Proteinuric Kidney Disease Research Articles

Tubulointerstitial injury in proteinuric chronic kidney diseases

Proteinuria is an independent risk factor for chronic kidney disease progression and cardiovascular diseases. Apart from its prognostic role, the load of proteins that pass across the disrupted glomerular capillary wall trigger multiple pathophysiologic processes. These include, among others, intratubular complement activation and excessive proximal tubular reabsorption of filtered proteins, especially albumin and albumin-bound free fatty acids, which can set off several pathways of cellular damage. The activation of these pathways can cause apoptosis of proximal tubular cells and paracrine effects that incite the development of interstitial inflammation and fibrosis, ultimately leading to irreversible kidney injury. In this review, we provide a comprehensive overview of the current understanding on the mechanisms underlying the tubular toxicity of ultrafiltered proteins in the setting of proteinuric chronic kidney diseases. The acquired knowledge is expected to be instrumental for the development of novel therapeutic classes of medications to be tested on top of standard of care with optimized renin-angiotensin-aldosterone blockade and sodium-glucose cotransporter-2 inhibition, in order to further improve the clinical outcomes of patients with proteinuric chronic kidney diseases.

Cardiac Effects of Renin-Angiotensin System Inhibitors in Nonproteinuric CKD.

In contrast to proteinuric chronic kidney disease (CKD), the relative cardioprotective benefits of antihypertensive medications in nonproteinuric CKD are unknown. We examined long-term cardiovascular outcomes and mortality in patients with nonproteinuric CKD treated with renin-angiotensin system inhibitors (RASIs) versus other antihypertensive medications. Among participants of the CRIC study (Chronic Renal Insufficiency Cohort) without proteinuria, we used intention-to-treat analyses with inverse probability of treatment weighting and Cox proportional hazards modeling to determine the association of RASIs versus other antihypertensive medications with a composite cardiovascular outcome (myocardial infarction, stroke, heart failure hospitalization, and death) and mortality. Secondary analyses included per-protocol analyses accounting for continuous adherence and time-updated analyses accounting for the proportion of time using RASIs during follow-up. A total of 2806 participants met the inclusion criteria. In the intention-to-treat analyses, RASIs versus other antihypertensive medications were not associated with an appreciable difference in cardiovascular events (adjusted hazard ratio [aHR], 0.94 [95% CI, 0.80-1.11]) or mortality (aHR, 1.06 [95% CI, 0.88-1.28]). In the per-protocol analyses, RASIs were associated with a lower risk of adverse cardiovascular events (aHR, 0.78 [95% CI, 0.63-0.97]) and mortality (aHR, 0.64 [95% CI, 0.48-0.85]). Similarly, in the time-updated analyses, a higher proportion of RASI use over time was associated with a lower mortality risk (aHR, 0.33 [95% CI, 0.14-0.86]). Among individuals with nonproteinuric CKD, after accounting for time-updated use, RASIs are associated with fewer cardiovascular events and a lower mortality risk compared with other antihypertensive medications. Patients with nonproteinuric CKD may benefit from prioritizing RASIs for hypertension management.

Sparsentan (SPAR) in Pediatric Patients with Rare Proteinuric Kidney Disease: Preliminary Findings from the EPPIK Study

Sparsentan (SPAR) in Pediatric Patients with Rare Proteinuric Kidney Disease: Preliminary Findings from the EPPIK Study

Proteinuric and Non-Proteinuric Diabetic Kidney Disease: Different Presentations of the Same Disease?

Background: Diabetic kidney disease (DKD) is a leading cause of end-stage kidney disease (ESKD) worldwide. This review examines the potential differences in clinical presentation, outcomes, and management between individuals with proteinuric DKD (P-DKD) and non-proteinuric DKD (NP-DKD). Methods: We analyzed articles published globally from 2000 and 2024. Results: Individuals with NP-DKD generally have lower blood pressure levels and a more favorable lipid profile. In contrast, histological studies show that P-DKD is associated with more severe glomerulosclerosis, mesangial expansion, arteriolar hyalinosis, interstitial-fibrosis/tubular atrophy, and immune complex deposits. Additionally, those with P-DKD are more likely to develop diabetic retinopathy and have a higher risk of all-cause mortality and progression to ESKD. Strategies to slow DKD progression, applicable to both NP-DKD and P-DKD, include non-pharmacologic and pharmacologic interventions such as renin–angiotensin system blockers, sodium-glucose co-transporter-2 inhibitors, finerenone, and glucagon-like protein receptor agonists. Conclusions: NP-DKD and P-DKD represent different presentations of the same underlying disease.

Characterization of the circulating markers of the renin-angiotensin-aldosterone system in telmisartan- or enalapril-treated dogs with proteinuric chronic kidney disease.

Effects of the renin-angiotensin-aldosterone system (RAAS) inhibitors enalapril and telmisartan on circulating RAAS in dogs with proteinuric chronic kidney disease (pCKD) are undescribed. To characterize the RAAS in untreated dogs with pCKD compared to healthy, life-stage- and sex-matched controls, and in dogs with pCKD after 30 days of treatment with enalapril or telmisartan. Dogs with pCKD (n = 36) and healthy controls (n = 20). Retrospective study of banked samples and previously collected data. Day 0 serum equilibrium concentrations of angiotensin I, II, III, IV, 1-5, and 1-7, and aldosterone, and urinary aldosterone-to-creatinine ratio (UACR) from pCKD dogs were compared to values on day 30 of treatment with enalapril (0.5 mg/kg PO q12) or telmisartan (1 mg/kg PO q24h) and to those of healthy dogs. Data were analyzed using linear mixed models. Compared with healthy dogs, pCKD dogs had significantly higher Ang I, III, 1-5, and 1-7 concentrations, and UACR. Relative to pretreatment values, day 30 Ang II concentrations were significantly increased and decreased in telmisartan- and enalapril-treated pCKD dogs, respectively (both P < .001). Mean (95% confidence interval) percentage change from pretreatment value in serum Ang 1-7 concentration was significantly greater in telmisartan- (753% [489%-1134%]) versus enalapril-treated (149% [69%-268%]) dogs (P < .001). Serum aldosterone decreased with treatment (P = .02 for enalapril, P < .001 for telmisartan), with no difference between groups at day 30. Circulating RAAS activity is higher in dogs with pCKD. Compared with enalapril, treatment with telmisartan caused significantly greater increases in the presumed beneficial peptide Ang 1-7.

SGLT-2 inhibitors: new horizons for rheumatologists.

Sodium glucose cotransporter 2 (SGLT2) inhibitors are a class of medications initially developed for the treatment of diabetes, although their cardiac and renal protective benefits are far reaching. There has been marked interest in the rheumatology community to adopt these medications into our clinical practice, particularly for chronic kidney disease with persistent proteinuria. SGLT2 inhibitors have been approved for patients with type 2 diabetes mellitus, heart failure with reduced or preserved ejection fraction, atherosclerotic cardiovascular disease in the setting of type 2 diabetes mellitus, as well as chronic kidney disease with proteinuria. Large studies on SGLT2 inhibitors have largely excluded patients with proteinuric chronic kidney disease due to autoimmune glomerulonephritis due to concerns for confounding from immunosuppression. The Dapagliflozin and Prevention of Adverse Outcomes in CKD Trial (DAPA-CKD) showed that SGLT2 inhibition decreased progression of renal disease in patients with IgA nephropathy. Expanding this to other autoimmune glomerulonephropathies, several small studies have shown improvements in proteinuria in patients with lupus nephritis treated with SGLT2 inhibitors. A study evaluating safety of SGLT2 inhibitors in patients with lupus identified no specific concerns even with concomitant use of immunosuppression. Small studies have shown that SGLT2 inhibitors can been utilized safely and efficaciously in patients with lupus nephritis. Additional research is needed to identify where these medications fit into the rheumatology treatment armamentarium.

Apical tubular complement activation and the loss of kidney function in proteinuric kidney diseases.

Many kidney diseases are associated with proteinuria. Since proteinuria is independently associated with kidney function loss, anti-proteinuric medication, often in combination with dietary salt restriction, comprises a major cornerstone in the prevention of progressive kidney failure. Nevertheless, complete remission of proteinuria is very difficult to achieve, and most patients with persistent proteinuria slowly progress toward kidney failure. It is well-recognized that proteinuria leads to kidney inflammation and fibrosis via various mechanisms. Among others, complement activation at the apical side of the proximal tubular epithelial cells is suggested to play a crucial role as a cause of progressive loss of kidney function. However, hitherto limited attention is given to the pathophysiological role of tubular complement activation relative to glomerular complement activation. This review aims to summarize the evidence for tubular epithelial complement activation in proteinuric kidney diseases in relation to loss of kidney function.

Recessive variants in MYO1C as a potential novel cause of proteinuric kidney disease.

Steroid-resistant nephrotic syndrome is the second leading cause of chronic kidney disease among patients < 25years of age. Through exome sequencing, identification of > 65 monogenic causes has revealed insights into disease mechanisms of nephrotic syndrome (NS). To elucidate novel monogenic causes of NS, we combined homozygosity mapping with exome sequencing in a worldwide cohort of 1649 pediatric patients with NS. We identified homozygous missense variants in MYO1C in two unrelated children with NS (c.292C > T, p.R98W; c.2273 A > T, p.K758M). We evaluated publicly available kidney single-cell RNA sequencing datasets and found MYO1C to be predominantly expressed in podocytes. We then performed structural modeling for the identified variants in PyMol using aligned shared regions from two available partial structures of MYO1C (4byf and 4r8g). In both structures, calmodulin, a common regulator of myosin activity, is shown to bind to the IQ motif. At both residue sites (K758; R98), there are ion-ion interactions stabilizing intradomain and ligand interactions: R98 binds to nearby D220 within the myosin motor domain and K758 binds to E14 on a calmodulin molecule. Variants of these charged residues to non-charged amino acids could ablate these ionic interactions, weakening protein structure and function establishing the impact of these variants. We here identified recessive variants in MYO1C as a potential novel cause of NS in children.

#57 Tubular biomarkers in proteinuric kidney diseases

Abstract Background and Aims Proteinuria is not only a biomarker of chronic kidney disease (CKD) and a risk predictor of adverse outcomes but also a driver of kidney disease progression. The excessive filtration of plasma proteins through the glomerular filtration barrier exerts a toxic effect on tubular cells which ultimately leads to fibrosis and end-stage kidney disease (ESKD. The aim of this study was to assess the levels of various tubular biomarkers in both serum and urine in patients with biopsied glomerular and proteinuric kidney diseases, and correlate them with renal histology and kidney outcomes. Method A retrospective study and observational study was conducted at a single center from January 2016 to December 2021. Serum and urine samples were collected on the same day of renal biopsy and were correlated with histological data from a cohort of 156 patients with proteinuric kidney diseases. Kidney outcomes were registered during a median follow-up period of 26 months and defined as a decrease in eGFR ≥ 40% from baseline or the development of end-stage kidney disease. The following urinary markers, adjusted to urine creatinine, were analyzed: β2-mcg (beta 2 microglobulin), α1-mcg (alpha 1 microglobulin), NGAL (Neutrophil Gelatinase-Associated Lipocalin), uKIM-1 (Kidney Injury Molecule-1), MCP-1 (Monocyte Chemoattractant Protein-1), uDKK-3 (urinary Dickkopf-3), and uUMOD (uromodulin). Serum markers sKIM-1 and uUMOD were also collected. Results Regarding the etiology of proteinuric kidney disease, the majority corresponded to glomerular disease (68.6%) followed by diabetic kidney disease (12.8%). Higher levels of proteinuria were associated with increased values of β2-mcg and α1-mcg levels and low levels of uUMOD and sUMOD. A significant correlation between the extent of interstitial fibrosis and specific biomarkers was observed: uDKK3 (rho = 0.804, p &amp;lt; 0.001), sKIM-1 (rho = 0.472, p &amp;lt; 0.001), sUMOD (rho = −0.370, p &amp;lt; 0.001), uUMOD (rho = −0.317, p &amp;lt; 0.001), MCP-1 (rho = 0.374, p &amp;lt; 0.001), uKIM-1 (rho = 0.368, p &amp;lt; 0.001), and β2-mcg (rho = 0.392, p &amp;lt; 0.001). Multivariate regression analysis identified uDKK3 as an independent predictor of interstitial fibrosis (Beta 0.728, p &amp;lt; 0.001) adjusted for age, serum creatinine and proteinuria. Elevated levels of MCP-1 and uKIM-1 were associated with a higher risk of significant cortical interstitial inflammation &amp;gt;10% in the logistic regression analysis adjusted for eGFR, proteinuria, and microhematuria: MCP-1 OR = 5.14, 95% CI (2.27−11.62), p &amp;lt; 0.001 and uKIM-1 OR = 1.64, 95% CI (1.05−2.58), p = 0.031. Patients with higher tertiles of β2mcg, MCP1, uDKK3, and KIM1s, and lower tertiles of uUMOD and sUMOD experienced a significantly reduced renal event-free survival in the analysis of Kaplan-Meier model (Fig.). Moreover, of all the evaluated markers, uDKK3 was identified as the best predictor of renal events [HR = 1.03, 95% CI (1.01−1.06), p = 0.008], independently of age, baseline eGFR, proteinuria, and the extent of interstitial fibrosis at the time of renal biopsy. Conclusion Tubular biomarkers may offer prognostic value in proteinuric kidney diseases, particularly uDKK3, exhibiting a notable correlation with interstitial fibrosis and serving as a potential predictor of CKD progression.

#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.

#366 Humanistic burden of immunoglobulin A nephropathy and focal segmental glomerulosclerosis on patients and care-partners (HONUS): results for Europe

Abstract Background and Aims Rare proteinuric kidney diseases are associated with clinical and economic burden, however, the humanistic burden associated with these conditions has not been directly evaluated. HONUS is a multi-national, cross-sectional survey study designed to evaluate the humanistic burden associated with two rare kidney diseases, immunoglobulin A nephropathy (IgAN) and focal segmental glomerulosclerosis (FSGS), from the patient and caregiver perspectives in the United States and Europe. The current analysis presents preliminary results from adults with IgAN or FSGS and their care-partners in Spain, Germany, France, or the United Kingdom. Method The study recruited adult patients (≥ 18 years old) with IgAN or FSGS and their adult care-partners. Participants completed an online survey including demographic and clinical characteristics, health-related quality of life (HRQoL) (i.e., Kidney Disease Quality of Life Instrument [KDQoL] including 12-Item Short Form Survey [SF-12]), anxiety and depression (i.e., Generalized Anxiety Disorder Assessment [GAD-7], Patient Health Questionnaire [PHQ-9]), and disease impact on work productivity (i.e., Work Productivity and Activity Impairment [WPAI]). Descriptive analyses were conducted. Results From Europe, 26 IgAN patients, 9 FSGS patients, and their care-partners (4 IgAN and 2 FSGS patients did not report having a care-partner) participated in the survey before November 2023. Mean age for IgAN and FSGS patients was 42.2 years and 51.4 years, with 61.5% and 44.4% being female, respectively. Over two-fifths of both IgAN (42.3%) and FSGS patients (44.4%) were in chronic kidney disease (CKD) stage 3, 4 or 5 (on dialysis), while over one-quarter had received a kidney transplant (IgAN: 26.9%; FSGS: 44.4%). Most patients had worse CKD status since diagnosis (IgAN: 61.5%; FSGS: 77.8%). Hypertension and anemia were the most common comorbidities in both groups. In terms of HRQoL, mean (SD) SF-12 physical and mental component scores (PCS, MCS) indicated IgAN patients were more impacted on the mental component (PCS: 47.3 [11.6], MCS: 43.2 [10.9]), with FSGS patients more impacted on the physical component (PCS: 40.6 [6.0], MCS: 43.8 [9.1]), reflecting generally worse HRQoL (lower scores) than previously published European general population scores (50.0 for PCS and MCS). Moderate to severe anxiety was reported by 30.8% of IgAN and 33.3% of FSGS patients, and moderate to severe depression by 30.8% of IgAN and 44.4% of FSGS patients. Among employed IgAN patients (69.2%), mean percent absenteeism (work time missed) was reported at 13.3%, presenteeism (impairment while working) at 17.7%, and overall work productivity loss at 17.7% due to IgAN-related reasons (only 3 FSGS patients [33.3%] were employed; outcomes not shown). Mean percent activity impairment was reported at 27.3% in IgAN and 43.3% in FSGS patients. Most paired care-partners were partners of patients (IgAN: 81.8%, FSGS: 71.4%), with a mean age of 46.6 years (IgAN) and 50.1 years (FSGS). Mean (SD) SF-12 PCS and MCS of IgAN care-partners were 53.3 (8.8) and 47.9 (10.8), respectively (FSGS: 47.0 [10.6], 49.4 [9.5]). Mild to moderate anxiety was reported in 31.8% (IgAN) and 42.9% (FSGS) of care-partners, with one IgAN care-partner (4.6%) reporting severe anxiety. Mild to moderate depression was reported in 27.3% (IgAN) and 71.4% (FSGS) of care-partners, with two IgAN care-partners (9.1%) reporting moderately severe or severe depression. Among employed IgAN care-partners (86.4%), mean percent absenteeism was reported at 14.2%, presenteeism at 9.3%, and overall work productivity loss at 9.9% due to IgAN-related reasons. Mean percent activity impairment was reported at 18.6% in IgAN and 17.1% in FSGS care-partners. Conclusion Patients with IgAN and FSGS in Europe experience impaired HRQoL compared to previously published European population estimates, as well as anxiety, depression, and impaired productivity. Care-partners of these patients also experience impaired HRQoL, in terms of mental components, and reduced overall productivity.

#2327 Extent of proteinuria in autosomal dominant Alport syndrome compared to X linked Alport syndrome

Abstract Background and Aims Alport syndrome (AS), as first described by Arthur Cecil Alport in late XIX century, encompasses a clinical picture of neurosensorial hypoacusia, ocular abnormalities, hematuria and proteinuric kidney disease progressing to end-stage kidney disease in the young adulthood. Differently from X-linked and autosomal recessive AS, autosomal dominant AS (ADAS), a more recently recognized entity, whose prevalence based on populational studies may be near to 1%, generally presents with a milder kidney involvement and with negligible extrarenal features. Nevertheless, some of these patients progress to chronic kidney disease (CKD) category G5, with marked intra and interfamilial variability. Although hematuria is almost universally present all three inheritance patterns, the magnitude of proteinuria, a reliable prognostic marker of the X-linked form has not been thoroughly studied in ADAS. We aimed to compare the extent of proteinuria between patients with X-Linked and autosomal dominant AS. Method Retrospective registry data on type of Alport hereditary pattern and spot urine protein to creatinine ratio per CKD category were collected. The 2021 CKD-EPI formula for calculation of glomerular filtration rate (eGFR) was used. Non-parametric test was used to analyze variables that did not follow normal distribution. Results We analyzed proteinuria and eGFR of 127 patients with Alport Syndrome. Information on patient gender, hereditary pattern and gene involved is illustrated it Table 1. Increased proteinuria was observed with CKD progression in all categories (p &amp;lt; 0.05). Within each CKD category, X-linked males had greater median proteinuria followed by, X-linked females and autosomal dominant patients (Table 2 and Fig. 1). No difference in median proteinuria was observed between X-linked females and those with autosomal dominant inheritance throughout CKD categories G1, G2, G4 and G5 (p = 0.142, 0.878, 0.327, 0.909 respectively). Difference in median proteinuria between X-linked females and autosomal dominant inheritance revealed statistical significance in CKD category G3 (p = 0.034), however the small sample size in this group must be taken into account. Conclusion Pathogenic variants in COL4A3, COL4A4, and COL4A5 are all causes of CKD, and proteinuria serves as a hallmark of disease progression. However, the extent of proteinuria in ADAS is significantly lower than that observed in XLAS. Additionally, some ADAS patients develop CKD with only albuminuria. While there is still much to be understood about this common condition, the renal mechanism of damage in ADAS appears to differ definitively from that in XLAS or ARAS.

Vitamin D in kidney: a two-edged sword?

A wide variety of both calcium-dependent and calcium-non-dependent actions are attributed to the vitamin and hormone vitamin D. One of the most vital components of the human body, vitamin D is essential to both health and illness. It is a member of the fat-soluble secosteroid family, which is obtained from diets or direct sun exposure, which is what turns 7-hydroxycholesterol into the precursor of vitamin D. Bio-activation is an alternate phase that provides an active version of vitamin D that contributes to several notable processes like detoxification, fertility, glucose regulation, bone remodelling, and calcium regulation. Numerous research investigations examine the discernible function of vitamin D in kidney illness. The basic physiological and pathological roles of vitamin D in the kidneys of both diabetics and non-diabetics were examined in this study. In this study we analyzed a basic physiological and pathological roles of Vitamin D in kidney in terms of diabetic and non-diabetic proteinuric kidney diseases. Further research in this field is of high importance.

Tubular biomarkers in proteinuric kidney disease: histology correlation and kidney prognosis of tubular biomarkers.

Proteinuria is not only a biomarker of chronic kidney disease (CKD) but also a driver of CKD progression. The aim of this study was to evaluate serum and urinary tubular biomarkers in patients with biopsied proteinuric kidney disease and to correlate them with histology and kidney outcomes. A single-center retrospective study was conducted on a cohort of 156 patients from January 2016 to December 2021. The following urinary and serum biomarkers were analyzed on the day of kidney biopsy: beta 2 microglobulin (β2-mcg), alpha 1 microglobulin (α1-mcg), neutrophil gelatinase-associated lipocalin (NGAL), urinary kidney injury molecule-1 (uKIM-1), monocyte chemoattractant protein-1 (MCP-1), urinary Dickkopf-3 (uDKK3), uromodulin (urinary uUMOD), serum kidney injury molecule-1 (sKIM-1) and serum uromodulin (sUMOD). A composite outcome of kidney progression or death was recorded during a median follow-up period of 26 months. Multivariate regression analysis identified sUMOD (β-0.357, P<.001) and uDKK3 (β 0.483, P<.001) as independent predictors of interstitial fibrosis, adjusted for age, estimated glomerular filtration rate (eGFR) and log proteinuria. Elevated levels of MCP-1 [odds ratio 15.61, 95% confidence interval (CI) 3.52-69.20] were associated with a higher risk of cortical interstitial inflammation >10% adjusted for eGFR, log proteinuria and microhematuria. Upper tertiles of uDKK3 were associated with greater eGFR decline during follow-up. Although not a predictor of the composite outcome, doubling of uDKK3 was a predictor of kidney events (hazard ratio 2.26, 95% CI 1.04-4.94) after adjustment for interstitial fibrosis, eGFR and proteinuria. Tubular markers may have prognostic value in proteinuric kidney disease, correlating with specific histologic parameters and identifying cases at higher risk of CKD progression.

Renin-Angiotensin System Signaling in Parietal Epithelial Cells

INTRODUCTION. Bowman's capsule surrounds the kidney glomerular tuft and consists of a monolayer of parietal epithelial cells (PECs) creating a physiologically functioning barrier between the urinary space and the renal interstitium. Pathophysiological PEC activation describes the phenotypic switch from their normal quiescent state to one of proliferation and migration to the glomerular tuft, leading to glomerular injury. The development of several proteinuric kidney diseases is closely associated with PEC activation, however, the mechanisms of functional receptor signaling in these cells are not well described. This study investigates the functional presence of renin-angiotensin system (RAS) components and corresponding intracellular mechanisms in PECs. Methods. The vibrodissociation method was utilized to obtain freshly isolated Bowman’s capsules from discarded adult male human transplant tissues and 12-week old Wistar male and female rats. Confocal fluorescent microscopy of freshly isolated Bowman’s capsule PECs was performed using Fluo-8 or DAF-FM fluorescent dyes to detect changes in intracellular Ca2+ concentrations and nitric oxide (NO) response to the variety of RAS peptides. RESULTS. In separate experiments on freshly isolated rodent and human Bowman’s capsule PECs, we demonstrate the changes in redox response to the stimulation of RAS components. In particular, the acute application of Ang II peptide caused a rapid increase in NO production. Interestingly, we did not indicate significant changes in intracellular Ca2+ influx. To find out which receptor is responsible for the NO release we preincubated PECs with AT1R and AT2R blockers (Losartan and PD123319 respectively). Our data indicate that RAS mediates NO production through the AT2R activation. There is no sex difference was observed in these experiments. Further experiments with the variety of nitric oxide synthase (NOS) pharmacology reveal the functional distribution of NOS in rodent PECs. CONCLUSION. Our study provides an overview of the RAS signaling within PECs. For the first time, we present evidence demonstrating a direct connection between Ang II and redox homeostasis in PECs. Further investigation using the developed approach will be essential for understanding the role of Bowman's capsule cells in the glomerulus and the development of potential treatment against the hyperplasia of activated PECs and corresponding chronic kidney pathologies. Funding Sources: R01 DK129227, R01 DK126720, VA CDA-2 1IK2BX005605-01. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Hyperkalemia treatment Standard.

Hyperkalemia is a common electrolyte disturbance in both inpatient and outpatient clinical practice. The severity and associated risk depends on the underlying cause and rate of K+ increase. Acute hyperkalemia requires immediate attention due to potentially life-threatening manifestations resulting from the rapid rise in plasma K+ concentration. Treatment is initially focused on stabilizing the cardiac membrane, followed by maneuvers to shift K+ into the cell, and ultimately initiating strategies to decrease total body K+ content. Chronic hyperkalemia develops over a more extended period of time and manifestations tend to be less severe. Nevertheless, the disorder is not benign since chronic hyperkalemia is associated with increased morbidity and mortality. The approach to patients with chronic hyperkalemia begins with a review of medications potentially responsible for the disorder, ensuring effective diuretic therapy, and correcting metabolic acidosis if present. The practice of restricting foods high in K+ potassium to manage hyperkalemia is being reassessed since the evidence supporting the effectiveness of this strategy is lacking. Rather, dietary restriction should be more nuanced focusing on reducing intake of non-plant sources of K+. Down titration and/or discontinuation of renin-angiotensin-aldosterone inhibitors should be discouraged since these drugs improve outcomes in patients with heart failure and proteinuric kidney disease. In addition to other conservative measures, K+ binding drugs and SGLT2 inhibitors can assist in maintaining use of these drugs.

Relationship of Thyroid Function with Renal Hemodynamics and Cholesterol Metabolism in Proteinuric Kidney Disease: A Pilot Study.

Nephrotic syndrome and hypothyroidism are respectively reported to influence renal hemodynamics and hypercholesterolemia. However, the relationship of proteinuria-associated thyroid function with renal hemodynamics and cholesterol metabolism has yet to be determined in a simultaneous analysis of thyroid, renal, and cholesterol variables. We investigated the hypothesis that the changes in thyroid hormones by proteinuria may contribute to changes in cholesterol metabolism and renal hemodynamics by proteinuria. Twenty-nine patients (17 men and 12 women) with proteinuric kidney disease (mean age 46 years) were enrolled in a pilot study. Data for serum free triiodothyronine (FT3), free thyroxine (FT4), total cholesterol, and filtration fraction (FF; assessed by para-aminohippuric acid clearance) were used in variable-adjusted correlation analyses. The patients had the following data (mean ± standard deviation): urinary protein 5.18 ± 3.28 g/day, FT3 2.18 ± 0.44 pg/mL, FT4 1.03 ± 0.26 ng/dL, FF 0.27 ± 0.07, and total cholesterol 327 ± 127 mg/dL. There was a significant positive correlation of FT3 with FF (β = 0.58, p = 0.01) and a significant inverse correlation of FT4 with total cholesterol (β = -0.40, p = 0.01). A positive correlation of FT3 with FF and an inverse correlation of FT4 with total cholesterol were demonstrated in patients with proteinuric kidney disease. The proteinuria-associated reduction in serum thyroid hormone levels was correlated with hypercholesterolemia and the reduced glomerular FF. Further studies of these relationships are required.

Understanding the podocyte immune responses in proteinuric kidney diseases: from pathogenesis to therapy.

The glomerular filtration barrier, comprising the inner layer of capillary fenestrated endothelial cells, outermost podocytes, and the glomerular basement membrane between them, plays a pivotal role in kidney function. Podocytes, terminally differentiated epithelial cells, are challenging to regenerate once injured. They are essential for maintaining the integrity of the glomerular filtration barrier. Damage to podocytes, resulting from intrinsic or extrinsic factors, leads to proteinuria in the early stages and eventually progresses to chronic kidney disease (CKD). Immune-mediated podocyte injury is a primary pathogenic mechanism in proteinuric glomerular diseases, including minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, and lupus nephritis with podocyte involvement. An extensive body of evidence indicates that podocytes not only contribute significantly to the maintenance of the glomerular filtration barrier and serve as targets of immune responses but also exhibit immune cell-like characteristics, participating in both innate and adaptive immunity. They play a pivotal role in mediating glomerular injury and represent potential therapeutic targets for CKD. This review aims to systematically elucidate the mechanisms of podocyte immune injury in various podocyte lesions and provide an overview of recent advances in podocyte immunotherapy. It offers valuable insights for a deeper understanding of the role of podocytes in proteinuric glomerular diseases, and the identification of new therapeutic targets, and has significant implications for the future clinical diagnosis and treatment of podocyte-related disorders.

Filtration and tubular handling of EWE-hC3Nb1, a complement inhibitor nanobody, in wild type mice and a mouse model of proteinuric kidney disease.

Tubular activation and deposition of filtered complement proteins have been implicated in the progression of proteinuric kidney disease. The potent C3b-specific nanobody inhibitor of the alternative pathway, EWE-hC3Nb1, is likely freely filtered in the glomerulus to allow complement inhibition in the tubular lumen and may provide a novel treatment option to prevent tubulointerstitial injury. However, more information on the pharmacokinetic properties and renal tubular handling of EWE-hC3Nb1 nanobody is required for its pharmacological application in relation to kidney disease. Here, we examined the pharmacokinetic properties of free EWE-hC3Nb1 in mouse plasma and urine, following subcutaneous injection in wild-type control and podocin knock out (KO) mice with severe proteinuria. Tubular handling of filtered EWE-hC3Nb1 was assessed by immunohistochemistry (IHC) on kidney tissue from control, proteinuric mice, and KO mice deficient in the proximal tubule endocytic receptor megalin. Rapid plasma absorption and elimination of EWE-hC3Nb1 was observed in both control and proteinuric mice; however, urinary excretion of EWE-hC3Nb1 was markedly increased in proteinuric mice. Urinary EWE-hC3Nb1 excretion was amplified in megalin KO mice, and substantial accumulation of EWE-hC3Nb1 was observed in megalin-expressing renal proximal tubules by IHC. Moreover, free EWE-hC3Nb1 was found to be rapidly cleared from plasma. In conclusion, filtered EWE-hC3Nb1 is reabsorbed by a megalin-dependent process in the proximal tubules. Increased load of filtered proteins in the tubular fluid may inhibit the megalin-dependent uptake of EWE-hC3Nb1 in proteinuric mice. Treatment with EWE-hC3Nb1 may allow investigation of the effects of complement inhibition in the tubular fluid.

The Effect of Hypervolemia Control on Proteinuria in Kidney Disease: A Prospective Interventional Study

The Effect of Hypervolemia Control on Proteinuria in Kidney Disease: A Prospective Interventional Study