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Classifying lupus nephritis: an ongoing story.

ABSTRACT: The role of the renal biopsy in lupus nephritis is to provide the diagnosis and to define the parameters of prognostic and therapeutic significance for an effective clinicopathological correlation. Various classification schemas initiated by World Health Organization in 1974 have been proposed until the most recent update by International Society of Nephrology/Renal Pathology Society in 2004. In this paper, we reviewed the new classification system with the associated literature to highlight the benefits and the weak points that emerged so far. The great advantage of the classification emerged to provide a uniform reporting for lupus nephritis all over the world. It has provided more reproducible results from different centers. However, the studies indicated that the presence of glomerular necrotizing lesion was no longer significant to determine the classes of lupus nephritis leading to loss of pathogenetic diversity of the classes. Another weakness of the classification that also emerged in time was the lack of discussions related to the prognostic significance of tubulointerstitial involvement which was not included in the classification. Therefore, the pathogenetic diversity of the classification still needs to be clarified by additional studies, and it needs to be improved by the inclusion of the tubulointerstitial lesions related to prognosis.

SUBMITTER: Kiremitci S

PROVIDER: S-EPMC4274910 | biostudies-other | 2014

REPOSITORIES: biostudies-other

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Project description:IntroductionTreatment with sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, has been shown to be efficacious in the MRL/lpr and NZB x NZW F1 mouse models of lupus nephritis, indicating a critical role for the mTOR pathway in both models. This type of demonstration of efficacy in animal models is usually a pre-requisite for advancement into clinical development. However, efficacy in an animal model often has not translated to the desired activity in the clinic. Therefore, a more profound understanding of the mechanistic similarities and differences between various animal models and human diseases is highly desirable.MethodsTranscriptional profiling was performed on kidneys from mice with lupus nephritis; from mice who had efficacious drug treatment; and from mice before they developed nephritis. Analysis of variance with false discovery rate adjusted to p < 0.05 and an average fold change of two or more was used to identify transcripts significantly associated with disease and response to therapy. Pathway analyses (using various bioinformatics tools) were carried out to understand the basis for drug efficacy in the mouse model. The relevance in human lupus of the pathways identified in the mouse model was explored using information from several databases derived from the published literature.ResultsWe identified a set of nephritis-associated genes in mouse kidney. Expression of the majority of these returned to asymptomatic levels on sirolimus treatment, confirming the correlation between expression levels and symptoms of nephritis. Network analysis showed that many of these nephritis genes are known to interact with the mTOR pathway. This led us to ask what human diseases are linked to the mTOR pathway. We constructed the mTOR pathway interactome consisting of proteins that interact with members of the mTOR pathway and identified a strong association between mTOR pathway genes and genes reported in the literature as being involved in human lupus.ConclusionsOur findings implicate the mTOR pathway as a critical contributor to human lupus. This broad pathway-based approach to understanding the similarities in, and differences between, animal models and human diseases may have broader utility.

Project description:IntroductionSystemic lupus erythematosus (SLE or lupus) is a chronic autoimmune disease, and kidney involvement with SLE, a.k.a. lupus nephritis (LN), is a frequent and severe complication of SLE that increases patient morbidity and mortality. About 50% of patients with SLE encounter renal abnormalities which, if left untreated, can lead to end-stage renal disease. Kidney biopsy is considered the criterion standard for diagnosis and staging of LN using the International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification, which was developed to help predict renal outcomes and assist with medical decision-making. However, kidney biopsy-based classification of LN is highly invasive and impractical for real-time monitoring of LN status. Here, nuclear magnetic resonance (NMR) spectroscopy-based metabolic profiling was used to identify urinary metabolites that discriminated between proliferative and pure membranous LN as defined by the ISN/RPS classification, and between LN and primary focal segmental glomerulosclerosis (FSGS).MethodsMetabolic profiling was conducted using urine samples of patients with proliferative LN without membranous features (Class III/IV; n = 7) or pure membranous LN (Class V; n = 7). Patients with primary FSGS and proteinuria (n = 10) served as disease controls. For each patient, demographic information and clinical data was obtained and a random urine sample collected to measure NMR spectra. Data and sample collection for patients with LN occurred around the time of kidney biopsy. Metabolic profiling analysis was done by visual inspection and principal component analysis.ResultsUrinary citrate levels were 8-fold lower in Class V LN compared to Class III/IV patients, who had normal levels of urinary citrate (P < 0.05). Class III/IV LN patients had > 10-fold lower levels of urinary taurine compared to Class V patients, who had mostly normal levels (P < 0.01). Class V LN patients had normal urinary hippurate levels compared to FSGS patients, who completely lacked urinary hippurate (P < 0.001).ConclusionsThis pilot study indicated differences in urinary metabolites between proliferative LN and pure membranous LN patients, and between LN and FSGS patients. If confirmed in larger studies, these urine metabolites may serve as biomarkers to help discriminate between different classes of LN, and between LN and FSGS.

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Classifying lupus nephritis: an ongoing story.

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