-
Kidney International Jun 2024Atacicept is a first-in-class, dual anti-B-cell Activation Factor-A Proliferation-Inducing Ligand fusion protein in clinical evaluation for treatment of IgA nephropathy.... (Randomized Controlled Trial)
Randomized Controlled Trial
Atacicept is a first-in-class, dual anti-B-cell Activation Factor-A Proliferation-Inducing Ligand fusion protein in clinical evaluation for treatment of IgA nephropathy. To compare efficacy and safety of atacicept versus placebo in patients with IgAN, this randomized, double-blind, placebo-controlled phase 2b clinical trial ORIGIN enrolled 116 individuals with biopsy-proven IgA nephropathy. Participants were randomized to atacicept 150, 75, or 25 mg versus placebo once weekly for up to 36 weeks. Primary and key secondary endpoints were changes in urine protein creatinine ratio based on 24-hour urine collection at weeks 24 and 36, respectively, in the combined atacicept 150 mg and 75 mg group versus placebo. The primary endpoint was met at week 24 as the mean urine protein creatinine ratio was reduced from baseline by 31% in the combined atacicept group versus 8% with placebo, resulting in a significant 25% reduction with atacicept versus placebo. At week 36, the key secondary endpoint was met as the mean urine protein creatinine ratio reduced from baseline by 34% in the combined atacicept group versus a 2% increase with placebo, resulting in a significant 35% reduction with atacicept versus placebo. The reduction in proteinuria was accompanied by stabilization in endpoint eGFR with atacicept compared to a decline with placebo at week 36, resulting in significant between-group geometric mean difference of 11%, approximating an absolute difference of 5.7 mL/min/1.73m. Endpoint galactose deficient IgA1 levels significantly decreased from baseline by 60% versus placebo. The safety profile of atacicept was like placebo. Thus, our results provide evidence to support a pivotal, phase 3 study of atacicept in IgA nephropathy.
Topics: Humans; Glomerulonephritis, IGA; Double-Blind Method; Female; Male; Recombinant Fusion Proteins; Adult; Middle Aged; Creatinine; Treatment Outcome; Proteinuria; Receptors, Fc; Young Adult; Glomerular Filtration Rate
PubMed: 38552841
DOI: 10.1016/j.kint.2024.03.012 -
Clinica Chimica Acta; International... Jan 2024One of the main barriers to early detection and subsequent prevention of kidney diseases is the accessibility and feasibility of testing, especially in urine research.... (Review)
Review
One of the main barriers to early detection and subsequent prevention of kidney diseases is the accessibility and feasibility of testing, especially in urine research. The proteinuria selectivity index (PSI or SI) is a method used to assess changes in glomerular permeability in glomerular diseases. It describes the pattern of proteinuria by comparing the clearance rates of large molecular proteins and transferrin, categorizing it as selective or non-selective. PSI is widely applied for kidney disease classification, prediction of corticosteroid efficacy, and prognosis. Herein, we reviewed the clinical applications and recent advancements of PSI in glomerular diseases, compared it with commonly used renal function biomarkers, and discussed the future research directions for PSI as a potential predictive marker for response to specific biologics.
Topics: Humans; Nephrotic Syndrome; Proteinuria; Kidney; Kidney Diseases; Kidney Glomerulus
PubMed: 38007057
DOI: 10.1016/j.cca.2023.117675 -
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 -
Pediatric Nephrology (Berlin, Germany) Nov 2023Nephrotic syndrome (NS) consists of the clinical triad of hypoalbuminaemia, high levels of proteinuria and oedema, and describes a heterogeneous group of disease... (Review)
Review
Nephrotic syndrome (NS) consists of the clinical triad of hypoalbuminaemia, high levels of proteinuria and oedema, and describes a heterogeneous group of disease processes with different underlying drivers. The existence of circulating factor disease (CFD) as a driver of NS has been epitomised by a subset of patients who exhibit disease recurrence after transplantation, alongside laboratory work. Several circulating factors have been proposed and studied, broadly grouped into protease components such as soluble urokinase-type plasminogen activator (suPAR), hemopexin (Hx) and calcium/calmodulin-serine protease kinase (CASK), and other circulating proteases, and immune components such as TNF-α, CD40 and cardiotrophin-like cytokine-1 (CLC-1). While currently there is no definitive way of assessing risk of CFD pre-transplantation, promising work is emerging through the study of 'multi-omic' bioinformatic data from large national cohorts and biobanks.
Topics: Humans; Nephrotic Syndrome; Proteinuria; Receptors, Urokinase Plasminogen Activator
PubMed: 36952039
DOI: 10.1007/s00467-023-05928-8 -
Current Aging Science 2024Sarcopenia is one of the most common geriatric syndromes in the elderly. It is defined as a decrease in muscle mass and function, and it can lead to physical disability,... (Review)
Review
Sarcopenia is one of the most common geriatric syndromes in the elderly. It is defined as a decrease in muscle mass and function, and it can lead to physical disability, falls, poor quality of life, impaired immune system, and death. It is known that, the frequency of sarcopenia increases in the kidney patient population compared to healthy individuals. Although it is known that kidney disease can lead to sarcopenia; our knowledge of whether sarcopenia causes kidney disease is limited. Prior studies have suggested that protein energy wasting may be a risk of de novo CKD. Proteinuria is an important manifestation of kidney disease and there is a relationship between sarcopenia and proteinuria in diabetes, geriatric population, kidney transplant, and nephrotic syndrome. Does proteinuria cause sarcopenia or ? Are they both the results of common mechanisms? This issue is not clearly known. In this review, we examined the relationship between sarcopenia and proteinuria in the light of other studies.
Topics: Humans; Sarcopenia; Proteinuria; Aged; Aging; Risk Factors; Muscle, Skeletal; Age Factors
PubMed: 38904152
DOI: 10.2174/0118746098232969231106091204 -
Journal of Cardiovascular Pharmacology Dec 2023The progression of chronic kidney disease results from the accumulation of extracellular matrix leading to end-stage renal disease. We previously demonstrated that a...
The progression of chronic kidney disease results from the accumulation of extracellular matrix leading to end-stage renal disease. We previously demonstrated that a broad-spectrum matrix metalloproteinase (MMP) inhibitor reduced renal injury in rat models of hypertension and diabetes. However, the isoforms and mechanisms involved are unclear. This study examined the role of MMP2 during the development of proteinuria and renal injury after induction of hypertension or diabetes in Dahl salt-sensitive (SS) and MMP2 knockout (KO) rats. Mean arterial pressure rose from 115 ± 2 to 145 ± 2 mm Hg and 116 ± 1 to 152 ± 3 mm Hg in MMP2 KO and SS rats fed a high-salt (8% NaCl) diet for 3 weeks. The degree of proteinuria, glomerular injury, renal fibrosis, and podocyte loss was lower in MMP2 KO rats than in SS rats. Blood glucose and HbA1c levels, and mean arterial pressure rose to the same extent in streptozotocin-treated SS and MMP2 KO rats. However, the degree of proteinuria, glomerulosclerosis, renal fibrosis, renal hypertrophy, glomerular permeability to albumin, and the renal expression of MMP2 and TGFβ1 were significantly reduced in MMP2 KO rats. Glomerular filtration rate fell by 33% after 12 weeks of diabetes in streptozotocin-treated SS rats compared with time-control rats, but glomerular filtration rate only fell by 12% in MMP2 KO rats. These results indicate that activation of MMP2 plays an essential role in the pathogenesis of hypertensive and diabetic nephropathy and suggests that an MMP2 inhibitor might slow the progression of chronic kidney disease.
Topics: Rats; Animals; Diabetic Nephropathies; Matrix Metalloproteinase 2; Streptozocin; Rats, Inbred Dahl; Hypertension; Kidney; Proteinuria; Renal Insufficiency, Chronic; Fibrosis; Blood Pressure; Sodium Chloride, Dietary; Diabetes Mellitus
PubMed: 37643020
DOI: 10.1097/FJC.0000000000001473 -
Innere Medizin (Heidelberg, Germany) Apr 2024Immunoglobulin A (IgA) nephropathy is the most frequent glomerulonephritis in adults in Central Europe. It is characterized by microhematuria and occasionally... (Review)
Review
Immunoglobulin A (IgA) nephropathy is the most frequent glomerulonephritis in adults in Central Europe. It is characterized by microhematuria and occasionally macrohematuria, proteinuria and a chronic loss of kidney function. The diagnosis is made based on a kidney biopsy. The progressive kidney damage must always be slowed down by normalizing blood pressure, using angiotensin inhibitors and consistently avoiding additional toxic substances. In many cases this is not sufficient and then sodium-glucose transporter 2 (SGLT-2) inhibitors and immunomodulators are used. In particular, the SGLT-2 inhibitors show a very significant reduction in proteinuria and slow down the deterioration of the estimated glomerular filtration rate (eGFR). While systemic corticosteroids are now only indicated in rare cases, a special budesonide formulation shows good effects. Further pathophysiologically based pharmacotherapies are currently being tested in clinical studies. These include, among others, the dual endothelin type A receptor and angiotensin II receptor antagonist sparsentan, which has already been shown to reduce proteinuria as well as inhibitors of complement activation, which is important for kidney damage. Initial findings for these as well as for the B‑lymphocyte proliferation inhibitor sibeprenlimab, suggest that they could enrich the armamentarium for the treatment of IgA nephropathy in the future.
Topics: Humans; Glomerulonephritis, IGA; Glomerulonephritis; Proteinuria; Glomerular Filtration Rate; Blood Pressure
PubMed: 38294502
DOI: 10.1007/s00108-024-01665-8 -
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 -
Molecular Therapy : the Journal of the... Nov 2023Focal segmental glomerulosclerosis (FSGS) is the most common glomerular disorder causing end-stage renal diseases worldwide. Central to the pathogenesis of FSGS is...
Focal segmental glomerulosclerosis (FSGS) is the most common glomerular disorder causing end-stage renal diseases worldwide. Central to the pathogenesis of FSGS is podocyte dysfunction, which is induced by diverse insults. However, the mechanism governing podocyte injury and repair remains largely unexplored. Asparagine endopeptidase (AEP), a lysosomal protease, regulates substrates by residue-specific cleavage or degradation. We identified the increased AEP expression in the primary proteinuria model which was induced by adriamycin (ADR) to mimic human FSGS. In vivo, global AEP knockout mice manifested increased injury-susceptibility of podocytes in ADR-induced nephropathy (ADRN). Podocyte-specific AEP knockout mice exhibited much more severe glomerular lesions and podocyte injury after ADR injection. In contrast, podocyte-specific augmentation of AEP in mice protected against ADRN. In vitro, knockdown and overexpression of AEP in human podocytes revealed the cytoprotection of AEP as a cytoskeleton regulator. Furthermore, transgelin, an actin-binding protein regulating actin dynamics, was cleaved by AEP, and, as a result, removed its actin-binding regulatory domain. The truncated transgelin regulated podocyte actin dynamics and repressed podocyte hypermotility, compared to the native full-length transgelin. Together, our data reveal a link between lysosomal protease AEP and podocyte cytoskeletal homeostasis, which suggests a potential therapeutic role for AEP in proteinuria disease.
Topics: Animals; Humans; Mice; Actins; Doxorubicin; Glomerulosclerosis, Focal Segmental; Kidney Diseases; Mice, Knockout; Microfilament Proteins; Podocytes; Proteinuria; Cysteine Endopeptidases
PubMed: 37689970
DOI: 10.1016/j.ymthe.2023.09.003 -
Metabolism: Clinical and Experimental Jan 2024Podocytes are critical for maintaining permselectivity of the glomerular filtration barrier, and podocyte injury is a major cause of proteinuria in various primary and... (Review)
Review
Podocytes are critical for maintaining permselectivity of the glomerular filtration barrier, and podocyte injury is a major cause of proteinuria in various primary and secondary glomerulopathies. Lipid dysmetabolism and inflammatory activation are the distinctive hallmarks of podocyte injury. Lipid accumulation and lipotoxicity trigger cytoskeletal rearrangement, insulin resistance, mitochondrial oxidative stress, and inflammation. Subsequently, inflammation promotes the progression of glomerulosclerosis and renal fibrosis via multiple pathways. These data suggest that lipid dysmetabolism positively or negatively regulates inflammation during podocyte injury. In this review, we summarize recent advances in the understanding of lipid metabolism and inflammation, and highlight the potential association between lipid metabolism and podocyte inflammation.
Topics: Humans; Lipid Metabolism; Podocytes; Proteinuria; Kidney Diseases; Inflammation; Lipids
PubMed: 37925142
DOI: 10.1016/j.metabol.2023.155718