Clinical Association Between MTOR Pathway Activity In Renal Tissue And Disease Outcome Of Lupus Nephritis

Objective: To study the expression of mammalian target of rapamycin(m TOR)pathway in different components(tubules,glomeruli,renal vessels,renal interstitium)in the kidneys of lupus nephritis(LN)and to investigate the correlation between the expression level of m TOR and the severity and renal prognosis of LN,providing the theoretical basis and clinical evidence for LN targeted therapy.Methods: 23 patients with biopsy-proven LN in the Department of Nephrology,the Second Xiangya Hospital,Central South University,from January 1,2016,to December 31,2020,were included.We collected basic information and laboratory examinations about the patients,performed routine renal histopathological staining.Immunofluorescence staining of p-S6 and p-AKT was carried out to study the expression of m TORC1 and m TORC2 in different renal components.According to the expression levels of m TORC1 in different components,patients were divided into high,medium and low groups,to compare the clinical manifestations,pathology,and prognosis.Results: 1.A total of 23 patients were included,including 19 females(82.6%),4 males(17.4%).The average age was 29.7 ± 2.3 years old,1patient(4.3%)whose e GFR decreased by ≥50% and 1 patient(4.3%)who reached end-stage renal disease.2.Activation of p-S6 protein,a downstream effector molecule of m TORC1,could be observed in the tubules,glomeruli,renal vessels,and renal interstitium in patients with LN.In addition,the expression level of p-S6 was closely related to hemoglobin,serum creatinine,e GFR,24-hour urine protein,urine red blood cells,SLEDAI score,and AI score.However,the expression level of p-AKT,a downstream effector molecule of m TORC2,in tubules,glomeruli,renal blood vessels,and renal interstitium was not significantly correlated with the clinical severity in patients with LN.3.Comparison of the grading of m TORC1 activation in the kidneys of patients with LN3.1 In the m TORC1 high-activation group of the tubules,the hemoglobin,e GFR,hemoalbumin,complement C3 were lower(P=0.033,0.025,0.039,0.020 respectively),and 24-hour urine protein,urine red blood cell count,anti-ds-DNA antibody positive rate,SLEDAI score,AI,cell and fibroblast crescent body ratio,and stromal cell infiltration degree were higher(P=0.001,0.005,0.009,0.018,0.010,0.005,0.023respectively).The proportion of kidney survival in the m TORC1high-activation group decreased significantly(Log rank=7.099,P=0.029).3.2 In the m TORC1 high-activation group of the glomerular,the e GFR was lower(P=0.035),and the serum creatinine,24-hour urine protein,urine red blood cell count,SLEDAI score,AI,cell and fibroblast crescents were higher(P=0.015,<0.001,0.005,0.024,0.017,0.017respectively).The proportion of kidney survival in the m TORC1high-activation group decreased significantly(Log rank=6.648,P=0.036).3.3 In the m TORC1 high-activation group of the renal vascular,hemoglobin,e GFR,complement C3 were lower(P=0.019,0.001,0.030,respectively),and the serum creatinine,urinary red blood cell count,anti-ds-DNA antibody positive rate,SLEDAI score,cell,and fibroblast crescent proportion,and stromal cell infiltration were higher(P=0.011,0.006,0.008,0.028,0.028,0.040 respectively).The proportion of kidney survival in the high-activation group of m TORC1 decreased significantly(Log rank=6.196,P=0.045).3.4 In the m TORC1 high-activation group of the renal interstitium,e GFR was lower(P=0.002),and the serum creatinine,24-hour urine protein,urine red blood cell count were higher(P=0.015,0.049 and 0.002,respectively).The proportion of kidney survival in the m TORC1high-activation group decreased significantly(Log rank=7.099,P=0.029).Conclusion: The m TORC1 pathway in the tubules,glomeruli,renal vessels,and renal interstitium in patients with LN was significantly activated,and the level of activation was mainly related to the severity of renal involvement and poor prognosis;the activity of the m TORC1 pathway in renal tissue(especially the level of tubular expression)could be used as an effective indicator of disease activity and long-term prognosis in patients with LN.