The present study was to evaluate the association of the serum transgelin-2, urinary IGFBp7, and urinary TIMP2, with renal impairment over a 24-month monitoring period in individuals with MM. Higher initial serum transgelin levels, urinary IGFBp7 and urinary TIMP2 had predictive value in detecting renal impairment at the end of the study period regardless of initial eGFR.

In our study cohort, the concentrations of U IGFBP-7/creatinine ratio, U TIMP2/creatinine ratio and serum transgelin levels were considerably higher in patients with MM compared to healthy controls. These findings corroborate the results of Woziwodzka et al. [1, 9].

TIMP-2 contributes to carcinogenesis and the development of MM by promoting tumor cell proliferation and metastasis [10]. However, Zakiyanov et al. and Mora-Gutiérrez et al. reported increased TIMP-2 levels in a number of nephropathies, including diabetes, vasculitis, tubulointerstitial fibrosis, and glomerulosclerosis [10, 11]. TIMP-2 is predominantly synthesized by the distal tubule, however, extrarenal production of TIMP-2 has been linked to the development of myeloma [12].

Transgelin expression is up-regulated in several cancer types indicating possible role in oncogenesis and shown to promote the proliferation and differentiation of mesenchymal stem cells from bone marrow. Further, transgelin is reportedly up-regulated in leukaemia and lymphoma cells [13].

This finding supports the work of Woziwodzka et al. who posited serum transgelin levels are involved in carcinogenesis and the emergence of cancer and may differ depending on the disease stage and tumor size. TIMP-2 has been shown to regulate NF-kB signaling, with higher TIMP-2 levels observed in inflammation (i.e., SIRS), and function as a vascular inflammatory modulator [14].

We observed statistically significant differences in U IGFBP-7/creatinine and U TIMP2/creatinine ratios between groups categorized according to MM disease stage in the present study. However, no statistically significant differences in serum transgelin levels were observed between MM disease stages. This finding corroborates the results of Woziwodzka et al. who reported positive correlations for urinary levels of IGFBP-7 and TIMP2 of with ISS stage. They also observed that the majority of patients with ISS stages II and III had higher urinary levels of IGFBP-7 than healthy individuals [9].

In the present study, individuals with an eGFR of < 60 mL/min/1.73 m2 had comparable U IGFBP-7/creatinine, and U TIMP2/creatinine ratios to patients with higher eGFR values but not with serum transgelin. Woziwodzka et al. reported no significant differences in urinary TIMP2 between patients with an eGFR of < 60 mL/min/1.73 m2 and patients with an eGFR of ≥ 60 mL/min/1.73 m2 [9]. Urbaniak-Kujda et al. posited TIMP-2 contributes to carcinogenesis, disease progress, and the development of osseous lesions in a study evaluated the utility of TIMP-2 as a a biomarker for kidney injury in myeloma [15]. Indeed, increased TIMP-2 production in stromal cells of the bone marrow may be essential for the development of osteolytic lesions in MM possible due to a weaker association betweenTIMP-2 levels and eGFR [16].

Woziwodzka et al. reported a significant increase in urinary IGFBP-7 levels in patients with an eGFR less than 60 mL/min/1.73 m2. Dittmann et al. also observed an association between serum levels of insulin-like growth factor-binding proteins and decreased eGFR [17].

The findings of the present study demonstrate that U IGFBP-7/creatinine and U TIMP2/creatinine ratios and serum transgelin levels have predictive value for renal insufficiency, a finding also reported by Woziwodzka et al. According to previous studies, the measurement of urinary NGAL levels may have utility as a more accurate predictor of RI in MM than serum levels as patients with renal involvement have higher urinary levels of NGAL and urinary FLC levels which are associated with eGFR [18].

In the present study, a significant association between serum transgelin levels and U TIMP2/creatinine ratio and disease-free survival were observed, however, U IGFBP-7/creatinine ratio was not associated with disease-free survival, these findings are inconsistent with the results of Bolomsky et al., who observed poor survival in patients with high urinary levels of IGFBp7 and TIMP2 and chromosomal abnormalities in MM cells with increased IGFBP-7 expression, an indicator of high-risk disease [19].

Our findings support a previous study by Yin et al. that posited transgelin-2 may represent as a therapeutic target given the specific expression of transgelin-2 by tumor cells. Transgelin-2 overexpression has also been shown to be associated with poor prognosis [20].

The combination of lenalidomide, dexamethasone, and bortezomib (a proteasome inhibitor) is the most common three-drug combination used to treat MM. Myeloma cells can be targeted by specific monoclonal antibodies (such as daratumumab, elotuzumab, isatuximab, and belantamab mafodotin), nuclear export inhibitors (such as selinexor), or histone deacetylase inhibitors (such as panobinostat) in cases of recurrent or treatment-resistant MM. Bortezomib is considered one of the most significant novel therapies for MM due to its numerous anti-myeloma effects including interruption of the cell cycle and activation of apoptosis, changes in the microenvironment of the bone marrow, and suppression of nuclear factor kappa B (NFB).

Patients with MM renal dysfunction may particularly benefit for treatment with bortezomib given its effect on improving renal function [21]. Bolomsky et al. also observed an association between treatment response to lenalidomide-dexamethasone and gene expression levels in bone marrow mononuclear cells [22].

The present study had several limitations. The present study comprised established cases of MM rather than patients with new diagnoses. Further, there were differences in sociodemographic and clinical characteristics between groups, patients were exposed to varying treatment plans, and a small sample size. Further studies using kidney biopsy samples may further elucidate the relationships of serum transgelin, urinary IGFBp7, and TIMP2 levels with renal dysfunction in MM. Additionally, studies comparing cases of MM renal involvement to a control group are required to validate the findings of the present study.