Soluble Urokinase-Type Plasminogen Activator Receptor (suPAR) Is a Renal Biomarker with Potential Clinical Applications in Monoclonal Gammopathy of Renal Significance (MGRS)
Authors: Kastritis Eftathios , Papassotiriou Ioannis , Roussou Maria , Gavriatopoulou Maria , Aimilia Mantzou , Psimenou Erasmia , Marinaki Smaragdi , Gakiopoulou Charikleia , Margeli Alexandra , Kanellias Nikolaos , Migkou Magdalini , Fotiou Despina , Ntanasis-Stathopoulos Ioannis , Papassotiriou Gerasimos-Petros , Papanota Aristea-Maria , Terpos Evangelos , Dimopoulos Meletios A. 
Published: November 2019

Monoclonal Gammopathy of Renal significance encompasses a spectrum of different renal pathologies that have a causal relationship with an underlying monoclonal protein produced by a, relatively indolent, plasma or other B-cell clone. These patients require anti-clonal treatment in order to salvage kidney function, however, there are few prognostic biomarkers that can help identify patients at higher risk for progression of renal disease. Increased plasma levels of soluble urokinase-type plasminogen activator receptor (suPAR) have been associated with focal segmental glomerulosclerosis and an elevated level of suPAR was independently associated with incident chronic kidney disease and an accelerated decline in the eGFR, in a large study (Hayek S et al, N Engl J Med 2015; 373:1916-1925). Increased Growth Differentiation Factor-15 (GDF-15) has been associated with the deterioration of renal function and progression to ESRD in diabetic patients but also in patients with AL amyloidosis. Neutrophil Gelatinase-Associated Lipocalin (NGAL) is one of the earliest and most robust markers of acute kidney injury while serum Cystatin C (CysC) reflects renal function more accurately than creatinine and correlates with both tumor burden and renal function in MM.
We measured serum levels of suPAR, NGAL, GDF-15 and CysC in the same frozen serum sample that was collected before any therapy was given. Measurements of the analytes were performed by means of immunoenzymatic techniques: suPAR (ViroGates A/S, Birkerod, Denmark), NGAL and GDF-15 (R&D Systems, Minneapolis, MN, USA), while CysC was measured with an immunoturbidimetric assay using the Roche Cobas 6000 Clinical Chemistry System.
The study included 23 patients with MGRS (MIDD: 18, C3GN: 3, PGNMID: 2), 57% were men, median age was 66 years (range 47-85). Median baseline eGFR (by CKD-EPI) was 30.5 ml/min/1.73 m2 (range 3-102) and at the time of initiation of therapy one (4%) required dialysis. Median baseline proteinuria was 1.7 gr/d (range 0.6-10.2). Median dFLC was 57 mg/L (range 2-2,239) and median BM infiltration was 10% (range 0-50%). At initial presentation 92% had hypertension, requiring a median of 2 different drug classes (range 1-5). Median baseline levels of suPAR were 8.02 ng/ml (range 2.2-21), of CysC were 2.33 mg/L (0.94-7.03), of NGAL were 150.6 ng/ml (range 51.7-573) and of GDF-15 were 2,144 pg/ml (range 548-6,956). A correlation of suPAR levels was found with proteinuria (r=0.691, p=0.001), serum albumin levels (r=-0.706, p<0.001) and age (p=0.012) but not with baseline eGFR (p=0.49). GDF-15 correlated with eGFR (r=-0.662, p=0.001) but also with proteinuria (r=-0.535, p=0.018), while NGAL (r=-0.714, p<0.001), CysC (r=-0.727, p<0.001) correlated strongly with eGFR but not with proteinuria or serum albumin (p>0.2 for all). All these biomarkers showed significant correlations with each other (p<0.007 for all in between correlations).
All patients received bortezomib-based therapy (with cyclophosphamide and dexamethasone); median follow up is 9 months and at 3 month landmark, 55% of evaluable patients had achieved a hematologic response while at 6 months 60% had a hematologic response. At the same time points a renal response (>50% reduction of proteinuria and <25% decline in eGFR) was 44% and 53% respectively. There was no significant correlation of baseline levels of suPAR, NGAL, GDF-15 or CysC with renal response; however, we found a trend towards an association of lower baseline suPAR with a higher probability of >50% reduction of proteinuria (p=0.096), which after adjustment for baseline proteinuria and eGFR became clearer (p=0.054).
We conclude that suPAR, NGAL, GDF-15 and CysC are markers with significant associations with renal function in patients with MGRS, but, from a clinical standpoint suPAR is probably the most promising marker with potential prognostic significance for renal outcomes. Additional follow up of the cohort and inclusion of additional patients will allow us to further evaluate this biomarker in MGRS.

Disclosures
Kastritis: Janssen: Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Honoraria; Prothena: Honoraria; Amgen: Honoraria, Research Funding; Genesis: Honoraria. Gavriatopoulou:Amgen: Honoraria; Janssen: Honoraria, Other: Travel expenses; Takeda: Honoraria, Other: Travel expenses; Genesis: Honoraria, Other: Travel expenses. Papassotiriou:Roche: Employment. Terpos:Janssen: Honoraria, Other: Travel expenses, Research Funding; Medison: Honoraria; Takeda: Honoraria, Other: Travel expenses, Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria; Genesis: Honoraria, Other: Travel expenses, Research Funding. Dimopoulos:Sanofi Oncology: Research Funding.