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).
“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.
Background and objectives: Patients who have systemic lupus erythematosus (SLE) and manifest antiphospholipid antibodies (APA) are at increased risk for thrombosis; however, it is difficult to predict who will clot.
This study tested the hypothesis that peak D-dimer level measured routinely during follow-up identifies whether a hypercoagulable state is developing and, therefore, the patient is at increased risk for thrombosis.
Design, setting, participants, & measurements: One hundred consecutive patients who had SLE with recurrent activity (71% renal SLE) and were evaluated for or enrolled in the Ohio SLE Study were studied.
D-dimer testing was done annually and usually at SLE flare or other serious illness.
When D-dimer was elevated, evaluation for thrombosis (large vessel, small vessel, or Libman-Sacks) was undertaken. Mean follow-up was 37.5 ± 15 SD months.
Results: Of those with peak D-dimer <0.5 μg/ml (n = 46), 0% thrombosed, 33% had APA. Of those with peak D-dimer 0.5 to 2.0 μg/ml (n = 19), 6% thrombosed, 44% had APA
Of those with peak D-dimer >2.0 μg/ml (n = 36), 42% thrombosed, 76% had APA.
The most common causes of elevated D-dimer in the absence of demonstrable thrombosis were SLE flare and systemic infection. D-dimer levels were usually elevated for several months before thrombosis.
Conclusions: Patients with SLE and normal D-dimer levels are at low risk for thrombosis, irrespective of APA status.
Those with persistent unexplained elevated D-dimer levels, particularly when >2.0 μg/ml, are at high risk for thrombosis.
Thrombosis is an important manifestation of human systemic lupus erythematosus (SLE). Virtually any organ can be involved.
The thrombosis can occur in large or small vessels (1–3) or can involve the cardiac valves (Libman-Sacks) (4,5). When large-vessel thrombosis occurs, usually it involves the deep veins (DVT) of the lower extremities (2).
Large-vessel thrombosis can also involve arteries as a consequence of thromboembolism (e.g., from thrombi on the mitral or aortic valve in those with Libman-Sacks, “paradoxical embolism” through an atrial-septal defect) (6). Arterial thrombosis can also occur in situ, apparently as successive layers of clot accumulate until the lumen is stenosed or completely occluded (7).
When small-vessel thrombosis occurs and the predominant site is arteriolar, the usual manifestation is a thrombotic microangiopathic hemolytic anemia (1,8).
The lung can also be involved in small-vessel thrombosis. This process is independent of DVT and pulmonary embolism (9,10).
At autopsy, these cases show noninflammatory fibrin microthrombi in pulmonary vessels (10–16).
This thrombotic process in its mildest form may represent the unexplained reversible hypoxia of SLE flare (10,17).
In its more severe and chronic form, it may manifest as restrictive lung disease that can progress to severe pulmonary hypertension (8–11,15).
The small-vessel thrombotic lung disease of SLE may be analogous to that seen in primary pulmonary hypertension (18).
Small-vessel thrombosis in SLE can also affect the kidney with a characteristic arteriopathy that shows, side by side, acute thromboses and chronic vascular lesions.
The latter include arterial fibrous intimal hyperplasia, arteriosclerosis, and organized thromboses with or without recanalization (19).
The most common risk factors for thrombosis in SLE are antiphospholipid antibodies (APA), including anticardiolipin antibodies (ACL; IgG or IgM) or the lupus anticoagulant (LAC) (2). Collectively, these are referred to as APA.
The clotting disorder associated with APA is referred to as the antiphospholipid syndrome (2).
ACL is present in approximately 39% and LAC in approximately 22% of patients with SLE. These estimates are the median of the reported values described in a systematic review of the literature (2).
ACL in high titer (>5 SD above the mean; e.g., IgG ACL >40 GPL units) (20–22) increases the risk for clotting by approximately two-fold; LAC increases clotting risk approximately six-fold (23).
The absolute risk for clotting in untreated patients who have SLE with ACL, LAC, or both has not been well established (24); however, in patients who had SLE with APA and previously thrombosed but were not currently receiving anticoagulation therapy, the risk for recurrent thrombosis was 19 to 29 per 100 patient-years (24).
When thrombosis occurs in patients with SLE and APA, long-term warfarin therapy, perhaps for a lifetime, is generally recommended (2,23,25–27).
Less clear is how to treat patients who have SLE and APA but have not yet thrombosed (20,24).
This study tested the hypothesis that periodic measurement of D-dimers can identify whether the patient with SLE is becoming hypercoagulable and, therefore, is at increased risk for thrombosis regardless of their ACL/LAC status.
D-dimer is a cross-linked peptide derived from fibrin thrombus (28). In vivo, fibrin clot normally undergoes fibrinolysis by plasmin, which releases D-dimer as a specific fibrin-splitting product.
Thus, D-dimers are elevated in patients who have formed clots. Elevated D-dimer can also be present in those who are forming and degrading fibrin at an abnormally high rate but who do not have evidence of a clinically significant clot.
In such patients, elevated D-dimers have been used to predict the risk for recurrent DVT (29–31), pulmonary embolus (32), myocardial infarction (33), progression of primary pulmonary hypertension (18), or death in patients with peripheral arterial disease (34). Normal D-dimer levels have also been used to exclude clinically significant clot burden to exclude DVT or pulmonary embolism (35–37).
The association of D-dimer level and risk for clotting has not been reported in patients with SLE. This work addresses that unmet need.
More information: Ling Qin et al, Urinary pro-thrombotic, anti-thrombotic, and fibrinolytic molecules as biomarkers of lupus nephritis, Arthritis Research & Therapy (2019). DOI: 10.1186/s13075-019-1959-y
Journal information: Arthritis Research & Therapy , Arthritis Research and Therapy.
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