Symposium 3.5 – Complicated lupus nephritis

Symposium Summary

Written by Jasna Trbojevic-Stankovic
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Management of refractory lupus nephritis

Hans-Joachim Anders, Germany

Intense immunosuppression is the treatment of choice for LN to control systemic autoimmunity and intrarenal inflammation. However, failing to respond to induction therapy with immunosuppressive drugs is associated with an unfortunate long-term kidney prognosis and lower overall survival. A major challenge in determining the optimal treatment approach for refractory lupus nephritis (RLN) is the lack of a consensus definition for complete response following induction treatment. Current treatment guidelines suggest evaluating the response to immunosuppressive drugs with biomarkers (i.e. serum creatinine level, haematuria, proteinuria), but the time point of assessment is not clearly defined.

Importantly, not all RLN cases are due to lupus. Some patients with RLN may also have unrecognized drug nonadherence, especially because oral medications prevail, and some individuals may have unrelated genetic factors promoting the persistence of proteinuria or CKD progression. Moreover, persistent proteinuria may not be an immunological phenomenon of LN and could be driven by hyperfiltration provoked by obesity or diabetes.

The latest KDIGO guidelines have proposed an algorithm for a structured approach to RLN aiming to assist practitioners.

Some centres perform kidney biopsies after completion of treatment for an episode of LN as a part of the treatment evaluation. These biopsies are often termed “repeat biopsies”. Several studies have reported that these biopsies show the activity of the disease at the tissue level, even in patients with normal routine blood and urine markers. Such data is essential and should be taken into consideration when deciding on the treatment. To provide evidence for this, a collaborative project within the frame of the Lupus Nephritis Trials Network has been designed. In this ongoing research project, the investigators will compare the results of treatment between the groups of patients who did and did not undergo repeat biopsy, concerning complete disease inactivity at month 24 and renal function at month 60 from treatment initiation. This will provide a rationale for performing repeat biopsies as a part of the treatment evaluation. In addition, genetic testing is also significant. For instance, lupus podocytopathy can be confirmed as a cause of RLN by functional genetics on patient-derived podocytes.

A better understanding of what RLN is and how definitions can be integrated into treatment pathways has the potential to enhance LN outcomes. Hence, the poor prognosis of RLN demands individualization of LN treatment, regular review of patient response, and the flexibility to switch or augment therapy.

Urinary exosomal miRNA expression profile in lupus nephritis

Benedetta Bussolati, Italy

Extracellular vesicles (EVs) are a heterogeneous group of particles released by almost any cell that include exosomes, micro-vesicles, and apoptotic bodies. During their formation, they incorporate different bioactive molecules from their cells of origin, such as soluble proteins, membrane receptors, nucleic acids (mainly small RNA species, such as micro RNAs (miRNA)), and lipids, which in turn can be transferred to target cells. MiRNAs are a family of small non-coding RNAs, which play an important role in a variety of biological processes, through their regulation of post-transcriptional gene expression.

The discovery of miRNAs in various biological fluids suggests that they may be functioning as paracrine or endocrine signals between cells. In the kidney, miRNAs are indispensable to the regulatory mechanisms for renal development, maintenance of renal function, and homeostasis processes. Urinary miRNAs may be filtered from the circulation but are more frequently released from nephron cells actively secreted into exosomes enriched in kidney-specific miRNAs. Changes in urinary miRNAs have been reported in several renal diseases. The fact that exosomal-derived urinary miRNAs can accurately reflect structural damage and renal dysfunction makes them good biomarkers for the diagnosis and prognosis of renal diseases. In LN, microRNA alterations may be directly related to the presence of autoantibodies against Dicer and Ago, proteins involved in miRNA maturation and stability. Alternatively, miRNAs can be expression of tissue alterations, as EV cargo reflects the physio pathological state of the originating cell facing the urinary lumen.

Figure 1 MiRNAs are altered in patients with LN

In LN, several exosomal-derived miRNAs have been identified as markers of early fibrosis, podocyte injury, type IV class of nephritis, and the presence of cellular crescents, and can discriminate active LN. For instance, Li et al. demonstrated that Type IV LN (LNIV) with crescents has a unique miRNA expression profile of urinary exosome and complex regulatory network. They found that miR-3135b, miR-654-5p, and miR-146a-5p in urinary exosomes could be used as novel non-invasive diagnostic markers for LNIV with crescents. Moreover, the microRNA miR-146a is a negative regulator of the interferon pathway. Under expression of miR-146a contributes to alterations in the type I interferon pathway in lupus patients by targeting the key signalling proteins. Additionally, miR-29c, miR-21, and miR-150 have been identified as novel markers that contribute to fibrosis in patients with LN. Specifically, miR-29c is identified as an early marker of fibrosis in LN.

All these findings may also provide potential novel strategies for therapeutic intervention. Preclinical data suggest that the inhibition of miR-654 expression aggravates pristine-induced LN. However, there is rare news on the advance of miRNA drugs. One miRNA generally targets tens and even hundreds of genes, which means that miRNA therapeutics would trigger a series of unknown and unpreventable consequences.

Urinary exosomal miRNA expression profile in lupus nephritis

Agnes Fogo, United States of America

LN can be defined as a glomerular immune complex disease that occurs in patients with systemic lupus erythematosus (SLE). The varying glomerular immune complex patterns are diagnosed according to the ISN/RPS classification. These include predominantly mesangial deposits (classes I, II), subendothelial deposits with endocapillary hypercellularity or prominent glomerular basement membrane (GBM) duplication and wire-loop lesions, often with necrotizing and crescentic lesions (classes III and IV, focal and diffuse LN), or membranous forms (class V).

Figure 2. Presenting clinical features of different LN classes
(Seshan S, Jennette JC. Arch Pathol Lab Med 2009; 133:233-48)

To improve the LN classification using an evidence-based approach and refine the definitions for glomerular lesions a working group for LN classification met in Leiden (Netherlands) in May 2016 to reach a consensus on this topic. Their recommendations for LN classification are summarized in Figure 3.

Figure 3. Working group for LN classification: Phase 1 recommendations for LN classification
(Bajema IM, Wilhelmus S, Alpers CE, et al. Kidney Int. 2018;93(4):789-796)

Decisively, the group proposed two important alterations in the classification system, namely to abandon the segmental and global designations in class IV, and to replace the A, C, and A/ C designations of classes III and IV by use of modified NIH LN activity and chronicity scoring indices.

Currently, the ISN/RPS lupus classification does not evaluate vascular lesions. The group believes in the importance of a standardized approach and terminology to distinguish ordinary arterial or arteriolar sclerosis from lupus-related lesions, such as vasculopathy associated with immune complex deposition, vasculitis, and TMA. They propose that lupus vasculopathy should be defined as luminal narrowing of arterioles or terminal interlobular arteries by intramural immune deposits, typically admixed with fibrinoid changes, without inflammation of the vessel wall. Regarding tubulointerstitial lesions, the group at this time advocates indicating in biopsy reports whether interstitial inflammation occurs in the presence or absence of interstitial fibrosis. In phase 2 it has to be determined whether interstitial fibrosis and tubular atrophy should be considered separately or combined into one parameter and whether making a distinction between interstitial inflammation in areas with or without interstitial fibrosis has clinical significance.

Further reading

Weidenbusch M, Bai Y, Eder J, Anders HJ; Lupus Nephritis Trials Network. Refractory lupus nephritis: a survey. Lupus. 2019;28(4):455-464. doi:10.1177/0961203319828516

Anders HJ, Hiepe F. Treatment Options for Refractory Lupus Nephritis. Clin J Am Soc Nephrol. 2019;14(5):653-655. doi:10.2215/CJN.03230319

Bojic M, Kozakowski N, Bécède M, Kerschbaumer A, Bobacz K. Myeloid bodies in the kidney biopsy of a patient with systemic lupus erythematosus. Kidney Int. 2017;92(1):271-272. doi:10.1016/j.kint.2016.12.025

Romagnani P, Giglio S, Angelotti ML, et al. Next generation sequencing and functional analysis of patient urine renal progenitor-derived podocytes to unravel the diagnosis underlying refractory lupus nephritis. Nephrol Dial Transplant. 2016;31(9):1541-1545. doi:10.1093/ndt/gfw234

Per-protocol Repeat Kidney Biopsy in Incident Cases of Lupus Nephritis (REBIOLUP). https://clinicaltrials.gov/ct2/show/NCT04449991

Li Y, Xu X, Tang X, et al. MicroRNA expression profile of urinary exosomes in Type IV lupus nephritis complicated by cellular crescent. J Biol Res (Thessalon). 2018;25:16. doi:10.1186/s40709-018-0088-0

Tang Y, Luo X, Cui H, et al. MicroRNA-146A contributes to abnormal activation of the type I interferon pathway in human lupus by targeting the key signaling proteins. Arthritis Rheum. 2009;60(4):1065-1075. doi:10.1002/art.24436

Garcia-Vives E, Solé C, Moliné T, et al. The Urinary Exosomal miRNA Expression Profile is Predictive of Clinical Response in Lupus Nephritis. Int J Mol Sci. 2020;21(4):1372. doi:10.3390/ijms21041372

Solé C, Cortés-Hernández J, Felip ML, Vidal M, Ordi-Ros J. miR-29c in urinary exosomes as predictor of early renal fibrosis in lupus nephritis. Nephrol Dial Transplant. 2015;30(9):1488-1496. doi:10.1093/ndt/gfv128

Seshan SV, Jennette JC. Renal disease in systemic lupus erythematosus with emphasis on classification of lupus glomerulonephritis: advances and implications. Arch Pathol Lab Med. 2009;133(2):233-248. doi:10.5858/133.2.233

Bajema IM, Wilhelmus S, Alpers CE, et al. Revision of the International Society of Nephrology/Renal Pathology Society classification for lupus nephritis: clarification of definitions, and modified National Institutes of Health activity and chronicity indices. Kidney Int. 2018;93(4):789-796. doi:10.1016/j.kint.2017.11.023