Studies On The Risk Factors Of Tubulointerstitial Lesions And Urinary Biomarkers Of Lupus Nephritis

Background and Objective：Lupus nephritis (LN) is a severe organ manifestation ofsystemic lupus erythematosus (SLE) and a major cause of morbidity. However,tubulointerstitial lesions (TIL) are also common in lupus nephritis. Despite of thecommon occurrence of tubulointerstitial disease, they were strongly associated with lessfavorable long-term renal prognosis. In the current situation, renal biopsy remains thegold standard for evaluating the severity of tubulointerstitial injury in lupus nephritis.Because of its invasiveness and potential risks, it is difficult to perform repeat-biopsiesfor several times on one patient. This is a challenge for monitoring the pathologicalchanges, adjusting therapeutic regimen in time and assessing the patients’ outcome. Thisstudy aimed to①analyze the outcomes of patients with different severity of TIL, andthe relationship between TIL and clinical and pathological parameters. Independent andimportant risk factors of the TIL were screened. Then a diagnostic predicting model ofTIL was established to predict the severity of TIL in lupus nephritis.②investigate thesignificance of urinary NGAL、KIM-1、L-FABP and IL-18level in order to assessingthe severity of the tubulointerstitial lesions in lupus nephritis.Subjects and Methods:1. Clinical and pathological parameters of309patients withlupus nephritis were collected. All patients were reviewed and reclassified according tothe ISN/RPS2003Classification System. Semiquantitative score was used to assess theseverity of the renal injury. Comparied the characteristics of TIL with different classes.Kaplan-Meier Curve was used to analyze the outcome of patients with different TIL.Risk factors of interstitial inflammatory cell infiltration, tubular epithelial celldegeneration, tubular atrophy and interstitial fibrosis were screened out bymultifactorial analysis. Then established a predicting model based on the multifactorialanalysis.2. The study cohort consisted of30lupus nephritis patients with different TIL. According to the degree of TIL, all patients were divided into two groups: nil or mild,and moderate-to-severe. The first morning voided urine samples were obtained.Urinary NGAL、KIM-1、L-FABP and IL-18level was detected by ELISA, and then,runk sum test was used to analyze the difference between groups. Fisher’s lineardiscriminant analysis was used to analyze their diagnosing significance in the severityof tubulointerstitial lesions in lupus nephritis.Results：1.①The age of onset of the309patients with biopsy-proven lupusnephritis ranged from11to73years, and male-to-female was1:3.61. According to the2003ISN/RPS classification of lupus nephritis,2cases were classified as class I,38cases as class II,36cases as class III (including class III+V)), and193cases as class IV(including IV+V),37cases as class V,3cases as class VI. The prevalence of theinterstitial inflammation, epithelial cell degeneration， tubular atrophy, and interstitialfibrosis, was86.5%,55.1%，66.5%, and66.9%， respectively. TIL determined therenal outcome in patients with lupus nephritis. The morbility of TIL had no sexdifferences, but it was different between different age, blood pressure, urinary proteinlevel and eGFR.②The severity of TIL in class II and V were much milder than that inclass III and IV. However, there was no significant difference between class III and IV.TIL contributed less to the pathological transformation by repeat biopsy. There was nodifference in TIL at the baseline biopsy between the patients who transformed to class IIand who maintained class IV at repeat biopsy, and between the baseline and repeatbiopsy.③Correlation analysis indicated that some glomerular active lesions were riskfactors of interstitial inflammatory cell infiltration and tubular epithelial celldegeneration. Glomerular sclerosis was risk factor of interstitial fibrosis. The lesions intubulointerstitium were interacted with each other.④Based on the results of logisticanalysis, hypercholesteremia, anemia, serum C3and lower eGFR were infependentimpact factors of TIL, we established a diagnostic model for predicting the severity ofTIL in lupus nephritis. The area under the curve was0.838. The sensibility andspecificity of the model by further validation was90.0%and52.9%, respectively.2.Urinary NGAL and KIM-1concentration was higher in patients with more severeinterstitial interstitial inflammation, and those who had more severe tubular atrophy andinterstitial fibrosis had higher NGAL, KIM-1, L-FABP concentration. Combining candidate urinary biomarkers, NGAL, KIM-1, L-FABP and IL-18， had a good value indiscriminating the severity of TIL in lupus nephritis.Conclusions：1. Tubulointerstitial lesions were common in lupus nephritis. TIL tendto be more severe in patients with advanced age, massive proteinuria, hypertension andlower eGFR. TIL determined the renal outcome in patients with lupus nephritis. Clinicalparameters were useful for evaluating the severity of TIL in lupus nephritis.2. Urinary NGAL, KIM-1, L-FABP may be the biomarkers of tubulointerstitial injuryin lupus nephritis.The performance characteristics to differentiate TIL status could beimproved, and misclassifications could be attenuated by combining candidate urinebiomarkers.