Clinical applications of urine proteomics to lupus nephritis

Lupus nephritis, which is a kidney disease caused by lupus, often leads to kidney failure, but it is thought that early treatment may prevent damage. Unfortunately, early treatment is not possible with the current diagnosis methods, which rely on detecting high levels of protein in the urine (proteinuria). When proteinuria is detected in lupus patients, their kidneys may already be damaged. Therefore, an earlier diagnostic test is urgently needed.

Dr. Fava will use this LRA Lupus Innovation Award to identify novel markers that suggest the development of lupus nephritis. These markers will be used to create a reliable selection of urine compounds that can predict the start of lupus nephritis before proteinuria can be detected.

What this study means for people with lupus

This research could lead to the development of a novel noninvasive test to detect lupus nephritis before kidney damage occurs, which may shift the management of lupus nephritis from treatment to prevention, providing more opportunities to avert irreversible kidney damage in lupus patients.

Lupus nephritis (LN) is diagnosed by kidney biopsy in patients with proteinuria. But proteinuria implies that underlying kidney injury has already occurred with ~30% of nephrons permanently lost by the time of diagnosis of LN. Per protocol kidney biopsy studies have demonstrated clinically significant immune mediated LN (class III and IV) before the onset of proteinuria. We identified urinary biomarkers of intrarenal inflammatory activity, regardless of proteinuria amount. We hypothesized that incipient LN can be detected by urinary biomarkers before the onset of proteinuria. A noninvasive biomarker to detect active intrarenal inflammation rather than nonspecific injury (such as proteinuria) may reshape the management of lupus nephritis (LN) and prevent irreversible damage. In fact, the identification of LN before kidney injury (proteinuria) could shift the management strategy of LN from treatment to prevention potentially leading to important benefits for patients, including less exposure to toxic medications and better preservation of renal mass. Futhermore, the study of preproteinuric LN is a unique opportunity to discover early pathogenic mechanisms that may be missed in established LN, in which there is a complex environment of inflammation, ischemia, and tissue damage, not to mention the effects of treatment.
We aim to develop noninvasive urinary biomarkers to 1) detect LN before onset of proteinuria and 2) guide tapering of immunosuppression in LN patients in “apparent remission” based on proteinuria.
Aim 1 – Develop a urine biomarker panel to identify new lupus nephritis BEFORE proteinuria. We found that urinary IL-16, CD163, and neutrophil granule content indicate intrarenal LN activity. These biomarkers will be quantitated in urine samples collected within 3 months before the onset of proteinuria in lupus patients who ultimately were diagnosed with LN by renal biopsy to determine if the biomarkers are elevated compared to patients who do not develop LN. A full urine proteomic profile will also be assessed to discover additional biomarkers that could contribute to a robust panel for predicting onset of LN before proteinuria.
Aim 2 – Develop a urine biomarker panel to guide tapering of immunosuppression in treated LN patients. Per protocol kidney biopsies in LN patients in proteinuric remission showed that a histological NIH activity index (AI) >2 associated with LN flare and increased mortality upon tapering of immunosuppression. We identified urinary biomarkers of AI >2 (IL-16, CD163, Galectin-1, and PRTN3): these will be quantitated (along with 1200 proteins) in urine samples from LN patients in apparent clinical remission who flared upon tapering immunosuppression versus LN patients who did not flare upon tapering.