Giada Bianchi

Introduction: Autosomal-dominant tubulointerstitial kidney disease (ADTKD) is characterized by chronic kidney disease (CKD) with an average age of end-stage renal disease (ESRD) of approximately 45 years, bland urinary sediment, the absence of proteinuria and autosomal dominant inheritance. While several causative genes have been found, there remain families in whom no molecular diagnosis has been identified (ADTKD-NMD). Methods: We identified BICC1 truncating variants in several families with ADTKD-NMD in the Wake Forest Rare Inherited Kidney Disease Registry and then screened families in our database and other referred families for BICC1 truncating variants. We performed segregation analysis and characterized affected individuals for clinical and histopathologic phenotypes. We analyzed oligomer formation of BICC1 mutants with wild-type BICC1-, ANKS3- and ANKS6 proteins through co-immunoprecipitation and Western blotting, and we tested for posttranscriptional regulation of the BICC1 target mRNA, Dand5 , in a Luciferase reporter assay. Results: We found 6 heterozygous truncating mutations in BICC1 segregating with the ADTKD phenotype in 8 independent pedigrees worldwide. Affected individuals developed kidney failure in the 6 ^th to 7 ^th decade of life that was characterized pathologically by tubular atrophy and interstitial fibrosis. The truncated gene products localized to cytoplasmic bodies and demonstrated various degrees of self-association or binding to the known interaction partners, ANKS3 and ANKS6. While the wild-type BICC1 gene product acts as a posttranscriptional repressor of target mRNAs, all truncation variants exhibited increased expression of substrate mRNA. Conclusions: Truncating variants in BICC1 are a novel cause of ADTKD, segregating with the disease phenotype and upregulating BICC1 target gene expression through a dominant-negative- or a gain-of-function mode of action. Translational Statement: Novel disease gene discoveries have a high potential for translational impact. Autosomal-dominant tubulointerstitial kidney disease (ADTKD) is reported to occur in 1-2 individuals per 100,000 but is underrecognized and underdiagnosed. Although several genes have been associated with ADTKD, many cases remain genetically unresolved. Our discovery of BICC1 as a novel gene in ADTKD will lead to improved disease recognition, prognostication and counseling. Through its role in gene regulation, BICC1 is a bona fide target for the molecular study of kidney fibrosis and atrophy, a final common pathway in CKD, as well as for the development of future therapies.

Light chain (AL), serum amyloid A (AA), transthyretin (ATTR), leukocyte cell derived chemotaxin 2 (ALECT2), and fibrinogen Aa (AFib) amyloidosis are some of the most common types of protein-deposition disorders involving the kidney. Each amyloidogenic protein differs in its origin and little is known about the exact mechanisms that govern renal tropism and tissue injury for each amyloid subtype. While amyloidogenic precursor protein is different in each subtype of amyloidosis, its aggregation into fibrils depositing in target organs and leading to disruption of tissue architecture and progressive organ failure is a common denominator. Each amyloidogenic protein is characterized by a unique pattern of deposition in the renal parenchyma with variability in expected clinical outcomes. In this review, we focus on describing the distinct pathophysiologic mechanisms at the level of the kidneys of AL, AA, ATTR, ALECT2, and AFib amyloidosis.

Key Points: Almyloid light chain amyloid patients post autologous stem cell transplantation with higher eGFR was not associated with better progression-free survival but was associated with increased overall survival (OS). Patients with kidney amyloidosis stage 3 at baseline had inferior OS compared with those who had stage 1. OS was better in those who had complete kidney response irrespective of the baseline kidney amyloidosis stage, compared with those without response. Background: We investigated how kidney function affected progression-free survival (PFS) and overall survival (OS) after autologous stem cell transplantation (ASCT) in patients with amyloid light chain (AL) amyloidosis. Methods: We performed a retrospective cohort study of 314 patients with AL amyloidosis who underwent ASCT between 2010 and 2020. In addition to the baseline demographics, comorbidities, and kidney amyloidosis stage, eGFR and other laboratory values were collected at day 0, day 100, 6 months, 1 year, 2 years, and 3 years after ASCT. The Cox proportional hazards models were used to estimate hazard ratio (HR) based on landmark analysis for the effects of eGFR and other longitudinal measures on PFS or OS. Results: Higher eGFR values at all time points after ASCT were not significantly associated with longer PFS but was associated with increased OS. Patients with kidney amyloidosis stage 3 at baseline had inferior OS compared with those who had stage 1 (HR [95% confidence interval] = 9.428 [1.134 to 78.381], P value = 0.0379). OS was better in those who had complete kidney response irrespective of the baseline kidney amyloidosis stage, compared with those without response (HR [95% confidence interval] = 7.581 [2.042 to 28.149], P = 0.0025). Conclusions: This retrospective study shows that kidney function has an effect on survival in patients with AL amyloidosis who undergo ASCT. Both higher eGFR at baseline and complete kidney response after ASCT favor improved survival outcomes.

Immunoglobulin light-chain (AL) amyloidosis is a plasma cell disorder characterized by progressive organ dysfunction secondary to deposition of organized immunoglobulin light-chain aggregates. Achievement of rapid and deep normalization of involved immunoglobulin free light chains is necessary to maximize chances of reversibility of organ dysfunction, which, in turn, results in improved quality and length of life. There are no US Food and Drug Administration (FDA)–approved therapies for patients with relapsed AL amyloidosis. B-cell maturation antigen–targeting (BCMA)-bispecific T-cell engagers teclistamab and elranatamab have shown high activity and acceptable safety profile in patients with relapsed and/or refractory multiple myeloma, leading to their FDA approval. Herein, we report on safety and efficacy of elranatamab for patients with relapsed and/or refractory AL amyloidosis. We treated 9 consecutive patients with advanced-stage AL amyloidosis with single-agent elranatamab, observing a 100% overall response and 67% complete response rate, including minimal residual disease negativity, with expected toxicities. Median time to hematological response was 9 days (range, 6-24), with deep suppression in involved free light chains observed within 1 cycle of therapy, translating in cardiac and renal responses at 3 to 6 months. These data support prospective studies exploring elranatamab for patients with relapsed AL amyloidosis.

AL amyloidosis is a disorder characterized by expansion of clonal plasma cells in the bone marrow and distant end organ damage mediated by misfolded immunoglobulin free light chains. There are currently limited data regarding the functional characteristics of AL amyloidosis plasma cells and their surrounding bone marrow microenvironment. We performed 5' single cell RNA sequencing on newly diagnosed, treatment naïve AL amyloidosis patients and healthy subjects. We identified generalized suppression of normal bone marrow hematopoiesis with distinct expansion of monocytes and subsets of CD4+ T cells in AL amyloidosis patients. We detected significant transcriptional changes broadly occurring among immune cells with increased TNF-a signaling and interferon response accompanied by increased inflammatory response in bone marrow plasma as measured via quantitative proteomics with specific elevation of co-stimulatory molecule soluble CD276 (sB7-H3). A transcriptionally distinct population of non-malignant plasma cells was disproportionately expanded in AL amyloidosis patients and characterized by increased expression of CRIP1. Finally, clonal AL amyloidosis plasma cells were identified based on their unique VDJ rearrangement and showed increased expression of genes involved in proteostasis when compared to autologous, polyclonal plasma cells. Inter-patient transcriptional heterogeneity was evident, with transcriptional states reflective of common genomic translocations easily identifiable. This study defines the transcriptional characteristics of AL amyloidosis plasma cells and their surrounding bone marrow microenvironment with identification of altered genes previously involved in the pathogenesis of other protein deposition disorders. Our data provide the rationale for functional validations of these genes in future studies.