Homogentisic acid is not only eliminated by glomerular filtration and tubular secretion but also produced in the kidney in alkaptonuria

Abstract

BACKGROUND The clinical effects of alkaptonuria (AKU) is delayed and ageing influences disease progression. Morbidity of AKU is secondary to high circulating homogentisic acid (HGA) and ochronosis. It is not known whether HGA is produced by or processed in the kidney in AKU. METHODS Data from AKU patients from four studies were merged to form a single AKU group. A control group of non‐AKU subjects was generated by merging data from two non‐AKU studies. Data were used to derive renal clearance and fractional excretion (FE) ratios for creatinine, HGA, phenylalanine (PHE) and tyrosine (TYR) using standard calculations, for comparison between the AKU and the control groups. RESULTS There were 225 AKU patients in the AKU group and 52 in the non‐AKU control group. Circulating HGA increased with age (pHGA) (pHGA (pHGA and FE_HGA were increased beyond the theoretical maximum renal plasma flow, confirming renal production and emphasizing the greater contribution of net tubular secretion than glomerular filtration to renal elimination of HGA. CONCLUSIONS The kidneys are crucial to elimination of HGA. Elimination of HGA is impaired with age resulting in worsening disease over time. The kidney is an important site for production of HGA. Tubular secretion of HGA contributes more to elimination of HGA in AKU than glomerular filtration does.