Biomarkers and Updates on Pediatrics Lupus Nephritis

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Key points

  • Lupus nephritis is frequently diagnosed in children with systemic lupus erythematosus and warrants close medical attention to avoid progression to end-stage renal disease.

  • Diagnosis of lupus nephritis requires at present a kidney biopsy.

  • Current laboratory tests used to monitor lupus nephritis lack accuracy, making appropriate management difficult.

  • Novel urine biomarkers hold promise for improving the approach to the surveillance of lupus nephritis and interpretation of patient response to therapy.

Epidemiology, course, and economic impact

Given the phenotypic differences of cSLE around the world, the prevalence of kidney involvement with cSLE likely also varies with racial background and environmental exposures. The incidence of SLE is thought to have increased 10-fold during the preceding 50 years in industrialized Western countries,2 which could indicate that cSLE in general, and LN in children in particular, also are becoming more frequent. Using information available in administrative databases and an algorithm that

Diagnosis of LN and classification

Kidney biopsies are required to establish the diagnosis of LN. Despite considerable variation in practice, there is consensus that reproducible daily proteinuria of at least 0.5 g, especially in the setting of an active urinary sediment, warrants a kidney biopsy in a child with cSLE who has not yet been diagnosed with LN.14, 15 Although clinically relevant biopsy findings are more common in the presence of significant proteinuria, the current approach results in at least 50% of newly diagnosed

Risk factors to poor outcome of LN

Clinical research has identified, albeit inconsistently, several risk factors for poor LN outcome3, 6, 16, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33; these include male gender, non-Caucasian race, nonadherence to treatment, presence of antiphospholipid or anti-dsDNA antibodies, persistent hypocomplementemia or proteinuria, nephrotic syndrome at presentation, failure to adequately respond to therapy by 3 months,34 flare of LN,35 or diagnosis with proliferative LN, especially in the setting of a

Monitoring of LN in clinical care

There are no studies that directly compare the clinical features of the various classes of LN between children and adults with SLE. However, the presentation of children with LN varies considerably, ranging from mild abnormalities on urinalysis, to anasarca caused by marked proteinuria, to posterior reversible encephalopathy owing to uncontrolled hypertension with nephritic syndrome.36

Shortcomings of traditional measures of LN

Whereas blood urea nitrogen and creatinine often stay in the normal range in cSLE, even if with profound histologic pathology, the urinary sediment and urinalysis are generally abnormal in untreated LN. Conversely, in pretreated patients only minor abnormalities on urinalysis, including mild proteinuria or hematuria, may be present in patients with severely active biopsy-proven LN. This finding is supported by the research of Christopher-Stine and colleagues,49 who reviewed 25 LN patients

Biomarkers and assessment of their quality

In its simplest definition, a biomarker is anything that can be measured to extract information about a biological state or process. The NIH Biomarkers Definitions Working Group has defined a biological marker (biomarker) as “A characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.”56 Biomarkers are the essential tools for the implementation of personalized

Types of LN biomarkers

Traditional measures of LN have limited responsiveness to change, and are unsuited to capture worsening or improvement of LN in a timely manner. This lack of early response measures to verify the effectiveness of LN therapies hinders clinical care, requires clinical trials of new medications for LN to study large populations and follow them over several years, and increases the risk of negative trials. In addition, traditional measures of kidney function, such as creatinine clearance or

Current treatment of lupus nephritis in children

The novel biomarkers introduced in the preceding sections are not used to support efficacy in clinical trials at present, although validation studies are ongoing to achieve biomarker qualification by regulatory bodies. Qualification would allow for the use of biomarkers in clinical care and research.127, 128 In addition, there is no known biomarker at present that a priori would support the choice of therapeutics for the treatment of LN. However, it seems reasonable to assume that novel

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      Of all the adipokines evaluated, only serum resistin was directly correlated with indicators of kidney injury (creatinine, BUN and proteinuria/creatininuria index). Much research has been done to identify the usefulness of these biomarkers for predicting not only the clinical course of the disease but also the type of histology of renal involvement in SLE,22–24 which plays a fundamental part in the diagnosis, treatment and prognosis of the disease. Studies such as the one by Brunner et al.,25 for example, identified how the combination of uMCP-1, urinary alpha-1 acid glycoprotein (uAAG) and urine ceruloplasmin were excellent biomarkers for predicting active proliferative LN when added to the use of the proteinuria/creatininuria index as a clinical marker of the disease.

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    Funding Sources: H.I.B. is supported by research grants from the National Institutes of Health, including 2P60AR047784, U01AR059509 and UL1 TR000077-04; M.B. is supported by a research grant from the National Institutes of Health, P50 DK096418 and two translational research grants from the Cincinnati Children’s Hospital Medical Center/University of Cincinnati Joint Center for Clinical and Translational Science and Training.

    Conflict of Interest: Nil.

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