Higher Levels Of Proteinuria Research Articles

Long-Term Follow-Up of Patients with Chronic Kidney Disease: Renal Function Decline and Associated Risk Factors

ABSTRACT Evaluating the chronic course of chronic kidney disease (CKD) and identifying associated risk factors is essential for effective management. This study aims to identify risk factors and monitor the decline in renal function through prolonged follow-up of CKD patients. This retrospective cohort study included 410 CKD patients diagnosed between 2015 and 2022. Data collected included demographics, comorbidities, and repeated measurements of glomerular filtration rate (GFR) and proteinuria. Statistical analyses examined the association between GFR decline and risk factors such as age, diabetes, hypertension, and proteinuria during the follow-up period. The cohort showed a progressive decline in GFR over time. Significant associations were found between GFR decline and age, diabetes, hypertension, and higher proteinuria levels (P < 0.001). Age was associated with a 0.32 ml/min decline in GFR per 1.73 m², while the coefficients for hypertension and diabetes were -2.98 and -4.21, respectively. A strong correlation was found between proteinuria and GFR decline (β = -6.78, P < 0.001). Early identification and management of risk factors are crucial for slowing CKD progression. These findings underscore the need for targeted interventions to preserve renal function and improve patient outcomes.

Impact Of Preeclampsia On Maternal And Neonatal Health: A Retrospective Cohort Study

Objective — Understanding the relationship between maternal characteristics of patients with preeclampsia (PE) and disease progression, as well as the impact on neonatal and parturient outcomes, is critical to the development of effective interventions to improve maternal and fetal outcomes in preeclamptic patients. Material and Methods — This retrospective study analyzed 94 patients with PE and focused on the relationship between maternal characteristics and laboratory findings, as well as on the impact on neonatal and parturient outcomes. Comprehensive laboratory and ultrasound examinations were performed, with primary outcomes classified into antenatal, perinatal and postpartum periods, and secondary outcomes focusing on neonatal health. Results — Patients with PE requiring maternal intensive care unit (ICU) admission had higher median serum creatinine, AST, and ALT levels vs. non-ICU patients. Patients who required postpartum medications to control blood pressure had elevated median values of urea concentration, systolic blood pressure, and diastolic blood pressure at diagnosis. A notable difference in ALT values was observed when primary cesarean section was indicated (p=0.036). Subgroup analysis revealed higher median birth weight in the Proteinuria 1+ subgroup vs. the Proteinuria 4+ subgroup (p=0.002). Patients with negative proteinuria levels demonstrated less need for neonatal intensive care unit (NICU) compared with higher proteinuria levels. In addition, a higher need for postpartum medical therapy was noted in patients of Proteinuria 4+ subgroup (74.2%). Conclusion — This study emphasizes the important role of laboratory data and blood pressure monitoring, advocating targeted interventions and clinical approaches to improve maternal postpartum outcomes (need for ICU). It also highlights the utility of urine dipstick testing for effective decision-making in the care of mothers and newborns in the postpartum period.

#1039 Characteristics and outcome of IgA nephropathy in Switzerland – a single center perspective

Abstract Background and Aims IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide leading to end-stage kidney disease (ESKD) in roughly 40% of affected patients by ten years. Geographic differences in clinical course and response to treatment may partly result from different disease entities. The purpose of this retrospective cohort analysis was to study all cases of IgAN from a single tertiary center with respect to clinical and histological characteristics, treatment practices and outcome. Method This retrospective cohort analysis identified 158 cases of adult biopsy-proven IgAN by chart review diagnosed between 1980 and 2017. Detailed phenotypisation including clinical, paraclinical, histological, treatment and outcome parameters was performed. Remission status was defined as described previously (Reich 2007). Statistical analysis was performed using Excel and SPSS software and included standard descriptive methods and included standard descriptive methods and student's t-test on a significance level of 0.05. Results Subjects were majorly male and of Caucasian descent. Mean estimated glomerular filtration rate (eGFR) according to Chronic Kidney Disease Epidemiology Collaboration formula at diagnosis was 55.3 ml/min/1.73 m2, mean proteinuria was 3.2 g/d. 70.3% of patients were hypertensive at presentation. Clinical presentation varied according to age. Thus, younger patients (18-39 years) presented more frequently with macrohematuria, asymptomatic urine abnormalities and by trend acute kidney injury whereas nephrotic syndrome and extrarenal symptoms were recorded in similar proportions of patients (Fig. 1). 28.5% of initial biopsies showed moderate to severe tubular atrophy and interstitial fibrosis (IFTA), 38% included crescents, 1.9% > 50% crescents. 86.1% of the patients were treated by renin-angiotensin-aldosterone-system inhibitors, 46.8% received immunosuppressive therapy including steroids in 46.2% and other immunosuppressive medications in 19.6% the most common being azathioprine (Fig. 2). There were 33.5% complete and 13.3% partial remissions. Progression to ESKD was noted in 42.1%. 51.4% of patients treated with immunosuppressive therapy experienced remission. Recurrence rate after transplantation was 18.4%. Patients treated by immunosuppressants had higher levels of baseline proteinuria (3.2 ± 2.3 vs. 1.6 ± 1.6 g/d, p < 0.00001), lower baseline eGFR (50 ± 31 vs. 61 ± 30 ml/min/1.73 m2, p = 0.04), higher number of crescents (9.4 ± 15.0 vs 2.3 ± 8.5%, p = 0.001), higher IFTA scores (1.7 ± 0.8 vs. 1.3 ± 0.6, p = 0.007) and higher fluorescence intensity scores for C3 (2.0 ± 0.9 vs. 1.6 ± 0.9, p = 0.02) on initial biopsy as compared to patients treated conservatively. Patients progressing to ESKD presented with higher blood pressure (146 ± 26 vs. 135 ± 18 mmHg systolic, p = 0.005; 89 ± 14 vs. 82 ± 14 mmHg diastolic, p = 0.006), lower eGFR (41 ± 29 vs. 64 ± 28 ml/min/1.73 m2, p = 0.00001), higher levels of proteinuria (3.4 ± 2.0 vs. 1.8 ± 1.9 g/d, p = 0.0001), higher number of crescents (9 ± 17 vs. 4 ± 9%, p = 0.03) and higher IFTA scores (1.8 ± 0.8 vs. 1.3 ± 0.6, p = 0.00001) as compared to patients without ESKD at last follow up. Baseline blood pressure (134 ± 18 vs. 147 ± 26 mmHg systolic, p = 0.004; 82 ± 14 vs. 89 ± 15 mmHg diastolic, p = 0.01), eGFR (60 ± 29 vs. 41 ± 27 mmHg, p = 0.0007), proteinuria (2.3 ± 1.9 vs. 3.2 ± 2.3 g/d, p = 0.03) and severity of IFTA (1.4 ± 0.6 vs. 1.8 ± 0.9, p = 0.003) differed significantly between patients who experienced any remission vs. those who did not achieve remission respectively. Conclusion This analysis gives insight into the characteristics and treatment practices of a Swiss single center cohort of IgAN patients from 1980-2017.

#887 Complement biomarkers in IgA nephropathy and IgA vasculitis with renal involvement: can urine rather than blood be the answer?

Abstract Background and Aims IgA nephropathy (IgAN) is the most common glomerulonephritis worldwide. Dysregulation of the complement system is considered a part of the pathogenesis and can occur both in the circulation and locally in the kidney. Despite this, most studies have focused on complement biomarkers in the blood, rather than in urine. Our aim was to evaluate a wide range of complement-related proteins in blood and urine at diagnosis and their association with disease activity in biopsy findings, proteinuria, and outcome. We added PTX-3, a protein expressed in activated endothelial cells, which can be both produced by and activate mesangial cells in IgAN and has a function in all three complement pathways. Adult-onset IgA vasculitis with renal involvement (IgAVN) shares many similarities with IgAN and cannot currently be distinguished by kidney biopsy or any established biomarker. We therefore also aimed to compare the same biomarkers between these two disorders. Method In a Swedish cohort of 96 patients with IgAN (n = 65) and IgAVN (n = 31), who had been followed prospectively for a median of 10.8 years, we performed the following analysis in plasma and urine in samples stored at the time of kidney biopsy. Analyses in plasma (p-) included C3bc, C4c, C5b-9, MASP2, MASP3, MAP1, FCN 1-3, MBL, CL11 and PTX-3 and in urine (u-) C3bc, C4c, C5b-9, MASP3, FCN2, FCN3, MBL and PTX-3. An in-house developed sandwich ELISA was used for all analyses. Kidney biopsies were classified according to the Oxford MEST-C score, describing (simplified for this small cohort) the presence vs absence (1 vs 0) of mesangial proliferation (M), endocapillary proliferation (E), segmental sclerosis (S), tubular atrophy/interstitial fibrosis (T) and crescents (C). Severe outcome was defined by a combination of an eGFR slope > 2.5 ml/min/1.73 m2 per year or end stage kidney disease. For statistical analysis, Mann-Whitney U test was performed for comparison between independent groups, Chi squared test and Fisher's test for categorical variables and Spearman's ranks test for correlation analysis. Median values are presented without IQR for this abstract. Results Urine samples were available in 59 patients (IgAN n = 39, IgAVN n = 20). Patients with detectable u-MBL (28.9%) and u-C5b-9 (27.1%) had higher levels of proteinuria than those with undetectable levels (1.5 g/d vs 0.71g/d; p = 0.009 and 2.3 g/d vs 0.7 g/d respectively; p < 0.001). Lower eGFR (71 ml/min/1.73 m2 vs 88 ml/min/1.73 m2; p = 0.034) were observed if u-C5b-9 was measurable. Detectable levels of u-PTX-3 and u-MBL were more often found in the presence of M1 vs M0 (53% vs 20%; p = 0.022 and 47% vs 12.5%; p = 0.011), E1 vs E0 (55% vs 14%; p = 0.001 and 40% vs 11%; p = 0.020) and C1 vs C0 (56% vs 11%; p = 0.003 and 44% vs 11%; p = 0.012). No differences in proteinuria or eGFR were seen in patients with or without detectable u-PTX-3. The degree of proteinuria was positively correlated to the levels of u-C3bc (r = 0.33; p = 0.011) and u-C4c (r = 0.39; p < 0.001). U-C4c levels were higher in patients with M1 vs M0 (54.4 Au/mL vs 23.8 Au/mL; p = 0.037) and T1 vs T0 (53.2 Au/mL vs 23.8 Au/mL; p = 0.034). Concerning the analyses in plasma (n = 95), lower p-MASP3 and p-CL11 levels were correlated with lower eGFR (r = 0.29; p = 0.004 and r = 0.31, p = 0.002). Moreover, lower p-MASP3 levels were detected in patients with E1 vs E0 (2918 ng/mL vs 3404 ng/mL; p = 0.002) and C1 vs C0 (3053 ng/mL vs 3427 ng/mL; p = 0.015). Both p-C5b-9 (13.3 Au/mL vs 8.2 Au/mL; p = 0.001) and p-FCN 1 (395 ng/mL vs 289 ng/mL; p = 0.001) were higher in patients with C1 vs C0. No single complement-related protein was associated with severe outcome, and no statistically significant differences in plasma or urine levels between patients with IgAN and IgAVN were observed. Conclusion Increased urinary levels of MBL and PTX-3 could be potential biomarkers of disease activity in both IgAN and IgAVN, whereas excretion of C5b-9 might be more unspecific and associated with chronic damage. However, these results need to be confirmed in larger and more ethnically diverse cohorts. The impact of treatment on these potential biomarkers for disease activity need to be evaluated in longitudinal studies.

#2682 Evaluation of clinical, pathological findings and treatment outcomes of patients diagnosed with lupus nephritis: a single center experience

Abstract Background and Aim Renal involvement of systemic lupus erythematosus (SLE) is known as lupus nephritis (LN). The prognosis of lupus patients with LN is worse than those without kidney involvement. Renal survival can be improved in patients with lupus nephritis with appropriate and timely treatment. The aim of our study is to compare the clinical and pathological findings of patients diagnosed with LN in our clinic by renal biopsy, the results of the treatment applied in our center, and renal survival with the literature. Method The local ethical committee approved the study design (date: 04/10/2021; reference number: 121/07) and all procedures were conducted in accordance with the Declaration of Helsinki. Forty-four patients diagnosed with lupus nephritis between January 2012 and January 2021 in the Nephrology Department of Ankara Dıskapı Yıldırım Beyazıt Education and Research Hospital were enrolled in this study. Patient data were analyzed retrospectively. Exclusion criteria were as follows: 1) Patients under 18 years of age, 2) patients with follow-up of period less than 6 months and who did not attend regular follow-ups, 3) patients with connective tissue diseases other than SLE. Results The mean age of the study population was 36.0 ± 10.8, and the majority were female. All patients had proteinuria at diagnosis. Class IV LN was the most common (36.4%). Majority of the patients were in the proliferative LN group (65.9%). A significant difference was found between patients diagnosed with proliferative LN (n = 29) and non-proliferative LN (n = 15) in terms of high serum creatinine levels, low serum complement, presence of anti-dsDNA antibodies and active urinary sediment with proliferative LN (p = 0.021, p = 0.024, p = 0.008, p = 0.008). Treatment responses at 6 and 12 months are shown in Table 1. A significant difference was found between the patients who were in complete remission (n = 16) at 12 months and those who were not in remission (n = 27) in terms of low systolic blood pressure and the estimated glomerular filtration rate (eGFR) at the time of diagnosis (p = 0.008, p = 0.016). It was observed that most of the patients who were not in complete remission at 12 months were in the proliferative LN group (p = 0.024). There was no significant difference in the partial and complete remission rates at 6 and 12 months between the group receiving steroids + cyclophosphamide (n = 14) and the group receiving steroid + mycophenolate mofetil (MMF) (n = 15) in the initial treatment of proliferative LN (p>0.05). In the group taking MMF treatment (n = 15) had a shorter time to reach complete remission than the group taking cyclophosphamide treatment, and it was statistically significant (Table 2) (p = 0.048). It was found that end-stage renal disease (ESRD) developed in 9% of the patients and 2 patients died during followed up period. Recurrence was detected in 8 patients, and it was observed that more than half of the patients with relapse could not achieve complete remission at 12 months. Patients with relapse had higher systolic blood pressure and serum total cholesterol level at the time of diagnosis compared to patients without recurrence (p = 0.013, p = 0.045). In addition, patients with relapse were found to have a higher level of proteinuria at the time of diagnosis (p = 0.036). Conclusion Lupus nephritis remains an important source of morbidity and mortality for SLE patients. SLE patients should be regularly examined for renal involvement. About 10-20% of patients diagnosed with lupus nephritis develop ESRD. Early diagnosis of LN and initiating appropriate treatment when diagnosed without delay is important for renal and patient survival. Although there were some different results, most of the statistically significant data in our study were found to be compatible with the existing literature. However, these data need to be confirmed by studies with high patient participation.

#1464 Alterations of podocytes in focal segmental glomerulosclerosis: a pilot study

Abstract Background and Aims The molecular features of idiopathic podocytopathies remain unexplored, preventing the development of effective therapies to control the mechanisms of disease initiation and progression. This includes idiopathic focal segmental glomerulosclerosis (FSGS), one of the most common forms of immune glomerulopathies (IG) and the cause of renal failure and replacement therapy. In FSGS, podocytes undergo pronounced cytoskeletal alterations. Along with a decrease in Wilms tumor protein (WT1) and α-SMA expression, there is evidence for increased expression of intermediate filament proteins (vimentin, desmin, nestin) and Wnt/β-catenin signaling upregulation in IG. Decrease in WT1 is associated with upregulation in Wnt/β-catenin and p53 to promote podocyte dysfunction and albuminuria. Upregulation desmin increases the mechanical stability of cells, allowing podocytes to undergo morphological changes on the tensile glomerular capillary wall. This pilot study was aimed to evaluate the significance of WT1, β-catenin, and desmin glomerular expression in early primary FSGS. Method We reviewed the histopathological and clinical data of patients with biopsy proven FSGS (N = 14, experimental group), IgA nephropathy (N = 12, positive control), without AKI, infectious diseases, heart failure, respiratory insufficiency and cancer pathology. Renal surgery specimens from patients without IG (N = 12) were studied as negative control. Glomerulosclerosis was assessed as percentage of all glomeruli. Mesangial lesions were measured semi-quantitatively in scores (0-3). Glomerular WT1, β-catenin, and desmin expression was assessed by IHC-P with quantitative morphometry of IHC-staining area (open software QuPath, Orbit Image Analysis). Molecule's co-expression was analyzed by IF-p and confocal microscopy (Zeiss LSM 710; study conducted in the Center for Collective Use “Confocal microscopy” by Pavlov Institute of Physiology Russian Academy of Sciences). Results We examined young and middle-aged patients with CKD stages 1-3 and moderate morphological changes in the glomeruli. Gender, age, eGFR and the percentage of glomeruli with segmental sclerosis were not significantly different between IG groups (all p for interaction >0.05). Patients with FSGS have lower levels of serum albumin (p < 0.001) and higher levels of proteinuria (p < 0.001) as compared to IgAN. Glomeruli from IgAN patients showed more mesangial cell proliferation (p = 0.001), expansion of the mesangial matrix (p = 0.05) and global glomerular sclerosis (p = 0.003) as compared to FSGS. An immunomorphological study showed lower WT1 expression in both IG groups compared to the negative control. In the IgAN, lower WT1 expression was associated with higher BC area (Fig. 1A, D). BC expression did not differ between FSGS and negative control (Fig. 1B,D). In the combined IG group, BC directly correlated with global (r = 0.63, p = 0.001) and segmental (r = 0.63, p = 0.001) glomerular sclerosis. In FSGS, a trend towards to increase in the area of desmin IHC-staining was detected, however, no significant differences between groups were found (Fig. 1C,D). BC and desmin were co-localized with the podocyte marker WT1 (Fig. 2). BC and desmin were also expressed in WT1-negative glomerular cells (Fig. 2). Differential molecular expression patterns in glomeruli have been identified. In IgAN, co-expressing WT1 and BC (orange) was dominate in glomerular cells (Fig. 2A); the proportion of IHC expression of WT1 and BC in glomerular cells was directly correlated (r = 0.63, p = 0.031). In FSGS, WT1+ cells predominantly co-expressed desmin (magenta) but not BC; some glomerular cells were only desmin-positive (Fig. 2B). BC was expressed to a lesser extent compared to IgAN, and in some cells it was co-expressed with desmin (Fig. 2B). Conclusion In FSGS, an increase in desmin expression could be an early feature of pathogenesis before significant decrease in the number of WT1+ podocytes and changes in β-catenin expression. Activation of desmin likely characterizes damage and decrease in the number of functioning podocytes.

#3029 Vitamin D-binding protein: a candidate biomarker for CKD progression

Abstract Background and Aims The toxic effects of filtered proteins on the tubules cause a more rapid progression of disease in individuals with higher levels of proteinuria, suggesting the presence of “high-risk candidate” proteins that could contribute to CKD progression. In our previous cross-sectional proteomic study, vitamin D-binding protein (VTDB) showed a significant association with kidney function. However, its persistent expression as a urinary protein in CKD patients remains unknown. Therefore, our aim was to investigate the persistent expression of VTDB in CKD patients and healthy controls during the follow-up period. Method The urinary proteomics was investigated using liquid chromatography-mass spectrometry in 18 follow-up CKD patients with stages 1-3 and 15 follow-up healthy individuals. Data analysis was performed by Mascot-SwissProt and STATA software. Parametric and nonparametric statistics were used to analyze results and the relationship between baseline characteristics and proteomic profile. Exponentially Modified Protein Abundance Index (emPAI) was used to estimate peptide count of proteins. Results The participant's baseline characteristics are presented in Table 1. The median (IQR) follow-up time for all participants was 368 (250-472) days. A statistically significant difference was found in the initial emPAI of VTDB between the HC and CKD groups. However, there was no statistically significant difference in the follow-up emPAI of VTDB between the two groups. Notably, emPAI values of VTDP decreased over the follow-up period compared to the initial values. Correlation analysis (Table 2) showed that the elevated levels of urinary VTDB emPAI are associated with decreased levels of initial and follow-up eGFR. A higher negative percentage change (a decline in eGFR over time) was also associated with elevated levels of VTDB protein over the follow-up period. Also, urinary VTDP protein has demonstrated a significant positive correlation with 24 h proteinuria. Conclusion In this proteomics study cohort, we observed persistent expression of urinary VTDB protein during the follow-up period in CKD patients compared to healthy controls. Additionally, a statistically significant negative correlation between VTDB protein and eGFR was observed. These findings need further validation using different measurement tools for urinary VTDB assessments and in a larger cohort of CKD patients. Declaration We have no conflict of interest to disclose.

#1644 Prognostic significance of hematuria on kidney survival in podocytopathies

Abstract Background and Aims Hematuria is common in podocytopathies, but its prognostic impact on kidney survival in these proteinuric diseases is not well-established. Our study examines the prevalence of hematuria at podocytopathy diagnosis and its association with renal survival. Method In our retrospective study, we analyzed 236 patients (median age 50 years, 60% male, median eGFR 65.5 mL/min/1.73 m2, median proteinuria 3.9g/g) with biopsy proven podocytopathies—48% membranous nephropathy (MN), 32% minimal change disease (MCD), 20% focal and segmental glomerulosclerosis (FSGS)—diagnosed at a tertiary center from 2010 to 2015. Hematuria was defined as the presence of 5 or more red blood cells (RBCs) per high-power field in 3 of 3 consecutive centrifuged urine specimens obtained at least 1 week apart. The follow-up period extended until the onset of end-stage kidney disease (ESKD: start of kidney replacement therapy or renal transplantation), death, or January 2022, with a median duration of 8.5 (95% CI: 8.1, 8.8) years. Results In our patient cohort, 31% (n = 73) presented with hematuria, having a median of 120 (IQR: 40-220) red blood cells (RBCs). Those with hematuria more frequently exhibited arterial hypertension (55% vs 36%, p 0.007) and had higher levels of proteinuria (5.3 vs 3.2g/g, p 0.01). However, no significant differences were noted in terms of age (53 vs 48 years, p 0.08), Charlson comorbidity score (2 vs 2, p 0.9), type of podocytopathy (MN 52 vs 47%, MCD 27 vs 34%, FSGS 21 vs 19%, p 0.5), eGFR (62.1 vs 68.8 mL/min, p 0.08), serum albumin levels (3.3 vs 3.4g/dL, p 0.6), total renal chronicity score on histology (0 vs 0, p 0.6), and treatment with ACE inhibitors/angiotensin receptor blockers (43% vs 50%, p 0.4) or immunosuppression (81% vs 74%, p 0.4). Thirty-two percent of the patients with hematuria reached ESKD versus 9% in the group without hematuria (p 0.001); there were no differences regarding mortality between the two groups. Mean kidney survival time for the entire cohort was 10.3 (95% CI: 9.9, 10.8) years; renal survival at 1, 3, 5 and 10 years were 97%, 92%, 88% and 82%, respectively. Patients with hematuria at diagnosis had a significant shorter kidney survival time (9.0 (95% CI: 8.0, 10.0) vs 11.0 (95% CI: 10.6, 11.4) years, p 0.001). In a multivariate Cox proportional hazard model (backward Wald), presence of hematuria at diagnosis (HR 3.64, 95% CI: 1.87, 7.07), lower eGFR (HR 0.96, 95% CI: 0.94, 0.97) and higher total renal chronicity score on histology (HR 1.10, 95% CI: 1.00, 1.22) were independent predictors of reduced kidney survival. Conclusion Hematuria is prevalent in the three podocytopathies and independently correlates with poorer kidney survival outcomes. This underscores the possible need for personalized treatment strategies in patients with podocytopathies presenting with hematuria.

#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 < 0.001), sKIM-1 (rho = 0.472, p < 0.001), sUMOD (rho = −0.370, p < 0.001), uUMOD (rho = −0.317, p < 0.001), MCP-1 (rho = 0.374, p < 0.001), uKIM-1 (rho = 0.368, p < 0.001), and β2-mcg (rho = 0.392, p < 0.001). Multivariate regression analysis identified uDKK3 as an independent predictor of interstitial fibrosis (Beta 0.728, p < 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 >10% in the logistic regression analysis adjusted for eGFR, proteinuria, and microhematuria: MCP-1 OR = 5.14, 95% CI (2.27−11.62), p < 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.

#1339 The characteristic of memory B-cell subsets in patients with IgA-nephropathy

Abstract Background and Aims Impaired B-cell development has been postulated to play an important role in the maintaining of autoimmune inflammation what makes memory B-cells a perspective target for a new therapeutic strategy in IgA-nephropathy (IgAN). However, to date there are few and controversial data about the precise role of circulating memory B-cell subsets in clinical progression of IgAN. The aim was to estimate the immunological profile of memory B-cell subpopulations in the peripheral blood of IgAN patients. Method The peripheral blood was obtained from 20 IgAN patients (aged of 32.0 (27.0-36.0) y.o., male/female ratio as 13/7) and 15 donors (aged of 38.0 (30.0-46.0) y.o., male/female ratio as 10/5). The diagnosis was confirmed by morphological examination of the biopsy material. The phenotype of B-cells subsets was determined by a panel of CD38-PE/CD19-ECD/CD27-PC5/IgD-APC antibodies; γδT-lymphocytes—by a panel of TCRγδ-FITC/TCRαβ-PE/HLA-DR-ECD/TCRVδ1-PC7/CD3-APC-A750/TCRVδ2-PB/ CD45-KRO antibodies using flow cytometry method (Cytoflex, Beckman Coulter, USA). The concentration of B-cell activating factor (BAFF) was measured using enzyme-linked immunosorbent assay. Statistical data processing was done in Statistica 10.0 program. Results Based on cell surface markers expression the following B-cells subsets were identified in the peripheral blood: naïve B-cells (CD19+CD27−IgD+), pre-switched B-cells (CD19+CD27+IgD+), switched B-cells (CD19+CD27+IgD−), plasmablasts (CD19+CD27+CD38+) and long-lived plasma cells (CD27hiCD38hi) (Fig. 1). The altered balance in B-cells maturation characterizing by a significant lower percent of pre-switched B-cells and plasmablasts (p < 0.05) as well as a higher trend (>55%) in the naive B-cells (p < 0.01) was established in IgAN patients as compared to healthy donors reflecting the exhaustion of peripheral blood plasmablasts due to constant generation of antibody-producing plasma cells. Moreover, the lower pre-switched B-cells percentage was detected in the blood, the more BAFF production was observed in serum of IgAN patients (R = 0.50; p < 0.05) and the higher proteinuria level was detected (R = 0.47; p < 0.05). The increased total number of γδТ-cells up to 9.42 (6.25-12.44)% in IgAN patients as compared to donors (p = 0.03) was correlated with total memory CD19+CD27+B-cells numbers (R = 0.54; p < 0.05) as well as pre-switched B-cells (R = 0.45; p < 0.05), plasmablasts (R = 0.57; p < 0.01) and long-lived plasma cells (R = 0.51; p < 0.05). A detailed subsets analysis revealed an elevated level of tissue-resident mucosa-associated cells (Vδ1+ and Vδ3+T-lymphocytes) as well as enhanced HLA-DR expression on them (p < 0.05) in combination with decreased normally circulating Vδ2+T-cells numbers (p < 0.01) as compared to healthy donors what characterized Vδ1+ and Vδ3+T-cells subsets as professional antigen presenting cells and indicated their possible role in the priming of antigen specific B-cells. Conclusion Suggesting that most peripheral B-lymphocytes are naïve, the obtained data may reflect a γδT-cells role in migration of pre-switched B-cells from the circulation to mucosa sites for possible further maturation and class-switching what allows us to consider these two parameters as potential useful biomarkers of IgAN disease prognosis in clinical practice.

Blood plasma and urinary biomarkers of oxidative stress in cats with urethral obstruction

BackgroundThis study aimed to investigate variations of the oxidative status in cats affected by urethral obstruction (UO) under Feline Idiopathic Cystitis (FIC) and Bacterial Cystitis (BC), in comparison with a group of healthy subjects. In both groups, the levels of several markers (either direct or indirect) indicative of the oxidative attack and of the antioxidant response were analyzed on plasma and urine samples. In particular, the plasma samples were evaluated for nitric oxide (NO), hydroperoxides derived by reactive oxygen activity (d-ROMs test), superoxide anion (O2−), glutathione peroxidase activity (GPx), superoxide dismutase activity (SOD), and ferric reducing antioxidant power (FRAP test); while on urine the levels of NO, d-ROMs, FRAP, SOD, malondialdehyde (MDA) and 8-hydroxydeoxyguanosine (8-OHdG) were measured. Urine of UO patients was also subjected to urine-culture test.ResultsThe analytical data on plasma showed that UO, independently of the FIC or BC etiology, induced the insurgence of oxidative stress conditions at the systemic level. In the urine of the UO patients, except for SOD that increased, the markers of redox status were markedly decreased due probably their compromised filtration, thus suggesting involvement of renal function (assessed also by the high levels of plasma creatinine and proteinuria) with no oxidative damage of the lower urinary tract. Moreover, the adoption of a novel oxidative stress index’ (OSI) allowed to establish, by means of a numerical value, the different degrees of oxidative stress conditions for single UO patients, both in terms of oxidative attack and antioxidant response.ConclusionsFeline urethral obstruction, induced by Idiopathic Cystitis and Bacterial Cystitis, causes oxidative stress conditions at the systemic level that do not interest the lower urinary tract. Despite to the high variability of the profiles of oxidative stress indexes both in healthy and UO patients, the determination of OSI made possible the evaluation of their single degrees of oxidative stress. Possibly the results of this investigation can be compared with those of correspondent pathologies both in humans and in other animal species.

Analysis of High Levels of Urine Proteins as a Sign of Impaired Kidney Function in Communities Around a Nickel Mining Industry in Morosi District, Southeast Sulawesi

The study is proposed to analyse the influence of individual and environmental factors on protein urine levels as a parameter for impaired kidney function in the community around Nickel mining industry in Morosi Sub-District, Southeast Sulawesi Indonesia. This quantitative study used a cross sectional study design. The population was people in 3 villages around the nickel mining industry aged 20-59 years. The sample size was 61 people using simple random sampling technique. Independent variable was age as representation of individual factor and environmental factors including house condition, water quality, waste management and household liquid waste. Protein urine as a parameter for impaired kidney function as the dependent variable. Data was collected by questionnaire and taking urine samples. Data were analysed using the multinomial logistic regression test with a significance level of 95%. The results show that the determinant of proteinuria levels in communities around the Morosi nickel mining industry was age (p=0.038<0.05), the water source quality (p=0.002<0.05). Solid waste management (p=0.05) and waste water management (p-value=0.045< 0.05). Meanwhile, the house condition had no effect on high proteinuria levels (p value> 0.05). In conclusion, impaired kidney function in communities around the Morosi nickel mining industry due to age, poor quality of water sources and poor management of solid waste and household liquid waste.

Donor Proteinuria and Allograft Function in Kidney Transplantation: Short- and Long-Term Results From a Retrospective Cohort Study.

Donor proteinuria (DP) is a common but rarely evaluated aspect of today's kidney transplant allocation process. While proteinuria after kidney transplantation is a risk factor for impaired graft function and survival, the long-term effects of DP in kidney transplantation have not yet been evaluated. Therefore, this study aims to investigate the impact of DP on the long-term outcome after kidney transplantation. A total of 587 patients were found to be eligible and were stratified into two groups: (1) those receiving a graft from a donor without proteinuria (DP-) and (2) those receiving a graft from a donor with proteinuria (DP+). At 36months, there was no difference in the primary composite endpoint including graft loss and patient survival (log-rank test, p = 0.377). However, the analysis of DP+ subgroups showed a significant decrease in overall patient survival in the group with high DP (p = 0.017). DP did not adversely affect patient or graft survival over 36months. Nevertheless, this work revealed a trend towards decreased overall survival of patients with severe proteinuria in the subgroup analysis. Therefore, the underlying results suggest caution in allocating kidneys from donors with high levels of proteinuria.

Patients with primary focal segmental glomerulosclerosis with detectable urinary CD80 are more similar to patients with minimal change disease in clinicopathological features

Background Focal segmental glomerulosclerosis (FSGS) is an important cause of refractory nephrotic syndrome (NS) in children and adults. Urinary CD80 is elevated in some patients with primary FSGS, however, its clinical value is not fully clarified. This study aims to evaluate the clinical and pathological significance of urinary CD80 in patients with primary FSGS. Methods Sixty-one adult patients with biopsy-proven primary FSGS, with standard treatment and long-term follow up, were enrolled retrospectively. Urinary CD80, on the day of kidney biopsy, was measured using commercial ELISA kits and adjusted by urinary creatinine excretion. Their associations with clinical and pathological parameters were investigated. Results Urinary CD80 was detectable in 30/61 (49.2%) patients, who presented with a higher level of proteinuria (10.7 vs. 5.8 g/24h; p = 0.01), a lower level of serum albumin (19.3 ± 3.9 vs. 24.2 ± 8.2 g/L; p = 0.005), a higher prevalence of hematuria (70.0 vs. 38.7%; p = 0.01), and showed a lower percentage of segmental glomerulosclerosis lesion [4.8 (3.7–14.0) vs. 9.1 (5.6–21.1) %; p = 0.06]. The cumulative relapse rate was remarkably high in these patients (log-rank, p = 0.001). Multivariate analysis identified that the elevated urinary CD80 was an independent risk factor for steroid-dependent NS (OR 8.81, 95% CI 1.41–54.89; p = 0.02) and relapse (HR, 2.87; 95% CI 1.29–6.38; p = 0.01). Conclusions The elevated urinary CD80 is associated with mild pathological change and steroid-dependent cases of primary FSGS adults, which indicates these patients are more similar to minimal change disease (MCD) in clinicopathological features.

Incidence of and Risk Factors for Active Tuberculosis Disease in Individuals With Glomerular Disease: A Canadian Cohort Study

Kidney failure is an established risk factor for active tuberculosis (TB) but the risk of TB has not been reported in specific kidney diseases. We sought to determine the incidence of and risk factors for active TB in patients with glomerular disease. Observational cohort study. A provincial kidney pathology registry (2000-2012) was used to identify 3,079 adult patients with IgA nephropathy, focal segmental glomerulosclerosis (FSGS), antineutrophil cytoplasmic antibody (ANCA)-related glomerulonephritis, lupus nephritis, membranous nephropathy, minimal change disease, or "other" glomerular diseases in British Columbia, Canada. Predictors included demographics, immigration status, comorbidities, immunosuppression use, estimated glomerular filtration rate (eGFR), and proteinuria. A diagnosis of active TB was ascertained using administrative data linkages and defined based on (1) the dispensation of 1 or more unique combinations of medications used to treat active TB, or (2) physician or hospital visits for active TB. The definition of TB was validated in an external cohort linked to the Provincial TB registry at the BC Centre for Disease Control (BCCDC). Standardized incidence ratios were calculated using the age-matched general population. Risk factors for active TB were identified using Cox proportional hazards regression analysis. The sensitivity and specificity of the outcome definition of active TB were 87.6% and 99.5%, respectively. During a median follow-up of 6.2 years, 41 patients developed active TB with an incidence of 197 of 100,000 person-years, approximately 23 times as high as the general population and>6 times higher than the threshold of 30 per 100,000 used to define high TB incidence. A high incidence was observed in all glomerular diseases (range, 110-403 per 100,000), in both Canadian- and foreign-born patients (range, 124-424 per 100,000), and in patients exposed or not to immunosuppression (282 vs 147 per 100,000). Factors associated with higher TB risk included immigration from a high-incidence country (HR, 3.90 [95% CI, 1.75-8.68]), diminished eGFR (HR, 2.81 [95% CI, 1.18-6.69]), higher levels of proteinuria (HR, 1.15 [95% CI, 1.04-1.27]), lupus nephritis (HR, 2.79 [95% CI, 1.37-5.68]), and immunosuppression use (HR, 2.13 [95% CI, 1.13-4.03]). A relatively low number of events contributed to uncertainty in risk estimates. Patients with glomerular disease have a high incidence of active TB irrespective of disease type, demographics, or use of immunosuppression. Prospective studies are needed to evaluate the utility of screening for latent TB infection in this population. Patients with kidney failure are at high risk of developing tuberculosis (TB), a major infection that can be prevented by identifying and treating patients who have had prior exposure to TB. The risk of TB in specific kidney diseases is unknown. In this Canadian study of 3,079 patients with glomerular disease, a group of autoimmune kidney conditions, the rate of TB was 23 times higher than in the general population. The rate was high irrespective of the use of immunosuppressive drugs or whether patients had immigrated to Canada from another country. These findings suggest that screening patients with glomerular disease for prior TB exposure may be beneficial; however, this needs to be evaluated in a prospective study.

Correlation of pathologic findings of IgA nephropathy with clinical and laboratory data with regards to the Oxford-MEST-C classification

The Oxford classification system has been found to have significant correlations with clinical and laboratory data in patients with IgA nephropathy. Studies have shown that higher grades of mesangial hypercellularity and endocapillary hypercellularity are associated with younger age, higher blood pressure, and higher levels of proteinuria. Segmental glomerulosclerosis has been found to be associated with more severe proteinuria, lower serum albumin levels, and higher levels of creatinine. Tubular atrophy/interstitial fibrosis has been associated with older age, higher serum creatinine levels, and lower estimated glomerular filtration rates.

Comparison of Urinary Protein/Creatinine Ratio as an Alternative to 24-h Proteinuria in Lupus Nephritis: TUNARI Study

Background: Lupus nephritis (LN) occurs in approximately 50% of people with systemic lupus erythematosus (SLE). The 24-h proteinuria (gold standard) is measured among other tests for the control and monitoring of LN activity. This study investigates the use of the protein/creatinine ratio (PCR) as an alternative for the detection of proteinuria and its accuracy compared to the gold standard in a predominantly non-white population. Methods: This was a prospective study conducted in Salvador, Brazil, between December 2021 and May 2022. We invited adult patients diagnosed with SLE and LN, regardless of their disease activity. The estimation of the PCR and 24-h proteinuria was performed using conventional methods. The analysis used was Spearman’s r correlation coefficient (r_s), coefficient of determination (r²), and concordance by the Bland-Altman method. A specific sensitivity was measured by the ROC curve with its respective cut-off by the Youden Index. Results: We compared 112 samples of 75 patients with LN, with a mean age of 34.5 ± 11.8 years. Of these patients, 85% were women, 87.9% were non-white. A high degree of correlation was observed between PCR with 24-h proteinuria (r_s = 0.77 and r² = 0.59). The ROC analysis shows an area under the curve of 0.92 and the cut-off point calculated by the Youden Index was 0.78 with a sensitivity of 90.0% and specificity of 82%. However, the Bland-Altman graph indicated decreasing concordance as the degree of proteinuria increased, despite showing concordance at high levels of proteinuria. Conclusion: The PCR shows high sensitivity to follow-up patients with LN when compared with 24-h proteinuria. Our findings suggest that PCR is a useful parameter for the evaluating and monitoring patients in complete remission. However, in cases of partial remission, the utility of PCR is limited.

#3032 EFFICACY AND SAFETY OF VOCLOSPORIN IN PATIENTS WITH PROTEINURIA ≥2 MG/MG: AN INTEGRATED ANALYSIS OF THE AURA-LV AND AURORA 1 STUDIES

Abstract Background and Aims Proteinuria has been established as a mediator of progressive renal damage in many nephropathies. However, recent studies of several monoclonal antibodies demonstrated a lack of efficacy in patients with lupus nephritis and moderate to high levels of proteinuria (UPCR ≥2 to ≥3 mg/mg), potentially due to an increase in renal antibody clearance.1-4 Given that, we examined the efficacy and safety of voclosporin in patients with lupus nephritis and a UPCR of ≥2 mg/mg using the pooled dataset from the Phase 2 AURA-LV and Phase 3 AURORA 1 trials. Method Both studies enrolled patients with biopsy-proven LN (Class III, IV, or V ± III/IV, biopsied within 6 months in AURA-LV or up to 2 years in AURORA 1) and proteinuria ≥1.5 mg/mg (≥2 mg/mg for Class V). Patients were randomized to receive either voclosporin (23.7 mg BID) or placebo and treated for up to one year (48 weeks [AURA-LV], 52 weeks [AURORA 1]); all patients received MMF and low-dose steroids. For this post-hoc analysis, changes in UPCR and renal response rates were evaluated in patients with baseline UPCR ≥2 mg/mg. Complete renal response (CRR) was defined as UPCR ≤0.5 mg/mg with stable renal function, low-dose steroids, and no rescue medication; partial renal response (PRR) was defined as a ≥50% reduction in UPCR from baseline. Safety outcomes were also assessed. Results The pooled analysis included 268 and 266 patients in the voclosporin and control arms, respectively. Of those, 217 and 215 patients had UPCR ≥2 mg/mg (baseline mean [SD], 5.2 [3.4] vs. 4.6 [2.9] mg/mg, respectively). A significantly greater percentage of voclosporin-treated patients achieved a CRR at one year compared to the control arm (41.0% vs. 21.9%; odds ratio [OR] 2.48, p<0.0001, Figure 1A). Similarly, significantly more patients in the voclosporin arm (69.6%) than control arm (50.0%) achieved a PRR at the same time point (OR 2.3, p<0.0001); this endpoint was met significantly earlier in voclosporin-treated patients as well (29 vs. 57 days, hazard ratio [HR] 2.0, p<0.0001). The median time to UPCR ≤0.5 mg/mg was also significantly earlier in the voclosporin arm (211 days); less than 50% of the control arm achieved this endpoint within the study period (OR 1.9, p<0.0001, Figure 1B). Adverse event rates were comparable in both arms (Table 1), and mean eGFR levels were similar and stable over the study period, a trend that was maintained for AURORA 1 patients who continued randomized treatment for another two years in the AURORA 2 study. Conclusion Consistent with results from the overall pooled study population, patients with UPCR ≥2 mg/mg at baseline treated with voclosporin achieved significantly higher renal response rates and significantly earlier reductions in UPCR than patients treated with MMF and low-dose steroids alone. These findings are clinically important given the lack of effective therapies available for patients with high baseline proteinuria.

Renal Dysfunction Phenotypes in Patients Undergoing Obesity Surgery.

Obesity surgery candidates are at an increased risk of kidney injury, but pre-operative evaluation usually neglects kidney function assessment. This study aimed to identify renal dysfunction in candidates for bariatric surgery. To reduce the sources of bias, subjects with diabetes, prediabetes under metformin treatment, neoplastic or inflammatory diseases were excluded. Patients' (n = 192) average body mass index was 41.7 ± 5.4 kg/m2. Among these, 51% (n = 94) had creatinine clearance over 140 mL/min, 22.4% (n = 43) had proteinuria over 150 mg/day and 14.6% (n = 28) albuminuria over 30 mg/day. A creatinine clearance higher than 140 mL/min was associated with higher levels of proteinuria and albuminuria. Univariate analysis identified sex, glycated hemoglobin, uric acid, HDL and VLDL cholesterol as being associated with albuminuria, but not with proteinuria. On multivariate analysis, glycated hemoglobin and creatinine clearance as continuous variables were significantly associated with albuminuria. In summary, in our patient population prediabetes, lipid abnormalities and hyperuricemia were associated with albuminuria, but not with proteinuria, suggesting different disease mechanisms might be implicated. Data suggest that in obesity-associated kidney disease, tubulointerstitial injury precedes glomerulopathy. A significant proportion of obesity surgery candidates present clinically relevant albuminuria and proteinuria along with renal hyperfiltration, suggesting that routine pre-operative assessment of these parameters should be considered.

Evaluating Efficacy and Safety of Tacrolimus Treatment in Membranous Nephropathy: Results of a Retrospective Study of 182 Patients.

Tacrolimus is recommended by KDIGO Clinical Practice Guidelines as an initial therapy for the treatment of membranous nephropathy (MN). However, little is known about the factors that influence response and recurrence of the disease after tacrolimus therapy, and there are limited data regarding the duration of tacrolimus treatment. Here, we present a real-world retrospective cohort study of 182 MN patients treated with tacrolimus, aiming to assess the efficacy and safety of tacrolimus in the treatment of MN. The clinical data of 182 patients with MN treated with tacrolimus and followed up for at least one year were analyzed retrospectively for the efficacy and safety of tacrolimus. The mean follow-up period was 27.3 (19.3-41.6) months. A total of 154 patients (84.6%) achieved complete or partial remission, and 28 patients (15.4%) did not. Multivariate Cox regression analysis showed that male and higher baseline BMI were independently associated with lower, while higher serum albumin was associated with higher probability of remission. Among the responders, 56 patients (36.4%) relapsed. After adjustments for age and sex, Cox regression analysis revealed that the longer period of full-dose tacrolimus was administered, the lower the incidence of relapse. However, high levels of serum creatinine and proteinuria at the onset of tacrolimus discontinuation were risk factors for relapse. During the treatment of tacrolimus, a decline in renal function (≥50% increase in serum creatinine after the onset of tacrolimus treatment) was the most common adverse reaction, observed in 20 (11.0%) patients, followed by elevated blood glucose and infection, but the latter two occurred mostly during treatment with tacrolimus plus corticosteroids. Tacrolimus is effective in the treatment of MN, but the relapse rate is high. Clinical studies with larger sample sizes are needed to further explore the use of tacrolimus in the treatment of membranous nephropathy.