This is true for very few other diseases. Table 2 Summary of biomarkers and applicability to pediatric lupus nephritis. of what they called the lupus erythematosus cell [154], has now culminated in a body of literature that is continuously growing, relying no longer only on astute clinical observations, but on cutting edge technology. When looking back at the biomarker discoveries over the last decade, it is intriguing to see, to what extent our understanding of the pathogenesis of several novel molecules have the potential to transform the way LN patients are treated and followed (Figure 1). Open in a separate window Figure 1 Biomarkers in lupus nephritis. Yet, presently there is still a lot of work to do, before we can tuck away the renal biopsy needles. (flare, monitoring of disease at baseline, outcome prediction etc.) and the method (??)-Huperzine A applied for detection of the individual markers [63]. While the combination of high anti-dsDNA antibody titers and hypocomplementemia (due to immune complex-mediated activation of the classical pathway) are strongly associated with an impending LN flare, there are patients who have persistent serological activity in the absence of clinically active LN [64C67]. Creatinine An abnormal serum creatinine level at presentation is considered a negative (??)-Huperzine A prognostic factor for progression to end-stage renal disease (ESRD); mostly, because an acutely elevated serum creatinine level is usually a surrogate marker of acute, proliferative GN with or without crescent formation, particularly in the presence of hypertension, as seen in class (??)-Huperzine A IV LN [68]. However, an acutely elevated serum creatinine is usually neither diagnostic nor is it indicative of a flare, given that changes (??)-Huperzine A in this biomarker take several days to become appreciated and various factors impact its correlation with actual glomerular filtration rate [69]. A chronically elevated serum creatinine level is usually a crude indicator of advanced renal scarring, irreversible damage and reduced renal reserve [70]. Urine biomarkers Urine sediment (leukocytes, red blood cells) In a pediatric lupus cohort with and without renal disease at presentation, isolated sterile pyuria and hypoalbuminemia were predictive of renal disease in longitudinal analyses [71]. Isolated sterile pyuria has been noted in up to 13% adults with SLE in a cross-sectional study [72]. However, sterile pyuria can be associated with multiple etiologies besides SLE, including the use of nonsteroidal anti-inflammatory drugs. The significance of isolated hematuria in SLE is usually unclear. Adult studies investigating the correlation between isolated hematuria and histopathological findings uncover conflicting data [73,74]. The resolution of hematuria and other urinary findings may take several months and should not be the sole factor to determine resolution of an LN flare. Urinary findings, such as hematuria or pyuria, may be masked by the presence of menstrual bleeding or nonrenal causes of inflammation, respectively. Microscopic examination of the urinary sediment in the clinical setting to distinguish those entities from LN-related changes is not usually feasible. Proteinuria The diagnosis of proteinuria can only be accurately IGLC1 made in children once orthostatic (fixed) proteinuria is usually ruled out. Orthostatic proteinuria is usually a common benign obtaining in children and adolescents, but can also be found in young adults [75]. This condition was described in the 1920s and renal biopsies on individuals with orthostatic proteinuria showed normal histopathology [76,77]. To rule out postural proteinuria, a urine sample has to be collected in the morning, immediately after the patient gets out of bed, minimizing the time spent in the upright position or ambulating. It is also important to advise the patient to vacant the bladder on the night prior to that morning, to ensure that all urine that is collected was produced while in a recumbent position [77]. While orthostatic proteinuria in itself is a benign entity, it can significantly contribute to pre-existing proteinuria due to renal pathology. Hence, even if a patient is known to have LN, it is best advised to base disease activity on early morning urine samples only. The presence of persistent proteinuria may be an indicator of active renal disease, but its absence does not make sure the contrary. In a recent study, Wakasugi biopsied a cohort of 195 adult SLE patients, of whom 86 did not have clinical renal involvement. LN, other than class I was found in 58% of the SLE patients without clinical LN [78] and 15% of this subgroup had proliferative LN and this lack of quantitative correlation between the presence of proteinuria and disease severity has been exhibited before [79]. Promising experimental biomarkers for lupus nephritis Ideally, biomarkers that allow diagnosis, detection of a flare, outcome prediction and risk stratification should be developed to allow the clinician to initiate treatment early, particularly in those patients who are identified as at high risk for progression and would benefit from aggressive immunosuppressive treatment. However, as of the present, biomarker discovery, particularly in children, has not come even near any of these goals. A few biomarkers that were discovered in the recent past have made their way from the experimental setting into clinical trials, and even to becoming point-of-care tests. In this section, the LN biomarkers that are currently considered to be at the forefront of research and that have been.
