Severe renal impairment as an adverse prognostic factor for survival in newly diagnosed multiple myeloma patients.

BACKGROUND: Renal impairment (RI) is associated with poor survival in newly diagnosed multiple myeloma (MM) patients. Renal function recovery has been one of the main therapeutic goals in those patients. METHODS: The records from 393 newly diagnosed MM patients in our hospital between January 2012 and December 2016 were retrospectively analyzed. RI was defined as an eGFR < 40 mL/min according to the novel IMWG criteria. RI patients were categorized based on their renal function at diagnosis: severe RI: eGFR < 30 mL/min, and mild RI: 30 mL/min ≤ eGFR <40 mL/min. We explored whether RI, and particularly severe RI, was an adverse prognostic factor for survival, and investigated the impact of renal function recovery on survival. RESULTS: Severe RI, hemoglobin <100 g/L, LDH ≥ 245 U/L, hyperuricemia, 1q21 amplification, and lack of novel agent treatment were associated with decreased overall survival (OS). Severe RI patients with renal response had a median OS of 27 months compared with 18 months for those patients without renal response (P = .030), but their median OS was still significantly lower than that for patients without severe RI, which was 51 months. In severe RI patients, the overall renal response rate in bortezomib-based regimens was significantly higher than that in nonbortezomib-based regimens. CONCLUSION: Our results suggest that severe RI is an adverse prognostic factor for survival in newly diagnosed MM patients, restoration of renal function may improve survival, and bortezomib-based regimens may be the preferred treatment in patients with severe RI.

[Effect of Serum Free Light Chain on Renal Function and Prognosis in Patients with Newly Diagnosed Multiple Myeloma].

OBJECTIVE: To analyze the effect of serum free light chain (sFLC) on renal function and prognosis in patients with newly diagnosed multiple myeloma (MM). METHODS: The clinical data of 70 newly diagnosed MM patients who received sFLC examination in Fujian Medical University Union Hospital were retrospectively analyzed from April 2012 to November 2016. Univariate analysis was used to analyze the risk factors that associated with renal impairment (RI) and prognosis. Logistic regression and Kaplan-Meier analyze were used to analyze the roles of sFLC in RI and the prognosis. RESULTS: Out of the 70 patients, 20 patients had RI at the initial diagnosis. Compared to normal renal function group, RI group had lower level of hemoglobin, elevated levels of serum uric acid, corrected calcium, serum creatinine, serum ß2 microglobulin, and involved sFLC, higher proportion of patients with ISS stage III, involved sFLC≥500 mg/L, hemodialysis (all P＜0.05). Multivariate logistic regression analysis showed that serum uric acid≥430 µmol/L, ISS stage III and a involved sFLC≥500 mg/L were all the independent risk factors for RI in patients with newly diagnosed MM patients (all P＜0.05). Receiver operating characteristic (ROC) curves analysis showed that the involved sFLC was 705.0 mg/L, which was a best cut-off value area under curve (AUC) for prediting RI in patients with MM was 0.727 (P=0.003), sensitivity was 65.0% and specificity was 82.0%). After a median follow-up period of 31 (1-84) months, the median overall survival (OS) of patients with involved sFLC≥500mg/L and involved sFLC＜500 mg/L were 52.0 and 27.0 months, respectively, there was no statistically significant difference (P=0.137). There was also no statistically significant difference in median OS between the high sFLC ratio group (κ/λ＞32 or ＜0.03) and the low sFLC ratio group (0.03≤κ/λ≤32) (27 months vs 40 months, P=0.436). CONCLUSION: The involved sFLC in the RI group is significantly higher than that in the normal renal function group in newly diagnosed MM patients. Serum uric acid≥430 µmol/L, ISS stage III and involved sFLC≥500 mg/L are the independent risk factors for RI. Monitoring sFLC in newly diagnosed MM patients is helpful to the prediction of RI, and the involved sFLC level or sFLC ratio may not affect the prognosis of newly diagnosed MM patients.

microRNA-199a may be involved in the pathogenesis of lupus nephritis via modulating the activation of NF-κB by targeting Klotho.

Klotho is considered to have renal protective effect by prohibiting the activation of the nuclear factor (NF)-κB pathway, while the role of microRNA-199a (miR-199a)/Klotho in lupus nephritis (LN) is still unknown. A single dose of pristane (0.5 ml) was intraperitoneally injected into 8 weeks-old female mice to establish the LN model. MiR-199a mimic or miR-199a inhibitor, Klotho plasmid or Klotho siRNA, and miR-199a inhibitor plus si-Klotho were transfected into lipopolysaccharides (LPS) stimulated human embryonic kidney 293 T (HEK293 T) cells. Western Blot was adopted to measure p-P65 expression. Tumor necrosis factor (TNF)-α and interleukin (IL)-1ß in the supernatant were determined by enzyme-linked immunosorbent assay (ELISA). The expression of Klotho was suppressed by miR-199a through direct binding to the three prime untranslated regions (3'-UTR). The high miR-199a level was accompanied by low Klotho expression in the LN kidney. MiR-199a promoted LPS-induced NF-κB activation and improved the secretion of TNF-α and IL-1ß by regulation of Klotho in HEK293 T cells. If miR-199a antagomir was administrated after 48 h of pristane administration, the expression of p-P65 and the secretion of TNF-α and IL-1ß were significantly down-regulated in LN kidney. Although the direct involvement and detailed mechanism of miR-199a in LN still need further investigation, our data show that MiR-199a could regulate the activation of NF-κB by directly targeting Klotho.

Icariin alleviates murine lupus nephritis via inhibiting NF-κB activation pathway and NLRP3 inflammasome.

AIMS: Lupus nephritis (LN) is a kidney inflammatory disease caused by systemic lupus erythematosus (SLE). Both NF-κB activation and NLRP3 inflammasome activation are implicated in LN pathogenesis, suggesting they are potential targets for LN treatment. Icariin, which is isolated from Chinese medicine Horny Goat Weed (Ying Yang Huo), has been shown to have anti-inflammation activity, and inhibit activations of both NF-κB and NLRP3 inflammasome. In present study, the effects of icariin on LN were evaluated in MRL/lpr mice. MAIN METHODS: We treated MRL/lpr mice with icariin for 8 weeks and then analyzed the renal function and kidney pathology. We monitored the levels of anti-dsDNA antibody and the deposition of immune complex after icariin treatment. We also detected the macrophage infiltration, NF-κB activation, NLRP3 inflammasome activation and inflammatory cytokine TNF-α production in MRL/lpr mice after icariin treatment. KEY FINDINGS: We found that MRL/lpr mice treated with icariin displayed significantly attenuated the renal disease. Icariin-treated mice showed significantly reduced serum anti-dsDNA antibody level and immune complex deposition. Icariin inhibited NF-κB activation and TNF-α production in MRL/lpr mice. Icariin inhibited CCL2 production and macrophage infiltration in MRL/lpr mice. Finally, icariin suppressed NLRP3 inflammasome activation and IL-1ß production in MRL/lpr mice. SIGNIFICANCE: Icariin alleviated murine lupus nephritis via inhibiting NF-κB activation and NLRP3 inflammasome activation.