Current treatments for lupus nephritis in children are toxic and sometimes ineffective. New tests for proteins that might be abnormal in lupus nephritis could help make the diagnosis earlier and might also point to new ways of treating the disease.
Combinations of Biomarkers Indicate Lupus Nephritis Pathology
Non-invasive renal protein biomarkers are associated with histological features of lupus nephritis
Brunner HI, Bennett MR, Mina R, Suzuki M, Petri M, Kiani AN, Pendl J, Witte D, Ying J, Rovin BH, Devarajan P. Arthritis & Rheumatism. 2012 February 10. doi: 10.1002/art.34426. [Epub ahead of print]
What is the topic?
Lupus-related inflammation of the kidney, or lupus nephritis, is one of the most common and serious complications of systemic lupus erythematosus. In fact, kidney involvement in lupus is one of the main determinants of how lupus will progress in the long run.
Currently, a definitive diagnosis of lupus nephritis can only accurately be made by use of a kidney biopsy, an invasive procedure in which a small piece of kidney is removed and studied. A kidney biopsy is necessary to diagnosis lupus nephritis because blood-related measures are considered too inaccurate to distinguish between acute kidney inflammation that may be reduced with drug treatments and long-term changes or scarring in the kidney that may not improve despite drug therapy.
Several biomarkers that may indicate lupus nephritis-related disease activity have been studied in recent years (referred to hereafter as “traditional measures”). However, none have been systematically studied to determine their relationship to specific histological features of lupus nephritis (i.e., how the biomarkers are related to how lupus nephritis activity appears in a piece of kidney under the microscope). Establishing such a relationship could be a very important step towards less invasive ways to diagnose and assess lupus nephritis-related disease activity over time.
What did the researchers hope to learn?
The researchers hoped to learn about the relationship between biomarkers of lupus in the blood or urine and specific histological features of lupus nephritis.
Who was studied?
A total of 76 patients with either childhood-onset or adult-onset systemic lupus were included in the study.
How was the study conducted?
Children and adults diagnosed with lupus were included in the study if they underwent a kidney biopsy as part of standard of care therapy for lupus and if a urine sample was available within 60 days of the kidney biopsy. On the day of the urine sample, information about patients was collected, including demographics, medications, and disease activity. In addition, several laboratory measures were obtained, including the presence or absence of anti-double-stranded DNA antibodies (anti-ds-DNA), and levels of proteinuria (protein in the urine, which indicates kidney damage), complement, and creatinine, as well as glomerular filtration rate (GFR, which indicates kidney function or dysfunction).
A portion of the Systemic Lupus Disease Activity Index (SLEDAI) relevant to kidney disease was used to clinically assess lupus nephritis activity. The Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SDI) Damage Index was used to assess kidney damage. Several different aspects of histological features of lupus nephritis were reported by a pathologist and reviewed, in a blinded manner, by a nephropathologist (a pathologist with expertise in kidney pathology), as per the guidelines of the Society of Nephrology/Renal Pathology (ISN/RPS). A numerical scoring system was used to quantify overall lupus nephritis disease activity or chronicity.
What did the researchers find?
The lupus nephritis patients included in the study were a median age of 23 years old (range: 9-51 years) and 26 of the 76 patients were 18 years or younger. At the time of urine collection, most of the patients were taking steroids, many were taking immune-suppressing drugs, and the median SLEDAI score was 8, indicating overall moderate disease activity. About 75% of the patients included in the study (and for whom such information was available) had elevated levels of anti-ds-DNA. Only 3 of the 76 patients had kidney damage at the time of kidney biopsy.
Of several traditional measures of kidney function evaluated, proteinuria (as indicated by the ratio of protein to creatinine in the urine), was the only lupus biomarkers that was significantly associated with histological measures of lupus nephritis activity. Additional analyses revealed that GFR (as estimated by age-appropriate clearance of creatinine) and levels of blood creatinine differed with histological features indicative of lupus nephritis chronicity, as did the biomarkers NGAL and MCP1. There was no single biomarker that was a good diagnostic measure of Class 5 lupus nephritis (a type of kidney damage associated with significant amounts of protein in the urine), but a combination of five of these biomarkers yielded a good diagnostic test for Class 5 lupus nephritis (according to standards of the ISN/RPS). Each of the individual traditional measures was considered either “good-to-excellent” or “excellent” in predicting poor lupus nephritis-related outcomes. However, a combination of 3-5 of the traditional measures (namely, MCP1, CP, AAG, TF, and protein-to-creatinine ratio) could best indicate poor outcomes in people with lupus nephritis. More refined analyses, which included only data from patients who had their urine collected within 24 hours of their kidney biopsy, indicated that two specific biomarkers (namely, NGAL and L-PGDS) were significantly lower in patients who had specific kinds of kidney histopathology.
The combination of at least 4 biomarkers (namely, MCP1, CP, AAG, and proteinuria, or protein-to-creatinine ratio) was excellent in estimating histological lupus nephritis disease activity. The combination of at least 3 biomarkers (NGAL, GFR, and MCP1) was an excellent diagnostic test for lupus nephritis chronicity. A combination of 5 biomarkers (MCP1, GFR, AAG, TF, and C4) was a good indicator of Class 5 lupus nephritis.
What were the limitations of the study?
Several factors could influence histological changes in the kidney of lupus nephritis patients, including medications being taken and multiple kidney pathologies within a single patient. Therefore, the findings of this study need to be confirmed in a larger cohort of lupus nephritis patients and should include various ethnic groups.
What do the results mean for you?
These results suggest the feasibility of using a combination of biomarkers indicative of lupus nephritis to inform doctors and patients about acute and/or chronic lupus nephritis-related disease activity and associated histological changes in the kidney. In spite of these results, additional biomarkers are needed to provide the highly accurate diagnostic tests that are urgently needed by clinicians to help guide lupus nephritis therapy. The results need to be validated in larger, heterogeneous cohorts of lupus patients.
The researchers hoped to learn about whether a protein in the blood called C4d could serve as an indicator of lupus nephritis activity in people with lupus.