P0745urine Timp-2 and Igfbp-7- New Biomarkers of Kidney Injury in Multiple Myeloma Patients

Abstract

Background and Aims Urine tissue inhibitor of metalloproteinases-2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7) seem to be novel kidney injury related biomarkers, especially in tubular cells damage. Free light chains (FLCs) are associated with renal failure in multiple myeloma (MM) and appear to have a prognostic value and indicate stages in MM. The aim of the study was to investigate the correlation between new biomarkers and acclaimed parameters of renal failure and markers of MM stages and prognosis. Method The study included 124 patients with MM in the mean age of 66 +/- 10 years, with median time from MM diagnosis of 30 (lower; upper quartile 14; 63) months. There were 7(6%) patients with smoldering MM, 80(65%) with ISS stage 1, 22 (18%)with stage 2 and 15 (12%) with stage 3 MM. Mean eGFR was 71 +/- 25 ml/min/1.73 m2 and 30 (24%) patients had eGFR <60 ml/min/1.73 m2. The examined parameters included creatinine, urine NGAL, urine and serum cystatin-C, urine and serum FLC kappa and lambda, serum monoclonal protein, IGFBP-7 and TIMP-2 in serum and urine, WBC count, IL-6, NT-proBNP, serum albumin and β2-microglobulin. IGFBP-7 and TIMP-2 in serum were measured in a subgroup of 73 patients, including 26 (36%) with eGFR <60 ml/min/1.73 m2. The association between between these parameters were determined by multivariate stepwise regression analysis. The p-value <0.05 was considered statistically significant. Results Except for urine cystatin C and urine TIMP-2, all the studied markers were higher among patients with eGFR <60 ml/min/1.73m2: urine NGAL: 23.3 (9.2; 68.4) vs. 7.8 (3.9; 16.8) ng/ml; p<0.001; urine IGFBP-7: ; serum IGFBP-7: 86.2 (29.3; 125.0) vs. 33.7 (13.2; 61.5) ng/ml; p=0.003; and serum TIMP-2: 628 (498; 663) vs. 431 (360; 614) ng/ml; p=0.011, respectively. Serum and urine IGFBP-7 and urine NGAL were also higher among patients with ISS grade 3 comparing to the rest of the group (p=0.008, p<0.001 and p=0.033, respectively). Patients with smoldering myeloma did not differ from those with symptomatic disease. No differences in studied markers were observed between patients with newly diagnosed MM in comparison to those who had been treated with one or more schemes. Only urinary IGFBP-7 differed between patients who were on treatment at the time of samples’ collection (median ng/ml) in comparison to untreated (median ng/ml; p=0.009). No differences in TIMP-2 and IGFBP-7 levels in patients divided according to MM state were observed (remission vs stable vs progressive disease). In whole studied group, urinary markers of tubular injury were interrelated: cystatin C correlated positively with NGAL monomer (R=0.22; p=0.016), IGFBP-7 (R=0.26; p=0.004) and TIMP-2 (R=0.22; p=0.016), NGAL correlated positively with IGFBP-7 (R=0.39; p<0.001) and TIMP-2 (R=0.25; p=0.005), and IGFBP-7 correlated positively with TIMP-2 (R=0.31; p<0.001). In multiple linear regression, the negative correlation between urinary IGFBP-7 and eGFR was independent of other studied urinary markers of tubular injury. However, after adjustment for confounders (age, smoldering versus symptomatic MM, ISS, LDH, remission versus stable or progressive disease, and the concentrations of involved urine light chains), only urinary NGAL was independently associated with eGFR. Conclusion Urine TIMP-2 and IGFBP-7 may be useful in investigating tubular renal damage in patients with chronic kidney injury among patients with MM. This can lead to noninvasive biomarker-targeted diagnostic interventions and contribute to early beginning of treatment that may improve life expectancy quality of life in MM.