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BMC Nephrology Aug 2023Primary membranous nephropathy (PMN) frequently causes nephrotic syndrome and declining kidney function. Disease progression is likely modulated by patient-specific and... (Observational Study)
Observational Study
BACKGROUND
Primary membranous nephropathy (PMN) frequently causes nephrotic syndrome and declining kidney function. Disease progression is likely modulated by patient-specific and therapy-associated factors awaiting characterization. These cofactors may facilitate identification of risk groups and could result in more individualized therapy recommendations.
METHODS
In this single-center retrospective observational study, we analyze the effect of patient-specific and therapy-associated covariates on proteinuria, hypoalbuminemia, and estimated glomerular filtration rate (eGFR) in 74 patients diagnosed with antibody positive PMN and nephrotic-range proteinuria (urine-protein-creatinine-ratio [UPCR] ≥ 3.5 g/g), treated at the University of Freiburg Medical Center between January 2000 - November 2022. The primary endpoint was defined as time to proteinuria / serum-albumin response (UPCR ≤ 0.5 g/g or serum-albumin ≥ 3.5 g/dl), the secondary endpoint as time to permanent eGFR decline (≥ 40% relative to baseline).
RESULTS
The primary endpoint was reached after 167 days. The secondary endpoint was reached after 2413 days. Multivariate time-to-event analyses showed significantly faster proteinuria / serum-albumin response for higher serum-albumin levels (HR 2.7 [95% CI: 1.5 - 4.8]) and cyclophosphamide treatment (HR 3.6 [95% CI: 1.3 - 10.3]). eGFR decline was significantly faster in subjects with old age at baseline (HR 1.04 [95% CI: 1 - 1.1]).
CONCLUSION
High serum-albumin levels, and treatment with cyclophosphamide are associated with faster proteinuria reduction and/or serum-albumin normalization. Old age constitutes a risk factor for eGFR decline in subjects with PMN.
Topics: Humans; Glomerulonephritis, Membranous; Nephrotic Syndrome; Cyclophosphamide; Proteinuria; Serum Albumin
PubMed: 37563703
DOI: 10.1186/s12882-023-03288-x -
Biomolecules Mar 2022Pre-eclampsia is a severe hypertensive disorder of pregnancy (HDP), mainly characterized by new-onset hypertension with proteinuria after 20-week gestation. Sirtuin1...
Pre-eclampsia is a severe hypertensive disorder of pregnancy (HDP), mainly characterized by new-onset hypertension with proteinuria after 20-week gestation. Sirtuin1 (SIRT1), a class III histone deacetylase, is associated with the regulation of various pathophysiological processes, including inflammation, immune response, metabolism, and autophagy. However, the effect of SIRT1 in the pathogenesis of pre-eclampsia remains to be elucidated. In this study, we found that the expression of SIRT1 was relatively lower in the placentas and serum samples of pre-eclampsia patients. Typical pre-eclampsia-like symptoms, such as hypertension, proteinuria, fetal growth restriction, kidney injury, and a narrow placental labyrinth layer, were observed in SIRT1 knockdown (SIRT1) mice. Of note, these performances could be improved after the intraperitoneal injection of SIRT1 agonist SRT2104. More importantly, we found that the efficacy of progesterone on attenuating symptoms of PE was profoundly better than that of metformin in SIRT1 mice. In addition, our results suggested that progesterone can promote the invasion and inhibit the apoptosis of trophoblasts. These data suggest that SIRT1 plays an important role in pre-eclampsia and that progesterone alleviates pre-eclampsia-like symptoms mediated by SIRT1 deficiency.
Topics: Animals; Female; Humans; Hypertension; Male; Mice; Placenta; Pre-Eclampsia; Pregnancy; Progesterone; Proteinuria; Sirtuin 1
PubMed: 35327614
DOI: 10.3390/biom12030422 -
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 -
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 the American Society of... Mar 2023The loss of integrity of the glomerular filtration barrier results in proteinuria that is often attributed to podocyte loss. Yet how damaged podocytes are lost remains...
SIGNIFICANCE STATEMENT
The loss of integrity of the glomerular filtration barrier results in proteinuria that is often attributed to podocyte loss. Yet how damaged podocytes are lost remains unknown. Germline loss of murine podocyte-associated Hdac1 and Hdac2 ( Hdac1/2 ) results in proteinuria and collapsing glomerulopathy due to sustained double-stranded DNA damage. Hdac1/2 deletion induces loss of podocyte quiescence, cell cycle entry, arrest in G1, and podocyte senescence, observed both in vivo and in vitro . Through the senescence secretory associated phenotype, podocytes secrete proteins that contribute to their detachment. These results solidify the role of HDACs in cell cycle regulation and senescence, providing important clues in our understanding of how podocytes are lost following injury.
BACKGROUND
Intact expression of podocyte histone deacetylases (HDAC) during development is essential for maintaining a normal glomerular filtration barrier because of its role in modulating DNA damage and preventing premature senescence.
METHODS
Germline podocyte-specific Hdac1 and 2 ( Hdac1 / 2 ) double-knockout mice were generated to examine the importance of these enzymes during development.
RESULTS
Podocyte-specific loss of Hdac1 / 2 in mice resulted in severe proteinuria, kidney failure, and collapsing glomerulopathy. Hdac1 / 2 -deprived podocytes exhibited classic characteristics of senescence, such as senescence-associated β-galactosidase activity and lipofuscin aggregates. In addition, DNA damage, likely caused by epigenetic alterations such as open chromatin conformation, not only resulted in podocyte cell-cycle entry as shown in vivo by Ki67 expression and by FUCCI-2aR mice, but also in p21-mediated cell-cycle arrest. Through the senescence secretory associated phenotype, the damaged podocytes secreted proinflammatory cytokines, growth factors, and matrix metalloproteinases, resulting in subsequent podocyte detachment and loss, evidenced by senescent podocytes in urine.
CONCLUSIONS
Hdac1 / 2 plays an essential role during development. Loss of these genes in double knockout mice leads to sustained DNA damage and podocyte senescence and loss.
Topics: Animals; Mice; Cell Cycle; Histone Deacetylase 1; Mice, Knockout; Podocytes; Proteinuria
PubMed: 36414418
DOI: 10.1681/ASN.2022050598 -
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 -
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