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Clinical Journal of the American... Sep 2023The efficacy of immunosuppression in the management of immunoglobulin A (IgA) nephropathy remains highly controversial. The study was conducted to assess the effect of...
BACKGROUND
The efficacy of immunosuppression in the management of immunoglobulin A (IgA) nephropathy remains highly controversial. The study was conducted to assess the effect of immunosuppression, compared with supportive care, in the real-world setting of IgA nephropathy.
METHODS
A cohort of 3946 patients with IgA nephropathy, including 1973 new users of immunosuppressive agents and 1973 propensity score-matched recipients of supportive care, in a nationwide register data from January 2019 to May 2022 in China was analyzed. The primary outcome was a composite of 40% eGFR decrease of the baseline, kidney failure, and all-cause mortality. A Cox proportional hazard model was used to estimate the effects of immunosuppression on the composite outcomes and its components in the propensity score-matched cohort.
RESULTS
Among 3946 individuals (mean [SD] age 36 [10] years, mean [SD] eGFR 85 [28] ml/min per 1.73 m 2 , and mean [SD] proteinuria 1.4 [1.7] g/24 hours), 396 primary composite outcome events were observed, of which 156 (8%) were in the immunosuppression group and 240 (12%) in the supportive care group. Compared with supportive care, immunosuppression treatment was associated with 40% lower risk of the primary outcome events (adjusted hazard ratio, 0.60; 95% confidence interval, 0.48 to 0.75). Comparable effect size was observed for glucocorticoid monotherapy and mycophenolate mofetil alone. In the prespecified subgroup analysis, the treatment effects of immunosuppression were consistent across ages, sexes, levels of proteinuria, and values of eGFR at baseline. Serious adverse events were more frequent in the immunosuppression group compared with the supportive care group.
CONCLUSIONS
Immunosuppressive therapy, compared with supportive care, was associated with a 40% lower risk of clinically important kidney outcomes in patients with IgA nephropathy.
Topics: Humans; Adult; Glomerulonephritis, IGA; Glomerular Filtration Rate; Kidney; Immunosuppression Therapy; Immunosuppressive Agents; Proteinuria
PubMed: 37314777
DOI: 10.2215/CJN.0000000000000215 -
European Journal of Nutrition Aug 2023Changes in dietary protein intake metabolically affect kidney functions. However, knowledge on potential adverse consequences of long-term higher protein intake (HPI)... (Review)
Review
PURPOSE
Changes in dietary protein intake metabolically affect kidney functions. However, knowledge on potential adverse consequences of long-term higher protein intake (HPI) for kidney health is lacking. To summarise and evaluate the available evidence for a relation between HPI and kidney diseases, an umbrella review of systematic reviews (SR) was conducted.
METHODS
PubMed, Embase and Cochrane Database of SRs published until 12/2022 were searched for the respective SRs with and without meta-analyses (MA) of randomised controlled trials or cohort studies. For assessments of methodological quality and of outcome-specific certainty of evidence, a modified version of AMSTAR 2 and the NutriGrade scoring tool were used, respectively. The overall certainty of evidence was assessed according to predefined criteria.
RESULTS
Six SRs with MA and three SRs without MA on various kidney-related outcomes were identified. Outcomes were chronic kidney disease, kidney stones and kidney function-related parameters: albuminuria, glomerular filtration rate, serum urea, urinary pH and urinary calcium excretion. Overall certainty of evidence was graded as 'possible' for stone risk not to be associated with HPI and albuminuria not to be elevated through HPI (above recommendations (> 0.8 g/kg body weight/day)) and graded as 'probable' or 'possible' for most other kidney function-related parameters to be physiologically increased with HPI.
CONCLUSION
Changes of the assessed outcomes may have reflected mostly physiological (regulatory), but not pathometabolic responses to higher protein loads. For none of the outcomes, evidence was found that HPI does specifically trigger kidney stones or diseases. However, for potential recommendations long-term data, also over decades, are required.
Topics: Humans; Albuminuria; Dietary Proteins; Systematic Reviews as Topic; Kidney Calculi; Nutritional Status
PubMed: 37133532
DOI: 10.1007/s00394-023-03143-7 -
Journal of Autoimmunity Sep 2023T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT) is a newly discovered immune checkpoint (IC) that exhibits...
OBJECTIVES
T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT) is a newly discovered immune checkpoint (IC) that exhibits immunosuppressive function in the regulation of immune system. Activation of TIGIT signaling has emerged as a promising approach for autoimmune disease immunotherapy, such as systemic lupus erythematosus (SLE).
METHODS
We generated a chimeric protein, TIGIT-immunoglobulin (Ig), by fusing the extracellular domain of murine TIGIT to the Fc region of mouse IgG2a, which was used to investigated the effect of activating the TIGIT signaling in murine lupus models (MRL/lpr and chronic graft-versus-host disease mice). Treated mice were harvested, and samples of serum, kidney, and spleen were collected for outcome evaluation. In vitro treatment of TIGIT-Ig in B cells was used for exploring the roles of TIGIT in toll-like receptor 7 (TLR7)-mediated B cell differentiation and antibody production.
RESULTS
TIGIT-Ig treatment delayed disease progression in both lupus models, accompanied by a decrease in the production of anti-double stranded DNA antibodies (anti-dsDNA), proteinuria, proteinuria/creatinine, and Ig kidney deposition. Additionally, the group treated with TIGIT-Ig displayed a decreased proportion of T helper cell (Th)1 cells, T follicular helper (Tfh) cells, and B-cell subsets, including germinal center B cells (GC B), plasmablasts, and plasma cells, compared to the group treated with control IgG. Interestingly, we also observed an increased proportion of Tregs in the spleen of the TIGIT-Ig group. We have discovered a new way in which activating the TIGIT pathway can regulate B-cell differentiation through the SPI-B-PAX5-XBP1 pathway, resulting in a reduction in autoantibodies.
CONCLUSION
Together, TIGIT may be a promising IC target for SLE treatment.
Topics: Animals; Mice; Lupus Nephritis; Mice, Inbred MRL lpr; Lupus Erythematosus, Systemic; Autoantibodies; Receptors, Immunologic; Proteinuria; Cell Differentiation; Disease Models, Animal
PubMed: 37481835
DOI: 10.1016/j.jaut.2023.103087 -
Kidney International Oct 2023Proteinuria is a prominent feature of chronic kidney disease. Interventions that reduce proteinuria slow the progression of chronic kidney disease and the associated...
Proteinuria is a prominent feature of chronic kidney disease. Interventions that reduce proteinuria slow the progression of chronic kidney disease and the associated risk of cardiovascular disease. Here, we propose a mechanistic coupling between proteinuria and proprotein convertase subtilisin/kexin type 9 (PCSK9), a regulator of cholesterol and a therapeutic target in cardiovascular disease. PCSK9 undergoes glomerular filtration and is captured by megalin, the receptor responsible for driving protein reabsorption in the proximal tubule. Accordingly, megalin-deficient mice and patients carrying megalin pathogenic variants (Donnai Barrow syndrome) were characterized by elevated urinary PCSK9 excretion. Interestingly, PCSK9 knockout mice displayed increased kidney megalin while PCSK9 overexpression resulted in its reduction. Furthermore, PCSK9 promoted trafficking of megalin to lysosomes in cultured proximal tubule cells, suggesting that PCSK9 is a negative regulator of megalin. This effect can be accelerated under disease conditions since either genetic destruction of the glomerular filtration barrier in podocin knockout mice or minimal change disease (a common cause of nephrotic syndrome) in patients resulted in enhanced tubular PCSK9 uptake and urinary PCSK9 excretion. Pharmacological PCSK9 inhibition increased kidney megalin while reducing urinary albumin excretion in nephrotic mice. Thus, glomerular damage increases filtration of PCSK9 and concomitantly megalin degradation, resulting in escalated proteinuria.
Topics: Humans; Mice; Animals; Nephrotic Syndrome; Proprotein Convertase 9; Low Density Lipoprotein Receptor-Related Protein-2; Cardiovascular Diseases; Proteinuria; Kidney Tubules, Proximal; Renal Insufficiency, Chronic; Mice, Knockout; Subtilisins
PubMed: 37406929
DOI: 10.1016/j.kint.2023.06.024 -
Urologie (Heidelberg, Germany) Jan 2024IgA nephropathy (IgAN) is the most frequent primary form of glomerulonephritis. The origin of IgAN is only partially understood and appears to involve the occurrence of...
IgA nephropathy (IgAN) is the most frequent primary form of glomerulonephritis. The origin of IgAN is only partially understood and appears to involve the occurrence of IgA, which is normally secreted by mucous membranes, in the circulation followed by its glomerular deposition and inflammatory changes. Clinically, IgAN mostly follows an inapparent course and the disease is often only first diagnosed by kidney biopsy when kidney function disorders are already manifested. Key prognostic indicators include the extent of proteinuria and the already manifested evidence of irreversible kidney damage. Treatment includes supportive measures. The effectiveness of high-dose systemic corticosteroid treatment in European patients is uncertain and controversial due to the adverse side effects. Nefecon (encapsulated budesonide) is the first specific drug licensed for treatment of high risk IgAN patients. A number of further approaches are currently in clinical trials.
Topics: Humans; Glomerulonephritis, IGA; Kidney Glomerulus; Proteinuria; Budesonide; Adrenal Cortex Hormones
PubMed: 38170257
DOI: 10.1007/s00120-023-02268-1 -
Physiological Reports Mar 2024The role of NRF2 in kidney biology has received considerable interest over the past decade. NRF2 transcriptionally controls genes responsible for cellular protection... (Review)
Review
The role of NRF2 in kidney biology has received considerable interest over the past decade. NRF2 transcriptionally controls genes responsible for cellular protection against oxidative and electrophilic stress and has anti-inflammatory functions. NRF2 is expressed throughout the kidney and plays a role in salt and water handling. In disease, animal studies show that NRF2 protects against tubulointerstitial damage and reduces interstitial fibrosis and tubular atrophy, and may slow progression of polycystic kidney disease. However, the role of NRF2 in proteinuric glomerular diseases is controversial. Although the NRF2 inducer, bardoxolone methyl (CDDO-Me), increases glomerular filtration rate in humans, it has not been shown to slow disease progression in diabetic kidney disease and Alport syndrome. Furthermore, bardoxolone methyl was associated with negative effects on fluid retention, proteinuria, and blood pressure. Several animal studies replicate findings of worsened proteinuria and a more rapid progression of kidney disease, although considerable controversy exists. It is clear that further study is needed to better understand the effects of NRF2 in the kidney. This review summarizes the available data to clarify the promise and risks associated with targeting NRF2 activity in the kidney.
Topics: Animals; Humans; NF-E2-Related Factor 2; Kidney; Diabetic Nephropathies; Proteinuria; Oleanolic Acid
PubMed: 38418382
DOI: 10.14814/phy2.15961 -
European Journal of Internal Medicine Dec 2023Cancer is the second leading cause of death among the adult population following cardiovascular diseases. Prevention and earlier diagnosis are among the cornerstones in... (Review)
Review
Cancer is the second leading cause of death among the adult population following cardiovascular diseases. Prevention and earlier diagnosis are among the cornerstones in the management of malignancies. Albuminuria is a diagnostic criterion for chronic kidney disease and has been associated with multiple conditions including cardiovascular diseases and systemic inflammation while the association between albuminuria and malignancy has been inadequately addressed. Large-scale observational studies with long follow-up periods demonstrate a statistically significant association between albuminuria and overall malignancy incidence, especially urothelial malignancy incidence. However, the underlying pathophysiology linking these two entities is not a straightforward causal relationship but most likely a multidirectional relationship including a causal link. In this narrative review, we evaluate the clinical studies investigating the association between albuminuria and malignancy along with potential underlying mechanisms linking them. We also summarize data on the impact of treatment modalities prescribed for albuminuria and/or proteinuria on the prevention or prognosis of malignancies.
Topics: Adult; Humans; Albuminuria; Cardiovascular Diseases; Proteinuria; Risk Factors; Neoplasms; Diabetes Mellitus, Type 2
PubMed: 37741791
DOI: 10.1016/j.ejim.2023.09.010 -
Nutrients Oct 2023Nephrotic syndrome (NS) poses a number of nutritional and metabolic problems due to glomerulus injured podocytes, which are responsible for the loss of barrier function,...
Nephrotic syndrome (NS) poses a number of nutritional and metabolic problems due to glomerulus injured podocytes, which are responsible for the loss of barrier function, causing proteinuria, altered fluid and electrolyte balances, and hypoalbuminemia [...].
Topics: Humans; Nephrotic Syndrome; Podocytes; Proteinuria; Epithelial Cells
PubMed: 37960268
DOI: 10.3390/nu15214615 -
Profilin1 is required for prevention of mitotic catastrophe in murine and human glomerular diseases.The Journal of Clinical Investigation Dec 2023The progression of proteinuric kidney diseases is associated with podocyte loss, but the mechanisms underlying this process remain unclear. Podocytes reenter the cell...
The progression of proteinuric kidney diseases is associated with podocyte loss, but the mechanisms underlying this process remain unclear. Podocytes reenter the cell cycle to repair double-stranded DNA breaks. However, unsuccessful repair can result in podocytes crossing the G1/S checkpoint and undergoing abortive cytokinesis. In this study, we identified Pfn1 as indispensable in maintaining glomerular integrity - its tissue-specific loss in mouse podocytes resulted in severe proteinuria and kidney failure. Our results suggest that this phenotype is due to podocyte mitotic catastrophe (MC), characterized histologically and ultrastructurally by abundant multinucleated cells, irregular nuclei, and mitotic spindles. Podocyte cell cycle reentry was identified using FUCCI2aR mice, and we observed altered expression of cell-cycle associated proteins, such as p21, p53, cyclin B1, and cyclin D1. Podocyte-specific translating ribosome affinity purification and RNA-Seq revealed the downregulation of ribosomal RNA-processing 8 (Rrp8). Overexpression of Rrp8 in Pfn1-KO podocytes partially rescued the phenotype in vitro. Clinical and ultrastructural tomographic analysis of patients with diverse proteinuric kidney diseases further validated the presence of MC podocytes and reduction in podocyte PFN1 expression within kidney tissues. These results suggest that profilin1 is essential in regulating the podocyte cell cycle and its disruption leads to MC and subsequent podocyte loss.
Topics: Animals; Humans; Mice; Cell Cycle Proteins; Cell Death; Kidney Diseases; Kidney Glomerulus; Podocytes; Profilins; Proteinuria
PubMed: 37847555
DOI: 10.1172/JCI171237 -
Nature Communications Jul 2023Elevation in soluble urokinase receptor (suPAR) and proteinuria are common signs in patients with moderate to severe coronavirus disease 2019 (COVID-19). Here we...
Elevation in soluble urokinase receptor (suPAR) and proteinuria are common signs in patients with moderate to severe coronavirus disease 2019 (COVID-19). Here we characterize a new type of proteinuria originating as part of a viral response. Inoculation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes increased suPAR levels and glomerulopathy in African green monkeys. Using an engineered mouse model with high suPAR expression, inhaled variants of SARS-CoV-2 spike S1 protein elicite proteinuria that could be blocked by either suPAR antibody or SARS-CoV-2 vaccination. In a cohort of 1991 COVID-19 patients, suPAR levels exhibit a stepwise association with proteinuria in non-Omicron, but not in Omicron infections, supporting our findings of biophysical and functional differences between variants of SARS-CoV-2 spike S1 protein and their binding to podocyte integrins. These insights are not limited to SARS-CoV-2 and define viral response proteinuria (VRP) as an innate immune mechanism and co-activation of podocyte integrins.
Topics: Animals; Mice; Chlorocebus aethiops; Humans; COVID-19; COVID-19 Vaccines; Podocytes; Receptors, Urokinase Plasminogen Activator; SARS-CoV-2; Integrins; Proteinuria
PubMed: 37479685
DOI: 10.1038/s41467-023-40165-5