**Author Listing - Lead/ Submitting Author (we will be communicating with this individual): Name, Institution, City and State where the work was done. Co-authors will be added in a separate section.**
Cindy Varga, Levine Cancer Institute Atrium Health, Charlotte, North Carolina

**Main Body of the Abstract**
There is an unmet need to understand the mechanisms by which amyloid deposition drives alterations in the kidney. RAIN (NCT03168906) was a phase 2b clinical trial in AL amyloidosis that collected renal biopsies prior to drug randomization. We leveraged these biopsies to perform transcriptional profiling and to employ a novel histologic scoring tool. Clinical data was correlated to histologic and molecular findings from 9 renal samples. A composite scarring injury score (CSIS) and amyloid score (AS) was assigned to each biopsy. Glomerular and tubulointerstitial (TI) compartments were micro-dissected and sequenced separately. Expression data was compared to healthy living donor (LD) profiles. Differentially expressed genes were determined. Cluster analysis revealed two distinct patient clusters (G1 and G2). There was a higher AS score in the TI compartment (6.5 vs. 4.5; p=0.0290) of G2. G2 versus G1: G2 contained more differentiated genes related to inflammation resulting in an increase in canonical PI3K/Akt signaling. Glomeruli showed activation of fibrotic pathways. Enriched ingenuity canonical pathways included ‘coagulation system’, ‘GADD45 signaling’, and ‘Wnt/Ca+ pathway’. AL versus LD: IPA analysis identified increased signaling of PI3K/Akt. Gene regulators of cellular proliferation were enriched in the amyloid group. Despite the small sample size, we  effectively identifed two distinct groups of AL patients based on molecular signature that correlated with amyloid burden. Pharmacological inhibition of the PI3K-Akt signaling pathways may be relevant in this disease. Detailed studies of a larger cohort at a single cell resolution will identify the response of individual kidney cell types to amyloid deposits.



**Author Listing - Lead/ Submitting Author (we will be communicating with this individual): Name, Institution, City and State where the work was done. Co-authors will be added in a separate section.**
Cindy Varga, Levine Cancer Institute Atrium Health, Charlotte, North Carolina

**Main Body of the Abstract**
There is an unmet need to understand the mechanisms by which amyloid deposition drives alterations in the kidney. RAIN (NCT03168906) was a phase 2b clinical trial in AL amyloidosis that collected renal biopsies prior to drug randomization. We leveraged these biopsies to perform transcriptional profiling and to employ a novel histologic scoring tool. Clinical data was correlated to histologic and molecular findings from 9 renal samples. A composite scarring injury score (CSIS) and amyloid score (AS) was assigned to each biopsy. Glomerular and tubulointerstitial (TI) compartments were micro-dissected and sequenced separately. Expression data was compared to healthy living donor (LD) profiles. Differentially expressed genes were determined_._ Cluster analysis revealed **two _distinct patient clusters_** (G1 and G2). There was a higher AS score in the TI compartment (6.5 vs. 4.5; p=0.0290) of G2. _G2 versus G1:_ G2 contained more differentiated genes related to inflammation resulting in an increase in canonical **PI3K/Akt signaling.** Glomeruli showed activation of fibrotic pathways. Enriched ingenuity canonical pathways included ‘coagulation system’, ‘GADD45 signaling’, and ‘Wnt/Ca+ pathway’. _AL versus LD:_ IPA analysis identified increased signaling of PI3K/Akt. Gene regulators of cellular proliferation were enriched in the amyloid group. Despite the small sample size, we  effectively identifed two distinct groups of AL patients based on molecular signature that correlated with amyloid burden. Pharmacological inhibition of the PI3K-Akt signaling pathways may be relevant in this disease. Detailed studies of a larger cohort at a _single cell resolution_ will identify the response of individual kidney cell types to amyloid deposits.



Gene Expression Sets and Renal Profiling from the RAIN (Renal AL Amyloid Involvement and NEOD00) Trial PA19 (#37)

We invite you to attend the XIX International Symposium on Amyloidosis to be held in Rochester, MN.

This symposium is organized as a hybrid meeting (with the focus on in-person) held from Sunday, May 26 through Thursday, May 30, 2024.

Together with the ISA Board and members of Mayo Clinic, a very attractive scientific hybrid program is being planned. The program will cover a variety of types of systemic amyloidosis: ATTR (hereditary and wild-type), AL (light-chain), AA and less frequent forms. There will be key lectures, specific symposia including those company sponsored, oral presentations and poster sessions of accepted abstracts.

COURSE DESCRIPTION
This program will provide a comprehensive review of state-of-the-art education in systemic amyloidosis: basic science, pathophysiology, diagnosis, current and emerging treatments. Scientific presentations will include competitive oral and poster abstracts. The rapid evolution of scientific discovery and expanding treatment options has created tremendous interest in the field and this meeting will fill and important gap in educating scientists and clinicians.