Urinary Plasminogen as a Marker of Disease Progression in Human Glomerular Disease.

RATIONALE & OBJECTIVE: Glomerular disorders have a highly variable clinical course, and biomarkers that reflect the molecular mechanisms underlying their progression are needed. Based on our previous work identifying plasminogen as a direct cause of podocyte injury, we designed this study to test the association between urine plasmin(ogen) (ie, plasmin and its precursor plasminogen) and end-stage kidney disease (ESKD). STUDY DESIGN: Multicenter cohort study. SETTING & PARTICIPANTS: 1,010 patients enrolled in the CureGN Cohort with biopsy-proven glomerular disease (focal segmental glomerulosclerosis, membranous nephropathy, and immunoglobulin A nephropathy). PREDICTORS: The main predictor was urine plasmin(ogen) at baseline. Levels were measured by an electrochemiluminescent immunoassay developed de novo. Traditional clinical and analytical characteristics were used for adjustment. The ratio of urine plasmin(ogen)/expected plasmin(ogen) was evaluated as a predictor in a separate model. OUTCOME: Progression to ESKD. ANALYTICAL APPROACH: Cox regression was used to examine the association between urinary plasmin(ogen) and time to ESKD. Urinary markers were log2 transformed to approximate normal distribution and normalized to urinary creatinine (Log2uPlasminogen/cr, Log2 urinary protein/cr [UPCR]). Expected plasmin(ogen) was calculated by multiple linear regression. RESULTS: Adjusted Log2uPlasminogen/cr was significantly associated with ESKD (HR per doubling Log2 uPlasminogen/cr 1.31 [95% CI, 1.22-1.40], P<0.001). Comparison of the predictive performance of the models including Log2 uPlasminogen/cr, Log2 UPCR, or both markers showed the plasmin(ogen) model superiority. The ratio of measured/expected urine plasmin(ogen) was independently associated with ESKD: HR, 0.41 (95% CI, 0.22-0.77) if ratio<0.8 and HR 2.42 (95% CI, 1.54-3.78) if ratio>1.1 (compared with ratio between 0.8 and 1.1). LIMITATIONS: Single plasmin(ogen) determination does not allow for the study of changes over time. The use of a cohort of mostly white patients and the restriction to patients with 3 glomerular disorders limits the external validity of our analysis. CONCLUSIONS: Urinary plasmin(ogen) and the ratio of measured/expected plasmin(ogen) are independently associated with ESKD in a cohort of patients with glomerular disease. Taken together with our previous experimental findings, urinary plasmin(ogen) could be a useful biomarker in prognostic decision making and a target for the development of novel therapies in patients with proteinuria and glomerular disease. PLAIN-LANGUAGE SUMMARY: Glomerular diseases are an important cause of morbidity and mortality in patients of all ages. Knowing the individual risk of progression to dialysis or transplantation would help to plan the follow-up and treatment of these patients. Our work studies the usefulness of urinary plasminogen as a marker of progression in this context, since previous studies indicate that plasminogen may be involved in the mechanisms responsible for the progression of these disorders. Our work in a sample of 1,010 patients with glomerular disease demonstrates that urinary plasminogen (as well as the ratio of measured to expected plasminogen) is associated with the risk of progression to end-stage kidney disease. Urine plasminogen exhibited good performance and, if further validated, could enable risk stratification for timely interventions in patients with proteinuria and glomerular disease.

Rationale and design of the Japanese Biomarkers in Nephrotic Syndrome (J-MARINE) study.

INTRODUCTION: Disease subtyping and monitoring are essential for the management of nephrotic syndrome (NS). Although various biomarkers for NS have been reported, their clinical efficacy has not been comprehensively validated in adult Japanese patients. METHODS: The Japanese Biomarkers in Nephrotic Syndrome (J-MARINE) study is a nationwide, multicenter, and prospective cohort study in Japan, enrolling adult (≥18 years) patients with minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), membranous nephropathy (MN), membranoproliferative glomerulonephritis (MPGN), C3 glomerulopathy (C3G), and lupus nephritis (LN). Baseline clinical information and plasma and urine samples will be collected at the time of immunosuppressive therapy initiation or biopsy. Follow-up data and plasma and urine samples will be collected longitudinally based on the designated protocols. Candidate biomarkers will be measured: CD80, cytotoxic T-lymphocyte antigen 4, and soluble urokinase plasminogen activator receptor for MCD and FSGS; anti-phospholipase A2 receptor and thrombospondin type-1 domain-containing protein 7A antibodies for MN; fragment Ba, C3a, factor I, and properdin for MPGN/C3G; and CD11b, CD16b, and CD163 for LN. Outcomes include complete and partial remission, relapse of proteinuria, a 30% reduction in estimated glomerular filtration rate (eGFR), eGFR decline, and initiation of renal replacement therapy. The diagnostic accuracy and predictive ability for clinical outcomes will be assessed for each biomarker. RESULTS: From April 2019 to April 2023, 365 patients were enrolled: 145, 21, 138, 10, and 51 cases of MCD, FSGS, MN, MPGN/C3G, and LN, respectively. CONCLUSION: This study will provide valuable insights into biomarkers for NS and serve as a biorepository for future studies.

Transforming growth factor beta (TGF ß) activity in urine of patients with glomerulonephritis

Several lines of experimental evidence have shown that transforming growth factor ß (TGF ß) may play a major role in glomerular diseases, mediating the inflammatory response through glomerulosis. In the present study we evaluated TGF ß activity in occasional urine samples from 7 normal individuals and from 15 patients (10 with focal glomerular sclerosis and 5 with membranous glomerulonephritis) using a CCL-64 mink lung cell growth inhibition assay. Urinary TGF ß activity (reported in relation to urine creatinine concentration, Ucr, mean +/- SD) was higher in patients with focal glomerular sclerosis (x/- 17.32 +/- 15.75 / 10 µg Ucr) and patients with membranous glomerulonephritis (x/- = 17.78 +/- 11.53 / 10 µg Ucr) than in normal individuals (x/- = 0.8 +/- 0.44 / 10 µg Ucr). We also observed that TGF ß activity in urine from patients with focal glomerular...

Reduction of urine volume ameliorates adriamycin-induced nephropathy

1. Adriamycin, a commonly used antineoplastic antibiotic, induces glomerular lesions in rats, resulting in persistent proteinuria and glomerulosclerosis. 2. The effect of urine volume on the progression of adriamycin-induced nephropathy was studied in 70 male Wistar rats (180-200 g) observed for 30 weeks and separated into 4 groups: healthy control group (HCG, N = 10) inoculated i.v. with 1 ml of saline, and nephrotic groups inoculated iv with a single dose of adriamycin of 3 mg/kg body weight. The nephrotic rats were separated into 3 groups (N = 20): nephrotic control group (NCG) receiving only adriamycin; dehydrated nephrotic group (DNG) water deprived for 36 h within each 48-h period, and furosemide nephrotic group (FNG) treated with 12 mg/dl furosemide, and 0.9 g/dl NaCl in the drinking water. 3. The 30-week survival rates of the DNG (100 per cent ) and HCG (100 per cent ) were significantly higher than those of the NCG (85 per cent ) and FNG (55 per cent ). 4. The proteinuria observed in the HCG (range, 7.38 +/- 0.7 to 13.6 +/- 1.27 mg/24 h) was significantly lower than that observed for all the nephrotic groups throughout the experiment. The DNG presented significantly less proteinuria (range, 42.71 +/- 6.83 to 140.10 +/- 19.22 mg/24 h) than the NCG (range, 35.32 +/- 7.64 to 250.00 +/- 25.91 mg/24 h) from week 10 on. There was no significant difference between the mean 24-h proteinuria of the NCG (range, 35.32 +/- 7.64 to 250.00 +/- 25.91 mg/24 h) and the FNG (range, 35.82 +/- 7.91 to 221.54 +/- 26.74). 5. The mean frequency of damaged glomeruli was 0.3 per cent +/- 0.3 for HCG, 42 per cent +/- 6 per cent for CNG, 40.8 per cent +/- 8 per cent for DNG, and 47 per cent +/- 14 per cent for FNG. The median value of the tubulointerstitial lesion, evaluated by a semiquantitative method, was 0 in HCG, 10 in CNG, 8.5 in DNG and 9.5 in FNG (P < 0.05 for all groups compared to HCG). 6. The data indicate that reduction of urine volume has a protective effect on adriamycin-induced nephropathy