24-hour Proteinuria Research Articles

#2291 ANCA negative vasculitis—the unmet need within small vessel vasculitis

Abstract Background and Aims ANCA negative small vessel vasculitis with renal involvement has been described in a number of cohorts. Though comprehensive studies comparing these individuals to ANCA positive patients are lacking and they are routinely excluded from clinical trials. Whilst the numbers are smaller than those with ANCA positivity, they still make up a large proportion of small vessel vasculitidies (Fig. 1). The absence of detectable circulating ANCA is thought to indicate a distinct spectrum of the disease. There remains unanswered questions regarding the pathophysiology, diagnosis and management of patients with seronegative AAGN. We present data from Croatian referral center. Method Study included 106 AAV patients with biopsy proven renal involvement in the period from 2007-2017. Category variables were analysed with Fisher Exact test and continuous with Kruskal-Wallis test. Statistical difference was then analysed post hoc with Chi-square test. Kaplan Meyer survival analysis and multivariate Cox proportional hazard regression analysis were used to explore difference between clinical phenotypes and finding significant predictors regarding outcomes which were defined as combined outcome end-stage renal disease and death (ESRDD), ESRD alone, the death outcome alone and relapse rate. Results 106 AAV patients with renal involvement were included: 66 (61.1%) MPA, 20 (18.5%) GPA, 20 (18.5%) RLV. 14 (13%) were PR3-ANCA positive, 57 (52.8%) MPO ANCA positive, 5 (4.6%) PR3-ANCA+MPO-ANCA and 32 (29.6%) ANCA negative patients. ANCA negative patients were comparatively younger (p = 0.02) and presented with more renal limited vasculitis (RLV; p < 0.001), lower BVAS (p = 0.003) and lower CRP (p = 0.001). ANCA negative patients usually presented with nephrotic syndrome compared to positive ones which presented with rapid progressive nephritic syndrome or acute nephritic syndrome (p = 0.027). 24-hour proteinuria levels were higher in ANCA negative group (p = 0.003). Though statistical difference was not reached, there was tendency for ANCA negatives to receive less plasmapheresis (p = 0.074). Histologically there were no differences between ANCA positive and ANCA-negative patients. On sub analysis ANCA negatives versus individual seropositive groups, there was tendency that ANCA negatives and MPO-ANCA patients had lower percentage of glomerular crescents (p = 0.092) but more acute tubular damage (p = 0.087). There were no differences in clinical outcomes between the groups. Conclusion ANCA negative vasculitis form a large proportion of small vessel vasculitidies and present with different clinical laboratory and histological (renal) characteristics than ANCA positive ones. More often than not disease seems to be renal limited and patients tend to be younger. Due to the rarity of the disease, there remains unanswered questions regarding the pathophysiology, diagnosis and management of these patients. This study highlights noteworthy distinctions between the two groups. Whether these differences warrant adjustments in treatment algorithms or a reconsideration of the classification of small vessel vasculitis remains to be determined. Further investigation into the pathogenetic mechanisms of seronegative AAVs is essential.

Autoimmune myelofibrosis revealing a systemic lupus erythematosus

Background: Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease, characterised by multi-organ affections. Haematological involvement is a common manifestation of SLE, consisting of autoimmune peripheral cytopenia. Autoimmune myelofibrosis (AIMF) is a rare cause of cytopenia in SLE; it could precede or be concurrent with the diagnosis of SLE. There are few studies that describe this association. Case description: We report a case of AIMF revealing the diagnosis of SLE in a 34-year-old female, presented with episodes of gingival bleeding associated with peripheral inflammatory polyarthralgia, photosensitivity and deterioration of general condition. Clinical examination revealed a soft pitting oedema in the lower limbs. Laboratory investigations showed a pancytopenia, inflammatory biological syndrome, with positive 24-hour proteinuria and anti-native DNA antibodies. A bone marrow biopsy showed diffuse myelofibrosis associated with maturation disorders and no tumour infiltrate. Renal biopsy revealed proliferative glomerulonephritis class III with immune deposits. Conclusion: The association of AIMF with SLE has been rarely reported, and it could be another cause for cytopenia in SLE.

RENOPROTECTIVE EFFECTS OF DAPAGLIFLOZIN IN NON-DIABETIC CKD PATIENTS

Objective: Sodium-glucose co-transporter 2 inhibitors (SGLT2i) have demonstrated significant cardiorenal protection benefits in recent years, irrespective of the presence of diabetes mellitus (DM). These agents have emerged as pivotal in reducing albuminuria and impeding chronic kidney disease (CKD) progression. This study aimed to evaluate the renal effects of dapagliflozin, an SGLT2i, in in non-diabetic proteinuric patients with CKD. Design and method: In this retrospective observational study we analyzed medical records of adult non-diabetic patients with CKD, in our outpatient department over the period of one year. exhibiting albuminuria, and under stable renin-angiotensin system blockade. The primary objectives were to assess dapagliflozin's impact on estimated glomerular filtration rate (eGFR) within the first month and changes in 24-hour proteinuria from baseline. Results: Between November 2022 and December 2023, dapagliflozin was prescribed to 37 patients (8 women) with a mean age of 59.8±11.6 years. Primary diagnoses of CKD included IgA Nephropathy (7/37), other glomerulonephritis (9/37), hypertension (6/37), unknown (9/37), and other (6/37). Baseline median creatinine was 1.60±0.6 mg/dL, eGFR was 54.1±21.6 mL/min/1.73m2, and proteinuria was 1047 mg/24h (IQR 420-2170), serum potassium 4.77±0.41mEq/L blood pressure 130±15 / 82±9 mmHg, body weight 85.1±16.8 kg. After the first month, median creatinine was 1.75±0.7 mg/dL (p=0.02 vs baseline), eGFR was 50,7±21,3 mL/min/1.73m2 (p=0.006 vs baseline). Two patients experienced >30% serum creatinine increase within 4 weeks, leading to SGLT2i discontinuation. After a median follow-up of 233 days (IQR 80-284), creatinine was 1.71±0.75 mg/dL (p=0.067 vs baseline), eGFR was 51.6±23.6 mL/min/1.73m2 (p=0.019 vs baseline), and proteinuria decreased by 33,7% from baseline (450, IQR 270-1110). One patient stopped SGLT2i due to recurrent urinary tract infection. No change was observed in serum potassium, body weight and blood pressure throughout the study period. Conclusions: Treatment with dapagliflozin in non-diabetic patients with CKD reduced effectively proteinuria with an initial, reversible, decline in serum creatinine.

Clinicopathological correlation of patients with lupus nephritis: Data from a tertiary center in Saudi Arabia.

Systemic lupus erythematosus mainly affects young women, and approximately half of systemic lupus erythematosus patients develop lupus nephritis (LN). However, data on the types and remission rates of LN in Saudi Arabia are limited. Therefore, we aimed to highlight the LN remission rates in our population. A retrospective record review was conducted between January 2007 and December 2020 in a tertiary center in the western region of Saudi Arabia to determine the remission rates among patients with biopsy-proven LN who met the EULAR\ACR 2019 classification criteria. We identified 59 patients with biopsy-proven LN, mostly in young women. The common histopathological pattern was Class IV LN in 26 patients (44%). Three induction protocols were identified, along with systemic steroids: the high-dose cyclophosphamide protocol in 21 patients (35.6%), low-dose protocol in 4 patients (6.8%), and mycophenolate mofetil (MMF) in 41 patients (69.5%). Partial response, defined as the reduction of the 24-hour proteinuria by 25% at 3 months and 50% at 6 months, was achieved in 18 patients (33.3%) at 3 months and decreased to 13 patients (24.1%) at 6 months. Complete clinical response, defined as 24-hour urinary protein between 500 and 700 mg at 12 months, was achieved in 44 patients (81.5%). Complete remission was higher among patients with Class IV LN (64.4%). The achievement of partial clinical response at 3 months was significantly lower among patients with hypertension (P = .041). This study presented the LN remission rates in a single center in Saudi Arabia. Similar to previous studies, Class IV LN were the most common histopathological finding in this study. Complete remission at 12 months was achieved in 44 (81%) patients. Delayed remission is associated with hypertension at the time of LN diagnosis.

SGLT2i relieve proteinuria in diabetic nephropathy patients potentially by inhibiting renal oxidative stress rather than through AGEs pathway

AimsTo estimate the effects of the sodium-glucose cotransporter 2 inhibitor (SGLT2i) on proteinuria and oxidative stress expression in type 2 diabetes patients.Materials and methods68 patients with type 2 diabetes mellitus (T2DM) were divided into three groups according urinary albumin-to-creatinine ratio (UACR), including T2DM with non-albuminuria group (UACR < 30 mg/g), T2DM with microalbuminuria group (30 ≤ UACR ≤ 300 mg/g), T2DM with macroalbuminuria group (UACR>300 mg/g). They all received SGLT2 inhibitors (SGLT2i) treatment for 12 weeks. The expression of advanced glycation end products (AGEs) in plasma and 8-hydroxy-2-deoxyguanosine (8-OHdG) in urine were measured as indications of oxidative stress. The 24-hour urine samples were collected to measure the concentration of proteinuria and 8-OHdG before and after 12 weeks SGLT2i treatment. Plasma renin activity (PRA), angiotensin II (Ang II) and Aldosterone (ALD) were measured to evaluate renin angiotensin aldosterone system (RASS) levels.ResultsAfter 12 weeks SGLT2 inhibitors treatment, the median values of 24-hour proteinuria decreased in macroalbuminuria compared to baseline (970 vs. 821 mg/d, P = 0.006). The median values of AGEs and 8-OHdG decreased in microalbuminuria and macroalbuminuria groups when compared to baseline, AGEs (777 vs. 136 ug/ml, P = 0.003) and (755 vs. 210 ug/ml, P = 0.001), 8-OHdG (8.00 vs. 1.88 ng/ml, P = 0.001) and (11.18 vs. 1.90 ng/ml, P < 0.001), respectively. Partial correlations showed that 8-OHdG were relevant to the baseline 24-h proteinuria (r = 0.389, p = 0.001), the reduction of OHdG (Δ8-OHdG) were positively correlated with the decrease of 24-h proteinuria (Δ24-h proteinuria) after 12 weeks of SGLT2i treatment (r = 0.283, P = 0.031). There was no significant correlation between 24-h proteinuria and AGEs in baseline (r = −0.059, p = 0.640) as well as between ΔAGEs and Δ24-h proteinuria (r = 0.022, p = 0.872) after12 weeks of SGLT2i treatment in T2DM patients.ConclusionsSGLT2i may reduce proteinuria in diabetic nephropathy patients, potentially by inhibiting renal oxidative stress, but not through the AGEs pathway and does not induce RAAS activation.Trial registrationThis clinical trial was registered on 15/10/2019, in ClinicalTrials.gov, and the registry number is NCT04127084.

Immune checkpoint expression patterns on T cell subsets in light-chain amyloidosis: VISTA, PD-1, and TIGIT as potential therapeutic targets.

Amyloid light chain (AL) amyloidosis is a rare plasma cell dyscrasia with dismal prognosis. This study aims to investigate the T-cell immune checkpoint expression patterns in systemic AL amyloidosis and its relationship with clinicobiological traits. We examined the frequencies of V-domain immunoglobulin suppressor of T cell activation+ (VISTA+), programmed cell death 1+ (PD-1+), T cell immunoglobulin and mucin-domain-containing-3+ (Tim-3+), T cell immunoreceptor with Ig and ITIM domains+ (TIGIT+) T cells in peripheral blood (PB) and bone marrow (BM) from 19 patients with newly diagnosed AL amyloidosis. Patients with AL amyloidosis had significantly higher percentages of VISTA+ and PD-1+ T cells in PB than healthy individuals (HIs), with no statistical differences in BM. The percentages of some double-positive T cells in PB were also considerably higher in AL amyloidosis than those in HIs. Additionally, the patients with renal involvement had more PD-1+ and TIGIT+ T cells than the patients without, and PD-1+CD3+%, PD-1+CD4+%, PD-1+Treg% were positively correlated with 24-hour proteinuria levels. Furthermore, the AL amyloidosis patients had higher counts of PD-1+ Treg in PB than multiple myeloma (MM) patients, while the MM patients had higher counts of TIGIT+ T cells than AL amyloidosis patients. Collectively, this is the first report of elevated proportions of VISTA+ and PD-1+ T cells in PB of AL amyloidosis patients, indicating an immunosuppressive milieu, and the increased PD-1+ and TIGIT+ T cells were associated with renal damage. VISTA, PD-1, and TIGIT may be potential targets for reversing T-cell exhaustion in AL amyloidosis.

Association of variants in AGTR1, ACE, MTHFR genes with microalbuminuria and risk factors for the onset of diabetic nephropathy in adolescents with type 1 diabetes in the population of Serbia.

Genetic studies may provide valuable information about patients who are at high risk of developing diabetes nephropathy. Before the appearance of albuminuria, there are genetic mutations that can predispose the development of kidney disease. The study included 130 adolescents with type 1 diabetes. Patients were divided into two groups according to the presence of microalbuminuria. This study was performed to examine clinical and laboratory differences between adolescents with type 1 diabetes with and without microalbuminuria and the distribution of the ACE, AGTR1, and MTHFR gene polymorphisms. The mean microalbuminuria in the first group 6.41±7.35 significantly differs from the second group 0.82±0.48 (p<0.001). HbA1c, 24-hour proteinuria, and day-time systolic blood pressure were significantly higher in the MA group (p<0.05). Smaller systolic blood pressure percentage nocturnal decline was observed in the microalbuminuric group (p 0.030). The frequencies of the ACE DD, ID, and II genotypes were 12.5%, 50.0%, and 37.5%, respectively, among T1D patients with MA, and 19.3%, 56.1%, 24.6%, in the control group without MA (P = .510). The frequencies of the AGTR1 AA, AC, and CC genotypes were 62.5%, 25.0%, and 12.5% among TID patients with MA, and 49.1%, 43.9%, 8.0%, in the group without MA (p 0.326). The frequencies of the MTHFR CC, CT and TT genotypes were 37.5%, 50.0%, 12.5% among TID patients with MA, and 37.7%, 45.6%, 16.7% in the group without MA (p 0.901). Our data suggest that common variants in the AGTR1, ACE, and MTHFR genes are not strongly associated with diabetic nephropathy in our patients with type 1 diabetes.

Association of 10 Polymorphisms in PLA2R1 and HLA DQA1 Genes with Primary Membranous Nephropathy Risk: A Meta-Analysis and a Meta-Regression.

Although, several studies have assessed the association of the phospholipase A2 receptor (PLA2R) and HLA-DQA1 SNPs with primary membranous nephropathy (PMN), results were inconsistent and between-studies heterogeneity needs to be investigated. The aim of this review was to summarize existing data on the contribution of 10 SNPs in the PLA2R and HLA-DQA1 genes to PMN susceptibility and to investigate the between-studies heterogeneity by subgroup analyses and meta-regressions. This study was performed according to the PRISMA guidelines for systematic reviews and meta-analyses. An electronic literature search for eligible studies among all papers published prior to January 10, 2024, was conducted through PubMed, EMBASE, Web of science and Scopus databases. Meta-analyses together with subgroup analyses and meta-regressions were performed for the 10 following SNPs: rs4664308, rs3749117, rs3749119, rs35771982, rs3828323, rs16844715, rs1511223, rs6757188, rs2715918, and rs2187668. Combined analyses revealed a significant increase in PMN risk conferred by the following alleles: rs4664308*A, rs3749117*T, rs3749119*C, rs35771982*G, rs3828323*C, rs16844715*C, rs1511223*A, rs2715918*A, and rs2187668*A, all P-values < .001. Moreover, the PLA2R-rs4664308/HLA-DQA1-rs2187668 interaction was significantly associated with an increased PMN risk, P < .001. However, there was a substantial between-studies heterogeneity for some SNPs. Subgroup analyses by ethnicity for the 9 PLA2R SNPs did not show any cross-ethnic disparity. Inversely, the risk conferred by the HLA-DQA1 rs2187668*A allele was significantly higher in Caucasians (OR [95% CI] = 3.929 [3.251-4.748]) than in Asians (OR [95% CI] = 2.537 [1.94-3.318], P = .007. Besides, meta-regressions revealed for the majority of investigated SNPs significant correlations of the effect size with albumin, 24-hours proteinuria, serum creatinine, and eGFR levels. Hence, the influence on PMN risk conferred by the PLA2R and HLA-DQA1 SNPs was rather noted in patients with a severe disease. This meta-analysis showed that 9 out of the 10 investigated SNPs in PLA2R and HLA-DQA1 genes were associated with increased PMN risk. Heterogeneity could be due to disparate patient groups in terms of disease presentation for almost all SNPs, and ethnicity for the HLA-DQA1 rs2187668 SNP. This review has been registered on PROSPERO: CRD42024506729. Available from: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024506729.

Twenty-four-hour urinary protein excretion in uncomplicated singleton pregnancy

Twenty-four-hour urinary total protein excretion is an essential parameter used for evaluation of renal function and early detection of gestational complications. However, data on reference ranges of 24-hour urinary total protein excretion in normal pregnancy are scarce. This study aimed to determine reference ranges for 24-hour urinary total protein excretion in a population with uncomplicated singleton pregnancies using a standard method for urinary total protein. In addition, the values of 24-hour urinary total protein were stratified by maternal age and prepregnancy body mass index. This study was based on a prospective cohort study in Shenzhen, China. The pregnant women were enrolled at their first prenatal clinical visit. All the participants were instructed to collect 24-hour urine samples during the following successive gestational periods: 6+0 to 13+6, 14+0 to 27+6, and 28+0 to 41+6 weeks. Total urinary protein excretion was analyzed by a colorimetric method. Ultimately, the study encompassed a total of 4844 pregnant women with uncomplicated pregnancies. The nonparametric percentile method was used to determine reference ranges for 24-hour urinary total protein excretion during different trimesters in women with uncomplicated pregnancies (excluding those with previous kidney disorders, gestational or chronic hypertension, preeclampsia, and pregestational diabetes mellitus, among others). The 24-hour urinary total protein levels expressed as medians and percentiles (5th, 95th) for each trimester were as follows: 72.0 (28.4, 165.0), 88.0 (34.0, 185.0), and 108.0 (37.5, 258.0) mg in the first, second, and third trimesters, respectively. A significant increase in 24-hour urinary total protein excretion was observed throughout pregnancy (all P values <.001). Moreover, 24-hour urinary total protein levels were higher in the older (≥35 years) than in the younger (<35 years) group from mid-gestation. Specifically, the median (interquartile range) 24-hour urinary total protein levels by age were 72.2 (50.6-100.0) vs 70.5 (50.5-100.0) mg, 85.8 (62.0-117.0) vs 96.0 (68.0-127.8) mg, and 106.6 (76.0-146.2) vs 114.7 (81.5-153.6) mg in the first, second, and third trimesters, respectively. In addition, 24-hour proteinuria was significantly increased in higher-weight (overweight or obese) subgroups compared with lower-weight (underweight or normal-weight) subgroups (all P values <.05). Our study provides reference values for 24-hour urinary total protein excretion with apparently uncomplicated pregnancies. Understanding these changes in low-risk pregnancies is essential for optimizing maternal management.

Outcomes Associated with Clone-Directed Therapies for Monoclonal Gammopathy of Renal Significance

Background: Monoclonal Gammopathy of Renal Significance (MGRS) is a category of diseases not meeting criteria for cancer, in which a clonal population of B-lymphoid or plasma cells produces a nephrotoxic protein leading to kidney injury. Informal consensus has arisen that therapy targeting the causal clone is most likely to be efficacious, and the primary goal of therapy is to prolong renal survival. Light chain (AL) amyloidosis has been extensively studied, yet there is a paucity of data describing outcomes associated with clone-directed therapy for the various subtypes of non-AL MGRS. Methods: This was a retrospective analysis of patients treated at two National Cancer Institute (NCI)-designated cancer centers in the United States. Medical records of adult patients seen between January 2010 and March 2023 were screened for MGRS. Patients were eligible if they had renal biopsy-confirmed histopathologic findings compatible with MGRS. AL amyloidosis was excluded. The primary outcome was renal survival, defined as time from diagnosis of MGRS to requiring renal replacement therapy (RRT) or renal transplant, with patients censored at last follow up or death. Baseline characteristics were described, including 24-hour proteinuria, estimated glomerular filtration rate (eGFR), whether a clonal population of B cells or plasma cells could be identified on histopathologic examination of marrow or lymph node biopsy, concentration of monoclonal protein, and involved serum free light chain concentration. Initial therapy was reported, although differences in outcomes across therapeutic strategies were not compared. Baseline clinical characteristics between patients who required RRT and those who did not were compared. Baseline clinical variables and time to RRT were compared across the two most common MGRS subtypes in the cohort: proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) and light chain deposition disease (LCDD). Continuous variables were compared across subgroups using Wilcoxon rank-sum test. Time-to-event outcomes were analyzed according to the Kaplan-Meier method. All analyses were conducted using R version 3.6.1. Results: In total, 65 patients were included, 23 (35%) of whom ultimately required RRT or transplant. Four patients died, all after RRT. Median baseline proteinuria was 2802 mg/24h (IQR 972.5 - 4492.0) and median eGFR was 33.0 mL/min (IQR 23 - 53) for the entire cohort. In all cases proteinuria was mostly albumin. Median baseline involved light chain concentration was 8.3 mg/dL (IQR 3.1 - 26.4). A majority of patients (n=33, 51%) had no identifiable serum monoclonal protein. The two most common MGRS subtypes were PGNMID (n = 26) followed by LCDD (n = 21). Clonal populations thought to be causing MGRS were identified in 41/64 patients (64%), including 37 (58%) with plasma cell clones, 1 (2%) with a lymphoplasmacytic lymphoma clone, and 3 (4.7%) with other B-cell clones. Clones were not identified in 23 (36%). The most common chemotherapy agents included bortezomib (n=42, 64%) and rituximab (n=14, 22%). Compared to patients not requiring RRT, patients requiring RRT had higher baseline proteinuria (median 3531 vs. 1980 mg/24h, p&amp;lt;0.001) and lower eGFR (median 16 v. 44 mL/min, p&amp;lt;0.001); differences in serum free light chain concentrations were not significant ( Figure 1). A clonal population thought to be causing MGRS was identified on bone marrow biopsy in a majority of LCDD patients (n = 20, 95%), while clones were infrequently found in PGNMID (n = 6, 23%). The vast majority (n=20, 95%) of patients with LCDD received bortezomib-based therapy. Initial therapy in patients with PGNMID was more evenly divided: 9 (35%) received bortezomib-based therapy, 10 (38%) received rituximab-based therapy, and 6 (23%) received other regimens. Despite differences in therapeutic approach, patients with LCDD and in patients with PGNMID had similar risk of RRT (cumulative risk 35% v. 43%, p=0.54; HR 0.83 (95% CI 0.52-1.33); p =0.44) ( Figure 2). Conclusion: Patients with MGRS remain at high risk of requiring RRT even with clone-directed therapy. Despite differences in pathogenic clones and therapeutic strategies, outcomes of patients with PGNMID and LCDD are similar. Because the severity of baseline renal function across MGRS histologies predicts renal survival, early diagnosis and treatment is likely critical to improving renal outcomes.

Immune Checkpoint Expression Patterns on T Cell Subsets in Light-Chain Amyloidosis: VISTA, PD-1, and Tigit As Potential Therapeutic Targets

Abstract Background: Systemic immunoglobulin light chain amyloidosis (AL amyloidosis) is a rare plasma cell dyscrasia with a poor prognosis. T-cell exhaustion can lead to impaired T cell-mediated antitumor immunity, but there is limited information available regarding the T-cell immunodeficiency status in AL amyloidosis. This study aims to investigate the T-cell immune checkpoint expression patterns in AL amyloidosis and its relationship with clinicobiological characteristics. Methods: Using multi-color fluorescent flow cytometry, we examined the expression levels of V-domain immunoglobulin suppressor of T cell activation (VISTA), programmed death 1 (PD-1), T cell immunoglobulin and mucin-domain-containing-3 (Tim-3), T cell immunoreceptor with Ig and ITIM domains (TIGIT) on CD3+, CD4+, CD8+ T-cell, and regulatory T cell (Treg) in peripheral blood (PB) and bone marrow (BM) from 19 patients with newly diagnosed AL amyloidosis. We used 36 PB and BM samples from patients with newly diagnosed multiple myeloma (MM) and 19 PB and 10 BM samples from healthy individuals (HIs) as controls. Results: Our results showed that PB from patients with AL amyloidosis had significantly higher percentages of VISTA+ and PD-1+ subsets within CD3+, CD4+, CD8+ T cells and Tregs when compared to HIs. No statistical differences for frequency of VISTA+, PD-1+, Tim-3+ and TIGIT+ T-cell in BM were observed between the two groups. The percentages of double-positive VISTA+ PD-1+, VISTA+ Tim-3+, VISTA+ TIGIT+, PD-1+ Tim-3+ and PD-1+ TIGIT+ T cells in PB from the patients with AL amyloidosis were also considerably higher than those in the HIs. Moreover, we discovered that the patients with renal involvement had greater percentages of PD-1+ or TIGIT+ subsets within CD3+, CD4+ T cells and Tregs than the individuals without renal involvement. Additionally, PD-1+CD3+%, PD-1+CD4+%, and PD-1+Treg% were found to be positively correlated with 24-hour proteinuria levels. Furthermore, we observed that the AL amyloidosis patients had significantly higher counts of PD-1+ Treg in PB than the MM patients, while the MM patients had significantly higher counts of TIGIT+ subsets within CD3+, CD4+ and CD8+ T cells than the AL amyloidosis patients. Conclusions: Our findings suggest that there are elevated proportions of VISTA+ and PD-1+ T cells in PB of AL amyloidosis patients, which are indicators of an immunosuppressive milieu. The rise in PD-1+ or TIGIT+ T cells was associated with renal damage. Notably, MM and AL amyloidosis have very distinct immunosuppressive patterns based on immune checkpoint alteration. Overall, VISTA, PD-1, and TIGIT may be considered as potential targets for reversing T cell exhaustion and enhancing T cell activity in AL amyloidosis.

Development of a New Equation for Estimated 24-Hour Proteinuria: Modified Urine Protein-Creatinine Ratio Adjusted by Urinary Creatinine Excretion

Development of a New Equation for Estimated 24-Hour Proteinuria: Modified Urine Protein-Creatinine Ratio Adjusted by Urinary Creatinine Excretion

Assessing the Accuracy of Diagnostic Tests to Quantify Proteinuria in Nephrotic Children: A Cross-Sectional Study

Objective: To assess the diagnostic accuracy of 24-hour proteinuria estimation and urine dipstick-taking spot urine protein creatinine ratio as the gold standard in children with steroid-sensitive nephrotic syndrome. Study Design: Cross-sectional analytical study. Place and Duration of Study: Department of Paediatric Nephrology, Sindh Institute of Urology and Transplantation, Karachi Pakistan, from Oct 2020 to Mar 2021. Methodology: Proteinuric children were enrolled to quantify proteinuria by 24-hour urine protein estimation, spot urine protein creatinine ratio and urine dipstick. Sensitivity analysis was performed, and receiver operating curves were plotted to assess the diagnostic accuracies of 24-hour proteinuria and urine dipstick against spot urinary protein creatinine ratio. Scatter plots compared the correlation of serum albumin and cholesterol with 24-hour urine protein estimation and spot urine protein creatinine ratio. Results: Forty-two children with a median age of 8 years (IQR 6–10) were included. Nephrotic range proteinuria was detected in 39(93%) children with spot ratio, 16(38%) cases using 24-hour proteinuria estimation and 50% with a urine dipstick.Twenty-four-hour protein estimation showed a sensitivity of 63.4%, and urine dipstick had a sensitivity of 53.8% in detecting nephrotic range proteinuria compared to spot ratio with a negative predictive value of 6.3% and 14.3%, respectively.Hypoalbuminemia and cholesterol correlated better with spot ratio than 24-hour proteinuria with r- values 0.0143 and 0.0713, respectively. Conclusion: Twenty-four-hour urine protein estimation and dipstick correlate with spot urine protein creatinine ratio in detecting nephrotic proteinuria with no statistical difference in diagnostic accuracy.

Laboratory, immunological evaluation and clinical treatment in patients with lupus glomerulonephritis hospitalized in a hospital tertiary

Objective: Laboratory and histological evaluation of patients with lupus glomerulonephritis treated at Hospital Getúlio Vargas, in Teresina, Piauí. Methods: Descriptive, retrospective study, whose data were collected by consulting electronic medical records and evaluation forms. Results: 33 patients were evaluated, with a mean age of 30.45±10.19 years, and female prevalence (96.97%). Most had altered creatinine values ​​(51.51%) and 24-hour proteinuria (81.81%). It was verified that C3 and C4 (57.57%, each) were altered, the Antinuclear Factor presented 63.63% of positivity, followed by the Anti-DNA (54.54%) and the Anti-SM that 24.24% were reactive. About 54.55% underwent renal biopsy, with histological type class IV (35.00%). The most used induction treatment was Pulse Therapy with Cyclophosphamide 6M 30/30 D (39.39%). There was a relationship significant difference between age and creatinine and Anti-SM values ​​(p&lt;0.05). Conclusion: Most patients have type IV lupus glomerulonephritis, are young adults, female, from the countryside, and have altered biochemical parameters with positivity for immunological ones.

Novel Diabetic Nephropathy-Based Hypertension Treatment for Type-2 Diabetes Mellitus and CKD Patients: A Mini Review

Diabetes mellitus is known to result in persistent renal impairment among individuals with the condition and is presently the primary aetiology of terminal-stage renal disease, with more than fifty percent of dialysis patients being affected. The prevalence of diabetes continues to rise, resulting in a decline in individuals' health status and imposing significant financial burdens on healthcare systems. Accurately distinguishing between the various types of diabetes is crucial in order to provide appropriate treatment that mitigates the severity of associated complications and their significant consequences. The co-occurrence of diabetes and renal disease has been found to be linked with a significant fourfold rise in both the frequency and fatality of cardiovascular disease. Pharmacological interventions aimed at reducing blood pressure have been a crucial component in the management of diabetic nephropathy for several decades. The past decade has witnessed a decline in the occurrence of end-stage renal disease, owing to enhanced care measures such as the administration of hypertension medication. It is assumed in clinical practice recommendations that angiotensin-converting enzyme inhibitors and angiotensin-receptor antagonists hold an equivalent status. The efficacy of low doses of ACEI and ARB in reducing proteinuria was found to be superior to that of high doses. The co-administration of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) has been observed to elicit a more pronounced reduction in 24-hour proteinuria and urinary albumin excretion rate (UAER) in comparison to the singular administration of either ACEI or ARB.

Effect of pioglitazone on proteinuria and cardiovascular events in patients with diabetic nephropathy

Introduction: Slowing the progression of diabetes to DN has established a great deal of interest in recent years. Objectives: Considering the enormous costs of managing patients with diabetes and the lack of similar studies on the Iranian population, the present study aimed at investigating the effect of pioglitazone on the progression of DN and the prevalence of cardiovascular events. Patients and Methods: The present prospective study was undertaken on 55 patients with type 2 diabetes who were divided into two groups. The group 1 patients received 30 mg of pioglitazone daily in addition to other blood sugar-controlling drugs. Patients in the group 2 recieved other anti-diabetic medications. During a six-month follow-up period, proteinuria and the occurrence of cardiovascular events were assessed. Results: The 24-hour urinary proteinuria decreased within the group 1 and these intragroup differences were significant (P&lt;0.001) during six months of follow-up compared to month two. There was no significant difference in the ratio of cardiovascular events in the group 1 compared to the group 2. Conclusion: Adding 30 mg of pioglitazone to other blood sugar-lowering medications could lower proteinuria in individuals with type 2 diabetes; however, it had no impact on the risk of cardiovascular events.

Clinicopathological Characteristics of Adult IgA Nephropathy in the United States

IgA nephropathy (IgAN) is a progressive autoimmune kidney disease and a leading cause of glomerular disease that can result in kidney failure (KF). The median age at diagnosis is 35 to 37 years and approximately 50% of patients will progress to KF within 20 years. We aimed to enhance the understanding of renal histology and chronic kidney disease (CKD) stage at the time of IgAN diagnosis using a large real-world biopsy cohort. This retrospective cohort study evaluated biopsy data and clinical characteristics from adult patients within the US who were diagnosed with IgAN between January 1, 2016 to May 31, 2020. Descriptive statistics were summarized and relationship(s) between each Oxford Classification (MEST-C) component score with 24-hour proteinuria or CKD stage were examined using regression analysis. A total of 4375 patients (mean age 47.7 years, 62.7% male) met eligibility criteria. Mild to moderate mesangial hypercellularity (47.3%), segmental sclerosis (65.0%), tubular atrophy≥25% (57.4%), and crescents (18.5%) were identified; and 74.6% of patients were at CKD stage≥3. Proteinuria≥1 g/d was associated with higher MEST-C scores, and the odds of mesangial hypercellularity, segmental sclerosis, tubular atrophy, and crescents increased with CKD stage. Most patients with IgAN in our US cohort were diagnosed at CKD stage≥3 and had high MEST-C scores and proteinuria that are suggestive of significant disease burden at the time of kidney biopsy. Strategies are required to raise awareness and promote earlier detection of asymptomatic urinary abnormalities before extensive irreversible kidney damage has occurred.

COL4A3 Mutation Induced Podocyte Apoptosis by Dysregulation of NADPH Oxidase 4 and MMP-2

Podocyte apoptosis is a common mechanism driving progression in Alport syndrome (AS). This study aimed to investigate the mechanism of podocyte apoptosis caused by COL4A3 mutations. We recruited patients with autosomal dominant AS (ADAS). Patients with minimal change disease (MCD) were recruited as controls. Microarray analysis was carried out on isolated glomeruli from the patients and validated. Then, corresponding mutant human podocytes (p.C1616Y) and 129 mice (p.C1615Y, the murine homolog to the human p.C1616Y) were constructed. The highest differentially expressed genes (DEGs) from microarray analysis were validated in transgenic mice and podocytes before and after administration of MMP-2 inhibitor (SB-3CT) and NOX4 inhibitor (GKT137831). We further validated NOX4/MMP-2/apoptosis pathway by real-time polymerase chain reaction (PCR), immunohistochemistry, and western blot in renal tissues from the ADAS patients. Using microarray analysis, we observed that DEGs, including NOX4/H2O2, MMP-2, and podocyte apoptosis-related genes were significantly upregulated. These genes were validated by real-time PCR, histologic analysis, and western blot in corresponding mutant human podocyte (p.C1616Y) and/or mice models (p.C1615Y). Moreover, we found podocyte apoptosis was abrogated and MMP-2 expression was down-regulated both invivo and invitro by NOX4 inhibition, urinary albumin-to-creatinine ratio, 24-hour proteinuria; and renal pathologic lesion was attenuated by NOX4 inhibition invivo. Furthermore, podocyte apoptosis was attenuated whereas NOX4 expression remained the same by inhibition of MMP-2 both invivo and invitro. These results indicated that NOX4 might induce podocyte apoptosis through the regulation of MMP-2 in patients with COL4A3 mutations. Our findings provided new insights into the mechanism of ADAS.

#6184 PULSE WAVE VELOCITY AND AMBULATORY BLOOD PRESSURE IN PATIENTS WITH RENAL HYPERFILTRATION

Abstract Background and Aims Recent studies have been implicated that abnormally increased glomerular filtration rate, defined as renal hyperfiltration, may be a risk factor for the development of renal damage and cardiovascular disease. Herein, we aimed to investigate the possible relationship between renal hyperfiltration(RHf) and pulse wave velocity, ambulatory blood pressure measurements and clinical parameters. Method All individuals included the study were between 18 and 65 years old. The eGFR (CKD-EPI) values of above 140 ml/min/1.73 m² were defined as RHf. Nineteen individuals in the renal hyperfiltration group and 20 in the control group were included. Blood and urine samples of the cases were examined. The individuals with diabetes, obesity, pregnancy, hypertension, cardiovascular disease, peripheral artery disease, cerebrovascular disease, chronic rheumatological disease, and thyroid dysfunction were excluded from the study. The parameters related arterial stiffness and ambulatory blood pressure measurements were obtained in all cases. The results were analyzed statistically. Results The two groups were similar in terms of gender, age, BMI and smoking. In RHf group, total cholesterol, 24-hour urine proteinuria and albuminuria, SBP, DBP, MAP and PP values ​​were found higher than control group. Interestingly, the differences of “night time” measurements of all these hemodynamic parameters were more pronounced in RHf group. The trend of “non-dipper” pattern was to be higher in the hyperfiltration group. In arterial stiffness parameters the augmentation pressure (AP), central systolic pressure (CSP), reflection magnitude (RM), central diastolic pressure (CBP), and pulse pressure amplification (PPA) were found significantly different. Pearson's corelation analysis revealed that AP, CSP, CBP was the positively; RM was negatively correlated with eGFR in hyperfiltration group (Table 1 and 2). Multivariate linear regression analysis revealed that AP, 24-hour proteinuria and mean arterial pressure were the independent parameters related to hyperfiltration. Logistic regression showed that only AP was an independent predictor of hyperfiltration (p = 0.001, OR = 0.84; 0.757-0.935, CI 95%). Conclusion We found that augmentation pressure is the most important independent parameter correlated with RHf among arterial stiffness measurements. The vascular risk may be increased in this population.

#5401 REAL-WORLD STUDY BETWEEN NEPHROTIC SYNDROME AND VENOUS THROMBOEMBOLISM

Abstract Background and Aims Nephrotic syndrome (NS) is a recognized risk factor of venous thromboembolism (VTE), however, there have been limited comprehensive epidemiologic data on VTE among NS patients. Therefore, we designed our study to assess the epidemiology and clinical correlates of VTE among hospitalized adults with NS in China. Method In this nationwide real-world study of 78,797 hospitalized patients with NS from 18 medical centers across China, VTE was identified by International Classification of Diseases, 10th revision (ICD-10) codes or imagological examinations during hospitalization. Multivariable logistic regression analysis was used to investigate the association between clinical variables and VTE through the R Programming software. Results A total of 1227 VTE cases were identified in the hospitalized NS population and the detection rate was 1.56%. Detection rate of VTE varied significantly in patients with different pathologic types of NS. Patients with membranous nephropathy (MN) had a significantly increased risk of VTE {Odds ratio [OR] 2.11 [95% confidence interval (CI) 1.12–4.36]}. While patients with focal segmental glomerulosclerosis (FSGS) did not show a significant high risk [OR 0.93 (95% CI 0.29–2.60)] compared with minimal change disease. We also found that male [OR 1.44 (95% CI 1.15–1.80)], age [OR 1.09 (95% CI 1.02–1.17)], anemia [OR 1.50 (95% CI 1.15–1.95)], cerebral bleeding [OR 3.23 (95% CI 1.69–6.16)], respiratory tract infection [OR 2.05 (95% CI 1.60–2.63)], respiratory failure [OR 2.24 (95% CI 1.42–3.53)], use of proton pump inhibitors (PPIs) [OR 2.19 (95% CI 1.54–3.12)], use of glucocorticoids [OR 1.46 (95% CI 1.03–2.09)] and immunosuppressants [OR 1.48 (95% CI 1.14–1.93), orthopedic operations [OR 1.97 (95% CI 1.22–3.18)], high-level D-dimer (&amp;gt;0.55 mg/L) [OR 2.62 (95% CI 1.87–3.65)] were associated with increased risk of VTE detection. While 24-hour urine protein quantification &amp;gt;10 g/d [OR 1.24 (95% CI 0.90–1.70)] showed little significant correlation with VTE. Hypertension [OR 0.74 (95% CI 0.58–0.95)] and the use of diuretics [OR 0.72 (95% CI 0.53–0.97)] were found to have a negative correlation with VTE detection. Conclusion The detection rate of VTE among patients with NS during hospitalization was 1.56%. Male, age, MN, anemia, cerebral bleeding, respiratory tract infection, respiratory failure, and use of PPIs, glucocorticoids and immunosuppressants, high D-dimer concentration were associated with VTE detection in NS. While 24-hour proteinuria did not show a significant association with VTE identification.