
Randomized Controlled Trial
Higher hemoglobin levels using darbepoetin alfa and kidney outcomes in advanced chronic kidney disease without diabetes: a prespecified secondary analysis of the PREDICT trial.
BACKGROUND
In the primary analysis of the PREDICT trial, a higher hemoglobin target (11-13 g/dl) with darbepoetin alfa did not improve renal outcomes compared with a lower hemoglobin target (9-11 g/dl) in advanced chronic kidney disease (CKD) without diabetes. Prespecified secondary analyses were performed to further study the effects of targeting higher hemoglobin levels on renal outcomes.
METHODS
Patients with an estimated glomerular filtration rate (eGFR) 8-20 ml/min/1.73 m without diabetes were randomly assigned 1:1 to the high- and low-hemoglobin groups. The differences between the groups were evaluated for the following endpoints and cohort sets: eGFR and proteinuria slopes, assessed using a mixed-effects model in the full analysis set and the per-protocol set that excluded patients with off-target hemoglobin levels; the primary endpoint of composite renal outcome, evaluated in the per-protocol set using the Cox model.
RESULTS
In the full analysis set (high hemoglobin, n = 239; low hemoglobin, n = 240), eGFR and proteinuria slopes were not significantly different between the groups. In the per-protocol set (high hemoglobin, n = 136; low hemoglobin, n = 171), the high-hemoglobin group was associated with reduced composite renal outcome (adjusted hazard ratio: 0.64; 95% confidence interval: 0.43-0.96) and an improved eGFR slope (coefficient: + 1.00 ml/min/1.73 m/year; 95% confidence interval: 0.38-1.63), while the proteinuria slope did not differ between the groups.
CONCLUSIONS
In the per-protocol set, the high-hemoglobin group demonstrated better kidney outcomes than the low-hemoglobin group, suggesting a potential benefit of maintaining higher hemoglobin levels in patients with advanced CKD without diabetes.
CLINICAL TRIAL REGISTRATION
Clinicaltrials.gov (identifier: NCT01581073).
Topics: Humans; Darbepoetin alfa; Anemia; Renal Insufficiency, Chronic; Kidney; Hemoglobins; Proteinuria; Neoplasms; Diabetes Mellitus
PubMed: 37289335
DOI: 10.1007/s10157-023-02362-w -
Journal of the American Medical... May 2023Screening for chronic kidney disease (CKD) requires an estimated glomerular filtration rate (eGFR, mL/min/1.73 m2) from a blood sample and a proteinuria level from a...
OBJECTIVE
Screening for chronic kidney disease (CKD) requires an estimated glomerular filtration rate (eGFR, mL/min/1.73 m2) from a blood sample and a proteinuria level from a urinalysis. We developed machine-learning models to detect CKD without blood collection, predicting an eGFR less than 60 (eGFR60 model) or 45 (eGFR45 model) using a urine dipstick test.
MATERIALS AND METHODS
The electronic health record data (n = 220 018) obtained from university hospitals were used for XGBoost-derived model construction. The model variables were age, sex, and 10 measurements from the urine dipstick test. The models were validated using health checkup center data (n = 74 380) and nationwide public data (KNHANES data, n = 62 945) for the general population in Korea.
RESULTS
The models comprised 7 features, including age, sex, and 5 urine dipstick measurements (protein, blood, glucose, pH, and specific gravity). The internal and external areas under the curve (AUCs) of the eGFR60 model were 0.90 or higher, and a higher AUC for the eGFR45 model was obtained. For the eGFR60 model on KNHANES data, the sensitivity was 0.93 or 0.80, and the specificity was 0.86 or 0.85 in ages less than 65 with proteinuria (nondiabetes or diabetes, respectively). Nonproteinuric CKD could be detected in nondiabetic patients under the age of 65 with a sensitivity of 0.88 and specificity of 0.71.
DISCUSSION AND CONCLUSIONS
The model performance differed across subgroups by age, proteinuria, and diabetes. The CKD progression risk can be assessed with the eGFR models using the levels of eGFR decrease and proteinuria. The machine-learning-enhanced urine-dipstick test can become a point-of-care test to promote public health by screening CKD and ranking its risk of progression.
Topics: Humans; Creatinine; Urinalysis; Proteinuria; Renal Insufficiency, Chronic; Glomerular Filtration Rate; Diabetes Mellitus
PubMed: 37027837
DOI: 10.1093/jamia/ocad051 -
The Journal of International Medical... Apr 2020To evaluate the association between proteinuria and maternal and neonatal outcomes in pregnant women with pre-eclampsia. (Observational Study)
Observational Study
OBJECTIVES
To evaluate the association between proteinuria and maternal and neonatal outcomes in pregnant women with pre-eclampsia.
METHODS
This retrospective study included patients beyond 20 weeks of gestation diagnosed with pre-eclampsia, who were admitted to Suzhou Municipal Hospital between December 2013 and December 2015. Demographic and clinical data were extracted from clinical records, including age, body mass index, newborn weight and Apgar score. Pre-eclampsia risk factors and perinatal outcomes were analysed.
RESULTS
A total of 407 patients were enrolled, of whom, 402 with pre-eclampsia were included in the final analyses, divided into two groups: patients with proteinuria ( = 364 [90.55%]) and patients without proteinuria ( = 38 [9.45%]). Newborn 5-min Apgar scores were statistically lower in the proteinuria group versus the group without proteinuria (9.77 versus 9.95). Compared with patients without proteinuria, patients with proteinuria had a significantly higher rate of births before 37 weeks of gestation (50.80% versus 31.60%), but the incidence of preterm membrane rupture was significantly lower (3.8% versus 13.2%).
CONCLUSION
Proteinuria may be associated with adverse maternal and neonatal outcomes in cases of pre-eclampsia.
Topics: Adult; Apgar Score; Body Mass Index; Female; Humans; Infant, Newborn; Middle Aged; Pre-Eclampsia; Pregnancy; Pregnancy Outcome; Proteinuria; Retrospective Studies; Risk Factors
PubMed: 32339047
DOI: 10.1177/0300060520908114 -
Nutrients Mar 2023Previous cohort studies have reported conflicting associations between alcohol consumption and chronic kidney disease, characterized by proteinuria and low glomerular... (Meta-Analysis)
Meta-Analysis Review
A Dose-Dependent Association between Alcohol Consumption and Incidence of Proteinuria and Low Glomerular Filtration Rate: A Systematic Review and Meta-Analysis of Cohort Studies.
Previous cohort studies have reported conflicting associations between alcohol consumption and chronic kidney disease, characterized by proteinuria and low glomerular filtration rate (GFR). This systematic review, which included 14,634,940 participants from 11 cohort studies, assessed a dose-dependent association of alcohol consumption and incidence of proteinuria and low estimated GFR (eGFR) of <60 mL/min/1.73 m. Compared with non-drinkers, the incidence of proteinuria was lower in drinkers with alcohol consumption of ≤12.0 g/day (relative risk 0.87 [95% confidence interval 0.83, 0.92]), but higher in drinkers with alcohol consumption of 36.1-60.0 g/day (1.09 [1.03, 1.15]), suggesting a J-shaped association between alcohol consumption and the incidence of proteinuria. Incidence of low eGFR was lower in drinkers with alcohol consumption of ≤12.0 and 12.1-36.0 than in non-drinkers (≤12.0, 12.1-36.0, and 36.1-60.0 g/day: 0.93 [0.90, 0.95], 0.82 [0.78, 0.86], and 0.89 [0.77, 1.03], respectively), suggesting that drinkers were at lower risk of low eGFR. In conclusion, compared with non-drinkers, mild drinkers were at lower risk of proteinuria and low eGFR, whereas heavy drinkers had a higher risk of proteinuria but a lower risk of low eGFR. The clinical impact of high alcohol consumption should be assessed in well-designed studies.
Topics: Humans; Glomerular Filtration Rate; Incidence; Risk Factors; Alcohol Drinking; Cohort Studies; Proteinuria
PubMed: 37049433
DOI: 10.3390/nu15071592 -
Biomolecules May 2023Obesity surgery candidates are at an increased risk of kidney injury, but pre-operative evaluation usually neglects kidney function assessment. This study aimed to...
Obesity surgery candidates are at an increased risk of kidney injury, but pre-operative evaluation usually neglects kidney function assessment. This study aimed to identify renal dysfunction in candidates for bariatric surgery. To reduce the sources of bias, subjects with diabetes, prediabetes under metformin treatment, neoplastic or inflammatory diseases were excluded. Patients' (n = 192) average body mass index was 41.7 ± 5.4 kg/m. Among these, 51% (n = 94) had creatinine clearance over 140 mL/min, 22.4% (n = 43) had proteinuria over 150 mg/day and 14.6% (n = 28) albuminuria over 30 mg/day. A creatinine clearance higher than 140 mL/min was associated with higher levels of proteinuria and albuminuria. Univariate analysis identified sex, glycated hemoglobin, uric acid, HDL and VLDL cholesterol as being associated with albuminuria, but not with proteinuria. On multivariate analysis, glycated hemoglobin and creatinine clearance as continuous variables were significantly associated with albuminuria. In summary, in our patient population prediabetes, lipid abnormalities and hyperuricemia were associated with albuminuria, but not with proteinuria, suggesting different disease mechanisms might be implicated. Data suggest that in obesity-associated kidney disease, tubulointerstitial injury precedes glomerulopathy. A significant proportion of obesity surgery candidates present clinically relevant albuminuria and proteinuria along with renal hyperfiltration, suggesting that routine pre-operative assessment of these parameters should be considered.
Topics: Humans; Albuminuria; Prediabetic State; Glycated Hemoglobin; Creatinine; Glomerular Filtration Rate; Proteinuria; Kidney Diseases; Bariatric Surgery; Obesity; Phenotype
PubMed: 37238660
DOI: 10.3390/biom13050790 -
Kidney International May 2024The circadian clock influences a wide range of biological process and controls numerous aspects of physiology to adapt to the daily environmental changes caused by...
The circadian clock influences a wide range of biological process and controls numerous aspects of physiology to adapt to the daily environmental changes caused by Earth's rotation. The kidney clock plays an important role in maintaining tubular function, but its effect on podocytes remains unclear. Here, we found that podocytes expressed CLOCK proteins, and that 2666 glomerular gene transcripts (13.4%), including autophagy related genes, had 24-hour circadian rhythms. Deletion of Clock in podocytes resulted in 1666 gene transcripts with the loss of circadian rhythm including autophagy genes. Podocyte-specific Clock knockout mice at age three and eight months showed deficient autophagy, loss of podocytes and increased albuminuria. Chromatin immunoprecipitation (ChIP) sequence analysis indicated autophagy related genes were targets of CLOCK in podocytes. ChIP-PCR further confirmed Clock binding to the promoter regions of Becn1 and Atg12, two autophagy related genes. Furthermore, the association of CLOCK regulated autophagy with chronic sleep fragmentation and diabetic kidney disease was analyzed. Chronic sleep fragmentation resulted in the loss of glomerular Clock rhythm, inhibition of podocyte autophagy, and proteinuria. Rhythmic oscillations of Clock also disappeared in high glucose treated podocytes and in glomeruli from diabetic mice. Finally, circadian differences in podocyte autophagy were also abolished in diabetic mice. Deletion Clock in podocytes aggravated podocyte injury and proteinuria in diabetic mice. Thus, our findings demonstrate that clock-dependent regulation of autophagy may be essential for podocyte survival. Hence. loss of circadian controlled autophagy may play an important role in podocyte injury and proteinuria.
Topics: Mice; Animals; Podocytes; Diabetes Mellitus, Experimental; Sleep Deprivation; Proteinuria; Diabetic Nephropathies; Mice, Knockout; Autophagy
PubMed: 38387504
DOI: 10.1016/j.kint.2024.01.035 -
EBioMedicine Apr 2023Proteinuria is associated with many glomerular diseases and a risk factor for the progression to renal failure. We previously showed that heparanase (HPSE) is essential...
BACKGROUND
Proteinuria is associated with many glomerular diseases and a risk factor for the progression to renal failure. We previously showed that heparanase (HPSE) is essential for the development of proteinuria, whereas peroxisome proliferator-activated receptor ɣ (PPARɣ) agonists can ameliorate proteinuria. Since a recent study showed that PPARɣ regulates HPSE expression in liver cancer cells, we hypothesized that PPARɣ agonists exert their reno-protective effect by inhibiting glomerular HPSE expression.
METHODS
Regulation of HPSE by PPARɣ was assessed in the adriamycin nephropathy rat model, and cultured glomerular endothelial cells and podocytes. Analyses included immunofluorescence staining, real-time PCR, heparanase activity assay and transendothelial albumin passage assay. Direct binding of PPARɣ to the HPSE promoter was evaluated by the luciferase reporter assay and chromatin immunoprecipitation assay. Furthermore, HPSE activity was assessed in 38 type 2 diabetes mellitus (T2DM) patients before and after 16/24 weeks treatment with the PPARɣ agonist pioglitazone.
FINDINGS
Adriamycin-exposed rats developed proteinuria, an increased cortical HPSE and decreased heparan sulfate (HS) expression, which was ameliorated by treatment with pioglitazone. In line, the PPARɣ antagonist GW9662 increased cortical HPSE and decreased HS expression, accompanied with proteinuria in healthy rats, as previously shown. In vitro, GW9662 induced HPSE expression in both endothelial cells and podocytes, and increased transendothelial albumin passage in a HPSE-dependent manner. Pioglitazone normalized HPSE expression in adriamycin-injured human endothelial cells and mouse podocytes, and adriamycin-induced transendothelial albumin passage was reduced as well. Importantly, we demonstrated a regulatory effect of PPARɣ on HPSE promoter activity and direct PPARy binding to the HPSE promoter region. Plasma HPSE activity of T2DM patients treated with pioglitazone for 16/24 weeks was related to their hemoglobin A1c and showed a moderate, near significant correlation with plasma creatinine levels.
INTERPRETATION
PPARɣ-mediated regulation of HPSE expression appears an additional mechanism explaining the anti-proteinuric and renoprotective effects of thiazolidinediones in clinical practice.
FUNDING
This study was financially supported by the Dutch Kidney Foundation, by grants 15OI36, 13OKS023 and 15OP13. Consortium grant LSHM16058-SGF (GLYCOTREAT; a collaboration project financed by the PPP allowance made available by Top Sector Life Sciences & Health to the Dutch Kidney Foundation to stimulate public-private partnerships).
Topics: Rats; Mice; Humans; Animals; Pioglitazone; PPAR gamma; Diabetes Mellitus, Type 2; PPAR-gamma Agonists; Endothelial Cells; Thiazolidinediones; Proteinuria; Kidney Diseases; Doxorubicin
PubMed: 36889064
DOI: 10.1016/j.ebiom.2023.104506 -
PloS One 2022Proteinuria results from kidney damage and can be a predictor of illness severity and mortality in the intensive care unit (ICU). However, the optimal timing of...
BACKGROUND
Proteinuria results from kidney damage and can be a predictor of illness severity and mortality in the intensive care unit (ICU). However, the optimal timing of proteinuria measurements and the reference values remain undetermined. Our objective was to identify the patterns of proteinuria change associated with mortality in ICU patients with sepsis or shock.
METHODS
This monocentric retrospective cohort study performed from April 2010 to April 2018 involved all ICU patients with sepsis or shock and at least two measurements of proteinuria from a 24h-urine collection during the first 10 days of ICU stay, the first of which was made within 48h after ICU admission. We identified proteinuria trajectories by a semi-parametric mixture model and analysed the association between the trajectories and the mortality at day 28 by Cox proportional-hazards model.
RESULTS
A total of 3,344 measurements of proteinuria from 659 patients were analysed. Four proteinuria trajectories were identified. Trajectories 1, 2, 3 and 4 comprised 127, 421, 60 and 51 patients, and were characterized by a first proteinuria of 1.14 [0.66-1.55], 0.52 [0.26-0.91], 2.92 [2.38-3.84] and 2.58 [1.75-3.32] g/24h (p<0.001) and a mortality of 24.4%, 38%, 20% and 43% (p = 0.002), respectively. Trajectories 3 and 4 had a high first proteinuria (>2g/24h). Only, the proteinuria of trajectory 4 increased within 3 days following the first measurement and was associated with increased mortality at day 28 (hazard ratio: 2.36 95%CI [1.07-5.19], p = 0.03), regardless of acute renal failure. The factors associated with trajectory 4 were cancer (relative risk: 8.91 95%CI [2.09-38.02], p = 0.003) and use of inotropic drugs (relative risk: 0.17 95%CI [0.04-0.69], p = 0.01).
CONCLUSION
This exploratory study of ICU patients with sepsis or shock identified four proteinuria trajectories with distinct patterns of proteinuria change over time and mortality rates. These results provide novel insights into renal pathophysiology and may be helpful to investigate subphenotypes of kidney injury among ICU patients in future studies.
Topics: Critical Illness; Hospital Mortality; Humans; Intensive Care Units; Proteinuria; Retrospective Studies; Sepsis; Shock
PubMed: 36001593
DOI: 10.1371/journal.pone.0272835