Novel Serum Prognostic Markers For Light Chain Amyloidosis And Secondary Coagulation Factor X Deficiency

Part ⅠObjective:To explore the prognostic value of new serum biomarkers including neutrophil gelatinase-associated lipocalin(NGAL)and kidney injury molecule-1(KIM-1)in light chain amyloidosis(AL).Methods:The baseline and post-treatment serum samples of AL patients who were diagnosed in Peking Union Medical College Hospital between December 2017 and October 2019 were collected.Biomarkers including NGAL and KIM-1 were detected using enzyme-linked immunosorbent essay(ELISA).A retrospective analysis was conducted to explore the association between the levels of biomarkers and clinical characteristics.Results:A total of 173 patients were involved in the study.The threshold of NGAL that predicted 1-year overall survival(OS)was 78.7ng/mL,which divided patients into high and low NGAL groups.Patients with high NGAL had more advanced Mayo 2004(P=0.002)and 2012(P=0.048)stages,higher levels of cardiac troponin I(cTnI,0.11 vs 0.05μg/L,P=0.007)and N-terminal pro-brain natriuretic peptide(NT-proBNP,3485 vs 2768 pg/mL,P=0.092),and lower level of estimated glomerular filtration rate(eGFR,73.1 vs 91.3 mL/min/1.73 m2,P<0.001).Within each stage of Mayo 2004 stages,the levels of both NGAL and KIM-1 were significantly higher in patients with eGFR<60 than those in patients with eGFR≥60.Whether among patients with eGFR≥90 or eGFR<90,patients with Mayo Ⅲ stage tended to have higher levels of NGAL.Patients with high NGAL tended to achieved lower cardiac(47.4%vs 62.5%,P=0.073)response rate,whose survival were significantly worse(estimated 3-year OS:54%vs 76.3%,P=0.005).Higher NGAL level(NGAL>78.7ng/mL)was associated with poor prognosis independently(HR:1.802,95%CI 1.032-3.145,P=0.038).A new risk stratification was built using NGAL>78.7ng/mL、dFLC>180mg/L、cTnI>0.08μg/L、NT-proBNP>3500 ng/L as the risk factors,which could discriminate patients with different degrees of risk effectively(P<0.001).The new risk stratification predicted prognosis better than both Mayo 2004 and 2012 stages.The C-index of the new stratification was 0.745,higher than those of Mayo 2004 and 2012 stages,0.667 and 0.708 respectively.Baseline KIM-1>2389.2pg/mL could predict chronic kidney disease(CKD)progression(Area=0.711,P=0.004),whose sensitivity(87.5%vs 55.4%)and specificity were both higher than eGFR.Patients with a reduction of NGAL level>25%achieved higher cardiac(88.1%vs 51.9%,P=0.001)and renal(78.8%vs 47.8%,P=0.016)response,as well as a better survival(estimated 3-year OS:95.3%vs 71.2%,P=0.002).Conclusion:NGAL was a new biomarker associated with both renal involvement and severe cardiac involvement.Baseline NGAL>78.7ng/mL predicted worse prognosis independently.The new risk stratification based on NGAL、cTnI、NT-proBNP、dFLC could predict outcomes more efficiently than Mayo 2004 and 2012 stages.KIM-1 was a new biomarker associated with renal involvement,which had the potential to predict the renal outcome.Part ⅡObjective:To describe the clinical manifestations,treatment and prognosis in patients with light chain amyloidosis(AL)with factor X deficiency in the Chinese population.Methods:The clinical data of newly diagnosed AL patients in Peking Union Medical College Hospital between June 2015 and December 2020 were collected and analyzed retrospectively.Results:The median FX level was 65.2%(range,1.4%-145.1%)in 148 patients.Among them,a total of 65(43.9%),16(10.8%)and 17(11.5%)patients suffered mild,moderate and severe FX deficiency.Among 136 patients diagnosed consecutively after March 2019,the percentage of mild,moderate and severe FX deficiency was 47.8%,11.0%and 5.1%.Patients with severe FX deficiency had lower rates of heart involvement(47.1%vs 75.6%,P=0.020)and higher renal(88.2%vs 64.9%,P=0.053)and hepatic(58.8%vs 25.2%,P=0.008)involvement rates,instead.There were 23 patients having bleeding symptoms,including 11 patients with Grade Ⅱ bleeding and 12 patients with Grade Ⅲbleeding.Of them,the numbers of patients with mild,moderate and severe FX deficiency were 1(4.3%)、8(34.8%)、14(60.9%)respectively.All of the 9 patients who had FX<10%had bleeding symptoms.The level of FX was negatively correlated with bleeding severity(p=-0.499,P=0.015).Patients with severe FX deficiency tended to achieve lower overall hematologic(57.1%vs 78.9%,P=0.094),cardiac(0 vs 46.4%,P=0.034)and renal(7.7%vs 41.8%,P=0.027)response,as well as shorted overall survival(30.0 months vs not reached,P=0.044).Bortezomib-based treatment helped improve FX levels and relieve bleeding symptoms to some degree.The level of FX increased in 10 of 11 patients.The median level of FX increased by 7.4%(range,1.5%-51.8%)and the degree of symptom improvement was correlated with the hematological response(p=0.583,P=0.006).Conclusion:Acquired FX deficiency was the common complication of AL patients.Patients with severe FX deficiency had higher risk of bleeding and more severe bleeding symptoms.Severe FX deficiency was associated with worse hematological and organ response and poor prognosis.Bortezomib-based treatment could improve FX levels and bleeding symptoms to some degree,whose response was correlated with hematological response.