Urinary Plasminogen as a Marker of Disease Progression in Human Glomerular Disease
Marina de Cos, Gohar Mosoyan, Kinsuk Chauhan, Jonathan P Troost, Jenny S Wong, Sean Lefferts, Paul Morgan, Kristin Meliambro, Marc Egerman, Justina Ray, Tom Parker, Daniel Levine, Surya Seshan, Yoni Bardash, Benjamin Horowitz, Candice A Kent, Melissa M Shaw, Alan Perlman, Dennis G Moledina, Steven G Coca, Kirk N Campbell...
Am J Kidney Dis. 2024 Aug;84(2):205-214.e1. doi: 10.1053/j.ajkd.2024.01.520. Epub 2024 Mar 5.
ABSTRACT
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.
A Mobile Health-Based Survey to Assess COVID-19 Vaccine Intent and Uptake Among Patients on Dialysis
Sri Lekha Tummalapalli, Daniel Cukor, Andrew Bohmart, Daniel M Levine, Thomas S Parker, Frank Liu, Alan Perlman, Vesh Srivatana, Meghan Reading Turchioe, Said A Ibrahim, Jeffrey Silberzweig...
Kidney Int Rep. 2022 Mar;7(3):633-637. doi: 10.1016/j.ekir.2021.12.006. Epub 2021 Dec 13.
Lilian Saro-Nunez, Amrei Aufderheide, Samuel Baskharoun, Alan Perlman
Ann Clin Lab Sci. 2018 Jul;48(4):496-500.
ABSTRACT
BACKGROUND: Elevated serum creatinine levels are a common finding in patients with urinoma (i.e. presence of urine outside of the urinary tract). Therefore, in the clinical circumstance of an urinoma, utilizing a creatinine-based estimated GFR (eGFR) to determine renal function is unreliable, as it fails to distinguish true renal failure from pseudorenal failure in patients with a urine leakage. Cystatin C, a 13 kDA molecular mass protein ubiquitously expressed by nucleated cells, offers superior accuracy in the setting of an urinoma, since unlike creatinine, it is essentially absent in excreted urine and poorly reabsorbed from the peritoneum and retroperitoneal space.
METHODS: We present the first case report to demonstrate the utility of cystatin C in an adult patient with native kidney function that experienced significant retro-peritoneal bladder leakage.
RESULTS: Our results demonstrate that cystatin C may be a more accurate measurement of GFR than the commonly used creatinine in the setting of an urinoma.
CONCLUSION: In order to achieve an accurate estimated GFR in the setting of a urinoma, physicians should consider the use of Cystatin C, which is less vulnerable to inaccurate interpretation.
Bortezomib for Reduction of Proteinuria in IgA Nephropathy
Choli Hartono, Miriam Chung, Alan S Perlman, James M Chevalier, David Serur, Surya V Seshan, Thangamani Muthukumar...
Kidney Int Rep. 2018 Mar 11;3(4):861-866. doi: 10.1016/j.ekir.2018.03.001. eCollection 2018 Jul.
ABSTRACT
INTRODUCTION: IgA nephropathy is the most common glomerulonephritis in the world. We conducted a pilot trial (NCT01103778) to test the effect of bortezomib in patients with IgA nephropathy and significant proteinuria.
METHODS: We treated 8 consecutive subjects from July 2011 until March 2016 with 4 doses of bortezomib. All subjects had biopsy-proven IgA nephropathy and proteinuria of greater than 1 g per day. They were given 4 doses of bortezomib i.v. at 1.3 mg/m2 of body surface area per dose. Changes in proteinuria and renal function were followed for 1 year after enrollment. The primary endpoint was full remission defined as proteinuria of less than 300 mg per day.
RESULTS: All 8 subjects received and tolerated 4 doses of bortezomib over a 2-week period during enrollment. The median baseline daily proteinuria was 2.46 g (interquartile range: 2.29-3.16 g). At 1-year follow-up, 3 subjects (38%) had achieved the primary endpoint. The 3 subjects who had complete remission had Oxford classification T scores of 0 before enrollment. Of the remaining 5 subjects, 1 was lost to follow-up within 1 month of enrollment and 4 (50%) did not have any response or had progression of disease.
CONCLUSION: Proteasome inhibition by bortezomib may reduce significant proteinuria in select cases of IgA nephropathy. Subjects who responded to bortezomib had Oxford classification T score of 0 and normal renal function.
OBJECTIVES: To evaluate the value of multiparametric quantitative ultrasound imaging in assessing chronic kidney disease (CKD) using kidney biopsy pathologic findings as reference standards.
METHODS: We prospectively measured multiparametric quantitative ultrasound markers with grayscale, spectral Doppler, and acoustic radiation force impulse imaging in 25 patients with CKD before kidney biopsy and 10 healthy volunteers. Based on all pathologic (glomerulosclerosis, interstitial fibrosis/tubular atrophy, arteriosclerosis, and edema) scores, the patients with CKD were classified into mild (no grade 3 and <2 of grade 2) and moderate to severe (at least 2 of grade 2 or 1 of grade 3) CKD groups. Multiparametric quantitative ultrasound parameters included kidney length, cortical thickness, pixel intensity, parenchymal shear wave velocity, intrarenal artery peak systolic velocity (PSV), end-diastolic velocity (EDV), and resistive index. We tested the difference in quantitative ultrasound parameters among mild CKD, moderate to severe CKD, and healthy controls using analysis of variance, analyzed correlations of quantitative ultrasound parameters with pathologic scores and the estimated glomerular filtration rate (GFR) using Pearson correlation coefficients, and examined the diagnostic performance of quantitative ultrasound parameters in determining moderate CKD and an estimated GFR of less than 60 mL/min/1.73 m2 using receiver operating characteristic curve analysis.
RESULTS: There were significant differences in cortical thickness, pixel intensity, PSV, and EDV among the 3 groups (all P < .01). Among quantitative ultrasound parameters, the top areas under the receiver operating characteristic curves for PSV and EDV were 0.88 and 0.97, respectively, for determining pathologic moderate to severe CKD, and 0.76 and 0.86 for estimated GFR of less than 60 mL/min/1.73 m2 . Moderate to good correlations were found for PSV, EDV, and pixel intensity with pathologic scores and estimated GFR.
CONCLUSIONS: The PSV, EDV, and pixel intensity are valuable in determining moderate to severe CKD. The value of shear wave velocity in assessing CKD needs further investigation.
Serum Inflammatory and Immune Mediators Are Elevated in Early Stage Diabetic Nephropathy
Alan S Perlman, James M Chevalier, Patrick Wilkinson, Hao Liu, Thomas Parker, Daniel M Levine, Betty Jo Sloan, Anna Gong, Raymond Sherman, Francis X Farrell...
Ann Clin Lab Sci. 2015 Spring;45(3):256-63.
ABSTRACT
BACKGROUND: Diabetes is the leading cause of end stage renal disease (ESRD) in the United States, representing 44% of incident cases [1]. In this study, serum and peripheral blood collected from diabetic patients in five stages of chronic kidney disease (CKD), as defined by glomerular filtration rate (GFR), were compared to healthy (non-CKD) subjects.
METHODS: Serum samples were analyzed for 39 inflammatory or immune mediator protein levels and peripheral blood samples were analyzed for expression of 35 gene transcripts.
RESULTS: In serum, MCP-1, FGF-2, VEGF, and EGF levels were elevated above controls at all stages of DN. Five mediator levels, GM-CSF, IL-1α, IL-1RA, IL-6, and MIP1β increased with disease progression until stage 4-5, at which point a decrease was observed paralleling a loss of functional renal mass that occurs in late stage CKD. Five mediator levels: GRO, IFNγ, MDC, Eotaxin, and G-CSF significantly differed from controls at one or more stages without apparent correlation with disease stage. Only a single mediator, sIL2RA, exhibited a linear increase with disease severity consistent with declining GFR. In peripheral blood, the transcript level of seven mediators, ICAM1, TNF-α, TGF-β, IL-8, IL17RA, IFNγ, and MYD88 were significantly elevated at all disease stages as compared to control.
CONCLUSION: Statistically significant differences in protein and transcripts levels between diseased and control can be detected in serum and peripheral blood utilizing high content profiling. These changes occur as early as stage 1-2 before a significant decline in renal function.
Prevention of recurrent episodes of rhabdomyolysis with tacrolimus in a transplant recipient with myopathy
Sharad Sathyan, Rawya Baskharoun, Alan S Perlman
Am J Ther. 2014 Sep-Oct;21(5):e171-4. doi: 10.1097/MJT.0b013e318274df46.
ABSTRACT
Genetic muscular disorders are known risk factors for rhabdomyolysis, which may result in acute kidney injury. Recurrent episodes of acute kidney injury can lead to chronic kidney disease and eventually end-stage renal failure. We describe a patient with chronic kidney disease that developed in the setting of recurrent rhabdomyolysis, resulting in the requirement for renal transplantation. After transplantation, the maintenance of tacrolimus trough concentrations above what is typically prescribed for standard renal transplant recipients appeared to confer protection from further episodes of rhabdomyolysis. This is consistent with previous case series that demonstrated a therapeutic benefit of the calcineurin inhibitor cyclosporine in collagen VI myopathies in the nontransplant population. This case report suggests the potential application of higher tacrolimus targets in patients who have undergone renal transplantation in the setting of recurrent rhabdomyolysis leading to end-stage renal failure.
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