Dataset Information

LDL Receptor-Related Protein 2 (Megalin) as a Target Antigen in Human Kidney Anti-Brush Border Antibody Disease.

ABSTRACT: Primary renal tubulointerstitial disease resulting from proximal tubule antigen-specific antibodies and immune complex formation has not been well characterized in humans. We report a cohort of patients with a distinct, underappreciated kidney disease characterized by kidney antibrush border antibodies and renal failure (ABBA disease). We identified ten patients with ABBA disease who had a combination of proximal tubule damage, IgG-positive immune deposits in the tubular basement membrane, and circulating antibodies reactive with normal human kidney proximal tubular brush border. All but one of the patients also had segmental glomerular deposits on renal biopsy specimen. Patients with ABBA disease were elderly and presented with AKI and subnephrotic proteinuria. Serum from all patients but not controls recognized a high molecular weight protein in renal tubular protein extracts that we identified as LDL receptor-related protein 2 (LRP2), also known as megalin, by immunoprecipitation and mass spectrometry. Immunostaining revealed that LRP2 specifically colocalized with IgG in the tubular immune deposits on the ABBA biopsy specimen but not the control specimen analyzed. Finally, ABBA serum samples but not control samples showed reactivity against recombinantly expressed N-terminal LRP2 fragments on Western blots and immunoprecipitated the recombinantly expressed N-terminal region of LRP2. This case series details the clinicopathologic findings of patients with ABBA disease and shows that the antigenic target of these autoantibodies is LRP2. Future studies are needed to determine the disease prevalence, stimulus for ABBA, and optimal treatment.

SUBMITTER: Larsen CP

PROVIDER: S-EPMC5791069 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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LDL Receptor-Related Protein 2 (Megalin) as a Target Antigen in Human Kidney Anti-Brush Border Antibody Disease.

Larsen Christopher P CP Trivin-Avillach Claire C Coles Paige P Collins A Bernard AB Merchant Michael M Ma Hong H Wilkey Daniel W DW Ambruzs Josephine M JM Messias Nidia C NC Cossey L Nicholas LN Rosales Ivy A IA Wooldridge Thomas T Walker Patrick D PD Colvin Robert B RB Klein Jon J Salant David J DJ Beck Laurence H LH

Journal of the American Society of Nephrology : JASN 20171026 2

Primary renal tubulointerstitial disease resulting from proximal tubule antigen-specific antibodies and immune complex formation has not been well characterized in humans. We report a cohort of patients with a distinct, underappreciated kidney disease characterized by kidney antibrush border antibodies and renal failure (ABBA disease). We identified ten patients with ABBA disease who had a combination of proximal tubule damage, IgG-positive immune deposits in the tubular basement membrane, and c ...[more]

PMID: 29074737

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Project description:INTRODUCTION:Radiolabeled, low-molecular-weight prostate-specific membrane antigen (PSMA) inhibitors based on the Glu-ureido pharmacophore show promise for the detection and treatment of castration-resistant prostate cancer; however, high renal retention of activity, related in part to overexpression of PSMA in kidneys can be problematic. The goal of the current study was to investigate the use of brush border enzyme-cleavable linkers as a strategy for reducing kidney activity levels from radiolabeled PSMA inhibitors. METHODS:PSMA-769 (6), a derivative of the prototypical PSMA inhibitor (((S)?1?carboxy?5?(4?iodobenzamido)pentyl)carbamoyl)glutamate (12) modified to contain a Gly-Tyr linker, and its protected tin precursor (11) were synthesized starting from the basic pharmacophore molecule Lys-urea-Glu. An analogue of 6 containing d?tyrosine in lieu of l?tyrosine (PSMA-769-d-tyrosine) and the corresponding tin precursor (d-11) also were synthesized. Both radioiodinated and 211At-labeled 6 were synthesized by radiohalogenation of 11 and deprotection in situ. Similarly, radioiodinated d-6 was synthesized from d-11. Paired label biodistribution of [125I]12 and [131I]6 was performed in normal mice and in SCID mice bearing both PC3 PIP (PSMA+) and PC3 flu (PSMA-) subcutaneous prostate carcinoma xenografts. The biodistribution of [131I]6 and [211At]6 was also evaluated in this tumor model. Biodistribution of the two radioiodinated diastereomers of 6 was evaluated in normal mice and urine samples were analyzed for the presence of 4?iodohippuric acid. RESULTS:Compounds [131I]6 and [211At]6 were synthesized from 11 in overall radiochemical yields of 32.5?±?0.1% (n?=?4) and 22% (n?=?1), respectively; radiochemical purity was >95%. In normal mice, renal uptake of [131I]6 was 1.4-, 2.8- and 161-fold lower than that seen for co-injected [125I]12 at 1?h, 4?h and 21?h, respectively. In tumor-bearing mice, kidney uptake of [131I]6 was similar to that for [125I]12 (P?>?0.05) at 1?h and 4?h but was 6- to 7-fold lower at 21?h; however, [131I]6 uptake in PC3 PIP tumors was also lower than that seen for [125I]12 at 21?h (12.6?±?3.4%ID/g vs. 36.8?±?12.4%ID/g). Uptake of [211At]PSMA-769 in PC3 PIP tumors was slightly higher than that seen for [131I]PSMA-769 at 4?h (9.6?±?1.6%ID/g versus 7.8?±?1.6%ID/g; P?=?0.002); its uptake in a number of normal tissues also was higher. In normal mice, kidney uptake of [125I]PSMA-769 at 4?h was about 73% of that seen for [131I]PSMA-769-d-tyrosine. Activity in the urine of mice receiving [125I]PSMA-769 contained mainly 4?[125I]iodohippuric acid while unmetabolized intact molecule was present in the case of [125I]PSMA-769-d-tyrosine. CONCLUSION:Use of this brush border enzyme-cleavable linker reduced kidney uptake and resulted in improved tumor:kidney uptake ratios. Although further structural improvements are needed, this linker approach might be useful as a component in strategies for reducing renal uptake of radiolabeled PSMA inhibitors.

Dataset Information

LDL Receptor-Related Protein 2 (Megalin) as a Target Antigen in Human Kidney Anti-Brush Border Antibody Disease.

Publications

LDL Receptor-Related Protein 2 (Megalin) as a Target Antigen in Human Kidney Anti-Brush Border Antibody Disease.

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