Summary: Clotting proteins are elevated in the urine of patients with lupus nephritis. The findings provide a new biomarker for the autoimmune disease.
Source: University of Houston
University of Houston researcher Chandra Mohan is reporting in Arthritis Research and Therapy that clotting proteins, both those that promote blood clots (pro-thrombotic) and those that work to dissipate them (thrombolytic), are elevated in the urine of patients who suffer from lupus nephritis (LN).
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“Among the proteins examined, urine plasmin emerged as the strongest independent predictor of kidney function and renal disease status,” reports Mohan, Hugh Roy and Lillie Cranz Cullen Endowed Professor of biomedical engineering.
“Urine biomarkers represent promising candidates for the early diagnosis as well as the monitoring of disease activity and therapeutic responses in lupus nephritis.” The discovery of the new biomarker for active LN opens the door for clinical monitoring of the disease.
Systemic lupus erythematosus (SLE) is an autoimmune disease that occurs when the body attacks its own tissues and organs. Inflammation from the disease can impact many different parts of the body including joints, skin, kidneys, blood cells, brain and heart. Lupus nephritis is one of the most frequent and severe clinical manifestations of SLE, representing a leading cause of morbidity and mortality.
New immunosuppressive drugs and biologics have brought improvements in recent SLE and LN survival rates, but early diagnosis and monitoring disease flares are still challenges that need to be addressed. Renal biopsy remains the gold standard for the diagnosis and prognosis of LN, but it’s invasive and cannot be used for routine monitoring of disease activity and treatment responses. Because of this, several studies focusing on screening and identifying non-invasive biomarkers for the early diagnosis and monitoring of SLE and LN are emerging.
Because coagulation system disorders have been reported in SLE and lupus nephritis patients and the frequency of thrombotic events was documented to be higher in SLE patients than in the general population, Mohan’s lab examined urinary proteins related to coagulation.
Finding elevations in both pro-thrombotic and thrombolytic proteins in the urine of patients with lupus nephritis was unexpected.
“When I first saw the presence of both I thought ‘This can’t be right, so let’s look at this in more detail with more urine samples and better assays,'” said Mohan, who describes the presence of both proteins as “a raging war” within the kidneys. If one or the other predominates, he said, there are medicines that can regulate the clotting in balance, but when both processes are equally upregulated, balancing this biological process becomes clinically challenging.
Urine samples for this study were obtained from 113 patients with LN who had previously been recruited from the renal clinic at UT Southwestern Medical Center between 2007 and 2011. Collaborating with Mohan on the study are lead author, Qing Ling, a practicing nephrologist, Michelle A. Petri, director of the Hopkins Lupus Center at Johns Hopkins Medicine, Baltimore, and Ramesh Saxena, professor of internal medicine -nephology at UT Southwestern Medical Center, Dallas.
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Urinary pro-thrombotic, anti-thrombotic, and fibrinolytic molecules as biomarkers of lupus nephritis
Objective This study evaluates the utility of urinary pro-thrombotic molecules such as tissue factor (TF), anti-thrombotic molecules such as tissue factor pathway inhibitor (TFPI), and fibrinolytic molecules such as plasmin and d-dimer as biomarkers of lupus nephritis (LN). Methods Urine samples from 113 biopsy-proven LN patients (89 active LN and 24 inactive LN), 45 chronic kidney disease patients, and 41 healthy controls were examined for d-dimer, plasmin, TF, and TFPI levels by ELISA. The area under the receiver operating characteristic curve (AUC) analysis, multivariate regression analysis, and Bayesian network analysis were performed to assess the diagnostic value of the assayed molecules in LN.
Results Although urinary d-dimer, plasmin, TF, and TFPI were all elevated in active LN compared to all control groups, and correlated with rSLEDAI and SLICC RAS disease activity indices, urine plasmin emerged as the strongest independent predictor of eGFR and renal disease status, by multivariate regression analysis and Bayesian network analysis. Whereas urine plasmin discriminated active LN from inactive disease with an AUC of 0.84, the combination of urine plasmin and TFPI discriminated ALN from ILN with an AUC of 0.86, with both surpassing the specificity and positive predictive value of traditional markers such as anti-dsDNA and complement C3.
Conclusion Both thrombogenic and thrombolytic cascades appear to be upregulated in lupus nephritis, with proteins from both cascades appearing in the urine. Of the coagulation cascade proteins surveyed, urine plasmin emerges as the strongest predictor of eGFR and clinical renal disease in patients with LN.