Progression Of Albuminuria Research Articles

The development and progression of albuminuria in South Asians with type 2 diabetes compared with Western Europeans. Results from the HinDu the Hague diabetes study.

Although South Asians have an increased risk to develop diabetes, data on the difference in development and progression of diabetic nephropathy between ethnic groups are not consistent. The aim of this study was to evaluate possible differences in the development and progression of albuminuria in South Asians and Western Europeans (WE) with type 2 diabetes in a large closed cohort of South Asians with type 2 diabetes. Data on 1269 South Asians and 2272 Dutch adults with type 2 diabetes who were treated in our diabetes clinic in 2006 or referred thereafter were extracted from electronic medical records. Microalbuminuria and macroalbuminuria were defined separately for men and women based on albumin/creatinine ratios in early morning urine samples. We defined 3 outcomes: (1) no albuminuria, (2) persistent microalbuminuria and (3) macroalbuminuria at the end of follow-up. Cox proportional hazard models were used to discriminate differences in time from diabetes diagnosis until development and progression of albuminuria between the two ethnic groups, adjusted for retinopathy, hypertension, smoking and age at diabetes diagnosis. South Asians have a higher adjusted risk for developing microalbuminuria: HR 1.4, (95% CI 1.2, 1.6) and macroalbuminuria: HR: 1.2 (1.0, 1.4) compared to Western Europeans. However, mean time to progress from micro- to macroalbuminuria was not different between the ethnic groups (3.9 ± 4.0 yrs vs. 3.4 ± 3.9 yrs respectively). South Asians have a higher adjusted risk to develop micro- and macroalbuminuria compared with Western Europeans. When microalbuminuria is present, time to progression from micro- to macroalbuminuria is not different between the two groups.

The importance of arterial stiffness in pediatric patients with type 1 diabetes mellitus: What's new?

Youths with type 1 diabetes (T1D) exhibits higher levels of pulse wave velocity (PWV) compared to healthy controls. Higher PWV in T1D subjects is associated with increased hazard of progression in albuminuria, decline in eGFR, cardiovascular (CV) events and mortality. In the recently published work by Georeli et al., increased PWV was associated with poor glycemic control as expressed by time-in-range (TIR) < 50 % in T1D children, adolescents and young adults. This finding is of great interest, since it is well known that glycemic control, as measured by TIR, is an important contributor of CV risk. The duration of TIR < 50 % is not reported by the authors, but is of importance, knowing that CGM provide data for the last 3–6 months, depending on the CGM model. In conclusion, PWV looks promising for risk stratification in T1D, but its exact role in T1D still remains to be fully explored.

The mechanosensitive ion channel Piezo1 contributes to podocyte cytoskeleton remodeling and development of proteinuria in lupus nephritis.

Piezo1 functions as a special transducer of mechanostress into electrochemical signals and is implicated in the pathogenesis of various diseases across different disciplines. However, whether Piezo1 contributes to the pathogenesis of lupus nephritis (LN) remains elusive. To study this, we applied an agonist and antagonist of Piezo1 to treat lupus-prone MRL/lpr mice. Additionally, a podocyte-specific Piezo1 knockout mouse model was also generated to substantiate the role of Piezo1 in podocyte injury induced by pristane, a murine model of LN. A marked upregulation of Piezo1 was found in podocytes in both human and murine LN. The Piezo1 antagonist, GsMTx4, significantly alleviated glomerulonephritis and tubulointerstitial damage, improved kidney function, decreased proteinuria, and mitigated podocyte foot process effacement in MRL/lpr mice. Moreover, podocyte-specific Piezo1 deletion showed protective effects on the progression of proteinuria and podocyte foot process effacement in the murine LN model. Mechanistically, Piezo1 expression was upregulated by inflammatory cytokines (IL-6, TNF-α and IFN-γ), soluble urokinase Plasminogen Activator Receptor and its own activation. Activation of Piezo1 elicited calcium influx, which subsequently enhanced Rac1 activity and increased active paxillin, thereby promoting cytoskeleton remodeling and decreasing podocyte motility. Thus, our work demonstrated that Piezo1 contributed to podocyte injury and proteinuria progression in LN. Hence, targeted therapy aimed at decreasing or inhibiting Piezo1 could represent a novel strategy to treat LN.

A Case of Rapidly Progressive Nephrotic-Range Proteinuria in a Patient with Purpuric Rash

A Case of Rapidly Progressive Nephrotic-Range Proteinuria in a Patient with Purpuric Rash

Empagliflozin Reduces Progressive Proteinuria by Potentially Reprogramming Energy Metabolism in Proximal Tubules in Young, Nondiabetic, Obese, Dahl Salt-Sensitive Rats

Empagliflozin Reduces Progressive Proteinuria by Potentially Reprogramming Energy Metabolism in Proximal Tubules in Young, Nondiabetic, Obese, Dahl Salt-Sensitive Rats

Renin-angiotensin blockade ameliorates the progression of glomerular injury in podocyte-specific Ctcf knockout mice.

Several studies have shown that the progression of proteinuria and renal tissue injury is associated with activation of the intrarenal renin-angiotensin system (RAS). CCCTC-binding factor (CTCF) is a DNA-binding factor that plays an essential role in the regulation of gene expression. In the present study, we aimed to investigate the phenotypic effects of CTCF deficiency in podocytes. Angiotensin II type 1 receptor blockers (ARBs) were administered to the podocyte-specific Ctcf knockout mice, and histological and biochemical analyzes were performed. We also investigated the changes in the expression of podocin in podocyte cell cultures with or without stimulation with angiotensin II from glomeruli isolated using magnetic beads from podocyte-specific Ctcf knockout mice. Mice in which Ctcf was deleted from podocytes developed glomerulopathy and mice developed severe progressive proteinuria, and impaired renal function. Moreover, ARBs suppressed the development of glomerulopathy in podocyte-specific Ctcf knockout mice. Both real-time polymerase chain reaction and western blotting showed that podocin expression was decreased in cell cultures stimulated with angiotensin II. Furthermore, RAS components gene expressions in podocyte cell cultures isolated from podocyte-specific Ctcf knockout mice were significantly increased. These results suggest that RAS is involved in the development of glomerulopathy in podocyte-specific Ctcf knockout mice. Elucidation of the pathophysiology of podocyte-specific Ctcf knockout mice may provide new insights into the relationship between podocyte injury and chronic glomerulonephritis.

The incidence and trends of proteinuria, azotemia and hypertension in cats receiving toceranib phosphate.

This retrospective study aimed to determine the incidence and trends of proteinuria, elevations in serum creatinine and urea, and systolic blood pressure in cats undergoing treatment with toceranib. In total, 32 cats treated with toceranib for malignancies were analyzed. Cats were included if urinalysis and urine protein:creatinine ratio (UPC) measurements were available at 28 days (T1) and 56 days (T2) after starting the treatment. Cats with concurrent lower urinary tract disease, including urinary tract malignancy, were excluded. Friedman's ANOVA compared variables between time points, and the Spearman test assessed the correlation between treatment duration and UPC. The median starting dose of toceranib was 2.68 mg/kg (range 1.7-3.9). In total, 15 (46.9%) cats received concurrent non-steroidal anti-inflammatory drugs. The most commonly treated tumors were oral squamous cell carcinoma (n = 10) and mast cell tumor (n = 5). None of the 32 cats developed progressive proteinuria or azotemia during the follow-up period (median 56 days; range 56-336). Notably, UPC and serum creatinine were significantly lower at T2 compared with baseline (P = 0.012 and 0.001, respectively). Among the four cats with baseline proteinuria, UPC decreased over time with or without concurrent telmisartan treatment (n = 2). All four of these cats experienced a reduction in tumor size with toceranib concurrently with their decreased UPC. There was no significant correlation between UPC and the duration of toceranib treatment (P = 0.089). Blood pressure was not significantly different over the assessed time points. The incidence of proteinuria, renal azotemia and hypertension in cats treated with toceranib for neoplasia appears to be low. Toceranib may be a viable treatment option even in cats with pre-existing proteinuria or renal disease, with careful monitoring of trends recommended.

Benefits of SGLT2 inhibitors on renal and cardiovascular protection, in diabetic patients

Introduction: Type 2 Diabetes Mellitus is major risk factors for both cardiovascular and renal diseases. Managing cardiovascular risk and the progression of renal disease is therefore essential in treating diabetic patient. Sodium-glucose cotransporter-2 inhibitors have been linked to a substantial decrease in cardiovascular and renal mortality, reduced hospitalizations for heart failure and slower progression of renal damage and albuminuria. Objectives: Our study aimed to evaluate the impact of SGLT2i on cardiovascular and renal protection in diabetic patients. Methods: Our study involved elderly patients, with type 2 diabetes, who were divided in two groups, one group received SGLT2i, while the other did not. Data were collected at the start of treatment, as well as at 3, 6, 9 and 12 months thereafter. During each evaluation, we assessed HbA1C, BMI, GFR and renal parameters, uric acid, NTproBNP, echocardiography, and both PAS and PAD values, in both groups. Results: Out of 300 elderly diabetic patients included in the study, 200 were started on dapagliflozin 10 mg. At 12 months, HbA1c, weight, systolic blood pressure, NTproBNP, uric acid, albuminuria, were decreases in group with dapagliflozin versus the other group without it, and estimated glomerular filtration rate was higher (75.3 – 87.19mL/min/1.73m2; p&lt;0.005). Follow up in patients with SGLT2i showed a significant decrease in left ventricular end-diastolic dimension (LV-EDD) (62.86 mm to 54.85 mm; P&lt; 0.001) and improvement in LV-EF. Conclusions: The use of Dapagliflozin demonstrated metabolic benefits in patients with T2DM, including notable decreases in HbA1c, blood pressure, weight, uric acid, and NTproBNP. Additionally, cardiovascular and renal benefits were observed. Therefore, SGLT2i have a significant impact on both cardiovascular and renal protection in diabetic patients.

Protocol and rationale for a randomized controlled SGLT2 inhibitor trial in pediatric and young adult populations with chronic kidney disease: DOUBLE PRO-TECT Alport.

Clinical trials have demonstrated positive cardiovascular and kidney outcomes of sodium-glucose-co-transporter-2 (SGLT2) inhibitors in adult patients with diabetic and other chronic kidney diseases (CKD). Whether benefits extend to children, teenagers, and young adults with early-stage CKD is unknown. For this reason, the DOUBLE PRO-TECT Alport trial (NCT05944016) will study the progression of albuminuria in young patients with Alport syndrome (AS), the most common hereditary CKD, to assess the safety and efficacy of the SGLT2-inhibitor dapagliflozin. Patients living with AS and chronically elevated albuminuria have a high risk of kidney failure before the age of 50 years. DOUBLE PRO-TECT Alport is a multicenter, randomized, double-blind, placebo-controlled trial (RCT). Participants (aged 10 to 39 years) must have a diagnosis of AS by genetic testing or kidney biopsy, be on a stable (> 3 months) maximum tolerated dose of a renin-angiotensin-system-inhibitor (RASi) and must have a Urinary Albumin to Creatinine Ratio (UACR) of >300 mg/g (pediatric) or >500 mg/g (adult).Eligible participants will be randomly assigned at a 2:1 ratio to 48 weeks of treatment with dapaglifozin 10 mg/day -to- matched placebo. Most participants are expected to be children with a normal glomerular filtration rate (eGFR). In addition to safety, the primary (change in UACR from baseline to Week 48) and key secondary (eGFR change from baseline to Week 52) efficacy outcomes will be analyzed with a mixed model repeated measures approach. Efficacy analyses will be performed primarily in the full analysis set according to the intention-to-treat principle. A sensitivity analysis will be performed using reference-based multiple imputation. DOUBLE PRO-TECT Alport will assess whether SGLT2-inhibitors can safely reduce change from baseline in UACR as a marker for progression of CKD in young patients living with AS.

Reconstituted HDL ameliorated renal injury of diabetic kidney disease in mice.

Diabetic kidney disease (DKD) is a devastating kidney disease and lacks effective therapeutic interventions. The present study was aimed to determine whether reconstituted high-density lipoprotein (rHDL) ameliorated renal injury in eNOS-/- dbdb mice, a mouse model of DKD. Three groups of mice, wild type C57BLKS/J (non-diabetes), eNOS-/- dbdb (diabetes), and eNOS-/- dbdb treated with rHDL (diabetes+rHDL) with both males and females were used. The rHDL nanoparticles were administered to eNOS-/- dbdb mice at Week 16 at 5 μg/g body weight in ~100 μL of saline solution twice per week for 4 weeks via retroorbital injection. We found that rHDL treatment significantly blunted progression of albuminuria and GFR decline observed in DKD mice. Histological examinations showed that the rHDLs significantly alleviated glomerular injury and renal fibrosis, and inhibited podocyte loss. Western blots and immunohistochemical examinations showed that increased protein abundances of fibronectin and collagen IV in the renal cortex of eNOS-/- dbdb mice were significantly reduced by the rHDLs. Taken together, the present study suggests a renoprotective effect of rHDLs on DKD.

Exploring the role of NLRP3 inflammasome in diabetic nephropathy and the advancements in herbal therapeutics.

Diabetic nephropathy (DN), a prevalent complication of diabetes mellitus (DM), is clinically marked by progressive proteinuria and a decline in glomerular filtration rate. The etiology and pathogenesis of DN encompass a spectrum of factors, including hemodynamic alterations, inflammation, and oxidative stress, yet remain incompletely understood. The NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome, a critical component of the body's innate immunity, plays a pivotal role in the pathophysiology of DN by promoting the release of inflammatory cytokines, thus contributing to the progression of this chronic inflammatory condition. Recent studies highlight the involvement of the NLRP3 inflammasome in the renal pathology associated with DN. This article delves into the activation pathways of the NLRP3 inflammasome and its pathogenic implications in DN. Additionally, it reviews the therapeutic potential of traditional Chinese medicine (TCM) in modulating the NLRP3 inflammasome, aiming to provide comprehensive insights into the pathogenesis of DN and the current advancements in TCM interventions targeting NLRP3 inflammatory vesicles. Such insights are expected to lay the groundwork for further exploration into TCM-based treatments for DN.

Protein glycation products associate with progression of kidney disease and incident cardiovascular events in individuals with type 1 diabetes

BackgroundDespite improved glycemic treatment, the impact of glycation on pathological consequences may persist and contribute to adverse clinical outcomes in diabetes. In the present study we investigated the association between serum protein glycation products and progression of kidney disease as well as incident major adverse cardiovascular events (MACE) in type 1 diabetes.MethodsFructosamine, advanced glycation end products (AGEs), and methylglyoxal-modified hydro-imidazolone (MG-H1) were measured from baseline serum samples in the FinnDiane study (n = 575). Kidney disease progression was defined as steep eGFR decline (> 3 mL/min/1.73 m2/year) or progression of albuminuria (from lower to higher stage of albuminuria). MACE was defined as acute myocardial infarction, coronary revascularization, cerebrovascular event (stroke), and cardiovascular death.ResultsFructosamine was independently associated with steep eGFR decline (OR 2.15 [95% CI 1.16–4.01], p = 0.016) in the fully adjusted model (age, sex, baseline eGFR). AGEs were associated with steep eGFR decline (OR 1.58 per 1 unit of SD [95% CI 1.07–2.32], p = 0.02), progression to end-stage kidney disease (ESKD) (HR 2.09 per 1 unit of SD [95% CI 1.43–3.05], p < 0.001), and pooled progression (to any stage of albuminuria) (HR 2.72 per 1 unit of SD [95% CI 2.04–3.62], p < 0.001). AGEs (HR 1.57 per 1 unit of SD [95% CI 1.23–2.00], p < 0.001) and MG-H1 (HR 4.99 [95% CI 0.98–25.55], p = 0.054) were associated with incident MACE. MG-H1 was also associated with pooled progression (HR 4.19 [95% CI 1.11–15.89], p = 0.035). Most AGEs and MG-H1 associations were no more significant after adjusting for baseline eGFR.ConclusionsOverall, these findings suggest that protein glycation products are an important risk factor for target organ damage in type 1 diabetes. The data provide further support to investigate a potential causal role of serum protein glycation in the progression of diabetes complications.

A review of the latest real-world evidence studies in diabetic kidney disease: What have we learned about clinical practice and the clinical effectiveness of interventions?

Diabetic nephropathy, also known as diabetic kidney disease (DKD), remains a challenge in clinical practice as this is the major cause of kidney failure worldwide. Clinical trials do not answer all the questions raised in clinical practice and real-world evidence provides complementary insights from randomized controlled trials. Real-life longitudinal data highlight the need for improved screening and management of diabetic nephropathy in primary care. Adherence to the recommended guidelines for comprehensive care appears to be suboptimal in clinical practice in patients with DKD. Barriers to the initiation of sodium-glucose cotransporter-2 (SGLT2) inhibitors for patients with DKD persist in clinical practice, in particular for the elderly. Attainment of blood pressure targets often remains an issue. Initiation of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in routine clinical practice is associated with a reduced risk of albuminuria progression and a possible beneficial effect on kidney function. Real-world evidence confirms a beneficial effect of SGLT2 inhibitors on the decline of glomerular filtration, even in the absence of albuminuria, with a lower risk of acute kidney injury events compared to GLP-1RA use. In addition, SGLT2 inhibitors confer a lower risk of hyperkalaemia after initiation compared with dipeptidyl peptidase-4 inhibitors in patients with DKD. Data from a large population indicate that diuretic treatment increases the risk of a significant decline in glomerular filtration rate in the first few weeks of treatment after SGLT2 inhibitor initiation. The perspective for a global approach targeting multifaceted criteria for diabetic individuals with DKD is emerging based on real-world evidence but there is still a long way to go to achieve this goal.

Plasma angiotensin-converting enzyme 2 (ACE2) is a marker for renal outcome of diabetic kidney disease (DKD) (U-CARE study 3)

IntroductionACE cleaves angiotensin I (Ang I) to angiotensin II (Ang II) inducing vasoconstriction via Ang II type 1 (AT1) receptor, while ACE2 cleaves Ang II to Ang (1–7) causing vasodilatation...

#1918 L-NAME accelerates the progression of diabetic kidney disease in mice

Abstract Background and Aims Diabetic kidney disease (DKD) represents one of the major causes of end stage kidney disease worldwide. Despite DN having such a high incidence, mouse models of DN rarely mimic all aspects of the human disease, besides showing very slow progression and sometimes maintenance issues. For this reason, in this project we aimed to develop an accelerated, reproducible and accessible mouse model of DN. Method For our experiments we chose 9-week-old female and male of the leptin receptor knock-out (BKS.Cg-Dock7m +/+ Leprdb/J) mice as type 2 diabetes model. As these mice are still not prone to develop severe kidney injury despite their diabetic condition, we administered the eNOS inhibitor L-NAME for 6 weeks, in order to suppress nitric oxide production and therefore to aggravate kidney damage. Mice were divided in three groups: one vehicle control group, one receiving 40/mg/kg/day of L-NAME and one receiving 80/mg/kg/day of L-NAME dissolved in drinking water. Blood pressure and glomerular filtration rate (GFR) were measured at different time points, together with glycemia and albuminuria. Weight and water intake were also monitored throughout the study. At the end of the experiment, animals were killed and blood and organs collected for further analysis. Results Mice treated with 80 mg/kg/day of L-NAME showed an average increase of 10 mmHg in systolic blood pressure, with a peak of 30 mmHg increase at week 4 of treatment. On the other hand, 40 mg/kg/day of L-NAME did show any effect on blood pressure. Despite the different effect on blood pressure, three weeks of L-NAME administration caused a significant reduction in GFR at both doses, with 5% reduction for the 40 mg-group and 23% for the 80 mg-group. For the 80 mg-group we observed an even further GFR decline after 5 weeks of treatment, with a 28% reduction. No change in GFR was observed in the controls. This decrease in GFR was accompanied by a 10-fold increase in urinary albumin for both experimental groups already after 3 weeks of treatment, which after 4 weeks slightly declined but remained significantly higher than the controls (p &amp;lt; 0.0001). At a histological level, PAS staining of kidney sections revealed that in particular mice treated with 80 mg of L-NAME have enlarged Bowman capsule and glomerular tuft area, besides a reduced glomerular capillary density, coinciding with mesangial expansion. We also stained for overall collagen deposition with picrosirius red staining in order to detect possible fibrosis formation. We then observed that 80 mg of L-NAME accelerates interstitial fibrosis in the cortical area of the kidney, which also overlapped with an increased deposition of collagen I. This increase in collage I was also detected in kidney cortex of mice treated with 40 mg of L-NAME, although their overall collagen deposition and therefore fibrotic tissue did not differ from the control group. The medullar region of kidneys was also analyzed, but none of the two experimental groups revealed significant differences in terms overall collagen or collagen I deposition. Unlike mesangial expansion and fibrosis, L-NAME did not influence microphages infiltration, as revealed by CD68 staining in kidney sections. This suggests that L-NAME treatment does not accelerate kidney damage by triggering or accelerating inflammatory processes. This was also confirmed by qPCR analysis of kidney tissue, where the expression pro-inflammatory markers, such as IL1β, TNFα and MCP-1, did not change in the experimental groups. Conclusion Our results show that L-NAME considerably accelerates the progression of DKD in diabetic mice, with GFR declining and progressive albuminuria already after 3 weeks. Such disfunction is confirmed at 6 weeks by histological analysis, where mesangial expansion and fibrosis were detected. This model can be used to assess the therapeutic potential of novel interventions aimed to slow down DKD.

#2584 Mapping Progression of DKD in ReninAAV UNx db/db mice utilizing time-series RNA sequencing

Abstract Background and Aims The Renin adeno-associated virus (AAV) uninephrectomized (UNx) db/db mouse model of diabetic kidney disease (DKD) recapitulates hallmarks of DKD with hypertension, including albuminuria and glomerulosclerosis. Despite previous characterization of the model, gaps persist in our understanding regarding temporal patterns of gene expression and pathophysiology in the glomeruli. This longitudinal study characterizes isolated glomeruli from ReninAAV UNx db/db mice during progression of DKD with hypertension. Method Female db/db (BKS.Cg-Dock7m +/+ Leprdb/J) received a single i.v. dose of LacZAAV (control) or ReninAAV. Untreated db/m mice (BKS.Cg-Dock7m +/+ Leprdb/J) served as healthy controls. One week after AAV injection, ReninAAV mice underwent UNx, recovered for three weeks, and were subsequently randomized and stratified into 4 groups according to fed blood glucose and body weight. ReninAAV UNx mice were terminated at 4, 8, 12 and 16 weeks (w4-w16) after UNx. Control groups were terminated at 16 weeks. Endpoints included urine and plasma biochemistry, kidney histology (i.e. Collagen 1a1 and Glomerulosclerosis) and RNA sequencing of glomeruli isolated by laser capture microdissection. Results ReninAAV UNx db/db mice showed progressive kidney fibrosis (Col1a1%-area) and albuminuria (uACR) compared to LacZAAV db/db and db/m mice across all timepoints investigated. Furthermore, a significant increase in glomerulosclerosis was observed from w12 and onwards compared to LacZAAV and db/m mice. When compared to LacZAAV mice, more than 1,700 glomerular differentially regulated genes and more than 250 uniquely regulated genes were found at each timepoint, including markers of fibrosis, inflammation and glomerular injury. Several glomerular drug targets exhibited time-specific regulated in ReninAAV UNx db/db mice (e.g. Slc5a2, Egfr, Agtr1a). Regulated genes were segmented into nine clusters with distinct temporal patterns. Among these, a continuous increase in expression of genes associated with extracellular matrix (ECM), small molecule transport and temporal stimulation of metabolic pathways. Finally, a correlation analysis revealed strong associations between ECM and ECM-related pathways vs. glomerulosclerosis and albuminuria. Conclusion The ReninAAV UNx db/db mouse model of hypertensive DKD demonstrates a progressive increase in fibrosis and albuminuria paralleled by dynamic changes in glomerular gene expression signatures. Notably, the identification of temporal patterns of gene expression and pathway regulation provides novel insights into DKD pathophysiology and progression. This underscores the ReninAAV UNx db/db mouse as an applicable model of human DKD in preclinical target and drug discovery.

#1549 The effect of sglt2 inhibitors (dapaglifozin) on albuminuria in patients of diabetic nephropathy above standard of care

Abstract Background and Aims Albuminuria is the hallmark of diabetic nephropathy (DN) and progression of albuminuria denotes declining renal functions culminating in End Stage Renal Disease. Intensive blood glucose control (HbA1c &amp;lt;7%), intensive blood pressure control (&amp;lt;130/90 mmHg), blockade of Renin Angiotensin Aldosterone System (RAAS) by Angiotensin converting enzyme inhibitors (ACE-i) and Angiotensin receptor blockers (ARBs) constitute the standard line of care for treatment of DN with proteinuria. Sodium Glucose cotransporter 2 inhibitors (SGLT2i) are drugs are recently introduced for proteinuria reduction with no data available in this part of the world. Hence, I, observed the antiproteinuric effect of SGLT2i in patients who have type2 diabetes mellitus (T2DM) with albuminuria and who are already on maximum doses of ACE-I or ARBs. My study population was on dapaglifozin due to easy availability and low cost. Method it is an observational study including patients who attended the out-patient clinic of Nephrology, at Medica Hospital, Kolkata between July 2022 to February 2023. Inclusion criteria: Exclusion criteria: Quantitative estimation of urine albumin was performed using the VITROS Chemistry Products mALB Reagent along with the VITROS Chemistry Products Calibrator Kit 24 on the VITROS 5,1 FS Chemistry System and the VITROS 5600 Integrated System. Blood sugar was measured by glucose oxidase method. eGFR by CKD EPI equation. Statistical Methodology Continuous variables were presented with mean and standard deviation and tested for normal distribution by the Kolmogorov-Smirnov test. Categorical variables were summarized using frequency and percentages. For testing of related samples, Wilcoxon sign ranked test is used. Statistical analyses were performed using the SPSS software with version 26.0. Results A total of 100 patients were included in the study, of which 3 patients were lost to follow up and 2 patients discontinued the study at 3 months due to fall in eGFR below 25 ml/min/1.73 m2 and 4 patients discontinued after 3 months because of fungal genital infections. After Dapaglifozin administration, a significant reduction in Urine Albumin-creatinine ratio (UACR) was observed, by a percentage decrease of 37.3% (p&amp;lt;0.001) at 3 months and of 70.2% (p&amp;lt;0.001) at 6 months from baseline. Similarly, there was an acute reduction in eGFR from baseline. A percentage decrease by 5.16% (p&amp;lt;0.001) was observed at 3 months &amp; a decrease by 5.69% (p&amp;lt;0.001) at 6 months from baseline. Conclusion Conventional approaches reduce but have not been able to stop disease progression in Diabetic Kidney Disease (DKD). SGLT2i can protect against the onset of DKD, slow disease progression independently. They have an antiproteinuric effect in patients with diabetic nephropathy which was sustained throughout the follow-up period in my study. Studies have also shown that SGLT2i reduce major adverse cardiovascular events in patients with T2DM and established cardiovascular disease. With the new results of EMPA-KIDNEY trial, SGLT2i are being used at even lower eGFR (&amp;lt;25 ml/min/1.73 m2 till on hemodialysis) and such vast health benefits, invention of SGLT2i are is a boon to the mankind.

Deletion of IRE1α in podocytes exacerbates diabetic nephropathy in mice

Protein misfolding in the endoplasmic reticulum (ER) of podocytes contributes to the pathogenesis of glomerular diseases. Protein misfolding activates the unfolded protein response (UPR), a compensatory signaling network. We address the role of the UPR and the UPR transducer, inositol-requiring enzyme 1α (IRE1α), in streptozotocin-induced diabetic nephropathy in mice. Diabetes caused progressive albuminuria in control mice that was exacerbated in podocyte-specific IRE1α knockout (KO) mice. Compared to diabetic controls, diabetic IRE1α KO mice showed reductions in podocyte number and synaptopodin. Glomerular ultrastructure was altered only in diabetic IRE1α KO mice; the major changes included widening of podocyte foot processes and glomerular basement membrane. Activation of the UPR and autophagy was evident in diabetic control, but not diabetic IRE1α KO mice. Analysis of human glomerular gene expression in the JuCKD-Glom database demonstrated induction of genes associated with the ER, UPR and autophagy in diabetic nephropathy. Thus, mice with podocyte-specific deletion of IRE1α demonstrate more severe diabetic nephropathy and attenuation of the glomerular UPR and autophagy, implying a protective effect of IRE1α. These results are consistent with data in human diabetic nephropathy and highlight the potential for therapeutically targeting these pathways.

Hypoxia-inducible factor-1α attenuates renal podocyte injury in male rats in a simulated high-altitude environment by upregulating Krüppel-like factor 4 expression.

Previous studies have shown that podocyte injury is involved in the development of proteinuria in rats under hypobaric hypoxia conditions. Prolyl hydroxylase inhibitors (PHIs) may reduce proteinuria. This study aimed to further investigate whether the protective effects of hypoxia-inducible factor 1α (HIF1α) on podocyte injury induced by hypobaric hypoxia are related to Krüppel-like factor 4 (KLF4). Rats were housed in a low-pressure oxygen chamber to simulate a high-altitude environment (5000m), and a PHI was intraperitoneally injected. Urinary protein electrophoresis was performed and the morphology of the podocytes was observed by electron microscopy. Rat podocytes were cultured under 1% O2, and siRNA was used to interfere with KLF4 expression. The protein expression levels of HIF1α, KLF4, CD2-associated protein (CD2AP) and nephrin were determined by western blotting. Compared with those in the experimental group, the rats in the intervention group on day 14 had lower urinary protein levels, increased protein expression levels of CD2AP and nephrin, and reduced podocyte injury. The results of in vitro experiments showed that the protein expression levels of KLF4, CD2AP and nephrin were greater in the PHI intervention group and lower in the HIF1α inhibitors group than in the low-oxygen group. The protein expression of CD2AP and nephrin in the siKLF4-transfected podocytes treated with PHI and HIF1α inhibitors did not differ significantly from that in the low-oxygen group. HIF1α may be involved in reducing progressive high-altitude proteinuria by regulating KLF4 expression and contributing to the repair of podocyte injury induced by hypobaric hypoxia.

AMPK ACTIVATION AMELIORATES ANGIOTENSIN II-INDUCED DOWNREGULATION OF PODOCYTE ZO-1

Objective: Angiotensin II (Ang II) promotes the development and progression of proteinuria and renal diseases and induces podocyte apoptosis. ZO-1 (zonular occludens-1) protein as a component of the slit diaphragm plays a pivotal role in glomerular permeability by connecting slit diaphragm structure and actin cytoskeleton. AMP-activated protein kinase (AMPK), as a sensor of cellular energy status, has been known to play an important role in the pathophysiology of metabolic diseases, including diabetes, and its renal complications. We investigated the role of AMPK on the changes of ZO-1 of podocyte induced by Ang II. Design and method: Mouse podocytes were incubated in media containing various concentrations of Ang II and AMPK-related agents. The changes of ZO-1 and permeability were observed by confocal imaging, western blotting, and permeability assay in the presence of Ang II. Results: Ang II induced the fusion of microvilli and the gap pores on podocytes, which were improved by AICAR, an AMPK activator. Ang II also reduced and disrupted the intercellular ZO-1 staining, resulting in increased podocyte intercellular permeability. The intensities of fluorescences and bands of ZO-1 protein were decreased by Ang II in a dose-dependent manner by confocal microscopy and western blot analysis, respectively. AICAR and metformin, AMPK activators, ameliorated the abnormal distributional changes and the protein of ZO-1. Losartan, Ang II type I receptor blocker, also ameliorated the decrease of ZO-1 protein. Conclusions: Our findings suggest that Ang II induces the relocation and suppression of podocyte ZO-1 via Ang II type 1 receptor which is ameliorated by AMPK-activating agents.