Molecular markers of injury in kidney biopsy specimens of patients with lupus nephritis.

Prediction of prognosis in patients who have lupus nephritis is inadequate, limiting individualization of potentially toxic therapy. Advances in tissue molecular techniques offer new approaches to study mechanisms underlying kidney injury, and add to prognostic information gleaned from biopsy specimens. Analysis of mRNA expression in formalin-fixed, paraffin-embedded renal biopsy specimens is limited by both quantity and quality of RNA, requiring RNA pre-amplification, which can introduce bias. Accordingly, we developed a new technique for RNA extraction from human kidney formalin fixed paraffin embedded biopsy specimens, and used Taqman low-density arrays Applied Biosystems, Carlsbad, CA to simultaneously measure 48 mRNAs in duplicate, in a single biopsy. We extracted mRNA from more than 150 blocks to determine the quantity and vintage of biopsy tissue suitable for analysis using this protocol. We then used Taqman low-density arrays to identify suitable housekeeping genes in lupus nephritis. Finally, we measured expression of 48 mRNA transcripts in archived lupus biopsy specimens (n = 54). We identified that the mRNA levels of three transcripts (MMP7, EGF, COL1A1) relate to pathological indices of kidney injury and kidney function at the time of biopsy; these were associated with parallel changes in expression of these proteins. This new method for measurement of kidney biopsy mRNA expression has enabled us to identify tissue biomarkers of kidney damage and function, and potentially can increase the information yielded from diagnostic kidney biopsy specimens to improve tailoring of therapy.

Persistent proteinuria and dyslipidemia increase the risk of progressive chronic kidney disease in lupus erythematosus.

Advances in immunotherapy have improved survival of patients with systemic lupus erythematosus who now face an increasing burden of chronic diseases including that of the kidney. As systemic inflammation is also thought to contribute directly to the progression of chronic kidney disease (CKD), we assessed this risk in patients with lupus, with and without a diagnosis of nephritis, and also identified modifiable risk factors. Accordingly, we enrolled 631 patients (predominantly Caucasian), of whom 504 were diagnosed with lupus within the first year and followed them an average of 11 years. Despite the presence of a chronic inflammatory disease, the rate of decline in renal function of 238 patients without nephritis was similar to that described for non-lupus patient cohorts. Progressive loss of kidney function developed exclusively in patients with lupus nephritis who had persistent proteinuria and dyslipidemia, although only six required dialysis or transplantation. The mortality rate was 16% with half of the deaths attributable to sepsis or cancer. Thus, despite the presence of a systemic inflammatory disease, the risk of progressive CKD in this lupus cohort was relatively low in the absence of nephritis. Hence, as in idiopathic glomerular disease, persistent proteinuria and dyslipidemia (modifiable risks) are the major factors for CKD progression in lupus patients with renal involvement.