The Primary Hyperoxalurias

Abstract

Primary hyperoxaluria (PH) results from endogenous (primary) overproduction of oxalic acid, as opposed to secondary hyperoxaluria, which is attributable to increased intestinal absorption (enteric) or excessive intake (dietary) of oxalate. Why are nephrologists interested in PH type 1 (PH1), the prevailing type, although it is far from being a primary renal disorder? First, the clinical treatment of patients with this “nephrologic liver disease” is quite challenging, particularly in end-stage renal failure (ESRF). Second, the study of PH1 has yielded better understanding of the pathogenesis of calcium oxalate (CaOx) crystal deposition and stone formation in general, with this disease serving as a model of nephrocalcinosis and urolithiasis. Finally, fascinating insights into the mechanisms of cellular trafficking have been obtained from the study of PH1; however, many questions remain unresolved. It has also become apparent that PH encompasses more than PH1 and PH2, and some patients who were previously classified as having secondary hyperoxaluria might actually have a type of PH. PH1 Metabolic and Genetic Basis PH1, which is an autosomal recessive disease, is caused by a defect in glyoxylate metabolism attributable to low or absent activity of the liver-specific peroxisomal enzyme alanine/glyoxylate aminotransferase (AGT) (392 amino acids, 43 kD) (Figure 1) (1,2). As a result, urinary excretion of oxalate and (in most cases) glycolate is greatly increased (2). Although massive intrarenal CaOx deposits were noted by Lepoutre in 1925 for a pediatric patient who was surgically treated for urolithiasis (abstract cited in reference 2), the disease was not named PH until 1957 (3) and the metabolic defect was localized in liver peroxisomes (therefore not within the cytosol, as previously thought) in 1986 (1). In contrast to PH1, patients with a primary peroxisomal disorder such as the Zellweger syndrome do not exhibit hyperoxaluria (2). Except for the AGT defect, peroxisomes in PH1 are normal in almost every respect; they appear only slightly smaller in electron microscopic evaluations (4). The functional deficiency of AGT in PH1 results in a failure to detoxify glyoxylate within the peroxisomes. Instead of being transaminated to glycine, glyoxylate is oxidized to oxalate and/or reduced to glycolate, resulting in greatly increased urinary excretion of oxalate and glycolate (Figure 1) (1,2,4). Glyoxylate itself is synthesized within the peroxisomes from glycine and glycolate (2).Figure 1: . Metabolic defects in primary hyperoxaluria type 1 (PH1) [alanine/glyoxylate aminotransferase (AGT)] and PH2 [glyoxylate reductase (GR)/hydroxypyruvate reductase (HPR)]. Glyoxylate reductase also exhibits hydroxypyruvate reductase activity. GO, glycolate oxidase; DAO, D-amino oxidase; LDH, lactate dehydrogenase.The gene coding for AGT, i.e., AGXT, is located on chromosome 2q37.3 and consists of 11 exons spanning approximately 10 kb (2,5). More than 30 mutations have been identified to date. There is considerable molecular heterogeneity; many patients are compound heterozygotes (frequently with only one allele identified), whereas populations with high rates of consanguinity, e.g., Israeli Arabs (6) or Northwest Africans (7), exhibit mutations in a homozygous pattern. One-half of the patients exhibit no detectable AGT catalytic activity, whereas the other half exhibit residual (2 to 48%) AGT activity (2,4). Why do individuals with residual AGT activity become ill, not differing clinically from patients with absent AGT activity? AGT is mistargeted from the peroxisomes to the mitochondria, as elegantly demonstrated by Danpure and co-workers (2,4,5). Although such patients often exhibit considerable residual enzymatic activity, only 10% of the immunoreactive AGT (cross-reacting material—positive) is localized within the peroxisomes; 90% is found within the mitochondria, where it is metabolically inactive. In his laureate speech, Gu[Combining Diaeresis]nter Blobel, the 1999 recipient of the Nobel Prize in Medicine, referred specifically to PH1, in which the altered sorting signal leads to erroneous intracellular localization of the enzyme (http://www.nobel.se). This protein-trafficking defect is unparalleled in human subjects (2). It is observed in approximately 30% of all patients with PH1, usually as the result of a 630G→A mutation (associated with a Pro11Leu polymorphism), which leads to a Gly170Arg amino acid substitution, or, less often, as the result of a 576T→A mutation (2,8). Pathophysiology Urine is a saturated solution, and its concentration can change very drastically within a short time (9). Stone formation or the development of nephrocalcinosis thus occurs when the delicate interplay between promotors (in PH1, especially oxalate) and inhibitors (e.g., citrate, magnesium, and glycosaminoglycans) of crystal formation is disturbed (9,10). In PH1, the urine is supersaturated with respect to CaOx (urinary CaOx saturation of >1