TF, TFPI and Plasmin as Novel Bio-markers in Early Diagnosis of Lupus Nephritis

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease affects various organs, characterized by diverse autoantibodies production,mainly anti-DNA and anti-nuclear antibodies . It demonstrates variations in incidence,prevalence, disease activity and prognosis according to race and ethnicity . Lupus nephritis (LN) is one of the most frequent and severe clinical manifestations of SLE, it affects over 60% of SLE patients representing a leading cause of morbidity and mortality . Early diagnosis and monitoring of the disease flares are still challenging , although of the novel immunosuppressive drugs and biologics, which brought improvements in recent SLE/LN survival rates .

The American College of Rheumatology (ACR) guidelines for the treatment of lupus nephritis , recommend change in treatment if response to therapy has not been achieved after 6 months of induction therapy. However, response to therapy is not well defined. In addition, renal damage can occur within 6 months while waiting to define this response. Decision support tools could help define response at the start of induction therapy and have the potential to improve outcomes .

Use of laboratory parameters for LN such as creatinine clearance, anti-ds DNA, proteinuria, urine protein-to-creatinine ratio (U-PCR),and complement levels are undesirable. These markers are of less sensitivity and specificity for evolve renal activity and injury in LN.They are not directly correlated with kidney damage, which can arise before kidney function affection. Outbreak of nephritis may occur in any condition in absence and new rise in the level of proteinuria.

Kidney biopsy is a gold standard to assess the histological category of LN and the level of activity and chronicity in glomeruli. But, it is an invasive procedure and continual biopsies are inappropriate in the observing and follow up of LN . It may have sampling error because of extent number of glomeruli obtained for LN activity and chronicity. So , many studies are focusing on identifying non-invasive biomarkers for the early diagnosis and follow up of the disease and the therapy response.

Urine is easily collected and can reflect the underlying renal affection more accurately than serum. Therefore, urine bio-markers represent promising candidates for the early disease diagnosis and monitoring .Thus, novel urinary bio-markers, which are able to distinguish lupus kidney activity and its extremity, anticipate kidney outbreak, and observe treatment reciprocation and illness breakthrough are clearly obligatory . Urinary bio-markers are more sensitive for lupus nephritis;they can appear in urine before functional derangement .

Coagulation system disorders and hyper-coagulability state have been reported in lupus nephritis, also the frequency of thrombotic events was documented to be higher in SLE patients than in the general population, and these events were associated with poor outcome .Both thrombo-genic and thrombolytic cascades appear to be up-regulated in lupus nephritis, with proteins from both cascades appearing in the urine .

Urinary levels of plasmin ,TF and TFPI are all elevated in active LN patients compared to inactive LN patients and healthy controls. All four proteins correlated with systemic disease activity and renal disease activity. Importantly, urine plasmin performed best among the four proteins in discriminating active LN from inactive disease, even better than traditional markers, such as anti dsDNA and complement C3. Furthermore, the combination of urine plasmin and TFPI showed higher specificity and negative predictive values than urine plasmin when compared to anti-dsDNA and complement C3.