Tubular Damage Is Ubiquitous in Newly-Diagnosed Patients with Multiple Myeloma: Comparison of Three Urinary and Two Serum Markers of Kidney Injury.
Authors: Dimopoulos Meletios A , Christoulas Dimitrios , Kastritis Efstathios , Gkotzamanidou Maria , Margeli Alexandra , Kanellias Nikolaos , Eleutherakis-Papaiakovou Evangelos , Papassotiriou Ioannis , Terpos Evangelos 
Published: October 2019

Abstract
Abstract 2919
Renal impairment is a common complication of multiple myeloma (MM). The CRAB criteria define the serum creatinine (sCr) level of >2 mg/dl as the cut-off value for starting therapy in MM patients. However, the measurement of sCr for the evaluation of renal impairment has several limitations. Furthermore, the estimation of glomerular filtration rate (GFR) by the MDRD equation has greater value in patients with stabilized sCr, while the majority of MM patients have acute renal damage, which may be irreversible. Thus, identification of individuals at higher risk of early kidney dysfunction is critical to the timely initiation of treatment to prevent permanent renal damage. For this reason, several markers of renal dysfunction have been used in renal disorders. Neutrophil gelatinase-associated lipocalin (NGAL) is a protein overproduced by proximal tubular cells in response to kidney injury, while kidney injury molecule-1 (KIM-1) is a type 1 transmembrane glycoprotein that is overexpressed in dedifferentiated proximal tubule epithelial cells after ischemic or toxic injury. Urinary NGAL and KIM-1 have never been evaluated in MM patients.
To assess the value of these molecules in MM, we measured urinary and serum NGAL, urinary KIM-1, urinary and serum cystatin-C (cys-C; a sensitive marker of GFR which is not secreted in the urine) in 48 newly diagnosed symptomatic MM patients (27M/21F, median age 65 years). The estimated GFR (eGFR) was calculated using the CKD-EPI equation (proposed by the CKD Epidemiology Collaboration and is widely accepted in renal impairment). Serum and urinary NGAL was evaluated using an ELISA method (BioPorto Diagnostics A/S, Gentofte, Denmark) with a protocol applied in the Siemens Advia 1800 clinical chemistry system. Serum and urinary cys-C was measured on the BN ProSpec analyser using a latex particle-enhanced nephelometric immunoassay (Dade Behring-Siemens Healthcare Diagnostics, Liederbach, Germany), while urinary KIM-1 was also measured using an ELISA (R&D Systems, Minneapolis, MN, USA). For the urinary measurements, a 24h urine collection was used.
Nine (19%) patients had sCr >2mg/dl, while 60% had eGFR ≥60 ml/min (CKD stages 1 & 2), 18.5% had eGFR 30–59 ml/min (CKD stage 3) and 21.5% eGFR <30 ml/min (CKD stages 4 & 5). The median values (range) for the studied markers in MM patients and in 120 healthy controls were: for urinary NGAL 36 ng/ml (0.5–2512 ng/ml) vs. 5.3 ng/ml (0.7–9.8 ng/ml), p<0.0001; for serum NGAL 162 ng/ml (53–576 ng/ml) vs. 63 ng/ml (37–106 ng/ml), p<0.0001; for urinary KIM-1 1.1 ng/ml (0.13–4.87 ng/ml) vs. 1.3 (0.1–5.3 ng/ml), p=0.345; for urinary Cys-C 0.05 mg/l (ND-13.9) vs. non-detectable, p<0.01; and for serum cys-C 1.0 mg/l (0.4–3.2 mg/l) vs. 0.7 (0.3–0.9 mg/l), p<0.01. Almost all patients (93%) had higher levels of urinary NGAL than the higher value of the controls; the respective frequency for the other markers was: 68% for serum NGAL and serum cys-C, 50% for urinary cys-C and only 10% for urinary KIM-1.
All studied markers correlated with eGFR: serum cys-C (r=−0.758, p<0.001), serum NGAL (r=−0.627, p<0.001), urinary cys-C (r=−0.498, p=0.008), urinary NGAL (r=−0.430, p=0.01) and urinary KIM-1 (r=−0.369, p=0.021). Only serum cys-C strongly correlated with the involved serum free light chain (r=0.806, p<0.001). Urinary NGAL correlated also with urinary cys-C (r=0.880, p<0.001), serum NGAL (r=0.503, p=0.002), 24-h proteinuria (r=0.431, p=0.01) and ISS stage (mean±SD values for ISS-1, ISS-2 and ISS-3 were: 31±29 ng/mL, 47±52 ng/mL and 408±695 ng/mL, respectively; p=0.03). Serum cys-C correlated also with ISS stage (the values for ISS-1, ISS-2 and ISS-3 were: 0.85±0.19 mg/L, 0.94±0.24 mg/L and 2.15±0.98 mg/L, respectively; p=0.01), while urinary cys-C correlated with 24-h proteinuria (r=0.564, p<0.001).
Our data suggest that almost all newly diagnosed symptomatic MM patients have tubular damage as assessed by elevated urinary NGAL suggesting that renal impairment is present very early in the disease course. Measurement of urinary NGAL and serum cys-C offers valuable information for the kidney function of MM patients and their measurement may help in the identification of patients with high risk for the development of acute renal function. The value of KIM-1 seems to be very low in myeloma reflecting the differences in the pathogenesis of myeloma-related renal dysfunction than toxic acute renal injury of other etiology.

Disclosures:
No relevant conflicts of interest to declare.