Proteinuric Chronic Kidney Disease Research Articles

#217 Renin-angiotensin-aldosterone system blockers effect in CKD progression in hypertensive elderly patients without proteinuria: PROERCAN trial

Abstract Background and Aims Evidence about nefroprotective effect with RAAS blockers in elderly patients with chronic kidney disease (CKD) without proteinuria is lacking. The primary outcome of our study is to evaluate the impact of RAAS blockers in CKD progression in elderly patients without proteinuria. Method Multicenter open-label, randomized controlled clinical trial including patients over 65 year-old with hypertension and CKD stages 3-4 without proteinuria. Patients were randomized in a 1:1 ratio to either receive RAAS blockers or other antihypertensive drugs and were followed up for three years (Figure). Primary outcome is estimated glomerular filtration rate (eGFR) decline at 3 years. Secondary outcome measures include BP control, renal and cardiovascular events and mortality. Results 88 patients were included with a mean age of 77.9 ± 6.1 years and a follow up period of 3 years: 40 were randomised to RAAS group and 48 to standard treatment. Etiology of CKD was: 53 vascular, 16 interstitial and 19 of unknown etiology. In the RAAS group eGFR slope during follow up was −4.3 ± 1.1 ml/min, whereas in the standard treatment group an increase on eGFR was observed after 3 years (+4.6 ± 0.4 ml/min), p = 0.024. We found no differences in blood pressure control, number of antihypertensive drugs, albuminuria, potassium serum levels, incidence of cardiovascular events nor mortality during the follow up period. Conclusion In elderly patients without diabetes nor cardiopathy and with non proteinuric CKD the use of RAAS blockers does not show a reduction in CKD progression.

#1551 The presence of proteinuria is associated with impaired cerebral oxygenation during exercise in chronic kidney disease

Abstract Background and Aims Cognitive impairment and reduced exercise tolerance are common in patients with chronic kidney disease (CKD), in part due to reduced brain function. Cerebral perfusion and oxygenation are significant determinants of brain activation and have been shown to be significantly impaired in CKD. This analysis aims to examine the impact of proteinuria on cerebral oxygenation during a mild physical stress in patients with pre-dialysis CKD. Method 66 patients with CKD stage 2-4 were included in this post-hoc analysis; 24-h urine samples were used for evaluation of proteinuria. All participants underwent a 3-min intermittent handgrip exercise (HG) at 35% of their maximal voluntary contraction. Changes in cerebral oxygenation (oxyhemoglobin-O2Hb) and deoxyhemoglobin-HHb) and regional blood volume (total hemoglobin-tHb) were continuously recorded during HG-exercise by near-infrared spectroscopy (NIRS). Results No significant differences between the 2 groups were detected in age (proteinuric vs nonproteinuric: 68.4 ± 10.6 vs 67.2 ± 10.8; p = 0.676), eGFR (41.3 ± 18.9 vs 46.3 ± 14.8; p = 0.248) and BMI (28.4 ± 4.9 vs 28.1 ± 4.8; p = 0.803). The MMSE score (proteinuric vs nonproteinuric: 28.0 ± 1.6 vs 28.0 ± 1.7; p = 0.938) and MVC (22.3 ± 7.0 vs 23.9 ± 7.5; p = 0.416) were not significantly different between groups. The average response in cerebral oxygenation during exercise was lower in patients with proteinuric CKD (O2Hb: 1.02 ± 0.87 vs 1.61 ± 0.95; p = 0.018 and diffO2Hb 1.53 ± .97 vs 2.07 ± 1.25; p = 0.065). The average tHb response (index of regional-blood-volume) was also lower in patients with proteinuria (0.51 ± 1.08 vs 1.16 ± 0.92 p = 0.013); however, no differences in HHb (-0.50 ± 0.55 vs -0.45 ± 0.54; p = 0.717) –an index of oxygen extraction capacity- among groups were detected. In univariate linear analysis the level of proteinuria did not show significant correlations with NIRS parameters. Conclusion The presence and not the level of proteinuria is associated with impaired brain activation during a mild physical task in patients with predialysis CKD. Future studies evaluating the role of proteinuria in the decline of cerebral function and cognitive impairment are needed.

#1452 Halting the progression of chronic kidney disease; an audit of the use of renin-angiotensin-aldosterone blockers and SGLT-2 inhibitors

Abstract Background and Aims Sodium-glucose cotransporters-2 inhibitors (SGLT2i) were initially developed for the treatment of type 2 diabetes. Multiple studies have demonstrated the renoprotective effect of SGLT2i, with the capacity to slow diabetic kidney disease and non-diabetic proteinuric chronic kidney disease progression. More recently, the EMPA-KIDNEY trial demonstrated a benefit in patients with chronic kidney disease with a wider range of albuminuria and glomerular filtration rate. We aim to identify the proportion of patients on renin-angiotensin aldosterone system blockade (RAASb) such as angiotensin converting enzyme inhibitor (ACEi), and angiotensin II receptor blocker (ARB), and sodium-glucose transporter-2 inhibitor (SGLT2i) in our Nephrology outpatients clinic. We also aim to encourage awareness and prescribing of RAASb and SGLT2i in eligible patients with CKD. Method A prospective audit was performed in Galway University Hospital (GUH) from September 2023 to October 2023. The audit questionnaire was completed by doctors reviewing patients in OPD. The use of ACEi/ARB/SGLT2i was recorded during the consultation. Results 165 patients were included in the audit with a mean (±SD) age of 62.1 ± 18.6 years. The 3 most common primary renal diagnoses were diabetic kidney disease; 20/165 (12.1%), hypertensive renal disease; 18/165 (10.9%) and IgA nephropathy; 15/165 (9.1%). The mean estimated glomerular filtration rate (eGFR) was 46.8 ± 24.5 ml/min/1.73 m². At baseline, 94/165 (57%) were already on RAASb, none on dual RAASb agents. 20/165 (12.1%) were already on SGLT2i, amongst these, 15/20 (75%) were also on RAASb at the time of the OPD consultation. 13/165 (7.9%) patients were maximised on RAASb and 4/165 (2.4%) commenced an SGLT2i at the clinic visit. Guideline directed medical therapy according to the EMPA-Kidney and UK Kidney Association Clinical Practice Guidelines would suggest missed opportunity on therapeutic optimisation with RAASb and SGLT2i in 66/83 (79.5%) patients; 26/66 (39.4%) were neither on RAASb or SGLT2i, 34/66 (51.5%) were on RAASb but not on SGLT2i, 3/66 (4.5%) were on SGLT2i but not on RAASb, and 3/66 (4.5%) were on sub-maximal RAASb with an SGLT2i. Conclusion There is new evidence to support the use of SGLT2i, in those with chronic kidney disease with a wide range of albuminuria. SGLT2i use is underutilised in our clinic. Ideally, these patients should be initiated on an SGLT2i after being established on a RAASb early in their diagnosis to ensure the optimal renoprotective effects of SGLT2i.

Podocyte-Specific Deletion of MCP-1 Fails to Protect against Angiotensin II- or Adriamycin-Induced Glomerular Disease.

Investigating the role of podocytes in proteinuric disease is imperative to address the increasing global burden of chronic kidney disease (CKD). Studies strongly implicate increased levels of monocyte chemoattractant protein-1 (MCP-1/CCL2) in proteinuric CKD. Since podocytes express the receptor for MCP-1 (i.e., CCR2), we hypothesized that podocyte-specific MCP-1 production in response to stimuli could activate its receptor in an autocrine manner, leading to further podocyte injury. To test this hypothesis, we generated podocyte-specific MCP-1 knockout mice (Podo-Mcp-1fl/fl) and exposed them to proteinuric injury induced by either angiotensin II (Ang II; 1.5 mg/kg/d, osmotic minipump) or Adriamycin (Adr; 18 mg/kg, intravenous bolus). At baseline, there were no between-group differences in body weight, histology, albuminuria, and podocyte markers. After 28 days, there were no between-group differences in survival, change in body weight, albuminuria, kidney function, glomerular injury, and tubulointerstitial fibrosis. The lack of protection in the knockout mice suggests that podocyte-specific MCP-1 production is not a major contributor to either Ang II- or Adr-induced glomerular disease, implicating that another cell type is the source of pathogenic MCP-1 production in CKD.

Metadherin orchestrates PKA and PKM2 to activate β-catenin signaling in podocytes during proteinuric chronic kidney disease

Podocyte damage is the major cause of glomerular injury and proteinuria in multiple chronic kidney diseases. Metadherin (MTDH) is involved in podocyte apoptosis and promotes renal tubular injury in mouse models of diabetic nephropathy and renal fibrosis; however, its role in podocyte injury and proteinuria needs further exploration. Here, we show that MTDH was induced in the glomerular podocytes of patients with proteinuric chronic kidney disease and correlated with proteinuria. Podocyte-specific knockout of MTDH in mice reversed proteinuria, attenuated podocyte injury, and prevented glomerulosclerosis after advanced oxidation protein products challenge or adriamycin injury. Furthermore, specific knockout of MTDH in podocytes repressed β-catenin phosphorylation at the Ser675 site and inhibited its downstream target gene transcription. Mechanistically, on the one hand, MTDH increased cAMP and then activated protein kinase A (PKA) to induce β-catenin phosphorylation at the Ser675 site, facilitating the nuclear translocation of MTDH and β-catenin; on the other hand, MTDH induced the deaggregation of pyruvate kinase M2 (PKM2) tetramers and promoted PKM2 monomers to enter the nucleus. This cascade of events leads to the formation of the MTDH/PKM2/β-catenin/CBP/TCF4 transcription complex, thus triggering TCF4-dependent gene transcription. Inhibition of PKA activity by H-89 or blockade of PKM2 deaggregation by TEPP-46 abolished this cascade of events and disrupted transcription complex formation. These results suggest that MTDH induces podocyte injury and proteinuria by assembling the β-catenin-mediated transcription complex by regulating PKA and PKM2 function.

The E3 ligase Trim63 promotes podocyte injury and proteinuria by targeting PPARα to inhibit fatty acid oxidation

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.

#2758 AMBIENT HEAT EXPOSURE AND ESTIMATED GLOMERULAR FILTRATION RATE TRAJECTORY: A POST-HOC ANALYSIS OF THE DAPA-CKD TRIAL

Abstract Background and Aims Higher ambient temperatures have been associated with higher rates of admission for kidney stones and acute kidney injury. Occupational heat stress is also a risk factor for impaired kidney function in several rural resource-poor settings. It is unclear if higher ambient heat exposure is associated with a faster loss of kidney function in patients with established, all-cause, chronic kidney disease (CKD). We therefore undertook a post-hoc analysis of the DAPA-CKD trial linking participant data to publicly available climate measurements. Method The DAPA-CKD trial randomized 4304 patients with proteinuric CKD (estimated glomerular filtration rate, eGFR, 25-75 mL/min/1.73 m2; urine albumin-to-creatinine ratio, ACR, 23-566 mg/mmol) to dapaglifozin or placebo in addition to standard of care. We examined the association between daily study centre-level ambient heat exposure (defined as a mean heat index, HI, >30; European Centre for Medium-Range Weather Forecasts ERA5 reanalysis dataset) and individual-level change in eGFR using both a linear-mixed effects model and a case-time series approach to address potential unmeasured individual- and centre-level confounding. Results Climate and eGFR data were available on 3915 (91%) participants across 361 centres in 21 countries. Over a median of 28 months, participants (mean age: 62 years; mean eGFR: 43mL/min/1.73 m2) were followed-up at centres where there was a median of 1 day (interquartile range: 0 to 64 days) with an HI>30. Each 30-day period of HI>30 over the study period was associated with a change in eGFR of -0.7% (95% CI: -1.0% to -0.3%), equivalent to an additional eGFR loss of between 1.2 and 4.0mL/min/1.73 m2 per year in a patient with an eGFR of 45mL/min/1.73 m2 located in a very hot versus temperate environment. Similar estimates were obtained using the case time series approach. This association persisted after adjustment for potential haemoconcentration effects on the day of testing and further analyses provided no evidence that these findings varied with baseline eGFR, albuminuria or randomised treatment arm (Figure 1), or by high- versus middle-income country study centre location. Conclusion Higher ambient heat exposure is associated with a more rapid decline in kidney function among patients with CKD. Efforts to mitigate heat exposure should be prospectively tested as part of a comprehensive strategy to slow the progression of kidney disease.

#2528 APOL1 GENOTYPING AND PROTEINURIC KIDNEY DISEASE IN EUROPE

Abstract Background and Aims Apolipoprotein L1 (APOL1) toxic gain-of-function variants (G1 or G2) are genetic factors driving a broad spectrum of progressive, proteinuric nephropathies referred to as APOL1-mediated kidney disease (AMKD). APOL1 genotyping is not routinely performed in kidney disease care, and prevalence of APOL1 variants among persons with chronic kidney disease (CKD) in Europe is not well known. These variants are common in persons of recent African ancestry. We report interim data of a global study estimating the prevalence of APOL1 genotypes in participants of recent African ancestry and proteinuric CKD, with a focus on data from Europe. Method Enrollment in this ongoing study will include up to 2,500 participants across different geographies who are of recent African ancestry and have focal segmental glomerulosclerosis (FSGS) or other proteinuric nondiabetic kidney disease (NDKD). The study includes a single visit during which blood samples are collected from participants to determine their APOL1 genotype using a validated polymerase chain reaction (PCR)-based assay. The percent of participants with two APOL1 variants and percent of participants in each genotype category (e.g., G1/G1, G1/G2, G2/G2) are assessed; genetic counseling services are available to participants, if desired. Results This interim analysis included 1,256 participants of whom 174 (13.9%) were from Europe. As shown in the table, among the 88 participants with FSGS and 86 participants with proteinuric NDKD, 54 (61.4%) and 32 (37.2%) have two APOL1 variants, respectively. Conclusion Our study will generate one of the largest global APOL1 genotyping data sets in participants with proteinuric kidney disease. These data begin to address a critical knowledge gap and highlight the importance of APOL1 genotyping in kidney disease care to identify AMKD, potentially optimize disease management, and enable referral for interventional clinical trials evaluating targeted therapies for AMKD.

#6359 DAPAGLIFLOZIN TREATMENT IN AUTOSOMAL DOMINANT ALPORT SYNDROME (ADAS)

Abstract Background and Aims Alport Syndrome (AS; ORPHA 63) is one of the most frequent hereditary kidney diseases (HKD). Its autosomal dominant form due to COL4A3-4 heterozygous mutations is being increasingly diagnosed thanks to the generalization of genetic studies. Since there is no curative treatment for the disease, management is based on drugs that slow its progression, mainly RAAS inhibitors. The SGLT2 inhibitor Dapagliflozin has demonstrated to slow chronic kidney disease (CKD) progression by decreasing proteinuria, however very few ADAS patients were included in its clinical trial. Our aim is to analyze whether dapagliflozin is associated with a decrease in proteinuria in ADAS patients. Method In this prospective observational study, we analyzed 12 ADAS patients that started dapagliflozin due to proteinuria in spite of maximum tolerated RAAS inhibitor treatment and eGFR > 25 ml/min/1.73 m2. We analyzed diabetes and hypertension presence (and its control), weight changes, possible adverse effects and laboratory variables before and after treatment initiation (Cr, eGFR, K, uric acid, albuminuria, proteinuria). Results During a mean follow-up period of 7±4 months, we observed 12 patients, 5 (41.7%) male, 61±10 years old. 2 (33.3%) had type 4 diabetes, 2 (16.7%) had impaired fasting glucose (IFG), 11 had hypertension diagnosis, 1 patient had obesity (BMI 36) and other 7 were overweight (mean BMI 28±2). 9 patients had the higher dose of an RAASi, the other three couldn’t achieved it because of hypotension events. 3 patients also took an antagonist of mineralocorticoid. Only one had another diuretic prescription (furosemide 40 mg/d). Mean proteinuria prior to Dapagliflozin initiation was 1.0±0.4 gr/d, protein-to-creatinine ratio (UPCR) 1275±635 mg/g and albumin-to-creatinine ratio (ACR) 784±418 mg/g. 10 out of the 12 patients had some grade of decrease in their proteinuria, with a mean decrease of 416±183 mg/g of UPCR (p = 0,046) and a mean decrease of 292±178 mg/g of ACR (p = 0,020). Looking only at patients without diabetes, they had a lesser degree of estimated glucosuria than diabetes patients, but maintained the improvement in proteinuria quite similar to the overall group (mean ACR improvement 244±95 mg/g). All patients had optimal blood pressure control, and there were no significant body weight losses. Mean eGFR previous to SGLT2i initiation was 50±22 ml/min/1.73 m2, and after 45±19 ml/min/1.73 m2 (p = 0,008), with a mean fall of 8±8%. There were no differences in potassium levels (p = 0,079) and a decrease of uric acid levels (6.7±1.3 mg/dl vs 6.0±1.4 mg/dl, p = 0,016). The two patients who didn’t achieve an improvement in their proteinuria were not diabetic patients and had optimal blood pressure control, one of them had a weight gain of two kilograms, and the other had no weight changes. They had a similar eGFR fall to the overall group. Possible adverse events were monitored, although we didn’t find any of them: no urine tract infections, hyperpotassemia, acute kidney injury, dehydration. No patient required treatment suspension. Two of them required a withdrawal in their other diabetes medications and the one on furosemide tried a lesser dose but had to increase it again. Conclusion Slower progression drugs are the main treatment of ADAS nowadays. Dapagliflozin had demonstrated its beneficial effects in other proteinuric CKD, but it hasn’t been well studied in ADAS. In our sample, it seems to achieve a proteinuria improvement without significant adverse effects and known bearable eGFR fall. Large studies must be considered to determine its beneficial use in a long-time basis.

#4321 ACTION3 PHASE 3 STUDY: EVALUATING A NOVEL THERAPEUTIC STRATEGY OF A CCR2 INHIBITOR (DMX-200) WITH ANGIOTENSIN RECEPTOR BLOCKADE IN FSGS

Abstract Background and Aims Focal segmental glomerulosclerosis (FSGS) is a disease of podocytes. Complications include nephrotic syndrome and progressive kidney failure. FSGS is a condition with high unmet need and there is no approved treatment. The angiotensin II receptor type 1 (AT1R) and chemokine receptor 2 (CCR2) are G protein coupled receptors that form functional heteromers. Simultaneous antagonism of these receptors suggested synergistic renoprotective effects in preclinical and early phase clinical studies of proteinuric kidney disease. DMX-200 (repagermanium) is a C-C chemokine receptor type 2 (CCR2) inhibitor that, when administered concurrently with an angiotensin II receptor blocker (ARB), is designed to inhibit recruitment of monocytes implicated in the inflammatory chemokine environment of chronic disease. In a Phase 2a open-label study of 27 patients with proteinuric chronic kidney disease, 25% of patients achieved > 50% reduction in uPCR with combined use of DMX-200 and irbesartan. A Phase 2a placebo-controlled cross-over study in 8 patients with primary FSGS receiving stable dose of irbesartan demonstrated evidence of promising efficacy with clinically relevant reduction in uPCR of 17% with DMX-200 compared with placebo. These encouraging data suggest that treatment with DMX-200 may result in clinically meaningful reduction in proteinuria when added to ARB in patients with glomerular diseases such as FSGS. Proteinuria reduction is a positive prognostic sign for preserving kidney function. The observations from earlier trials have led to the initiation of an international randomised double-blind, placebo-controlled Phase 3 clinical trial (ACTION3) to further evaluate the efficacy of DMX-200 in patients with FSGS receiving an ARB. Method Eligible patients are adults (18-80 years) with biopsy-proven primary FSGS, genetic FSGS or FSGS of undetermined cause (FSGS-UC), and uPCR of >1.5g/g based on 24hr urine collection and eGFR of ≥25 ml/min/1.73 m2. Blood pressure ≤160/100 mmHg and BMI ≤40kg/m2. Patients with secondary FSGS or those treated with strong immunomodulatory agents (other than corticosteroids) are excluded. All patients are required to receive concomitant ARB treatment at a dose of at least 50% of the maximum approved dose according to the relevant product label. Patients receiving ACE-inhibitors are required to switch to an ARB. Other background therapies such as SGLT-2 inhibitors and mineralocorticoid receptor antagonists are permitted if receiving a stable dose in the 3 months prior to screening. Patients are randomized in a 1:1 ratio to DMX-200 (120 mg twice daily) or placebo. The primary objective is to evaluate the efficacy of DMX-200 on reduction in PCR after 35 weeks of treatment and eGFR slope after 104 weeks of treatment. Secondary objectives are safety and tolerability of DMX-200 and to evaluate the effect of DMX-200 on response criteria and composite endpoint of worsening kidney function. Exploratory objectives include assessment of changes in inflammatory biomarkers such as MCP-1 and the pharmacokinetic profile of DMX-200. Two interim analyses (IA) are planned, first planned IA for futility will be performed by an Independent Data Monitoring Committee after the first ​72 randomized patients (36 patients per group) complete 35 weeks ​of treatment. A second IA will be performed once approximately​ 144 enrolled patients complete 35 weeks ​of treatment.​ The final analysis will be performed once approximately 286 patients complete 104 weeks of treatment. The study is currently open in 11 countries at approximately 75 investigational sites and will be expanded to include more countries and sites subject to a successful first interim analysis. Results ACTION3 is a trial in progress and is expected to be completed in 2026. Conclusion ACTION3 is a Phase 3 randomized, placebo-controlled efficacy and safety trial which evaluates the novel approach of combining an investigational CCR2 inhibitor, DMX-200, with angiotensin receptor blockade in patients with FSGS.

#6929 SGLT2 INHIBITORS IN IGA NEPHROPATHY: REAL LIFE EXPERIENCE AT OUR CENTRE

Abstract Background and Aims SGLT2 inhibitors (SGLT2i) have a beneficial effect in diabetic and non-diabetic proteinuric chronic kidney disease (CKD), demonstrated in large randomized controlled trials. However, there is limited information about real life experience with SGLT2i in non-diabetic CKD like IgA nephropathy (IgAN). Method All patients with biopsy-proven IgA nephropathy since 2015 were evaluated for SGLT2i use. We collected data on age, gender, the use of renin-angiotension-aldosterone system inhibitors (RAASi), eGFR, glycosuria and proteinuria at baseline, at 6 months and at one year of follow-up. Glomerular filtration rate (eGFR) was estimated using the CKD-EPI equation. Data was analyzed using Jamovi®. Results 51 patients had IgAN diagnosed by kidney biopsy from April 2015 until March 2021. Eleven of these started SGLT2i between December 2020 and February 2022 (at their physician's description). Their median age was 52, nine were male and all were taking RAASi. The initial median proteinuria was 1 g/g (range 0.5-2.0 g/g), median eGFR was 57.5 mL/min (range 16.8-104 mL/min). At 6 months, the median proteinuria was 0.7 g/g (range 0.8-4.8 g/g), median eGFR was 42.6 mL/min (range 13.9-108 mL/min). One year after beginning SGLT2i, 8 patients have laboratory values and the median value of proteinuria was 0.85 g/g (range 0.2-3.0 g/g) and the median eGFR was 40.5 mL/min (range 14.5-85.4 mL/min). All patients had glycosuria at all urine evaluations confirming no discontinuations of the SGLT2i. No serious adverse events were reported and none of the patients needed dialysis or died. There were no significant differences between proteinuria and eGFR between evaluations at the start, 6 months and 1 year of follow-up. Conclusion SGLT2i have become important drugs in IgAN. Our first cases who started SGLT2i showed good compliance (using glycosuria as an indirect tool to monitor adherence) and no adverse events, irrespective of their initial eGFR. The small sample was probably a limitation to the lack of significant results.

Zinc(Ⅱ)-induced Neuroimmunological Renal Chronic Kidney Disease Prevention and Suppressive Progression

Zinc(Ⅱ) supplementation with 30 mg/day should become likely therapeutic chronic kidney disease (CKD) prevention implications with immense importance of CKD-associated immunological and neurological complications. Zinc induced neuroimmunological suppressive CKD progression with Stage 2 ～ 3A, 3B, zinc supplementation (30 mg/day) may be beneficial for nutritional status in CKD children and adolescents, and zinc could reduce urinary protein excretion composed of albumin and/or minimize proteinuria excretion in proteinuric CKD. In CKD 4-5 stage, risk of cardiovascular disease (CVD) become higher that zinc supplementation of 25 mg/day in zinc homeostasis has a beneficial effect for CVD in vascular dysfunction. Thus, zinc intake of 30 mg/day and serum zinc level of 60～76 μg/dL could slow down CKD Stage 4 progression. Zinc induced CKD Stage 5 (eGFR < 15) is involved that zinc is actively bound to several proteins that the decrease of circulating zinc levels in CKD is partly caused by renal losses of zinc, becoming zinc-deficiency with advanced stage CKD and ESRD in CKD. Serum zinc and serum albumin levels are 37.4 ± 5.4 and 2.6 ± 0.6 µg/dL, respectively, for as eGFR 6.6 (5.2–8.3). Zn intake of 45-75 mg/day and serum zinc level of ≤78.3 µg/dL are beneficial for HD and maintenance hemodialysis (MHD) patients, in which Zinc 15 mg/day and Selenium 50–70 μg/day that are recommended may be thought to prevent ESRD stage. Zinc induced NAD(P)H oxidase (Nox) activation occurring ROS generation in CKD cell involves assembly that ROS include the superoxide anion (O2•–), hydrogen peroxide (H2O2), and hydroxyl radicals (OH•), and in the kidney. Zinc(Ⅱ) ions-binding protein molecular mechanism is involved that Zn2+ ions-several protein complexes coordinated binding model of ligands of such as albumin, a-macroglobulin and transferrin in several proteins had been found on the binding specificity by Zn2+ ions-centered tetrahedral geometric coordination, in which causing zinc-activated serine, histidine and aspartate hydrogen residues enhance renal function activity and resulting inhibition of CKD progression proceeds.

Evolution of hypoxia and hypoxia-inducible factor asparaginyl hydroxylase regulation in chronic kidney disease.

The roles of hypoxia and hypoxia inducible factor (HIF) during chronic kidney disease (CKD) are much debated. Interventional studies with HIF-α activation in rodents have yielded contradictory results. The HIF pathway is regulated by prolyl and asparaginyl hydroxylases. While prolyl hydroxylase inhibition is a well-known method to stabilize HIF-α, little is known about the effect asparaginyl hydroxylase factor inhibiting HIF (FIH). We used a model of progressive proteinuric CKD and a model of obstructive nephropathy with unilateral fibrosis. In these models we assessed hypoxia with pimonidazole and vascularization with three-dimensional micro-computed tomography imaging. We analysed a database of 217 CKD biopsies from stage 1 to 5 and we randomly collected 15 CKD biopsies of various severity degrees to assess FIH expression. Finally, we modulated FIH activity in vitro and in vivo using a pharmacologic approach to assess its relevance in CKD. In our model of proteinuric CKD, we show that early CKD stages are not characterized by hypoxia or HIF activation. At late CKD stages, some areas of hypoxia are observed, but these are not colocalizing with fibrosis. In mice and in humans, we observed a downregulation of the HIF pathway, together with an increased FIH expression in CKD, according to its severity. Modulating FIH in vitro affects cellular metabolism, as described previously. In vivo, pharmacologic FIH inhibition increases the glomerular filtration rate of control and CKD animals and is associated with decreased development of fibrosis. The causative role of hypoxia and HIF activation in CKD progression is questioned. A pharmacological approach of FIH downregulation seems promising in proteinuric kidney disease.

Impact of Baseline Clinical Variables on SGLT2i's Antiproteinuric Effect in Diabetic Kidney Disease.

Proteinuria is a major risk factor for the progression of chronic kidney disease (CKD). Sodium-glucose cotransporter 2 inhibitors (SGLT2i) demonstrated a nephroprotective and antiproteinuric effect in people with type 2 diabetes (T2DM) and proteinuric CKD. We conducted a retrospective study to evaluate clinical and laboratory variables that can help predict proteinuria reduction with SGLT2i therapy. Patients affected by T2DM and CKD who started any SGLT2i were included in the study. Patients were stratified into two subgroups, Responder (R) and non-Responder (nR), based upon the response to the therapy with SGLT2i, namely the reduction in a 24 h urine proteins test (uProt) of ≥30% from baseline levels. The aim of the study is to analyse differences in baseline characteristics between the two groups and to investigate the relationship between them and the proteinuria reduction. A Kruskal-Wallis test, unpaired t-test and Chi2 test were used to test the difference in means and the percentage (%) between the two groups. Linear and logistic regressions were utilized to analyse the relationship between proteinuria reduction and basal characteristics. A total of 58 patients were enrolled in the study: 32 patients (55.1%) were in the R group and 26 patients (44.9%) in the nR group. R's patients had a significant higher uProt at baseline (1393 vs. 449 mg/24 h, p = 0.010). There was a significant correlation between baseline uProt and proteinuria reduction with SGLT2i in both univariate (β = -0.43, CI -0.55 to -031; p < 0.001) and multivariate analyses (β = -0.46, CI -0.57 to -0.35, p < 0.001). In the multivariate analysis, there was a significant positive correlation between the estimated glomerular filtration rate (eGFR) and proteinuria reduction (β = -17, CI -31 to -3.3, p = 0.016) and a significant negative correlation with body mass index (BMI) (β = 81, CI 13 to 50, p = 0.021). The multivariate logistic regressions show a positive correlation of being in the R group with diabetic retinopathy at baseline (Odds Ratio (OR) 3.65, CI 0.97 to 13.58, p = 0.054), while the presence of cardiovascular disease (CVD) at baseline is associated with being in the nR group (OR 0.34, CI 0.09 to 1.22, p = 0.1), even if these statements did not reach statistical significance. In this real-life experience, following the administration of SGLT2i, a reduction of more than 30% in proteinuria was observed in more than half of the patients, and these patients had a significantly higher baseline proteinuria value. Variables such as eGFR and BMI are variables that, considered in conjunction with proteinuria, can help predict treatment response before therapy initiation. Different phenotypes of diabetic kidney disease may have an impact on the antiproteinuric response.

Clinical features of generalized lipodystrophy in Turkey: A cohort analysis.

To describe the Turkish generalized lipodystrophy (GL) cohort with the frequency of each complication and the death rate during the period of the follow-up. This study reports on 72 patients with GL (47 families) registered at different centres in Turkey that cover all regions of the country. The mean ± SD follow-up was 86 ± 78 months. The Kaplan-Meier estimate of the median time to diagnosis of diabetes and/or prediabetes was 16 years. Hyperglycaemia was not controlled in 37 of 45 patients (82.2%) with diabetes. Hypertriglyceridaemia developed in 65 patients (90.3%). The Kaplan-Meier estimate of the median time to diagnosis of hypertriglyceridaemia was 14 years. Hypertriglyceridaemia was severe (≥ 500 mg/dl) in 38 patients (52.8%). Seven (9.7%) patients suffered from pancreatitis. The Kaplan-Meier estimate of the median time to diagnosis of hepatic steatosis was 15 years. Liver disease progressed to cirrhosis in nine patients (12.5%). Liver disease was more severe in congenital lipodystrophy type 2 (CGL2). Proteinuric chronic kidney disease (CKD) developed in 32 patients (44.4%) and cardiac disease in 23 patients (31.9%). Kaplan-Meier estimates of the median time to diagnosis of CKD and cardiac disease were 25 and 45 years, respectively. Females appeared to have a more severe metabolic disease, with an earlier onset of metabolic abnormalities. Ten patients died during the follow-up period. Causes of death were end-stage renal disease, sepsis (because of recurrent intestinal perforations, coronavirus disease, diabetic foot infection and following coronary artery bypass graft surgery), myocardial infarction, heart failure because of dilated cardiomyopathy, stroke, liver complications and angiosarcoma. Standard treatment approaches have only a limited impact and do not prevent the development of severe metabolic abnormalities and early onset of organ complications in GL.

Hyperkalemia and the Use of New Potassium Binders a Single Center Experience from Vestfold Norway (The PotBind Study).

Hyperkalemia is a common metabolic complication of chronic kidney disease (CKD) and is associated with several serious adverse events. We aimed to treat/prevent hyperkalemia using the new of potassium-binders, allowing maintained renin-angiotensin-aldosterone system inhibitors (RAASi) treatment in proteinuric CKD and/or congestive heart failure (CHF) patients. We conducted a retrospective cohort study in long-term users of potassium binders for chronic hyperkalemia. Patients aged 18 years and older, treated with potassium-binders and who met the reimbursement criteria and indication for RAASi treatment were included. Fifty-seven percent of the patients were males and mean age was 65 years. During the study period, no patients were admitted to hospital due to hyperkalemia after initiation of potassium binders. Potassium maximum values were significantly lower after treatment. Few patients reported major side effects, and discontinuation was mostly due to normokalemia. We found no significant changes in bicarbonate, serum creatinine or GFR stage after starting potassium binder treatment. All patients on RAASi treatment before initiating potassium-binders were retained on RAASi treatment. New potassium binders in clinical practice are an easy and safe treatment with few side effects and good tolerance, that significantly lowers the risk of hyperkalemia. Furthermore, and most importantly, patients can be maintained on RAASi treatment.

Lupus nephropathy beyond immunosuppression: Searching for nephro and cardioprotection.

Renal involvement in systemic lupus erythematosus (SLE) represents one of the most frequent organ manifestations, often leading to end-stage kidney disease (ESKD). Several therapies have been tested in patients with lupus nephritis (LN) to prevent further organ damage. The effectiveness of immunosuppressive therapy as a treatment for LN is abundant, supported by multiple clinical trials that have shown its efficacy in preventing the development of chronic kidney disease (CKD). In addition to immunosuppressive therapy, several traditional and recent therapies aimed at nephroprotection in patients with proteinuric chronic kidney disease are gaining importance in the setting of LN. Thus, immunosuppressive therapy should be accompanied by nephro- and cardioprotective measures to control cardiovascular risk factors and proteinuria to ensure a better renal prognosis. Despite this, the literature on these specific measures is relatively scarce, with recommendations focused on the blockade of the renin-angiotensin-aldosterone system (RAAS). This review explores the pharmacological options available for cardiovascular and renal protection outside the usual treatment schemes.

Pathogenic variant detection rate by whole exome sequencing in Thai patients with biopsy-proven focal segmental glomerulosclerosis

The spectra of underlying genetic variants for various clinical entities including focal segmental glomerulosclerosis (FSGS) vary among different populations. Here we described the clinical and genetic characteristics of biopsy-proven FSGS patients in Thailand. Patients with FSGS pathology, without secondary causes, were included in our study. Clinical laboratory and pathological data were collected. Whole-exome sequencing (WES) was subsequently performed. 53 unrelated FSGS patients were recruited. 35 patients were adults (66.0%), and 51 patients were sporadic cases (96.2%). Clinical diagnosis before kidney biopsy was steroid-resistant nephrotic syndrome (SRNS) in 58.5%, and proteinuric chronic kidney disease in 32.1%. Using WES, disease-associated pathogenic/likely pathogenic (P/LP) variants could be identified in six patients including the two familial cases, making the P/LP detection rate of 11.3% (6/53). Of these six patients, two patients harbored novel variants with one in the COL4A4 gene and one in the MAFB gene. Four other patients carried previously reported variants in the CLCN5, LMX1B, and COL4A4 genes. Four of these patients (4/6) received immunosuppressive medications as a treatment for primary FSGS before genetic diagnosis. All four did not respond to the medications, emphasizing the importance of genetic testing to avoid unnecessary treatment. Notably, the mutation detection rates in adult and pediatric patients were almost identical, at 11.4% and 11.1%, respectively. In conclusion, the overall P/LP variant detection rate by WES in biopsy-proven FSGS patients was 11.3%. The most identified variants were in COL4A4. In addition, three novel variants associated with FSGS were detected.

Neuroimmunological renal function for zinc(Ⅱ) induced CKD prevention and modulatory progression

Zinc (Ⅱ) supplementation (30 mg/day) should become likely therapeutic chronic kidney disease (CKD) prevention implications with immense importance of CKD-associated immunological and neurological complications of central nervous system (CNS) disorder and peripheral nervous system (PNS) condition. Zinc induced neuro immunological inhibitive CKD progression with Stage 2～3A, 3B, zinc supplementation may be beneficial for nutritional status in CKD children and adolescents, and zinc could reduce urinary protein excretion composed of albumin and/or minimize proteinuria excretion in proteinuric CKD. In CKD 4～5 stage, risk of cardiovascular disease (CVD) become higher that zinc supplementation of 25 mg/day in zinc homeostasis has a beneficial effect for CVD in vascular dysfunction, in which zinc induced CKD Stage 5 (eGFR < 15) is involved that zinc is actively bound to several proteins that the decrease of circulating zinc levels in CKD is becoming zinc-deficiency with advanced stage CKD and ESRD in CKD. Zinc 15 mg/day and Selenium 50–70 μg/day that are recommended may be thought to prevent ESRD stage. Zinc induced NAD (P)H oxidase (Nox) activation occurring ROS generation in CKD cell involves assembly that ROS include the superoxide anion (O2•–), hydrogen peroxide (H2O2), and hydroxyl radicals (OH•) in the kidney. Zinc(Ⅱ) ions-binding protein molecular mechanism is involved that Zn2+ ions induced binding ligands of such as albumin, a-macroglobulin and transferrin in several proteins had been found on the binding specificity by Zn2+ ions-centered tetrahedral geometric coordination, in which causing zinc-activated serine, histidine and aspartate hydrogen residues enhance renal function activity and resulting inhibition of CKD progression proceeds.

Magnitude of the Potential Screening Gap for Fabry Disease in Manitoba: A Population-Based Retrospective Cohort Study.

Fabry disease is a rare disorder caused by the deficient activity of α-galactosidase A (GLA) that often leads to organ damage. Fabry disease can be treated with enzyme replacement or pharmacological therapy, but due to its rarity and nonspecific manifestations, it often goes undiagnosed. Mass screening for Fabry disease is impractical; however, a targeted screening program for high-risk individuals may uncover previously unknown cases. Our objective was to use population-level administrative health databases to identify patients at high risk of Fabry disease. Retrospective cohort study. Population-level health administrative databases housed at the Manitoba Centre for Health Policy. All residents of Manitoba, Canada, between 1998 and 2018. We ascertained the evidence of GLA testing in a cohort of patients at high risk of Fabry disease. Individuals without a hospitalization or prescription indicative of Fabry disease were included if they had evidence of 1 of 4 high-risk conditions for Fabry disease: (1) ischemic stroke <45 years of age, (2) idiopathic hypertrophic cardiomyopathy, (3) proteinuric chronic kidney disease or kidney failure of unknown cause, or (4) peripheral neuropathy. Patients were excluded if they had known contributing factors to these high-risk conditions. Those who remained and had no prior GLA testing were assigned a 0% to 4.2% probability of having Fabry disease depending on their high-risk condition and sex. After applying exclusion criteria, 1386 individuals were identified as having at least 1 high-risk clinical condition for Fabry disease in Manitoba. There were 416 GLA tests conducted during the study period, and of those, 22 were conducted in individuals with at least 1 high-risk condition. This leaves a screening gap of 1364 individuals with a high-risk clinical condition for Fabry disease in Manitoba who have not been tested. At the end of the study period, 932 of those individuals were still alive and residing in Manitoba, and if screened today, we expect between 3 and 18 would test positive for Fabry disease. The algorithms we used to identify our patients have not been validated elsewhere. Diagnoses of Fabry disease, idiopathic hypertrophic cardiomyopathy, and peripheral neuropathy were only available via hospitalizations and not physician claims. We were only able to capture GLA testing processed through public laboratories. Patients identified to be at high risk of Fabry disease by the algorithm did not undergo GLA testing due to a clinical rationale that we were unable to capture. Administrative health databases may be a useful tool to identify patients at higher risk of Fabry disease or other rare conditions. Further directions include designing a program to screen high-risk individuals for Fabry disease as identified by our administrative data algorithms.