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CSL112 (Apolipoprotein A-I [human]) is an intravenous preparation of apolipoprotein A-I (apoA-I), formulated with phosphatidylcholine (PC) and stabilized with sucrose, in development to prevent early recurrent cardiovascular events following acute myocardial infarction (AMI). This phase 1 study was designed to determine if moderate renal impairment (RI) influenced the pharmacokinetics (PK) and safety of CSL112. Thirty-two subjects, 16 with moderate RI (estimated glomerular filtration rate [eGFR] ≥ 30 and < 60 mL/min/1.73 m 2 ) and 16 age-, sex-, and weight-matched subjects with normal renal function (eGFR ≥ 90 mL/min/1.73 m 2 ) were randomized 3:1 to receive a single infusion of CSL112 2 g (n = 6) or placebo (n = 2), or CSL112 6 g (n = 6) or placebo (n = 2). PK sampling was at prespecified times from 48 hours prior to 144 hours following infusions, with final safety assessments at 90 days. Renal and hepatic safety, and adverse events (AEs) were monitored throughout the study. Plasma apoA-I and PC PK profiles were similar between renal function cohorts at both doses. For CSL112 6 g mean ± SD apoA-I AUC 0 - last was 7670 ± 1900 and 9170 ± 2910 mg·h/dL in normal renal function and moderate RI subjects, respectively. Renal apoA-I clearance was <1% of CSL112 dose. In moderate RI, sucrose clearance was slower; however, approximately 70% was excreted within 48 hours in both renal function cohorts. No CSL112-related serious AEs or clinically significant renal or hepatic safety changes were observed. Dose adjustment of CSL112 is not required in subjects with moderate RI, supporting its further investigation in AMI patients with moderate RI., (© 2018 The Authors. Clinical Pharmacology in Drug Development Published by Wiley Periodicals, Inc. on behalf of The American College of Clinical Pharmacology.)

Cubilin is an endocytic receptor highly expressed in renal proximal tubules, where it mediates uptake of albumin and filtered forms of apoA-I/HDL. Cubilin deficiency leads to urinary loss of albumin and apoA-I; however, the consequences of cubilin loss on the homeostasis of blood albumin and apoA-I/HDL have not been studied. Using mice heterozygous for cubilin gene deletion (cubilin HT mice), we show that cubilin haploinsufficiency leads to reduced renal proximal tubular uptake of albumin and apoA-I and significantly increased urinary loss of albumin and apoA-I. Moreover, cubilin HT mice displayed significantly decreased blood levels of albumin, apoA-I, and HDL. The levels of albumin and apoA-I protein or mRNA expressed in the liver, kidney, or intestine of cubilin HT mice did not change significantly. The clearance rate of small HDL3 particles (density>1.13 g/ml) from the blood increased significantly in cubilin HT mice. In contrast, the rate of clearance of larger HDL2 particles from the blood did not change significantly, indicating a decreased half-life for HDL particles capable of filtering through the glomerulus. On the basis of these findings, we conclude that cubilin deficiency reduces renal salvage and delivery back to the blood of albumin and apoA-I, which decreases blood levels of albumin and apoA-I/HDL. These findings raise the possibility that therapeutic increase of renal cubilin expression might reduce proteinuria and increase blood levels of albumin and HDL., (Copyright © 2014 by the American Society of Nephrology.)

High--resolution two--dimension electrophoresis technique for protein with silver staining was used to characterise urinary high density lipoprotein (HDL)--apolipoproteins. Sequential ultracentrufugation method was used to isolate urinary lipoprotein particles of the same density as serum HDL. Immunostaining of electroblotted proteins further confirmed the presence of HDL--Apos in urine. HDL--Apolipoprotein A--1, A--11 and C were identified in urine of normal subjects, diabetic patients and patients with biopsy proven glomerular proteinuria. An in-house ELISA method was used to quantify urinary HDL--Apo A--1. Selectivity indices were also determined. A high degree of association was found between selectivity index and urinary HDL--Apo A--1 (r = 0.87) and also between HFL--APO A--1 loss/24 h and total protein loss/24 h (r = 0.91). This appear to indicate that HDL loss in urine was a function of glomerular selectivity. Urinary HDL--Apo A--1 levels were significantly raised in the patients with glomerular proteinuria (p less than 0.01). HDL--Apo A--1 levels appear to be a marker for glomerular proteinuria. Consistent with glomerular proteinuria serum lipids and protein loss were significantly higher in patients with glomerular proteinuria (p less than 0.001) but HDL--Cholesterol was lower (p less than 0.001).