Multiple myeloma is a neoplastic disease of plasma cells that is prevalent in older individuals. Bone pain and pathological fractures due to osteolytic bone lesions, hypercalcemia, renal insufficiency, and bone marrow failure are the primary clinical features of MM [1].

The three new criteria recently been added to the diagnostic requirements of multiple myeloma by the International Myeloma Working Group (IMWG) are: 60% of marrow plasma cells are monoclonal; a free light chain (FLC) ratio of greater than 100 if the implicated serum FLC level is equal or greater than 100 mg/L,; and multiple localized lesions on magnetic resonance imaging (MRI) [2].

Approximately 25% of MM patients develop renal dysfunction which is associated with poor prognosis, particularly if renal dysfunction is persistent or progressive. However, the early and accurate identification of patients at risk of renal impairment is challenging using routine laboratory tests such as serum creatinine and estimated glomerular filtration rate [3].

As renal injury is a poor prognostic factor and increases the risk of future problems in patients with multiple myeloma, early identification is essential to allow prompt treatment for disease control and restoration of renal function [4]. Histological analysis of renal biopsy specimens remains the gold standard technique for the diagnosis of MM-related renal dysfunction; however, the significant morbidity and mortality associated with renal biopsy preclude its use as a screening tool. Accordingly, there is increasing interest in the development of non-invasive, accurate, and applicable diagnostic markers based on the pathogenesis of MM-related kidney disease [5].

The measurement of urinary levels of tissue inhibitor of matrix metalloproteinase 2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7), both function in promoting G1 cell cycle arrest, has demonstrated utility in predicting acute kidney injury [1, 6]. Additionally, TIMP-2 has utility as a marker of injury to distal renal tubular cells, while proximal cells have been shown to secrete IGFBP-7[1].

Transgelin-2 (SM22), a cytoskeletal actin-binding protein, is expressed by stem cells, fibroblasts, immune cells, and certain epithelial cells. Transgelin has also been shown to have utility as a marker of renal injury, glomerulosclerosis, and interstitial fibrosis [7]. Increased expression of transgelin has been observed in tubulointerstitial injury and glomerular injury, and is posited to be tissue-specific depending on the underlying disease etiology [1].

The study’s objective was to evaluate the utility of urinary IGFBP-7, urinary TIMP-2, and serum transgelin levels as biomarkers for the prediction of renal impairment in patents with multiple myeloma.

Study Design

This was a prospective study comprising a total of 90 patients attending the hematology and oncology units at Tanta and Kafr El Sheikh University Hospitals from July 2020 to January 2021. All patients had been diagnosed with multiple myeloma according to IMWG criteria. Exclusion criteria were recent infectious illness, hepatitis B virus infection, hepatitis C virus infection, AIDS, and neoplasms other than myeloma.

The control group comprised 30 healthy participants who were age- and sex-matched relatives of patients who were free from chronic or acute illness. Reference values used for non-routine laboratory tests in the present study were based on values from the control group.

Data Collection

The following sociodemographic and clinical data were retrieved from medical records in all patients: age, sex, date of initial diagnosis, and treatment protocol. We also used laboratory reports to obtain urinary light chain concentrations and serum levels of creatinine, albumin, beta 2-microglobulin, monoclonal protein, and creatinine. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2009 formula was used to calculate estimated glomerular filtration rate based on serum creatinine [8].

Measurement of Serum Transgelin, and Urinary IGFBP-7, and TIMP-2 Levels

Serum transgelin and urinary IGFBP-7 and TIMP-2 levels were measured in urine and serum samples taken from patients and control groups under strict aseptic conditions. All samples were processed and then stored at a temperature below 20° C. Serum transgelin levels were quantified using ELISA kits for transgelin from Lifespan BioSciences, Inc (catalog no: LS-F12693). Human IGFBP7 ELISA kits from Abcam was used to measure urinary IGFBP-7 levels (catalog no: ab229894). Quantikine ELSA Human TIMP-2 Immunoassays were used to measure urinary TIMP-2 levels (R &D systems, Catalog Number DTM200). All urinary biomarker levels were normalized by dividing by urine creatinine.

Transgelin, IGFBP-7, and TIMP-2 were chosen due to the availability, reasonable price, and simple methodology of respective ELISA techniques.

Patient Follow-up

Follow up information was gathered 24 months later at the final follow-up visit from medical records including treatment response, date and reason of death, and laboratory tests results including serum creatinine and eGFR. Patients were divided into four categories according to response to treatment as follows: complete response, partial response, steady disease (SD), or progressing disease (PD).

Data Processing

All data were evaluated using IBM SPSS software package version 20.0.