Elevated Urinary ApoAI in Renal Disease

Computer rendering of a glomerulus in the kidney.
Computer rendering of a glomerulus in the kidney.
Levels are particularly high in proximal tubulopathies.

Children with kidney disease, especially children with diseases affecting proximal tubules, have increased levels of urinary apolipoprotein AI (apoAI), according to results published in Pediatric Nephrology. The study adds to emerging evidence of apoAI’s role in the kidney.

“Urine apoAI is particularly elevated in proximal tubulopathies, dysplasia and proteinuric glomerular disease, but only modestly parallels the magnitude of albuminuria,” said Valentina Kon, M.D., Margaret T. and H. Laird Smith Chair and professor of pediatrics at Vanderbilt University Medical Center and a pediatric nephrologist at Monroe Carell Jr. Children’s Hospital at Vanderbilt.

Ongoing research from Kon and colleagues suggests that kidney disease may not only cause an increase in the quantity of urine apoAI, but that some urine apoAI may be modified by various reactive oxygen and nitrogen species or resulting reactive carbonyls, including isolevuglandins (IsoLG). Such modifications lead to structural and functional changes in the lipoproteins and are considered central in the pathogenesis of many different diseases.

ApoAI Elevation

The Pediatric Nephrology study enrolled 228 children between the ages of three and 18 seeking care in the Vanderbilt Pediatric Nephrology Clinic, plus an additional 40 healthy children from a general pediatric setting.

Nine disease entities were represented in the study, including nephrolithiasis, tubulopathy, polycystic kidney disease (PCKD), congenital anomalies of kidney and urinary tract (CAKUT), glomerulonephritis (GN), transplant, nephrotic syndrome (NS) in relapse, NS in remission and hypertension.

Levels of urinary apoAI in the nephrology clinic cohort were elevated compared to the control group (median 0.074 versus 0.019 μg/mg), with levels varying among the different diseases. While urinary apoAI levels were higher in patients with tubulopathies, renal dysplasia/CAKUT, GN and NS in relapse, apoAI levels were consistent with controls in patients with nephrolithiasis, PCKD, transplants, NS in remission, PCKD or hypertension.

“These findings suggest the potential utility of measuring urinary apoA1 to identify abnormal renal handling of lipoproteins and reflecting renal disease.”

Disease Distinctions

Of particular interest to Kon was the difference in urinary apoAI levels between proximal versus distal tubulopathies.

“Within the tubulopathy group, patients with disorders principally affecting proximal tubules, including Fanconi syndrome, Dent disease, Lowe syndrome, and cystinosis, had higher urinary apoAI levels than patients with primarily distal tubule dysfunction including distal renal tubular acidosis, diabetes insipidus and Bartter syndrome,” she said.

Kon also noted that urinary apoAI levels were elevated for diseases with disruption of the glomerular filtration barrier (GN and NS), yet apoAI levels did not always correlate with albuminuria, a marker of glomerular dysfunction. Within the NS relapse group, although patients with minimal change disease (MCD) and focal and segmental glomerulosclerosis (FSGS) showed a comparable degree of albuminuria, FSGS patients had significantly higher urinary apoAI levels than those with MCD.

The findings suggest there may be distinct pathways for tubular uptake of albumin and apoAI. The study also found irregular, high molecular weight forms of urinary apoAI in patients with certain renal diseases, particularly patients with FSGS in relapse.

A Role For Isolevuglandins

Kon and colleagues’ ongoing research suggests that among urinary proteins, apoAl is particularly vulnerable to IsoLG adduction. The formation of IsoLG-protein adducts has been linked to numerous diseases, including end-stage renal disease.

“We measured IsoLG adducts in the urine samples of our pediatric cohort and found a significant correlation between urinary apoAl and urinary IsoLG adducts,” Kon said. “Critically, the apoAl fraction from urine samples was found to be markedly enriched in IsoLG adducts compared to the urinary fraction containing all proteins, specifically albumin.”

Collectively, the research points to the idea that urinary apoAI, especially apoAI modified by IsoLG, may serve as a biomarker. “These findings suggest the potential utility of measuring urinary apoA1 to identify abnormal renal handling of lipoproteins and reflecting renal disease,” Kon said.