Forms Of Chronic Kidney Disease Research Articles

#1798 Infection-related outcomes in CKD patients with lupus nephritis: a nationwide cohort study

Abstract Background and Aims Although absolute risks of infection in patients with lupus nephritis (LN) are believed high, it is not known whether they differ from those of patients with other etiologies of moderate and advanced chronic kidney disease (CKD). The aim of this study was to compare infection outcomes between patients with LN-CKD and other forms of CKD. Method Using data from the Swedish Renal Registry (2006-2021), we compared infection-related outcomes between LN-patients with moderate and advanced, non-dialysis, CKD and patients with 1) diabetic kidney disease (DKD), 2) primary glomerular diseases (PGD, i.e. IgA nephropathy, focal segmental glomerulosclerosis, membranous nephropathy), and 3) autosomal dominant polycystic kidney disease (ADPKD). Cause-specific Cox proportional hazard models were used to estimate the adjusted hazard ratios of death due to infection, first all-cause infection-related hospitalization and first cause-specific infection-related hospitalization (sepsis, pulmonary, gastrointestinal, genitourinary, and other infections). Results We identified 317 patients with LN (61 years, 76% women, median eGFR 30 mL/min per 1.73 m²), 8877 patients with DKD (71 years, 33% women, eGFR 24 mL/min per 1.73 m²), 2296 patients with PGD (57 years, 30% women, eGFR 29 mL/min per 1.73 m²) and 1855 patients with ADPKD (59 years, 45% women, eGFR 26 mL/min per 1.73 m²). Over a median follow-up of 2.8 [1.2; 5.0] years, 667 (5%) deaths due to infection and 4034 (30%), infection-related (first-time) hospitalizations occurred, including 2127 (16%) pulmonary, 1507 (11%) genitourinary, 1130 (8%) gastrointestinal, 615 (5%) other infections, and 450 (3%) sepsis. In multivariable analyses, and when compared to DKD, patients with LN had a similar risk of death due to infection (adjusted HR 1.15 [95% CI: 0.62-2.11]) and sepsis (HR 1.24 [0.64-2.4]), but a higher risk of all infection-related hospitalization (HR 1.31 [1.04-1.65]), the latter being mainly driven by pulmonary, gastrointestinal, and other infections (Figure panel A). The risks of death due to infection (HR LN vs PGD 2.78 [1.62-4.77], HR LN vs ADPKD 2.34 [1.31-4.19]), of infection-related hospitalization (HR 1.87 [1.52-2.31], HR 1.43 [1.16-1.77]), and of cause-specific infection-related hospitalization were higher in LN than in PGD and ADKPD, respectively, except for the risk of sepsis which was similar between LN and ADPKD. The risk of genitourinary infection tended to be lower in LN than in ADPKD, although the 95% CI slightly overlapped (Figure panels B-C). Conclusion LN patients had higher risk of infection-related hospitalization than all other investigated CKD etiologies, and a higher risk of death due to infections than patients with PGD and ADPKD. Our findings highlight the need for improvements in infection prevention in patients with LN. Whether a more tailored immunosuppressive treatment approach could further improve outcomes in this high-risk population remains to be investigated.

#1804 Long-term outcomes of CKD patients with lupus nephritis: a nationwide cohort study

Abstract Background and Aims Health trajectories of patients with lupus nephritis (LN) are poorly understood in the setting of moderate and advanced chronic kidney disease (CKD). Furthermore, data on comparison of outcomes of LN to other forms of CKD are scarce. Therefore, the aim of this study was to compare long-term outcomes between LN and CKD from other etiologies. Method Using data from the Swedish Renal Registry (2006-2021), we compared clinical outcomes between patients with moderate and advanced CKD related to LN (LN-CKD), and patients with CKD due to primary glomerular diseases (PGD-CKD, i.e. IgA nephropathy, focal segmental glomerulosclerosis, membranous nephropathy), and due to other common CKD etiologies with high cardiovascular risk (Other-CKD, mostly diabetes and nephrosclerosis). Cox proportional hazard models were used to estimate the adjusted hazard ratios of mortality, major cardiovascular events (MACE), heart failure (HF), kidney replacement therapy (KRT) and acute kidney injury (AKI). Models were adjusted for age, sex, comorbidities, clinical and biological data including kidney function, medications and healthcare utilization. Results At baseline, patients with LN-CKD (N = 317, 61 years, 76% women, median eGFR 30 mL/min per 1.73 m²) and PGD-CKD (N = 2296, 57 years, 30% women, eGFR 29 mL/min per 1.73 m²), were younger and had lower prevalence of cardiovascular disease than patients with Other-CKD (N = 34778, 75 years, 36% women, eGFR 25 mL/min per 1.73 m²). Over a median follow-up of 6.2 [3.3; 9.8] years, 19029 deaths (51%), 15768 (42%) MACE and 8390 (22%) KRT events occurred. The unadjusted 5-year absolute risks of death and MACE were high both in patients with LN-CKD (27% and 25%) and Other-CKD (50% and 44%), but lower in those with PGD-CKD (16% and 14%), whereas the 5-year absolute KRT risk was higher in patients with PGD-CKD (PGD-CKD: 37%, LN-CKD: 23%, Other-CKD: 23%). In multivariable analyses and as compared to PGD-CKD, patients with LN-CKD had a higher risk of death (adjusted HR: 1.63 [95% CI: 1.32-2.02]), MACE (1.65 [1.31-2.08]), HF (1.68 [1.31-2.14]) and AKI (1.45 [1.02-2.05]) and showed a lower risk of KRT (HR: 0.81 [0.64-1.02]), although the 95% CI slightly overlapped (Figure, panel A). In contrast, the risks of adverse events were similar between patients with LN-CKD and those with Other-CKD (Figure, panel B). Conclusion While LN-CKD had a lower risk of KRT than PGD-CKD, they exhibited a higher risk of death, MACE, KRT, HF and AKI, reaching the risk magnitude of patients with high cardiovascular burden (Other-CKD). Our findings may inform decisions for care planning in patients with advanced CKD and LN.

#2344 Empagliflozin attenuates renal fibrosis through the DsbA-L-CAS-STING pathway in unilateral ureteral obstruction model

Abstract Background and Aims Chronic kidney disease (CKD) is associated with an increase in morbidity and mortality. Renal fibrosis is a common pathway leading to the progression of CKD. Recent studies have reported an improvement of CKD with use of sodium glucose cotransport 2 inhibitors (SGLT2i) in both patients with DM and those without it. However, the mechanism of SGLT2is effect upon CKD has not been elucidated. In current study, we examined the effect of SGLT2i on renal fibrosis in rats caused by unilateral ureteral obstruction (UUO). Methods Male Sprague Dawley rats (9-10 weeks, weighing 320-360 g) were randomly assigned to two groups (n=8 each). One group received empagliflozin after UUO induction while the other group was left untreated. Kidneys were harvested two weeks after UUO. We evaluated the mitochondrial damage pathway presumed to contribute to the inflammation. Results UUO has resulted in marked renal fibrosis and triggered the activation of the cGAS-STING pathway. Kidneys in the empagliflozin treated group exhibited reduced size compare to the untreated group. Creatinine levels were lower in the empagliflozin group. Empagliflozin has been shown to attenuate renal fibrosis in histopathology. Western blot analysis revealed increased expression of disulfide-bond A oxidoreductase-like proteins (DsbA-L) was decreased cGAS-STING-NFκB in the empagliflozin group compared to the non-empagliflozin treated group (Fig. 1). Conclusion SGLT2i mitigated the progression of renal damage and fibrosis. This reno-protective effect is associated with increased DsbA-L and decreased of cGAS and STING pathway. These findings suggest that SGLT2i may alleviate mitochondrial damage in the UUO model. In addition, SGLT2i could be a promising medication to treat various forms of CKD.

Ubiquitin-Specific Protease 18 in Chronic Kidney Disease-Another Emerging Biomarker to Consider?

Ubiquitin-specific protease 18 (USP18) is a protein recognized for its dual enzymatic and non-enzymatic nature. It is involved in many physiological processes like the cell cycle and cell signaling. It also suppresses heart muscle remodeling upon an increase in the afterload. The role of USP18 in kidney pathology remains unknown. The objective of the study was to assess the relationship between serum and urine USP18 levels, the factors contributing to cardiovascular risk, and the markers of kidney disease activity at different stages of chronic kidney disease (CKD). One hundred participants, aged between 24 and 85 years (mean 53.1 ± 17.1 years), were included. Five groups (n = 20 each) were recruited according to their renal status (healthy individuals, patients with proteinuric glomerulonephritis, patients with non-proteinuric CKD, patients who were treated with hemodialysis, and kidney transplant recipients). The measurements of serum and urine USP18 levels were performed using ELISA. The median serum USP18 level was the highest in healthy participants (1143.0 pg/mL) and kidney transplant recipients (856.6 pg/mL), whereas, in individuals with different forms of CKD, it fitted within the range of 402.1-471.9 pg/mL. Urinary USP18 reached the highest level in the group of CKD patients not yet on dialysis (303.3 pg/mL). Only in this group did it correlate with serum creatinine and urea concentrations. Our results suggest the inhibition of cardioprotective USP18 signaling when kidney function is impaired. Moreover, an increased level of urinary USP18 may indicate chronic tubular damage.

Transglutaminase-mediated stiffening of the glomerular basement membrane mitigates pressure-induced reductions in molecular sieving coefficient by reducing compression

Proteinuria, the presence of high molecular weight proteins in the urine, is a primary indicator of chronic kidney disease. Proteinuria results from increased molecular permeability of the glomerular filtration barrier combined with saturation or defects in tubular protein reabsorption. Any solute that passes into the glomerular filtrate traverses the glomerular endothelium, the glomerular basement membrane, and the podocyte slit diaphragm. Damage to any layer from the filter has reciprocal effects on other layers to increase glomerular permeability. The GBM is thought to act as a compressible ultrafilter that has increased molecular selectivity with increased pressure due to compression that reduced the porosity of the GBM with increased pressure. In multiple forms of chronic kidney disease, crosslinking enzymes are upregulated and may act to increase GBM stiffness. Here we show that enzymatically crosslinking porcine GBM with transglutaminase increases the stiffness of the GBM and mitigates pressure-dependent reductions in molecular sieving coefficient. This was modeled mathematically using a modified membrane transport model accounting for GBM compression. Changes in the mechanical properties of the GBM may contribute to proteinuria through pressure-dependent effects on GBM porosity.

Kidney Stones Account for Increased Imaging Studies in Autosomal Dominant Polycystic Kidney Disease.

ADPKD patients may have more imaging studies than patients with other forms of chronic kidney disease (CKD). We characterized the imaging burden of ADPKD patients relative to a CKD population to determine which factors lead to increased imaging in ADPKD patients. We retrospectively reviewed patients seen at Yale Nephrology between January 2012 and January 2021. We collected demographic, clinical, and imaging data through automated query and manual chart review. 807 ADPKD patients were matched to 4,035 CKD controls based on criteria of sex, race, ethnicity, CKD stage, hypertension, and diabetes, but not age. The number of abdominal imaging studies were compared between ADPKD and CKD groups, and the impact of kidney stone diagnosis was further evaluated. Chi-squared and t-tests were used to evaluate demographic variables, and Kruskal Wallace and negative binomial regression models were used to evaluate differences between abdominal imaging studies. Patients with ADPKD had a greater number of total abdominal imaging studies (p<0.0001), ultrasounds (p<0.0001), and MRIs (p=0.02) compared to controls. In patients with preserved renal function (eGFR > 60 ml/min/m2), these differences persisted. Kidney stones were significantly more common among patients with ADPKD (p<0.0001). In multivariable assessment of imaging study counts using a negative binomial model controlling for kidney stones, ADPKD was no longer a significant predictor. In ADPKD patients, pyelonephritis, cyst complications, lower eGFR, diabetes, coronary artery disease, kidney stones, lower BMI, and being male, Black and younger increased the likelihood of having more imaging studies. The higher prevalence of abdominal imaging studies in ADPKD patients correlated with the increased incidence of kidney stones observed in this population.

Ablation of Brg1 in fibroblast/myofibroblast lineages attenuates renal fibrosis in mice with diabetic nephropathy

AimsDiabetic nephropathy (DN) is one of the most common complications of diabetes and represents a prototypical form of chronic kidney disease (CKD). Interstitial fibrosis is a key pathological feature of DN. During DN-associated renal fibrosis, resident fibroblasts trans-differentiate into myofibroblasts to remodel the extracellular matrix, the underlying epigenetic mechanism of which is not entirely clear. MethodsDiabetic nephropathy was induced in C57B6/j mice by a single injection with streptozotocin (STZ). Gene expression was examined by quantitative PCR and Western blotting. Renal fibrosis was evaluated by PicroSirius Red staining. ResultsWe report that expression of Brg1, a chromatin remodeling protein, in renal fibroblasts was up-regulated during DN pathogenesis as assessed by single-cell RNA-seq. Treatment with high glucose similarly augmented Brg1 expression in primary renal fibroblasts in vitro. Importantly, Brg1 ablation in quiescent renal fibroblasts or in mature myofibroblasts equivalently attenuated renal fibrosis in the context of diabetic nephropathy in mice. Additionally, administration with a small-molecule Brg1 inhibitor PFI-3 ameliorated renal fibrosis and improved renal function in mice induced to develop DN. SignificanceIn conclusion, our data provide novel genetic evidence that links Brg1 to fibroblast-myofibroblast transition and renewed rationale for targeting Brg1 in the intervention of DN-associated renal fibrosis.

Preoperative Age and Its Impact on Long-Term Renal Functional Decline after Robotic-Assisted Partial Nephrectomy: Insights from a Tertiary Referral Center.

Background and Objectives: to investigate the impact of age on renal function deterioration after robotic-assisted partial nephrectomy (RAPN) focusing on a decline to moderate and severe forms of chronic kidney disease (CKD). Materials and Methods: This is a single center prospective analysis of patients who underwent RAPN. The outcomes include the development of de novo CKD-S 3a [estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2)] and de novo CKD-S 3b (eGFR < 45 mL/min/1.73/m2). Multivariable analysis (MVA) via Cox regression identified predictors for CKD-S 3a/b. Kaplan -Meier Analyses (KMA) were fitted for survival assessment. Multivariable linear regression was utilized to identify the predictors of last-eGFR. Results: Overall, 258 patients were analyzed [low age (<50) n = 40 (15.5%); intermediate age (50-70) n = 164 (63.5%); high age (>70) n = 54 (20.9%)] with a median follow-up of 31 (IQR 20-42) months. MVA revealed an increasing RENAL score [Hazard Ratio (HR) 1.32, p = 0.009], age 50-70 (HR 6.21, p = 0.01), age ≥ 70 (HR 10.81, p = 0.001), increasing BMI (HR 1.11, p < 0.001) and preoperative CKD 2 (HR 2.43, p = 0.014) are independent risk factors associated with an increased risk of CKD-S 3a; conversely, post-surgical acute kidney injury was not (p = 0.83). MVA for CKD-S 3b revealed an increasing RENAL score (HR 1.51, p = 0.013) and age ≥ 70 (HR 2.73, p = 0.046) are associated with an increased risk of CKD-S 3b. Linear regression analysis revealed increasing age (Coeff. -0.76, p < 0.001), increasing tumor size (Coeff. -0.31, p = 0.03), and increasing BMI (Coeff. -0.64, p = 0.004) are associated with decreasing eGFR at last follow-up. We compare the survival distribution of our cohort stratified by age elderly patients experienced worsened CKD-S 3a/b disease-free survival (p < 0.001; p < 0.001, respectively). Conclusions: Age is independently associated with a greater risk of significant and ongoing decline in kidney function following RAPN. Recognizing the impact of aging on renal function post-surgery can guide better management practices. Further investigations are required.

Bone and Parathyroid Scintigraphy Findings in Sagliker Syndrome.

Sagliker syndrome (SS) is a rare, exaggerated form of chronic kidney disease (CKD)-mineral and bone disorder resulting from untreated secondary hyperparathyroidism due to CKD. Herein, we describe a 34-year-old male patient whose Tc-99m-methylene diphosphonate bone scintigraphy and Tc-99m-sestamibi parathyroid scintigraphy revealed hints of SS and exhibited its defining characteristics.

Inspiring Tactics with the Improvement of Mitophagy and Redox Balance for the Development of Innovative Treatment against Polycystic Kidney Disease.

Polycystic kidney disease (PKD) is the most common genetic form of chronic kidney disease (CKD), and it involves the development of multiple kidney cysts. Not enough medical breakthroughs have been made against PKD, a condition which features regional hypoxia and activation of the hypoxia-inducible factor (HIF) pathway. The following pathology of CKD can severely instigate kidney damage and/or renal failure. Significant evidence verifies an imperative role for mitophagy in normal kidney physiology and the pathology of CKD and/or PKD. Mitophagy serves as important component of mitochondrial quality control by removing impaired/dysfunctional mitochondria from the cell to warrant redox homeostasis and sustain cell viability. Interestingly, treatment with the peroxisome proliferator-activated receptor-α (PPAR-α) agonist could reduce the pathology of PDK and might improve the renal function of the disease via the modulation of mitophagy, as well as the condition of gut microbiome. Suitable modulation of mitophagy might be a favorable tactic for the prevention and/or treatment of kidney diseases such as PKD and CKD.

Autosomal Dominant Tubulointerstitial Kidney Disease Case with Sever Acute Kidney Injury in Activities Beyond the Usual: An Unusual Presentation of the Disease

Introduction: Autosomal dominant tubulointerstitial kidney disease (ADTKD) is associated with multiple gene mutations and is recognized under various names, including medullary cystic kidney disease type 2, familial juvenile hyperuricemic nephropathy, uromodulin-associated kidney disease, and medullary cystic kidney disease type 2. A comprehensive understanding of these rare disorders can shed light on the pattern of tubulointerstitial fibrosis observed in various forms of chronic kidney disease. Case Presentation: Here, a case of a patient is presented who experienced acute kidney injury (AKI) following severe physical activity and an atypical manifestation of this genetic disorder. Typically, ADTKD leads to a gradual loss of kidney function, but the patient presented with AKI. The patient's renal function returned to normal following appropriate therapy. The patient's brother had a similar history of renal disease following physical activities, prompting suspicion of a shared genetic disorder. Conclusions: A genome-wide association study (GWAS) was conducted, and the results revealed the presence of the mucin 1 (MUC1) mutation, confirming the diagnosis of ADTKD. This case highlights the importance of recognizing atypical presentations of genetic disorders and utilizing advanced genetic studies for accurate diagnosis and management.

Identification of common and specific fibrosis-related genes in three common chronic kidney diseases

Background Kidney fibrosis is the common final pathway of virtually all advanced forms of chronic kidney disease (CKD) including diabetic nephropathy (DN), IgA nephropathy (IgAN) and membranous nephropathy (MN), with complex mechanism. Comparative gene expression analysis among these types of CKD may shed light on its pathogenesis. Therefore, we conducted this study aiming at exploring the common and specific fibrosis-related genes involved in different types of CKD. Methods Kidney biopsy specimens from patients with different types of CKD and normal control subjects were analyzed using the NanoString nCounter® Human Fibrosis V2 Panel. Genes differentially expressed in all fibrotic DN, IgAN and MN tissues compared to the normal controls were regarded as the common fibrosis-related genes in CKD, whereas genes exclusively differentially expressed in fibrotic DN, IgAN or MN samples were considered to be the specific genes related to fibrosis in DN, IgAN and MN respectively. Quantitative real-time PCR (qRT-PCR) was performed to validate the expression of the selected genes. Results Protein tyrosine phosphatase receptor type C (PTPRC), intercellular cell adhesion molecule-1 (ICAM1), vascular cell adhesion molecule-1 (VCAM1), interleukin 10 receptor alpha (IL10RA) and CC chemokine receptor 2 (CCR2) were identified as the potential common genes for kidney fibrosis in different types of CKD, while peroxisome proliferator-activated receptor alpha (PPARA), lactate oxidase (LOX), secreted phosphoprotein 1 (SPP1) were identified as the specific fibrosis-associated genes for DN, IgAN and MN respectively. qRT-PCR demonstrated that the expression levels of these selected genes were consistent with the NanoString analysis. Conclusions There were both commonalities and differences in the mechanisms of fibrosis in different types of CKD, the commonalities might be used as the common therapeutic targets for kidney fibrosis in CKD, while the differences might be used as the diagnostic markers for DN, IgAN and MN respectively. Inflammation was highly relevant to the pathogenesis of fibrosis. This study provides further insight into the pathophysiology and treatment of fibrotic kidney disease.

Chronic kidney disease of unknown aetiology in Africa: A review of the literature.

During the last two decades, an epidemic of a severe form of chronic kidney disease (CKD) unrelated to traditional risk factors (diabetes and hypertension) has been recognized in low- to middle-income countries. CKD of unknown aetiology (CKDu) mainly affects young working-age adults, and has become as an important and devastating public health issue. CKDu is a multifactorial disease with associated genetic and environmental risk factors. This review summarizes the current epidemiological evidence on the burden of CKDu and its probable environmental risk factors contributing to CKD in Africa. PubMed/Medline and the African Journals Online databases were searched to identify relevant population-based studies published in the last two decades. In the general population, the burden of CKD attributable to CKDu varied from 19.4% to 79%. Epidemiologic studies have established that environmental factors, including genetics, infectious agents, rural residence, low socioeconomic status, malnutrition, agricultural practise and exposure to agrochemicals, heavy metals, use of traditional herbs, and contaminated water sources or food contribute to the burden of CKD in the region. There is a great need for epidemiological studies exploring the true burden of CKDu and unique geographical distribution, and the role of environmental factors in the development of CKD/CKDu.

β2-Adrenergic receptor agonists as a treatment for diabetic kidney disease.

We have previously shown that the long-acting β2-adrenergic receptor (β2-AR) agonist formoterol induced recovery from acute kidney injury in mice. To determine whether formoterol protected against diabetic nephropathy, the most common cause of end-stage kidney disease (ESKD), we used a high-fat diet (HFD), a murine type 2 diabetes model, and streptozotocin, a murine type 1 diabetes model. Following formoterol treatment, there was a marked recovery from and reversal of diabetic nephropathy in HFD mice compared with those treated with vehicle alone at the ultrastructural, histological, and functional levels. Similar results were seen after formoterol treatment in mice receiving streptozotocin. To investigate effects in humans, we performed a competing risk regression analysis with death as a competing risk to examine the association between Veterans with chronic kidney disease (CKD) and chronic obstructive pulmonary disease (COPD), who use β2-AR agonists, and Veterans with CKD but no COPD, and progression to ESKD in a large national cohort of Veterans with stage 4 CKD between 2011 and 2013. Veterans were followed until 2016 or death. ESKD was defined as the initiation of dialysis and/or receipt of kidney transplant. We found that COPD was associated with a 25.6% reduction in progression from stage 4 CKD to ESKD compared with no COPD after adjusting for age, diabetes, sex, race-ethnicity, comorbidities, and medication use. Sensitivity analysis showed a 33.2% reduction in ESKD in Veterans with COPD taking long-acting formoterol and a 20.8% reduction in ESKD in Veterans taking other β2-AR agonists compared with those with no COPD. These data indicate that β2-AR agonists, especially formoterol, could be a treatment for diabetic nephropathy and perhaps other forms of CKD.NEW & NOTEWORTHY Diabetic nephropathy is the most common cause of ESKD. Formoterol, a long-acting β2-adrenergic receptor (β2-AR) agonist, reversed diabetic nephropathy in murine models of type 1 and 2 diabetes. In humans, there was an association with protection from progression of CKD in patients with COPD, by means of β2-AR agonist intake, compared with those without COPD. These data indicate that β2-AR agonists, especially formoterol, could be a new treatment for diabetic nephropathy and other forms of CKD.

SIRT2 alleviated renal fibrosis by deacetylating SMAD2 and SMAD3 in renal tubular epithelial cells

Transforming growth factor-β (TGF-β) is the primary factor that drives fibrosis in most, if not all, forms of chronic kidney disease. In kidneys that are obstructed, specific deletion of Sirt2 in renal tubule epithelial cells (TEC) has been shown to aggravate renal fibrosis, while renal tubule specific overexpression of Sirt2 has been shown to ameliorate renal fibrosis. Similarly, specific deletion of Sirt2 in hepatocyte aggravated CCl4-induced hepatic fibrosis. In addition, we have demonstrated that SIRT2 overexpression and knockdown restrain and enhance TGF-β-induced fibrotic gene expression, respectively, in TEC. Mechanistically, SIRT2 reduced the phosphorylation, acetylation, and nuclear localization levels of SMAD2 and SMAD3, leading to inhibition of the TGF-β signaling pathway. Further studies have revealed that that SIRT2 was able to directly interact with and deacetylate SMAD2 at lysine 451, promoting its ubiquitination and degradation. Notably, loss of SMAD specific E3 ubiquitin protein ligase 2 abolishes the ubiquitination and degradation of SMAD2 induced by SIRT2 in SMAD2. Regarding SMAD3, we have found that SIRT2 interact with and deacetylates SMAD3 at lysine 341 and 378 only in the presence of TGF-β, thereby reducing its activation. This study provides initial indication of the anti-fibrotic role of SIRT2 in renal tubules and hepatocytes, suggesting its therapeutic potential for fibrosis.

Noscapine alleviates unilateral ureteral obstruction-induced inflammation and fibrosis by regulating the TGFβ1/Smads signaling pathways

Renal fibrosis is a common pathway leading to progressive renal function loss in various forms of chronic kidney disease. Many fibrogenic factors regulate renal fibrosis; two key players are post-injury inflammation and transforming growth factor-β1 (TGF-β1)-induced myofibroblast differentiation. Myofibroblast differentiation is tightly regulated by the microtubule polymerization. Noscapine, an antitussive plant alkaloid, is a potent microtubule-interfering agent previously identified as a potential anticancer compound. Here, we examined how noscapine affects renal fibrogenesis in an in vitro renal fibroblast model and an in vivo unilateral ureteral obstruction (UUO) model. UUO mice were intraperitoneally treated with noscapine at 1 day before UUO surgery and daily thereafter. At 7 days post-surgery, kidneys were collected for further analysis. To analyze whether noscapine inhibits downstream TGF-β1-related signaling, we pre-incubated NRK-49F fibroblasts with noscapine and then performed TGF-β1 stimulation. In UUO mice, noscapine attenuated extracellular matrix protein deposition and the expression levels of type I collagen, type IV collagen, α-smooth muscle actin, and fibronectin. In addition, noscapine decreased tubulointerstitial inflammation in UUO kidneys by reducing TLR2 expression, modulating NLRP3 inflammasome activation, reducing macrophage infiltration, and antagonizing the M2 macrophage phenotype. Furthermore, noscapine pre-incubation suppressed the TGF-β1-induced fibroblast-myofibroblast transformation by downregulating the TGF-β/Smads signaling pathways in NRK-49F cells. These results suggest that noscapine reduces tubulointerstitial inflammation and fibrosis in the kidneys of UUO mice and inhibits the fibroblast-myofibroblast transformation induced by TGF-β1. Noscapine is an over-the-counter antitussive that has been used safely for several decades. Therefore, noscapine is an attractive therapeutic agent for inhibiting renal tubulointerstitial fibrosis.

The Role of Oxidative Stress in Kidney Injury.

Acute kidney injury and chronic kidney disease are among the most common non-communicable diseases in the developed world, with increasing prevalence. Patients with acute kidney injury are at an increased risk of developing chronic kidney disease. One of kidney injury's most common clinical sequelae is increased cardiovascular morbidity and mortality. In recent years, new insights into the pathophysiology of renal damage have been made. Oxidative stress is the imbalance favoring the increased generation of ROS and/or reduced body's innate antioxidant defense mechanisms and is of pivotal importance, not only in the development and progression of kidney disease but also in understanding the enhanced cardiovascular risk in these patients. This article summarizes and emphasizes the role of oxidative stress in acute kidney injury, various forms of chronic kidney disease, and also in patients on renal replacement therapy (hemodialysis, peritoneal dialysis, and after kidney transplant). Additionally, the role of oxidative stress in the development of drug-related nephrotoxicity and also in the development after exposure to various environmental and occupational pollutants is presented.

Association of indoor use of pesticides with CKD of unknown origin.

Chronic kidney disease (CKD) is a growing global health problem. Recently, an epidemic of CKD of unknown origin (CKDu), a form of CKD seen mostly in agricultural communities, has been emerged. One of the proposed causes of CKDu is pesticide use in farmers. On the other hand, the research on relation between indoor use of pesticides and CKDu is little. In this study, we aimed to investigate the association between indoor use of pesticide as well as the exposure time with CKDu. This study was done as part of the population-based cohort of Prospective Epidemiological Research Studies in Iran. We used the baseline data of the Zahedan Adult Cohort Study. All subjects with diabetes mellitus and/or hypertension, estimated glomerular filtration rate (eGFR) between 60-89 ml/min/1.73 m2, and unavailable creatinine measurement were excluded. Subjects with an eGFR of less than 60 ml/min/1.73 m2 were defined as having CKDu, and their data were compared with those with an eGFR of more than 90 ml/min/1.73 m2. Data regarding indoor pesticide use and duration of exposure were obtained through a questionnaire. After applying the exclusion criteria, 1079 subjects remained in the study. Female sex, single marital status, low physical activity, triglyceride (TG) levels of more than 150 mg/dl, body mass index (BMI) of more than 25 kg/m2, non-smokers, indoor pesticide use, and high pesticide exposure time were associated with CKDu. The effects of age, female sex, TG levels more than 150 mg/dl, pesticide use (OR 1.36; 95% CI 1.01-1.84), and high exposure time (third tertile of exposure time) compared to non-users (OR 1.64; 95% CI 1.07-2.51) remained significant in multivariable analysis. We found a positive association between pesticide use, as well as longer exposure time to pesticides, and impaired kidney function in cases without diabetes mellitus and hypertension. Further longitudinal studies should be carried out to confirm these findings.

#3186 INVESTIGATING TREM2 MACROPHAGES IN CHRONIC KIDNEY DISEASE

Abstract Background and Aims Kidney macrophages have been implicated in interstitial fibrosis and inflammation in various forms of chronic kidney disease (CKD), but subsets with different markers and putative functions have been identified through the application of single cell technologies. A recent study from the Greka Lab revealed distinct macrophage populations in the human kidney bearing lymphatic endothelium hyaluronan receptor-1 (LYVE1) and triggering receptor expressed on myeloid cells-2 (TREM2). Notably, TREM2+ macrophages, which have been implicated in limiting metabolic toxicity in chronic diseases, were enriched in diabetic mouse kidneys and human kidneys from obese individuals (Subramanian et al. BioRvix 2021). To support these findings, we aimed at characterizing LYVE1+ and TREM2+ macrophages in kidney samples taken from subjects with CKD-associated co-morbidities, including hypertension, diabetes mellitus and obesity. Method We performed immunofluorescence microscopy of samples collected from the cortex of kidneys donated for transplantation but deemed unsuitable for implantation. Each sample was stained with anti-CD163, -LYVE1, and -TREM2 antibodies, plus Hoechst to stain nuclei. Two identically sized fields of view were imaged in each sample. Macrophages were identified based on CD163 expression and the expression of the LYVE1 and TREM2 in macrophages delineated. Macrophage subsets were compared according to age, BMI, eGFR and the presence of hypertension, obesity and diabetes. Results of 49 donors assessed, 19 (39%) were “healthy”, six (12%) “hypertensive” without obesity or diabetes, 16 (33%) “obese” with no evidence of diabetes, and 8 (16%) “diabetic” (all had type 2 diabetes and 6/8 were also obese) The median eGFR at donation was 95 mL/min/1.73 m2 and none of the donors had a history of CKD. Gender, median age and cause of death were not significantly different as well (Table 1). “Healthy”, “hypertensive” and “obese” donors had similar numbers of total macrophages, LYVE1+ and TREM2+ macrophages per region of interest. In contrast, “diabetic” subjects had a tendency towards a higher macrophage count (P = .10) and significantly higher numbers of LYVE1+ (P = .02) and TREM2+ macrophages (P = .002), compared to “healthy” ones (see Figure 1). The median LYVE1+/CD163+ ratio was 0.69 and did not differ substantially between the groups (P = .18), while the TREM2+/CD163+ ratio was higher among “diabetic” compared to “healthy” donors (0.43 vs 0.34, P = .06). Conclusion Diabetes is associated with an increase in kidney macrophages, particularly in those expressing TREM2. Further investigation is required to determine the role these cells may play in CKD progression.

Osteopontin as a Biomarker in Chronic Kidney Disease.

Osteopontin (OPN) is a ubiquitously expressed protein with a wide range of physiological functions, including roles in bone mineralization, immune regulation, and wound healing. OPN has been implicated in the pathogenesis of several forms of chronic kidney disease (CKD) where it promotes inflammation and fibrosis and regulates calcium and phosphate metabolism. OPN expression is increased in the kidneys, blood, and urine of patients with CKD, particularly in those with diabetic kidney disease and glomerulonephritis. The full-length OPN protein is cleaved by various proteases, including thrombin, matrix metalloproteinase (MMP)-3, MMP-7, cathepsin-D, and plasmin, producing N-terminal OPN (ntOPN), which may have more detrimental effects in CKD. Studies suggest that OPN may serve as a biomarker in CKD, and while more research is needed to fully evaluate and validate OPN and ntOPN as CKD biomarkers, the available evidence suggests that they are promising candidates for further investigation. Targeting OPN may be a potential treatment strategy. Several studies show that inhibition of OPN expression or activity can attenuate kidney injury and improve kidney function. In addition to its effects on kidney function, OPN has been linked to cardiovascular disease, which is a major cause of morbidity and mortality in patients with CKD.